Background and Objectives: Infections are the most common and potentially life-threatening complications of the treatment of children with acute lymphoblastic leukemia (ALL). The aim of this study was to determine epidemiological, clinical and microbiological characteristics of infections in pediatric patients with ALL. Materials and Methods:  Twenty-three children (16 male and 7 female, mean age 5.9 years [range 1.3 to 12.2 years]) with ALL, treated at the Division of Hematology, Oncology and Clinical Genetics, Department of Pediatrics, Clinical Hospital Center Rijeka, Croatia, from January 1, 2015 to December 31, 2020, were included in the study Results: One hundred and four infectious episodes (IEs) were reported (average 4.5 IE per patient). IEs were more frequent in the intensive phases of antileukemic treatment. Neutropenia was present in 48 IEs (46.2%) with a duration greater than 7 days in 28 IEs (58.3%). The respiratory tract was the most common infection site (48.1%). We documented 49 bacterial (47.1%), 4 viral (3.9%), 4 fungal (3.9%) and 10 mixed isolates (9.6%), while in 37 IEs (35.6%) pathogen was not isolated. The most common causes of bacteremia were coagulase-positive staphylococci. The most frequent empirical therapy was third- and fourth-generation cephalosporins, followed by piperacillin/tazobactam. Modification of the first-line antimicrobial therapy was performed in 56.9% of IEs. Granulocyte-colony stimulating factor was administered in 53.8% of IEs, and intravenous immunoglobulins in 62.5% of IEs. One patient required admission to the intensive care unit. No infection-related mortality was reported. Conclusions: ALL patients have frequent IEs. Close monitoring, identification of risk factors, rapid empirical use of antibiotics in febrile neutropenia, and timely modification of antimicrobial therapy play a key role in reducing infection-related morbidity and mortality in children with ALL.

The hematopoietic transcription factor Ikaros (IKZF1) regulates normal B cell development and functions as a tumor suppressor in precursor B cell acute lymphoblastic leukemia (B-ALL). MicroRNAs (miRNAs) are small regulatory RNAs that through post-transcriptional gene regulation play critical roles in intracellular processes including cell growth in cancer. However, the role of Ikaros in the regulation of miRNA expression in developing B cells is unknown. In this study, we examined the Ikaros-regulated miRNA targets using patient-derived IKZF1-mutated B-ALL xenograft-derived cell lines. Inducible expression of wild-type Ikaros (the Ik1 isoform) caused B-ALL growth arrest and exit from the cell cycle. Global miRNA expression analysis revealed a total of 31 miRNAs regulated by IK1, and ChIP-seq analysis showed that Ikaros bound to several Ik1-responsive miRNA genes. Examination of the prognostic significance of miRNA expression in B-ALL indicate that the IK1-regulated miRNAs hsa-miR-26b, hsa-miR-130b and hsa-miR-4649 are significantly associated with outcome in B-ALL. Our findings establish a potential regulatory circuit between the tumor-suppressor Ikaros and the oncogenic miRNA networks in IKZF1-mutated B-ALL. These results indicate that Ikaros regulates the expression of a subset of miRNAs, of which several may contribute to B-ALL growth.

B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic disorder characterized by the abnormal proliferation and accumulation of immature B-lymphoblasts arrested at various stages of differentiation. Despite advances in treatment, a significant percentage of pediatric patients with precursor B-ALL still relapse. Therefore, alternative therapies are needed to improve the cure rates for pediatric patients. TPEN (N, N, N’, N’-tetrakis(2-pyridylmethyl)-ethylenediamine).is a pro-oxidant agent capable of selectively inducing apoptosis in leukemia cells. Consequently, it has been suggested that TPEN could be a potential agent for oxidative therapy. However, it is not yet known whether TPEN can selectively destroy leukemia cells in a more disease-like model, for example, the bloodstream and bone marrow (BM), in vitro. This investigation is an extension of a previous study that dealt with the effect of TPEN on ex vivo isolated/purified refractory B-ALL cells. Here, we evaluated the effect of TPEN on whole BM from nonleukemic patients (control) or pediatric patients diagnosed with de novo B-ALL or refractory B-ALL cells by analyzing the hematopoietic cell lineage marker CD34/CD19. Although TPEN was innocuous to nonleukemic BM (n=3), we found that TPEN significantly induced apoptosis in de novo (n = 5) and refractory B-ALL (n = 6) leukemic cell populations. Moreover, TPEN significantly increased the counts of cells positive for the oxidation of the stress sensor protein DJ-1, a sign of the formation of H2O2, and significantly increased the counts of cells positive for the pro-apoptotic proteins TP53, PUMA, and CASPASE-3 (CASP-3), indicative of apoptosis, in B-ALL cells. We demonstrate that TPEN selectively eliminates B-ALL cells independent of age, diagnosis status (de novo or refractory), sex, karyotype, or immunophenotype. Understanding TPEN-induced cell death in leukemia cells provides insight into more effective therapeutic oxidation-inducing anticancer agents.

The clinical outcome for children diagnosed with acute lymphoblastic leukemia is a testimony to the success of modern medicine. Over the past several decades, survival has climbed from ∼ 10% to > 90% for certain subgroups. Yet, the outcome for those with relapsed disease is often poor and survivors struggle with a multitude of healthcare issues, some of which are lifelong. In recent years, the advent of widespread sequencing of tumors has made available previously unrecognized subtypes of leukemia patients who have the potential to benefit from the addition of targeted therapies. Indeed, the promise of precision medicine encompassing a person's environment, genetics and lifestyle is likely to have profound impact on further tailoring therapies that are likely to improve outcomes, diminish toxicity and ultimately pave the pathway for a healthier population.

Acute lymphoblastic leukemia is the most common malignancy in children and is characterized by numerous genetic and epigenetic abnormalities. Epigenetic mechanisms, which involve DNA methylations and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. Emerging studies are increasing our understanding of the epigenetic role of leukemogenesis and have demonstrated the potential of DNA methylations and histone modifications as a biomarker for lineage and subtypes classification, predicting relapse, and disease progression in ALL. Epigenetic abnormalities are relatively reversible when treated with some small molecule-based agents compared to genetic alterations. In this review, we conclude the genetic and epigenetic characteristics in ALL and discuss the future role of DNA methylation and histone modifications in predicting relapse, finally focus on the individual and precision therapy targeting epigenetic alterations.

Purpose: This study aimed to identify the risk factors for acute pancreatitis (AP) and its impact on outcomes in Polish children treated for ALL. Methods: The study group included 2303 children who received intensive chemotherapy for ALL. The group was subdivided into patients with at least one episode of AP and those who did not develop AP following treatment for ALL. Results: The cumulative incidence of AP in the study group was 4.08%. Older age was an independent risk factor for AP development (OR 1.05; 95%CI: 1.006 – 1.098; p=0.03). The overall mortality related to AP was 2.13%. The probabilities of disease-free survival (p-DFS) and event-free survival (p-EFS) were 0.84 vs. 0.86, log-rank: p=0.65 and 0.75 vs. 0.80, log-rank: p=0.12, respectively in both subgroups. A total of 22 out of 94 patients (23.4%) with AP were re-exposed to asparaginase (ASP) during the subsequent phases of the treatment. Only one re-exposed to ASP patient (4.5%) developed a second episode of AP. There were no significant differences in p-DFS and p-EFS between patients re-exposed and not re-exposed to asparaginase (0.78 vs. 0.86, log-rank p=0.27 and 0.63 vs. 0.79, log-rank p=0.09 respectively). Conclusions: The incidence of AP in children with ALL is low and related to the patient’s age. AP development doesn’t seem to impact p-DFS and p-EFS in children with ALL. The recurrence of AP following re-exposure to asparaginase in patients with ALL and a history of AP is low (4.5%). Re-exposure to asparaginase after the first episode of AP doesn’t improve either p-DFS or p-EFS in children with ALL.

Methotrexate (MTX), a structurally related substance to folic acid, is an important chemotherapeutic agent used for decades in the treatment of pediatric acute lymphoblastic leukemia (ALL) and other types of cancer as non Hodgkin lymphomas and osteosarcomas. Despite the successful outcomes observed, the primary drawback is the variability in the pharmacokinetics and pharmacodynamics between patients. The main adverse events related to its use are mainly nephrotoxicity, mucositis and myelosuppression especially when used in high doses. The potential adverse reactions and toxicities associated with MTX are a cause for concern and may lead to dose reduction or treatment interruption. Genetic variants in MTX transport genes have been linked to toxicity. Pharmacogenetic studies conducted in the past focused on single nucleotide polymorphisms (SNPs) in the coding and 5′-regulatory regions of genes. Recent studies have demonstrated a significant role of miRNAs in the transport and metabolism of drugs, and in the regulation of target genes. The last few years, the number of annotated miRNAs is continually rising, as well as the studies of miRNA polymorphisms and MTX toxicity. Therefore, the objective of the present study is to investigate the role of miRNA variants related to MTX adverse effects.

Although automated Acute Lymphoblastic Leukemia (ALL) detection is essential, it is challenging due to the morphological correlation between malignant and normal cells. The traditional ALL classification strategy is arduous, time-consuming, often suffers inter-observer variations, and necessitates experienced pathologists. This article has automated the ALL detection task, employing deep Convolutional Neural Networks (CNNs). We explore the weighted ensemble of deep CNNs to recommend a better ALL cell classifier. The weights are estimated from ensemble candidates' corresponding metrics, such as accuracy, F1-score, AUC, and kappa values. Various data augmentations and pre-processing are incorporated for achieving a better generalization of the network. We train and evaluate the proposed model utilizing the publicly available C-NMC-2019 ALL dataset. Our proposed weighted ensemble model has outputted a weighted F1-score of 88.6%, a balanced accuracy of 86.2%, and an AUC of 0.941 in the preliminary test set. The qualitative results displaying the gradient class activation maps confirm that the introduced model has a concentrated learned region. In contrast, the ensemble candidate models, such as Xception, VGG-16, DenseNet-121, MobileNet, and InceptionResNet-V2, separately produce coarse and scatter learned areas for most example cases. Since the proposed ensemble yields a better result for the aimed task, it can experiment in other domains of medical diagnostic applications.

Natural killer (NK) cells play a crucial role in innate immunity, particularly in combating infections and tumors. However, in hematological cancers, NK cells often exhibit impaired functions. Therefore, it is very important to activate its endosomal toll-like receptors (TLRs) as a potential strategy to restore its antitumor activity. We stimulate NK cells from the peripheral blood mononuclear cells from children with acute lymphoblastic leukemia and NK cells isolated, the NK cells were stimulated with specific TLR ligands (Poly I:C, Imiquimod, R848, and ODN2006) and evaluated changes in IFN-γ, CD107a, NKG2D, NKp44 expression, Granzyme B secretion, cytokine/chemokine release, and cytotoxic activity. Results revealed that Poly I:C and Imiquimod enhanced activation of both immunoregulatory and cytotoxic NK cells, increasing IFN-γ, CD107a, NKG2D, and NKp44 expression. R848 activated immunoregulatory NK cells, while ODN2006 boosted CD107a, NKp44, NKG2D, and IFN-γ secretion in cytotoxic NK cells. R848 also increased secretion of various cytokines/chemokines. Importantly, R848 and ODN 2006 significantly improved cytotoxicity against leukemic cells. Overall, TLR stimulation enhances NK cell activation, suggesting TLR8 (R848) and TLR9 (ODN 2006) ligands as promising candidates for antitumor immunotherapy.

Despite the progress achieved regarding survival rates in childhood B-acute lymphoblastic leukemia, relapsed and/or refractory disease still poses a therapeutic challenge. Inotuzumab ozogamicin is a CD22-directed monoclonal antibody conjugated to calicheamicin, which has been approved for adults with CD22+ refractory/relapsed B lineage acute lymphoblastic leukemia and has already demonstrated promising results in the pediatric setting. The Food and Drug Administration approved inotuzumab ozogamicin (Besponsa, Pfizer) for pediatric patients 1 year and older with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia. Herein, we present the case of a 23-month-old girl with high-risk B-acute lymphoblastic leukemia, who experienced very early isolated medullary relapse and invasive pulmonary aspergillosis. She was finally successfully transplanted upon achieving remission and minimal residual disease negativity with two cycles of inotuzumab ozogamicin after failure of three lines salvage treatment with conventional chemotherapy, blinatumomab and bortezomid.

Long non-coding RNA (lncRNA) aberrant expression have been found in several types of cancer, including acute lymphoblastic leukemia (ALL), but lncRNA mapped in transcribed ultraconserved regions (T-UCRs) are little explored. The T-UCRs uc.112, uc.122, uc.160 and uc.262 were evaluated in pediatric ALL and uc.112 expression was higher in T-ALL compared to patients with B-ALL and in patients with hyperdiploid karyotype. These findings suggest a potential role of this uc.112 in pediatric ALL and emphasize the need for further investigation of T-UCR in pediatric ALL.

Artificial intelligence methods may help in unveliling information hidden in high-dimensional oncological data. Flow cytometry studies of haematological malignancies provide quantitative data with the potential to be used for the construction of response biomarkers. Many computational methods from the bioinformatics toolbox can be applied to these data but have not been exploited in their full potential in leukaemias, specifically for the case of childhood B-cell acute lymphoblastic leukemia. In this paper we analysed flow cytometry data obtained on diagnosis from 54 paediatric B-cell acute lymphoblastic leukemia patients from two local institutions. We constructed classifiers based on the Fisher’s Ratio to quantify differences in expression levels of immunophenotypical markers between patients with relapsing and non-relapsing disease. The distribution of the marker CD38 was found and validated to have a strong discriminating power between both patient cohorts, thus providing a classifier.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although prognosis continually improved along years, a significant proportion of patients still relapse from the disease due to leukemia resistance to therapy. Methotrexate (MTX), a folic acid antagonist, is a chemotherapy agent commonly used against ALL and a immune-system suppressant for rheumatoid arthritis, that presents multiple and complex mechanisms of action and resistance. Previous studies have shown that MTX modulates the nuclear factor kappa B (NF-κB) pathway, an important family of transcription factors involved in inflammation, immunity, cell survival, and proliferation, frequently hyperactivated in ALL. Using gene set enrichment analysis (GSEA) on publicly available gene expression data from 161 newly diagnosed pediatric ALL patients, we found “TNF-α signaling pathway” to be the most enriched Cancer Hallmark in MTX poor responder patients. Transcriptomic analysis in a panel of ALL cell lines (6 BCP-ALL and 7 T-ALL) also identified the same pathway as differentially enriched among MTX resistant cell lines, as well as in slowly dividing cells. To better understand the crosstalk between NF-κB activity and MTX resistance, we genetically modified the cell lines to express luciferase under a NF-κB biding site promoter. We observed that the fold change in NF-κB activity triggered by TNF-α (but not MTX) treatment correlated with MTX resistance and proliferation across the lines. At the individual gene level, NFKB1 expression was directly associated with a poorer clinical response to MTX, and with both an increased TNF-α-triggered NF-κB activation and MTX resistance in the cell lines. Despite these results, pharmacological inhibition (with BAY 11-7082 and parthenolide) or stimulation (with exogenous TNF-α supplementation) of the NF-κB pathway did not alter MTX resistance of the cell lines significantly, evidencing a complex interplay between MTX and NF-κB in ALL.

Relapsed acute lymphoblastic leukemia (ALL) represents a continuous challenge for the clinician. Despite recent advances in treatment, the risk of relapse remains significant. The clinical, biological, cytogenetic, and molecular characteristics may be different at the time of relapse. Current comprehensive genome sequencing studies suggest that most relapsed patients, especially those with late relapses, acquire new genetic abnormalities, usually within a minor clone that emerges after ALL diagnosis. We report the case of a 23-year-old young woman diagnosed with Philadelphia chromosome negative B-cell acute lymphoblastic leukemia. The patient underwent allogeneic stem cell transplantation (allo-HSCT) after complete remission. Although having favorable prognostic factors at diagnosis, the disease relapsed early after allo-HSCT. The cytogenetic and molecular exam at relapse was positive for the Philadelphia chromosome, respectively for the bcr-abl transcript. What exactly led to the relapse of this disease in a more aggressive cytogenetic and molecular form, although there were no predictive elements in the diagnosis of this relapse?

Alterations in the composition and diversity, metabolism, and products of the microbiome, and of the gut microbiome (GM), have been shown to be closely associated with the onset and progression of many human diseases, including cancer (i.e. hematological neoplasms). Acute lymphoblastic leukemia (ALL) is the most common form of childhood malignancy. Affected cases present typical alterations of GM, followed by inflammation, which contribute to its progression, response to therapy, as well as possible relapses. Recent evidence also reports that GM influences the development and functions of the newborn's hematopoietic system through the process of developmental programming during fetal life, as well as its susceptibility to the onset of onco-hematological pathologies, namely ALL. Furthermore, in children with ALL, GM has been found to vary in composition, variety, and functions during the clinical stages of ALL, and such variation may influence and predict the complications and prognosis of ALL after chemotherapy treatment or stem cell hematopoietic transplant. Here, we suggest some therapeutic strategies, which can be applied at two levels of intervention to recover the microbiome, and consequently prevent/delay ALL or arrest its progression.

Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated high rates of response in recurrent B-cell Acute Lymphoblastic Leukemia in children and young adults. Despite this success, a fraction of patients experience relapse after treatment. Relapse is often preceded by recovery of healthy B cells, which suggests loss or dysfunction of CAR T cells in bone marrow. This site is harder to access, and thus is not monitored as frequently as peripheral blood. Understanding the interplay between B cells, leukemic cells and CAR T cells in bone marrow is paramount in ascertaining the causes of lack of response. In this paper, we put forward a mathematical model representing the interaction between constantly renewing B cells, CAR T cells and leukemic cells in the bone marrow. Our model accounts for the maturation dynamics of B cells and incorporates effector and memory CAR T cells. The model provides a plausible description of the dynamics of the various cellular compartments in bone marrow after CAR T infusion. After exploration of the parameter space, we found that the dynamics of CAR T product and disease were independent of the dose injected, initial B-cell load and tumor burden. We also show theoretically the importance of CAR T product attributes in determining therapy outcome, and have studied a variety of possible response scenarios, including second dosage schemes. We conclude by setting out ideas for the refinement of the model.

Advances in molecular biology, polymerase chain reaction (PCR), and next-generation sequencing (NGS) have transformed the concept of minimal residual disease (MRD) from a philosophical idea into a measurable reality. Acute promyelocytic leukemia (APL) led the way in this transformation, initially using PCR to detect MRD in patients in remission, and more recently, aiming to eliminate it entirely with modern treatment strategies. Along the way, we have gained valuable insights that, when applied to other forms of acute leukemia, hold the potential to significantly improve outcomes in these challenging diseases. In this review, we explore the current use of MRD in the management of acute leukemia and delve into the biological processes that contribute to MRD persistence, including its overlap with leukemia stem cells and the role of the bone marrow microenvironment.

Acute leukemias constitute some of the most common malignant disorders. Despite significant progress made in the treatment of these disorders, their etiology remains unknown. A large and diverse group of genetic and environmental variables have been proposed. The role of a variety of factors, including pre-existing and acquired genetic mutations, exposure to radiation and various chemicals during pre-conception, pregnancy and throughout life have been explored. The effects of inherited genetic variations and disorders, pre-existing diseases, infectious agents, hobbies, occupations, prior treatments and a host of other factors have been proposed, but none is universally applicable to all cases. Variation in the incidence and prognosis based on the age, sex, race, type of the disease, geographic area of residence and other factors are intriguing, but remains unexplained. Advances in genomic profiling, including genome‐wide gene expression, DNA copy number, and single nucleotide polymorphism [SNP] genotype may shed some light on the role of genetics in these disparities. Separate two-hit hypothesis for the development of acute myeloblastic and lymphoblastic leukemia have been proposed. The latter combines genetics and infection factors resulting in leukemogenesis. A number of pre- and post-natal environmental conditions and exposure to infections, including a mycovirus infected Aspergillus flavus, have been suggested. The exact nature, timing, sequence of the events and mechanisms resulting in occurrence of leukemia requires further investigations. This review summarizes some of the above factors and the direction for future research on the etiology of acute leukemias.

Epigenetic alterations have contributed greatly to human carcinogenesis. Conventional epigenetic studies have been predominantly focused on DNA methylation, histone modifications and chromatin remodelling. However, recently, RNA modification (m6A-methylation) also termed ‘epitranscriptomics’ has emerged as a new layer of epigenetic regulation due to its diverse role in various biological processes. In this review, we have summarized the therapeutic potential of m6A-modifiers in controlling haematological disorders especially acute myeloid leukemia (AML). It is a type of blood cancer affecting specific subsets of blood-forming hematopoietic stem/progenitor cells (HSPCs) which proliferate rapidly and acquire self-renewable capacities with impaired terminal cell-differentiation and apoptosis leading to abnormal accumulation of white blood cells, and thus an alternative therapeutic approach is required urgently. Here, we have described how RNA m6A-modification machineries EEE (Editor/writer: Mettl3, Mettl14; Eraser/remover: FTO, ALKBH5 and Effector/reader: YTHDF-1/2) could be reformed into potential druggable candidate or as RNA modifying drug (RMD) to treat leukemia. Moreover, we have shed-light on the role of microRNA and suppressor of cytokine signalling (SOCS/CISH) in increasing anti-tumor immunity towards leukemia. We anticipate, our investigation will provide a fundamental knowledge in nurturing the potential of RNA modifiers in discovering novel therapeutics or immunotherapeutic procedures.

In the last years, molecularly targeted agents and immune based treatments (ITs) have deeply changed the landscape of anti-cancer therapy. Indeed, ITs proved to be very effective in metastatic solid tumors, where outcomes were extremely poor with standard approaches. Such a scenario has been only partially reproduced in hematologic malignancies. In acute myeloid leukemia (AML), as innovative drugs are eagerly awaited in relapsed/refractory setting, different ITs have been explored, but the results are still unsatisfactory. In this work, we will discuss the most important clinical studies to date adopting ITs in AML, providing the bases to understand how this approach, although still in its infancy, may represent a promising therapeutic tool for the next future treatment of AML patients.

Assessing the suitability of older adults with acute myeloid leukemia (AML) to intensive chemotherapy or stem cell transplantation remains a long-standing challenge. Geriatric assessment, which evaluates multiple dimensions of health, may influence a patient's ability to tolerate intensive or mild intensity approach, including treatment related mortality. Prospective studies are needed to validate different fitness criteria as well as to compare the effectiveness of geriatric assessment–based fitness against other criteria, in order to identify which aspects of the geriatric assessment are linked to treatment tolerance. Hopefully, validation studies should include different group of patients receiving either intensive or lower-intensity chemotherapy. At a minimum, the geriatric assessment should measure comorbidity burden, cognition, physical function, and emotional health—factors previously associated with mortality in AML. These assessments should be conducted before starting chemotherapy in order to minimize the treatment's impact on the results. While treatment tolerance has traditionally been evaluated through toxicity rates in solid tumor patients, AML treatment often results in high toxicity rates regardless of intensity. Therefore, early mortality should be the primary endpoint for assessing treatment tolerance, given its significant and clear implications. Other important endpoints might include declines in functional status, quality of life, and treatment adjustments or discontinuation due to toxicities. Validating these fitness criteria is essential for guiding treatment choices, improving supportive care, determining trial eligibility, interpreting study outcomes, and informing drug labeling.

In this retrospective analysis, we examined the prognostic value of serum albumin at diagnosis prior to any therapy in a cohort of patients with acute myeloid leukemia (AML) irrespective of treatment modality. Data were collected retrospectively in a cohort of 257 AML patients who received treatment between 2002 to 2019. The cohort included patients who received conventional 7+3 induction, patients who were not candidates for induction receiving lower-intensity chemotherapy or targeted therapy, and patients who were placed on clinical trials. Patients were classified into two groups, by serum albumin level at presentation, normal albumin (≥3.5 g/dL) and hypoalbuminemia [HA](

The treatment of acute myeloid leukemia (AML) with adverse genetics remains unsatisfactory, with very low response rates to standard chemotherapy and shorter durations of remission commonly observed in these patients. The complex biology of AML with adverse genetics is continuously evolving. Herein, we discuss recent advances which have investigated the contribution of cell intrinsic mechanisms as well as of the immune system to myeloid leukemogenesis in this specific subset of AML. We focus on the biological rationales for combining targeted therapy and immunotherapy, which are currently being investigated in ongoing trials, and could hopefully ameliorate the poor outcomes for these patients

Acute myeloid leukemia (AML) remains a challenging hematologic malignancy. The presence of TP53 mutations in AML poses a therapeutic challenge, considering that standard treatments face significant setbacks in achieving meaningful responses. There is a pressing need for the development of innovative treatment modalities to overcome resistance to conventional treatments attributable to the unique biology of TP53-mutated (TP53mut) AML. This review underscores the role of TP53 mutations in AML, examines the current landscape of treatment options, and highlights novel therapeutic approaches, including targeted therapies, combination regimens, and emerging immunotherapies as well as agents being explored in preclinical studies, for their potential to address the unique hurdles posed by TP53mut AML.

Acute myeloid leukemia (AML) is the second common hematologic malignancy in children. The incidence of childhood AML is much lower than acute lymphoblastic leukemia (ALL), which makes the childhood AML a rare disease in children. The role of genetic abnormalities in AML classification, management and prognosis prediction is much more important than before. The WHO classification of myeloid neoplasms and the European LeukemiaNet (ELN) classification were both revised in 2022. The application of the new information in childhood AML will be upcoming in the next few years. The frequency of each genetic abnormality in adult and childhood AML is different, therefore, in this review we emphasize in well-known genetic subtypes in childhood AML, including Core-binding factor AML (CBF AML), KMT2Ar (KMT2A/11q23 rearrangement) AML, normal karyotypes AML with somatic mutations, unbalanced cytogenetic abnormalities AML, NUP98 11p15/NUP09 rearrangement AML and acute promyelocytic leukemia (APL). Current risk group classification, management algorithm in childhood AML and novel treatment modalities, such as targeted therapy, immune therapy, chimeric antigen receptor (CAR) T-cell therapy are reviewed. Finally, the indications of hematopoietic stem cell transplantation (HSCT) in AML are discussed.

Acute promyelocytic leukemia (APL) currently represents one of the malignant hemopathies with the best therapeutic responses following the introduction of all-trans retinoic acid (ATRA) and later of arsenic trioxide (ATO) treatment. As a result, patients with APL achieve long-term responses in a large proportion after first-line therapy, so that performing hematopoietic stem cell transplant as consolidation of first complete remission is no longer necessary. Even in the case of relapses, most patients obtain a new remission thanks to the therapy with ATO and ATRA, but to maintain it, a consolidation treatment as effective as possible is necessary. The experience accumulated from studies published in the last two decades shows the effectiveness of hematopoietic stem cell transplantation (HSCT) in improving the evolution of patients who achieve a new complete re-mission. Thus, the recommendations of expert groups indicate transplantation as consolidation therapy in patients with a second complete remission with the mention of the use of autologous HSCT in cases with complete molecular remission and allogeneic HSCT for patients with the persistence of minimal residual disease or early relapse. However, there is a variety of contro-versial aspects related to the role of HSCT in APL, from obtaining outcome data almost exclusively from retrospective studies and historical analyzes to questions related to the type of transplanta-tion, the impact of minimal residual disease, conditioning regimens, or the role of other thera-peutic options. All these questions justify the performance of controlled prospective studies in the following years.

It has been previously shown that aldehyde dehydrogenase (ALDH) family member ALDH1A1 has a significant association with acute myeloid leukemia (AML) patient risk group classification, and that AML cells lacking ALDH1A1 expression can be readily killed by chemotherapy. In the past, however, a redundancy between the activities of subgroup members of the ALDH family has hampered conclusive evidence for addressing the role of specific ALDH genes. We here describe the bioinformatics evaluation of all nineteen member genes of the ALDH family as prospective actionable targets for the development of methods aimed to improve AML treatment. We implicate ALDH1A1 in the development of recurrent AML, and we show that from the nineteen members of the ALDH family, ALDH1A1 and ALDH2 have the strongest association with AML patient risk group classification. Furthermore, we discover that the sum of the expression values for RNA from the genes ALDH1A1 and ALDH2 has a stronger association with AML patient risk group classification and survival than either one gene alone. In conclusion, we identify ALDH1A1 and ALDH2 as prospective actionable targets for the treatment of AML in high risk patients. Substances that inhibit both enzymatic activities can constitute potentially effective pharmaceutics.

There is remarkable morphologic and genetic heterogeneity in acute myeloid leukemia (AML). In a small percentage of cases of AML, increased eosinophils and/or basophils are present in the bone marrow and sometimes in the peripheral blood. This is often a puzzling diagnostic situation but also an important finding that requires special investigation. Unique chromosomal rearrangements have been correlated with an increased number of eosinophils and basophils in AML. Identification of the underlying genetic lesion that promotes eosinophilia and basophilia can dramatically change both the prognosis and the treatment of the patient. Thus clinicians must be vigilant in searching for the cause of eosinophilia and/or basophilia in patients with AML, since the different causes may lead to different treatments and survival outcomes. In this article we examine the significance of increased eosinophils and/or basophils in the context of AML, provide guidance that simplifies the differential diagnosis, and prognostic and therapeutic information about specific subtypes of AML associated with eosinophilia and/or basophilia. Evidence supporting personalized (molecularly targeted) therapy for these patients is also presented.

Identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly targeted strategies designed to improve the outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3, is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD), present in 30%-35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus has encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance is induced by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades however, currently little is known which divergent signaling pathways are controlled by each of these FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways regulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise for development of more durable and personalized therapeutic approaches targeting mutant FLT3, to improve the treatment of AML.

Leukemia is a cancer of the bone marrow, a spongy tissue that secretes into the bones and serves as the site for the production of blood cells. One of the most prevalent kinds of leukemia in adults is acute myeloid leukemia (AML). Leukemia has non-specific signs and symptoms that are also similar to those of other interpersonal illnesses. The only way to accurately diagnose leukemia is by manually examining a stained blood smear or bone marrow aspirate under the microscope. However, this approach takes more time and is less precise. This paper describes a method for the automatic recognition and classification of AML in blood smears. Classification techniques include decision trees, logistic regression, support vector machines, and naive bayes.

Acute myeloid leukemia (AML) is a hematological malignancy that is the culmination of genetic and epigenetic alterations in the hematopoietic progenitor cells, leading to uncontrolled proliferation at the expense of normal hematopoiesis and bone marrow exhaustion. Although the outcomes for pediatric AML have improved in recent decades, at least one third of children still have relapses. Recent studies have notably highlighted the important role of dysregulated epi-genetic mechanisms in myeloid leukemogenesis. Epigenetic modifications are frequently reversible compared to genetic alterations, thus providing opportunities for targeted epigenetic therapy. In this review, we summarize the landscape of epigenetic alterations and the progress to date in epigenetic targeted therapy, and focus on the future role of epigenetic abnormalities in predicting relapse and the precision therapy in pediatric AML.

Leukemia cutis (LC) is defined as leukemic infiltration of the epidermis, the dermis, and the subcutaneous tissue. Leukemia cutis may follow or occur simultaneously with the diagnosis of systemic leukemia. However, cutaneous lesions are occasionally diagnosed as the primary manifestation of leukemia. Leukemic skin infiltrations demonstrate considerable variation regarding number of changes, distribution, and morphology. The highest incidence of LC is observed in chronic lymphocytic leukemia, monocytic and myelomonocytic acute myeloid leukemia, and in T-cell lineage leukemia. Although the pathogenic mechanism of the invasion of leukemic cells into the skin is not well understood, chemokine receptors and adhesion molecules as well as genetic characteristics of leukemia are thought to play a role. Leukemic skin lesions may be localized or disseminated and may occur alone or in combination on any site of the skin, most frequently in the trunk and extremities. The most common clinical presentations of leukemia cutis are papules, nodules, macules, plaques, and ulcers. In most patients, complete or partial resolution of cutaneous infiltrations occurs simultaneously with hematologic remission. However, in patients with resistant disease or recurrent skin infiltration, local radiotherapy can be used. This review presents recent data on the pathogenesis, diagnosis and treatment of leukemic skin involvement in different types of leukemia

The expression of the oncogene zinc-finger protein 217 (ZNF217) has been reported to play a central role in cancer development, resistance, and recurrence. Therefore, targeting ZNF217 has been proposed as a possible strategy to fight cancer, making necessary to discover novel com-pounds. The present work aims to characterize the chemopreventive properties of cucurbitacin D , a compound with a broad range of anticancer effectsin relation to the ZNF217 expression. Different cucurbitacins were isolated from the Vietnamese plant Elaeocarpus hainanensis. The purified compounds were tested on nucleophosmin-mutated acute myeloid leukemia and other hematology cancer to study their effects on viability, apoptosis, cell cycle and on the expression of ZNF217. Cucurbitacin D reduced the number of acute myeloid leukemia cells by increasing apoptosis and blocking cell cycle progression. It also significantly decreased ZNF217 expression but only in the OCI-AML3 Nucleophosmin-mutated cell line, but not in other hematologic cancers. The reduction in ZNF217 expression contributed significantly to the blocking of cell cycle progression but not to apoptosis as established by the silencing of the same gene. The obtained results suggest Cucurbitacin D as a promising molecule to target the mutated Nu-cleophosmin or its pathway in acute myeloid leukemia cells, although further studies are needed for in depth investigatiion of its specificity.

Leukemia is a form of blood cancer that results in an increase in the number of white blood cells in the body. The correct identification of Leukemia at any stage is essential. The current traditional approaches rely mainly on field expertise' knowledge, which is time consuming. The poor understanding and a long period of examination might damage the human body. In this situation an automated Leukemia identification delivers more reliable and accurate diagnostic information. To effectively diagnose acute lymphoblastic Leukemia from blood smears pictures, a new strategy based on traditional image analysis techniques with machine learning techniques, and a composite learning approach was constructed in this experiment. To identify the type of acute Leukemia first, four well-known machine learning models were utilized. It was discovered that Support Vector Machine (SVM) Provides the highest accuracy in this scenario. To boost the performance, a deep learning model Resnet50 was hybridized with SVM model. Finally, it was revealed that this composite approach achieved 99.9% accuracy.

Searching for bioactive compounds within the huge chemical space is like trying to find a needle in a haystack. Isatin is a unique natural compound which is endowed with different biopertinent activities specially in cancer therapy. Herein, we envisaged that adopting a hybrid strategy of isatin and α,β-unsaturated ketone would afford new chemical entities with strong chemotherapeutic potential. Of interest, compounds 5b and 5g demonstrated significant antiproliferative activities against different cancer genotypes according to NCI assay. Concomitantly, their IC50 against HL-60 cells were 0.38 ± 0.08 and 0.57 ± 0.05, respectively, demonstrating remarkable apoptosis and mod-erate cell cycle arrest at G1 phase. Intriguingly, an impressive safety profile for 5b was reflected by a 37.2 times selectivity against HL-60 over PBMC from a healthy donor. This provoked us to further explore their mechanism of action by in vitro and in silico tools. Conclusively, 5b and 5g stand out as strong chemotherapeutic agents that hold a clinical promise against acute myeloid leukemia.

The MLL gene is a site of frequent rearrangement in acute leukemia with multiple fusion partners, but MLL-SEPT6 rearrangement is rare in clinical leukemia practice, and only 13 cases have been reported. We describe the case of an acute myelogenous leukemia child with MLL-SEPT6 rearrangement whose age of onset and accompanying gene mutations differs from previous reports. Considering the poor prognosis of leukemia children with MLL-SEPT6 rearrangement and the unsatisfactory results of existing treatments, the study of this case may provide new theories for diagnosis and treatment of MLL-SEPT6-associated childhood acute leukemia.

Achieving complete remission (CR) is crucial for acute myeloid leukemia (AML) patients undergoing curative therapy, but relapse often occurs within months, highlighting the need for strategies to prolong leukemia-free survival (DFS). Our phase III study compared the efficacy and safety of azacitidine (AZA) versus best supportive care (BSC) in elderly AML patients who achieved CR after intensive induction and consolidation therapy. This ancillary study (QOL-ONE Trans-2) evaluated biological changes in bone marrow using Next Generation Sequencing (NGS). We analyzed baseline, randomization, and 6-month post-remission samples from 24 patients (median age 71, 12 males). High-throughput NGS targeted 350 myeloid malignancy-related genes, considering variants with a Variant Allele Frequency (VAF) ≥ 4%. At diagnosis, all patients had 5 to 17 (median 10) mutations, with DNMT3A (42%), NPM1 (33%), and TET2 (33%) being most frequent. FANCA mutations in 4 patients were linked to a higher relapse risk (HR 4.96, p=0.02) for DFS at both 2 and 5 years. Further HLA-specific NGS analyses are ongoing to confirm these results and their therapeutic implications.

Background: Myeloid sarcoma (MS), also known as granulocytic sarcoma or chloroma, is a rare disease entity characterized by the emergence of an extramedullary tumour which may be antecedent, coexisting or manifest secondarily to an ongoing malignancy of lymphoid origin. Owing to its low prevalence, scientific reports addressing this matter comprise mainly retrospective studies with a limited number of participants, rather low-quality research and only few case reports. Despite MS’s rarity, the need for enhancing diagnostic tools and refinement of therapeutic regimens is broadly recognised among physicians. Case summary: In this case series, we present the clinical histories of two patients diagnosed with MS. The former (Case 1) exhibited MS of the sternum alongside chronic myeloid leukemia (CML), while in case of the latter (Case 2) MS was the initial manifestation of a current acute myeloid leukemia (AML). Regardless of treatment institution comprising chemotherapy (CHTH) and radiotherapy (RT), the patient afflicted by CML did eventually pass due to cardiorespiratory insufficiency secondary to an infection, whereas the second one is in clinical remission up to this date, that is 16 months since MS had been diagnosed. Furthermore, a comprehensive analysis of previously reported cases was conducted which involves MS in patients with AML and CML. Conclusion: The objective of this report is to emphasize the heterogeneity among the clinical manifestations of MS, to underline the relevance of histopathological and molecular diagnostic tools in opting for the appropriate therapy and that, in spite of it occurring rather uncommonly, physicians should think of MS in presence of pathological masses in patients under risk of hematological malignancies.

Background: The receptor activator of the nuclear factor-kB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway is a determining pathway in the balance between bone formation and resorption; disruptions in this complex can affect bone metabolism. Methods: This study analyzed the changes in RANKL, OPG and 25(OH)D levels, the RANKL/OPG ratio, and other bone turnover markers (BTM) from diagnosis to complete remission in children with acute lym-phoblastic leukemia (ALL). This is a prospective observational cohort study. This study was carried out in the Instituto Mexicano del Seguro Social in Mexico City. Thirty-three patients (4-17 years) with newly diagnosed B-cell ALL were included. The patients were treated with the HP09 chemotherapy protocol. Children who had previously been treated with corticosteroids were excluded. A pe-ripheral blood sample at diagnosis and remission was collected to determine the 25(OH)D and BTM concentrations. Results: Increased RANKL (p=0.001) and osteocalcin (p

Acute myeloid leukemia (AML) is an aggressive malignancy characterized by rapid growth and uncontrolled proliferation of undifferentiated myeloid cells. Metabolic reprogramming is commonly observed in the bone marrow of AML patients, as leukemia cells require increased ATP supply to support disease progression. In this study, we examined the potential role of mesothelin as a metabolic modulator in myeloid cells in AML. Mesothelin is a well-known marker of solid tumors that promotes cancer cell proliferation and survival. We initially analyzed alterations in mesothelin expression in the myeloblast subpopulations, defined as SSC-Alow/CD45dim, obtained from bone marrow of AML patients using flow cytometry. Our results showed overexpression of mesothelin in 34.8% of AML patients. Subsequently, metabolic changes in leukemia cells were evaluated by comparing the oxygen consumption rates (OCR) of bone marrow samples derived from adult AML patients. Notably, higher OCR was observed in the mesothelin-positive compared to the mesothelin-low and non-expressing groups. Treatment with recombinant human mesothelin protein enhanced OCR and increased the mRNA expression of glycolytic enzymes and mitochondrial complex II in KG1α AML cells. Notably, siRNA targeting mesothelin in KG1α cells led to reduction of glycolysis-related gene expression but had no effect on the mitochondrial complex gene. The collective results demonstrate that mesothelin induces metabolic changes in leukemia cells, facilitating acquisition of a rapid supply of ATP for proliferation in AML. Therefore, targeting of mesothelin presents a potentially promising approach for mitigating the progression of AML through inhibition of glycolysis and mitochondrial respiration in myeloid cells.

Background: After allogeneic hematopoietic stem cell transplantation (allo-HSCT), acute leukemia relapse is common, and asymmetric bone marrow recurrence hasn’t been reported. Because the anatomical distribution of acute leukemia clones in the bone marrow after allo-HSCT is presumed to be diffuse, bone marrow aspirations are performed in single site. Case presentation: We identified two acute leukemia patients, whose leukemic burden in bilateral bone marrow specimens differed significantly. The first case was a 20-year-old man who was diagnosed with acute myelomonocytic leukemia and received haploidentical allo-HSCT. He had been in complete remission for two years and off immunosuppressive medications for a year, with normal peripheral blood count. Routine bone marrow biopsy of his left posterior iliac bone marrow showed 52% leukemia blasts, while the right side had 0% blasts ten days later. Due to the discordant results, the patient refused further intervention and died of high leukocyte syndrome four months later. The second case was a 23-year-old woman who was diagnosed with acute B lymphoblastic leukemia and received HLA-identical sibling allo-HSCT. Although 62% of blasts were found in her left iliac marrow on day +122, 0 % of blasts were found on a sample obtained from the right iliac crest on day +128. Whole-body 18F-FDG PET/CT scans confirmed that the leukemic infiltration in her bone marrow was asymmetric. Considering the higher leukemic burden on the left, we chose the left posterior iliac crest aspiration for further response evaluation. After chemotherapy combined with donor lymphocyte infusion, she achieved transient hematologic complete remission. She died of septic shock with heart failure at +258 days after allo-HSCT before infusion of anti-CD19 donor chimeric antigen receptor T cells. Conclusions: To our knowledge, these are the first case reports of asymmetric bone marrow infiltration of blasts in acute leukemia patients after allo-HSCT. Bilateral posterior iliac crest aspirations or 18F-FDG-PET/CT scans may help distinguish such distribution. If discordant bone marrow specimens are observed, physicians should restrict future bone marrow studies to the more involved side.

A specialized microenvironment in the bone marrow, composed of stromal cells including mesenchymal stem cells (MSCs), support hematopoietic stem cells (HSCs) self-renewal and differentiation but also regulates leukemia development and progression. The reciprocal direct interaction between MSCs and CD34+ HSCs under physiological and pathological conditions has not been well characterized yet. Here, we established a direct co-culture model between MSCs and CD34+ HSCs or MSCs and acute myeloid leukemia cells (THP-1, Molm-13, and primary cells from patients) to study cell-cell communication. Following MSCs-CD34+ HSCs co-culture, the expression of adhesion markers N-cadherin and connexin 43 increased in both cell types, forming gap junction channels. Moreover, the clonogenic potential of CD34+ HSCs was increased. However, direct contact of acute myeloid leukemia cells with MSCs reduced the expression levels of connexin 43 and N-cadherin in MSCs. The impairment in gap junction formation could be ascertained to a defect in the acute myeloid leukemia derived MSCs. Interestingly, CD34+ HSCs and acute myeloid leukemia cell lines restrained MSCs from engaging into osteoblastic differentiation upon prolonged direct cell-cell contact. In conclusion, under physiological conditions, connexin 43 and N-cadherin interaction preserves stemness of both CD34+ HSCs and MSCs, a process that is compromised in acute myeloid leukemia, pointing out to the possible role of gap junctions in modulating stemness.

AML is a highly aggressive and heterogeneous form of hematological cancer. Proteomics-based stratification of patients into more refined subgroups may contribute to a more precise characterization of the patient-derived AML cells. Here, we reanalyzed liquid chromatography-tandem mass spectrometry (LC-MS/MS) generated proteomic and phosphoproteomic data from 26 chemoresistant/relapse (RELAPSE) and 15 relapse-free (REL_FREE) AML patients. We considered not only the RELAPSE and REL_FREE characteristics but also integrated the French-American-British (FAB) classification, along with considering the presence of nucleophosmin 1 (NPM1) mutation and cytogenetically normal AML. We found a significant number of differentially enriched proteins (911) and phosphoproteins (257) between the various FAB subtypes in RELAPSE patients. Patients with the myeloblastic M1/M2 subtype showed higher levels of RNA processing-related routes and lower levels of signaling related to terms like translation and degranulation, when compared to the M4/M5 subtype. Moreover, we found that high abundance of proteins associated to mitochondrial translation and oxidative phosphorylation, particularly observed in the RELAPSE M4/M5 NPM1 mutated subgroup, distinguishes relapsing from non-relapsing AML patient cells with the FAB subtype M4/M5. Thus, the discovery of subtype-specific biomarkers through proteomic profiling may complement the existing classification system for AML and potentially aid in selecting personalized treatment strategies for individual patients.

Background. Gene rearrangements affecting KMT2A are frequent in acute myeloid leukemia (AML) and are often associated with a poor prognosis. KMT2A gene fusions are often detected by chromosome banding analysis and confirmed by fluorescence in-situ hybridization. However, small intragenic insertions, termed KMT2A partial tandem duplication (PTD), are particularly challenging to detect using standard molecular and cytogenetic approaches. Methods. We have validated the use of a custom hybrid capture based next-generation sequencing (NGS) panel for comprehensive profiling of AML patients seen at our institution. This NGS panel targets the entire consensus coding DNA sequence of KMT2A; to deduce the presence of a PTD we used the relative ratio of KMT2A exons coverage. We sought to corroborate the KMT2A-PTD NGS results using (1) multiplex-ligation probe amplification (MLPA) and (2) optical genome mapping (OGM). Results. We analyzed 932 AML cases and identified 41 individuals harboring a KMT2A-PTD. MLPA, NGS and OGM confirmed the presence of a KMT2A-PTD in 22 of the cases analyzed where orthogonal testing was possible. Two false positive PTD calls by NGS could be explained by the presence of cryptic structural variants impacting KMT2A and interfering with PTD analysis. OGM revealed the nature of these previously undetected gene rearrangements in KMT2A, while MLPA yielded in-conclusive results. MLPA analysis for KMT2A-PTD is limited to exon 4, whereas NGS and OGM resolved KMT2A-PTD sizes and copy number levels. Conclusion. KMT2A-PTDs are complex gene rearrangements that cannot be fully ascertained using a single genomic platform. MLPA, NGS panels and OGM are complementary technologies applied in standard of care testing for AML patients. MLPA and NGS panels are designed for targeted copy number analysis; however, our results show that integration of concurrent genomic alterations is needed for accurate KMT2A-PTD identification. Unbalanced chromosomal rearrangements overlapping with KMT2A can interfere with the diagnostic sensitivity and specificity of copy number based KMT2A-PTD detection methodologies.

Active vitamin D derivatives (VDDs) – 1α,25-dihydroxyvitamin D3/D2 and their synthetic analogs – are well-known inducers of cell maturation with the potential for differentiation therapy of acute myeloid leukemia (AML). However, their dose-limiting calcemic activity is a significant obstacle to using VDDs as an anticancer treatment. We have shown that different activators of the NF-E2-related factor-2/Antioxidant Response Element (Nrf2/ARE) signaling pathway, such as the phenolic antioxidant carnosic acid (CA) or the multiple sclerosis drug monomethyl fumarate (MMF), synergistically enhance the antileukemic effects of various VDDs applied at low concentrations in vitro and in vivo. This study aimed to investigate whether glutathione, the major cellular antioxidant and the product of the Nrf2/ARE pathway, can mediate the Nrf2-dependent differentiation-enhancing activity of CA and MMF in HL60 human AML cells. We report that glutathione depletion using L-buthionine sulfoximine attenuated the enhancing effects of both Nrf2 activators concomitant with downregulating vitamin D receptor (VDR) target genes and the activator protein-1 (AP-1) family protein c-Jun levels and phosphorylation. On the other hand, adding reduced glutathione ethyl ester to dominant negative Nrf2-expressing cells re-stored both the suppressed differentiation responses and the downregulated expression of VDR protein, VDR target genes, as well as c-Jun and P-c-Jun levels. Finally, using the transcription factor decoy strategy, we demonstrated that AP-1 is necessary for the enhancement by CA and MMF of 1α,25-dihydroxyvitamin D3-induced VDR and RXRα protein expression, transactivation of the vitamin D response element, and cell differentiation. Collectively, our findings suggest that glutathione mediates, at least in part, the potentiating effect of Nrf2 activators on VDDs-induced differentiation of AML cells, likely through the positive regulation of AP-1.

Lp16-PSP from Lentinula edodes strain C91-3 has been reported previously in our laboratory to have selective cytotoxic activity against a panel of human cell lines. Herein, we have used several parameters in order to characterize the Lp16-PSP-induced cell death using HL-60 as model cancer. The results of phase contrast microscopy, nuclear examination, DNA fragmentation detection and flow cytometry revealed that high doses of Lp16-PSP resulted in the induction of apoptosis in HL-60 cells. The colorimetric assay showed the activation of caspase-8, -9 and -3 cascade highlighting the involvement of Fas/FasL-related pathway. Whereas, western blot revealed the cleavage of caspase-3, increased expression of Bax, the release of cytochrome c and decreased expression of Bcl-2 in a dose-dependent manner, suggesting the intrinsic pathway might be involved in Lp16-PSP-induced apoptosis either. Low doses of Lp16-PSP resulted in the anchorage-independent growth inhibition, induction of G1 phase arrest accompanied by the increased expression of p21WAF1/CIP1 along with the decreased expression of cyclin D, E, and cdk6. Our findings suggest that induction of apoptosis and p21WAF1/CIP1 mediated G1 arrest might be one of the mechanisms of the action of Lp16-PSP, however, further investigations on multiple leukemia cell lines and in vivo models are of ultimate need.

Using multi-color flow cytometry analysis, we studied the immunophenotypical differences between leukemic blasts/LSCs from patients with AML/MDS and hematopoietic stem and progenitor cells (HSPCs) from patients in complete remission (CR) following their successful treatment. The panel of markers included CD34, CD38, CD45RA, CD123 as representatives for a hierarchical hematopoietic stem and progenitor cell (HSPC) classification as well as programmed death ligand 1 (PD-L1). Rather than restricting the evaluation on a 2- or 3-dimensional analysis, we applied a t-distributed stochastic neighbor embedding (t-SNE) approach to get a deeper insight and segregation between leukemic and normal HPSCs. For that purpose, we created a t-SNE map, which resulted in the visualization of 27 cell clusters based on their similarity concerning the composition and intensity of antigen expression. Two of these clusters were “leukemia-related” containing a great proportion of CD34⁺/CD38^- hematopoietic stem cells (HSCs) or CD34⁺ cells with a strong coexpression of CD45RA/CD123, respectively. CD34⁺ cells within the latter cluster were also highly positive for PD-L1 reflecting their immunosuppressive capacity. Beyond this proof of principle study, the inclusion of additional markers will be helpful to refine the differentiation between normal HSPCs and leukemic cells, particularly in the context of minimal disease detection and antigen-targeted therapeutic interventions. Furthermore, we suggest a protocol for the assignment of new cell ensembles in quantitative terms, via a numerical value, the Pearson coefficient, based on a similarity comparison of the t-SNE pattern with a reference.

This article provides a thorough overview of biomarkers, pathophysiology, and molecular pathways involved in the transition from acute kidney injury (AKI), acute kidney disease (AKD) to chronic kidney disease (CKD). It categorizes the biomarkers of AKI into stress, damage, and functional markers, highlighting their importance in early detection, prognosis, and clinical application. The pathophysiological mechanisms underlying AKI, AKD, including renal hypoperfusion, sepsis, nephrotoxicity, and immune responses, with the impact on renal injury. In addition, various molecules play pivotal roles in inflammation and hypoxia, triggering maladaptive repair, mitochondrial dysfunction, immune system reactions, and cellular senescence of renal cell. Key signaling pathways, such as Wnt/β-Catenin, TGF-β/SMAD, and Hippo/YAP/TAZ, promote fibrosis and impact renal function. The Renin-Angiotensin-Aldosterone System (RAAS) triggers a cascade leading to renal fibrosis, with aldosterone exacerbating oxidative stress and cellular changes that promote fibrosis. Clinical evidence suggests RAS inhibitors may protect against CKD progression, especially post-AKI, though more extensive trials are needed to confirm their full impact.

Background: Ventilatory strategies in acute respiratory distress syndrome patients aim to mitigate the risk of acute lung injury (ALI). However, prolonged utilization of these strategies may precipitate alveolar carbon dioxide elevation and pH reduction. This scoping review endeavors to present extant knowledge concerning hypercapnia effects in experimental models, with or without ALI, specifically focusing on delineating the immunologically mediated pulmonary tissue damage; Methods: A systematic exploration encompassing PubMed, Web of Science, ScienceDirect, Cochrane Reviews, and Scielo databases was undertaken. Articles published between January 1, 2008, and December 31, 2022, were screened for their elucidation of hypercapnia's immunological impact on lung tissue, utilizing experimental or biological models, irrespective of ALI presence; Results: Following duplicate removal and predefined criteria filtering, 30 pertinent articles scrutinizing hypercapnia's influence on pulmonary epithelium were identified. It was observed that hypercapnia induces perturbations in innate immune response gene transcription, mediated via Nuclear Factor-kappa B attenuation. Furthermore, a compromised innate immune response against injurious agents was noted. Concurrently, disruption and subsequent resealing of alveolar epithelial cells were evidenced, primarily through Na/K-ATPase endocytosis, impeding fluid reabsorption at the alveolar epithelium level; Conclusions: In experimental settings, with or without ALI, hypercapnia's immunomediated mechanisms exacerbate innate immune system impairment and disrupt the respiratory epithelium's repair and healing processes.

Background: This systematic review aims to investigate whether percutaneous transhepatic gallbladder drainage (PTGDB), as definitive treatment, is superior to emergency cholecystectomy (EC) in high-risk patients with acute cholecystitis (AC). Material and methods: A systematic literature search was performed until December 2022 using Scopus, Medline/PubMed and Web of Science databases in order to compare PTGDB as definitive treatment vs EC in AC. Results: Seventeen studies (1 Randomized Control Trials and 16 observational studies) have been included with a total of 783,672 patients (32,634 treated with PTGDB vs 4,663 who underwent laparoscopic cholecystectomy, 343 who underwent open cholecystectomy and 746,032 who underwent cholecystectomy, but without laparoscopic or open approach being specified). The quality assessment (ROBINS-I) of the not randomized studies showed a serious risk, differently the evaluation of the randomized study (RoB 2) showed a low risk of bias. Analysis of the results shows that PTGDB, despite being minimally invasive, do not have different incidence of complications than EC (RR 0.77 95% CI [0.44 to 1.34]; I2 = 99%; P=0.36). A lower postoperative mortality was reported in patients who underwent EC (2.37%) than in PTGDB group (13.78 %) (RR 4.21; 95% CI [2.69 to 6.58]; P < 0.00001), furthermore the risk of hospital readmission for biliary complications (RR 2.19 95% CI [1.72 to 2.79]; I2 = 48 %; P<0.00001) and hospital stay (MD 4.29 95% CI [2.40 to 6.19]; P<0.00001) were lower in EC group. Conclusions: No advantage in using PTGDB as a definitive treatment over EC in the management of critically ill patients with AC has been demonstrated; the results of our systematic review and meta-analysis suggest using EC as the treatment of first choice, even for very high-surgical-risk patient in which PTGDB should be reserved. The major limitation of this systematic review and meta-analysis is associated to a low quality of evidence for the serious bias in the not randomized studies. For this reason, new high powered and well-designed clinical trials are needed to recommend PTGDB as definitive treatment in patients unfit for surgery or those who refuse to undergo surgery.

Human bocavirus (HBoV) is an emerging virus that has been detected worldwide that could be associated with cases of acute gastroenteritis (AGE). However, its contribution to AGE has not been elucidated. This study aimed to describe the frequency, clinical features, and HBoV genotypes circulation in children up to 5 years with or without AGE symptoms in Acre, Northern Brazil. A total of 480 stool samples were collected between January and December 2012. Fecal samples were used for extraction, nested PCR amplification, and sequencing for genotyping. Statistical analysis was applied to verify the association between epidemiological and clinical characteristics. Overall HBoV-positivity was 10% (48/480), being HBoV-positivity rates of 8.4% (19/226) and 11.4% (29/254) recorded among diarrheic and non-diarrheic children, respectively. The most affected age group was between 7 and 24 months (50%). HBoV infection was more frequent in children living in urban areas (85.4%), using water from the public network (56.2%), and living with adequate sewage facilities (50%). Co-infection with other enteric viruses was 16.7% (8/48) and the most prevalent coinfection was RVA+ HBoV (50%, 4/8). HBoV‐1 was the most frequent species detected, responsible for 43.8% (21/48) of cases, followed by HBoV-3 (29.2%, 14/48) and HBoV-2 (25%, 12/48). In the present study, HBoV infections are not associated with AGE, as most HBoV cases belonged to the non-diarrheal group without AGE symptoms. Future studies are warranted to determine the role of HBoV in causing acute diarrhea disease.

The simplified, combined protocol admits children with a mid-upper-arm circumference (MUAC) of <125 mm or edema to malnutrition treatment with ready-to-use therapeutic food (RUTF) prescribing 2 daily RUTF sachets to children with MUAC <115 mm or edema and 1 daily sachet to those with MUAC ≥115 mm but <125 mm. This treatment has previously been shown to result in non-inferior programmatic outcomes compared to standard treatment. We aimed at observing its effectiveness in a routine setting at scale, including via delivery by community health workers (CHW). A total of 27 601 children were admitted to the simplified, combined treatment. Treatment resulted in 96% overall recovery with a mean LOS of 40 days and a mean RUTF consumption of 63 sachets per child treated. Among children admitted with MUAC <115 mm or edema 94% recovered with a mean LOS of 55 days and consuming an average of 97 RUTF sachets. Recovery in all sub-groups studied exceeded 90%.Treatment by CHWs resulted in similar (96%) recovery as treatment by formal health care workers (96%). The simplified, combined protocol results in high recovery and low RUTF consumption per child treated, and can safely be adopted by CHWs to provide treatment in the community-level.

Idiopathic acute pancreatitis (IAP) presents a diagnostic challenge and refers to cases where the cause of acute pancreatitis remains uncertain despite a comprehensive diagnostic evalua-tion. Endoscopic ultrasound (EUS) has emerged as a valuable tool in the diagnostic workup of IAP. This review explores the pivotal role of EUS in detecting the actual cause of IAP, as-sessing its accuracy, timing, safety, and future technological improvement. Following PRISMA guidelines, 60 pertinent studies were selected and analysed. EUS emerges as a cru-cial diagnostic tool, particularly when conventional imaging fails. It can offer intricate visu-alization of the pancreas, biliary system, and adjacent structures. High accuracy of EUS is evident in detecting the actual causes of IAP such as microlithiasis, small bile duct stones, pancreas divisum, and small pancreatic tumors. Optimal timing for EUS is post-resolution of the acute phase of the disease. EUS, when conducted by experienced endoscopists, it boasts minimal safety concerns, and is crucial to prevent complications. EUS-guided interventions, including fine-needle aspiration, collection drainage, and biopsies, aid in cytological analy-sis. With high diagnostic accuracy, safety, and therapeutic potential, EUS is able to improve patient outcomes when managing IAP. Further refinement of EUS techniques and cost-effectiveness assessment of EUS-guided approaches need to be explored in multicenter prospective studies. This review underscores EUS as a transformative tool in unraveling IAP's enigma and advancing diagnostic and therapeutic strategies.

Background. There are scant data about the effectiveness of high flow nasal cannula (HFNC) oxygen therapy in patients hospitalized with severe acute respiratory failure (ARF) in non-intensive medical wards, particularly regarding the effect on arterial oxygenation compared to conventional oxygen therapy (COT) and non-invasive ventilation (NIV) or continuous positive airway pressure (CPAP). Methods. In a retrospective observational study, oxygenation parameters were measured before and immediately after HFNC initiation in 37 consecutive patients hospitalized in a geriatric ward in 2017. Results. HFNC was used as escalation therapy for untreatable hypoxia after failure of NIV/CPAP (n=18) or COT (n=19). Twenty-two patients died, 2 were transferred to the intensive care unit, while 13 were discharged alive. A “do not intubate” status was identified in 17 of the 22 deceased patients. Partial pressure of oxygen (pO2, p< 0.0001), oxygen saturation (SO2, p< 0.0001), pO2/fraction of inspired oxygen ratio (p=0.004) and peripheral SO2 measured by pulse oximetry (p< 0.0001) significantly increased soon after HFNC application. Oxygenation improvements were greater after escalation from NIV/CPAP and in patients discharged alive. Conclusion. HFNC significantly improved oxygenation in severe ARF after failure of COT or NIV/CPAP and may be particularly suitable for older patients hospitalized in non-intensive medical wards.

Acute pancreatitis (AP) is a leading gastrointestinal disease that cause hospitalization. Initial management in the first 72 h after the diagnosis of AP is pivotal, which can influence the clinical outcomes of the disease. Initial management, including fluid resuscitation, pain control, nutritional support, antibiotic use, and endoscopic retrograde cholangiopancreatography (ERCP) in gallstone pancreatitis, plays a fundamental role in AP treatment. Recent updates for fluid resuscitation, including treatment goals, the type, rate, volume, and duration, have triggered a paradigm shift from aggressive hydration with normal saline to goal-directed and non-aggressive hydration with lactated Ringer’s solution. Evidence of the clinical benefit of early enteral feeding is becoming definitive. Routine use of prophylactic antibiotics is generally limited, and the procalcitonin based algorithm of antibiotic use has recently been investigated to distinguish between inflammation and infection in patients with AP. Although urgent ERCP (within 24 h) should be performed for patients with gallstone pancreatitis and cholangitis, urgent ERCP is not indicated in patients without cholangitis. Furthermore, convalescent treatment, including cholecystectomy in gallstone pancreatitis and alcohol intervention in alcoholic pancreatitis, is also important for improving the prognosis and prevent recurrence in patients with AP. This review focuses on recent updates on the initial and convalescent management strategies for AP.

This case report describes a 71-year-old female with multiple comorbidities who presented with symptoms suggestive of stroke and was subsequently found to have severe acute kidney injury (AKI) due to acute interstitial nephritis (AIN). The patient has normal kidney function at baseline. She has been on hydrochlorothiazide and metoprolol succinate for hypertension for several years. Due to severe acute kidney injury, a kidney biopsy was performed, revealing severe Acute Interstitial Nephritis secondary and multiple intratubular oxalate crystals. The patient's renal function improved after withdrawing HCTZ, volume repletion and initiating prolonged prednisone taper. We attempt to provide some insights through our paper into the mechanism of acute renal failure from crystal nephropathy and its management.

Aortic dissection is a clinicopathological entity caused by rupture of the intima leading to a high mortality if not treated. Over time, diagnostic and investigative methods, antihypertensive therapy, and early referrals have resulted in improving outcomes according to registry data. Some data has also emerged from recent studies suggesting a link between Human Cytomegalovirus (HCMV) infection and aortic dissection. Furthermore, the use of microRNAs have also become increasingly widespread in the literature. These have been noted to play a role in aortic dissections with elevated levels noted in studies as early as 2017. This review aims to provide a broad and holistic overview of the role of miRNAs, while studying the role of HCMV infection in the context of aortic dissections. The role of long non-coding RNAs, circular RNAs and microRNAs are explored to identify changes in expression during aortic dissections. The use of such biomarkers may one day be translated into clinical practice to allow early detection and prognostication of outcomes and drive preventative and therapeutic options in the future.

Background： Sepsis-induced acute lung injury (ALI) is characterized by disruption of the epithelial barrier and activation of alveolar macrophages (AMs), which leads to uncontrolled pulmonary inflammation. However, effective treatments for ALI are unavailable. This study aimed to discover potential diagnostic molecular biomarkers based on bioinformatics, which will benefit the diagnosis and treatment of sepsis-induced ALI. Methods: GSE10474 was analyzed for differentially expressed genes (DEGs) in sepsis patients with ALI (sepsis + ALI) compared with sepsis patients without ALI. Functional enrichment analysis and protein-protein interaction (PPI) network were performed. on the DEGs via R package “clusterProfiler”, and visualized via Cytoscape. Prediction analysis of microarrays (PAM) was performed to identify diagnostic biomarkers and the diagnostic ability of diagnostic biomarkers was accessed via receiver operating characteristic (ROC) curves. Moreover, interactions among diagnostic biomarkers were analyzed via GeneMANIA. We also analyzed the function of diagnostic biomarkers and predicted their corresponding drugs via Cytoscape plugin BiNGO and web tool DGIdb. At last, we analyzed the transcriptional regulation of the diagnostic biomarkers via the web tool miRNet. Results: 71 genes were found to be differentially expressed in the sepsis + ALI group, mainly involved in immune-related biological processes and pathways. STRING database indicated 31 DEGs have protein-protein interactions. In addition, the PAM identified 6 diagnostic biomarkers, including HIST1H4H, CDKN1A, HMOX1, NQO2, RHOB, and TREM1, from these 31 DEGs. Conclusion: In conclusion, through bioinformatics analyses, we identified 6 potential diagnostic biomarkers and targets for sepsis-induced ALI.

Background: This study aimed to present the development process and characteristics of the Korean Registry of Acute Myocardial Infarction for Regional Cardiocerebrovascular Centers (KRAMI-RCC). Methods: We developed KRAMI-RCC, a web-based registry for patients with AMI. Patients from 14 RCCs were registered for more than 3 years from July 2016. It includes an automatic error-checking system, and user training and on-site monitoring are performed to manage data quality. Results: A total of 11,700 AMI patients were registered in KRAMI-RCC over 3 years (73.9% men). The proportions of patients with ST-elevation and non-ST-elevation myocardial infarction at discharge were 43.4% and 56.6%, respectively. Of the total 3-year patients, 5.6% died in the hospital and 4.4% died 12 months after discharge. The case fatality within 12 months was 9.7%. Prehospital care data showed delayed arrival time after onset of symptoms (median 153 min) and low transportation rate by public ambulance (25.2%). Post-hospital care data showed lower participation rate in the second rehabilitation program (16.8%). Conclusions: The recently developed KRAMI-RCC registry has been more focused on pre-hospital and post-hospital data, which will be helpful in understanding the current state of AMI disease management and in making policy decisions to reduce case fatality in Korea.

Aims: Clinical evidence indicates that innate immune cells may contribute to the onset and outcome of acute coronary syndrome (ACS). Our prospective study aimed at analysing neutrophil phenotypes in ACS and their role in predicting 1-year major cardiovascular events. Methods: Blood neutrophil phenotypes were analysed by flow cytometry. Differential blood cell count and plasma levels of soluble markers were recorded at admission and at 6-month follow-up. Results: 108 patients categorized in chronic stable coronary artery disease (n=37), unstable angina (UA) (n=19), Non-ST-Elevation Myocardial Infarction (NSTEMI) (n=25), and ST-Elevation Myocardial Infarction (STEMI) (n=27) were included. STEMI and NSTEMI patients displayed higher neutrophil count and neutrophil-to-lymphocyte ratio (NLR) than stable and UA patients (P<0.0001), which normalized at 6-month after MI. STEMI patients were characterized by elevated percentages of band cells in low-density neutrophils (P=0.007) and in high-density neutrophils (P=0.019) compared to the other patients. Multivariable logistic regression analysis revealed that plasma levels of total MPO was associated with STEMI when compared to stable (OR: 1.434; 95% CI: 1.119-1.837; P<0.0001), UA (1.47; 1.146-1.886; P=0.002), and NSTEMI (1.213; 1.1-1.134; P=0.0001) patients, while increased neutrophil SSC signal intensity was associated with NSTEMI compared to stable patients (3.828; 1.033-14.184; P=0.045). Based on multivariable Cox regression analysis, elevated plasma levels of PCSK9 and low-density neutrophil percentage predicted 1-year outcome independently of cardiovascular risk factors (c-index: 0.915; IQR: 0.908-0.929). Conclusions: Changes in neutrophil phenotype are concomitant to ACS. These changes may differ between STEMI and NSTEMI. They may also contribute to ACS risk and patient outcome.

Background: The assessment of the incidence and characteristic of acute and chronic post-operative endophthalmitis (POE) after cataract surgery in Poland during 2010 - 2015. Patients and methods: All hospitalizations of patients, in the National Database of Hospitalizations, who underwent cataract surgery alone or in combined procedures in Poland between January 2010 and December 2015, with a billing code of endophthalmitis, were selected. Acute endophthalmitis was identified if symptoms occurred within 1 - 42 days from the cataract surgery and chronic endophthalmitis if symptoms occurred ≥ 43 days after cataract surgery, respectively. Results: In total, 1331 cases of POE after 1,218,777 cataract extractions were identified. The overall incidence of POE decreased from 0.125% in 2010 to 0.066% in 2015. In multiple logistic regression analyses, increasing age was significantly associated with acute POE, while type II diabetes mellitus, extracapsular cataract extraction and one-day surgery were significantly associated with chronic POE. The combined cataract surgery and male sex were significant risk factors for both acute and chronic POE. A total of 62.51% of all eyes affected by POE received antibiotic treatment and 37.49% had vitrectomy treatment. Conclusions: During the study period, the total incidence of post-operative endophthalmitis after cataract surgery decreased significantly.

INTRODUCTION Recently there has been a significant increase in age in the United States. It is necessary to better understand the physiological and surgical needs of these patients in order to optimize outcomes. The vast majority of procedures performed in adult patients are low-risk operations, such as laparoscopic cholecystectomy. Our aim is to investigate the outcomes, including length of stay, morbidity, mortality, re-admission and discharge disposition of the elderly population (>80) undergoing low-risk operations in our tertiary community hospital. METHODS A retrospective chart review was done at a tertiary community hospital. The time frame utilized was 2011-2015. Patients were excluded only on the basis of their age (< 80) at the time of operation. RESULTS There were a total of 30 patients who underwent laparoscopic cholecystectomy from 2011 to 2015. 21 patients (70%) were female and 9 (30%) were male. No patients were converted to an open procedure. The average age was 86.4 years and average ASA classification prior to surgery was 2.88. Higher ASA class, specifically those that were class III/IV were more likely to have an increased length of stay that was statistically significant. Overall age greater than 80 was an independent risk factor for transfer to a higher level of care upon discharge (SNF, LTAC, etc.), a surrogate marker for physical decompensation following surgery. CONCLUSIONS Routine surgery, such as the laparoscopic cholecystectomy, effects the elderly population in a more substantial way, and early recognition coupled with increased education for physicians regarding geriatric patients can help to reduce length of stay, morbidity, and overall physical and mental deconditioning.

Background: The morbidity of myocardial infarction is keeping raise in this decade. Because of high safety and operability , percutaneous coronary intervention(PCI) has been used to conquer this disease for more than 20 years.An important complication of PCI is contrast induced nephropathy(CIN), which raises our attention. Previously, we started a study to explore the correlation between acute kidney injury and myonecrosis after scheduled percutaneous coronary intervention. Our study showed that the rate of CI-AKI in patients with post-procedural myocardial injury and undergoing elective PCI was higher than that in patients free of injury. Methods: In this study,forty male rats were randomly divided into four groups: control group (n=8), CM group (n=12), AMI group (n=8) and AMI+CM group (n=12), then velocity of renal artery blood flow (VRABF), computer tomography (CT), serum creatinine(Scr), reactive oxidative species (ROS), periodic acid-Schiff (PAS) and TUNEL were used to estimate the injury of kidney. We analyzed 327 non-ST-segment elevation acute coronary syndrome subjects undertaking elective PCI. Serum levels of creatinine (SCr) and the eGFR before coronary angiography, and 24–72 h after contrast administration were recorded to assess the renal function. Results: The data showed that VRABF was lower in AMI+CM group than CM group from 0 minute to 24h and CT number in cortex was higher in AMI+CM group than CM group at 4-hour. As well as the level of Scr in AMI+CM group displayed a significantly increase at 24-hour compared with CM group. The histopathologic scores and percentage of tubular cell apoptosis were higher in AMI+CM group at 24-hour. In 327 patients, we found that CI-AKI occurred more often in subjects with post-procedural myonecrosis (PMN) than in those without PMN (20.8% versus 5.8%, respectively, P=0.001). Conclusion: Compared to the elective patient, the injury of CIN exhibited a higher severity in AMI patient.

(1) Background: LUS has emerged as a simple, rapid and non-invasive method for the dynamic assessment of pulmonary congestion, a major prognostic factor and a therapeutic target in AHF. (2) Methods: In the single-center prospective observational study, 42 patients hospitalized for AHF in the post-emergency polyvalent medicine department of CHU Grenoble were successively included between May 2021 and July 2022. Clinical examination, LUS and electrolyte panel results were collected daily. Vital status was assessed 30 days after the last LUS. The primary endpoint was the evolution of the number of B-lines according to the dose of diuretic administered ; (3) Results: We performed 188 LUS. Our patients were elderly (85.8 [SD 8.1]) and comorbid. The median number of B-lines decreased from 17 at admission to 7 in the middle of the hospital stay, then stagnated until discharge. Simultaneously, the median dose of diuretics, initially stable at a maximum of 40 mg/d IV, decreased to 20mg/d IV by the end of hospital stay. Patients with CKD had a higher mean number of B-lines at entry (24.2 [SD 11.6]) compared to those without CKD (8.2 [SD 8.8]). However, the evolution of B-lines number was independent of creatinine levels. 30-day all-causes mortality was significantly related to the number of B-lines at discharge (15.2 [SD 10.1] in deceased patients versus 3.9 [SD 5.4] in living patients, p

Background/Objectives: Infectious Endocarditis often requires surgical intervention, with postoperative acute kidney injury (AKI) posing a significant concern. This retrospective study aimed to investigate AKI incidence, its impact on short-term mortality, and identify modifiable factors in patients with endocarditis scheduled for valve surgery. Methods: This single center study enrolled 130 consecutive endocarditis patients from 2013 to 2021 undergoing valve surgery. Creatinine levels were monitored pre- and postoperatively, and AKI was defined by Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Patient demographics, comorbidities, procedural details, and complications were recorded. Primary outcomes included AKI incidence, the relevance of creatinine levels for AKI detection, and the association of AKI with 30-, 60- and 180-day mortality. Modifiable factors contributing to AKI were explored as secondary outcomes. Results: Postoperatively, 35.4% developed AKI. The highest creatinine elevation occurred on the 2nd postoperative day. Best predictive value for AKI was a creatinine level of 1.35 mg/dl on the 2nd day (AUC: 0.901; sensitivity: 0.89, specificity: 0.79). Elevated creatinine levels on the 2nd day were robust predictors for short-term mortality at 30, 60 and 180 days postoperatively (AUC ranging from 0.708 to 0.789). CK-MB levels at 24 hours postoperatively and minimum hemoglobin during surgery were identified as independent predictors for AKI in logistic regression. Conclusions: This study highlights the crucial role of creatinine levels in predicting short-term mortality in surgical endocarditis patients. A specific threshold (1.35 mg/dl) provides a practical marker for risk stratification, offering insights for refining perioperative strategies and optimizing outcomes in this challenging patient population.

Despite a large amount of research on synchronous and mutually induced kidney and heart damage, the basis of the disease is still not fully clarified. Healthy mitochondria are essential for normal kidney and heart function. Mitochondrial dysfunction occurs when the clearance or process of generation and fragmentation of mitochondria is disturbed. The kidney is the second organ after the heart in the number of mitochondria. Kidney tubules are rich in mitochondria due to the high energy requirements for absorption processes of large amounts of ultrafiltrate and dissolved substances. The place of action of oxidative stress is the influence on the balance in the production and breakdown of mitochondrial reactive oxygen species . A more precise determination of the place and role of key factors that play a role in the onset of the disease is necessary for understanding the nature of the onset of the disease and the creation of therapy in the future. The narrative review integrates results found in previously performed studies which have evaluated oxidative stress participation in renocardial syndrome type 3.

The KOSovan Acute Coronary Syndrome (KOS-ACS) Registry is established as a prospective, continuous, nationwide, web-based registry that is operated online. The KOS-ACS registry is designed with the following objectives: 1) to obtain data on the demographic, clinical, and laboratory characteristics of ACS patients treated in Kosovo; 2) to create a national database with information on health care in ACS patients treated in Kosovo; 3) to identify the national features of associations between ACS characteristics and clinical outcomes, including mortality, complications, length of hospital stay, and quality of clinical care; and 4) to propose a practical guide for improving the quality and efficiency of ACS treatment in Kosovo. The Kosovo Society of Cardiology and University of Prishtina will be responsible for the development of the KOS-ACS registry and centralized data analysis at the national level. The KOS-ACS Registry will enroll all patients admitted, at any of the registered clinical centers, with the diagnosis of ACS and who will be clinically managed at any of the Kosovo hospitals. Data on patient demographics, clinical characteristics, previous and hospital drug treatment, and reperfusion therapy will be collected. The type of ACS (Unstable angina, NSTEMI or STEMI) will also be clearly defined. The time from first medical contact to balloon inflation (FMC-to-balloon) and door-to-ballon time will be registered. In-hospital death and complications will be registered. Data on post-hospital primary outcome (MACE: cardiac death, all-cause mortality, hospitalization, stroke, need for coronary revascularization) of patients, at 30 days and 1 year, will be included in the Registry.

Heart failure is a global major healthcare problem with millions of hospitalizations annually and with a very high mortality. There is an increased interest in finding new and reliable biomarkers for the diagnostication, prognostication and therapeutical guidance of patients hospitalized for acute heart failure. There is data to sustain the role of CA 125, a worldwide used marker of ovarian cancer, in patients with heart failure. Several studies have shown links between CA 125 levels and congestion seen in acute heart failure, high mortality and readmission rates at 6 months follow up after discharge from acute heart failure and also a role of CA 125 in the guidance of heart failure therapy. There are also clinical trials that showed that several particularities of CA 125 make it even better than NTpro BNP ( a classical and more utilised marker of heart failure) in several scenarios of acute heart failure.

There is evidence that kidney involvement is frequently observed in COVID-19 patients, and can manifest as mild proteinuria to advancing acute kidney injury (AKI). One of the mechanisms is microvascular and macrovascular thrombosis caused by the hypercoagulation phase of the disease. Thromboelastography (TEG) is a valuable examination to detect significant hemostatic abnormalities, including the hypercoagulable state. This study analyzed the coagulation profiles, including TEG parameters, in COVID-19 patients who developed AKI compared to those who did not during their intensive care unit (ICU) stay, to identify predictors of AKI. Our single-center cohort retrospective study involved adult patients of COVID-19 in the ICU of Sardjito Hospital in Yogyakarta, Indonesia between May and September 2021. Patients were divided into two groups of AKI and non-AKI based on 2012 KDIGO definition and the elaboration by Indonesian Society of Nephrology. Variables showing a significant difference in the two groups were then analyzed using univariate and multivariate binary logistic regression. A total of 60 COVID-19 patients were included in the study, and 35% of them developed AKI. Compared to non-AKI patients, those with AKI exhibited a greater prevalence of diabetes mellitus (66.7% versus 35.9%, P = 0.023), higher D-Dimer levels (970 versus 685 ng/mL, P = 0.045), and higher values in TEG parameters of maximum amplitude/MA (74.6 versus 65.9 mm, P = 0.001) and coagulation index/CI (2.3 versus 1.0, P = 0.033). TEG parameter of MA emerged as the sole significant predictor for the development of AKI (OR, 6.33; 95% CI, 1.56 to 25.64). Our study validated the kidney involvement of COVID-19 infection, and showed that diabetes mellitus, high D-Dimer levels, and hypercoagulability serve as prominent risk factors in the development of AKI. Furthermore, TEG parameter of MA exceeding 70 mm is the single independent significant predictor of AKI.

Background Research in the subject of the influence of SARS-CoV-2 mechanisms on human’s homeostasis remains actual problem. Particular interest is the study of pathomorphological changes in the appendix in children with COVID-19. Objectives Aim of the study: morphological and molecular biological evaluation of the appendix in children of different age groups with COVID-19. Methods Groups were formed on the basis of anamnestic, clinical and morphological data: I (n = 42; aged 2 to 18 years, average - 10.8 years) – with an established clinical diagnosis: coronavirus infection (COVID-19; PCR+); II (n = 55; aged 2 to 18 years, average - 9.7 years) – with a confirmed clinical diagnosis of acute appendicitis; collected before the onset of the COVID-19 pandemic in 2017-2019; III (n = 38; aged 2 to 18 years, average - 10.3 years) - control group. Histological and immunohistochemical studies were conducted using primary antibodies to CD3, CD4, CD68, CD163, CD20, CD138 and to pro-inflammatory (IL-1, IL-6) and anti-inflammatory (IL-4, IL-10) cytokines. Results In most samples of appendix in children with COVID-19 were discovered signs of destructive phlegmonous-ulcerative and gangrenous appendicitis. An increase in CD3+, CD4+, CD68+, CD163+, CD20+ CD138+ immunocompetent cells was found in the appendix of children with COVID-19. As well, there is an increase in pro-inflammatory (IL-1, IL-6) and anti-inflammatory (IL-4, IL-10) cytokines. Conclusions The aforementioned pathological and immunohistochemical changes were more pronounced in the group of children aged 6-12 years (childhood).

In this work, we tried to emphasize whole transcriptome expression changes in the Wistar rats brainstem two hours after acute stress. Most of the genes were upregulated. We detected massive shift of neuropeptides Crh, Trh,Cga, Tshb, Uts2b, Tac4, Lep and neuropeptide receptors Hcrtr1, Sstr5, Bdkrb2, Crhr2 signaling, as well as Glutamate Grin3b, Grm2 and GABA Gpr156, Acetylcholine Chrm4,Chrne, Adreno- Adra2b receptors expression uprising. Intensive increase in expression of intermediate filaments Krt83/Krt86/Krt80/Krt84/Krt87/Krt4/Krt76 and motor proteins Myo7a, Klc3 was detected. Remarkably, at this time we also observed signs of microglia activation. Both expression of anti-inflammatory cytokines Il13, Ccl24 and proinflammatory cytokin’s receptors Il9r, Il12rb1, Tnfrsf14, Tnfrsf13c, Tnfrsf25, Tnfrsf1b were increased. In the Wnt signaling pathway, we have seen increased expression of ligands-receptors Wnt1, Wnt11, Ror2, and also negative regulators Notum, Sfrp5, Sost. Also we conducted cDNA libraries normalization with duplex specific nuclease and compared results. On the basis of our RNAseq data, we chose reference genes for RT-qPCR best suitable for experiments with acute stress.

Abstract: Acute pancreatitis (AP) is a common gastrointestinal disease with high morbidity and mortality rate. Unfortunately, neither the etiology nor the pathophysiology of AP are fully un-derstood and causal treatment options are not available. Recently we demonstrated that Hepa-ranase (Hpa) is adversely involved in the pathogenesis of AP and inhibition of this enzyme ameliorates the manifestation of the disease. Moreover, a pioneer study demonstrated that As-pirin has inhibitory effect on Hpa. Another compound, which possesses a mild pan-creato-protective effect against AP, is Trehalose, a common disaccharide. We hypothesize that combination of Aspirin, Trehalose, PG545 (Pixatimod) and SST0001 (Roneparstat), specific inhib-itors of Hpa, may exert pancreato-protective effect better than each drug alone. Thus, the current study examines the pancreato-protective effects of Aspirin, Trehalose, PG545 and SST0001 in ex-perimental model of AP induced by Cerulein in wild-type (WT) and Hpa over-expressing (Hpa-Tg) mice. Cerulein-induced AP in WT mice was associated with significant rises in the se-rum levels of Lipase (X4) and amylase (X3) with enhancement of pancreatic edema index, inflammatory response, and autophagy. Responses to cerulein were all more profound in heparanase transgenic (Hpa-Tg) mice vs wild-type (WT) mice, evident by X7 and X5 folds increase in lipase and amylase levels, respectively. Treatment with Aspirin or Trehalose alone and even more so in combination with PG545 or SST0001 were highly effective, restoring the serum level of lipase back to the basal level. Importantly, a novel newly synthesized compound termed Aspirlose effectively ameliorated the pathogenesis of AP as a single agent. Collectively, the results strongly indicate that targeting Hpa by using anti-Hpa drug combinations constitute a novel therapy for this common orphan disease.

The definition of Early Cholecystectomy (EC) is still debatable. This paper aims to find whether the timing of EC affects outcomes. This is a multicentric prospective observational study including patients with acute calculous cholecystitis (ACC) who had cholecystectomy within ten days from the onset of symptoms. Kruskall-Wallis test, Fisher’s Exact test and Spearman rank correlation were used for statistical analysis. The patients were divided into three groups depending on the timing of the operation: 0-3 days, 4-7 days, or 8-10 days from the onset of symptoms. 1117 patients were studied over a year. The time from the onset of symptoms to EC did not affect the postoperative complications and mortality, the conversion and the reintervention rate. It was a significant risk factor for intraoperative complications (0-3 days, 2.8%; 4-7 days, 5.6%; 8-10 days, 7.9%; p=0.01) and subtotal cholecystectomies (0-3 days, 2.7%; 4-7 days, 5.6%; 8-10 days, 10.9%; p&lt;0.001). ACC is an evolutive inflammatory process and, as the days go by, the local and systemic inflammation increases which makes surgery more complex and difficult with higher risk of intraoperative complications. We recommend performing EC for ACC as soon as possible within the first ten days of the onset of symptoms.

In this study, a case of acute cattle death was investigated. The pathogen was identified, and its molecular characteristics and vector were analysed. This study provides a reference for the prevention and control of babesiosis and the healthy breeding of cattle. In this study, unengorged and engorged Rhipicephalus microplus ticks were collected from the Chongqing area. The unengorged ticks were cultured on cattle under laboratory conditions, and the engorged ticks were cultured to lay eggs. In the process, the cattle suddenly died at 12 days from the bite of an unengorged R. microplus tick. In addition, the larvae hatched from R. microplus eggs, which were cultured on the other cattle, and the experimental cattle died in approximately 14 days. Blood was collected from a second dying and stored at 4 ℃ for one week. Two millilitres of anticoagulated blood was injected subcutaneously into the third cow without piriformis infection. On the fourth day, the body temperature rose to 41 ℃ with slight lymphadenopathy. On the fifth day, the cow suddenly fell and died approximately 4 hours later. DNA was extracted from the blood of all dead cattle and amplified by PCR with piriformis universal primers. The results showed that the cattle were infected with Babesia bovis. The phylogenetic tree based on 18S rRNA showed that the Chongqing strain of B. bovis, which caused the death of cattle, was closely related to the Yunnan strain in China and had the same taxonomic status as the Spanish strain. This case report will draw people's attention to B. bovis once again, and positive control measures should be taken to reduce the losses of farmers to achieve the goal of healthy breeding.

Excessive intake of fluoride, one of the trace elements to maintain health, leads to liver injury. Tetramethylpyrazine (TMP) is a kind of traditional Chinese medicine monomer with good antioxidant and hepatoprotective function. The aim of this study was to investigate the effect of TMP on liver injury induced by acute fluorosis. A total of 60 1-month-old male Institute of Cancer Research mice without carriage of pathogenic bacteria were selected. All mice were fed adaptively for one week, and then randomly divided into 5 groups: control (K) group, model (F) group, low-dose (LT) group, medium-dose (MT) group and high-dose (HT) group. The control and model group were given distilled water, while 40 mg/kg (LT), 80 mg/kg (MT) and 160 mg/kg (HT) TMP were fed by gavage for two weeks with the maximum gavage volume of mice is 0.2ml/10g/d. Except for the control group, all groups were given fluoride (35 mg/kg) by intraperitoneal injection on the last day of the experiment. The results of this study showed that compared with the model group, TMP alleviated the pathological changes of liver induced by fluoride and improved the ultrastructure of liver cells; TMP significantly decreased the levels of ALT, AST and MDA (P <0.05), and increased the levels of T-AOC, T-SOD and GSH (P <0.05). The results of mRNA detection showed that TMP significantly increased the mRNA expression levels of Nrf2, HO-1, CAT, GSH-Px and SOD in liver compared with model group (P <0.05). In conclusion, TMP can inhibit oxidative stress by activating Nrf2 pathway and alleviate liver injury induced by fluoride.

Abstract: COVID-19 Long Haulers, an estimated 3% to 12% of people infected globally with coronavirus having latter devasting symptoms 12 weeks after the initial infection is on the rise. We conducted a collaborative study with the long covid patient organization in Greece in order to estimate the prevalence, symptoms and problems that adult long haulers experience and then propose a management plan for these patients. Symptoms were obtained from 208 patients using unstructured qualitative free text entries in an anonymized online questionnaire. The majority of respondents (68.8%) were not hospitalized and had been diagnosed more than six months ago with lingering symptoms (66,8%). Eighteen different symptoms (fatigue, tachycardia, shortness of breath, parosmia etc) were mentioned in both hospitalized and community patients. Interestingly, patients with initial mild symptoms suffer from the same persistent symptoms as those who were hospitalized. Awareness of long covid sequelae seems to be low even among medical doctors. Treatment options incorporating targeted rehabilitation programs are either not available or still excluded from the management plan of long covid patients. Since long COVID is a multi-systemic entity, we propose a holistic interventional approach using a multidisciplinary medical team in order to securely and effectively diagnose and treat these specific patients. Academic and medical community must collaborate with long covid patients’ organizations so as to provide personalized medicine.

Introduction: Decompensated heart failure (HF) is a complex and debilitating syndrome, which constitutes a severe emergency condition with high morbidity and mortality. The kidneys play fundamental roles in the pathophysiology of HF and, in the context of decompensations, acute kidney injury (AKI) has a bilateral cause-and-effect relationship, which can significantly worsen prognosis. However, the interaction between AKI and decompensated HF is poorly understood. Objective: This study aimed to assess the occurrence of AKI in patients hospitalized due to decompensated HF and to analyze its prognostic impact during hospitalization. Methods: Prospective single-center observational study that included patients hospitalized due to decompensated HF in a tertiary-level teaching hospital, conducted between July 2017 and January 2020. Patients who developed AKI during hospitalization were compared with those who did not develop it, until hospital discharge or death. AKI was defined as a serum creatinine increase greater than or equal to 0.3 mg/dl in 48 hours, a 1.5-fold increase in baseline creatinine in seven days or urinary volume <0.5 ml/kg/h during six hours, according to the Acute Kidney Injury Network (AKIN) criteria. The endpoints analyzed were death, need for invasive mechanical ventilation (IMV) and length of hospital stay. The Wilcoxon, Mann-Whitney and unpaired student t tests were used. Results: Ninety-nine patients were included, with a mean age of 65.4 ± 14 years, of which 47 (47.5%) were male and 52 (52.5%) were female. Reduced ejection fraction was observed in 77.8% of patients, whilst 22.2% had a diagnosis of HF with preserved EF. The decompensation clinical classifications were: dry and warm = 7 (7.1%), wet and warm = 72 (72.7%), wet and cold = 15 (15.1%) and dry and cold = 5 (5.1%). The average left ventricular ejection fraction was 38.3% ± 15. AKI ocurred in 22 patients (22.2%). Comparison between patients who evolved with and without AKI showed higher mortality (36.4% vs 10.4%, p = 0.004) and the need for IMV (54.5% vs 13%, p = 0.0001) in the first group. There was no significant difference regarding the length of in-hospital stay (22.9 ± 19 vs 18.8 ± 16 days, p = 0.26). Conclusions: The occurrence of AKI was frequent in patients with decompensated HF requiring hospitalization, affecting approximately one out of five patients. This complication was significantly associated with increased mortality and the need for IMV during hospitalization.

The study evaluates the toxic effects of acute and sub-acute oral administration of methanol extracts of Geophila obvallata in rats. During acute study, a dose of 1600, 2900 and 5000 mg/kg bw of extract was orally administered to rats. Rats were observed for signs of toxicity for two weeks. During sub-acute study (28 days), the extract, at doses of 100, 500 and 1000 mg/kg bw were administered orally to rats while control rats were given only tap water. At the end of the study, samples were collected for analyses. In acute toxicity studies, the extract did not induce death after single dose administration. Hence, the LD50 was estimated above 5000mg/kg. The results of sub-acute toxicity study show that no significant changes were observed in the body weights, organ weights, kidney function and organ histology. There were significant changes in hematology and biochemical indices investigated at elevated doses of 500 and 1000 mg/kg bw compared to the control. GOE may be considered non-toxic at a dose of 100 mg/kg with promising applications in drug therapy.

There are presently more than 18 known aflatoxins (>18) most of which have been insufficiently studied for their incidence, health-risk, and mechanisms of toxicity to allow effective intervention and control means that would significantly and sustainably reduce their incidence and adverse effects on health and economy. Among these, aflatoxin B1 (AFB1) has by far been the most studied; and yet, many aspects of the range and mechanisms of the diseases it causes remain to be elucidated. Its mutagenicity, tumorigenicity, and carcinogenicity, which are the best known still suffer from many limitations regarding the relative contribution of the oxidative stress and the reactive epoxide derivative (Aflatoxin-exo 8,9-epoxide) in the induction of the diseases, as well as its metabolic and synthesis pathways. Additionally, despite the well-established additive effects for carcinogenicity between AFB1 and other risk factors, e.g., hepatitis viruses B and C, and the algal hepatotoxic microcystins, the mechanisms of this synergy remain unclear. This study reviews the most recent advances in the mechanisms of toxicity of aflatoxins and the adverse health effects that they cause in humans and animals.

Background: Evaluation of nutrition programs is essential to guarantee the effectiveness of community-based management of acute malnutrition (CMAM). Methods: The Rainbow Project Supplementary Feeding Programs (SFPs) in Zambia were evaluated between years 2015-17, following implementation of new recommendations based on previous evaluations (years 2012-14). Outcomes of the program were compared with International Standards and with those of 2012-14. Cox proportional risk regression analysis was performed to identify predictors of mortality and defaulting. Results: Data for 900 under age 5 years malnourished children (48.8% male; mean age 19.7months ±9.9) were analyzed. Rainbow 2015-17 program outcomes met International Standards, for general malnutrition or stratified moderate acute malnutrition (MAM) and severe acute malnutrition (SAM). When comparing with 2012-14 outcomes, better performance was noted: mortality rates were reduced by half (5.6% vs 3.1%, p = 0.01; for SAM: 12.4% vs 6.7%, p = 0.006), with significant improvement in average weight gain and mean length of stay (p<0.001), and increased awareness of HIV status (+30%; p < 0.001). HIV infection (5.5; 1.9–15.9), WAZ < −3 at baseline (4.6; 1.3–16.1) and kwashiorkor (3.5; 1.2–9.5) remained the major predictors of mortality. Conclusion: The effectiveness of the Rainbow SFPs for child malnutrition treatment and prevention in Zambia has significantly improved after evaluation and implementation activities, with impressive outcomes which resulted in a 50% reduction in mortality.

A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and as such provides a semi-selective barrier between the blood and the interstitial space. Compromise of the lung EC barrier due to inflammatory or toxic events may results in pulmonary edema, which is a cardinal feature of acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS). The EC functions are controlled, at least in part, via epigenetic mechanisms mediated by histone deacetylases (HDACs). Zinc-dependent HDACs represent the largest group of HDACs and are activated by Zn2+. Members of this HDAC group are involved in the epigenetic regulation primarily via modifying the structure of chromatin upon removal of acetyl groups from histones. In addition, they can deacetylate many non-histone histone proteins, including those located in extra nuclear compartments. Recently, the therapeutic potential of inhibiting zinc-dependent HDACs for EC barrier preservation has gained momentum. However, the role of specific HDAC subtypes in EC barrier regulation remains largely unknown. This review aims to provide an update on the role of zinc-dependent HDACs in endothelial dysfunction and its related diseases. We will broadly focus on biological contributions, signaling pathways and transcriptional roles of HDACs in endothelial pathobiology associated mainly with lung diseases and we will discuss the potential of their inhibitors for lung injury prevention.

The molecular basis of Down syndrome (DS) predisposition to leukemia is not fully understood but involves various factors such as chromosomal abnormalities, oncogenic mutations, epigenetic alterations, and changes in selection dynamics. Myeloid leukemia associated with DS (ML-DS) is preceded by a preleukemic phase called transient abnormal myelopoiesis driven by GATA1 gene mutations and progresses to ML-DS through additional mutations in cohesin genes, CTCF, RAS, or JAK/STAT pathway genes. DS-related ALL (ALL-DS) differs from non-DS ALL in terms of cytogenetic subgroups and genetic driver events and aberrant expression of CRLF2, JAK2 mutations, and RAS pathway activating mutations are frequent in ALL-DS. Recent advancements in single-cell multi-omics technologies have provided unprecedented insights into the cellular and molecular heterogeneity of DS-associated hematologic neoplasms. Single-cell RNA sequencing and digital spatial profiling enable the identification of rare cell subpopulations, characterization of clonal evolution dynamics, and exploration of the tumor microenvironment's role. These approaches may help identify new druggable targets and tailor therapeutic interventions based on distinct molecular profiles, ultimately improving patient outcomes with the potential to guide personalized medicine approaches and the development of targeted therapies.

Background/Objectives: Current guidelines recommend intravenous thrombolysis (IVT) followed by mechanical thrombectomy (MT) for patients with acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). This combined approach, known as bridging therapy (BT), is believed to increase the likelihood of a favorable functional outcome when administered within 4.5 hours of symptom onset. However, the benefits of BT over direct mechanical thrombectomy (d-MT) remain debated. This study aimed to compare the outcomes of AIS-LVO patients undergoing MT within 6 hours of symptom onset, with and without prior IVT. Methods: Within the prospective TINL STROKE-registry, AIS-LVO patients admitted to the Department of Neurology, University of Pécs, between February 2023 and June 2024 were investigated. The primary endpoint was the proportion of patients reaching functional independence at 90 days, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary endpoints included clinical improvement at 72 hours (National Institute of Health Stroke Scale [NIHSS] score of ≤1 or a change from baseline [ΔNIHSS] of ≥4) and successful recanalization (modified Thrombolysis in Cerebral Infarction [mTICI] score ≥2). Safety outcomes were evaluated based on thrombus migration and intracranial hemorrhage (ICH). Results were compared using linear and logistic regression analyses adjusted for baseline variables. Results: Of 82 patients, 51 (62.2%) received BT, while 31 (37.8%) underwent d-MT. The BT group showed a significantly higher rate of functional independence (45.7% vs. 17.2%, p=0.014) and a lower 90-day mortality rate (13.7% vs. 35.5%, p=0.029). Multivariate analysis revealed that IVT was independently associated with favorable functional outcome (p=0.011) and reduced mortality (p=0.021). No significant differences were observed in terms of clinical improvement at 72 hours, successful recanalization, thrombus migration, or hemorrhagic transformation between the groups. Conclusions: This study supports current guidelines recommending BT for thrombectomy-eligible AIS-LVO patients, offering new insights into the ongoing clinical debate.

Individualized nursing care allows a systematic assessment and intervention, considers the patient's preferences, values, and context, and contributes to a positive care trajectory. However, its operationalization has proven to be challenging. This research aims to determine which items of nursing care individualization are most integrated into nurses' clinical practice, and those that are less included. A cross-sectional study was conducted on 122 eligible and registered nurses at a Hospital Center, in Ophthalmology (operating room and inpatient ward), Cardiology Service, Internal Medicine, and Medical Emergency Unit, in Portugal. The Indi-vidualized Care Scale nursing version (ICS-Nurse) was used for the assessment, including three sub-dimensions: clinical situation, personal life situation, and decisional control over care-related decisions. Analyses were performed using Cronbach's Alpha and Principal Component Analysis to confirm the relationships between the variables, suggested by the literature and previous studies. In the results, no statistically significant differences were identified between the sociodemographic profile and the sub-dimensions of individualization. Nurses overall have a good perception of the importance of individualized care (4.06 ± 0.46 ICS-A-NURSE), but face difficulties in its implementation during the last shift worked (3.97 ± 0.49 ICS-B-NURSE). The sub-dimensions more integrated into the care environment were clinical situations and decisional control, and the less integrated were the personal lives of patients. This study identifies key aspects of the individualization of nursing care in acute and perioperative settings, as its omission represents a failure to address the multidimensional health needs of patients, families, and caregivers. We suggest the development of training programs that promote a holistic approach, as well as future studies that consider patient outcomes related to the individualization of nursing care.

Understanding the interplay between infections and severe acute malnutrition is critical in attaining good clinical outcomes in managing malnourished children. However, review studies describing the profile of the associated pathogens in the malnourished African pediatric population are sparse in the literature. We aimed to identify the spectrum of pathogens from studies reporting infections in malnourished African children, as well as the antibiotic resistance pattern and clinical outcomes. A systematic literature of the PubMed database was conducted following PRISMA guidelines from January 2001 to June 2024. The search algorithm was ((marasmus) OR (kwashiorkor) OR (severe acute malnutrition) OR (protein energy malnutrition)) AND (Africa). For a more comprehensive retrieval, an additional search algorithm was deployed: (HIV OR tuberculosis) AND (severe acute malnutrition). We included 67 studies conducted between 2001 and 2024. Most of the studies were from East Africa (n=53, 79.1%) and Southern Africa (n=5, 7.4%). A total of 7,056 pathogens were identified comprising 3,030 Viruses, 2,381 bacteria, 1,452 parasites and 193 fungal pathogens. The predominant pathogens were HIV, Mycobacterium tuberculosis, and malaria parasites accounting for 42.5%, 25.2%, and 17.1% respectively. Antibiotic susceptibility testing was documented in only three studies. Fatality rates were reported in 49 studies and ranged from 2% to 56% regardless of the category of pathogen. This review affirms the deleterious effect of infections in malnourished patients and suggests a gross underdiagnosis as studies were found from only 17 (31.5%) African countries. Moreover, data on fungal infections in malnourished African children was nearly absent despite being at risk. There is also a need to prioritize research investigating African children with severe acute malnutrition for fungal infections besides other opportunistic pathogens and improve the availability of diagnostic tools and the optimized usage of antibiotics through the implementation of antimicrobial stewardship programmes.

Background: Breast cancer and other neoplasms, such as acute lymphocytic leukaemia, are a severe hazard to public health globally. L-glutamine-degrading enzymes are required for the treatment of malignancies such as acute lymphocytic leukemia and breast cancer. L-glutaminase, an amidohydrolase, has been shown to be an effective chemotherapeutic tool for treating a variety of malignancies. The aim of the study: Molecular characterization is used in the study and production of bacterial L- glutaminase as an anticancer agent from a variety of Egyptian soil locales. The type of the study: Screening experimental study. Methodology: In the current study, many bacterial isolates were tested on mineral L-glutamine agar selective medium (MGA) to evaluate if they generated L-glutaminase. The most effective positive bacterial isolates that produce L-glutaminase, however, were discovered by morphological and biochemical analysis. The primary positive isolate producing L-glutaminase was also identified utilizing molecular detection by 16S rRNA sequencing homology technique. The properties of bacteria-produced L- glutaminase were investigated. The anticancer activity was assessed with an MTT assay. Results: Sole bacterial isolates that only needed L-glutamine for metabolic nitrogen grew well on MGA. The optimal conditions for producing positive bacterial isolates were pH 7.4 and 37 ̊C. The morphological and biochemical investigations of soil samples from diverse soil conditions in Egypt revealed that Bacillus subtilis subsp. niger (ATCC 9372) was the primary positive bacterial isolate producing L-glutaminase. At a pH of 7.4 and a temperature of 37 °C, the activators KCL, ZnSO4, FeSO4, K2HPO4, and MgSO4 offered ideal conditions for defining L-glutaminase production. L-glutaminase from Bacillus subtilis was detected to be a highly bioavailable and efficient anticancer treatment. The original yield [productivity] from MGA was 6.3 U/ml, but invitro coupled transcription and translation production raised it to 89± 1 U/ml. L-glutaminase had a molecular mass of approximately 36 kDa. The purification of L-glutaminase resulted total activity of 21,883 ± 15.67 (U), specific activity of 379.14 ± 7.35 (U/mg of protein), and purification fold of 1.82 ± 3.06. The enzymatic activators Ni2+ and Mg 2+ increased L-glutaminase activity by 20%, 27%, respectively. The compound showed significant anticancer activity (IC50 = 38.72, 8.6, 6.41, 19.02, 49.83, and 9.45 μg/ml) against cancer cell lines from the liver (HepG-2), colon (HCT- 116), breast (MCF-7), lung (A-549), lymphocytic (CCL-120), and cervical (Hela). The kinetic parameters Km and Vmax were 15.2^ 10 -3 M and 119.86 μmol/ml/min, indicating a higher affinity for the substrate. The enzyme demonstrated high efficacy at pH 6.5 and temperature 35. The enzyme was thermostable at 58 ̊C for 1 hour. Conclusion: Acute lymphocytic leukemia and breast cancer are two instances of auxotrophic malignancies for which L-glutamine is the sole metabolic source, and Bacillus subtilis- derived L-glutaminase was a suitable enzyme in their treatment.

Background: This is a propensity matched, single centre study of limited versus extended resections for Type A acute aortic dissections (AAAD). Methods: Retrospective data for 440 patients with acute Type A aortic dissection repairs (Limited Resection, LR-215, Extended Resection, ER-225). 109 pairs were propensity matched to LR versus ER. Multivariate analysis was performed for inpatient death, long term survival and composite of inpatient death/TIA/stroke. Kaplan Meier survival curves were compared at 1, 3, 5, 10 and 15 years using the log-rank test. Results: Mean age was 66.9±13 years and mean follow up was 5.3±4.7 years. 48.9% had LR. In-hospital mortality was 10% (LR;6% vs ER;13.8%, p<0.01). ER, NYHA class, salvage surgery and additional procedures were predictors of increased mortality in unmatched data. Propensity matched data showed no difference in TIA/stroke rates, LOS, in-patient mortality or composite outcomes. LR had better survival (LR; 77.1% vs ER; 51.4%, p<0.001). ER (OR; 1.97, 95%CI; 1.27, 3.08, p=0.003) was a significant predictor of worse long term survival. At 15 years, aortic re-operation was 17% and freedom from re-operation and death was 42%. Conclusions: Type A aortic dissection repair has high mortality and morbidity although results have improved over two decades. ER was predictor of worse perioperative results and long term survival.

ABSTRACT：Background: Diagnosing rhabdomyolysis has usually defined at least five or ten times the upper limit creatine kinase level; but it is conservative for Exertional rhabdomyolysis. The aim was to analysis the biomarkers during a military operation in an extreme environment with high physical demand. Material and Methods: Seventeen male military personnel (age: 27.83 ± 2.96 years; weight: 76.31 ± 7.67 kg; and height 174.92 ± 5.91 cm) participated for this investigation. The creatine kinase (CK); blood urea nitrogen (BUN); creatinine (Cr); sodium (Na); potassium (K); aspartate amino transferase (AST) and alanine amino transferase (ALT) were analyzed. Urine specific gravity (USG) the hydration status was monitored. The Generalized Linear Models for repeated measures and the Friedman’s two-way test were used to comparative moments. Results: The BUN; Cr; Na; and K mean values showed a nonsignificant. The statistical significance of the test was found in CK and AST. There was considerable variability of CK between subjects during the operation. The moderate correlation between CK and Cr was found during study. Conclusion: Elevated CK levels after the operation were characterized as physiological pattern. These results reinforce that CK values are not predictors of renal function in activities with intense and continuous physical demand

Secondary prevention after SCA (acute coronary syndrome) is of paramount importance to reduce the incidence of MACE and improve prognosis in follow-up. The control of avoidable risk factors, lifestyle modifications, but especially careful control of cholesterolemia (with a target of LDL-C

Background: Boronic acids form di-ester bonds with cis-hydroxyl groups in carbohydrates. The formation of these adducts could impair the physical and chemical properties of the precursors, even their biological activity. Methods: Two carbohydrate-derivatives from D-fructose and D-arabinose and phenylboronic acid were synthesized in a straightforward one-step procedure and chemically characterized by spectroscopy and X-ray diffraction crystallography. Also, an acute toxicity test was performed to determine their Lethal Dose50 (LD50) by using the Lorke’s method. Results: Analytical chemistry assays confirmed adducts by the generation of the diester bonds with a β-D-pyranose of carbohydrates, including signals corresponding to the formation of new bonds, like the stretching of B-O bonds. The NMR spectra yielded information about the stereoselectivity in the synthesis reaction by the finding of just one signal in the range for the anomeric carbon in the 13C NMR spectra of both adducts. The acute toxicity tests showed that LD50 value for both compounds is 1265 mg/kg, while Effective Dose 50 for sedation is 531 mg/kg. However, differences were in the onset and lapse of sedation. Conclusions: These adducts are bioactive and highly safe agents. Further biological evaluation is desirable to explore medical purposes.

Background: Breast cancer and other neoplasms like acute lymphocytic leukemia pose a serious threat to public health worldwide. Treatment for malignancies including acute lymphocytic leukemia and breast cancer requires enzymes that break down L-glutamine. An amidohydrolase called L-glutaminase can be an effective chemotherapeutic tool for treating various cancers. Methods: On mineral L-glutamine agar selective medium (MGA), a few bacterial isolates were examined in the current investigation to see if they produced L-glutaminase. However, the most effective positive bacterial isolates generating L-glutaminase were identified using morphological and biochemical testing. Molecular detection using the direct Southern blotting approach was also used to determine the main positive isolate that produces L-glutaminase. L-glutaminase synthesis by bacteria was evaluated for its characteristics. Using an MTT test, the anticancer activity was evaluated. Results: exclusive bacterial isolates that used L-glutamine as their sole source of metabolic nitrogen exhibited favorable growth on MGA. PH 7.4 and a temperature of 37 0C were the ideal environmental and physiological conditions for developing positive bacterial isolates. From the soil samples taken from various soil conditions in Egypt, the morphological and biochemical analyses showed that Bacillus cereus 14579 was the main positive bacterial generating L-glutaminase isolate. At a pH of 7.4 and a temperature of 37 °C, the following activators—KCL, ZnSO4, FeSO4, K2HPO4, and MgSO4—provided the high-grade circumstances for characterizing L-glutaminase synthesis. Bacillus cereus-produced L-glutaminase has shown excellent bioavailability and effectiveness as an anticancer therapy. The yield [productivity] was 5.2 U/ml during the original manufacture from MGA, but it increased to 42.96 U/ ml by bacterial recombinant DNA manufacturing. The molecular mass of L-glutaminase was roughly 37 KDa. L-glutaminase was purified, yielding final enzyme recovery of 55 1.23%, total activity 12,990± 19.76 ( U), specific activity 384.66± 8.92( U/ mg of protein), and purification fold 2± 2.99. Furthermore, the L-glutaminase activity was raised by 19%, 23%, 15%, and 9%, respectively, by the enzymatic activators Mn2+, K+, Na+, and Fe3+. It demonstrated strong DPPH scavenging activity (IC50 = 61 μg/ mL) and anticancer activity( IC50 = 40.72, 9.7, 7.39, 20.61, 51.28, and 11.55 μg/ mL, respectively) against human liver (HepG-2), colon ( HCT-116), breast ( MCF-7), lung( A-549), lymphocytic( CCL-120), and cervical( Hela) cancer cell lines. A stronger affinity for its substrate was shown by the kinetic parameters of Km and Vmax, which were 13.2 10-5 M and 119.86 μmol/ ml/ min, respectively. Conclusion: Acute lymphocytic leukemia and breast cancer are examples of auxotrophic malignancies for which L-glutamine serves as the only metabolic source, and L-glutaminase generated by Bacillus cereus was an appropriate enzyme in the therapy of these diseases.

Background: Acute kidney disease (AKD) is a known risk factor for increased mortality and evolution towards chronic kidney disease (CKD) in adults. The data regarding children are scarce. The purpose of our study is to explore the risk factor for AKD and impact of AKD following an acute kidney injury (AKI) episode in children on mortality and new-onset CKD. Methods: We retrospectively evaluated 736 children with ages between 2 and 18 years old with AKI admitted in a tertiary care hospital from the west Romania over a 9 years period. Results: AKD incidence following AKI was 17%. Patients that developed AKD were older, with higher baseline serum creatinine values, urea, C reactive protein and lower proteins, haemoglobin and sodium. They were more often exposed to sepsis, critical illness and nephrotoxic medications and presented certain susceptibilities like CKD, neoplasia, anemia, heart failure, arterial hypertension, stem cell transplant and female gender. AKI causes that increased the risk of AKD were intrinsic ones. AKD increased the overall mortality by three times. The factors that independently increased the risk of evolution towards CKD were AKD, acute tubular necrosis and higher baseline serum creatinine values. Conclusions: AKD is an independent risk factor for mortality and new-onset CKD in children.

OBJECTIVES: To assess the predictive value of serum trypsin and Trypsinogen Activation Peptide (TAP) for the severity of AP by means of a single center cohort study as well as a systematic review of the current literature. METHODS: The literature search was conducted using Medline (PubMed), EMBASE and the Cochrane Central Register. A total of 142 patients with acute pancreatitis (AP) were included in the cohort study and parameters of the revised Atlanta criteria of 2012 and the APACHE II were assessed. RESULTS: The review showed promising results for the predictive value of serum trypsinogen-2, but conflicting results for serum TAP and trypsin. In the cohort study, patients were observed for 4 days after diagnosis of AP: 9 patients had severe AP, 35 patients had moderate AP and 81 patients had mild AP. The ratio of the geometric mean of severe vs mild AP for trypsin was 0.72 (95% CI: 0.51-1.00), p=0.053 and for TAP 0.74 (95% CI: 0.54-1.01), p=0.055 respectively. CONCLUSION: The cohort study showed an inverse correlation of serum levels of TAP and trypsin with severity of AP. Serum TAP and trypsin have an inferior predictive value of severity of AP compared to the clinical APACHE II score.

Background: Limited data exist on postoperative acute kidney injury (AKI) in patients underwent esophageal cancer surgery. The purpose of the study was to evaluate the incidence, risk factors and consequences of postoperative acute kidney after esophagectomy. Methods: This was a retrospective cohort study. The study was conducted in a tertiary specialized cancer center in Italy. All patients undergoing elective esophageal cancer surgery between 2016 and 2021 were included in the study. AKI was defined according to Kidney Disease: Improving Global Outcomes criteria (both serum creatinine and urine output), within 48 hours after surgery. Preoperative and intraoperative data were registered. We also collected data concerning progression of AKI, need for kidney replacement therapy, mortality, medical (pulmonary, cardiovascular, septic) and surgical complications within 30 days from surgery, as well as length of hospital stay. Results: Incidence of postoperative AKI was 32%. The independent risk factors were body mass index and the invasive surgical approach. Persistent AKI accounted for 15% of the cases and it was associated with increased risk of major cardiovascular events (odds ratio 4.14, 95% CI 1.05-15.8, p-value 0.036), pulmonary complications (OR 3.67, 95% CI 1.04-14.9, p-value 0.050) and increased length of hospital stay (AME 7.2, 0.5-13.9, p-value 0.035). Conclusions: Postoperative AKI is common after esophageal cancer surgery. BMI and totally invasive surgical approach are independent risk factors. Persistent AKI lasting more than 48 hours increased the risk for cardiovascular and pulmonary complications, with prolonged length of hospital stay.

Although acute heart failure (AHF) is a common disease associated with significant symptoms, morbidity and mortality, the diagnosis, risk stratification and treatment of patients with hypertensive acute heart failure (H-AHF) still remain a challenge in modern medicine. Despite great progress in diagnostic and therapeutic modalities, this disease is still accompanied by a high rate of both in-hospital (from 3.8% to 11%) and one-year mortality (from 20% to 36%). Considering the high rate of re-hospitalization (22% to 30% in the first three months), the treatment of this disease represents a major financial blow to the health system of each country. This disease is characterized by heterogeneity in precipitating factors, clinical presentation, therapeutic modalities and prognosis. Since heart decompensation usually occurs quickly (within a few hours) in patients with H-AHF, establishing a rapid diagnosis is of vital importance. In addition to establishing the diagnosis of heart failure itself, it is necessary to see the underlying cause that led to it, especially if it is de novo heart failure. Given that hypertension is a precipitating factor of AHF and in up to 11% of AHF patients, strict control of arterial blood pressure is necessary until target values are reached in order to prevent the occurrence of H-AHF, which is still accompanied by a high rate of both early and long-term mortality.

Idiosyncratic drug induced liver injury (DILI) is an unpredictable reaction of exposed individual on a certain drug, and the drug-induced autoimmune hepatitis (DIAIH) presents a DILI phenotype that mimics idiopathic autoimmune hepatitis (AIH) when considering the clinical, biochemical, serological and histological parameters. We present a case of a 48-year-old male that was hospitalized due to severe hepatocellular liver injury two months after the self-treatment with the muscle-building dietary supplement based on arginine-alpha-ketoglutarate, L-citrulline, L tyrosine, creatine malate and beet extract. His immunology panel was positive with increased IgG levels, and the radiologic methods showed no signs of chronic liver disease. He underwent corticosteroid treatment with adequate response. After the therapy withdrawal, a clinical relapse occurred. Seven months after the initial presentation liver MR suggested the initial cirrhotic changes of the right liver lobe. Liver biopsy revealed abundant lymphoplasmacytic infiltrate with piecemeal necrosis and grade 2 fibrosis. He responded well on the corticosteroid treatment again, and was further treated with low dose prednisone without additional relapses. Several years later, further management confirmed presence of liver cirrhosis with no histological or biochemical signs of the disease activity. DIAIH is a DILI phenotype difficult to distinguish from idiopathic AIH despite a wide armamentarium of diagnostic methods. Regular patient monitoring and clinical open-mindedness with the adjustment of therapeutic approaches according to the disease course are more important than strict labelling of the disease.

Acute kidney injury (AKI) is a clinical syndrome where a rapid decrease in kidney function and/or urine output is observed, which may result in the imbalance of water, electrolyte and acid base, and is associated with poor prognosis and prolonged hospitalization. Therefore, early diagnosis and treatment to avoid the severe AKI stage is important. While several biomarkers, such as urinary L-FABP and NGAL, can be clinically useful, there is still no gold standard for early detection of AKI and there are limited therapeutic options against AKI. miRNAs are non-coding and single-stranded RNAs that silence their target genes in the post-transcriptional process and are involved in a wide range of biological processes. Recent accumulated evidence has revealed that miRNAs may be potential biomarkers and therapeutic targets for AKI. In this review article, we summarize the current knowledge about miRNAs as promising biomarkers and potential therapeutic targets for AKI, as well as the challenges in their clinical use.

Background and Objectives: The current study aimed to determine the impact of fasciotomy on mortality and morbidity in children and adults with crush-related AKI following the 2023 Kahramanmaraş earthquakes. Materials and Methods: The study included individuals who had suffered crush injuries after the 2023 Kahramanmaraş earthquakes and were identified as having acute kidney injury (AKI). Patients with AKI were divided into two groups based on age: those under 18 years and those over 18 years. A comparative analysis was conducted between the mortality and morbidity rates of patients who underwent fasciotomy and those who did not. Disseminated intravascular coagulopathy (DIC), sepsis, and adult respiratory distress syndrome (ARDS) have all been identified as contributors to morbidity. Results: The study was conducted with a total of 40 patients (21 males and 19 females) aged between four and 83 years. A total of 21 patients underwent fasciotomy and the patients underwent varying numbers of fasciotomy, ranging from zero to 11. The mortality rate was 12.5%, corresponding to five adult patients. No instances of mortality were reported in the paediatric cohort. The application of fasciotomy in instances of crush-induced AKI did not result in elevated levels of mortality in either the paediatric or adult demographic. Within the adult population, a substantial difference in the duration of dialysis was observed between individuals who underwent fasciotomy and those who did not. A statistically significant increase in the number of fasciotomy incisions was observed in patients diagnosed with sepsis compared with those without sepsis. The study found a significant positive correlation between the number of fasciotomy incisions and dialysis days. Conclusions: Neither adult nor paediatric patients with crush-induced AKI showed an increased risk of death after fasciotomy. The number of fasciotomy incisions significantly correlated with the development of sepsis. Despite experiencing delays in hospital admission for paediatric patients, the incidence of both crush syndrome and mortality rates among children remained relatively low.

Laminitis is considered as an important underlying cause of lameness diseases, yet its specific pathogenesis remains unclear. Autophagy is an intracellular degradation mechanism that controls recycling of membrane-associated integrin and may aid in the progression of metabolic diseases. But the significance of autophagy for initiation and development of laminitis is unknown. The present study aimed to explore autophagy activity in the laminar tissue of dairy cows with oligofructose-induced laminitis. Twelve healthy non-pregnant Holstein cows were randomly divided to 2 groups of 6 cows each, entitled the control group and the oligofructose overload group (OF group), respectively. At 0 h, cows in OF group were gavaged with oligofructose (17 g/kg BW) dissolved in warm deionized water (20 mL/kg BW) through oral rumen tube, and dairy cows in control group were gavaged with the same volume of deionized water by the same method. At -72 h before perfusion as well as 0 h, 6 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h, and 72 h after perfusion, clinical evaluations in both groups were monitored. After 72 h, laminar tissues of dairy cows in both groups were collected to examine genes and proteins. We found the significantly higher (P<0.05) levels of mRNA ATG5, ATG12, and Becilin1, but P62 and mTOR were extensively lower (P<0.01) in the laminar tissue of the OF group than the control group. Protein expression level of Becilin-1 was higher significantly (P<0.05), and the protein expression level of LC3II was lower significantly (P<0.05) in OF group than control group. However, the expression of P62 reduced (P>0.05) non-significantly in OF group than control group. The distribution of Beclin1 protein in laminar tissue increased (P<0.01) significantly, and distribution of P62 protein decreased (P<0.05) significantly in OF group than control group. In conclusion, laminar tissue damage occurred during the onset of laminitis, which promoted the occurrence of autophagy, and confirmed that autophagy was involved in the regulation and pathogenesis of laminitis in dairy cows.

Alginate extraction is from seaweed, and lignin separation is from by-product corn (stalks and leaves). Alginate/lignin is a synthetic polymer rich in biological activity of great interest. Antioxidant activities of alginate/lignin were evaluated, such as total antioxidant activity, reducing power activity, DPPH free radical scavenging activity, and α – glucosidase inhibition activity. The test of anticancer activity was on four cell lines (Hep G2, fibroblast, MCF-7, and NCI H460). Determination of physical-chemistry characteristics of alginate/lignin was through FTIR, DSC, SEM_EDS, SEM_EDS mapping, XRD, XRF, and 1H-NMR. A study of acute toxicity of alginate/lignin was on Swiss albino mice. The results showed alginate/lignin possessed antioxidant activity such as total antioxidant activity, reducing power activity, especially, α – glucosidase inhibition activity, and no free radical scavenging activity. Alginate/lignin did not be typical in cancer cell lines. Alginate/lignin existed in a thermally stable regular spherical shape in the investigated thermal region. Some specific functional groups of alginate and lignin did not exist in alginate/lignin crystal. Elements such as C, O, Na, and S were popular in the alginate/lignin structure. LD0 and LD100 of alginate/lignin in mice were 3.91 g/kg and 9.77 g/kg, respectively. Alginate/lignin is the potential for application as pharmaceutical materials, functional foods, and supporting diabetes treatment.