Compared to the general population, patients with inflammatory bowel disease (IBD) are less likely to be vaccinated, putting them at an increased risk of vaccine-preventable illnesses. This risk is further compounded by the immunosuppressive therapies commonly used in IBD management. Therefore, developing new treatments for IBD that maintain immune function is crucial, as successful management can lead to better vaccination outcomes and overall health for these patients. Here, we investigate the potential of recombinant banana lectin (rBanLec) as a supporting therapeutic measure to improve IBD control and possibly increase vaccination rates among IBD patients. By examining the therapeutic efficacy of rBanLec in a murine model of experimental colitis, we aim to lay the foundation for its application in improving vaccination outcomes. After inducing experimental colitis in C57BL/6 and BALB/c mice with 2,4,6-trinitrobenzene sulfonic acid, we treated animals orally with varying doses of rBanLec 0.1-10 µg/ml (0.01 – 1 µg/dose) during the course of the disease. We assessed the severity of colitis and rBanLec’s modulation of the immune response compared to control groups. rBanLec administration resulted in a dose-dependent reduction in colitis severity (less pronounced weight loss, less shortening of the colon) and an improved recovery profile, highlighting its therapeutic potential. Notably, rBanLec-treated mice exhibited significant modulation of the immune response, favoring anti-inflammatory pathways (primarily reduction in a local [TNFα]/[IL-10]) crucial for effective vaccination. Our findings suggest that rBanLec could mitigate the adverse effects of immunosuppressive therapy on vaccine responsiveness in IBD patients. By improving the underlying immune response, rBanLec may increase the efficacy of vaccinations, offering a dual benefit of disease management and prevention of vaccine-preventable illnesses. Further studies are required to translate these findings into clinical practice.

Litsea martabanica root's antioxidant and AChE activity showed promise as a pesticide detoxification agent in our previous study. In addition to roots, its leaves can help mitigate pesticide exposure, although there is limited scientific evidence supporting their efficacy. However, the use of roots in many countries, such as Thailand, could contribute to environmental degradation, as highland communities traditionally cut down whole trees to obtain them. This study aims to evaluate the antioxidant activity and anti-pesticide potential of water extracts from L. martabanica leaves instead of its roots through in vitro and in vivo investigations. The findings showed that L. martabanica water extracts and fractions demonstrated varied antioxidant activity. The water extract, obtained using traditional extraction methods, was chosen for in vivo experiments. Rats received the extract followed by chlorpyrifos exposure for 16 days. Results indicated reduced acetylcholinesterase activity in chlorpyrifos-exposed rats, while treatment with leaf extract led to increased activity, suggesting its potential as a detoxifying agent. Histopathological examination revealed no liver cell necrosis and showed liver cell regeneration, indicating potential protection against free radical-induced liver damage without affecting rat liver weight or biochemical profiles. Utilizing L. martabanica leaves for healthcare purposes holds promise without negative environmental impact.

This paper presents an approach to improve the robustness of tip-tilt controllers for fast-steering mirror (FSM)-based laser beam steering (LBS) systems in the presence of dynamic disturbances such as external shocks. To this end, we propose the addition of a disturbance observer (DOB)-based anti-shock controller in parallel to the original linear servo control loop to improve its control performance in the presence of external shocks. To increase the tip-tilt control performance against external shocks, the DOB-based control method, which is an improved control method for eliminating nonperiodic disturbances, is implemented in the original tip-tilt control system. Results indicate that the control error of the DOB-based anti-shock controller decreased, resulting in an efficient improvement in its disturbance-rejection performance.

A novel interaction between the enzyme platelet-activating factor acetyl hydrolase (PAF-AH) and certain non-steroidal anti-inflammatory drugs (NSAIDs), such as sulindac, celecoxib, diclofenac and nimesulide, has been uncovered by this in-silico research. PAF-AH is known for its critical role in maintaining the fluidity and functionality of cell membranes by hydrolysing phospholipids and removing oxidized fatty acids. Since tumour microenvironments are largely marked by inflammation and oxidative stress, the discovery that these non-steroidal anti-inflammatory drugs can bind to the active pocket of PAF-AH. Suggests that they may be able to modulate its activity and thereby influence its role in cancer pathogenesis. Such modulation could lead to significant anti-tumour effects, including the reduction of inflammation, the inhibition of angiogenesis and the suppression of metastasis, particularly in cancers of the breast, colon, prostate, and lung. However, in certain con-texts, this interaction may cause the opposite effect, leading to cancer development. Therefore, this study is a gateway for the development of therapeutic strategies based on PAF-AH modulation and highlights the importance of the tumour microenvironment in the assessment of potential effects of NSAIDs. Furthermore, this finding may guide the selection of NSAIDs for the anti-inflammatory treatment of cancer patients, ruling out in-discriminate use of drugs that may promote neoplastic progression. This may also indicate the potential for repositioning specific NSAIDs within cancer treatment, thereby contributing to more precise and personalized therapeutic approaches.

Arguably the most important parameter in treating cognitive decline associated with Alzheimer’s disease is the length of time in which improvement, if achieved at all, is sustained. However, monotherapies such as donepezil and memantine are associated with a more rapid decline than no treatment in patients over multi-year follow-ups {Kennedy, 2018 #535}. Furthermore, anti-amyloid antibody treatment, which at best simply slows decline, is associated with accelerated cerebral atrophy [2], resulting in earlier dementia-associated brain volumes for those treated at the MCI stage than untreated patients. In contrast, a precision medicine approach, in which the multiple potential drivers of cognitive decline are identified for each patient and then targeted with a personalized protocol (such as ReCODE), has led to documented improvement in patients with cognitive decline [3]; [4]; [5], but long-term follow-up (>5 years) has not been reported previously. Therefore, we report here sustained cognitive improvement, in some cases for over a decade, in patients treated with a precision medicine protocol—something that has not been reported in patients treated with anti-cholinesterase, glutamate receptor inhibitory, anti-amyloid, or other therapeutic methods. These case studies warrant long-term cohort studies to determine how frequently such sustained cognitive improvements occur in patients treated with precision medicine protocols.

The most important prognostic factors in curatively treated prostate cancer at the initial diagnosis are T and N stage, histological subtype, Gleason score, initial PSA, PSA density and percentage of core biopsy positivity. Newer, but non-standard prognostic factors are urine PCA3 and genetic markers of prostate cancer. A simple, but seemingly underestimated standard test is serum Calcium (Ca) level, which has been shown by a previous study group to be a good predictor of lethal prostate cancer, but there is scarce evidence regarding the prognostic value of calcium levels at diagnosis. We aimed to determine whether a Ca level in the upper part of normal values has a prognostic value in curatively treated prostate cancer. We have retrospectively included 84 consecutive patients with prostate cancer, who underwent curative radiotherapy (primary or adjuvant; external beam RT with or without brachytherapy). We have performed statistical analysis of available prognostic factors. Ca level at diagnosis was found to be a statistically significant predictor of disease-free survival.

In order to tackle the issue of severe rocking phenomenon under seismic conditions in structures equipped with steel spring isolation bearings, this paper investigates a novel type of anti-rocking bearing. Firstly, the structural configuration and working principle of the novel anti-rocking bearing are introduced, and a design method for bearing parameters is proposed. Secondly, a finite element analysis model is established using SAP2000 software to conduct nonlinear dynamic time history analysis under seismic loading. The analysis results show that the structural arrangement of the novel anti-rocking bearing reduces both the vertical displacement difference and the rocking angle of the isolation layer. The bearing exhibits a certain level of anti-rocking effect, but it may cause significant tensile forces in some bearings, necessitating the installation of anti-tensile reinforcement. The effectiveness of the anti-rocking effect improves as the stiffness of the steel tension rod in the bearing increases; however, it also leads to higher maximum tension in individual bearings as well as the total tension in all bearings. For structures equipped with the novel anti-rocking bearing, the acceleration amplifies under most cases, with amplification coefficients ranging from 0.82 to 1.55. The performance of the novel anti-rocking bearing varies significantly for different seismic waves. The stiffness of the steel tension rod should be determined considering the reference pressure of the bearing and the maximum designed tension of the bearing. Through the finite element simulation of the bearing, the mechanical properties of the bearing are basically the same as the theoretical analysis results. For the cylinder and the joint bearing, certain structural measures need to be taken to ensure its strength and stiffness.

Background and Objectives: Age-related macular degeneration (AMD) is one of the major causes of central vision loss in the older age group and its dry form accounts for the majority of cases. Although several causes and mechanisms for the development and progression of AMD have previously been identified, the pathogenesis of this complex disease is still not entirely understood. As the inflammation and involvement of the immune system are strongly suggested to have a central role to promote the degenerative process and to stimulate the onset of complications, we aimed to analyze the prevalence of serum anti-retinal (ARA) and anti-endothelial cell antibodies (AECA) in patients with dry AMD and to determine their relationship with the clinical features of the disease, notably area of geographic atrophy (GA). Materials and Methods: We enrolled 41 patients with dry AMD and 50 sex- and age-matched healthy controls without AMD. The presence of ARA was determined by indirect immunofluorescence using monkey retina as an antigen substrate, while the presence of AECA was determined using cultivated human umbilical vein endothelial cells and primate skeletal muscle. Results: ARA were detected 36 (87.8%) AMD patients (titers range from 1:20 to 1:320) and in 16 (39.0%) (titers range from 1:10 to 1:40) of controls (p=0.0000). Twenty of the 41 patients (48.8%) were positive for AECA, while in a control group AECA were present only in 5 sera (10.0%). The titers of AECA in AMD patients ranged from 1:100 to 1:1000 and in the control group the AECA titers were 1:100 (p=0.0001). There were no significant correlations between the presence of AECA and disease activity. Conclusions: This study provides evidence for the possible involvement of an autoimmune process against retina and retinal vessel antigens in the pathogenesis of geographic atrophy associated with dry AMD.

KLEPTOSE® CRYSMEB is a methylated cyclodextrin derivative displaying less methylated group substitution than randomly methylated cyclodextrin. It has demonstrated an impact on atherosclerosis and neurological diseases. linked in part to cholesterol complexation and immune response, but the impact on inflammatory cascade pathways was not clear. Thus, the impact of KLEPTOSE® CRYSMEB on various pharmacological targets was assessed using human umbilical vein endothelial cells in physiological and inflammatory conditions, followed by screening against twelve human primary cell-based systems designed to model complex human tissue and disease biology of the vasculature, skin, lung, and inflammatory tissues using the BioMAP® Diversity PLUS® Panel. Finally, the anti-inflammatory mechanism was investigated on peripheral blood mononuclear cells to evaluate anti-inflammatory or pro-resolving properties. The results showed that KLEPTOSE® CRYSMEB can modulate the immune system in vitro and potentially manage vascular issues by stimulating the expression of molecules involved in the crosstalk between immune cells and other cell types. It showed anti-inflammatory effects driven by pro-inflammatory cytokine secretion inhibition and could have different impacts on different tissue types. Moreover, this cyclodextrin showed no clear impact on pro-resolving lipid mediators. Finally, it appeared that the mechanism of action of KLEPTOSE® CRYSMEB seems to not be shared by well-known anti-inflammatory molecules.

GCTs are developmental tumors and likely to reflect ontogenetic and teratogenetic determinants. The objective was to identify syndromes with or without congenital anomalies and non-syndromic defects as potential risk factors. Patients with extracranial GCTs (eGCTs) registered in MAKEI 96/MAHO 98 between 1996 and 2017 were used. According to Teilum's holistic concept malignant and benign teratomas were registered. We used a case control study design with Orphanet as a reference group for syndromic defects and the Mainz birth registry (EUROCAT) for congenital anomalies at birth. Co-occurring genetic syndromes and/or congenital anomalies were assessed accordingly. Odds ratios and 95% confidence intervals were calculated and p-values for Fisher’s exact test with Bonferroni correction if needed. A strong association was confirmed for Swyer (OR 338.6, 95% CI 43.7-2623.6) and Currarino syndrome (OR 34.2, 95% CI 13.2-88.6). We additionally found 17 isolated cases of eGCT with a wide range of syndromes, however not significantly associated following Bonferroni correction. All these cases pertained to girls. Regarding non-syndromic defects, no association with eGCTs could be identified. In our study we confirmed a strong association for Swyer and Currarino syndromes with additional congenital anomalies.

Bladder cancer (BC) possesses distinct molecular profiles that influence progression depending on its biological nature and delivered treatment intensity. Muscle-invasive BC (MIBC) and non-MIBC (NMIBC) demonstrate great intrinsic heterogeneity regarding different prognoses, survival, progression, and treatment outcomes. Transurethral resection of bladder tumor (TURBT) is the standard of care in treating NMIBC and serves both diagnostic and therapeutic purposes, despite the prevalent recurrence and progression among many patients. In particular, flat urothelial car-cinoma in situ and urothelial carcinoma with lamina propria invasion are the major precursors of MIBC. A new‐generation photosensitizer, 5‐Aminolevulinic acid (5-ALA), demonstrates high tumor specificity by illuminating the tumor lesion with a specific wavelength of light to produce fluorescence, and has been studied for photodynamic diagnosis to detect precise tumor areas by TURBT. Additionally, it has been applied for treatment by producing its cytotoxic reactive oxygen species, as well as screening for urological carcinomas by excreting porphyrin in the blood and urine. Moreover, 5-ALA may contribute to screening before and after TURBT in NMIBC. Here, we summarize the updated evidence and ongoing research on photodynamic technology for NMIBC, providing insight into the potential for improving patient outcomes.

The many limitations of implementing anticancer strategies under the term “precision oncology” have been extensively discussed. While some authors propose promising future directions, others are less optimistic and use phrases such as illusion, hype and false hypotheses. The reality is revealed by practicing clinicians and cancer patients in various online publications, one of which has stated that “in the quest for the next cancer cure, few researchers bother to look back at the graveyard of failed medicines to figure out what went wrong.” The message is clear: novel therapeutic strategies with catchy names (e.g., synthetic “lethality”) have not fulfilled their promises despite decades of extensive research and clinical trials. The main purpose of this review is to discuss key challenges in solid tumor therapy that surprisingly continue to be overlooked by the nomenclature committee on cell death and numerous other authors. These challenges include: the impact of chemotherapy-induced genome chaos (e.g., multinucleation) on resistance and relapse, oncogenic function of caspase 3, cancer cell anastasis (recovery from late stages of apoptosis), and pitfalls of ubiquitously used preclinical chemosensitivity assays (e.g., cell “viability” and tumor growth delay studies in live animals) that score such pro-survival responses as “lethal” events. Studies outline herein underscore the need for new direction in the management of solid tumors.

Lactococcus lactis subsp. cremoris C60 is a probiotic strain of lactic acid bacteria (LAB) which induces various immune modifications in myeloid lineage cells. These modifications subsequently reg-ulate T cell function, resulting in enhanced immunity both locally and systemically. Here, we report that C60 suppresses tumor growth by enhancing macrophage function via metabolic al-terations, thereby increasing adenosine triphosphate (ATP) production in a murine melanoma model. Intragastric (i.g.) administration of C60 significantly reduced tumor volume compared to saline administration in mice. The anti-tumor function of intratumor (IT) macrophage was up-regulated in mice administered with C60, as evidenced by an increased inflammatory phenotype (M1) rather than an anti-inflammatory/reparative (M2) phenotype, along with enhanced anti-gen-presenting ability, resulting in increased tumor antigen-specific CD8+ T cells. Through this functional modification, we identified that C60 establishes a glycolysis-dominant metabolism, rather than fatty acid oxidation (FAO), in IT macrophages, leading to increased intracellular ATP levels. To address the question of why orally supplemented C60 exhibits functions in distal places, we found a possibility that bacterial cell wall components, which could be distributed throughout the body from the gut, may induce stimulatory signals in peripheral macrophages via Toll-like receptors (TLRs) signaling activation. Thus, C60 strengthens macrophage anti-tumor immunity by promoting a predominant metabolic shift towards glycolysis upon TLR-mediated stimulation, thereby increasing substantial energy production.

Abstract: Abnormal growth of oligodendrocyte precursor cells (OPCs) importantly contributes to the progression of glioblastoma tumors. Hence, molecules that block OPC growth may be of therapeutic importance in treating gliomas. 2-methoxyestradiol (2ME), an endogenous tubulin interacting metabolite of estradiol is effective against multiple proliferative disorders. Based on its anti-carcinogenic and anti-angiogenic actions it is undergoing phase II clinical trials. We hy-pothesize that 2ME may prevent glioma growth by targeting OPC growth. Here we tested this hypothesis by assessing the impact of 2ME on growth of OPC cell line “Oli-neu” and dissected the underlying mechanism(s). Treatment with 2ME inhibited OPC growth in a concentra-tion-dependent manner and accompanied with significant upregulation in expression of p21 and p27, negative cell cycle regulators. Moreover, treatment with 2ME altered OPC morphology from multi-arm processes to rounded cells. At concentrations of 1uM and greater 2ME induced apoptosis with increased expression of caspase 3, PARP and caspase-7 fragments, externalized phosphatidylserine staining / apopercentage and increased mitochondrial activity. Flow-cytometry and microscopic analysis demonstrated that 2ME triggers endoreduplication in a concentration-dependent fashion. Importantly, 2ME induced cyclin E, JNK1/2 and p53 expres-sion as well as OPC cell fusion, key mechanisms driving endoreduplication or whole-genome duplication. Importantly, inhibition of p53 with pfithrin-α rescued 2ME-induced endoreduplica-tion. The pro-apoptotic and endoreduplication actions of 2ME were accompanied with upregula-tion of survivin, cyclin A, Cyclin B, Cyclin D2, ppRB. Taken together our findings provide evi-dence that 2ME not only inhibits OPC growth and triggers apoptosis, but also activates OPCs in a survival - fight or flight mode leading to endoreduplication. This inherent survival character-istic of OPCs may, in part be responsible for drug resistance in gliomas as observed for many tubulin interacting drugs. Importantly, the fate of OPCs after 2ME treatment may depend on cell-cycle status of the individual cells. Combining tubulin-interfering molecules with drugs, such as pfithrin-α, that inhibit endoreduplication may help inhibit OPC/glioma growth and lim-it drug resistance.

Global navigation satellite system (GNSS) array antenna receivers are widely used to suppress wideband interference in navigation countermeasures. However, existing array antenna receivers all adopt digital array structure and digital beamforming technique, and it has limited analog-front-end (AFE) dynamic range. In strong interference scenarios, AFE saturation will occur, which limits the maximum interference suppression ability of the array receiver. Aiming at this issue, this paper proposes a robust wideband interference suppression method for GNSS array antenna receivers based on hybrid beamforming technique. Firstly, a novel fully connected hybrid array receiver structure is proposed; Secondly, the corresponding hybrid beamforming method is proposed at the same time, and it realizes the complete elimination of strong interference by jointly suppression in analog domain and digital domain. After mathematical simulation experiments, it is verified that compared to the digital beamforming-based anti-jamming technique, the proposed method can effectively suppress strong wideband interference, and the maximum interference suppression ability is improved by 36 dB.

Despite notable advancements in immunotherapy in the past decades, allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a promising, potentially curative treatment modality. Only a limited number of studies has performed a direct comparison of two prevalent rabbit anti-thymocyte globulin (r-ATG) formulations — specifically, Thymoglobuline (ATG-T, formerly Genzyme) and Grafalon (ATG-G, formerly Fresenius). The primary objective of our retrospective analysis was to compare the outcomes of adult patients undergoing matched or mismatched unrelated donor (MUD/MMUD) allo-HCT, with a graft-versus-host disease (GvHD) prophylaxis based on either ATG-T or ATG-G. A total of 87 patients undergone allo-HCT between 2012 and 2022 were included. We observed no significant differences between ATG-T and ATG-G concerning the occurrence of acute graft-versus-host disease (aGvHD), regardless of its severity. Conversely, chronic graft-versus-host disease (cGvHD) occurred less frequently in the ATG-T group compared to ATG-G (7.5% vs. 38.3%, p=0.001). Patients treated with ATG-T manifested a higher incidence of cytomegalovirus (CMV) reactivations (70% vs. 31.9%, p<0.001), with a shorter time between transplant and CMV (<61 days, 77.8% vs. 33.3%, p=0.008) and a higher median CMV copy number (1000 vs. 0, p=0.004). Notably, despite a higher occurrence of CMV reactivations in the ATG-T cohort, most patients were asymptomatic compared to ATG-G (85.7% vs. 43.8%, p=0.005). Finally, we observed no significant differences in terms of 5-year overall survival (OS) and 3-year probability of relapse while comparing ATG-T and ATG-G (32.0% vs 40.3%, p=0.423; 63.9% vs 55.7%, p=0.438, respectively).

Wilms tumor (WT), the most prevalent type of renal cancer in children, exhibits overall survival rates exceeding 90%. However, chemotherapy resistance, which occurs in approximately 10% of WT cases, is a major challenge for the treatment of WT, particularly for advanced-stage patients. In this study, we aimed to discover potential mutation markers and drug targets associated with chemotherapy resistance in advanced stage WT. We performed exome sequencing to detect somatic mutations and molecular targets in 43 WT samples, comprising 26 advanced stage WTs, of which 7 cases are chemotherapy-resistant. Our analysis revealed four genes (ALPK2, C16orf96, PRKDC, and SVIL) that correlated with chemotherapy resistance and reduced disease-free survival in ad-vanced-stage WT. Additionally, we identified driver mutations in 55 genes within the chemo-therapy-resistant group, including 14 druggable cancer driver genes. Based on the mutation profile of the resistant WT samples, we propose potential therapeutic strategies involving platinum-based agents, PARP inhibitors, and antibiotic/antineoplastic agents. Our findings provide insights into the genetic landscape of WT and offer potential avenues for targeted treatment, particularly for patients with chemotherapy resistance.

Uterine Tumor Resembling Ovarian Sex Cord Stromal Tumor (UTROSCT) is a rare uterine mesenchymal neoplasm, which resembles ovarian sex cord tumors of the ovary. Although, in general, UTROSCT exhibits benign behavior with a favorable prognosis, this neoplasm is nonetheless classified as being of an uncertain ma-lignant potential, given its low rate of recurrence and the fact that it rarely pro-duces metastases (lymph nodes, epiploic appendix, omentum, small bowel, subcutaneous, lungs). Its histogenesis too is uncertain. Typically, UTROSCT oc-curs in peri-menopausal or menopausal women but can sometimes be observed in young women. Usually, this neoplasm can be found in the uterine corpus as a nodular intramural lesion, less frequently submucosal, subserosal or poly-poid/intracavitary. UTROSCT can cause abnormal bleeding, pelvic pain, enlarged uterus, mass sensation, but sometimes it is found purely by chance. This neo-plasm can be considered polyphenotypic on morphological, immunohistochem-ical, and genetic analyses. Generally, on microscopic examination, UTROSCT shows a predominant pattern of the cords, nests, and trabeculae typical of sex cord tumors of the ovary while, immunohistochemically, it is characterized by a co-expression of epithelial, smooth muscle, and sex cord markers. The aim of this review is to report clinical and pathological data and genetic alterations to estab-lish its impact on the prognosis and management of patients affected by this rare entity.

The pharmacological effects of the fruiting body of Ophiocordyceps sinensis (Os) exerted antioxidant, anti-virus, and immunomodulatory, whereas the anti-inflammatory effects and active components of Os mycelial submerged culture (OMSC) are not known. This study aimed to investigate the active compounds in the fermented liquid (FLOS), hot water (WEOS), and 50-95% (EEOS-50, EEOS-95) ethanol extracts of OMSC and their anti-inflammatory effects and potential mechanisms in LPS-stimulated microglial BV2 cells. The results demonstrated that all of the OMSC extracts could inhibit NO production in BV2 cells. EEOS-95 exhibited the strongest inhibitory effects (41 % inhibitory ability at 500 µg/mL), and its ergosterol, GABA, total phenolic, and total flavonoid contents were significantly higher than those of the other extracts (18.60, 18.60, 2.28, and 2.14 mg/g, p < 0.05, respectively). EEOS-95 also has a strong inhibitory ability against IL-6, IL-1β and TNF-α with IC50 of 617, 277 and 507 µg/mL, respectively, which is higher than that of 1 mM melatonin. The anti-inflammatory mechanism of EEOS-95 seems to be associated with up-regulation of PPAR-γ/Nrf-2/HO-1 antioxidant-related expression and down-regulation of NF-κB/COX-2/iNOS pro-inflammatory expression signaling. Therefore, we hypothesized that EEOS-95 can prevent neurodegenerative diseases, but the effect on the application in vivo should be further investigated.

Our report presents the findings from a treatment program that involved plant-based diets (PBDs) and supplements for 1,750 elderly cardiology patients diagnosed with COVID-19 between April 2020 and June 2023. At the start of the program, there was no published data supporting the use of PBDs for COVID-19 patients. However, after 18 months, studies were released that indicated the effectiveness of PBDs in decreasing the incidence and severity of COVID-19. Our treatment protocol differed from these studies in several ways. We carefully controlled the quality, quantity, and processing method of the foods we provided, opting for raw instead of cooked vegetables. Additionally, we incorporated supplementation that complemented the nutrients lacking in a PBD and enhanced the anti-viral, anti-inflammatory, antioxidant, antithrombotic, and immunomodulatory properties of a PBD. Our patients recovered faster (12±1.4 days vs. 20.9±4.3 days), with lower severity (2% vs. 10-20%), hospitalizations (0 vs. 5-10%), and deaths (0 vs. 15-17%) compared to the general population. These favorable outcomes are particularly noteworthy given Indonesia's high COVID-19 morbidity and mortality rates, among the highest in Asia. The findings of this report provide valuable insights for practitioners in managing high-risk elderly COVID-19 patients, particularly in avoiding severity and mortality.

This study introduces a compact Raman spectrometer with a 1064 nm excitation laser coupled with a fiber probe and an inexpensive motorized stage, offering a promising alternative to widely used Raman imaging instruments with 785 nm excitation lasers. The benefits of 1064 nm excitation for biomedical applications include further suppression of fluorescence background and deeper tissue penetration. The performance of the 1064 nm instrument in detecting cancer in human bladder resectates is demonstrated. Raman images with 1064 nm excitation were collected ex vivo from 10 human tumor and non-tumor bladder specimens and the results are compared to previously published Raman images with 785 nm excitation. K-Means cluster (KMC) analysis is used after pre-processing to identify Raman signatures of control, tumor, necrosis, and lipid-rich tissues. Hierarchical cluster analysis (HCA) groups the KMC centroids of all specimens as input. The tools for data processing and hyperspectral analysis were compiled in an open source Python library called SpectraMap (SpMap). In conclusion, the 1064 nm Raman system can differentiate between tumor and non-tumor bladder tissues in a similar way to 785 nm Raman spectroscopy. These findings hold promise for future clinical hyperspectral imaging.

Elastic yarns are the key component of high-performance compression garments. However, it remains a challenge to fabricate anti-fatigue yarns with high mechanical force and long elongation for generating compression garments with prolonged wear. In this paper, we report the development of anti-fatigue double-wrapped yarns with excellent mechanical properties by wrapping high-denier Spandex with nylon filaments in opposite twists. In particular, 560D high-denier Spandex as the core was untwisted which can maximumly reduce the interaction between the core and wrapping filaments, enabling high elongation of the double-wrapped yarns. In addition, we chose 70D nylon filaments with a tensile force of 387.40 ± 8.82 cN as the wrapping materials to provide sufficient force for double-wrapped yarns. Notably, opposite twists were induced for the inner and outer wrapping filaments to achieve a balanced stable yarn structure. By systematically optimizing manufacturing parameters including inner wrapping density, outer wrapping density, taking-up ratio, and drafting ratio, we obtained double-wrapped yarn with excellent tensile force (952.00 ± 24.03 cN) and elongation (357.28% ± 9.10%). Notably, the stress decay rate of optimized yarns was only 12.0% ± 2.2%. In addition, the optimized yarn was used as the weft-lining yarn for generating weft-lined fabrics, the elastic recovery rate of the obtained fabric was only 2.6% after cyclic stretching, much lower than the control fabric. Our design of anti-fatigue double-wrapped yarns could be widely used for fabricating high-performance compression garments.

Human fungal pathogen Candida albicans causes oral infectious diseases such as oral thrush in immunocompromised patients with hyposalivation, diabetes mellitus, prolonged use of anti-biotics or immunosuppressive medicines and poor oral hygiene. An anti-fungal medication classified as a BCS class II drug, Clotrimazole has high permeability and low solubility in water. It is commercially available as lozenges, which do not uniformly distribute the drug within saliva for local therapy. This results in higher dose frequency and lower patient compliance. Therefore, in this study we proposed a niosomal based subgingival film formulation of clotrimazole for enhancing drug efficacy by improving drug solubilization capacity and improving patient compliance by prolonging the release of drug at the targeted site and reducing the dose frequency to show effective anti-fungal activity. The prepared niosomal film showed good entrapment efficiency and anti-fungal activity. Niosomal film showed better release pattern than drug loaded film.

Background: Pancreatic neuroendocrine tumors (pNETs) represents a rare subset of pancreatic cancer. Functional tumors caused hormonal changes and clinical syndromes, while non-functional ones are often diagnosed late. Surgical management need a multidisciplinary planning, involving enucleation, distal pancreatectomy with or without spleen preserving, cen-tral pancreatectomy, pancreaticoduodectomy or total pancreatectomy. Minimally invasive ap-proach increased in the last decade compared to the open technique. The aim of this study is to analyze current diagnostic and surgical trends for pNETs, to identify better interventions and their outcomes. Methods: The study adhered to PRISMA guidelines, conducting a systematic review of literature from May 2008 to March 2022 across multiple databases. Several combinations of keywords was used ("NET", "pancreatic", "surgery", "laparoscopic", "minimally invasive", "robotic”, “enuclea-tion”,“parenchima sparing”) and relevant article references was manually checked. Manuscript quality was evaluated. Results: The study screened 3867 manuscripts, twelve studies were selected, primarily from Ita-ly, the United States, and China. A total of 7767 surgical treated patients was collected from 160 included centers. The mean age was 56,3 y.o. Enucleations (EN) and distal pancreatectomy (DP) was the most common performed surgery and represents 43.4% and 38.6% of the total interven-tions, respectively. Pancreatic fistula, post operative bleeding, re-operation and follow up was recorded and analyzed. Conclusions: Enucleation show better postoperative outcomes and lower mortality rates com-pared to pancreaticoduodenectomy (PD) or distal pancreatectomy (DP), despite similar risks of postoperative pancreatic fistula (POPF). DP was preferred over enucleation for pancreas body-tail, while laparoscopic enucleation is better for head pNETs.

Analyzing BRCA1/2 tumor pathogenic variants (TPVs) in epithelial tubal/ovarian cancers (EOC) has become an essential part of the diagnostic workflow in many centers to guide treatment options and genetic cascade testing. However, there is no standardization of testing procedures, including techniques, gene assays, or sequencers used, and data on the execution of tumor tests remains scarce. Therefore, we evaluated characteristics of BRCA1/2 tumor testing in advanced-stage EOC with real-world national data. Pathology reports of patients diagnosed with EOC in 2019 in the Netherlands were obtained from the Dutch Pathology Registry (PALGA), and data regarding histological subtype and BRCA1/2 tumor tests were extracted. A total of 999 patients with advanced-stage EOC were included. Tumor tests were performed for 502 patients (50.2%) and BRCA1/2 TPVs were detected in 14.7%. Of all tests, 48.6% used hybrid capture techniques and 26.5% used PCR-based techniques. More than half of the tests (55.0%) analyzed other genes in addition to BRCA1/2. Overall, this study highlights the heterogeneity in the execution of BRCA1/2 tumor tests. Despite a lack of evidence of quality differences, we emphasize that adequate reporting and internal and external quality monitors are essential for high-quality implementation and execution of reliable BRCA1/2 tumor testing, which is crucial for identifying all patients with BRCA1/2 TPVs.

: Since the COVID-19 pandemic, people have become aware that materials (products) can transmit infection and have begun to focus on questions such as how bacteria and germs, the sources of in-fection, maintain their infectivity on material surfaces, and the extent to which materials can or cannot prevent this. and to what extent materials can and cannot prevent it. The SIAA, a non-profit organization of many Japanese companies, had created an entirely separate interna-tional standard for materials' antibacterial, antiviral, and antibiofilm properties (products). The authors have studied the academic basis for the operation of the standards and were deeply in-volved as researchers in establishing one of the standards. This paper describes the interna-tional standards and some representative examples of the authors' actual use of these standards and explains the current status and future problems.

Tumor heterogeneity is a major obstacle in cancer therapy. We offer a novel perspective on tumor heterogeneity, informed by expanding upon the current view on tumor evolution. It is commonly known that in cancer, it is the advantageous genes and mutations that drive tumor capacities and the progression. We recognize an earlier, often overlooked, but necessary thus crucial step preceding the activation of advantageous genes functionality, namely, cellular response. We suggest that cancer is driven by an adaptive action taken by any organism when confronted with adversity - a cellular response to generate specific cancer capacities demanded to overcome survival threat - the responses that prompt the utilization of the functionality of advantageous genetic mutations and genes to attain these capacities and drive the disease. The ongoing development of cancer capabilities, as cells endeavor to obtain a competitive advantage, results in increased molecular chaos, observed as tumor heterogeneity. When the evolutionary drive for survival is impeded by therapeutic inhibition of critical genes, cell death occurs, a phenomenon thus termed oncogene addiction. We summarize the implications of this new framework for understanding tumor evolution and anti-cancer drug discovery, as well as understanding of basic cancer biology.

To develop peptide drugs targeting integrin receptors, synthetic peptide ligands endowed with well-defined selective binding motifs are necessary. The snake venom KTS-containing disintegrins, that selectively block collagen α1β1 integrin, were used as lead compounds for the synthesis and structure-activity relationship of a series of linear peptides containing the KTS-pharmacophore and alternating natural amino acids and 3-aminobenzoic acid (MABA). To ensure a better stiffness and metabolic stability, one, two and three MABA residues, were introduced around the KTS pharmacophore motif. Molecular dynamics simulations have determined that the solution conformation of MABA peptide 4 is more compact, underwent larger conformational changes until convergence, and spent most of the time in a single cluster. The peptides’ binding affinity has been characterized by enzyme linked immunosorbent assay in which the most potent peptide 4 inhibited with IC50 of 324±8 µM and 550±45 µM the binding of GST-α1-A domain to collagen IV fragment CB3, and the cell adhesion to collagen IV using α1-overexpressor cells, respectively. Docking studies and MM-GBSA calculations confirmed that peptide 4 binds a smaller region of the integrin near the collagen- binding site and penetrated deeper into the binding site near Trp1. Peptide 4, inhibited tube formation by endothelial cell migration in the Matrigel angiogenesis in vitro assay. Peptide 4 was acutely tolerated by mice, showed stability in human serum, decreased tumor volume and angiogenesis, and significantly increased the survival of mice injected with B16 melanoma cells. These findings propose that MABA-peptide 4 can further serve as an α1β1-integrin antagonist lead compound for further drug-optimization in angiogenesis and cancer therapy.

Rheumatoid arthritis (RA) is a complex illness with both hereditary and environmental compo-nents. Globally, in 2019, 18 million people had RA. RA is characterised by persistent inflammation of the synovial membrane that lines the joints, cartilage loss, and bone erosion. Phenolic molecules are the most prevalent secondary metabolites in plants, with a diverse spectrum of biological ac-tions that benefit functional meals and nutraceuticals. These compounds have received a lot of at-tention recently because they have antioxidant, anti-inflammatory, immunomodulatory, and anti-rheumatoid activity by modulating tumour necrosis factor, mitogen-activated protein kinase, nu-clear factor kappa-light-chain-enhancer of activated B cells, and c-Jun N-terminal kinases, as well as other preventative properties. This article discusses dietary polyphenols, their pharmacological properties, and innovative delivery technologies for the treatment of RA, with a focus on their possible biological activities. Nonetheless, commercialization of polyphenols may be achievable only after confirming their safety profile and completing successful clinical trials.

Epithelial ovarian cancer (EOC) has not significantly benefited from advances in immunotherapy, mainly because of the lack of well-defined actionable antigen targets. Using proteogenomic analyses of primary EOC tumors, we previously identified 91 aberrantly expressed tumor-specific antigens (TSAs) originating from unmutated genomic sequences. Most of these TSAs derive from non-exonic regions, and their expression results from cancer-specific epigenetic changes. The present study aimed to evaluate the immunogenicity of 48 TSAs selected according to two criteria: presentation by highly prevalent HLA allotypes and expression in a significant fraction of EOC tumors. Using targeted mass spectrometry analyses, we found that pulsing with synthetic TSA peptides leads to a high-level presentation on dendritic cells. TSA abundance correlated with the predicted binding affinity to the HLA allotype. We stimulated naïve CD8 T cells from healthy blood donors with TSA-pulsed dendritic cells and assessed their expansion with two assays: MHC-peptide tetramer staining and TCR Vβ CDR3 sequencing. We report that these TSAs can expand sizeable populations of CD8 T cells and, therefore, represent attractive targets for EOC immunotherapy.

Tumor to stroma ratio is a highly debated prognostic factor in the management of several solid tumors and there is no universal agreement on its practicality. In our study we proposed to confirm or dismiss the hypothesis that a simple measurement of stroma quantity is an easy-to-use and strong prognostic tool. We have included 74 consecutive patients with colorectal cancer who underwent primary curative abdominal surgery. The tumors have been grouped into stroma-poor (stroma <10%), medium-stroma (between 10 and 50%) and stroma-rich (over 50%). The proportion of tumor stroma ranged from 5% to 70% with a median of 25%. Very few, only 6.8% of patients had stroma-rich tumors, 4% stroma-poor tumors and 89.2%tumors with a medium quantity of stroma. The proportion of stroma, at any cut-off, had no statistically significant influence on the disease specific survival. This can be explained by the low proportion of stroma-rich tumors in our patient group and the inverse correlation of stroma proportion with tumor grade. The real-life proportion of stroma-rich tumors and the complex nature of the stroma-tumor interaction has to be further elucidated.

Lipofuscin is indigestible garbage that accumulates in the autophagic vesicles and cytosol of post-mitotic cells with age. Drs. Brunk and Terman postulated that lipofuscin accumulation is the main or at least a major driving factor in aging. They even posited that the evolution of memory is the reason why we get lipofuscin at all, as stable synaptic connections must be maintained over time, meaning that the somas of neurons must also remain in the same locale. In other words, they cannot dilute out their garbage over time through cell division. Mechanistically, their position certainly makes sense given that rendering a large percentage of a post-mitotic cell’s lysosomes useless must almost certainly negatively affect that cell and the surrounding microenvironment. Here, I explore the possibility that the accumulation of lipofuscin may to some extent exacerbate every other kind of age-related damage. I do not think that lipofuscin removal will reverse/prevent all forms of aging, just the major component facing us currently. In this piece, I will review what is known about lipofuscin accumulation from evolutionary and mechanistic standpoints and discuss a method of removing it from single cells in vitro.

Today, there are commercially available high-performance electric wheelchairs, capa-ble of responding to strong limitations. However, despite these advancements, there is a significant portion of the population with severe disabilities who cannot access this mobility solution due to safety reasons. Indeed, either due to motor issues preventing reliable control of the wheelchair's commands, or associated visual or cognitive pathologies, the use of an electric wheelchair by these individuals would put them at risk and could also constitute a danger to those around them. This is why our research team is working on the development of augmented wheelchairs that allow a greater autonomy. We are mainly developing a system compatible with all electric wheel-chairs on the market, capable of making them anti-collision and anti-fall on uneven ground (sidewalks, stairs, etc.). In this article, we present our solution regarding the anti-collision function, in particular the sensors used to do this, as well as the strategy. We will focus on the shortcomings and weaknesses of various types of sensors and demonstrate how, by combining them in a certain way, we can develop a collision avoidance device capable of managing the diversity of everyday life situations. The two types of sensors that will be combined here are an in-house developed special near infrared sensor from the laboratory and a commercially available ultrasonic sensor. We will present the internal operation of the sensors, their limitations, experimental tests involving integration with the wheelchair, and the structure of the complete device.

Opuntia ficus-indica (L.) Mill. belongs to the Cactaceae family and the genus Opuntia; it is a succulent plant that adapts to extreme climatic conditions. The aerial part of the plant consists of the cladodes, morphological changes of branches that appear green, are covered with thorns, and are essential to reduce excessive perspiration of water. The composition of cladodes is very varied, and the main constituents are water, fibers, polysaccharides, proteins, fatty acids, vitamins, sterols, minerals, and polyphenols. Polyphenols are responsible for many beneficial activities for human health, such as antioxidant, anti-inflammatory, antitumor, and nutritional properties. The purpose of this manuscript was to compare the properties of cladodes belonging to the same plant but with different stages of maturity. Relative extracts were tested both in vitro and on a cell line and antioxidant and anti-apoptotic properties were found. The antioxidant activity was tested by the ORAC test, the DPPH test, and the measurement of cellular accumulation of ROS. Anti-apoptotic activity was evaluated by the annexin/PI assay and measurement of caspases 9 and 3 expression. The results obtained have shown that the extracts considered possess antioxidant and anti-apoptotic properties. However, the different stages of maturity of cladodes are essential for the performance of both functions. In addition, important variations have been made in the dissolution of extracts that have brought greater safety in their use. In conclusion, this manuscript provides further information on cladodes of Opuntia ficus-indica, which can be used as adjuvants in many human pathologies.

Fermented foods and ingredients, including fermentates derived from lactic acid bacteria (LAB) in dairy products, can modulate the immune system. Here we describe the use of reconstituted skimmed milk powder to generate novel fermentates from Lactobacillus helveticus strains SC232, SC234, SC212, and SC210, and from Lacticaseibacillus casei strains SC209 and SC229, and demonstrate using in vitro assays that these fermentates can differentially modulate cytokine secretion by bone marrow derived dendritic cells (BMDCs) when activated with either the viral ligand, loxoribine, or an inflammatory stimulus, lipopolysaccharide. Specifically, we demonstrate that SC232 and SC234 increase cytokines IL-6, TNF-α, IL-12p40, IL-23, IL-27 and IL-10, and decreased IL-1β in primary bone marrow derived dendritic cell (BMDCs) stimulated with a viral ligand. In contrast exposure of these cells to SC212 and SC210 resulted in increased IL-10, IL-1β, IL-23, and decreased IL-12p40 following activation of the cells with the inflammatory stimulus LPS. Interestingly SC209 and SC229 had little or no effect on cytokine secretion by BMDCs. Overall, our data demonstrates that these novel fermentates have specific effects and can differentially enhance key immune mechanisms that are critical to viral immune responses, or can suppress responses involved in chronic inflammatory conditions, such as Ulcerative Colitis (UC), and Crohn’s disease (CD).

The ultimate goal of our review is to draw clinician’s attention, especially of those who are managing pediatric patients with permanent, long-standing, ventriculoperitoneal or, less commonly, ventriculo-atrial shunts. This specific subgroup of patients may eventually suffer from severe, intractable headaches which may negatively impair their quality of daily living. In the absence of any other clinical condition that could be attributed as the cause of the headache, shunt overdrainage should not be overlooked but, on the contrary, should be seriously taken into consideration in the therapeutic armamentarium of such cases, that are difficult to be handled.

Despite significant advances in tumor biology and clinical therapeutics, metastasis remains the primary cause of cancer-related deaths. While RNA-seq technology has been used extensively to study metastatic cancer characteristics, challenges persist in acquiring adequate transcriptomic data. To overcome this challenge, we propose MetGen, a generative contrastive learning based on deep learning model. MetGen generates synthetic metastatic cancer expression profiles using primary cancer and normal tissue expression data. Our results demonstrate that MetGen generates comparable samples to actual metastatic cancer samples, and we discuss the learning mechanism of MetGen. Additionally, we demonstrate MetGen's interpretability using metastatic prostate cancer and metastatic breast cancer. MetGen has learned highly relevant signatures in cancer, tissue, and tumor microenvironment, such as immune response and the metastasis process, which potentially fosters a more comprehensive understanding of metastatic cancer biology. The development of MetGen represents a significant step toward the study of metastatic cancer biology by providing a generative model that identifies candidate therapeutic targets for the treatment of metastatic cancer.

Gastric inflammation-related disorders are commonly observed digestive system illnesses char-acterized by the activation of proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α). This results in the induction of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PEG2) and matrix metallopeptidase-9 (MMP-9). These factors contribute to the pathogenesis of gastric in-flammation disorders. We examined the preventive effects of Lonicera japonica Thunb. ethanol ex-tract (Lj-EtOH) on gastric inflammation induced by TNF-α in normal GES-1 cells. The GES-1 cell line was used to establish a model that simulated the overexpression of COX-2/PGE2 and MMP-9 proteins induced by TNF-α, to examine the anti-inflammatory properties of Lj extracts. The re-sults indicated that Lj-EtOH exhibits significant inhibitory effects on COX-2/PEG2 and MMP-9 ac-tivity, attenuates cell migration, and provides protection against TNF-α-induced gastric inflam-mation. The protective effects of Lj-EtOH are associated with the modulation of COX-2/PEG2 and MMP-9 through activation of TNFR–ERK 1/2 signaling pathways as well as the involvement of c-Fos and nuclear factor kappa B (NF-κB) signaling pathways. Based on our findings, Lj-EtOH ex-hibits a preventive effect on human gastric epithelial cells. Consequently, it may represent a novel treatment for the management of gastric inflammation.

Most neurodegenerative diseases, including Alzheimer's disease, ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage are associated with inflammation. Tumor necrosis factor (TNF) is a pleiotropic pro-inflammatory cytokine that regulates cerebral infarction in stroke pathology, and its action is influenced by the bioavailability of its membrane-bound receptors, TNFR1 and TNFR2, and microglial activation. During the initial onset of these diseases, the soluble variant of the cytokine presents with prolonged and excessive activation of TNFR1, resulting in cell death and long-term neurological impairments. Therapeutic interventions for neurodegenerative diseases have targeted TNF to limit the onset of neuroinflammation. First-generation therapeutics have been demonstrated to inhibit membrane-bound TNF to TNFR2 receptor binding, resulting in severe side effects such as infections and cancer. As such, second-generation drugs, including XPro1595, have been developed to selectively inhibit soluble TNF and impede the effects of TNFR1 while still allowing for TNFR2 activation. Early results in murine TBI models demonstrate reduced glial reactivity by 50%, reduced dendritic degeneration by 30%, increased plasticity by 15%, and improved functional outcomes by 20% post-TBI. This scoping review of TNF receptors in various neurodegenerative diseases seeks to evaluate current and future therapeutic strategies as well as highlight potential strategies to eliminate confounding variables present in the current literature.

Triple-negative breast cancer (TNBC) is an aggressive and highly metastatic type of tumor. TNBC is often enriched in tumor-infiltrating neutrophils (TINs), which support cancer growth in part by counteracting tumor-infiltrating lymphocytes (TILs). Prior studies identified the enhancer of zeste homolog 2 (EZH2) as a pro-tumor methyltransferase in primary and metastatic TNBC. We hypothesized that EZH2 inhibition in TNBC cells per se would exert anti-tumor activity by altering the tumor immune microenvironment. To test this hypothesis, we used CRISPR to generate EZH2-knockout (KO) and overexpressing lines from parent (wild-type -WT) 4T1 cells, an established murine TNBC model. In vitro, EZH2 KO and OE cells showed little change in replicative capacity and invasiveness, but marked changes in surface marker profile and cytokine/chemokine secretion compared to WT cells. On in vivo injection, EZH2 KO cells showed significantly reduced primary tumor growth and a 10-fold decrease in lung metastasis compared to WT cells, while EZH2 OE cells were unchanged. Compared to WT tumors, TIN:TIL ratios were greatly reduced in EZH2 KO tumors but unchanged in EZH2 OE tumors. Our findings show a tumor-intrinsic role of EZH2 in the 4T1 TNBC model in regulating TIN/TIL poise, primary tumor progression and lung metastasis in vivo.

Stem cell-based regeneration strategies have shown therapeutic efficacy in various fields of regenerative medicine. These include bone healing after bone augmentation, often complicated by pain, that is managed by using non-steroidal anti-inflammatory drugs (NSAIDSs). Information is limited about how NSAIDSs affect the therapeutic potential of stem cells. Therefore, we investigated the effects of ibuprofen and diclofenac in low and high therapeutic doses on the properties of human mesenchymal stromal cells isolated from the dental pulp (DPSCs) and cultured in vitro. Ibuprofen and diclofenac significantly reduced the viability of DPSCs, while the expression of mesenchymal stem cell surface markers was unaffected. Both ibuprofen and diclofenac treatment significantly upregulated the expression of HGF, while the expression of VEGFA remained unchanged. Ibuprofen significantly altered the expression of several apoptosis-related genes, including upregulation of CASP9 and BCL2, with decreased CASP3 expression. BAK, CASP3, CASP9, and BCL2 expressions were significantly increased in the diclofenac-treated DPSCs, while no difference was demonstrated in BAX expression. Our results suggest that concomitant use of the NSAIDSs ibuprofen or diclofenac with stem cell therapy may negatively impact cell viability and alter the expression of apoptosis-related genes, which can affect the efficacy of stem cell therapy.

Diabetes mellitus (DM) is a metabolic disorder characterized by the deficiency of insulin production and is one of the concerning health problems worldwide, especially in developing countries. Considering the systemic toxicity associated with current antidiabetic medications and their limited efficacy, there is an urgent need to discover new plant-based natural antidiabetics. Since time immemorial, medicinal plants have played an important role in the management of health disorders. In recent years, herbal medicine has experienced exponential growth in popularity worldwide, owing to its natural origin and fewer side effects, appealing to both developing and developed nations. Ecuador has a rich cultural history in ethnobotany that plays a crucial role in their people's lives. Several Ecuadorian medicinal plants have hypoglycemic or an-ti-hyperglycemic properties that are rich with bioactive phytochemicals. These medicinal plants were extensively used in traditional medicine preparation in Ecuador for many decades to treat diabetes because of their cost-effectiveness, available traditional knowledge, and low toxicity. Many Ecuadorian medicinal plants are reported to have antidiabetic properties that reduce blood sugar levels, and oxidative stress, regulate intestinal function, improve insulin resistance, inhibit α-amylase and α-glucosidase, lower gluconeogenic enzymes, stimulate glucose uptake mechanisms, and play an important role in glucose and lipid metabolism, yet there is a substantial lack of integrated approach between the existing ethnomedicinal practice and pharmacological research. Therefore, this review aims to discuss and explore the traditional medicinal plants used in Ecuador for treating DM and their bioactive phytochemicals, which are mainly responsible for their anti-diabetic properties.

Anti-interferon (IFN)-γ autoantibodies are linked to varicella-zoster virus (VZV) infection. Given the elevated risks of herpes zoster (HZ) in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKi), we aimed to examine the relationship between anti-IFN-γ autoantibodies with HZ development in JAKi-treated patients. In twenty-four RA patients with new-onset HZ and forty-two without HZ, serum titers of anti-IFN-γ autoantibodies, plasma levels of IFN-γ, monocyte chemoattractant protein-1 (MCP-1), and IFN-γ inducible protein-10 (IP-10) were measured by ELISA. Significantly lower MCP-1 levels were observed in patients with HZ compared to those without (median, 98.21pg/ml, interquartile range (IQR) 77.63-150.30pg/ml versus 142.3pg/ml, IQR 106.7-175.6pg/ml, p<0.05). There was no significant difference in anti-IFN-γ titers, IFN-γ levels, or IP-10 levels between patients with and without HZ. Three of 24 patients with HZ had severe HZ with multi-dermatomal involvement. Anti-IFN-γ titers were significantly higher in patients with severe HZ than in those with non-severe HZ (median 24.8ng/ml, IQR 21.0-38.2ng/ml versus 10.5ng/ml, IQR 9.9-15.0ng/ml, p<0.005). In conclusion, patients with HZ had significantly lower MCP-1 levels than those without HZ, and patients with severe HZ had significantly higher titers of anti-IFN-γ than those with non-severe HZ. Given small sample size, our results need further validation in future studies.

Hyperplastic nodules (HNs) are benign polypoid lesions of the colorectal mucosa reportedly caused by hyperplasia of the crypt epithelial cells. They differ from hyperplastic polyps because the crypts do not have histologically serrated changes. HNs often occur in the rectal mucosa and tend to be multifocal. We have proposed a new colitis nucleomigrans (CN) concept as the third type of microscopic colitis. Our histopathological criteria of CN include: i) chained nuclear migration to the middle part of the surface-lining columnar epithelium, ii) apoptotic nuclear debris scattered in the eosinophilic cytoplasm underneath the nuclei, and iii) mild to moderate chronic inflammation in the lamina propria. Immunostaining for cleaved-caspase 3 revealed apoptotic bodies. In this study, we report that most HN lesions share the histological features with CN, representing polypoid CN. We evaluated 108 lesions of HN in total, and 94 (87%) were reclassified as polypoid CN. In the polypoid CN, the lamina propria mucosae were uniformly edematous, suggesting that accelerated apoptosis of the mucosal surface epithelium may cause osmotic dysregulation to form localized mucosal elevations.

As a key mediator of chronic pain, neurotrophin nerve growth factor (NGF) binds to two neurotrophin receptors: p75 neurotrophin receptor (p75NTR) and tyrosine kinase receptor A (TrkA). The formation of the p75NTR-NGF-TrkA complex is implicated in the potentiation of chronic pain signals, making it an attractive target for therapeutic explorations. NGF analogues and monoclonal antibodies (mAbs) targeting NGF represent two distinct approaches in modulating the intricate signaling pathways involved in pain transduction mediated by the p75NTR-NGF-TrkA complex. While NGF analogues offer the advantage of tailored design to fine-tune neurotrophic responses, monoclonal antibodies provide a more systemic and comprehensive blockade of NGF, inhibiting its interactions with both p75NTR and TrkA receptors. However, the use of mAbs may pose challenges related to potential side effects and interference with the physiological functions of NGF. As a result, balancing the benefits and drawbacks of the two approaches is critical for advancing therapeutic strategies towards the alleviation of p75NTR-NGF-TrkA-mediated pain. In this study, therefore, a novel structural and biophysical approach was employed for the design of NGF analogues to suppress p75NTR-NGF-TrkA-related chronic pain signaling. Employing high-throughput structural modeling and biophysics-based intermolecular binding affinity calculations, this article for the first time puts forward a set of NGF analogues, including in particular NGF analogues with four site-specific mutations, for whose dimerizations the K d at 37 ^◦C were reduced by three orders of magnitude (from 10^-9 M to 10^-6 M) compared to the K d at 37 ^◦C for the dimerization of native NGFs. Overall, the integration of structural and biophysical perspectives enhances our understanding of the rational design of NGF analogues as promising candidates for the development of NGF-targeted analgesic therapies, which balances the benefits and drawbacks of anti-NGF antibodies and NGF analogues for advancing therapeutic strategies towards the alleviation of p75NTR-NGF-TrkA-mediated pain.

Berberis vulgaris L. (Berberidaceae) is a shrub that has been widely used in European folk medicine as an anti-inflammatory and antimicrobial agent. The purpose of our study was to elucidate the mechanisms of antiproliferative action of the plant’s methanolic root extract (BVR) against colon cancer cells. Cytotoxicity and pro-apoptotic activity were determined in human colon adenocarcinoma cell lines (LS180 and HT-29) and control colon epithelial CCD841 CoN cells. According to the MTT assay, after 48 h of cell exposure, the IC50 values were as follows: 4.3; 46.1 and 50.2 µg/mL for LS180, HT-29, and CCD841 CoN cells, respectively, showing the greater sensitivity of cancer cells to BVR. The Cell Death Detection ELISAPLUS kit demonstrated that BVR induced programmed cell death only against HT-29 cells. RT-qPCR with relative quantification method showed significant changes in the expression of genes related to apoptosis in both colon cancer cell lines. The genes BCL2L1 (126.84-366.66%), BCL2L2 (277.08-330.12%), CASP3 (180.36-261.36%) and CASP9 (158.08-213.46%) had significantly elevated expression, while BCL2 (23.08-52.06%) had reduced expression. Furthermore, in a panel of antioxidant tests, BVR showed positive effects (63.93±0.01, 122.92±0.01, and 220.29±0.02 mg Trolox equivalents (TE)/g in the DPPH•, ABTS•+ and ORAC assays, respectively). In the lipoxygenase (LOX) inhibition test, BVR revealed 62,60±0.87% of enzyme inhibition. The chemical composition of BVR was determined using UHPLC-UV-CAD-MS/MS analysis and confirmed the presence of several known alkaloids, including berberine, as well as other alkaloids and two derivatives of hydroxycinnamic acid (ferulic and sinapic acid hexosides). This is the first such extensive assessment of the biological activity of BVR. The results are very promising and encourage for the use of BVR as a comprehensive chemopreventive agent (anti-inflammatory, antioxidant, and pro-apoptotic) in colorectal cancer.

Abstract Background: Periodontitis is associated with systemic chronic inflammatory diseases. There is limited evidence on the influence of anti-cytokine therapies on the periodontal condition and microbiome in the tooth pocket of such patients, so the aim of this study was to elucidate this issue. Methods: In this observational trial, the periodontal status and the gingival crevicular fluid of 13 patients with different chronic inflammatory diseases were obtained before initiation of anti-cytokine treatment and 14 weeks after. Gingival crevicular fluid was collected for 16S rRNA gene sequencing from a clinically healthy tooth and the deepest measured pocket. Results: In participants with advanced attachment loss at baseline, the clinical attachment level significantly decreased from 2.9 (2.3-3.4) to 2.4 (1.3-3.0) mm (p = 0.04), and the bleeding- on-probing index dropped from 19.4 (10.0-21.0) to 7.3 (6.9-9.9) mm (p = 0.02) without any further periodontal treatment. Shannon’s diversity index significantly increased in the deepest pockets of patients (p = 0.039). Conclusion: The data showed alterations in diversity of the subgingival microbiome and improvement of periodontal parameters over the course of the study, implying a shift towards a healthier condition after starting anti-cytokine therapy. Additional investigations are needed to analyze whether the administration of selective biologicals can improve periodontal conditions in patients with or without chronic inflammatory diseases.

A large core size and bending resistance are very important properties of mid-infrared energy transfer fibers, but large core sizes usually lead to a deterioration of bending properties. A negative-curvature nested node-free anti-resonant hollow-core fiber (AR-HCF) based on quartz is proposed. It was made by adding a nested layer to a previous AR-HCF design to provide an additional anti-resonance region while keeping the gap between adjacent tubes strictly correlated to the core diameter to produce a node-free structure. These features improve the fiber’s bending resistance while achieving a larger core diameter. The simulation results show that the radial air-glass anti-resonant layer is increased by the introduction of the nested anti-resonant tube, and the weak interference overlap between the fiber core and the cladding mode is reduced, so the fiber core’s limiting loss and the sensitivity to bending are effectively reduced. When the capillary wall thickness t of the fiber is 0.71 μm, the core diameter D is 70 μm, the ratio of the inner diameter of the cladding capillary to the core diameter d/D is 0.62, and the diameter of the nested tube is d0=29 μm, the fiber has a lower limiting loss at the wavelength of 2.79 μm, and the limiting loss is 3.28×10-4 dB/m. At the same time, the optimized structure also has good bending resistance. When the bending radius is 30 mm, the bending loss is only 4.72×10-2 dB/m. To our knowledge, this is the first research to achieve an anti-bending low-loss micro-structure hollow fiber with a bending radius of less than 30 mm in the 2.79 μm band. An anti-bending low-loss anti-resonant hollow-core fiber with this structure constitutes a reliable choice for the light guiding system of a 2.79 μm band erbium laser therapy instrument.

In all mammals, the circulating pool of MLT is synthesized in the pineal gland, during the night darkness hours. Its main function is that of synchronizing the organism in the photoperiod. In contrast, extra-pineal MLT is synthesized in peripheral organs, does not follow any circadian rhythm nor circulates and plays a detoxifying and cytoprotective action. Circulating MLT may stimulate both innate and acquired immune responses by its circadian action and by activating high affinity receptors on immunocompetent cells. Extra-pineal MLT may have anti-oxidant and anti-inflammatory effects dampening the innate immune response. These two seemingly divergent roles may be considered as two faces of the same coin. In fact, the integration of both circulating and extra-pineal MLT functions might generate a balanced and effective immune response against microbial pathogens. The studies described in this review investigated the effect of exogenous MLT in various models of infectious diseases using extremely different doses and treatment schedules. None of them evaluated the possibility to integrate the non-circadian anti-inflammatory effect with the circadian immunoenhancing action of MLT. As a consequence, in spite that most studies agree that MLT has a beneficial effect against infections, it seems difficult to draw any definite conclusion about its possible therapeutic use.

Background: Amyotrophic lateral sclerosis (ALS) is an incurable disease. There are no defined valid biomarkers for evaluating therapeutic outcomes of this disease. Numerous approaches have been made to meet this impact. Stem cells, one of these approaches, that might give various hopeful results that can be interpreted as a treatment for ALS This study aims to evaluate Mesenchymal Stem Cell (MSC) therapy as a promising novel treatment modality by estimating some parameters, such as immunological and biochemical factors. Methods: This study course involved 15 confirmed patients with ALS and was designed as an open-label, one-arm retrospective study to evaluate potential diagnostic biomarkers of repeated infusions of autologous bone marrow-derived mesenchymal stem cells (BM-MSC) administered at a dose of 1×106cells/kg BW with 1-month interval, in equal amounts in both intravenous (IV) and intrathecal (IT) simultaneously, by various biochemical and immunological parameters were evaluated during the three-month follow-up period. Results: Our study indicated that in the case of Immunological biomarkers ,Tumor Necrosis Factor-alpha (TNF-α) levels in the Cerebrospinal fluid (CSF) showed a significant decrease at month three after transplantation compared to levels at month zero, and the P-value was (P<0.01). No statistically significant changes were observed for other immunological and biochemical parameters and P-value (P>0.05). Conclusions: These results can indicate the benefit of stem cell transfusion in patients with ALS and suggest some diagnostic biomarkers. Several studies are required to approve these results.

CD44 is a type I transmembrane glycoprotein, which is associated with poor prognosis in various solid tumors. Since CD44 plays critical roles in tumor development by regulating cell adhesion, survival, proliferation, and stemness, it has been considered a target for tumor therapy. Anti-CD44 monoclonal antibodies (mAbs) have been developed and applied to antibody-drug conjugates and chimeric antigen receptor-T cell therapy. We previously developed anti‐pan-CD44 mAbs, C₄₄Mab-5 and C₄₄Mab-46, which can recognize both CD44 standard (CD44s) and variant isoforms. In the present study, a defucosylated mouse IgG_2a version of the anti-pan-CD44 mAbs (5-mG_2a-f and C₄₄Mab-46-mG_2a-f) was generated to evaluate the antitumor activities against CD44-positive cells. Both 5-mG_2a-f and C₄₄Mab-46-mG_2a-f recognized CD44s-overexpressed CHO-K1 (CHO/CD44s) cells and esophageal tumor cell line (KYSE770) in flow cytometry. Furthermore, both 5-mG_2a-f and C₄₄Mab-46-mG_2a-f could activate effector cells in the presence of CHO/CD44s cells and exhibited the complement‐dependent cytotoxicity against both CHO/CD44s and KYSE770 cells. Furthermore, the administration of 5-mG_2a-f and C₄₄Mab-46-mG_2a-f significantly suppressed CHO/CD44s and KYSE770 xenograft tumor development compared with the control defucosylated mouse IgG_2a. These results indicate that 5-mG_2a-f and C₄₄Mab-46-mG_2a-f could exert antitumor activities against CD44-positive cancers and could be a promising therapeutic regimen for tumors.

To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This amazing feat is accomplished through synchronised phosphate transport by myriads of ciliated cells lining the renal proximal tubules. These respond in real time to changes in the phosphate and composition of the renal filtrate, and to hormonal instructions. How they do this has stimulated decades of research. New analytical techniques, coupled with incredible advances in computer technology, have opened new avenues for investigation at a sub-cellular level. There has been a surge of research into different aspects of the process. These have verified long held beliefs and are also dramatically extending our vision of the intense, integrated, intracellular activity which mediates phosphate absorption. Already, some have indicated new approaches for pharmacological intervention to regulate phosphate in common conditions, including chronic renal failure and osteoporosis, as well as rare inherited biochemical disorders. It is a rapidly evolving field. The aim here is to provide an overview of our current knowledge, to show where it is leading, and where there are uncertainties. Hopefully this will raise questions and stimulate new ideas for further research.

Understanding clinical significance of variants of unknown significance (VUS) reported in next-generation sequencing (NGS) has become essential in cancer treatment. Our study examined six widely used in silico tools: PolyPhen-2, Align-GVGD, MutationTaster2, CADD, REVEL, and Chat-GPT. We utilized a dataset of gene variants known to potentially affect immune therapy. No single tool could comprehensively determine mutation variant pathogenicity. MutationTaster2021 showed the highest overall accuracy and MCC among the tools. Notably, REVEL and Chat-GPT exhibited 100% specificity, suggesting their proficiency in accurately identifying pathogenic variants and minimizing false positives. In contrast, CADD displayed optimal sensitivity, making it suitable for effectively ruling out benign variants.

Antler is the fastest growing tissue. Because is based on proto-oncogenes, to avoid the risk of cancer, antlers evolved strong anticancer mechanisms, and thus its extract (DVA) is effective also against the few human tumours studied so far. We assessed whether DVA is a general anticancer compound testing direct effects in cells of different tumours: glioblastoma (GBM), colorectal and breast cancer, and leukaemia. DVA reduced viability of tumour but not healthy cells. Mobility decreased at least at the longest test (72 h). Intraperitoneal/oral 200 mg DVA/kg administration in GBM xenograft mice for 28 d reduced tumour weight 66.3% and 61.4% respectively, and also spleen weight. In addition, tumours treated with DVA showed symptoms of liquefactive necrosis. Serum cytokines showed DVA up-regulated factors related with tumour fighting and down-regulated those related with inducing immune tolerance to the tumour. DVA shows general anticancer effects in the lines tested and, in GBM mice, also strong indirect effects apparently mediated by the immune system.

With the rapid development of tumor immunotherapy, nanoparticle vaccines have attracted much attention as a potential therapeutic strategy. The potential role of the mannose-modified lipid calcium phosphate nanoparticle vaccine in enhancing the anti-tumor immune response was investigated. The aim of this study was to investigate the effect of mannose modification on the immune response of nanoparticles in regulating the tumor microenvironment through systematic review and analysis and to explore its potential clinical application in tumor therapy. Currently, despite the potential advantages of nanoparticle vaccines in immunotherapy, achieving an effective immune response in the tumor microenvironment remains a challenge. Tumor immune escape and overexpression of immunosuppressive factors limit its clinical application. Therefore, this study will explore how to intervene in the immunosuppressive mechanism in the tumor microenvironment through mannose-modified lipid calcium phosphate nanoparticle vaccines so as to improve the immunotherapy effect of tumor patients and provide new ideas and strategies for the field of tumor therapy.

This study addresses the challenge of treating skin cancer effectively, especially in visible areas like the face, where traditional methods may be undesirable. Current options, including surgery and radiation therapy, have limitations such as complexity, expense, and imprecise dose delivery. The proposed solution involves additively manufacturing personalized patches using diagnostic imaging data, offering a targeted and controlled dose of beta-emitting isotopes like Y-90. The patches, tailored to the tumor's shape and depth, aim to minimize damage to healthy tissues and structures. Through 3D printing technology we demonstrated the feasibility of creating individualized applicators filled with radioisotopes, that have the potential to deliver therapeutic doses while ensuring patient comfort and affordability. This innovative approach, based on radiation delivery simulations, offers a promising future alternative to conventional radiation therapy methods. Clinical trials are required to validate its efficacy and safety, but the potential for reduced radiation exposure and enhanced treatment precision positions this personalized and targeted therapy as a valuable advancement in skin cancer treatment.

Over the last several years, large-scale cancer genomics studies involving multi region, multi-sample sequencing indicate that most or at least many cancer patients may have one or more “clonal" mutations in their tumors. Clonal mutations are those that are present in all of a patient’s cancer cells. They can be identified via multiregion, multisample biopsies - or circulating tumor cells/cell-free DNA. Achilles Therapeutics is currently the only company targeting patient-specific, clonal mutations. They have opted to utilize an immunotherapy approach. However, I recently devised another approach for exploiting clonal mutations called “Oncolytic Vector Replication Contingent on Omnipresent Mutation Engagement” (OVERCOME). It is based on the identification of patient-specific, clonal mutations and targeting them using a bioengineered facultative intracellular bacterium. It would be initially non-replicating, but transiently regain the ability to replicate (and also transiently become hyper-virulent) upon mutation detection via molecular switches.

Curcumin, as the main active component of Turmeric (Curcuma Longa), has been demonstrated with various bioactivities. However, its potential therapeutic applications are hindered by challenges such as poor solubility and bioavailability, rapid metabolism, and pan-assay interference properties. Recent advancements have aimed to overcome these limitations by developing novel curcumin analogues and modifications. This brief review critically assesses recent studies on synthesising different curcumin analogues, including metal complexes, nano particulates, and other curcumin derivatives, focused on the antioxidant, anti-inflammatory, and anticancer effects of curcumin and its modified analogues. Exploring innovative curcumin derivatives offers promising strategies to address the challenges associated with its bioavailability and efficacy and valuable insights for future research directions.

Nitraria tangutorum Bobrov is a berry shrub with white flowers and red fruits, which grows in the deserts in the Tibetan Plateau, Mongolia, and western China. Its fruit N. tangutorum fruit (NTF) contains various bioactive compounds, with anti-fatigue, anti-inflammatory, and neuroprotective functions. However, the high saccharide content of NTF makes it unsuitable for diabetic patients. In this study, we fermented NTF to obtain N. tangutorum fermented juice (NTJ), and N. tangutorum fermented residue (NTR), which are suitable for diabetics to consume. We characterized the bioactive compounds in NTF, NTR, and NTJ, and found that fermentation increased the diversity of bioactive compounds, and greatly reduced sucrose, glucose, and fructose content while generating trehalose, which has the potential to manage blood glucose levels. Further, NTJ displays anti-diabetic potential due to various compounds anti-diabetic properties. This study provides a basis for further clinical research on NTJ's anti-diabetic function in humans.

Recently intraductal carcinoma of the prostate (IDCP) has attracted increasing interest owing to its unfavorable prognoses. To effectively identify the IDCP-specific gene expression profile, we took a novel approach of characterizing a typical IDCP case using spatial gene expression analysis. A formalin-fixed, paraffin-embedded sample was subjected to Visium CytAssist Spatial Gene Expression analysis. IDCP within invasive prostate cancer sites was recognized as a distinct cluster separate from other invasive cancer clusters. Highly expressed genes defining the IDCP cluster, such as MUC6, MYO16, NPY, and KLK12, reflected the aggressive nature of high-grade prostate cancer. IDCP sites also showed increased hypoxia markers HIF1A, BNIP3L, PDK1, and POGLUT1; decreased fibroblast markers COL1A2, DCN, and LUM; and decreased immune cell markers CCR5 and FCGR3A. Overall, these findings indicate that the hypoxic tumor microenvironment and reduced accessibility to immune cells, which reflect the pathological characteristics of IDCP, may influence the aggressiveness of high-grade prostate cancer.

The review explores the therapeutic potential of mangrove plants as sources of bioactive compounds, particularly focusing on their anti-inflammatory properties. Mangroves, found in tropical and sub-tropical tidal coasts, exhibit unique ecological and biological activities. The review compiles and examines 136 research findings published between 1982 and 2018, with 41 studies specifically addressing the anti-inflammatory properties of mangroves in Indian coastal regions, including the Andaman and Nicobar Islands. It summarizes the chemical structures, molecular weights, formulas, solvents, and biological activities of these mangroves, as reported by various researchers over time. The data underscore the significant potential of tropical Indian mangroves in anti-inflammatory applications. However, a notable research gap exists regarding the extraction of bioactive compounds from mangrove species in the Andaman and Nicobar Islands compared to other regions such as Gujarat, Maharashtra, Goa, Karnataka, Kerala, Tamil Nadu, Andhra Pradesh, Odisha, West Bengal, and Puducherry. Overall, the compilation provides valuable insights into mangrove-based studies for drug discovery research, emphasizing the need for further exploration and exploitation of these natural resources.

Stallion mules have been used as working equids in several countries. Aggressiveness, under the influence of testosterone, resulted in the necessity for surgical castration before work training. The gonadotropin-releasing hormone (GnRH) vaccine may be an alternative method for immunocastration in mules. The objectives were to evaluate the effect of GnRH vaccine on anti-GnRH antibody production, serum testosterone level, clinical adverse effects, and behavior toward human manipulation. Twenty-five mules were separated into 3 groups: Control-intact, Control-castrated, and Treatment. Treatment was further divided into subgroups according to condition (intact or unilateral cryptorchid) and age. Treatment received 195 µg GnRH vaccine intramuscularly at week 0, 4, and 8. Anti-GnRH antibody increased at week 6 and 10, then gradually decreased to baseline at week 22. Treatment-intact-young had the highest anti-GnRH antibody, resulting in lower serum testosterone levels during week 2-6 and 12-16 compared to Control-intact. Subcutaneous edema adjacent to the injection site was detected only in Treatment-intact after booster vaccination. During week 6-22, the behavioral scores of Treatment significantly changed toward at ease with human contact compared to a score before vaccination. In conclusion, mules responded to GnRH vaccine, which could temporarily suppress testosterone for up to 16 weeks.

Glioblastomas (GBMs) are aggressive and invasive cancers of the brain, associated with high rates of tumor recurrence and poor patient outcomes despite initial treatment. Targeting cell migration is therefore of interest in highly invasive cancers such as GBMs, to prevent tumor dissemination and regrowth. One current aim of GBM research focusses on assessing anti-migratory properties of novel or repurposed inhibitors, including plant-based drugs which display anti-cancer properties. We investigated the potential anti-migratory activity of plant-based products with known cytotoxic effects in cancers, using a range of two-dimensional (2D) and three-dimensional (3D) migration and invasion assays as well as immunofluorescence microscopy to determine specific anti-migratory and phenotypic effects of three plant-derived compounds, Turmeric, Indigo and Magnolia bark, on established glioma cell lines. Migrastatic activity was observed in all three drugs, with Turmeric exerting the most inhibitory effect on GBM cell migration into scratches and from the spheroid edge at all timepoints investigated (p < 0.001). We also observed novel cytoskeletal phenotypes affecting actin and focal adhesion dynamics. By determining the migrastatic activity of Turmeric, Indigo and Magnolia on GBM cell migration, we demonstrate a potential role for Turmeric as a novel GBM anti-migratory therapeutic, in combination with the current standard of care, to prevent tumor recurrence and promote patient survival.

Ovarian tumors in mares are not common in comparison to other neoplasms and are divided into three categories: gonadal stromal tumors, coelomic epithelium surface tumors, and germinative cell tumors [12]. Some ovarian neo-plasms histologically show a mixture of multiple cell types in the same tumor, such as fibrothecoma, therefore the dif-ferentiation between fibroma and thecoma is often difficult [1]. According to World Health Organization, fibrothecoma is classified as sex cords stromal tumor (pure stromal tumor) [13]. Neoplasms, such as fibrothecoma have a very scarce morphology, clinical signs, ultrasonographic view and endocrine profile. To diagnose this type of tumor, a broad clini-cal examination is needed, but histopathology remains the most accurate. Herein, we report a case of incidentally found ovarian fibrothecoma during diagnostic laparotomy in 6-year-old KWPN mare which was presented to the clinic with colic symptoms. After unilateral ovariectomy, the altered right ovary, based on histopathological features was diag-nosed as fibrothecoma.

Inflammation is a cause of number of disorders. Many anti-inflammatory drugs are available to cure and prevent inflammation and its related disorders. Some of the drugs are from plant and animal origin. Among animals snake venom is also utilized as treatment option of certain disorders. In the current study the venom of N. oxiana from Northern areas of Pakistan is assayed to determine its anti-inflammatory activity. The Naja oxiana is also called central Asian cobra is endemic to Central Asia. Naja oxiana belong to family Elapidae and it is highly venomous snake. The venom has many enzymatic proteins as well as nonenzymatic proteins that is neurotoxins. The venom is lethal having very high mortality rate and the death may occur due to respiratory failure in 45 minutes to 24 hrs depending upon the nature and amount of venom. As the venom is highly toxic so initially after venom milking its protein estimation was done and toxicity profile and LD50 was determined to find out its therapeutic dose at which anti-inflammatory activity was observed. The toxicity and anti-inflammatory activity was determined on mice model. Inflammation was induced by carrageenan induced peritonitis method. The inflammatory markers ROS, TNF-α and IL-β were determined by ELIZA in peritoneal fluid. The LD50 of crude venom, fraction 1 and fraction 2 was found as 34 µg/kg, 7.4 µg/kg and 416 µg/kg respectively. Anti-inflammatory activity crude venom, fraction 1 and fraction 2 was found at dose 19 µg/kg, 1.8 µg/kg and 267 µg/kg respectively. The levels of inflammatory markers reduced after therapeutic dose administration of venom and its fractions that indicates that it can be utilized as anti-inflammatory agent and so can be effective in various disorders.

We study Einstein's gravity coupled to nonlinear electrodynamics with two parameters in Anti-de Sitter spacetime. Magnetically charged black holes in an extended phase space is investigated. We obtain the mass and metric functions, their asymptotic and corrections to the Reissner--Nordstr\"{o}m metric function when the cosmological constant vanishes. The first law of black hole thermodynamics in extended phase space is formulated and the magnetic potential and the thermodynamic conjugate to the coupling are obtained. We proved the generalized Smarr relation. The heat capacity and the Gibbs free energy are computed and phase transitions are studied. It was shown that the electric field of charged objects at the origin and electrostatic self-energy are finite within the nonlinear electrodynamics proposed.

MicroRNAs, short non-protein coding RNAs, are overexpressed in GCTs. Circulating levels of germ cell tumor (GCT)- associated miRNAs, such as miR-371a-3p, can be utilized as efficient and cost-effective alternatives in diagnosing and managing patients presenting with GCTs. This quality of miRNAs has demonstrated favorable performance characteristics as a reliable blood-based biomarker with high diagnostic accuracy compared to current serum tumor markers (STMs) including α-fetoprotein (AFP), beta human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH). The conventional STMs exhibit limited specificity and sensitivity. Potential clinical implications of miRNAs include impact on de-escalating or intensifying treatment, detecting recurrence at earlier stages, and lessening the necessity of cross-sectional imaging or invasive tissue biopsy for non-teratomatous GCTs. Here we also highlight the outstanding issues that must be addressed prior to clinical implementation. Standards for measuring circulating miRNAs and determining ideal cutoff values are essential for integration into current clinical guidelines.

In our study, we assessed the effects of verbenone, the most widely studied bark beetle aggregation inhibitor, on saproxylic beetles of a Mediterranean pine forest in Tuscany. Verbenone pouches were devised in the laboratory and then applied to Ips sexdentatus pheromone traps so that catches could be compared to those of traps with just the bait. The trial was carried out in spring-summer 2023, collecting insect catches every two weeks. A total of 9440 beetles were collected, belonging to 32 different families and 57 species. About 80% of captures were bark beetles, mainly Orthotomicus erosus. Beetle predators accounted for about 17% of the captures, with a total of 12 species. Some of these predator species had never been studied yet in relation to verbenone effects, like other saproxylic beetles recorded in this study. A significant reduction of captures was recorded for some beetles (e.g. I. sexdentatus and O. erosus), for other species no differences emerged, and in some cases captures increased significantly when verbenone was present in the traps (i.e.. Hylurgus ligniperda, Corticeus pini, Aulonium ruficorne). The diversity of caught saproxylic beetles increased significantly in verbenone traps, highlighting possible implications of the use of verbenone when managing bark beetle outbreaks.

The massive amount of human biological, imaging and clinical data produced by multiple and diverse sources, necessitates integrative modeling approaches able to summarize all this information into answers to specific clinical questions. In this paper, we present a hypermodeling scheme able to combine models of diverse cancer aspects regardless of their underlying method or scale. Describing tissue-scale cancer cell proliferation, biomechanical tumor growth, nutrient transport, genomic-scale aberrant cancer cell metabolism, and cell signaling pathways that regulate the cellular response to therapy, the hypermodel integrates mutation, miRNA expression, imaging, and clinical data. The constituting hypomodels as well as their orchestration and links are described. Two specific cancer types, Wilms tumor (nephroblastoma) and non-small cell lung cancer, are addressed as proof of concept study cases. Personalized simulations over the actual anatomy of a patient have been carried out. The hypermodel has also applied to predict tumor control after radiotherapy and the relationship between tumor proliferative activity and response to neoadjuvant chemotherapy. Our innovative hypermodel holds promise as a digital twin based clinical decision support system and the core of future in silico trial platforms, although additional retrospective adaptation and validation is necessary.

Background: Extracellular Vesicles are pivotal mediators in intercellular communication, facilitating the exchange of biological information among healthy, pathological and tumor cells. Between the diverse subtypes of extracellular vesicles, exosomes have unique properties, clinical and therapeutical applications, even towards cancer. Breast cancer ranks as one of the most prevalent malignancies across the globe. Both the tumor core and its surrounding microenvironment engage in a complex, orchestrated interaction that facilitates the cancer’s growth and spread. Methods: The most valuable and significant PubMed Literature about extracellular vesicles and adipose–derived stem cells exosomes was selected and analyzed in order to report their biological properties and potential applications, in particular on the Triple–Negative Breast Cancer. Results: Adipose–derived stem cells exosomes represent a potential tool to target the tumor core of the Triple–Negative Breast Cancer, its microenvironment and surrounding tissues including metastasis. The authors are developing a supportive Triple–Adipose–derived stem cells Exosomes [T.A.E.] Technology against breast cancer in order to perform a selective preconditioning of the cancer before or while the traditional oncological treatments are running. Conclusion: The possibility to exploit the impact of Adipose–derived stem cells exosomes within the T.A.E. Technology against the Triple–Negative breast cancer is real, highlighting a new era for supportive measures against breast cancer.Keywords: Extracellular vesicles; Exosomes; Adipose–derived stem cells, Tumor microenvironment, Triple–Negative Breast Cancer, T.A.E. Technology.

Marine microalgae are a rich reservoir of natural compounds, including bioactives. Nonetheless, these organisms remain fairly unexplored despite their potential biotechnological applications. Culture collections with diverse taxonomic groups and lifestyles are a good source to unlock this potential and discover new molecules for multiple applications such as the treatment of human pathologies or the production of aquaculture species. In the present work extracts from 33 strains (including 20 dinoflagellates, 4 diatoms and 9 strains from other 7 algal classes), cultivated under identical conditions were examined for antiviral, antibacterial, anti-inflammatory and anti-cancer activities. Among these, antiviral and anti-inflammatory activities were detected in a few strains while antibacterial tests showed positive results in most assays. In turn, most trials did not show any anti-cancer activity. Wide differences were observed between species within the same class, in particular dinoflagellates which were better represented in this study. These preliminary findings pave the way for in-depth characterization of extracts with highest signals in each test, identification of compounds responsible of the biological activities found, and a further screening of the CCVIEO culture collection.

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are significantly changing treatment strategies for human malignant diseases including oral cancer. Cancer cells usually escape from immune system and acquire proliferative capacity and invasive/metastatic potential. We have focused on the two immune checkpoints, PD-1/PD-L1 and CD47/SIRPα in the tumor microenvironment of oral squamous cell carcinoma (OSCC), and performed a retrospective analysis of the expression of seven immune-related factors (PD-L1, PD-1, CD4, CD8, CD47, CD56 and CD11c), and examined their correlation with clinicopathological status. As a result, there were no significant findings relating seven immune-related factors and several clinicopathological statuses. However, the immune-checkpoint related factors (PD-1, PD-L1, CD47) were highly expressed in non-keratinized epithelium-originated tumors when compared to those in keratinized epithelium-originated tumors. It is of interest that immunoediting via immune checkpoint-related factors was facilitated in non-keratinized sites. Several researchers reported that keratinization of oral mucosal epithelia affected the immune response, but our present finding is the first study to show a difference of the tumor immunity in the originating-epithelium of OSCC, keratinized or non-keratinized. Tumor immunity, an immune escape status of OSCC might be different in the originating-epithelium, keratinized or non-keratinized.

Currently, in some domestic and foreign mines, the backfill drilling pipeline experience a rupture phenomenon even when the wear degree is low. This results in a delay in production due to the filling becoming 'sick'. This paper presents, for the first time, the damage mechanism from a mechanical perspective and re-derives the anti-extrusion strength model of the backfill drilling pipeline. We investigate the influence of law on the anti-extrusion strength of pipelines from the perspective of stratum and cement ring. We then verify the theoretical and simulation results through engineering examples. The results demonstrate that the Mises stress criterion is a suitable modification principle for the anti-extrusion strength model of the backfill drilling pipeline. The anti-extrusion strength of the pipeline is related to the elastic modulus and Poisson's ratio of the stratum, and the thickness of the cement ring. It is negatively affected by the depth of the stratum. For hard strata, a cement ring with a smaller elastic modulus is suitable, while for soft stratum, a cement ring with a larger elastic modulus is recommended. When the missing angle of the cement ring is less than 60°, the stress concentration factor increases up to 2.2. The stress unloading capacity of the cement ring ranges from 32.7% to 37.8%, and optimal performance of the cement ring is achieved when it has high strength and low rigidity. The backfill filling pipeline of a copper mine abroad was destroyed due to external extrusion force exceeding its anti-extrusion strength value. The modified pipeline anti-extrusion strength model is 18.2% higher than the casing API strength value. This finding can inform the design of the backfill filling pipeline for China's kilometer-deep wells in the future.

52 years have passed since President Nixon launched the "War on Cancer". The goals outlined by the President were not achieved because cancer treatment applied such as chemotherapy, radiotherapy, and targeted therapy have not fully met expectations. We suggest a new chemotherapeutic strategy: disrupting the communication between cancer cells and their microenvironment by chemical means. Immunological synapses that form between cancer cells and immune or other stromal cells provide an attractive target for this approach. Synapses form ligand-receptor clusters within interface of the interacting cells. Despite their differences, synapses share common properties: intercellular protein clusters; the proximity of these proteins; and their cooperative interaction making a synapse an unified functional unit. Synapses provide the limited space for the focused intercellular exchange of signaling molecules and particles. Therefore, destruction of synapses is expected to cause collapse of various tumor types. Additionally, the clustered arrangement of synapse components offers opportunities to increase treatment safety by reducing the concentration of cell impermeable agents used, to enhance its specificity applying cross-linking reagents, thus restricting modifications of surface-exposed molecules. By attaching a cleavable cell permeable toxic agent to a crosslinker should further enhance a killing potential in treating cancer. The proposed approach promises to be simple, universal, and less expensive than existing cancer therapy methods.

Circulating tumor cells (CTCs) are cells released from the primary tumor and intravasate into the blood or lymphatic vessels, where they are transported to distant sites and act as seeds that initiate cancer metastases. Recent advances in CTC research have shown their relevance as prognostic markers for early and metastatic disease detection, predictive biomarkers for relapse, and response to medical intervention or therapy. The rapidly evolving landscape of CTC biology has opened new avenues for understanding cancer progression, metastasis, and treatment response. Additionally, translating these findings into clinical applications holds promise for improving cancer diagnostics, prognosis, and personalized therapeutic strategies. This review discusses the significance of CTCs in cancer research and their associated challenges. We explore recent developments in the detection and characterization of CTCs and their implications in cancer research and clinical practice.

Inflammation is an important biological response to any tissue injury. The immune system responds to any stimulus, such as irritation, damage, or infection, by releasing pro-inflammatory cytokines. Overproduction of pro-inflammatory cytokines, including TNF-α and IL-1b, can lead to several diseases eg.,, cardiovascular diseases, joint disorders, cancer, and allergies. Emerging science suggests that whole grains may lower the markers of inflammation. Whole grains are a significant source of dietary fibres and phenolic acids that have inverse association with the risk of inflammation. The dietary fibres and phenolic acids composition of whole grains is very distinct over different grains. Whole grains (cereals and pseudo-cereals) are rich in both dietary fibres e.g., arabinoxylan, β-glucan and phenolic acids e.g., hydroxycinnamic acids, hydroxybenzoic acids, which are predominantly present in the bran layer. Although the biological mechanisms underlying widely reported association between whole grains consumption and a lower risk diseases are not fully understood. The modulatory effects of whole grains on inflammation also likely to be influenced by several mechanisms, including the effect of dietary fibres and phenolic acids, while some of these effects are direct, others involve gut microbiota, which transform important bioactive substances into more useful metabolites that moderate inflammatory signaling pathway. Thus, the aim of this review is two folded: first is to discuss the types of dietary fibres and phenolic acids commonly found in cereals and pseudo-cereals, and their health benefits observed in animal and human studies. Second, we review existing literature on the linkage between consumption of whole grains and markers of subclinical inflammation, the role of dietary fibres, phenolic acids, and gut microbiota on the anti-inflammatory activity of whole grains intake. Altogether, scientific data on the ant-inflammatory properties of whole grains are encouraging, further researches are needed to cover the gap between the emerging sciences of whole grains dietary fibres, phenolic acids and inflammation.

(1) Background: TNF inhibitors (TNFi) have revolutionized the treatment of rheumatoid arthritis (RA). However, 30-40 % of RA patients do not respond adequately to those biologics. In addition to neutralizing soluble TNF, TNFi have the ability to bind the transmembrane form of TNF, tmTNF. Importantly, tmTNF can act itself as a receptor that induces a “Reverse Signaling” (RS) in cells. We previously showed that certolizumab, a Fab’ TNFi, activates RS in human primary monocytes, at least in part through the transcription factor NRF2 that is known to regulate the expression of genes involved in anti-inflammatory response and oxidative stress. (2) Methods: Here, we have developed an assay for the prediction of clinical response of RA patients to TNF inhibitors. This assay is based on mRNA quantitation of CD36 activation and of 6 genes induced by NRF2 following tmTNF RS in fresh monocytes. (3) Results: We could predict the response to anti-TNF monoclonal antibodies (mAbs) with 93.3 % accuracy. However, our method was not suitable for the prediction of the response to TNF soluble receptor etanercept. (4) Conclusions: We have developed a rather simple, short-term, test that can be standardized. Predicting the response to TNF mAbs will help physicians offer the best available treatment and provide patients with personalized medicine.

Background: Peripheral Ossifying Fibroma (POF) is a benign gingival tumor generally presenting as a slow-growing mass, usually not ulcerated, and without bleeding. Histopathological exam shows fibrous connective tissue with spots or extensive areas of intralesional calcifications, which can also be detectable on radiograms. Methods and case presentation: We present the case of a 4-year-old male with a retro-incisive swelling of the hard palate, associated with speaking and feeding difficulties. On CT scans, a small intralesional calcification was detected. After conscious sedation, the patient was subjected to diode laser excision (910 nm, 2W, CW, 300 m fiber) with-out post-operative complications. A review was conducted by searching the words “peripheral ossifying fibroma” AND “children” OR “infant” and including manuscripts of the last 15 years. Results: POF is an uncommon lesion of the oral mucosa and may sporadically affect the palatal mucosa in children. Considering its epidemiology and conventional clinical presentation as epu-lis, the pre-operative diagnosis may be relatively difficult. Risk factors could be represented by plaque, calculus, or trauma, all supporting a possible reactive pathogenesis, but a certain etiology is still missing. The main problem of POF is the recurrence rate, which is particularly high (8-20%), thus suggesting that a deep excision is recommended with full extension to the hard tis-sue of bone and to the adjacent periodontal ligament. Diode laser surgery may be recommended for such treatments, especially in pediatric patients, associated with intraoperative conscious se-dation. Data emerging from the relevant literature on POF management in children have been collected and discussed. Conclusions: The authors suggest the use of diode laser for the complete excision of POF, especially in less-compliant patients as children, with a low grade of comorbidi-ties and good outcomes, giving the surgeon a viable alternative to conventional surgery.

The corpus luteum is a temporary endocrine gland formed in the ovary after ovulation, and it plays a critical role in reproductive processes. Tumors rely on the development of an adequate blood supply to ensure the delivery of nutrients and oxygen and the removal of waste products. While angiogenesis occurs in various physiological and pathological contexts, the corpus luteum and tumors share similarities in the signaling pathways that promote angiogenesis. In the corpus luteum and tumors, apoptosis plays a crucial role in controlling cell numbers and ensuring proper tissue development and function. Interestingly, there are similarities in the apoptotic-regulated signaling pathways involved in apoptosis between the corpus luteum and tumors. However, the regulation of apoptosis can differ due to their distinct physiological and pathological characteristics. Thus, we reviewed the biological events of the corpus luteum and tumors in similar microenvironments of angiogenesis and apoptosis for studying novel research methods.

Osteosarcoma (OS) are the most prevalent malignant bone tumors in adolescents and young adults.. OS cells grow in a permissive local microenvironment which modulates their behavior and facilitates all steps in tumor development (e.g., proliferation/quiescence, invasion/migration, drug resistance) and contributes to their intrinsic heterogeneity. The lung parenchyma is the most common metastatic site in OS, and metastatic foci are frequently associated with a poor clinical outcome. Although multiple factors may be responsible for the disease, including genetic mutations (e.g., Rb, p53), the molecular mechanism of development of OS remains unclear and the conventional treatment for OS is still based on a sequential approach that combines chemotherapy and surgery. Also, despite the increase in clinical trials, the survival rates for OS have not improved. Non-specific targeting therapies thus show poor therapeutic effects with side effects at high doses. For these reasons, many efforts have been done to characterize the complex genome of osteosarcoma thanks to the whole exome analysis with the aim to identify predictive biomarkers to give to these patients a better therapeutic option. This review aims to summarize and discuss the main recent advances in OS molecular research for precision medicine.

Erastin (ER) induces cell death by utilizing the process of ferroptosis via generation of reactive oxygen species (ROS). Ferroptosis is characterized by accumulation of ROS within the cell, leading to an iron-dependent oxidative damage-mediated cell death. Here, we have examined ferroptosis-dependent mechanism(s) of cytotoxicity of ER in K-RAS mutant human ovarian tumor OVCAR-8 and NCI/ADR-RES cell lines. We used these cell lines to decipher the mechanisms of ER as NCI/ADR-RES cells express higher activities of SOD, glutathione peroxidase and transferases than OVCAR-8 cells. We found that ER was equally cytotoxic to both cells; ER formed more ROS in OVCAR-8 cells than in NIH/ADR-RES cells. Ferrostatin-1, an inhibitor of ferroptosis, inhibited ER-induced cell death in both cell lines. In contrast, RSL3 (RAS-selective lethal 3), an inducer of ferroptosis, significantly enhanced cell death in both cell lines. ER induced significant lipid peroxidation only in OVCAR-8 cells. We found that RSL3 was more cytotoxic to NCI/ADR-RES cells and significantly enhanced ER-induced lipid peroxidation in both cells, indicating GPX4 was involved in the process of ER-mediated ferroptosis. ER treatment also differentially modulated several ferroptosis related genes (e.g., HMOX1/OH1, and CHAC1) in these cells, indicating ER-induced cell death may be mediated differently in OVCAR-8 and NCI/ADR-RES ovarian cells. Our studies suggest that combinations of ER and RSL3 may contribute significantly to the treatment of ovarian cancers, including those that are resistant to other therapeutic agents due to the presence of P-gp or tumors with Ras mutation in the clinic. ER induced ferroptosis may also be an important treatment modality for resistant tumors expressing MDR1 in the clinic.

The implementation of sentinel lymph node (SLN) biopsy is changing the scenario in the surgical treatment of early-stage cervical cancer and the oncologic safety of replacing bilateral pelvic lymphadenectomy with SLN biopsy is currently under investigation. One of the undisputed values of SLN biopsy is its diagnostic accuracy in detecting low-volume metastases (LVM) via pathologic ultrastaging. In early-stage cervical cancer, the reported incidence of LVM ranges from 4 to 20%. The prognostic impact and the role of adjuvant treatment in patients with LVM is still unclear. Some non-prespecified analyses in prospective studies showed no impact on the oncologic outcomes compared to node-negative disease. However, the heterogeneity of the studies, the differences in the disease stage and the use of adjuvant treatment, and the concomitant pelvic lymphadenectomy (PLND) make any conclusion on this topic hard. Current guidelines suggest considering micrometastasis (MIC) as a node-positive disease, while isolated tumor cells (ITC) as a node-negative disease, with a low level of evidence. This review aims to highlight the unanswered questions about the definition, identification, prognostic and therapeutic role of LVM and underline the present and future challenges we are facing. We hope this review will guide further research, giving robust evidence on LVM and their impact on clinical practice.

Achieving the thermal conductivity required for efficient heat management in semiconductors and other devices requires the integration of thermally conductive ceramic fillers at concentrations of 60 vol% or higher. However, the increased filler content often negatively affects the mechanical properties of the composite matrix, limiting its practical applicability. To address this issue, in this paper, we present a new strategy to reduce the required ceramic filler content: the use of a thermally conductive ceramic composite filler with carbon nanotubes (CNT) grown on aluminum nitride (AlN). We have combined catalyst coating technology with vacuum filtration to ensure that the catalyst is uniformly applied to micrometer-sized AlN particles, followed by efficient and uniform synthesis of CNTs using a water-assisted process in a vertical furnace. By carefully controlling the number of vacuum filtration cycles and the growth time of the CNTs, we demonstrate precise control over the number and length of the CNT layers, thereby adjusting the properties of the composite to the intended specifications. When AlN/CNT hybrid fillers are incorporated into silicone rubber, while maintaining the mechanical properties of rubber, the thermal diffusivity achieved at reduced filler levels exceeds that of composites using AlN-only or simultaneous AlN and CNTs formulations. This demonstrates the critical role of CNTs on AlN surfaces. Our study represents a significant advancement in the design of thermally conductive materials with potential implications for a wide range of applications.

Despite past efforts towards therapeutical innovation, cancer remains a highly incident and lethal disease, with current treatments many times lacking efficiency and leading to severe side-effects. Hence, it is imperative to develop new, more efficient, and safer therapies. Bee venom has proven to have multiple and synergistic bioactivities, including antitumor effects. Nevertheless, some toxic effects have been associated with its administration. To tackle these issues, in this work, bee venom-loaded niosomes were developed, for cancer treatment. The vesicles had a small (150.4 ± 3.7 nm) and homogeneous (PDI of 0.162 ± 0.008) particle size, and revealed good therapeutic efficacy in in vitro gastric, colorectal, breast, lung, and cervical cancer models, with GI50 values between 12.37 ng/mL and 14.72 ng/mL. Additionally, they also revealed substantial anti-inflammatory activity, with an IC50 of 28.98 ng/mL, effects that have been reported to be complementary to direct antitumor activity. Finally, the niosomes' safety was assessed, both in vitro, on skin, liver and kidney cells, and ex vivo, in a HET-CAM assay, and results showed that compound encapsulation increased its safety. Hence, small and homogeneous bee venom-loaded niosomes were successfully developed, with substantial anticancer and anti-inflammatory effects, making them potentially promising primary or adjuvant cancer therapies.

Background: DICER1, cancer predisposition syndrome (CPS), seems to escape timely diagnosis in pediatric patients. Case report 1: A 16-year-old female patient was referred to the endocrinology ward due to a large goiter. Her medical history indicated normal sexual maturation, with menarche occurring at 13.5 years. Over the past 2.5 years, she developed pronounced androgenic symptoms, including a deepened male voice, facial, back and neckline acne, hirsutism, and menstrual irregularities leading to secondary amenorrhoea. A thyroid ultrasound identified a multinodular goiter with cystic-solid lesions containing calcifi-cations. An abdominal ultrasound identified a 5.7x6.9 cm solid mass in the right adnexal region, displacing the uterus to the left. Histopathological examination confirmed a Sertoli-Leydig cell tumor. The patient was subjected to total thyroidectomy. Histopathology revealed benign follicular cell-derived neoplasms. Thyroid follicular nodular disease was diagnosed bilaterally. DNA analysis using NGS, confirmed by the Sanger method, revealed a pathogenic heterozygotic variant c.2953>T [p.Gln985*] in exon 18 of DICER1 gene. Case report 2: A 12-year-old male patient was admitted to the pediatric surgery unit due to a 33 ml goiter. A month prior to admission, the patient discovered a palpable nodule in his neck, accompanied by hoarseness. An ultrasound revealed a multinodular goiter. Molecular analysis revealed a pathogenic heterozygotic variant c.2782C>T [p.Gln928Ter] in exon 17 of DICER1 gene. Subsequently, a total thyroidectomy was performed, and histopathological examination revealed thyroid follicular nodu-lar disease bilaterally. Conclusion: Multinodular goiter, although rare in pediatric population, when accompanied by characteristic ultrasound and histopathological features, and by additional features such as androgen excess, warrants exclusion of DICER1 syndrome.

The role of inflammation in the pathophysiology of acute myocardial infarction (AMI) is well established. Recognizing inflammation's pivotal role in AMI, this manuscript systematically traces historical studies, spanning from early attempts to the present landscape. Several anti-inflammatory trials targeting inflammation in post-AMI have been performed. The review includes key trials, examining their designs, patient demographics, and primary outcomes. Efficacy and challenges are analyzed, shedding light on the translational implications of trial outcomes. The article also discusses emerging trends, ongoing research, and potential future directions in the field. Practical applications and implications for clinical practice are considered, providing a holistic view of the evolving landscape of anti-inflammatory interventions in the context of AMI.

Tumor infiltrating lymphocytes (TILs) are an emerging biomarker predictive of response to immunotherapy across a spectrum of solid organ malignancies. The characterization of TILs in gastric cancer (GC) treated with contemporary, multiagent neoadjuvant chemotherapy (NAC) is understudied. In this retrospective investigation, we analyzed the degree of infiltration, phenotype, and spatial distribution of TILs via immunohistochemistry within resected GC specimens treated with or without NAC at a Western center. We hypothesized that NAC executes immunostimulatory roles evidenced by an increased number of anti-tumor TILs in the tumor microenvironment. We found significantly elevated levels of conventional and memory CD8+ T cells, and total TILs (CD4+, CD8+, Treg, B cells) within chemotherapy-treated tumors compared to chemotherapy-naïve specimens. We also revealed important associations between survival and pathologic response with enhanced TIL infiltration. Taken together, our findings advocate for an immunostimulatory role of chemotherpy and underscore the potential synergistic effect of combining chemotherapy with immunotherapy in resectable gastric cancer.

The development of new and effective antimicrobial compounds is an urgent need with the emergence of resistant bacteria. Natural plant flavonoids are known to be effective molecules but their activity and selectivity have to be increased. Based on previous aurone potency, we designed new aurone derivatives bearing acetamido and amino groups at the position 5 of the A ring and managing various monosubstitutions at the B ring. A series of 31 new aurone derivatives were first evaluated for their antimicrobial activity with five derivatives being the most active (compounds 10, 12, 15, 16, and 20). The evaluation of their cytotoxicity on human cells and of their therapeutic index (TI) showed that compounds 10 and 20 have the highest TI. Finally, screening against a large panel of pathogens confirmed that compounds 10 and 20 possess a large spectrum antimicrobial activity, including on bioweapon BSL3 strains, with MIC values as low as 0.78 µM. These results demonstrate that 5-acetamidoaurones are far more active and safest compared with 5-aminoaurones, and that benzyloxy and isopropyl substitutions at the B ring are the most promising strategy in the exploration of new antimicrobial aurones.

Cancer treatment is a significant focus in medicine owing to the increasing global incidence. Patients with advanced cancers that do not respond to conventional therapies have limited options and an unfavorable prognosis. Consequently, researchers are investigating complementary approaches to conventional treatments. One such approach is alkalization therapy, which aims to neutralize the acidic tumor microenvironment (TME) by increasing its pH level. The acidic TME promotes inflammation, tumor progression, and drug resistance. Alkalization therapy has been demonstrated to be effective for various cancers. In addition, natural products, such as triterpenoids, parthenolides, fulvic acid, Taxus yunnanensis, and apple pectin have the potential to alleviate symptoms, maintain physical fitness, and improve treatment outcomes of cancer patients through their anti-inflammatory, antioxidant, and anticancer properties. In this review, we focus on the effects of alkalization therapy and natural products on cancer. Furthermore, we present a case series of advanced cancer patients who received alkalization therapy and natural products alongside standard treatments, resulting in long-term survival. We posit that alkalization therapy together with the supplementation of natural products may confer benefits to cancer patients by mitigating the side effects of chemotherapy and complementing standard treatments. However, further research is warranted to validate these clinical findings.

Plant-based proteins, like those derived from hemp and rapeseed can significantly contribute to a balanced diet and human daily nutritional requirements by providing essential nutrients such as protein, fiber, vitamins, minerals, and antioxidants. According to numerous recent research papers the consumption of plant-based proteins has been associated with numerous health benefits, including reduced risk of chronic diseases such as heart disease, diabetes, and certain cancers. Plant-based diets are often lower in saturated fat and cholesterol and higher in fiber and phytonutrients, which can support overall health and well-being. Present research investigates the nutritional attributes, functional properties, and potential food applications of hemp and rapeseed protein for a potential use in new food product development, with a certain focus on identifying anti-nutritional factors and bioactive compounds. Through comprehensive analysis, anti-nutritional factors and bioactive compounds were elucidated, shedding light on their impact on protein quality and digestibility. The study also delves into the functional properties of hemp and rapeseed protein, unveiling their versatility in various food applications. Insights from this research contribute to a deeper understanding of the nutritional value and functional potential of hemp and rapeseed protein, paving the way for their further utilization in innovative food products with enhanced nutritional value and notable health benefits.

Hashimoto's thyroiditis (HT) is essentially featured by self-tissue destruction by means of the adaptive immune responses that evade immune regulation. Vitamin D carries out an immunomodulatory role that appears to promote immune tolerance. The aim of this study is to elaborate a narrative review about the relationship between vitamin D status and HT and the role of vitamin D supplementation to reduce HT risk by modulating the immune system. There is an extensive literature confirming that vitamin D levels are significantly lower in HT patients compared to healthy people. On the other hand, after the supplementation with cholecalciferol in patients with HT and vitamin D deficiency, thyroid autoantibody titer decreased significantly, However, there are no conclusive results on the effect of vitamin D supplementation on the thyroid function. The confirmation of the beneficial effects of vitamin D in the prevention and treatment of autoimmune thyroid diseases require additional randomized, double-blind, placebo-controlled trials with longer follow-up.

In patients with primary central nervous system lymphoma (PCNSL), the choice of surgical strategy for histopathologic assessment is still controversial, particularly in terms of preoperative corticosteroid (CS) therapy. To provide further evidence for clinical decision-making, we retrospectively analyzed data from 148 consecutive patients who underwent surgery at our institution. Although patients treated with corticosteroids preoperatively were significantly more likely to require a second or third biopsy (p=0.049), it was only necessary in less than 10% of the cases with preoperative corticosteroid treatment. The choice of surgical procedure did not affect diagnostic accuracy (p&gt;0.05). Preoperative CSF sampling did not provide additional information but was associated with delayed surgery (p=0.02). Surprisingly, diagnostic accuracy was significantly lower when patients were treated with anticoagulation or dual antiplatelet therapy (p=0.015). In conclusion, preoperative CS therapy can challenge the histological diagnosis of PCNSL. At the same time, our data suggest that preoperative CS treatment only presents a relative contraindication for an early surgical intervention. The standard surgical approach is stereotactic biopsy, but other approaches can be individually considered. If a definitive diagnosis cannot be made after the first surgical intervention, the timing of a repeat biopsy after discontinuation of CS remains a case-by-case decision.

Deep learning (DL) algorithms used for DOTATATE PET lesion detection typically require large, well-annotated training datasets. These are difficult to obtain due to low incidence of gastroenteopancreatic neuroendocrine tumors (GEP-NETs), and the high cost of manual annotation. Furthermore, networks trained and tested with data acquired from site specific PET/CT instrumentation, acquisition and processing protocols have reduced performance when tested with offsite data. This lack of generalizability requires even larger, more diverse training datasets. The objective of this study is to investigate the feasibility of improving DL algorithm performance by better matching the background noise in training datasets to higher noise, out-of-domain testing datasets. 68Ga-DOTATATE PET/CT datasets were obtained from two scanners: Scanner1, a state-of-the-art digital PET/CT (GE DMI PET/CT; n=83 subjects), and Scanner2, an older-generation analog PET/CT (GE STE; n=123 subjects). Set1, the data set from Scanner1 was reconstructed with standard clinical parameters (5 minutes; Q.Clear) and list-mode reconstructions (VPFXS 2, 3, 4, and 5-minutes). Set2, data from Scanner2, representing out-of-domain clinical scans, used standard iterative reconstruction (5 minutes; OSEM). Reconstructed datasets were divided into training, validation, and testing datasets in a 60%, 20%, 20% proportion, and a deep neural network was trained with each: Network1 for Scanner1 and Network2 for Scanner2. DL performance (Network1) was tested with out-of-domain test data (Set2). To evaluate the effect of training sample size, we tested DL model performance using a fraction (25%, 50%, and 75%) of Set1 for training. Scanner1, list-mode 2-minute reconstructed data demonstrated the most similar noise level compared that of Set2, resulting in the best performance (F1=0.713). This was not significantly different compared to the highest performance, upper-bound limit using in-domain training for Network2 (F1=0.755; p-value=0.103). Regarding sample size, the F1 score significantly increased from 25% training data (F1=0.478) to 100% training data (F1=0.713; p&lt;0.001). List-mode data from modern PET scanners can be reconstructed to better match the noise properties of older scanners. Using existing data and their associated annotations dramatically reduces the cost and effort in generating these datasets, and significantly improves the performance of existing DL algorithms. List-mode reconstructions can provide an efficient, low-cost method to improve DL algorithm generalizability.

Our goal was to determine the cellular immune response (CIR) among a random sample of the Borriana COVID-19 cohort (Spain) to identify its associated factors and their relationship with infection, reinfection and sequelae. We conducted a nested case-control study using a randomly selected sample of 225 individuals age 18 and older, including 36 individual naïve to SARS-CoV-2 infection, and 189 infected patients. We employed flow cytometry-based immunoassays for intracellular cytokine staining, utilizing Wuhan and BA.2 antigens and chemoluminescence microparticle immunoassay for detection SARS-CoV-2 antibodies. Logistic regression models were used. A total of 215 (95.6%) participants exhibited T-cell response (TCR) to at least one antigen. Positive responses of CD4+ and CD8+ T cells were 89.8% and 85.3% respectively. No difference in CIR was found for naïve and infected patients. Patients who experienced sequelae exhibited higher CIR than those without. A positive correlation was observed between TCR and Anti-Spike IgG levels. Factors positive associated with TCR included A-blood group, number of SARS-CoV-2 vaccine doses received, and Anti-N IgM; factors inversely related were the time elapsed since the last vaccine dose or infection, and B-blood group. These findings contribute valuable insights into the nuance immune landscape shaped by SARS-CoV-2 infection and vaccination.

Abstract Epithelial ovarian carcinoma (EOC) is the fifth-leading cause of cancer-related death in women, largely reflecting early, prediagnosis dissemination of malignant disease to the peritoneum. EOC is poorly responsive to immune check-point inhibitors due to immunologic features including limited tumor mutational burden (TMB), poor infiltration by immune cells and active immunosuppression. Thus, novel strategies are needed to overcome the frequent lack of preexisting immunity in patients with EOC. We developed and tested an autologous dendritic cell (DC)-based vaccine (DCVAC) which has recently been shown to be safe and to significantly improve progression-free survival (PFS) in two independent randomized phase II clinical trials enrolling patients with EOC (SOV01, NCT02107937; SOV02, NCT02107950). In addition, our exploratory data analyses suggest that the clinical benefits of DCVAC were more pronounced in patients with EOC with lower than-median TMB and scant CD8+ T cells infiltration. Thus, DC-based vaccine stands out as a promising clinical tool to jumpstart anticancer immunity in patients with immunologically „cold“ EOC. Our findings underscore the need for personalized immunotherapy and clinical relevance of potential tumor-related biomarkers within immunotherapy field. Additional clinical trials are needed to address these strategies as well as the potential value of TMB and immune infiltrate at baseline as biomarkers to guide the clinical management of EOC.

This study investigated the inhibitory effect of Siegesbeckia orientalis ethanolic extract (SOE) on growth and metastasis of hepatic tumors in C57BL/6JNarl mice, which is the model of tumor-igenesis induced by subcutaneous injection of Hepa1-6 murine hepatoma cells on the back of mice. Feeding 25 mg SOE/kg BW daily for 14 days effectively reduced the hepatoma weight in tu-mor-bearing mice by 59.7%. SOE intervention reduced the expression of anti-apoptotic Bcl-2 gene in tumor tissue by 48.5% and down-regulated the antioxidant system, by reducing the gene ex-pression of catalase (48.0%), glutathione peroxidase (46.3%), and superoxide dismutase (32.0%). In addition, SOE intervention increased the production of ROS by 21.4%, and the gene expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 by 135.3%, 179.3% and 91.7%, respectively, indicating that SOE intervention promoted the acute inflammatory response. Results of H&E staining analysis showed that SOE had the ability to inhibit angiogenesis in tumor tissue. Fur-thermore, SOE treatment inhibited the expression of migration-related genes, such as MMP-2, MMP-7, MMP-9 and β-catenin, and the inhibition rates were 24.8%, 27.4%, 10.4% and 21.9%, respectively. These results imply that SOE had the ability to suppress tumor metastasis. On the other hand, SOE intervention decreased the serum contents of inflammatory cytokines, such as TNF-α, IL-1β and IL-6 by 27.4%, 30.4%, and 30.7%, respectively, indicating that SOE intervention has an anti-inflammatory effect on normal tissues of mice. Since SOE intervention had no signif-icant effect on liver and kidney weights, and no mice died throughout the experiment, it shows that it is safe to feed SOE under this experimental condition. Based on the above results, SOE has a great potential to be used in the treatment of hepatoma.

The advent of deep learning (DL) has revolutionized medical imaging, offering unprecedented avenues for accurate disease classification and diagnosis. DL models have shown remarkable promise for classifying brain tumor from Magnetic Resonance Imaging (MRI) scans. However, despite their impressive performance, the opaque nature of DL models poses challenges in understanding their decision-making processes, particularly crucial in medical contexts where interpretability is essential. This paper explores the intersection of medical image analysis and DL interpretability, aiming to elucidate the decision-making rationale of DL models in brain tumor classification. Leveraging state-of-the-art DL frameworks with transfer learning, we conduct a comprehensive evaluation encompassing both classification accuracy and interpretability. Using state-of-the-art DL frameworks with transfer learning, we conduct a thorough evaluation covering both classification accuracy and interpretability. We employ adaptive path-based techniques to understand the underlying decision-making mechanisms of these models. Grad-CAM and Grad-CAM++ highlight critical image regions where the tumors are located.

Currently, hepatitis B virus (HBV) core antibody (anti-HBc antibody) and HBV core-related antigen (HBcrAg) are widely used as serum markers for diagnosis based on the HBV core region. While anti-HBc is very significant for clinical diagnosis, the clinical significance of quantitative assay of anti-HBc antibody has been reevaluated with improvements in diagnostic performance, including its association with clinical stage and prediction of carcinogenesis and reactivation. In addition, concerning the new HBcrAg, a high-sensitivity assay method has recently been established, and its diagnostic significance, including the prediction of reactivation, is being reevaluated. On the other hand, the quantitative level of anti-HBc antibody expressed in different units among assay systems, complicating the interpretation of the results. However, it is difficult to standardize assay systems as they vary in advantages, and caution is needed in interpreting the assay results. In this review, the clinical usefulness and remaining problems of anti-HBc antibody and HBcrAg were summarized.

A three-arm, randomized, placebo controlled clinical study has been performed to evaluate the effects of a lyophilized pineapple extract titrated in bromelain (Brome-Inf®), and purified bro-melain on pain, swelling, trismus and quality of life (QoL) after the surgical removal of the lower third molars. Moreover, the need for non-steroidal anti-inflammatory drugs (NSAIDs) has also been evaluated and compared with a placebo group. The study included 42 people that required the extraction of a single mandibular third molar under local anesthesia. The patients were ran-domized and distributed to receive Brome-Inf®, purified bromelain or placebo and started the treatment the day of surgery and continued it for the next 7 days. The primary outcome was the requirement of NSAIDs in the three groups. The outcome variables were pain, swelling and trismus, which were measured postoperatively at 1, 3, and 7 days. The differences in the efficacy of the freeze-dried pineapple extract and single-component bromelain were also evaluated. At the end of the study, the assumption of ibuprofen (from days 1-7) was statistically higher in the placebo group (p

The realization of a BRST cohomology of the 4D topological gauge-affine gravity is established in terms of a superconnection formalism. Identification of fields in the quantized theory is occurred directly as usual in terms of superconnection and its supercurvature components with the double covering of the general affine group GA¯(4,R). Then, by means of an appropriate decomposition of the metalinear double-covering group SL¯(5,R) with respect to the general linear double-covering group GL¯(4,R) one can easily obtain the enlargements of the fields while remaining consistent with the BRST algebra. This leads to the descent equations allowing us to build the observables of the theory by means of the BRST algebra constructed using a sa¯(5,R) algebra-valued superconnection. In particular, we discuss the construction of topological invariants with torsion.