Retinoblastoma (Rb) is a rare cancer that nonetheless represents the most common ocular malignancy in children. Rb exists as familiar and sporadic cancer and the increasing incidence of the sporadic one and its pathogenesis is mostly unknown. To date the management of retinoblastoma requires intensive chemotherapy and sometimes invasive surgery in order to preserve vision and quality of life in Rb patients. The discovery of the epigenetic nature of non-hereditable/sporadic Rb led to the development of high-throughput precision investigation strategies for the study of its epigenetic landscape. Here we investigated the effect of the demethylating 5-Aza-2’- deoxycytidine (Decitabine; DAC) agent on preclinical models to assess its possible use as anti-cancer drug in the treatment of Rb patients. We found that DAC treatment induced cell cycle arrest and apoptosis in Weri-Rb-1 cells. We investigated the variation of differential gene expression profile in Rb cells in relation to time of exposure to DAC with respect to controls. Network map analysis evidences 15 hub/driver genes, which share pathways of regulation of TNF-, FAS-, p53-dependent apoptotic signaling and NF-kB pro-survival pathways. Furthermore, a computing expression profile analysis of publicly available datasets of patients’ primary tumors and normal retina cell-derived organoids vs WeriWeri-Rb-1 DEGs depicted the relevancy of these 15 hub genes on retinoblastoma genesis. The antiproliferative effect of DAC treatment on Rb was confirmed in vivo, both in subcutaneous xenograft and orthotopic models also showing the changes the gene methylation status in treated Weri-Rb-1, shedding a new light on the reprogramming antiproliferative dynamics induced by the epigenetic therapy and on the role of this therapeutic approach to spare children sight and life.

Histone deacetylases inhibitors (HDACi) have shown promising therapeutic outcomes in haematological malignancies such as leu-kaemia, multiple myeloma and lymphoma, with dis-appointing results in solid tumours when used as monotherapy. As a result, combination therapies either with radiation or other deoxyribonucleic acid (DNA) damaging agents have been suggested as ideal strategy to improve their efficacy in solid tumours. Numerous in vitro and in vivo studies have demonstrated that HDACi can sensitise malignant cells to both electromagnetic and particle types of radiation by inhibiting DNA damage repair. Although the radiosensitising ability of HDACi has been reported as early as 1990s, the mechanisms of radiosensitisation are yet to be fully understood. This review brings forth the various protocols used to sequence the administration of radiation and HDACi treatments in the different studies. The possible contribution of these various protocols on the ambiguity that surrounds the mechanisms of radiosensitisation is also highlighted.

Menin inhibitors are new and promising agents currently in clinical development that target the HOXA/MEIS1 transcriptional program which is critical for leukemogenesis in histone-lysine N-methyltransferase 2A rearranged (KMT2Ar) and in NPM1-mutated (NPM1mut) acute leukemia. The mechanism of action of this new class of agents is based on the disruption of menin-KMT2A complex (constitute of chromatin remodelling proteins), leading to the differentiation and apoptosis of AML cells expressing KMT2A or mutated NPM1. This new class of drugs has been tested alone, or in combination with synergistic drugs, in phase I and II clinical trials (AUGMENT-01 and 02, KOMET-01 and 07, SAVE, COVALENT trial and others), showing promising results in terms of response rates and safety in heavily pre-treated acute leukemia patients. In this review, we summarise the key findings on menin inhibitors, focusing on the mechanism of action and preliminary clinical data of this emerging and promising class of agents, in particular revumenib and ziftomenib.

Objective: We report a case of acute pancytopenia and liver injury after concomitant administration of low-dose methotrexate (MTX), and high-dose esomeprazole and metamizole. Case summary: A 71-year-old patient with chronic systemic idiopathic erosive arthritis was admitted after a pelvic ring fracture. After hospital admission, she received MTX in addition to esomeprazole and metamizole. Subsequent laboratory tests revealed pancytopenia and elevated liver enzymes. The follow-up clinical examinations were unremarkable, with the exception of sub-febrile temperatures. Further investigations did not detect a definitive etiology. Due to the suspicion of methotrexate-induced hematotoxicity and hepatotoxicity, antagonizing therapy with calcium folinate was administered, after which the blood counts and liver parameters normalized. Discussion: Due to the administration of high-dose metamizole immediately before the administration of low-dose MTX, the pre-existing hematotoxic pharmacodynamic effect of MTX was acutely enhanced by that of metamizole, although folic acid was administered preemptively. In addition, the concomitant administration of high-dose esomeprazole and normal dose torasemide resulted in a pharmacokinetic interaction with MTX by decreasing its renal secretion and elimination, further enhancing the concentration-dependent hematotoxic and hepatotoxic side effects of MTX. Conclusions: The relatively high demand for analgesics in patients with chronic rheumatic diseases already being treated with MTX and proton pump inhibitors necessitates that clinicians consider drug-drug interactions as potential causes of adverse drug reactions after the administration of metamizole or nonsteroidal anti-inflammatory drugs. In this category of patients, it is strongly recommended to switch to analgesics of other classes.

(1) Background: BRCA mutation and homologous recombination deficiency (HRD) are used to administrate PARP inhibitors (PARPi) maintenance therapy. It is known that PARPi efficacy is related to platinum sensitivity and that the latter can be demonstrated from the CA-125 elimination rate constant (KELIM). This study aims to investigate if KELIM can be another tool in the identification of patients that could be benefit from PARPi therapy.; (2) Methods: Retrospective analysis of patients with high-grade serous advanced ovarian cancer that underwent cytoreduction and was further tested for HRD status. The HRD status was tested either by myChoice HRD CDx assay or by RediScore assay. KELIM score was measured in both neoadjuvant and adjuvant settings with the online tool biomarker-kinetics.org.; (3) Results: Thirty-nine patients had available data for estimating both HRD status and KELIM score. When assuming KELIM as a binary index test with the value 1 as the cut-off point, the sensitivity was 0.86, 95% CI (0.64-0.97), and the specificity 0.83, 95% CI (0.59-0.96). On the other hand, when assuming KELIM as a continuous index test, the AUC was 81% and the optimal threshold, using the Youden index, was identified as 1.03 with a sensitivity of 85.7% and a specificity of 83.3%; (4) Conclusions: KELIM score seems to be a new, cheaper and faster tool to identify patients that can benefit from PARPi maintenance therapy.

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.

Heart failure (HF) is a growing issue in developed countries and most patients present with a reduced ejection fraction. This condition significantly impairs quality of life and represents a threat not only for patients, but also for the entire healthcare system due to its high management cost. In the last decade, new medical treatments and devices have been developed to reduce HF hospitalizations and improve prognosis, while reducing the overall mortality rate. Medical therapy does not achieve the same results in all patients and, whenever it fails, technology comes in handy: novel devices for the management of HF have reduced symptoms. They have also improved the treatment of fluid retention and life threatening arrhythmias. The present review article gives to the readers a comprehensive overview of the most recent and important findings that need to be considered in HF with reduced ejection fraction patients. Both novel medical treatments and devices have been presented and discussed.

Lung adenocarcinoma is the most prevalent form of lung cancer, and drug resistance is a significant obstacle in its treatment. This study aimed to investigate the overexpression of long non-coding RNAs (lncRNAs) as a mechanism that promotes intrinsic resistance in tumor cells from the onset of treatment. Drug-tolerant persister cells (DTP) are a subset of cancer cells that survive and proliferate after exposure to therapeutic drugs, making them an essential object of study for cancer treatment. The molecular mechanisms underlying DTP cell survival are not fully understood; however, long non-coding RNAs (lncRNAs) have been proposed to play a crucial role. DTP cells from lung adenocarcinoma cell lines were obtained after a single exposure to tyrosine kinase inhibitor TKIs (erlotinib or osimertinib). After establishing DTPs, RNA sequencing was performed to investigate the differential expression of the lncRNAs. Some lncRNAs and one mRNA were found to be overexpressed in DTP cells. The clinical relevance of lncRNAs was evaluated in a cohort of patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA). RT-qPCR validated the overexpression of lncRNAs and mRNA in residual DTP cells and LUAD biopsies. Knockdown of these lncRNAs increases the sensitivity of DTP cells to therapeutic drugs. This study provides an opportunity to investigate the involvement of lncRNAs in the genetic and epigenetic mechanisms underlying intrinsic resistance. The identified lncRNAs and CD74 mRNA may serve as potential prognostic markers or therapeutic targets to improve the overall survival of patients with lung cancer.

In this study, a simple machine learning-based quantitative structure-activity relationship (QSAR) model was developed to predict the inhibitory potency (pIC50 values) of FLT3 tyrosine kinase inhibitors, pivotal in treating Acute Myeloid Leukemia (AML). Distinctively, our model leverages an extensive and diverse dataset, 14 times larger than those employed in prior studies within this field, enabling an unparalleled scope of compound analysis. This vast dataset, combined with further exploration of molecular descriptors, enabled predictions of extraordinary precision, covering a broader spectrum of FLT3 inhibitors than was previously possible. The Random Forest Regressor (RFR) algorithm, selected for its superior predictive performance, was trained with 1080 inputs and validated through comprehensive external and internal methods. It achieved an remarkable coefficient of determination (R^2) of 0.941 and a standard deviation of 0.235 on a test set of 270 compounds, highlighting the efficacy of model in predicting FLT3 inhibitory activity. Key molecular descriptors were identified, enhancing our understanding of structural requirements for inhibitor potency. Additionally, we developed a user-friendly computational tool that enables the rapid prediction of pIC50 values. Utilizing this tool, potential FLT3 inhibitors were identified through ligand-based virtual screening. This study represents a major advancement in FLT3 inhibitor discovery by utilizing a simple QSAR-machine learning model. It enables more efficient and precise identification of potential drug candidates at an early stage, promising a faster development of targeted therapies and streamlining the ligand-based drug design process.

Rectal cancer presents a significant burden globally, often requiring multimodal therapy for locally advanced cases. Long-course chemoradiotherapy (LCRT) and short-course radiotherapy (SCRT) followed by surgery have been conventional neoadjuvant approaches. Recent trials favor LCRT due to improved local control. However, tumor distant recurrence remains a concern, prompting exploration of Total Neoadjuvant Therapy (TNT) as a comprehensive treatment strat-egy. Immune checkpoint inhibitors (ICIs) show promise, particularly in mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, potentially revolutionizing neoadjuvant regimens. Non-operative management (NOM) represents a viable alternative post-neoadjuvant therapy for selected patients achieving clinical complete response (cCR). Additionally, monitoring minimal residual disease (MRD) using circulating tumor DNA (ctDNA) emerges as a non-invasive method for treatment response assessment. This review synthesizes current evidence on TNT, ICIs, NOM and ctDNA, elucidating their implications for rectal cancer management and highlighting avenues for future research and clinical application.

Objective: to retrospectively evaluate the incidence rate (IR) of echocardiographic signs suspected for pulmonary hypertension (PH) in Systemic sclerosis (SSc) patients after the introduction of a combination therapy with bosentan and sildenafil for treatment or prevention of digital ulcers. Methods: patients attending the Scleroderma Unit of the Universital Hospital of Careggi from July 2010 to July 2023 were enrolled. Patients older than 18 years old, with an history of digital ulcers, treated with bosentan and sildenafil in combination for at least 12 months were included. Patients with a diagnosis of PH preceding the introduction of the therapy were excluded. Demographical data, disease duration, laboratoristic and instrumental data (pulmonary function tests, echocardiographic estimation of pulmonary artery pressure (PAPs) and ultrasonographic value of renal resistive index) were collected. The IR of echocardiographic signs suspected for pulmonary hypertension and their 95% confidence interval were calculated in events/1000 patients-years.Results: forty-seven patients were enrolled; mean disease duration was 12,14 years (SD 5,87). Mean duration of the combination treatment was 78.33 (SD 41.37) months and total at-risk time was 3525 months. Two patients (4,2%) presented echocardiographic signs of PH (sPAP 50 mmHg and 40 mmHg); the IR was calculated to be 6.8/1000 patients-years (95% CI 6,02-7,7). In one of the 2 patients RHC excluded PAH, while the other patient refused to undergo to RHC and PAH could not be confirmed/excluded. A stability of PFTs and echocardiografic PAPs was observed during the observation time. Conclusions: the results of this retrospective study suggest that combination therapy with endothelin receptor antagonist and Phosphodiesterase-5 (PDE5) inhibitors could help in preventing PAH in SSc; prospective case-control studies on larger population are needed to improve knowledge in this field.

Despite the recent availability of immune checkpoint inhibitors, not all patients affected by Non-Small Cell Lung Cancer (NSCLC) benefit from immunotherapy. The reason for this variability relies to a variety of factors which may allow the identification of novel biomarkers. Presently, a variety of biomarkers are under investigation, including the PD1/PDL1 axis, the tumor mutational burden, and the Microbiota. This latter is made by all bacteria and other microorganisms hosted in our body. The gut microbiota is the most represented and has been involved in different physiological and pathological events, including cancer. In this light, it appears that all conditions modifying gut microbiota can influence cancer, its treatment, and its treatment-related toxicities. The aim of this review is to analyze all conditions influencing the gut microbiota and, therefore, affecting response to immunotherapy, iRAEs and their management in NSCLC patients. The investigation of the landscape of these biological events can allow novel insights for optimal management of NSCLC immunotherapy.

Lumpy skin disease (LSD), caused by a virus within the Poxviridae family and Capripoxvirus genus, induces nodular skin lesions in cattle, spreading through direct contact and insect vectors, significantly affecting global cattle farming. Despite available vaccines, their effectiveness is limited by poor bioavailability and adverse effects. Our study aimed to identify potential inhibitors targeting LSD-associated DNA polymerase protein, selecting LSDV039 for further investigation through comprehensive analysis and computational methods. Virtual screening revealed rhein and taxifolin as potent binders among 380 phytocompounds, with respective affinities of -8.965 and -7.195 kcal/mol. Canagliflozin and tepotinib exhibited strong affinities (-9.858 and -8.856 kcal/mol) among 718 FDA-approved antiviral drugs. Molecular dynamics simulations of canagliflozin, tepotinib, rhein, and taxifolin highlighted taxifolin's superior stability and binding energy. Rhein displayed compactness in RMSD and RMSF but fluctuations in Rg and SASA, while canagliflozin demonstrated stability compared to tepotinib. The study highlights the promising potential of repurposed drugs and phytocompounds as LSD therapeutics. However, extensive validation through in-vitro, in-vivo, and clinical trials is crucial for their practical application.

Introduction. Psoriatic disease (PsD), encompassing psoriasis, psoriatic arthritis, inflammatory bowel disease, and uveitis, presents a significant burden due to its chronic and diverse inflammatory nature, affecting various clinical domains including skin, joints, and internal organs. Psoriasis, affecting up to 3% of the global population, not only poses physical challenges but also profoundly impacts patients' psychological well-being, ranking among the most debilitating chronic conditions. Furthermore, PsD exhibits a spectrum of manifestations ranging from skin lesions like plaque psoriasis to systemic complications such as cardiovascular comorbidities, necessitating comprehensive assessment and management strategies. The increasing understanding of the aetiopathogenic mechanisms of these immune-mediated diseases and of the proinflammatory intracellular signalling pathways involved in Psoriatic disease (PsD) has facilitated the identification and development of new small molecules capable of inhibiting JAK proteins, emerging as effective treatment options for rheumatic and dermatological manifestations JAK inhibitors act rapidly, within a few days, with a striking beneficial class effect on pain. The oral formulation they share makes them a well-tolerated class of drugs, with a clear advantage over FAME in terms of convenience of administration, improving therapeutic compliance. Material and method. This observational, retrospective study conducted in a single-centre dermatology-rheumatology consultation of a second-level hospital in Granada, Spain, focused on patients diagnosed with Psoriatic Arthritis (PsA) over the last two years, who initiated treatment with Tofacitinib or Upadacitinib due to DMARD failure, excluding those with major contraindications to JAK inhibitors. Results: This study analyzed data from 32 patients diagnosed with Psoriatic Arthritis (PsA), focusing on their demographics, disease characteristics, and treatment history. The majority of patients (75%) initiated treatment with Tofacitinib, while the remainder started with Upadacitinib. The mean age of the patients differed between the two treatment groups. All patients met the CASPAR criteria for PsA diagnosis, with predominantly peripheral joint involvement. The average time from PsA diagnosis to initiation of JAKinhib treatment was 6.5 years, slightly longer for Upadacitinib users. Most patients presented with cutaneous psoriasis, and a minority exhibited radiographic erosions. Before JAKinhib therapy, all patients had previously received DMARDs. A subset of patients received concomitant DMARD therapy, predominantly methotrexate. Additionally, a proportion of patients were on low-dose corticosteroids. Baseline CRP and ESR levels were indicative of systemic inflammation. Disease activity measures at baseline indicated moderate disease activity, with a substantial proportion of patients having mild psoriasis involvement. Upadacitinib recipients with psoriasis primarily exhibited mild involvement. This study provides valuable insights into the characteristics and treatment patterns of PsA patients initiating JAKinhib therapy. Discusion. In this study, the efficacy, safety, and real-world outcomes of Janus kinase inhibitors (JAKinhibs) in the treatment of Psoriatic Arthritis (PsA) were assessed and compared with findings from pivotal randomized controlled trials (RCTs). Both Tofacitinib and Upadacitinib demonstrated significant efficacy in PsA patients refractory to DMARDs and TNF inhibitors, with rapid improvement in joint and skin activity indices. Although patients in this cohort exhibited younger age, higher female prevalence, and shorter disease duration compared to those in RCTs, treatment responses were comparable or even superior. Notably, despite fewer concurrent DMARDs and a higher proportion of patients receiving monotherapy, JAKinhibs maintained a favorable safety profile, with a low frequency of mild adverse events leading to treatment discontinuation. These findings emphasize the robust efficacy and tolerability of JAKinhibs in real-world clinical settings, supporting their role as effective therapeutic options for PsA patients.

fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF). Join us on a journey that unravels the mysteries of molecular intricacies, delves into advanced imaging techniques, and sheds light on therapeutic pathways. Unveiling the role of cardiac amyloidosis, particularly sub-clinical isolated cardiac amyloidosis (ICA), the narrative unfolds the heightened risk of AF in the elderly. State-of-the-art imaging techniques like cardiac magnetic resonance (CMR) and molecular imaging step into the spotlight, unraveling diagnostic and prognostic nuances of AF and HFpEF. Embarking on the molecular voyage, the article navigates through next-generation sequencing and comprehensive genomic profiling, shedding light on genetic alterations shaping the AF-HFpEF landscape. This molecular compass lays the groundwork for personalized medicine, illuminating pathways to identify therapeutic bullseyes and biomarkers. In the realm of medical strategies, the discussion homes in on the promising notes struck by SGLT2 inhibitors, particularly dapagliflozin, orchestrating a reduction in AF burden. Characters like spironolactone and dronedarone make appearances, each weaving a distinct tale, revealing their potential roles in steering the ship for AF- HFpEF patients. The subplot involving obesity in HFpEF unfolds, with the LEGACY study portraying the benefits of weight reduction. The pivotal intervention of catheter ablation emerges as the hero, boasting positive outcomes in reducing hospitalization rates and overall mortality for AF-HFpEF patients. However, cautionary tales echo about its impact on left atrial function, adding layers of complexity that beckon careful consideration and monitoring. Amidst the narrative, critical discussions unfold about the limitations of current research, echoing the need to define acute heart failure, refine imaging techniques, and tailor management strategies. The narrative passionately advocates for a personalized touch in addressing AF-HFpEF, recognizing the unique blend of clinical and molecular personas. In essence, this review paints a vivid mural of AF-HFpEF, skillfully bridging the realms of molecular intricacies and the artistry of clinical management.

Chronic diseases, such as type 2 diabetes (T2D), are difficult to manage because they demand continuous therapeutic review and monitoring. Beyond achieving the target HbA1c, new guidelines for the therapy of T2D have been introduced with the new groups of antidiabetics (GLP-1ra and SGLT2-in). Despite new guidelines, clinical inertia, that can be caused by physicians, patients or healthcare system, results in T2D not being effectively managed. This opinion paper explores the shift in T2D treatment, challenging assumptions and evidence-based recommendations, particularly for family physicians, considering the patient's overall situation in decision-making. We looked for the possible reasons of clinical inertia and poor application of guidelines in the management of T2D. Guidelines for antidiabetic drugs should be more precise, providing case studies and clinical examples to define clinical contexts and contraindications. Knowledge communication can improve confidence and should include clear statements on areas of decision-making not supported by evidence. Precision medicine initiative in diabetes aims to identify subcategories of T2D patients (including frail patients) using clustering techniques from data science applications, focusing on CV and poor treatment outcomes. Clear, unconditional recommendations for personalized T2D management may encourage drug prescription, especially for family physicians dealing with diverse patient contexts and clinical settings.

Proton-pump inhibitors (PPIs) are the most administered first-line treatment for eosinophilic esophagitis (EoE). However, only around half of EoE patients respond histologically to PPI at double dosage. In addition, 70% of responders maintain EoE in remission after tapering the PPI dose. In order to avoid endoscopy with biopsies − the only accurate method of assessing PPI response − efforts have been made to identify PPI responder patients. Clinical or endoscopic features and biomarkers evaluated so far however, have not proved good enough in predicting PPI response. Although new approaches based on omics technologies have uncovered promising biomarkers, the specialized and complex procedures required are difficult to implement in clinical settings. Alternatively, PPI pharmacogenetics based on identifying variations in CYP2C19 and STAT6 genes have shown promising results in EoE, and could easily be performed in most laboratories. Other genetic variations have also been associated with PPI response and may explain those cases not related to CYP2C19 or STAT6. Here, we give an overview of PPI treatment in EoE and evidence of how genetic variations in CYP2C19 and other genes could affect PPI effectiveness, and also discuss studies evaluating the role of pharmacogenetics in predicting PPI response in patients with EoE.

Heart failure (HF) management in type 1 diabetes (T1D) is particularly challenging due to its increased prevalence and the associated risks of hospitalization and mortality, driven by diabetic cardiomyopathy. Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) offer a promising avenue for treating HF, specifically the preserved ejection fraction variant most common in T1D, but their utility is hampered by the risk of euglycemic diabetic ketoacidosis (DKA). This review investigates the potential of SGLT2-i in T1D HF management, alongside the emergent Continuous Ketone Monitoring (CKM) technology as a means to mitigate DKA risk, through a comprehensive analysis of clinical trials, observational studies, and reviews. The evidence suggests SGLT2-i significantly reduce HF hospitalization and enhance cardiovascular outcomes. However, their application in T1D patients remains limited due to DKA concerns. CKM technology emerges as a crucial tool in this context, offering real-time monitoring of ketone levels, which enables the safe incorporation of SGLT2-i into treatment regimes by allowing for early detection and intervention in the development of ketosis. The synergy between SGLT2-i and CKM has the potential to revolutionize HF treatment in T1D, promising improved patient safety, quality of life, and reduced HF-related morbidity and mortality. Future research should aim at clinical trials directly assessing this integrated approach, potentially guiding new management protocols for HF in T1D.

Pseudomonas aeruginosa is an opportunistic pathogen that poses a significant threat to individuals with chronic respiratory ailments, such as cystic fibrosis (CF). The pathogen is highly prevalent in CF individuals and is responsible for chronic infection, resulting in severe tissue damage and poor patient outcome. However, early detection and immediate treatment are critical to prevent bacterial persistence and establishment of chronic infection. Presently, antibiotics including aminoglycosides, beta-lactams, polymyxins, and fluoroquinolones along with anti-inflammatory medications are being used to treat P. aeruginosa infections in CF patients. However, prolonged antibiotic administration has led to the emergence of widespread multidrug resistance in P. aeruginosa (CF isolates), contributing to antimicrobial resistance (AMR) and failure of antimicrobial therapies. Thus, exploring viable alternatives such as antivirulence therapeutics can be vital towards managing pseudomonal infections in CF patients and mitigating the risk of AMR. In this direction, antivirulence strategies achieving targeted inhibition of bacterial virulence pathways/factors, including quorum sensing, efflux pumps, lectins, and iron chelators, have been widely explored against CF isolates of P. aeruginosa. Simultaneously, there have been discussions about the sufficiency of in vitro findings and their successful translation in pulmonary infection models (in vivo) for the clinical implementation of antivirulence therapies hence, this review article presents a bird’s eye view on the pulmonary infections involving P. aeruginosa in CF patients by laying emphasis on factors contributing to bacterial colonization, persistence, and disease progression along with the current line of therapeutics against P. aeruginosa in CF while underscoring the limitation of antimicrobial approaches. We further collate scientific literature and comprehensively discuss the various antivirulence strategies that have been successfully tested against P. aeruginosa isolates from CF patients. This could pave the way towards a paradigm shift towards clinical therapy of pseudomonal infections in CF and can potentially override conventional antimicrobial treatments.

Objective: Aims to investigate the effects of empagliflozin (EMPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, on renal fibrosis in male diabetic Sprague-Dawley (SD) rat model. Methods: Streptozotocin(STZ) were injected to establish diabetes model, EMPA (10 mg/kg·d) or normal saline (NS) were administered for four weeks. The changes in renal fibrosis-related biomarkers, include vimentin (VIM), collagen types I(Col-I), collagen types III(Col-III), fibroblast-specific protein 1(FSP-1), connective tissue growth factor (CTGF), fibronectin (FN) were evaluated. Renal pathology, serum glucose levels and urinary protein excretion were also assessed. Results: Biomarkers of renal fibrosis were significantly reduced in the EMPA group compared to those in the NS group after 4-week treatment, including VIM (519.84±83.37 vs. 663.27±91.84 ng/ml, P<0.05), Col-I (21.27±1.46 vs. 25.71±2.82 ng/ml , P<0.05) and Col-III (7.06±1.12 vs. 9.43±1.36 ng/ml, P<0.05), FSP-1 (4.38±0.81 vs. 5.70±0.78 ng/ml, P<0.05), and CTGF (1147±217 vs. 1556±235 pg/ml, P<0.05),respectively. Nevertheless, compared to normal control (NC) group, the levels of renal fibrosis-related biomarkers in the EMPA group showed no significant differences except for VIM, which was VIM (336.66±28.87 vs. 519.84±83.37 ng/mL, P<0.001). NS group rats showed notable renal tubular dilation and casts, EMPA group exhibited only mild tubular dilation. Conclusion: These findings suggest that empagliflozin reverse renal fibrosis potentially through inhibiting CTGF-mediated epithelial-mesenchymal transition.

Immune checkpoint inhibitors (ICI’s) are in the forefront of advanced Non Small Cell Lung Cancer (NSCLC) treatment. Still, only 27- 46% of patients respond to initial therapy with ICI’s and of those, up to 65% develop resistance within four years. After disease progression (PD), treatment options are limited, with 10% Objective Response Rate (ORR) to second or third-line chemotherapy. In this context, ICI rechallenge is an appealing option for NSCLC. Most data on the efficacy of ICI rechallenge are based on retrospective real-world studies of small, heavily pretreated, and heterogeneous patient groups. Despite these limitations, these studies suggest that ICI monotherapy rechallenge in unselected NSCLC patient populations who discontinued initial ICI due to PD is generally ineffective, with a median Progression-Free Survival (PFS) of 1.6-3.1 months and a Disease Control Rate (DCR) of 21.4%-41.6%. However, there is a subpopulation that benefits from this strategy, and further characterization of this subgroup is essential. Furthermore, immunotherapy rechallenge in patients who discontinued initial immunotherapy following treatment protocol completion and progressed after an immunotherapy-free interval showed promising efficacy, with a DCR of 75-81%, according to post-hoc analyses of several clinical trials. Future research of ICI rechallenge for NSCLC should focus on better patient stratification, to reflect the underlying biology of immunotherapy resistance more accurately.

The ErbB/HER family of protein-tyrosine kinases (ErbB) and the phosphatidylinositol 3-kinase (PI3K) represent crucial targets in the treatment of head and neck squamous cell carcinoma (HNSCC). We previously reported that a combination therapy using Afatinib (ErbB inhibitor) and Copanlisib (PI3K inhibitor), both FDA-approved kinase inhibitors, suppressed the growth of HPV-positive HNSCC. In our current study, we further evaluated the efficacy and clinical potential of this combination therapy for treating HPV-negative HNSCC in vitro and in animal model. We found that the combination treatment of Afatinib and Copanlisib dramatically enhanced inhibition of cell proliferation and reduced cell survival when compared to treatment with either inhibitor in two HPV negative HNSCC cell lines. Notably, this combination led to significant inhibition of xenograft tumor growth in mice, without any apparent effects on body weight. Copanlisib alone effectively blocked PI3K/Akt signaling, but caused up-regulation of HER2 and HER3 phosphorylation as previously reported in other types of cancer. However, the combination treatment with Copanlisib and Afatinib completely blocked phosphorylation of the ErbB family (including HER3) and Akt, while also remarkedly increasing apoptosis. These results suggest that co-targeting the ErbB family and PI3K kinases by a combination treatment of Afatinib and Copanlisib can have clinical potential for patients.

Background This study aimed to determine the association between immune checkpoint inhibitors (ICIs) and the risk of herpes zoster (HZ) incidence in patients with lung cancer. Method We obtained national claims data of 51,021 patients from South Korea with lung cancer between August 2017 and December 2021. The study population was classified into ICIs and non-ICIs groups based on prescription of ICIs at least once during the study period. To estimate the effects of ICIs treatment compared with those without ICIs treatment on HZ incidence, we used the Cox proportional hazards model adjusted for sex, age, comorbidities, and concomitant use of immunosuppressive drugs. Stratified analyses based on sex, age, and comorbidities were conducted to identify corresponding risk factors. Results Of the 51,021 study participants, 897 (1.8%) were prescribed ICIs, and 2,262 (4.4%) were diagnosed with HZ. Approximately 75.6% of the patients were male, and the prevalence of diabetes, cardiovascular disease, and chronic lung disease in the ICIs group was significantly lower than that in the non-ICIs group. The Kaplan–Meier plot showed that the probability of incidence of HZ in the ICIs group was lower than that in the non-ICIs group. Additionally, treatment with ICIs was associated with a 31% lower risk of developing HZ when compared to that seen without ICIs treatment (95% confidence interval [CI], 0.48–1.00). This association was stronger in females (hazard ratio [HR], 0.42; 95% CI, 0.19–0.94) and those less than 68 years of age (HR, 0.58; 95% CI, 0.34–0.99). Conclusion In these real-world data from an Asian population with lung cancer, ICIs treatment might be associated with a reduced risk of HZ compared to that without ICIs treatment.

Angiotensin-converting enzyme (ACE) inhibitors are used primarily in the treatment of hypertension, heart failure, and in the acute phase of myocardial infarction. Lisinopril [N2-[(1S)-1-car-boxy-3-phenylpropyl]-L-lysyl-L-proline], enalapril [(S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline] and ramipril [2-aza-bicyclo-[3.3.0]-octane-3-carboxylic acid] are all five-membered heterocycles and three of the most prevalent ACE inhibitors in clinical use worldwide. ACEi-induced angioedema (ACEi-AE) is clinically characterized by self-limited edema of the dermis and subcutaneous lipid tissue, localized on face skin, oral mucosa and tongue in most cases. However, severe episodes of intestinal AE misdiagnosed as acute appendicitis and laryngeal AE requiring incubation have been reported. The pathophysiology of ACEi induced-AE is attributed to the accumulation of bradykinin, which is a potent vasodilator with proinflammatory activity that is normally degraded by angiotensin-converting enzyme (ACE) and aminopeptidase P; however, a small proportion of treated patients is affected. Given that patients do not respond to anti-H1 antihistamines and steroids, the early clinical recognition and the ACEi discontinuation are the treatment of choice for the long term management of ACEi-AE.

We conducted this systematic review with the objective to understand the efficacy and safety of proton pump inhibitors [PPIs] in the pediatric population. We have used PubMed to identify randomized controlled trials [RCTs] published between 1st June 2010 and 30th June 2023, in patients from birth to 18 years old, with gastroesophageal reflux disease [GERD], who received treatment with any PPI. The literature yielded 76 articles and 13 met inclusion criteria. For infants, PPIs were equal to placebo in reducing GERD symptoms in 4 articles. In 1, the number of GER episodes and esophageal acid exposure were lower in infants who received PPIs and left lateral position, but there was no significant improvement in symptoms. In another publication, the combination of PPIs and feeding modifications [FM] was not more effective than PPIs alone. For children and adolescents, PPIs were effective in improving symptoms and achieving mucosal and histological healing, which was subsequently maintained. To conclude, PPIs are not effective to reduce symptoms related to GERD in infants, but are effective in older children, along with histological remission. Generally, PPIs are well tolerated, but it is important to not forget the possible adverse events [AE], especially if they are used for a long time.

Novel drugs profoundly changed the outcomes in CLL patients and traditional prognostic/predictive factors that were delineated in the era of chemo-immunotherapy need to be validated in the contest of these new targeted therapies. Currently, the most important prognostic genetic biomarkers are immunoglobulin heavy chain variable (IGHV) mutational status, genetic aberrations including del(17p)/TP53 abnormalities and the complex karyotype. In this review we discuss the prognostic/predictive role of these genetic markers in relation to novel treatments. Moreover, we present and discuss the new score systems that were elaborated and validated in the era of new drugs. Given the deeper responses obtained with small molecules, new prognostic/predictive markers, including measurable residual disease, and validated prognostic scores could possibly be incorporated into routine prognostic scores, to better identify “very-high” CLL patients, who will need more effective treatments.

The introduction of biologic therapies has led to dramatic improvements in the management of moderate-to-severe psoriasis. Even though the efficacy and safety of the newer biologic agents are difficult to match, oral administration is considered an important advantage by many patients. Current research is focused on development of oral therapies with improved efficacy and safety compared to available alternatives, as exemplified by deucravacitinib, the first oral allosteric Tyk2 inhibitor approved for the treatment of moderate-to-severe psoriasis in adults. Recent advances in our knowledge of psoriasis pathogenesis have also led to the development of targeted topical molecules, mostly focused on intracellular signaling pathways, such as AhR, PDE-4 and Jak-STAT. Topical tapinarof, an AhR modulator, and roflumilast, a PDE-4 inhibitor, have exhibited favorable efficacy and safety outcomes have been approved by the FDA for the topical treatment of plaque psoriasis. This revision focuses on the most recent oral and topical therapies available for psoriasis and specially on those that are currently under evaluation and development for the treatment of psoriasis.

Malaria, leishmaniasis, and African trypanosomiasis are protozoan diseases that constitute a major global health problem, especially in developing countries; however the development of drug resistance coupled with the toxicity of current treatments have hindered their management. The implication of certain enzymes (dihydrofolate reductase, DHFR) or proteins (potassium channels) in the pathogenesis of these protozoan diseases is undeniable. In this study, a series of three DHFR inhibitors (6-5 fused heterocyclic derivatives X, Y and Z) and one K+ channel blocker (E4031) were screened for their inhibitory effect on Leishmania donovani, Plasmodium falciparum, and Trypanosoma brucei. Resazurin assay was used to assess antitrypanosomal and antileishmanial activities of test compounds, whereas the antimalarial activity was appraised through SYBR Green I test. Moreover, cytotoxicity of test compounds was evaluated on Vero, Raw 264.7 and HepG-2 cells using the resazurin-based test, whilst their pharmacokinetic properties were predicted using the online tool pkCSM. As a result, compound Y revealed a selective (selectivity index range: 2.69 - &gt;61.4; Vero, Raw 264.7 and HepG-2 cells) and broad-spectrum antiprotozoal activity against L. donovani promastigotes (IC50: 12.4 µM) and amastigotes (IC50: 4.28 µM), P. falciparum (IC50: 0.028 µM), and T. brucei brucei (IC50: 0.81 µM). In addition, compound X inhibited the growth P. falciparum (IC50: 0.0052 µM) and T. brucei brucei (IC50: 6.49 µM). In silico screening of the active antiprotozoal compounds revealed positive drug-likeness scores as none of Lipinski's rule of five’s criteria was violated by these compounds. However, in-depth pharmacokinetic and mechanistic studies are warranted to support discovery of novel antiprotozoal agents against malaria, leishmaniasis, and African trypanosomiasis by repurposing K+ channel blocker and DHFR inhibitors.

The current review comprehensively explores the multifaceted landscape of anaplastic lymphoma kinase (ALK) and its pivotal role, specifically within non-small cell lung cancer (NSCLC). It traces the trajectory of ALK's discovery, notably its fusion with nucleolar phosphoprotein (NPM)-1 in anaplastic large cell non-Hodgkin's lymphoma (ALCL) in 1994. It unfolds the subsequent impact of ALK gene alterations across various malignancies, including inflammatory myofibroblastoma (IMT) and NSCLC. The prevalence of intricate ALK rearrangements affecting roughly 3–5% of NSCLC patients prompted the approval of six ALK-tyrosine kinase inhibitors (TKIs) by 2022, revolutionizing the treatment landscape for advanced metastatic ALK+ NSCLC. Second-generation TKIs like alectinib, ceritinib, and brigatinib have notably emerged to combat resistance issues initially associated with crizotinib, the pioneer ALK-TKI approval. Moreover, this review delves into the intersection of ALK and immunotherapy, exploring the potential of immune checkpoint inhibitors in ALK-altered NSCLC tumors. Despite promising preclinical data, challenges encountered in trials evaluating combinations like nivolumab-crizotinib, primarily due to severe hepatic toxicity, underscore the need for cautious exploration of these novel approaches. Additionally, the review delves into innovative avenues such as ALK vaccines and biosensors, shedding light on their promising potential within ALK-driven cancers. This comprehensive analysis encompasses molecular mechanisms, therapeutic strategies, and immune interactions associated with ALK-rearranged NSCLC. Ultimately, the review is a pivotal resource guiding future research and therapeutic interventions in ALK-targeted therapy for NSCLC.

Biochemical recurrence (BCR) after primary treatments for prostate cancer (PC) is an extremely heterogeneous phase and at least a stratification in low and high-risk cases for early progression in metastatic disease is necessary. At now PSA-DT represents the best parameter to define low and high risk BCR PC, but a real precision medicine is strongly suggested to define a tailored management of patients with BCR. Before defining management, it is necessary to exclude the presence of low volume metastasis associated with PSA progression using new generation imaging preferably with PSMA PET/CT. Low risk BCR cases should be actively observed without early systemic therapies. Early treatment of low risk BCR with continuous androgen deprivation therapy (ADT) can produce disadvantages such the development of castration resistance before the appearance of metastases (non-metastatic castration resistant PC). Patients with high risk BCR benefit from early systemic therapy. The primary end point must be metastasis-free survival (MFS), even with the same overall survival (OS). The EMBARK study is able to impact on the management of high risk BCR, by introducing the concept of anticipation and intensification through the use of androgen receptor signaling inhibitors (ARSI) and ADT combination therapy. In high risk (PSA-DT ≤ 9 months) BCR cases, the combination of enzalutamide with leuprolide significantly improves MFS when compared to leuprolide alone, maintaining the quality of life unchanged in an asymptomatic phase of the disease. The possibility of using ARSI alone in this early disease setting is suggested by the EMBARK study (arm with enzalutamide alone) with less evidence than the intensification of the combination therapy. Continued use versus discontinuation upon reaching undetectable PSA levels of enzalutamide plus leuprolide intensified therapy needs to be better defined with further analysis. Real world analysis must verify the significant results obtained in the context of a phase 3 study.

The aim of this review was to search in literature, data regarding the inflammasome, involvement in, oral pathologies (mainly periodontitis) and other diseases and the approaches to control the inflammasome-related pathogenic mechanisms. The review also investigated how phytochemicals and pharmaceutical substances could be used to inhibit the inflammasome activity. Inflammasomes are involved in inflammatory, autoimmune and autoinflammatory diseases. Pharmaceutical substances can control the inflammasome by three mechanisms: inhibiting of intracellular signaling pathways (Allopurinol and SS-31), blocking inflammasome components (VX-765, Emricasan and VX-740), and inhibiting cytokines mediated by the inflammasome (Canakinumab, Anakinra and Rilonacept). Phytochemical inhibit the inflammasome, by neutralization of reactive oxygen species. Biomaterials functionalized by the adsorption of therapeutic agents on different nanomaterials may represent a future research direction to facilitate multimodal and sequential treatment in oral pathologies.

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

Ras homolog enriched in brain (Rheb1 and Rheb2), a small GTPase, regulates neuronal activity and has drawn attention for its implications in cancer development, especially breast cancer. This study explores the multifaceted role of Rheb1 in cancer, elucidating its involvement in crucial cel-lular processes such as proliferation, apoptosis resistance, migration, invasion, metastasis, and inflammatory responses. Despite these acknowledged connections, a comprehensive understanding of the intricate interplay between Rheb1 and cancer remains elusive. This review consolidates cur-rent knowledge on the impact of Rheb1 on cancer hallmarks and examines the potential of Rheb1 as a therapeutic target in cancer treatment. The review underscores the need for a more profound comprehension of the molecular mechanisms underlying Rheb1-mediated oncogenic processes. Furthermore, the review emphasizes the exploration of Rheb1 inhibitors as a promising avenue for cancer therapy. This study, by bringing to light the complex associations between Rheb1/Rheb2 and cancer, delivers valuable insights to the scientific community. These insights are instrumental in guiding the identification of novel targets and advancing the development of effective therapeu-tic strategies for treating cancer.

Antiphospholipid syndrome (APS) is a group of autoimmune diseases caused by antiphospholipid antibodies (aPLs) characterized by arteriovenous thrombosis and a morbid pregnancy. We deliberated a case report of seven cases to investigate whether inhibitors of tissue necrosis factor-α could reduce pregnancy dangers caused by APS. The seven patients are with increased tumor necrosis factor, poor improvement after receiving traditional inhibitory drugs. To address these situations, the tumor necrosis factor inhibitors were prescribed after getting the patient's informed consent, and the state of illness was carefully watched for. After treatment, symptoms of contractions and abdominal pain disappeared and the B ultrasound examination showed embryo survived with good obstetric outcomes. Subsequently, maternal and neonatal health is compromised. An intervention by the administration of TNF-α inhibitors was posited to be an effective way of reducing dangerous pregnancies like preterm pregnancies, premature deliveries, abortions and miscarriages. We reviewed outcomes from seven cases in an attempt to establish how TNF- α Inhibitors could save pregnancies. We focused on key pregnancy outcomes like birth weight, gestational weeks and preterm miscarriage to tell the outcomes of TNF- α Inhibitors in pregnancy. After careful evaluation of the results surrounding these aspects, we found that TNF- α Inhibitors could prolong gestational period. Other positive outcomes include the attainment of birth weights approach the threshold, zero incidence of preterm miscarriage.

4-(2-Methyloxazol-4-yl)benzenesulfonamide was synthesized by the reaction of 4-(2-bromoacetyl)benzenesulfonamide with an excess of acetamide. The obtained compound was evaluated as a potential inhibitor of human monoamine oxidase (MAO) A and B and was found to inhibit these enzymes with IC50 values of 3.47 μM for MAO-B and 43.3 μM for MAO-A. Thus, the new selective MAO-B inhibitor was identified, which may be used as the lead compound for development anti-Parkinson’s disease agents.

In advanced Parkinson’s disease (PD), and especially in PD related dementia (PDD), psychotic symptoms are common. One of the manifestations of psychosis in PD is delusional misidentification syndrome, a phenomenon in which the patient believes the identity of a person, object or location has been duplicated or altered. Our patient, a 75-year-old female, was diagnosed with idiopathic Parkinson’s disease at the age of 68. Recently, her cognition deteriorated and she developed the believe that she lived in a replica of her real home. The delusion resolved completely with rivastigmine patches. Also visual hallucinations improved on treatment. This suggests that the dysfunctional connections were likely to be cholinergic.

(1) Background: National health system databases represent one of the most obvious sources of information about epidemiology of adverse drug reactions including drug-induced allergy and anaphylaxis. (2) Methods: Retrospective analysis of data from national database of pharmacovigilance in the Russian Federation (analyzed period 02.04.2019 - 21.06.2023) was performed. The prevalence of anaphylactic reactions (ARs) was determined, the structure of drugs involved was estimated together with patients’ characteristics. (3) Results: ARs were reported in 8.3% of drug-induced allergic reactions (2304/27,727), mean age of patients was 48.2 ± 15.8 years, 53.2% were females. Main causative groups of drugs were antibiotics, ABs (44.62%), local anesthetics, (19.97%), and cyclooxygenase (COX)-inhibitors (10.07%). Fatal ARs was reported in 9.5% (218/2304), mean age 48.0 ± 16.7 years, 56.2% females. Pediatric population accounted for 5.8% (133/2304), mean age 11.8± 4.5 years, 51.9% females. Elderly population accounted for 2.8% (65/2304), mean age 73.0±5.3 years, 43.5% (27/65) females. ABs were the leading causative groups of ARs in the elderly (40%), children (42.86%), and among fatal cases (50%). (4) Conclusions: ARs accounted for 8.3% of all drug-induced allergic reactions, and ABs were the most common causative agents. Females predominated in all groups except elderly patients.

Histone deacetylase 6 (HDAC6) regulates many physiological processes that are involved in cancer development and progression such as cell proliferation, apoptosis, motility, epithelial to mesenchymal transition, by deacetylation of multiple substrates and association with interacting proteins. Due to its the ability to remove misfolded proteins, induce autophagy, and regulate unfolded protein response, HDAC6 plays a protective role in responses to stress and enables tumor cells survival. HDAC6 is often overexpressed in tumors, including colorectal cancer (CRC) and is correlated with poor disease prognosis. However, it has been shown in animal models that HDAC6 is not essential for normal mammalian development. Therefore, it represents a good target for the development of novel cancer therapeutics. Selective inhibition of HDAC6 impairs growth and progression of many tumors without inducing major adverse events in experimental animals. In CRC, HDAC6 inhibitors have shown potential to reduce tumor progression and to enhance the therapeutic effect of other drugs. As HDAC6 is involved in regulation of immune responses, HDAC6 inhibitors have shown potential to improve antitumor immunity by increasing immunogenicity of tumor cells, augmenting immune cell activity and alleviating immunosuppression in tumor microenvironment. Therefore, HDAC6 inhibitors may represent promising candidates to improve the effect and to overcome resistance to immunotherapy.

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme and one of the causes of tumor resistance to topoisomerase 1 inhibitors such as topotecan. Inhibitors of this Tdp1 in combination with topotecan may improve the effectiveness of therapy. In this work, we synthesized usnic acid derivatives, which are hybrids of its known derivatives - tumor sensitizers to topotecan. New compounds inhibit Tdp1 in the micromolar and submicromolar concentration range; some of them enhance the effect of topotecan on the metabolic activity of cells of various lines according to the MTT test. One of the new compounds (compound 7) not only sensitizes Krebs-2 and Lewis carcinomas of mice to the action of topotecan, but also normalizes the state of the peripheral blood of mice, which is disturbed in the presence of a tumor. Thus, the synthesized substances may be the prototype of a new class of additional therapy for cancer.

Esophagogastric cancers are among the most common and deadly cancers worldwide. This review traces their chronology from 3000 BCE to the present. The first several thousand years were devoted to palliation, before advances in operative technique and technology led to the first curative surgery in 1913. Systemic therapies were introduced in 1910, and radiotherapy shortly thereafter. Operative technique improved massively over the 20th century, with operative mortality rates reducing from over 50% in 1933 to less than 5% by 1981. In addition to important roles in palliation, endoscopy became a key non-surgical curative option for patients with limited-stage disease by the 1990s. The first nonrandomized studies on combination therapies (chemotherapy +/- radiation +/- surgery) were reported in the early 1980s, with survival benefit only for subsets of patients. Randomized trials over the next decades had similar overall results, with increasing nuance. Disparate conclusions led to regional variation in global practice. Starting with the first FDA approval in 2017, multiple immunotherapies now encompass more indications and earlier lines of therapy. As standards of care incorporate these effective yet expensive therapies, care must be given to disparities and methods for increasing access.

This review paper presents a flashback on the evolution of the disease throughout the centuries, describes in summary pathophysiologic mechanisms, discusses briefly the mechanism of action of the diuretics, presents their role in decongesting heart failure patients and unfolds the data behind ultrafiltration in the management of acutely or chronically decompensated heart failure (ADHF), focusing on all the available data and advancements in this field. Acutely decompensated heart failure (ADHF) presents a critical clinical condition characterized by worsening symptoms and signs of heart failure, necessitating prompt intervention to alleviate congestion and improve cardiac function. Diuretics have traditionally been the mainstay for managing fluid overload in ADHF. Mounting evidence suggests that due to numerous causes, such as coexisting renal failure or chronic use of the loop diuretics, an increasing rate of diuretic resistance is noticed and needs to be addressed. There has been a series of trials that combined diuretics of different categories, without the expected results. Emerging evidence suggests that ultrafiltration may offer an alternative or adjunctive approach.

The new coronavirus SARS-CoV-2 is the cause of the COVID-19 pandemic, which has created an incomparable global health problem. PLpro is a key protein involved in viral polyprotein processing and immune system evasion, making it a prime target for the development of antiviral drugs to combat COVID-19. The review begins by elucidating the functional and structural properties of SARS-CoV-2 PLpro, underscoring its significance in viral pathogenicity and replication. Employing homology modeling, a tertiary structure model of PLpro is constructed, laying the groundwork for subsequent investigations. To expedite the search for potential therapeutic candidates, the study harnesses computational methodologies. Molecular docking techniques are employed to explore binding sites for antiviral drugs within the catalytic region of PLpro. This computational approach not only aids in drug development but also provides crucial preliminary data before experimental research commences. The stability of drug-PLpro complexes is assessed through comprehensive all-atom molecular dynamics (MD) simulations, affording dynamic insights into drug-PLpro interactions. By evaluating binding energy estimates from MD simulations, stable drug-PLpro complexes with potential antiviral properties are identified. However, it is emphasized that experimental validation is imperative to confirm these computational findings, necessitating in vitro and in vivo tests to assess safety and efficacy. This pivotal stage bridges the computational realm with real-world clinical applications. The review emphasizes the imperative need for enhancements in the existing PLpro-targeting drugs currently on the market. Their actions are insufficient for clinical use and necessitate thorough characterization and improvement. The Supervised Molecular Dynamics (SuMD) simulation technique reveals critical information about drug unbinding pathways, shedding light on opportunities for refinement. In addition to optimizing existing drugs, the investigation of sub-structurally similar molecules emerges as a promising avenue for drug development. In conclusion, the review underscores the pivotal role of targeting SARS-CoV-2 PLpro in the ongoing battle against COVID-19. By integrating molecular dynamics simulations, structural modeling, and computational insights, a robust foundation is established for identifying promising antiviral drug candidates. The continual need for improvement in existing drugs and the exploration of novel compounds remain paramount in the global effort to combat COVID-19. The evolution and management of COVID-19 hinge on the symbiotic relationship between computational insights and experimental validation, illustrating the interdisciplinary synergy crucial to this endeavor.

Objective: To evaluate the use of CDK4/6 inhibitors as a risk factor for medication-related osteonecrosis of the jaw (MRONJ) in a cohort of patients with metastatic breast cancer treated with denosumab. Methods: multicentre, retrospective, observational study. All patients with breast cancer treated with denosumab (January 2011-December 2022) were included. The relationship between CDK4/6 inhibitors and MRONJ was analysed. Results: 243 patients were included, ninety-five (44.2%) used a CDK4/6 inhibitor. There were 21 patients with MRONJ. In patients treated with denosumab without CDK4/6 inhibitors the incidence of MRONJ and mean time to the occurrence of MRONJ was 6.6% (8/120) and 16.8 months (SD 7.8) respectively. In patients treated with denosumab and CDK4/6 inhibitor 13.7% (13/95) and 15.4 month (SD 8.7) respectively. The difference in the incidence was not significant (p=0.085). Conclusion: it suggest that the incidence of MRONJ in patients with metastatic breast cancer treated with denosumab was higher and the onset of MRONJ occurred earlier in the presence of CDK4/6 inhibitors. Although the difference was not significant, given that the use of this combination is very common in routine clinical practice, it would be advisable to carry out larger prospective studies to clarify the risk of this association.

This comprehensive review delves into the intricate relationship between Sodium-GlucoseCo-Transporter 2 (SGLT2) inhibitors and AF, highlighting the multifaceted actions of thesedrugs and their significant cardiovascular benefits. Mechanisms: SGLT2 inhibitors inducesubstantial hemodynamic changes, impacting blood pressure, adipose tissue function, andinflammation. They enhance glycemic control while potentially reducing oxidative stress andinflammation, and they modulate atrial electrophysiology, collectively contributing to the reductionof AF risk. Clinical Evidence: This review synthesizes a wealth of clinical evidence,drawing from observational studies and randomized controlled trials, consistently demonstratinga correlation between SGLT2 inhibitors, particularly dapagliflozin and empagliflozin, anda decreased risk of AF. This protective effect is most pronounced in patients with type 2 diabetesand heart failure, underscoring their potential as therapeutic agents for high-risk populations.Potential Benefits: SGLT2 inhibitors offer a spectrum of potential benefits, includingsubstantial reductions in AF risk, particularly in patients with type 2 diabetes and heart failure.These drugs have consistently demonstrated benefits in reducing heart failure hospitalizations,cardiovascular mortality, and stroke risk, which indirectly contribute to better AF management.Furthermore, SGLT2 inhibitors exhibit renoprotective properties by slowing theprogression of chronic kidney disease and reducing albuminuria, offering substantial benefitsfor AF patients with comorbid kidney disease. Metabolic improvements involving weight loss,blood pressure reduction, and favorable changes in lipid profiles contribute to enhanced cardiovascular health and reduced AF risk. Originally designed for diabetes management, thesemedications offer a holistic approach to AF risk reduction, particularly in patients with type 2diabetes and heart failure.

Radiotherapy for cancer has been known to affect the responses of immune cells, especially those of CD8+ T cells that play a pivotal role in anti-tumor immunity. Clinical success of immune checkpoint inhibitors led to an increasing interest into the ability of radiation to modulate CD8+ T cell responses. Recent studies that carefully analyzed the CD8+ T cell responses following radiotherapy suggest the beneficial roles of radiotherapy on anti-tumor immunity. In addition, numerous clinical trials that evaluate the efficacy of combining radiotherapy with immune checkpoint inhibitors are undergoing. In this review, we summarize the current status of knowledge regarding the changes of CD8+ T cells following radiotherapy from various preclinical and clinical studies. Furthermore, key biologic mechanisms that underlie such modulation, including both direct and indirect effects, are described. Lastly, we discuss the current evidence and essential considerations for harnessing radiotherapy as a combination partner for immune checkpoint inhibitors.

Dacomitinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the treatment of patients with advanced non-small cell lung cancer (NSCLC) and EGFR-activating mutations. Proton pump inhibitors decreased dacomitinib exposure. This anal-ysis summarizes the effect of H2RA on dacomitinib exposure. A within-patient comparison of steady-state trough concentrations (Ctrough,ss) of dacomitinib and its active metabolite and active moiety with and without concomitant use of H2RA was conducted using a linear mixed effects model with pooled data from 11 clinical studies in patients with NSCLC. An oral absorption PBPK model was constructed and verified using clinical PK data after a single dose of dacomitinib in healthy volunteers to estimate the effect of gastric pH altered by an H2RA on dacomitinib PK. The adjusted geometric mean of dacomitinib Ctrough,ss of dacomitinib parent, metabolite and active moiety following co-administration with H2RA was approximately 86%, 104% and 100% relative to that following dacomitinib 45 mg administration without H2RA (P>0.05). The PBPK modeling showed negligible change in dacomitinib Cmax and AUC over 0-24 hours after H2RA administra-tion, when compared with those administered dacomitinib alone. Co-administration of an H2RA with dacomitinib is not expected to have any clinically relevant effect on dacomitinib exposure.

Advanced cutaneous melanoma is considered the most aggressive type of skin cancer with variable rates of treatment response. Nowadays, there are available some classes of immunotherapy and target therapy for its treatment. Immunotherapy can inhibit tumor growth and its recurrence by triggering host's immune system, while targeted therapy acts inhibiting specific molecules or signaling pathways. However, melanoma response to these treatments are highly heterogenous, and frequently become resistant. Epigenome (DNA/histone modification) contribute to cancer initiation and progression. Epigenetic alterations are divided into four levels of gene expression regulation: DNA methylation, histone modification, chromatin remodeling and non-coding RNAs regulation. The deregulation of lysine methyltransferase enzymes is associated with tumor initiation, invasion, development of metastases, changes in immune microenvironment and drug resistance. The study of lysine histone methyltransferase (KMT) inhibitors is important to cancer epigenetic mechanisms understanding and to biological processes. In addition to immunotherapy and target therapy, the research and development of KMT inhibitors is ongoing. Many studies are exploring the therapeutic implications and possible side effects of these compounds, besides their adjuvant potential to the approved current therapies. Importantly, as with any drug development, safety, efficacy, and specificity are crucial considerations when developing KMT inhibitors for clinical applications.

We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumour distribution of ZST316, an arginine analogue with inhibitory activity towards dimethylarginine dimethylaminohydrolase 1 (DDAH1) and vasculogenic mimicry, and its active metabolite L-257 in a xenograft model of triple negative breast cancer (TNBC). The method proved to be reproducible, precise, and highly accurate for the measurement of both compounds in plasma and tumour tissue following acute and chronic (five days) intraperitoneal administration of ZST316 (30mg/Kg daily) in six-week-old SCID mice inoculated with MDA-MB-231 TNBC cells. ZST316 was detected in tumour tissue and plasma after 1 hour (6.47 and 9.01M, respectively) and 24 hours (0.13 and 0.16M, respectively) following acute administration, without accumulation during chronic treatment. Similarly, the metabolite L-257 was found in tumour tissue and plasma after 1 hour (15.06 and 8.72M, respectively) and 24 hours (0.17 and 0.17M, respectively) following acute administration of ZST316, without accumulation during chronic treatment. The half-live after acute and chronic treatment ranged between 4.4-7.1hrs (plasma) and 4.5-5.0hrs (tumour) for ZST316, and 4.2-5.3hrs (plasma) and 3.6-4.9hrs (tumour) for L-257. The results of our study demonstrate the a) capacity to accurately measure ZST316 and L-257 concentrations in plasma and tumour tissue in mice using the newly developed HPLC-MS/MS method, b) rapid conversion of ZST316 into L-257, c) good intra-tumour penetration of both compounds, and d) lack of accumulation of both ZST316 and L-257 in plasma and tumour tissue during chronic administration. The new HPLC-MS/MS method is useful to investigate the in vivo effects of ZST316 and L-257 on vasculogenic mimicry, tumour mass, and metastatic burden in xenograft models of TNBC.

The cyclin-dependent kinase (Cdk) 1–cyclin B (CycB) complex plays critical roles in cell cycle regulation. Before Drosophila male meiosis, CycB is exported from the nucleus to the cytoplasm via the nuclear porin 62kD (Nup62) subcomplex in the nuclear pore complex. When this is inhibited, Cdk1 is not activated, and meiosis does not initiate. We investigated the mechanism that controls cellular localization and activation of Cdk1. Cdk1–CycB continuously shuttled into and out of the nucleus in the prolonged G2 phase before meiosis. Overexpression of CycB, but not that with nuclear localization signal sequences, rescued reduced cytoplasmic CycB and inhibition of meiosis in Nup62-silenced cells. Full-scale Cdk1 activation occurred in the nucleus shortly after its rapid nuclear entry. Cdk1-dependent centrosome separation did not occur in Nup62-silenced cells, while Cdk1 interacted with Cdk-activating kinase and Twine/Cdc25C in the nucleus of Nup62-silenced cells, suggesting the involvement of another suppression mechanism. Silencing of roughex rescued Cdk1 inhibition and initiated meiosis. Nuclear exports of Cdk1 ensured its escape from inhibition by cyclin-dependent kinase inhibitor. The complex reentered the nucleus via importin β at the onset of meiosis. We propose a model regarding the dynamics and activation mechanism of Cdk1–CycB to initiate male meiosis.

Cathepsins (Caths) are lysosomal proteases that participate in various physiological and pathological processes. Accumulating evidence suggests that cathepsins play a multifaceted role in radiotherapy response. Firstly, cathepsins contribute to the remodelling of the tumor microenvironment by degrading extracellular matrix components, promoting angiogenesis, and facilitating tumor invasion and metastasis. Their proteolytic activity influences the tumor's response to radiation by affecting oxygenation, nutrient availability, and immune cell infiltration within the tumor microenvironment. Furthermore, cathepsins have been implicated in DNA damage repair processes, including non-homologous end joining and homologous recombination. Cathepsin-mediated DNA repair mechanisms can promote radioresistance in cancer cells, limiting the efficacy of radiotherapy. Additionally, cathepsins have been associated with the activation of prosurvival signalling pathways, such as PI3K/Akt and NF-κB, which can confer resistance to radiation-induced cell death. Radiotherapy plays a crucial role in the treatment of various malignancies. However, the effectiveness of radiotherapy can be limited by intrinsic or acquired resistance mechanisms in cancer cells. In recent years, there has been growing interest in understanding the role of cathepsins, a family of proteases, in modulating the response of tumor cells to radiotherapy. In this study, we shed light on the regulation and expression of cathepsin B in colon carcinoma cell line (Caco-2) before and after exposure to radiation were investigated. Radiation-induced upregulation of cathepsin B in dose-independent manner. Proteolytic inhibition of cathepsin B by cathepsin B specific inhibitor CA074 has increased the cytotoxic effect of ionizing irradiation in caco-2 cells. Similar results were also obtained after cathepsin B knockout by CRISPR CAS9. These results showed that cathepsin B could contribute to ionizing radiation resistance and abolishing of cathepsin B either by inhibition its proteolytic activity or expression has increased in caco-2 cells susceptibility to ionizing irradiation.

Diabetes mellitus (DM) and chronic kidney disease (CKD) are common in middle aged and elderly individuals. DM may accelerate the aging process, and the age-related declines in the estimated Glomerular Filtration Rate (eGFR), can pose a challenge to diagnose diabetic kidney disease (DKD) using standard diagnostic criteria especially with absence of severe albuminuria among the elderly. In the presence of CKD and DM, elderly patients may need multidisciplinary care due to susceptibility to various health issues e.g., cognitive decline, auditory or visual impairment, various comorbidities, complex medical regimens, and increased sensitivity to medication adverse effects. As a result, it can be challenging to apply recent therapeutic advancements for the general population to the elderly. We review the evidence that the benefits from these newer therapies apply equally to elderly and non-elderly patients and propose a framework for the management of DKD by discussing the nonpharmacological measures and pharmacological management with renin angiotensin system inhibitors (RASi), Sodium Glucose Co-Transporter two inhibitors (SGLT2i), non-steroidal mineralocorticoids receptor antagonists (MRAs), and Glucagon Like Peptide 1 Receptor Agonists (GLP1-RAs).

The uterine leiomyoma is the most common benign tumor in women of childbearing age. It may lead to problem of conception or complications during gestational period. The methods of treatment can be surgical (myomectomy and hysterectomy, embolization of arteries) and therapeutic treatment (Ulipristal acetate, Leuprolide acetate, Cetrorelix, Goserelin, Mifeprestone). Both approaches are efficient, but are incompatible with pregnancy planning. Therefore, there is a call for medical practice in developing therapeutical means of preventing leiomyoma onset in patients planning on pregnant. Based on the analysis of GWAS data on the search for mononucleotide polymorphisms associated with the risk of leiomyoma, meta-transcriptomic and meta-methylomic studies, target proteins have been proposed. Prospective therapeuticals of leiomyoma may be based on chemical compounds, humanized recombinant antibodies, vaccines based on markers of the uterine leiomyoma cells that are absent in the adult organism, DNA and RNA preparations. Three different nosological forms of the disease associated with driver mutations in the MED12, HMGA2 and FH genes should be considered when developing or prescribing drugs. E.g. synthetic inhibitors and vaccines based on matrix metalloproteinases MMP11 and MMP16 are expected to be effective only for the prevention of the occurrence of MED12-dependent nodules.

This study presents a transversal investigation, that we performed at Fundeni hospital, into the therapeutic benefits and efficacy of Emicizumab, a non-factor therapy, in the context of hemophilia A. Ten patients diagnosed with hemophilia A were closely monitored, using clinical and laboratory resources, during the course of Emicizumab treatment, with an average of 12.8 months. Among these patients, six exhibited anti-factor VIII inhibitors, changing the medical approach and adding complexity to their clinical profiles. A comprehensive approach was adopted to assess the coagulation status of patients under Emicizumab therapy. The study employed several key coagulation monitoring tools, of which including thrombin generation time (TGT) and thrombelastography (TEG). These methodologies proved highly valuable results in evaluating the patients' coagulation profiles during the treatment regimen. Additionally, traditionally coagulation assays were utilized to gain a comprehensive understanding of the overall coagulation dynamics. Noteworthy, impressive outcomes emerged from the study. During prophylaxis with Emicizumab all patients had experienced a reduced number of bleeding events. Moreover, a subset of these patients underwent major surgical procedures (orthopedic joint replacements) with successful outcomes. These findings underscore the potential of Emicizumab therapy as an effective option for hemophilia A patients, including those that presented a prompt production of anti-factor VIII inhibitors. As for the outcomes, this transversal study sheds some light on the positive impact of Emicizumab therapy in addressing the coagulation challenges posed by hemophilia A. The utilization of global coagulation assays, such as thrombin generation time, thrombelastography and combined with traditional coagulation assays, used as monitoring tools highlights their significance once more in evaluating the therapeutic response. This research contributes by providing physicians with valuable insights to the field, offering a potential avenue for improved patients’ care and treatment strategies that translate in enhanced quality of life for hemophilia A patients undergoing Emicizumab therapy.

Influenza viruses cause acute respiratory infections responsible for significant mortality and morbidity around the world. Various factors, such as antigenic drift, allow influenza strains to avoid being fully suppressed by seasonal vaccines. This has led to the increased scrutiny of antivirals as treatment and prophylaxis options for seasonal outbreaks and potential pandemics. Unfortunately, many influenza antivirals suffer from a lack of adequate clinical trials, as well as a lack of toxicity data. This is especially true of umifenovir (arbidol), a drug popularly used for the prevention and treatment of influenza strains in China and Russia. Neuraminidase inhibitors, though widely prescribed, display a potential for future resistance. Adamantanes, while proven to be effective in treating influenza A, are already encountering rapid and widespread cross-resistance and are effectively obsolete. Baloxavir marboxil, a newer antiviral, shows promise in treating acute uncomplicated influenza and may avoid the development of resistance when co-administered with other antiviral drugs. Indeed, the low genetic barrier to resistance associated with influenza antivirals could potentially be overcome by co-administration with other antivirals. This review explores the most widely prescribed antivirals for influenza treatment, their mechanisms of action, and the data currently available about their susceptibility to resistance and efficacy.

The effective treatment of human immunodeficiency virus (HIV), also known as acquired immunodeficiency syndrome (AIDS), has transformed a highly lethal disease into a chronic and manageable condition. However, better methods need to be developed for eliminating the virus from reservoirs, enhancing patient access and adherence to therapy, and improving treatment in the long term to reduce adverse effects. From the perspective of drug discovery, one promising strategy is the development of anti-HIV prodrugs. This approach aims to enhance the efficacy and safety of treatment, promoting the development of more appropriate and convenient systems for patients. In this review, we discussed the use of the prodrug approach for HIV antiviral agents and emphasized nucleoside reverse transcriptase inhibitors. We comprehensively described various strategies that are used to enhance factors such as water solubility, bioavailability, pharmacokinetic parameters, permeability across biological membranes, chemical stability, drug delivery to specific sites/organs, and tolerability. These strategies might help researchers conduct better studies in this field. We also reported successful examples from the primary therapeutic classes while discussing the advantages and limitations. In this review, we highlighted the key trends in the application of the prodrug approach for treating HIV/AIDS..

An analysis of the relationship between plasma cytokines and the effectiveness of treatment with TNFαinhibitors was performed in 81 patients with moderate-to-severe psoriasis. Treatment efficacy was assessed by PASI score, and patients were classified into a positive effect (PASI≥75) and no effect group (PASI≤50). A positive effect was reached in 11 (41%) patients for etanercept, 14 (52%) for adalimumab, and 26 (96%) for infliximab. Data analysis did not show  differences in baseline TNFα levels and subsequent treatment effectiveness. The CART algorithm showed that at the baseline level of VEGF ≥ 32 pg/ml and IL17F &lt; 26 pg/ml, there was an 83% probability of a positive effect. Random forest analysis showed the importance of VEGF, ICAM1, sCD40L, IL17F and IL31 baseline levels in the prediction of treatment effectiveness.   Significant differences between the groups before/after the treatment were found only for TNFα: the median values were more than 50 times higher in no effect compared with positive effect group. There were differences before/after therapy in the levels of IL20, ICAM1, IL22, IL23 in the no effect group. The treatment affected the cytokine profile in most cases regardless of the effectiveness of therapy.

Malignant neoplasms arising from the gastrointestinal (GI) tract are among the most common cancer types with a high mortality rate. Despite advances in treatment in a small subgroup harboring targetable mutations, the outcome remains poor, accounting for one in three cancer-related deaths observed globally. As a promising therapeutic option in various tumor types, immunotherapy with immune checkpoint inhibitors has also been evaluated in GI cancer, albeit with limited efficacy except for a small subgroup expressing microsatellite instability. In the quest for more effective treatment options, energetic efforts have been placed to evaluate the role of several immunotherapy approaches comprising of cancer vaccines, adoptive cell therapies and immune checkpoint inhibitors. In this review, we report our experience with personalized dendritic cell cancer vaccine and cytokine-induced killer cell therapy in three patients with GI cancers and summarize current clinical data on combined immunotherapy strategies.

De novo metastatic hormone-sensitive PC (mHSPC) accounts for 5-10% of all prostate cancer (PC) diagnoses but it is responsible for nearly 50% of PC-related deaths. Since 2015, the prognosis of mHSPC has slightly improved thanks to the introduction of new hormonal agents and chemotherapy combined with androgen deprivation therapy from the first-line setting. This review describes the current therapeutic opportunities in de novo mHSPC, focusing on potential molecular biomarkers identified in the main clinical trials that have changed the standard of care, the genomic features of de novo mHSPC, and the principal ongoing trials that are investigating new therapeutic approaches and the efficacy of a biomarker-guided treatment in this setting. The road towards a personalized treatment for de novo mHSPC is still long considering that the randomized clinical trials, which have furnished the basis of the current therapeutic options, stratified patients according to clinical criteria that not necessarily reflect the biological rationale of the chosen therapy. The role of transcriptomic profiling of mHSPC as predictive biomarker requires further validation, as well as it remains to ascertain how the genomic alterations detected in mHSPC, that are considered predictive in the castration-resistant disease, can be exploited in the mHSPC setting.

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

Homologous recombination deficiency (HRD) has become an important prognostic and predictive biomarker for patients with high-grade serous ovarian cancer who may benefit from poly-ADP ribose polymerase inhibitors (PARPi) and platinum-based therapies. HRD testing provides relevant information to personalize patients’ treatment options, and it has been progressively incorporated in diagnostic laboratories. In this study, we evaluated the feasibility of in-house HRD testing deployable in a diagnostic clinical setting, comparing results from two commercially available next-generation sequencing (NGS)-based tumor tests (SOPHiA DDMTM HRD Solution and AmoyDx HRD Focus Panel) with the reference assay from Myriad MyChoice CDx. A total of 85 ovarian cancer samples were subjected to HRD testing. An overall strong correlation was observed across the three assays evaluated, regardless of the different underlying methods employed to assess genomic instability, with the highest pairwise correlation between Myriad and SOPHiA (R=0.87, p-value=3.39x10-19). The comparison of the assigned HRD status to the reference Myriad’s test revealed a positive predictive value (PPV) and negative predictive value (NPV) of 90.9% and 96.3% for SOPHiA’s test, while AmoyDx’s test achieved 75% PPV and 100% NPV. This is the largest HRD testing evaluation using different methodologies and provides a clear picture of the robustness of NGS-based tests currently offered in the market. Our data show that the implementation of in-house HRD testing in diagnostic laboratories is technically feasible and it can be reliably performed with commercial assays. Also, the turnaround time is compatible with clinical needs, being an ideal alternative to offer to a broader number of patients, while still maintaining high-quality standards at more accessible price tiers.

Skin cancer is a prevalent and heterogenous disease with several subtypes, such as melanoma, basal cell carcinoma, and squamous cell carcinoma. Among them, melanoma is the most aggressive subtype, with a higher propensity to spread compared to most solid tumors. The application of OMICS approaches has revolutionized the field of melanoma research by providing comprehensive insights into the molecular alterations and biological processes underlying melanoma development and progression. This review aims to offer an overview of melanoma biology, covering its transition from primary to malignant melanoma, as well as the key genes and pathways involved in the initiation and progression of this disease. Utilizing online databases, we extensively explored the general expression profile of genes, identified the most frequently altered genes, and gene mutations, and examined genetic alterations responsible for drug resistance. Additionally, we studied the mechanisms responsible for immune checkpoint inhibitors resistance in melanoma.

Abstract Forensic institutions throughout the country house patients with severe psychiatric illness and history of criminal violations. Improved medical care, hygiene, and nutrition led to unmatched longevity in this population which previously lived on average 15 to 20 years shorter than the public at large. On the other hand, longevity has contributed to increased prevalence of age-related diseases, including neurodegenerative disorders, which complicate clinical management. Forensic institutions, originally intended for the treatment of younger individuals, are ill-equipped for the growing number of older offenders. Moreover, as antipsychotic drugs became available in 1950s and 1960s, we are observing the first generation of forensic detainees who had aged on dopamine blockers. Although the consequences of long-term treatment with these agents are unclear, schizophrenia-associated gray matter loss, may contribute to the development of early dementia. Taken together, increased lifespan and subsequent cognitive deficit observed in long-term psychiatric institutions brought forth questions and dilemmas unencountered by the previous generations of clinicians, such as: 1. Does the presence of neurocognitive dysfunction justify antipsychotic dose reduction or discontinuation despite a lifelong history of schizophrenia and violent behavior? 2. Should neurolipidomic interventions become the standard of care in elderly individuals with lifelong schizophrenia and dementia? 3. Can patients with schizophrenia and dementia meet the Dusky standard and stand trial? 4. Should neurocognitive disorders in elderly with lifelong schizophrenia be treated differently than age-related neurodegeneration? In this article, we describe strategies for potentially slowing the development of neurocognitive disorders in forensic patients with chronic mental illness by adopting a three-prong strategy: 1. Approaching lifelong psychosis from microbial and immunological perspective. 2. Identify modifiable risk factors for age-related diseases in forensic institutions. 3. Utilizing novel receptor-independent treatments for chronic psychosis.

Tyrosinases (TYR) play an important role in oxidizing phenols and catechols, leading to the formation of catechols and ortho-quinones, respectively. In mammals, TYR catalyzes the conversion of L-Tyrosine to quinone, a pivotal step in melanogenesis, which generates melanin pigments responsible for protecting against UV radiation and oxidative stress. Given TYR's importance in melanin-related disorders and cosmetic applications, the inhibition of TYR has garnered attention for controlling melanin production. However, current inhibitors like hydroquinone, arbutin, and kojic acid (KA) have limitations in terms of side effects and effectiveness. A novel class of TYR inhibitors featuring arylpiperidine and arylpiperazine components has demonstrated potent inhibitory activity. This study presents a computational analysis of these inhibitors using molecular docking, molecular dynamics (MD) simulations, and the Linear Interaction Energy (LIE) method was used to estimate binding free energies. The arylpiperidine and arylpiperazine inhibitors exhibit remarkable stability within the TYR active site during simulations. The van der Waals interactions are notably sustained, indicating effective inhibition mechanisms. The results from LIE calculations closely align with experimental binding affinities. In summary, these results contribute to the understanding of TYR inhibition and underscore the potential of arylpiperidine and arylpiperazine derivatives as effective agents for modulating melanin production in both cosmetic and pharmaceutical applications. Overall, this study sheds light on the intricate interactions between inhibitors and TYR, opening avenues for the development of novel therapies and interventions.

Worldwide, the COVID-19 pandemic, which was brought on by the brand-new coronavirus SARS-CoV-2, has claimed a sizable number of lives. Despite the urgency, COVID-19 does not have any particular antiviral treatments at this time. As a result, scientists are concentrating on repurposing already existing antiviral medications or creating brand-new ones. The SARS-CoV-2 main protease, which is necessary for viral replication, has been identified as a possible target for a family of medicines called main protease inhibitors (MPIs). Studies of the major proteases from SARS-CoV and MERS-CoV, which have remarkably similar structures and functions to SARS-CoV-2, have provided insight for the creation of MPIs. By analyzing the MPI trials for SARS-CoV and MERS-CoV, this review sheds light on the possible therapeutic uses of MPIs for COVID-19. The review talks about how MPIs work, how effective they are against SARS-CoV and MERS-CoV, and how safe they are. The paper also emphasizes current developments in the creation of MPIs for SARS-CoV-2, including as computational studies, in vitro and in vivo research, and clinical trials. According to the review, there is a lot of hope for MPIs in the treatment of COVID-19, and numerous medications are in the works. Although more research is needed to assess their safety and effectiveness in clinical settings, these medications may offer patients with COVID-19 a much-needed therapeutic option. The review also emphasizes the importance of ongoing research into the structure and function of the SARS-CoV-2 main protease, as this information will be critical for the development of effective MPIs and other antiviral drugs in the future.

A major public health emergency has been created by the COVID-19 pandemic, which is brought on by the SARS-CoV-2 virus. Due to its crucial function in viral replication, the primary protease (Mpro) of the virus is a prime target for therapeutic research. In this study, we used molecular modeling and molecular dynamics simulations to examine the potential therapeutic uses of Mpro inhibitors for the treatment of COVID-19. Using induced fit docking and molecular dynamics simulations, we confirmed the top compounds after screening a library of compounds for their ability to bind to Mpro. Simulation interaction diagrams were used to investigate protein-ligand interactions, and MM-GBSA was used to determine binding energies. The Swiss ADME server was used to predict ADME properties. According to our findings, numerous substances are strong COVID-19 medication candidates since they have excellent ADME features and high binding affinities. This work serves as a foundation for additional experimental research and drug development initiatives aimed at Mpro.

Tdp1 and Tdp2 are DNA repair enzymes that repair DNA damages caused by various agents, including anticancer drugs. Thus, these enzymes resist anticancer therapy and could be the reasons of resistance to such widely used drugs as topotecan and etoposide. In the present work, we found compounds capable of inhibiting both enzymes among derivatives of (-)-usnic acid. Both (+)- and (-)-enantiomers of compounds act equally effectively against Tdp1, and only (-)-enantiomers inhibited Tdp2. Surprisingly, the compounds protect HEK293FT wild type cells from the cytotoxic effect of etoposide but potentiate it against Tdp2 knockout cells. We assume that the sensitizing effect of the compounds in the absence of Tdp2 is associated with effective inhibition of Tdp1, which could take over the functions of Tdp2.

Urothelial cell carcinoma (UCC, bladder cancer) remains a difficult to treat malignancy with rising incidence worldwide. In the U.S., UCC is the sixth most incident neoplasm and ~90% of diagnoses are made in those &gt;55 years of age, ~four times more commonly observed in men than women. The most important risk factor for developing bladder cancer is tobacco smoking, which accounts for ∼50% of cases followed by occupational exposure to aromatic amines and ionizing radiation. The standard of care for advanced UCC includes platinum-based chemotherapy and programmed cell death (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors, administered as frontline, second-line, or maintenance therapy. UCC is highly aggressive and remains generally incurable since these cancers are associated with intrinsic and acquired drug resistance. UCC is highly lethal in the metastatic state and characterized by genomic instability, high PD-L1 expression, DNA damage-response mutations, and high tumor mutational burden. Although immune checkpoint inhibitors (ICIs) achieve long-term durable responses in other cancers, their ability to achieve similar results with metastatic UCC (mUCC) is not as well-defined. Here, we discuss the novel therapies to improve the management of mUCC.

Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer, such as glioblastoma and prostate cancer, where they have been found overexpressed. This finding is opening new frontiers for MAOs inhibitors as potential antiproliferative agents. In light of our previous studies demonstrating how a polyamine scaffold can act as MAOs inhibitor, our aim was to search for novel analogues with even greater inhibitory potency for human MAOs and, possibly, endowed with antiproliferative activity. A small in house library of polyamine analogs (2-7) was selected to investigate the effect of a constrained linkers between the inner amine functions of a polyamine backbone on the inhibitory potency. Compound 4 and 5, characterized by a dianiline (4) or dianilide (5) moiety emerged as the most potent, reversible and mainly competitive MAO inhibitors (Ki < 1uM). Additionally, they exhibited a high antiproliferative activity in three tumor cell lines, in particular in the LN-229 line, a glioblastoma model (GI50 < 1uM). The scaffold of compound 5, in particular, could represent a potential starting point for future development of anticancer agents endowed with MAO inhibitory activity.

The RNA-binding protein Human antigen R (HuR) regulates stability, translation, and nucleus-to-cytoplasm shuttling of its target mRNAs. The protein has been progressively recognized as a relevant therapeutic target for several pathologies like cancer, neurodegeneration, as well as inflammation. Inhibitors of mRNA binding to HuR might thus be beneficial against a variety of diseases. Here we present the rational identification of structurally novel HuR inhibitors. In particular, by combining chemoinformatics approaches, high throughput virtual screening and RNA–protein pull-down assays, we show that the 4-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazineyl)benzoate ligand exhibits dose-dependent HuR inhibition in binding experiments. Importantly, the chemical scaffold is new with respect to the so-far known HuR inhibitors, opening up a new avenue for the design of pharmaceutical agents targeting this important protein.

The Main Protease (Mpro) plays a pivotal role in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is considered a highly conserved viral target. Disruption of the catalytic activity of Mpro produces a detrimental effect on the course of the infection, making this target one of the most attractive for the treatment of COVID-19. The current success of the SARS-CoV-2 Mpro inhibitor Nirmatrelvir, the first oral drug for the treatment of severe forms of COVID-19, has further focused the attention of researchers on this important viral target, making the search for new Mpro inhibitors a thriving and exciting field for the development of antiviral drugs active against SARS-CoV-2 and related coronaviruses.

Small molecule kinase inhibitors (SMKIs) are one of the heightened concerns in the field of drug research and development. There are seventy-nine (up to July 2023) small molecule kinase inhibitors have been approved by FDA and hundreds kinase inhibitors candidates in clinical trials, which shed light on the treatment of some major diseases. As an important strategy of drug design, computer-aided drug design (CADD) plays an indispensable role in the discovery of SMKIs. CADD methods, such as docking, molecular dynamic, pharmacophore have been applied to the design and optimization of small molecule kinase inhibitors. In the review, we provide an overview of recent advances in CADD and SMKIs; and the application of CADD for discovery of SMKIs.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer care and shown remarkable efficacy clinically. This efficacy is, however, limited to subsets of patients with significant infiltration of lymphocytes into the tumor microenvironment. To extend their efficacy to patients who fail to respond or achieve durable responses, it is now becoming evident that complex combinations of immunomodulatory agents may be required to extend efficacy to patients with immunologically “cold” tumours. Oncolytic viruses (OVs) have the capacity to selectively replicate within and kill tumour cells resulting in the induction of immunogenic cell death and the augmentation of anti-tumour immunity and have emerged as a promising modality for combination therapy to overcome the limitations seen with ICIs. Pre-clinical and clinical data has demonstrated that OVs can increase immune cell infiltration into the tumour and induce anti-tumour immunity, thus changing a “cold” tumour microenvironment that is commonly associated with poor response to ICIs, to a “hot” microenvironment which can render patients more susceptible to ICIs. Here, we review the major viral vector platforms used in OV clinical trials, their success when used as a monotherapy and when combined with adjuvant ICIs, as well as pre-clinical studies looking at the effectiveness of encoding OVs to deliver ICIs locally to the tumour microenvironment through transgene expression.

Background: This study assessed the nephrotoxicity of oral BRAF inhibitors (BRAFi), regorafenib (REG) and encorafenib (ENC), in metastatic colorectal cancer (mCRC), through an analysis of re-ports from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) da-tabase. Methods: A descriptive and disproportional analyses were performed for all reports with ENC and REG as the primary suspect. Results: A total of 379 reports had at least one renal ADR, mainly related to REG (93.1%). Potential safety signals for REG particularly included chromaturia (n = 44; ROR = 12.00, CI 95% = 8.92-16.16; IC = 2.36, IC025-IC075 = 2.06-2.66), hydronephrosis (10; 8.70, 4.67-16.19; 1.85, 1.23-2.47), nephrotic syn-drome (7; 5.73, 2.73-12.03; 1.47, 0.73-2.21), renal impairment (53; 4.16, 3.17-5.45; 1.39, 1.12-1.66), dys-uria (19; 3.06, 1.95-4.81; 1.06, 0.61-1.52), renal failure (38; 1.66, 1.20-2.28; 0.49, 0.17-0.81), and acute kidney injury (AKI) (43; 1.46, 1.08-1.97; 0.37, 0.07-0.67). For ENC, consistent disproportionalities were observed for AKI (n = 11; ROR = 3.79, CI 95% = 2.09-6.90; IC = 1.32, IC025-IC075 = 0.72-1.91) and dysuria (4; 6.50, 2.43-17.39; 1.86, 0.88-2.85). Conclusions: These findings highlighted some not extensively reported renal ADRs that required further investigations to better characterize the safety profile of BRAFi in patients with mCRC.

Background: Atherosclerotic plaque (AP) vulnerability can be assessed by coronary artery imaging techniques. Modern lipid-lowering therapy (LLT) has a stabilizing effect on the AP and reduces the likelihood of progression of vascular remodeling. Methods: Databases searched comprised PubMed, and the Web of Science up to April 2023. In total, 8 relevant articles were selected, and all of them are original clinical studies. Results Based on the results of ODISSEY-J-IVUS, there was a decrease in the percentage change in the normalized total volume of AP by 3.1% in the monotherapy group and by 4.8% in the combined LLT group (p = 0.23). According to GLACOV study normalized total atheroma volume decreased by 0.9 mm3 in the placebo group and by 5.8 mm3 in the evolocumab group (95% CI -7.3 -2.5; p<0.001). Plaque regression was observed in 64.3% of patients receiving evolocumab versus 47.3% of those on placebo. The dynamics of the minimum thickness of the fibrous cap varied within 18.0-62.67 microns while on combined LLT and 13.2-33.19 microns on monotherapy (PACMAN-AMI, Gao F). In the HUYGENS study, a lipid arc regression of 57.5° was obtained on combined LLT and by 31.4° with the statin alone. Conclusion: significant progress in the development of cardiovascular imaging has made it possible to expand our understanding of the morphology of AP, the features of coronary vessel remodeling, and the development of acute cardiovascular complications.

Little is known about the effect of statin use in lung cancer development in idiopathic pulmonary fibrosis (IPF). We analyzed the database of the National Health Insurance Service to further investigate the clinical impacts of statin on lung cancer development and overall survival (OS) in IPF patients. The analysis included 9,182 individuals diagnosed with IPF, of which 3,372 (36.7%) were statin users. Compared to statin non-users, the time from diagnosis of IPF to lung cancer development and OS were longer in statin users in IPF patients. In Cox proportional hazard regression models, higher statin compliance, statin use, and being female had an inverse association with lung cancer risk, while older age at diagnosis of IPF and smoking history were associated with higher risk of lung cancer in IPF patients. For OS, statin use, female sex, higher exercise frequency, and diabetes were associated with longer survival. In contrast, older age at diagnosis of IPF and smoking history were associated with shorter OS in IPF patients. These data from a large population indicate that statin had an independent protective association with lung cancer development and mortality in IPF patients.

Background/Aims: Conflicting results have been reported regarding the interaction between proton pump inhibitors (PPIs) and clopidogrel. We investigated whether concomitant PPI use influenced the risk of recurrence in patients with stroke and myocardial infarction (MI). Methods: This study used two databases for different designs, the Korean National Health Insurance Service (NHIS) database for a self-controlled case series design, and the national sample cohort of the NHIS database converted to the Observational Medical Outcomes Partnership-Common Data Model version for a cohort study. Results: In the PPI co-prescription group, recurrent hospitalization with stroke occurred in 17.6% of the 8,201 patients with history of stroke, and recurrent MI occurred in 17.1% of the 1,216 patients with history of MI during 1 year. According to the self-controlled case series, the overall relative risk (RR) of recurrent stroke was 2.09 [95% confidence interval (CI); 1.83-2.38], and the RR showed an increasing trend with PPI duration. In the cohort study, there was a higher incidence of recurrent stroke in the PPI co-prescription group [Hazard ratio (HR): 1.34, 95% CI: 1.01-1.76, P=0.04]. The overall RR of recurrent MI was 1.47 (95% CI; 1.02-2.11) in the self-controlled case series; however, there was no statistically significant difference in recurrent MI in the cohort study (HR:1.42, 95% CI:0.79-2.49, P=0.23). The impact of individual PPIs on stroke and MI showed different patterns. Conclusions: PPI co-prescription with clopidogrel was associated with recurrent stroke; however, its association with recurrent MI remains inconclusive. The influence of individual PPIs should be clarified in the future.

The advent of immunotherapy has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC), improving the prognosis of this disease and becoming a key part of the treatment, especially in the population without an oncogenic driver mutation. Two different groups of immune checkpoint inhibitors (ICIs) are used in lung cancer: Anti- Cytotoxic T-lymphocyte antigen-4 (Anti-CTLA 4) and Anti- T-cell receptor programmed cell death-1 or its ligand (Anti-PD-1 and Anti PD-L1). Here in, we review an uptodate on the use of immunotherapy for advanced NSCLC.

Bromodomain (BRD)-containing proteins are involved in many biological processes, most notably epigenetic regulation of transcription, and BRD protein dysfunction has been linked to many diseases, including tumorigenesis. However, the role of BRD proteins in the pathogenesis of uterine fibroids (UFs) is entirely unknown. The present study aimed to determine the expression pattern of BRD9 protein in UFs and matching myometrium and further assess the impact of BRD9 inhibitors on UF phenotype and epigenetic/epitranscriptomic changes. Our studies demonstrated that the levels of BRD9 were significantly upregulated in UFs compared to matched myometrium, suggesting that the aberrant BRD protein expression may contribute to the pathogenesis of UFs. We then evaluated the potential roles of BRD9 using its specific inhibitor I-BRD9. Targeted inhibition of BRD9 suppressed the UF tumorigenesis with increased apoptosis and cell cycle arrest, decreased cell proliferation, and extracellular matrix deposition in UF cells. The latter is the key hallmark of UFs. Unbiased transcriptomic profiling coupled with downstream bioinformatics analysis further and extensively demonstrated that targeted inhibition of BRD9 impacted the cell cycle- and ECM-related biological pathways, reprogrammed the UF cell epigenome and epitranscriptome, and altered miRNA-mediated gene regulation in UFs. Taken together, our data support the critical role of BRD9 in UF cells and the strong interconnection between BRD9 and other pathways controlling the UF progression. Targeted inhibition of BRD proteins might provide a non-hormonal treatment option for this most common benign tumor in women of reproductive age.

Background. The type-2 sodium-glucose cotransporters inhibitors (SGLT2i) are a new relevant therapeutic option for patients affected by chronic heart failure with reduced ejection fraction (HFrEF). The aim of this study was to evaluate, in a real-world population from a single center, the feasibility of introducing SGLT2i and their interaction with other recommended drug classes. Methods. We evaluated the consecutive patients affected by chronic heart failure (CHF) since January 2022. At baseline clinical visit the therapy taken by the patients as well as that prescribed were accurately collected. During a 6-12 month follow-up the the changes in concomitant therapy were analyzed. Results. At baseline, among 350 patients evaluated, only 17 (5%) were already taking SGLT2i, 13 with HFrEF, 2 with CHF with mild reduced (HFmrEF) and 2 with preserved ejection fraction (HFpEF). After baseline evaluation, SGLT2i were prescribed to 220 (63%) of all the patients enrolled, among whom 178 (84%) of HFrEF patients, 25 (42%) of HFmrEF and 17 (22%) of HFpEF. After follow-up, SGLT2i therapy was highly tolerated and it was associated with a significant increased prescription of sacubitril/valsartan and a reduced use of diuretics. Finally, a significant improvement in functional status and left ventricular systolic function after SGLT2i therapy was observed. Conclusions. In this single center “real world” study, SGLT2i were prescribed in HFrEF patients most of all already in therapy with the other classes of drugs currently recommended for their treatment. Moreover, a further optimization in prescribed ther-apy was observed during a short term follow-up. These data further support the use of this thera-peutic approach in routine clinical practice.

A number of agents, including immune checkpoint inhibitors, have become available for the treatment of hepatocellular carcinoma (HCC). However, the objective response rate of these drugs is currently only 30% to 40%, with a high incidence of side effects. There are also no prac-tical biomarkers to predict their therapeutic effects. Most of the systemic therapies for HCC are performed in general hospitals without research facilities. Such hospitals can perform imaging tests, like CT and MRI, as well as pathological diagnosis using tumor tissue sampling and im-munohistochemical staining. However, analyzing tumor genomic or transcriptomic profiles is difficult because of limitations in facilities, personnel, and cost. Therefore, in this review, we provide an overview of the wide range of research that has been conducted on HCC biomarkers from blood, tissue, or imaging information that can be used practically in general hospitals for predicting the therapeutic effect of systemic therapies before treatment begins. For general hos-pitals that treat HCC patients, we recommend conducting treatment after assessing the state within the tumor tissue as much as possible by collecting blood and tissue samples and per-forming pre- treatment MRI image evaluations.

Atopic dermatitis (AD) is a chronic skin disease marked by inflammation, erythema, dryness and pruritic lesions. Due to the intermittent nature of the disease, management strategies for AD focus on flare prevention following remission. A 24-year-old patient with mild-to-moderate AD lesions, previously non-responsive to topical corticosteroids (TCS), was treated with pimecrolimus for 12 days and emollient plus cream (EC) every day. After the initial 12-day treatment course, the patient was advised to use pimecrolimus if his symptoms reoccured. AD symptoms improved substantially between Weeks 0 and 12 with daily use of EC. However, by Week 12, his symptoms had relapsed, necessitating retreatment with pimecrolimus. Overall, the patient experienced flare-free periods between Weeks 3 and 12 and between Weeks 13 and 16. No tolerability issues were reported. This case report demonstrates the use of a complementary approach of daily administration of maintenance EC and intermittent application of pimecrolimus for flare management, which was effective for treating a patient with mild-to-moderate AD resistant to TCS.

Breast cancer (BC) is the most common malignancy and the second cause of cancer specific death in women from high-income countries. More than 70% of all breast cancer are hormone receptor-positive BC, and elevated estrogen circulating in blood has been proved to be a strong risk for BC development. This is due to its contribution to enhance proliferation of cancerous cells, angiogenesis and metastasis stimulation and therapy resistance. The estrogen (E) metabolism–gut microbiome axis is functional with underlying individual variations in E levels. It is reasonable that the estrobolome (bacterial genes whose products are capable of metabolizing E) could contribute to the risk of hormone-driven malignancies including BC and may serve as a potential biomarker and target. Gut microbial β -glucuronidase (GUS) enzymes have been suggested to be involved in the estrobolome. Furthermore, bacterial GUS enzymes within the gastrointestinal tract have been postulated to contribute to hormone breast cancer. In this review, we discuss the recent knowledge about the role of GUS enzyme in the pathogenesis of breast cancer. We focus on the role of GUS in (i)-the microbioma and estrogen metabolism, (ii) diet, estrobolome, and the BC development, (iii) other activities of the bacterial β-glucuronidase, and (iv) the new molecular target for BC therapeutic application.

Several tumor types have been efficiently treated with PARPis, which are now approved for the treatment of ovarian, breast, prostate, and pancreatic cancer. The BRCA1/2 genes and mutations in many additional genes involved in the HR pathway may be responsible for the HRD phenomenon. In the present study, an NGS assay was used to analyze 513 genes associated with targeted and immuno-oncology therapies in 406 samples. In addition, the %gLOH values of 24 samples were also calculated using the Affymetrix technology to compare the results obtained by the two methodologies. HR variations occurred in 20.93% of the malignancies, while BRCA1/2 gene alterations in 5.17%. %LOH was highly correlated with alterations in the BRCA1/2 genes since 76.19% (16/21) of the BRCA1/2 positive tumors had a high %LOH value (p=0.007). Moreover, the LOH status was highly correlated with the TP53 and KRAS statuses, but there was no association with the TMB value. Lin's Concordance Correlation Coefficient for the 24 evaluable samples simultaneously examined by both assays was 0.87, indicating a nearly perfect agreement. In conclusion, the addition of gLOH analysis could assist the detection of additional patients eligible for PARPis

Evinacumab, a human monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3), has recently been approved by U.S. Food and Drug Administration as an add-on therapy for homozygous familial hypercholesterolemia (HoFH) in patients of 12 years and older. Its role as a triglyceride-lowering drug is also emerging in the literature. However, it has not been approved for this indication yet, neither in the adult nor in the pediatric population. We describe the case of a 10-year-old boy who underwent an allogeneic hematopoietic stem cell transplant for acute lymphoblastic leukemia complicated by chronic graft–versus–host disease (GVHD) and presented life-threatening refractory hypertriglyceridemia due to the concomitant use of ruxolitinib and sirolimus. After the failure of the insulin treatment and due to the technical impossibility of performing lipid apheresis, we underwent the child to evinacumab treatment, obtaining a dramatic rapid reduction in triglyceride and cholesterol levels. This is the first report of a pediatric patient younger than 12 years in Europa receiving evinacumab to treat severe hypertriglyceridemia. The therapy with angiopoietin-like proteins inhibitors has been effective, safe, and well-tolerated in our patient, suggesting that evinacumab may be used in the pediatric population when other therapeutic strategies are ineffective or contraindicated.

Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) making up 80% of cases. Some genetic factors leading to NSCLC development include genetic mutations and PD-L1 expression. PD-L1 proteins are targeted in an NSCLC treatment called targeted gene therapy. However, this treatment is effective in a low percentage of patients. This study aimed to create machine learning models to use features like the number of mutations and the level of PD-L1 proteins in cancer cells, along with others, to predict whether a patient will receive clinical benefit from gene therapy treatment. This was done by downloading and merging datasets from cbioportal.org to create a sample size for the model. Features with high correlations to clinical benefit were identified. Three machine-learning models were created using these features to predict clinical benefits in patients, and each model’s accuracy was evaluated. All three models were accurate between 55-85%, with two of the models averaging an accuracy around 75%. Doctors can use these models to more accurately predict whether gene therapy treatment is likely to work in a patient before prescribing it to them.

Gliomas are aggressive, primary central nervous system tumours arising from glial cells. Glioblastomas are the most malignant. They are known for their poor prognosis or median overall survival. Current standard of care is overwhelmed by the heterogeneous, immunosuppressive tumour microenvironment promoting immune evasion and tumour proliferation. The advent of immunotherapy with its various modalities – immune checkpoint inhibitors, cancer vaccines, oncolytic viruses, chimeric antigen receptor T cells and NK cells have shown promise. Clinical trials incorporating combination therapies of the above have overcome the microenvironment resistance and yielded survival and prognostic benefit. Rolling these new therapies out in the real-world scenario in a low cost, high throughput manner is the unmet need of the hour. These will bring practice changing implications to the glioma treatment landscape. In this review article, we focus on describing the hallmarks of the glioma microenvironment and its interplay with the different emerging modalities of immunotherapy.

In this work, the inhibition properties of new bio-based lignine ILs on the corrosion of mild steel in an aqueous solution of 0.01 M NaCl were investigated by Potentiostatic Electrochemical Impedance Spectroscopy (PEIS), Cyclic Potentiodynamic Polarization (CPP). Moreover, the surface was characterized using SEM, EDS, and optical profilometry. The influence of cation and anion on the inhibitor properties and a possible synergistic effect were investigated. The IL choline syringate showed a promising performance, reducing the corrosion current after 24-hour immersion in 0.01 M sodium chloride, from 1.66 µA/cm2 for the control to 0.066 µA/cm2 with 10 mM of the IL present. In addition to the performance as a corrosion inhibitor, both components of this IL also meet or exceed current additional desired properties of such compounds, being readily available, economically efficient, and well tolerated in organisms and the environment.

The possibility of treating more patients for a longer time, has exploded the concept of anticipation in the systemic treatment of metastatic prostate cancer (mPC). The genetic analysis of Damage DNA Repair (DDR) mutations in pathogenetic variants (PV) and the development of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors led to the first valid precision medicine option tailored for mPC. PARP inhibitors are repeating the same evolutionary path experienced for androgen receptor signaling inhibitors (ARSI), starting from the late stage of second line mCRPC in a limited population and time frame. Inevitably also PARP inhibitors will be absorbed by the concept of anticipation and intensification of care. The anticipation of PARP inhibitors in the first line mCRPC therapy is already underway and further one in mHSPC will soon be verified. According to the crosstalk between androgen receptors (AR) and DNA repair, the new message that is emerging is that the combination of PARP inhibitors with ARSI, disconnects PARP from the genetic analysis. Most of the recent trials analyzing PARP inhibitors plus abiraterone or enzalutamide, enrolled first line mCRPC irrespectively to gene PV. The conclusion of the PROPEL trial was that the advantage was independent to PV status, however the highest advantage was reported in BRCA1/2 mutated subgroup. The conclusion of the MAGNITUDE trial was different, with a significant advantage only in the DDR mutated subgroup and the DDR non-mutated was closed for further enrollment. The combination of PARP inhibitors with ARSI represents a significant strategy in the concept of anticipation and intensification of care in mPC. However, it should not nullify the advantages of precision medicine linked to the genetic analysis of DDR.

The multitarget therapeutic strategy, as opposed to the more traditional ‘one disease-one tar-get-one drug’, may hold promise in treating multifactorial neurodegenerative syndromes, such as Alzheimer’s disease (AD) and related dementias. Recently, combining a photopharmacology approach with the multitarget-directed ligand (MTDL) design strategy, we disclosed a novel donepezil-like compound, namely 2-(4-((diethylamino)methyl)benzylidene)-5-methoxy- 2,3-dihydro-1H-inden-1-one (1a), which in the E diastereomeric form (and about tenfold less in the UV-B photo-induced isomer Z) showed the best activity as dual inhibitor of the AD-related targets acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Herein, we investigated further photoisomerizable 2-benzylideneindan-1-one analogs 1b-h with the unconjugated tertiary amino moiety bearing alkyls of different bulkiness and lipophilicity. For each compound the thermal stable E diastereoisomer, along with the E/Z mixture as produced by UV-B light irradia-tion in the photostationary state (PSS, 75% Z), was investigated for the inhibition of human ChEs and MAOs. The pure E-diastereoisomer of the N-benzyl(ethyl)amino analog 1h achieved low nanomolar AChE and high nanomolar MAO-B inhibition potencies (IC50s 39 and 355 nM, re-spectively), whereas photoisomerization to the Z isomer (75% Z in the PSS mixture) resulted in a decrease (about 30%) of AChE inhibitory potency, and not in the MAO-B one. Molecular docking studies were performed to rationalize the different E/Z diastereoselectivity of 1h toward the two target enzymes.

The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer. These agents have demonstrated significant clinical benefits in terms of both progression-free survival and overall survival. However, resistance to CDK4/6 inhibitors remains a challenge, limiting their long-term efficacy. Understanding the complex mechanisms driving resistance is crucial for the development of novel therapeutic strategies and improvement of patient outcomes. Translational research efforts, such as preclinical models and biomarker studies, offer valuable insight into resistance mechanisms and may guide the identification of novel combination therapies. This review paper aims to outline the reported mechanisms underlying CDK4/6 inhibitor resistance, drawing insights from both clinical data and translational research in order to help direct the future of treatment for hormone receptor positive metastatic breast cancer.

In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options for patients. However, individuals without targetable mutations pose a clinical challenge, as they may not respond to standard treatments like immune-checkpoint inhibitors (ICIs) and novel targeted therapies. While the mechanism of action of ICIs seems promising, the lack of a robust response limits their widespread use. Although the expression levels of programmed death ligand 1 (PD-L1) on tumor cells are used to predict ICI response, identifying new biomarkers, particularly those associated with the tumor microenvironment (TME), is crucial to address this unmet need. Recently, inflammatory cytokines such as interleukin-1 beta (IL-1β) have emerged as a key area of focus and hold significant potential implications for future clinical practice. Combinatorial approaches of IL-1β inhibitors and ICIs may provide a potential therapeutic modality for NSCLC patients without targetable mutations. In this review, we discuss the role of IL-1β in NSCLC, its involvement in inflammatory pathways, and explore its potential role in the treatment of NSCLC.

Meningiomas are cerebral cancers that arise from abnormal cell development in the meninges and defensive layers covering the mind and spinal line. They can attack areas close to the cerebrum tissue and apply tension to neighboring designs, prompting different neurological side effects. Recent advances in atomic science and genomics have revealed insights into the fundamental subatomic adjustments and flagging pathways involved in the improvement of meningoma. Cabozantinib, a chemotherapeutic agent, has shown promising results in preclinical and clinical studies in various malignancies, including meningia. It inhibits angiogenesis, reduces cancer development, and prompts cell passage, providing areas of strength for clinical examination. Inhibition of VEGFR2 signaling has shown promise results in clinical trials in various cancer types, including a variety of cancers. This review summarizes the current knowledge on the pathophysiology and potential therapeutic effects of cabozanteb as a therapeutic agent for intracranial meninga.

Metastasis is the main cause of anti-cancer therapies failure, leading to unfavorable prognosis for patients. The true challenge to increase cancer patient life expectancy by making cancer a chronic disease with periodic but manageable relapses, relies on the development of efficient therapeutic strategies specifically directed against key targets in the metastatic process. Traditional chemotherapy with classical alkylating agents, microtubule inhibitors and antimetabolites has demonstrated its limited efficacy against metastatic cells due to their capacity to select chemo-resistant cell populations that undergo epithelial to mesenchymal transition (ETM) thus promoting the colonization of distant sites that in turn sustain the initial metastatic process. This scenario has prompted efforts aimed at discovering a wide variety of small molecules as potential anti-metastatic drugs directed against more specific targets known to be involved in the various stages of metastasis. In this short reviews we will give an overview of the most recent advances related to three main large families of antimetastatic small molecules: intracellular tyrosine kinase inhibitors, integrin antagonists and small interfering (siRNAs). Although the majority of these small molecules are not yet approved and not available in the drug market, any information related to their stage of development could represent a precious and valuable tool to identify new targets in the endless fight against metastasis.

Similarly to our healthy organs, tumor tissue also generates an ecosystem. This implies that stromal cells acquire an altered phenotype in tandem with tumor cells, thereby promoting tumor survival. Cancer cells are fueled by abnormal blood vessels, allowing them to develop and proliferate. Tumor-associated fibroblasts adapt their cytokine and chemokine production to the needs of tumor cells, alter the peritumoral stroma by generating more collagen, thereby stiffening the matrix, all promoting the epithelial-mesenchymal transition and tumor cell invasion. Chronic inflammation and the mobilization of pro-tumorigenic inflammatory cells further facilitate tumor expansion. All of these events can impede the effective administration of tumor treatment, so the successful inhibition of tumorous matrix remodeling could further enhance the success of tumor treatment. Numerous publications describe efforts to inhibit tumor matrix components, but the true breakthrough has yet to be achieved. If, on the other hand, we assume that tumorous blood vessels and inflammatory cells are residents of the tumorous stroma, then two steps forward have occurred.

Targeted cancer therapy has grown exponentially in the last decade, representing the largest frontier in the modern concept of precision medicine. This renaissance is largely due to our rapidly evolving ability to biochemically harness our immune systems to target cancer-specific antigens. Combined with an increasing armamentarium of surgical and non-invasive techniques for cancer mitigation we have upgraded cancer therapy from a non-specific assault on cell-division to a multi-modal, targeted approach. This renaissance has resulted in an increase in the perioperative footprint of patients with advanced cancer. The scope of the perioperative clinician has evolved from one of passive/reactive management of complications to a proactive approach that starts in the preoperative optimization phase and continues into the postoperative period. The perioperative world should not exist in a silo, and thus involvement of the oncology team is paramount. To provide safe oncologic care, it is essential to be up to date in newer cancer therapies, lest we act on erroneous and/or outdated information. Oncologists should weigh in on immune status, recent chemotherapeutic exposures, and potentially evolving toxicities. These might involve critical changes to perioperative infectious prophylaxis, steroid administration, and coagulopathy management. First, patients living beyond the typical life-expectancy for their cancer will carry a high burden of cancer-related downstream effects. General metabolic issues will include malnutrition, cachexia, and gastric outlet obstruction. Severe protein-calorie malnutrition, as well as hepatic and renal dysfunction can impact the metabolism and clearance of drugs. The cardiovascular, endocrinologic, pulmonary, and central nervous system implications of new cancer therapies will be discussed extensively below. Second, we have to enhance our ability to manage a cancer population who may be experiencing increasing novel chemotherapeutic toxicities. Newer agents differ from historical agents, which were blunt-force tools aimed at nonspecific destruction of cell-division. These drugs are efficacious but physiologically costly. Newer immunogenic therapies have a slightly improved acute safety profile, and a more complex chronic toxicity profile that may be overt or insidious. Chronic toxicities can present overtly or as a smoldering undertone to other active medical conditions such as sepsis, pneumonia, failure to thrive, or renal failure. The new therapies discussed in this review occur in the context of an overall increasingly multi-faceted cancer care machine. An example is screening for esophageal cancer in patients with Barrett's esophagus, or periodic chest CTs for patients with a strong history of tobacco use. These interventions are more likely to detect disease while it is still resectable, and resections will commonly accompany neo-adjuvant therapy. These approaches commonly involve new immunotherapies whose efficacy is higher-yield with a lower disease burden. In a recent example, the immune-checkpoint inhibitors (ICIs) ipilimumab plus nivolumab have significantly increased survival rate for squamous cell esophageal cancer when combined with standard chemotherapy. Surgical resection has evolved to one that often accompanies neoadjuvant chemo and radiation. The increasing efficacy of this approach may de-necessitate many major resections, and increase the number of sub-anatomic resections and minimally invasive procedures. Improved techniques - notably for hepatectomy, whipple procedure, prostatectomy, nephrectomy - have increased the safety profile and decreased the perioperative physiologic burden. This has enabled a broader subset of patients (due to cancer burden or due to medical comorbidities) to qualify for the operation, and increased the involvement of anesthesia and their perioperative services. With an increase in surgical candidacy comes an increase in post-surgical complications, and post-surgical maintenance such as drains, embolizations, imaging studies, etc. In the non-OR anesthesia realm, there have been considerable advancements in cancer “micro-treatments” such as hepatic metastasis embolization, tumor ablation, and peri-tumor vascular embolization. There are an ever-increasing number of IR-guided embolizations for bleeding tumors, aspiration of malignant effusions, and drainage of abscesses. This review serves to provide insight into new categories of chemotherapy and their perioperative implications.

LOXL2, a copper-dependent amine oxidase, has emerged as a promising therapeutic target in hepatocellular carcinoma (HCC). Increased LOXL2 expression in HCC has been linked with aggressive phenotype and represents a poor prognostic factor. Here, we focus on mechanisms by which LOXL2 orchestrates multiple oncogenic functions in HCC development. We are reviewing current knowledge about the roles of LOXL2 in the modulation of the HCC tumor microenvironment, formation of premetastatic niches, and epithelial-mesenchymal transition. Also, we are highlighting the complex interplay between LOXL2 and hypoxia, angiogenesis, and vasculogenic mimicry in HCC. At the end of the review, we summarize current LOXL2 inhibitors and discuss their potential in HCC precision treatment.

Over the last decade, the therapeutic scenario for advanced non-small-cell lung cancer (NSCLC) has undergone a major paradigm shift. Immune checkpoint inhibitors (ICIs) have shown a meaningful clinical and survival improvement in different settings of the disease. However, the real benefit of this therapeutic approach remains controversial in selected NSCLC subsets, such as those of the elderly with active brain metastases or oncogene-addicted mutations. This is mainly due to the exclusion or underrepresentation of these patient subpopulations in most of the pivotal phase III studies; this precludes the generalization of the ICI efficacy in this context. Moreover, no predictive biomarkers of ICI response exist that can help with patient selection for this therapeutic approach. Here, we critically summarize the current state of ICI efficacy in the most common “special” NSCLC subpopulations.

Background: This study analyzes sex-based differences in renal structure and response to the Angiotensin-Converting Enzyme (ACE) inhibitor enalapril in a mouse model of atherosclerosis. Methods: ApoE-/- mice (8 weeks old) received enalapril (5 mg/kg/day, subcutaneous) or PBS as a control for an additional 14 weeks. Each group consisted of six males and six females. Results: Females exhibited elevated LDL-cholesterol levels, while males presented higher creatinine levels and proteinuria. Enalapril effectively reduced blood pressure in both groups, but proteinuria decreased significantly only in females. Plaque size analysis and assessment of kidney inflammation revealed no significant sex-based differences. However, males displayed more severe glomerular injury, with increased mesangial expansion, mesangiolysis, glomerular foam cells and activated parietal epithelial cells (PECs). Enalapril mitigated mesangial expansion, glomerular inflammation (particularly in females), and the hypertrophy of PECs in males. Conclusion: This study demonstrates sex-based differences in the response to enalapril in a mouse model of atherosclerosis. Males exhibited more severe glomerular injury, while enalapril provided renal protection, particularly in females. These findings suggest potential sex-specific considerations for ACE inhibitor therapy in chronic kidney disease and atherosclerosis cardiovascular disease. Further research is needed to elucidate the underlying mechanism behind these observations.

Skin melanoma presents increasing prevalence and poor outcomes. Progression to aggressive stages is characterized by overexpression of the transcription factor E2F1 and activation of downstream prometastatic gene regulatory networks (GRNs). Appropriate therapeutic manipulation of the E2F1-governed GRNs holds the potential to prevent metastasis however, these networks entail complex feedback and feedforward regulatory motifs among various regulatory layers, which make it difficult to identify druggable components. To this end, computational approaches such as mathematical modeling and virtual screening are important tools to unveil the dynamics of these signaling networks and identify critical components that could be further explored as therapeutic targets. Herein, we integrated a well-established E2F1-mediated epithelial-mesenchymal transition (EMT) map with transcriptomics data from E2F1-expressing melanoma cells to reconstruct a core regulatory network underlying aggressive melanoma. Using logic-based in silico perturbation experiments of a core regulatory network, we identified that simultaneous perturbation of Protein kinase B (AKT1) and oncoprotein murine double minute 2 (MDM2) drastically reduces EMT in melanoma. Using the structures of the two protein signatures, virtual screening strategies were performed with the FDA-approved drug library. Thus, by combining drug repurposing and computer-aided drug design techniques, followed by molecular dynamics simulation analysis identified two potent drugs (Cialis and Finasteride) that can efficiently inhibit AKT1 and MDM2 protein signatures respectively, and with better therapeutic properties. We proposed that these two drugs could be considered for the development of therapeutic strategies for the management of aggressive melanoma.

Kinases play an important role in regulating various intracellular signaling pathways that control cell proliferation, differentiation, survival and other cellular processes and their deregulation causes more than 400 diseases. Consequently, macrocyclization can be considered a noteworthy approach to develop new therapeutic agents for human diseases. Macrocyclization has emerged as an effective drug discovery strategy over the past decade to improve target selectivity and potency of small molecules. Small compounds with linear structures upon macrocyclization can lead to changes in their physicochemical and biological properties by firmly reducing conformational flexibility. A number of distinct protein kinases exhibit similar binding sites. Comparison of protein binding site provides crucial insights for the drug discovery and development. Binding site similarities are helpful to understand polypharmacology, identifying potential off-targets and repurposing of known drugs. In this review, we focused on comparing binding sites of those kinases for which macrocyclic inhibitors are available/studied so far. Furthermore, we calculated the volume of binding site pocket for each targeted kinase and then compared it with the binding site pocket of the kinase for which only acyclic inhibitors were designed till date. Our review and analysis of several explored kinases might be useful to target new protein kinases for macrocyclic drug discovery.