Search Results (1,791)

Background/Objectives: In recent years there has been a consistent development of clinical studies surrounding the incorporation of the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (VEN) into the treatment of acute myeloid leukemia (AML) Methods: A search of the literature showed a tremendous development of experimental and clinical studies evaluating the impact of VEN-based regimens in the treatment of AML patients. This review comprehensively analyzes the available scientific evidence—including prospective clinical trials, retrospective cohorts, and real-world studies—to summarize current knowledge on the efficacy and safety of venetoclax-based regimens in AML patients. Results: Recent studies have evaluated VEN-based regimens in newly diagnosed (ND) and refractory/relapsed (R/R) AML patients, showing the efficacy of these treatments. VEN with hypomethylating agents (HMAs) became the standard-of-care for elderly/unfit AML patients. Recent studies strongly support the effectiveness of VEN-based regimens in frontline treatment of adult AML patients eligible for intensive treatments. VEN-based therapies were also used in combination with targeted therapies, thus generating triplet therapeutic regimens that are under evaluation for the treatment of some AML subtypes. However, the response to VEN+HMAs is highly variable and in part depends on tumor genetics; some patients are resistant or relapse following VEN-based treatments and future studies will be required to develop therapeutic strategies able to circumvent resistance and to identify patients at high risk of relapse. Prospective randomized trials are required to establish the real efficacy of VEN in various clinical settings and to refine maintenance and discontinuation strategies, aiming to improve long-term outcomes and to make more safe treatments based on VEN. Full article

Worster-Drought syndrome (WDS), also known as congenital suprabulbar paresis, is a rare neurodevelopmental disorder characterized by feeding, swallowing, drooling, and speech disturbances. Currently, it is classified as a subtype of cerebral palsy. However, the limited number of studies and the clinical and radiological overlap with related entities such as congenital bilateral perisylvian syndrome (CBPS) and Foix-Chavany-Marie syndrome (FCMS) have contributed to persistent uncertainty regarding its proper classification. In this review, we summarize the current knowledge on the WDS based on data from published case series. Special emphasis is placed on proposed etiological mechanisms, including recent genetic findings potentially contributing to WDS, as well as on the diagnostic process, ongoing classification dilemmas, and spectrum-based perspective. We point out the need to establish standardized diagnostic criteria and conduct large-scale genetic and neurodevelopmental research. Addressing these gaps may help clarify the underlying pathophysiology, reappraise the classification framework, and ultimately minimize misdiagnosis and time to proper diagnosis to improve outcomes for individuals affected by WDS. Full article

Biological heterogeneity among different breast cancer (BC) subtypes results in markedly varying clinical outcomes. Identification and analysis of key gene biomarkers that are differentially regulated during radiation therapy (RT) may pose multiple clinical challenges for BC treatment. The purpose of the study is to identify and analyze the expression of key gene biomarkers and their networks that are differentially regulated after hypofractionated RT. Patients with BC (cT0-T2, N0, M0) were treated with hypofractionated whole breast RT 25 Gy in five fractions, 4 to 8 weeks before breast conservation surgery (BCS). Biopsy (pre-RT; n = 5) and surgical (post-RT; n = 14 or 15) BC tumor samples were used for NanoString targeted sequencing. We identified 165 and 244 differentially expressed genes (DEGs; p < 0.05) in BC tumor samples from BC patients post-RT using the nCounter BC360 and IO360 panels, respectively. Gene networks and pathway analysis revealed that RT increases the gene signature of tumor inflammation (TIS), cytotoxicity, and apoptosis, while downregulating the gene signatures of tumor cell proliferation, differentiation, and cell adhesion, and increases the claudin-low gene score. RT-induced mammary stemness and enhanced infiltration of stroma, mast, and macrophage cells in the BC tumor microenvironment (TME). Further, the nCounter IO360 (immuno-oncology) panel analysis validated the findings of BC360 and demonstrated that RT increased the myeloid inflammation signature and chemokine expression, modulated B, T, NK, and DC cell activities, and enhanced residual cancer burden (RCB) in BC tumors, thus creating an immunosuppressive TME. Collectively, RT sensitized BC tumors by increasing the gene signature of TIS, cytotoxicity, apoptosis, and mammary stemness. RT facilitated an immunosuppressive environment and increased RCB, suggesting that the therapeutic potential of RT is highly individualized for each patient based on their unique tumor biology, genetic makeup, and TME. Full article

Tick-borne encephalitis virus (TBEV) is primarily transmitted by Ixodes spp. and poses significant health risks, leading to morbidity and mortality in humans. Two of the five subtypes, Siberian and Far Eastern are known to circulate in Mongolia. In 2021, Ixodes persulcatus ticks were collected from Bulgan aimag (province) using flagging and dragging methods and subsequently screened for TBEV using PCR. Positive samples underwent sequencing using an Oxford Nanopore Technologies-based hybrid capture approach, resulting in two coding-complete TBEV genomes from separate tick pools. Phylogenetic analysis classified both genomes within the Siberian subtype, grouping them with other Mongolian sequences from I. persulcatus collected in 2014, 2020, 2021, and 2023. The study sequences, PX654173 and PX654174, showed high genetic similarity (99.9% and 99.8%, respectively) to the sequence PQ479142, obtained from I. persulcatus ticks in Selenge, Mongolia, in 2021. The estimated time to most recent common ancestor (TMRCA) of the Siberian genotype was approximately 981 CE (95% HPD: 646–1347) with the emergence of a distinct Mongolian clade of TBEV around 1888 CE (95% HPD: 1834–1934). These findings highlight the value of expanded whole-genome sequencing to improve our understanding of TBEV’s genetic diversity and evolutionary history in Central Asia. Full article

Differentiated thyroid cancer (DTC), including papillary and follicular subtypes, is generally associated with favorable prognosis; however, a subset of patients develops recurrent, metastatic, or radioiodine-refractory diseases with limited therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently emerged as a biologically relevant process in thyroid cancer, yet its role in differentiated disease remains incompletely defined. Unlike many other malignancies, thyroid cancer arises within an organ intrinsically shaped by iodine-dependent redox reactions required for thyroid hormone biosynthesis. This unique oxidative environment imposes selective pressure on tumor cells to adapt redox balance, lipid metabolism, and antioxidant defenses, all of which are central regulators of ferroptosis. Accumulating evidence indicates that ferroptosis susceptibility in DTC is dynamically modulated by differentiation status, oncogenic signaling, metabolic rewiring, and tumor microenvironmental interactions. Notably, progression toward radioiodine-refractory disease is accompanied by dedifferentiation and reinforcement of anti-ferroptotic programs, linking ferroptosis resistance to therapeutic failure. In this review, we synthesize recent original studies and contemporary reviews to provide a focused overview of ferroptosis in DTC, excluding anaplastic disease. We discuss thyroid-specific redox and iodine metabolism, genetic and metabolic determinants of ferroptosis sensitivity, lipid remodeling, and immune–microenvironmental interactions, and highlight translational opportunities for targeting ferroptosis in radioiodine-refractory DTC. By reframing ferroptosis as a context-dependent vulnerability rather than a universal death pathway, this review outlines a conceptual roadmap for integrating ferroptosis modulation into existing therapeutic strategies for DTC. Full article

Background: Breast cancer susceptibility gene 1 (BRCA1) is a pivotal regulator of DNA repair, and its loss through germline mutations is strongly linked to the development of aggressive breast cancers with characteristic clinical and pathological features. Beyond genetic disruption, epigenetic silencing via promoter hypermethylation has emerged as a non-mutational mechanism of tumour suppressor inactivation and a potential biomarker for guiding therapeutic decisions. Here, we investigate BRCA1 promoter methylation, its impact on gene expression, and its association with clinicopathological features in a cohort of African women with breast cancer. Methods: Matched tumour and adjacent normal tissues from 27 Black African women with breast cancer were analysed for BRCA1 promoter methylation and gene expression using bisulfite pyrosequencing and quantitative real-time PCR. Associations with clinicopathological variables were assessed using Spearman’s correlation analyses. Results: Five CpG sites within the BRCA1 promoter were significantly hypermethylated in breast tumours compared with matched adjacent normal tissues and showed an inverse association with BRCA1 mRNA expression. Elevated promoter methylation was enriched in hormone receptor-negative and triple-negative breast cancer subtypes and was not influenced by neoadjuvant chemotherapy. BRCA1 promoter methylation occurred independently of BRCA1 mutational status. No significant associations were observed between BRCA1 methylation and age, body mass index, smoking status, or alcohol consumption. Conclusions: Our findings provide evidence of BRCA1 epigenetic silencing in breast tumours from African women, particularly within aggressive hormone receptor-negative subtypes. These results suggest that BRCA1 promoter methylation may represent a clinically informative biomarker for patient stratification and highlight the importance of validation in larger, population-representative cohorts before clinical translation. Full article

Background/Objectives: Acute promyelocytic leukemia (APL) is a high-risk subtype of acute myeloid leukemia and requires rapid diagnosis to avoid early mortality. Current clinical diagnostic and genetic tests are time-consuming, expensive, and complex. Notably, all these tests depend on bone marrow aspiration and are intensely invasive, resulting in poor patient compliance. This study aimed to develop a rapid, explainable, and accurate auxiliary tool for cell-level detection of abnormal promyelocytes in peripheral blood smears, which can serve as a key clue for suspecting APL. Methods: We developed a multi-stage deep learning (DL) model that automatically read images of peripheral blood smears (PBSs), accurately segmented cells, and identified abnormal promyelocytes using only image data. We retrospectively reviewed a total of 114 bone marrow smears (42 APL patients and 72 non-APL patients) and 158 PBSs (30 APL patients and 128 non-APL patients) at the Fifth Affiliated Hospital of Harbin Medical University and collected 223,123 cell images for training. Then, the efficacy of EfficientDet in APL screening was evaluated with an additional 150 PBSs (50 from APL patients and 100 from non-APL patients) and finally compared with manual microscopy. Results: EfficientDet exhibited superior overall screening performance compared with pathologists in the identification of abnormal promyelocytes. Conclusions: Our findings suggest that the DL approach we describe herein is promising as a practical tool for abnormal promyelocyte detection and early APL screening, raising attention to suspected cases of APL for expert evaluation and further reducing diagnostic delays. Full article

Background/Objectives: Inherited retinal diseases (IRDs) represent a genetically heterogeneous group of disorders caused by mutations in over 280 genes with more than 3100 identified variants. While gene-specific replacement therapies have achieved landmark success with voretigene neparvovec (Luxturna) for biallelic RPE65-associated retinal dystrophy, developing individual therapies for each genetic subtype remains impractical. This review examines gene-agnostic therapeutic approaches utilizing neuroprotection and immunomodulation that target common pathophysiological mechanisms shared across multiple IRD genotypes. Methods: We reviewed the literature on neuroprotective and immunomodulatory gene therapy strategies for IRDs, focusing on neurotrophic factors and complement system modulation. Results: Neuroprotective approaches delivering neurotrophic factors—including pigment epithelium-derived factor (PEDF), ciliary neurotrophic factor (CNTF), rod-derived cone viability factor (RdCVF), brain-derived neurotrophic factor (BDNF), fibroblast growth factors (FGFs), glial cell line-derived neurotrophic factor (GDNF), and proinsulin—have demonstrated photoreceptor preservation across multiple preclinical IRD models regardless of the underlying genetic mutation. The recent FDA approval of CNTF cell-based gene therapy (Encelto) for macular telangiectasia type 2 validates this therapeutic paradigm. Complement system inhibition represents another gene-agnostic strategy, with intravitreal complement inhibitors approved for geographic atrophy secondary to age-related macular degeneration and gene therapy approaches targeting C3, C5, or delivering soluble complement regulators under investigation for IRDs. Combination strategies simultaneously addressing multiple pathogenic pathways may offer synergistic benefits. Conclusions: Gene-agnostic approaches targeting neuroprotection and immunomodulation offer a therapeutic paradigm capable of benefiting patients across the spectrum of IRD genotypes, potentially transforming treatment for conditions where mutation-specific therapies remain unavailable. Full article

Bipolar disorder (BD) is characterized by mood swings between mania and depression, sharing overlapping symptomatic and genetic risk factors with other mood disorders. Long non-coding RNAs (lncRNAs) show specific spatiotemporal precision in distinct cell types in the human brain, and understanding the precise mechanisms of lncRNAs in mood switching in BD is fundamental to deciphering the key molecular networks underlying BD diagnosis and therapy. In this review, we summarize the classification of BD subtypes, the differences between BD and multiple mood disorders, and the functional potential of lncRNAs in BD. Future studies of these lncRNAs will facilitate the development of RNA-based diagnosis for BD. Full article

Diagnostic testing of foot-and-mouth disease virus (FMDV) currently utilizes reverse transcription quantitative PCR (RT-qPCR) to detect the presence of viral RNA and double antibody sandwich ELISAs (DAS-ELISAs) to determine viral serotype. Serotype identification is critical to support informed vaccine selection to combat outbreaks. While DAS-ELISAs are capable of serotype identification, the test suffers from low sensitivity and requires a viral isolate for successful detection. In this study, we developed FMDV-ONTAPS: an Oxford Nanopore Technologies Amplicon P1 Sequencing protocol involving reverse transcription-PCR to amplify P1 of the FMDV genome, and Nanopore sequencing of the amplicons to provide genetic data for serotype and subtype/topotype identification. FMDV isolates representing all seven serotypes were successfully sequenced with this method. Additionally, the protocol successfully provided serotype identification from a variety of specimen matrices obtained from experimentally infected animals that included milk, serum, oral and nasal swabs, tissue suspensions, vesicular fluid, and oral fluid. The limit of detection for FMDV cell culture isolates was comparable for both sequencing and RT-qPCR detection. RT-qPCR Cq values for clinical samples evaluated ranged from 8 to 28.21. Sequencing was successful for all samples except for a single tissue suspension sample (Cq of 28.21). Identification of FMDV serotype in clinical samples is critical for effective outbreak response, and Nanopore sequencing offers a timelier and more sensitive alternative to DAS-ELISAs. Full article

Johne’s disease, caused by Mycobacterium avium subsp. paratuberculosis (MAP), is endemic in Saudi Arabia and contributes to substantial production losses in small-ruminant herds. This study investigated MAP infection in 388 locally raised small ruminants (151 sheep and 237 goats) using IS900 real-time PCR (qPCR) on fecal samples and indirect ELISA on serum samples. Ziehl–Neelsen (ZN) staining and pathological assessment were applied as supportive tools in necropsied cases. Overall, qPCR detected MAP DNA in 135/388 animals (34.8%), with higher positivity in goats (100/237; 42.1%) than in sheep (35/151; 23.1%). ELISA detected MAP antibodies in 120/388 animals (30.9%), including 90/237 goats (37.9%) and 30/151 sheep (19.8%). Based on clinical examination (presence/absence of clinical signs), qPCR-positive animals were categorized as subclinical (n = 15; 10 goats and 5 sheep) or clinically progressed (n = 120; 90 goats and 30 sheep). Gross and histopathological findings were assessed in a necropsied subset (n = 20; 10 subclinical and 10 clinically progressed), revealing mild focal granulomatous enteritis with scant acid-fast bacilli in subclinical cases and diffuse lepromatous-type granulomatous lesions with abundant bacilli in clinically progressed animals. Genotyping and subtyping were performed on tissue-derived DNA from six necropsied cases using DMC, IS900, and F57 targets, and IS900 sequencing confirmed the circulation of both Type C/II and Type S/I MAP strains. Collectively, these findings demonstrate widespread MAP infection among small ruminants in Saudi Arabia, with higher detection rates and more pronounced pathology in goats, and highlight the genetic heterogeneity of circulating MAP strains. Full article

Introduction: Brain metastases represent a major clinical challenge due to a distinct immunosuppressive microenvironment and limited, heterogeneous efficacy of PD-1/PD-L1 immune checkpoint inhibition. The adenosine pathway, mediated by the ectonucleotidases CD39 and CD73, has emerged as an alternative immune escape mechanism, yet its relevance in brain metastases across tumor entities remains insufficiently characterized. Methods: We conducted targeted panel sequencing of brain metastases from multiple primary tumor entities and evaluated compartment-resolved expression of CD39, CD73, and PD-L1 by immunohistochemistry, distinguishing tumor cell and immune cell expression. Tumor mutational burden (TMB), recurrent gene alterations, and gene fusions were analyzed and integrated with immune marker profiles to define immunogenomic subtypes. Results: Brain metastases displayed a heterogeneous mutational landscape with recurrent alterations including TP53, KRAS, PIK3CA, and APC. CD39 and CD73 expression was frequent and highly variable, occurring on both tumor cells and tumor-infiltrating immune cells, and only partially overlapping with PD-L1 expression. A substantial subset of cases exhibited an adenosine-high phenotype despite low or absent PD-L1. Marker-associated enrichment analyses identified distinct genetic correlates, including enrichment of KRAS alterations in tumors with CD39/CD73 positivity on malignant cells, and APC/PIK3CA-associated patterns linked to immune compartment marker expression. TMB did not significantly differ across major tumor entity groups. Gene fusions were detected in a subset of tumors but were largely independent of immune phenotypes. Conclusions: Adenosine pathway activation is a frequent, genetically associated immune escape feature of brain metastases that complements PD-L1-based stratification. Integrating CD39/CD73 with PD-L1 enables actionable immunogenomic subtyping and supports rational immunotherapy strategies targeting adenosine-mediated immunosuppression. Full article

The 2025 approval of the selective NaV1.8 blocker suzetrigine for acute pain marked a pivotal advance in analgesic drug development. Yet the subsequent failure of Vertex’s next-generation NaV1.8 inhibitor VX993 to demonstrate clinical analgesia underscores enduring challenges in translating mechanistic promise into patient benefit. This review examines why promising targets and compounds, spanning NaV and TRP channels, often falter and outlines a path toward more reliable target selection and validation. I first summarize the pain pathway, from nociceptor transduction through spinal processing to cortical perception, emphasizing how inflammation and peripheral sensitization reshape excitability. Historically serendipitous, pain drug discovery now prioritizes molecular precision. Most approved chronic pain therapies act in the CNS and are limited by modest efficacy and adverse effects. Nociceptor-enriched targets (NaV1.7/1.8/1.9; TRP channels) remain attractive, yet redundancy among NaV subtypes and the necessity of blocking targets at the correct anatomical sites complicate translation. Human genetics and multi-omics provide a powerful, unbiased engine for target discovery. Rare high-impact variants offer strong causal hypotheses, while common polygenic contributions illuminate broader susceptibility. Large biobanks increasingly reveal a mismatch between legacy pain targets and genetically supported candidates across neuronal and non-neuronal cells. Human DRG transcriptomics highlight NaV channel redundancy. Human in vitro electrophysiology and PK/PD analyses show suzetrigine achieves ~90–95% NaV1.8 engagement, yet neurons can still fire unless additional channels are blocked. Species differences and drug distribution (including BBB/PNS penetration and P-gp efflux) critically influence efficacy; centrally accessible blockade (e.g., for NaV1.7 or TRPA1) may be necessary to achieve robust analgesia, challenging peripherally restricted strategies. Osteoarthritis illustrates how obesity-driven metabolic inflammation, synovial immune activation, subchondral bone remodeling, and specific nociceptor subtypes converge to drive mechanical pain. Multi-omic integration across diseased human tissues can pinpoint causal processes and cell types, enabling more selective and safer target choices. I propose a practical framework for target validation that integrates: (i) rigorous human genetic support; (ii) cell-type and site-of-action mapping; (iii) human-relevant electrophysiology and PK/PD with verified target engagement; (iv) species-appropriate models; (v) consideration of modality (small molecule, biologic, RNA, targeted protein degradation). Advancing genetically and anatomically aligned targets, tested at the right sites and exposures, offers the best path to genuinely effective, better-tolerated pain therapeutics. Full article

The features of patients with multiple urothelial tumors remain to be elucidated. We intend to differentiate primary upper tract urothelial carcinoma with synchronous urothelial bladder cancer (UTUC + sUBC) and UTUC with metachronous UBC (UTUC + mUBC) cases to determine whether these temporal patterns reflect biologically distinct processes. A subgroup analysis of a retrospective cohort of UTUC (n = 114) was performed comparing UTUC + sUBC (n = 14) with UTUC + mUBC (n = 29). IHC expression of cytokeratin 5/6 (CK5/6), CK20, GATA3, and p53 was evaluated to assess relevant subtypes. Genetic characterization comprised TERTp, FGFR3, RAS, and TP53 status. Kaplan–Meier analyses estimated the progression-free survival (PFS) and overall survival (OS) of both UTUC subgroups, and the log-rank test was used to assess differences between subgroups. Our study reveals no significant differences in phenotype or genomic profile between synchronous and metachronous UTUC-UBC cases (p > 0.05). Nevertheless, patients with synchronous UBC revealed significantly worse outcomes in PFS (2y-PFS 23.1% vs. 52.1%, p = 0.029) and OS (2y-OS 40.4% vs. 84.4%, p = 0.016) than those with metachronous disease. These discrepancies could arise from as yet-uncharacterized molecular features or microenvironmental influences. Full article

Introduction: PMBCL is an aggressive type of lymphoma characterized by high heterogeneity in clinical, molecular, and genetic features. In PMBCL, disturbances in the NFkB pathway and deregulation of BCL-2 and mTOR family proteins are observed, which may contribute to impaired apoptosis. Therefore, many strategies have been established to target the functioning of these pathways. Early clinical trials of mTOR, NFkB and Bcl-2 inhibitors suggest their activity in many hematological cancers, but their activity as monotherapy agents may still be insufficient; therefore, combinations of these compounds with other molecules acting on those active in a given cancer subtype are being sought. Materials and Methods: In vitro studies were conducted on a single PMBCL cell line, Karpas 1106P. We administered three novel drugs: AZD2014 (vistusertib), an inhibitor of the serine-threonine kinase mTOR; IMD-0354, an NFκB inhibitor; and ABT-199 (venetoclax), a highly selective inhibitor for BCL-2. Drugs were administered alone, in pairs and in combination of all three agents. Results: Based on the results of our own research, for the Karpas cell line individually, ABT-199 had the strongest pro-apoptotic effect on cancer cells, while in pairs the most potent induction of apoptosis occurred following treatment with AZD2014+ABT-199. The combination of three drugs did not have a stronger effect than either a single drug used alone or any two-drug combination. Conclusions: These results provide preliminary in vitro evidence that targeting the BCL-2 and mTOR pathways may enhance pro-apoptotic activity in a PMBCL cell model; however, further validation in additional cell lines and in vivo models is needed before translational implications can be considered. Full article