Rethinking the pathogenesis of endometriosis: Complex interactions of genomic, epigenetic, and environmental factors.

AIM: Endometriosis is a complex, multifactorial disease. Recent advances in molecular biology underscore that somatic mutations within the epithelial component of the normal endometrium, alongside aberrant epigenetic alterations within endometrial stromal cells, may serve as stimulators for the proliferation of endometriotic tissue within the peritoneal cavity. Nevertheless, pivotal inquiries persist: the deterministic factors driving endometriosis development in certain women while sparing others, notwithstanding comparable experiences of retrograde menstruation. Within this review, we endeavor to synopsize the current understanding of diverse pathophysiologic mechanisms underlying the initiation and progression of endometriosis and delineate avenues for future research. METHODS: A literature search without time restriction was conducted utilizing PubMed and Google Scholar. RESULTS: Given that aberrant clonal expansion stemming from cancer-associated mutations is common in normal endometrial tissue, only endometrial cells harboring mutations imparting proliferative advantages may be selected for survival outside the uterus. Endometriotic cells capable of engendering metabolic plasticity and modulating mitochondrial dynamics, thereby orchestrating responses to hypoxia, oxidative stress, inflammation, hormonal stimuli, and immune surveillance, and adeptly acclimating to their harsh surroundings, stand a chance at viability. CONCLUSION: The genesis of endometriosis appears to reflect the evolutionary principles of mutation, selection, clonal expansion, and adaptation to the environment.

Association between rare, genetic variants linked to autism and ultrasonography fetal anomalies in children with autism spectrum disorder.

BACKGROUND: Recent evidence suggests that certain fetal anomalies detected upon prenatal ultrasound screenings are associated with autism spectrum disorder (ASD). In this cross-sectional study, we aimed to identify genetic variants associated with fetal ultrasound anomalies (UFAs) in children with ASD. METHODS: The study included all children with ASD who are registered in the database of the Azrieli National Center of Autism and Neurodevelopment and for whom both prenatal ultrasound and whole exome sequencing (WES) data were available. We applied our in-house integrative bioinformatics pipeline, AutScore, to these WES data to prioritize rare, gene-disrupting variants (GDVs) probably contributing to ASD susceptibily. Univariate statistics and multivariable regression were used to assess the associations between UFAs and GDVs identified in these children. RESULTS: The study sample comprised 126 children, of whom 43 (34.1%) had at least one UFA detected in the prenatal ultrasound scan. A total of 87 candidate ASD genetic variants were detected in 60 children, with 24 (40%) children carrying multiple variants. Children with UFAs were more likely to have loss-of-function (LoF) mutations (aOR = 2.55, 95%CI: 1.13-5.80). This association was particularly noticeable when children with structural anomalies or children with UFAs in their head and brain scans were compared to children without UFAs (any mutation: aOR = 8.28, 95%CI: 2.29-30.01; LoF: aOR = 5.72, 95%CI: 2.08-15.71 and any mutation: aOR = 6.39, 95%CI: 1.34-30.47; LoF: aOR = 4.50, 95%CI: 1.32-15.35, respectively). GDVs associated with UFAs were enriched in genes highly expressed across all tissues (aOR = 2.76, 95%CI: 1.14-6.68). There was a weak, but significant, correlation between the number of mutations and the number of abnormalities detected in the same children (r = 0.21, P = 0.016). CONCLUSIONS: The results provide valuable insights into the potential genetic basis of prenatal organogenesis abnormalities associated with ASD and shed light on the complex interplay between genetic factors and fetal development.

Decoding drug resistance in Mycobacterium tuberculosis complex: genetic insights and future challenges.

INTRODUCTION: Tuberculosis (TB), particularly its drug-resistant forms (MDR-TB and XDR-TB), continues to pose a significant global health challenge. Despite advances in treatment and diagnosis, the evolving nature of drug resistance in Mycobacterium tuberculosis (MTB) complicates TB eradication efforts. This review delves into the complexities of anti-TB drug resistance, its mechanisms, and implications on healthcare strategies globally. AREAS COVERED: We explore the genetic underpinnings of resistance to both first-line and second-line anti-TB drugs, highlighting the role of mutations in key genes. The discussion extends to advanced diagnostic techniques, such as Whole-Genome Sequencing (WGS), CRISPR-based diagnostics and their impact on identifying and managing drug-resistant TB. Additionally, we discuss artificial intelligence applications, current treatment strategies, challenges in managing MDR-TB and XDR-TB, and the global disparities in TB treatment and control, translating to different therapeutic outcomes and have the potential to revolutionize our understanding and management of drug-resistant tuberculosis. EXPERT OPINION: The current landscape of anti-TB drug resistance demands an integrated approach combining advanced diagnostics, novel therapeutic strategies, and global collaborative efforts. Future research should focus on understanding polygenic resistance and developing personalized medicine approaches. Policymakers must prioritize equitable access to diagnosis and treatment, enhancing TB control strategies, and support ongoing research and augmented government funding to address this critical public health issue effectively.

How we diagnose Myelodysplastic syndromes.

The Myelodysplastic syndromes (MDS) are a heterogenous group of clonal bone marrow (BM) stem cell myeloid neoplasms, characterized by ineffective hematopoiesis that results in dysplasia in hematopoietic cells and peripheral cytopenias, especially anemia, and a propensity to leukemic transformation. The suspicion of MDS is raised by a typical but not specific clinical picture and routine laboratory findings, but the gold standard for MDS diagnosis is still BM examination with the presence of uni-or multi-lineage dysplasia and increased blast percentage, together with exclusion of other reasons. Cytogenetics is also an essential part of the diagnostic and prognostic processes. Flow cytometry and full genetic characterization are helpful but not mandatory for MDS diagnosis. This review summarizes the current steps of diagnostic approach for a patient suspected of having MDS. We also express our hopes that within the near future, non-invasive technologies, especially digital and peripheral blood genetics, will mature and be introduced into practice.

The Role of ctDNA and Liquid Biopsy in the Diagnosis and Monitoring of Head and Neck Cancer: Towards Precision Medicine.

Recent data have shown a continued rise in the worldwide annual incidence and mortality rates of head and neck cancers. The present standard for diagnosis and monitoring for disease recurrence or progression involves clinical examination, imaging, and invasive biopsy techniques of lesions suspected of being malignant. In addition to limitations relating to cost, time, and patient discomfort, these methodologies have inherent inaccuracies for detecting recurrence. In view of these limitations, the analysis of patient bodily fluid samples via liquid biopsy proposes a cost-effective and convenient alternative, which provides insight on the biogenetic and biomolecular underpinnings of oncologic disease processes. The monitoring of biomarkers for head and neck cancer via liquid biopsy, including circulating tumor DNA, circulating tumor cells, and circulating cell-free RNA, has shown clinical utility in the screening, diagnosis, prognostication, and monitoring of patients with various forms of head and neck cancer. The present review will provide an update on the current literature examining the use of liquid biopsy in head and neck cancer care and the clinical applicability of potential biomarkers, with a focus on viral and non-viral circulating tumor DNA. Possible future avenues for research to address specific shortcomings of liquid biopsy will be discussed.

Review of susceptibility genes in developmental dysplasia of the hip: A comprehensive examination of candidate genes and pathways.

Developmental dysplasia of the hip (DDH) is one of the most prevalent skeletal deformities, primarily due to the incompatibility between the acetabulum and femoral head. It includes complete dislocation, partial dislocation, instability with femoral head subluxation, and a range of imaging abnormalities that reflect inadequate acetabular formation. Known risk factors for DDH include positive family history, sex, premature birth, non-cephalic delivery, oligohydramnios, gestational diabetes mellitus, maternal hypertension, associated anomalies, swaddling clothes, intrauterine space restriction, and post-term pregnancy. Various research designs have been employed in DDH studies to identify relevant genes, including candidate gene association studies (CGAS), genome-wide association studies (GWAS), restriction fragment length polymorphism (RFLP), and whole exome sequencing (WES). To date, multiple DDH-associated genes have been identified in various populations. Despite extensive research into the epidemiology, risk factors, and genes associated with DDH, its pathogenesis remains unclear. This study provides a comprehensive summary of DDH research designs and evidence for relevant gene mutations through a PubMed search.

Cavernous Malformations of the Central Nervous System: A Comprehensive Review of Pathophysiology, Diagnosis, and Management.

Cavernous malformations (CMs) of the central nervous system (CNS) are vascular anomalies characterized by clusters of dilated, thin-walled blood vessels prone to leakage and hemorrhage. These malformations can occur throughout the CNS, including the brain and spinal cord, and present with a wide range of clinical manifestations, from asymptomatic cases to severe neurological deficits. Advances in neuroimaging, particularly magnetic resonance imaging (MRI), have greatly improved the diagnosis and understanding of CMs, enabling more precise differentiation from other vascular lesions. The management of CMs has evolved alongside advancements in surgical and radiosurgical techniques, offering various therapeutic options depending on the lesion's characteristics and patient symptoms. While conservative management is often appropriate for asymptomatic or minimally symptomatic lesions, surgical resection or stereotactic radiosurgery may be indicated in cases with recurrent hemorrhage or significant neurological impairment. This comprehensive review explores the pathophysiology, clinical presentation, diagnosis, and management of CMs, highlighting current evidence-based practices and emerging therapeutic approaches. The review also addresses the genetic and molecular underpinnings of CMs, particularly in hereditary cases, and discusses potential future directions in research and treatment. By synthesizing the latest knowledge in the field, this review aims to enhance clinical decision-making and promote further investigation into the optimal management of CMs in the CNS.

Correlation between gene mutations and clinical characteristics in papillary thyroid cancer: a retrospective analysis of BRAF mutations and RET rearrangements.

INTRODUCTION: Activation of the MAPK pathway by genetic mutations (such as BRAF and RET) initiates and accelerates the growth of papillary thyroid carcinoma (PTC). However, the correlation between genetic mutations and clinical features remains to be established. Therefore, this study aimed to retrospectively analyze major genetic mutations, specifically BRAF mutations and RET rearrangements, and develop a treatment algorithm by comparing background and clinical characteristics. METHOD: One hundred thirteen patients with primary PTC were included in this study. BRAF mutations were detected via Sanger sequencing and RET rearrangements were detected via fluorescence in situ hybridization (FISH) analysis, and reverse transcription polymerase chain reaction (RT-PCR). The patients were categorized into two groups based on the presence of BRAF mutations and RET rearrangements and their clinical characteristics (age, sex, TNM, stage, extratumoral extension, tumor size, unifocal/multifocal lesions, vascular invasion, differentiation, chronic thyroiditis, preoperative serum thyroglobulin level, and 18F-fluorodeoxyglucose (FDG) uptake) were compared subsequently. RESULT: After excluding unanalyzable specimens, 80 PTC patients (22 males and 58 females, mean age: 57.2 years) were included in the study. RET rearrangements were positive in 8 cases (10%), and BRAF mutation was positive in 63 (78.6%). The RET rearrangement group was significantly associated with younger age (p = 0.024), multifocal lesion (p = 0.048), distant metastasis (p = 0.025) and decreased 18F-fluorodeoxyglucose uptake (p < 0.001). The BRAF mutation group was significantly associated with unifocal lesions (p = 0.02) and increased 18F-FDG uptake (p = 0.004). CONCLUSION: In this study, an increase in M classification cases was found in the RET rearrangements group. However, genetic mutations were not associated with the clinical stage, and no factors that could be incorporated into the treatment algorithm were identified.

The New Era of Therapeutic Strategies for the Management of Retinitis Pigmentosa: A Narrative Review of the Pathomolecular Mechanism for Gene Therapies.

Retinitis pigmentosa, or RP, is a group of inherited retinal degenerations involving progressive loss of photoreceptor cells- rods and cones- ultimately causing severe vision loss and blindness. RP, although a very common ailment, continues to be an incurable disease with little to be done medically. However, with the breakthroughs in gene therapy and stem cell transplantation in recent years, a new door has been opened to the treatment of RP. This narrative review summarizes the pathomolecular mechanisms of RP, focusing on the genetic and molecular abnormalities that lead to the process of retinal degeneration. In this section, we talk about the current theories of how RP develops, gene mutations, oxidative stress, and inflammation. We also delve into new therapeutic approaches such as gene therapy, stem cell transplantation and genome surgery, which are designed to either replace or repair the damaged photoreceptors to restore vision and ultimately enhance the life of the RP patient. Another topic covered is the obstacles and research frontiers of these revolutionary treatments. This article is intended to give a complete overview of the molecular processes of RP and the promising treatment strategies that could change the way this devastating disease is treated.

Triple therapy boosts survival in NSCLC patients with brain metastases: a retrospective cohort study of chemotherapy, ICIs, and antiangiogenic agents.

BACKGROUND: Treatment of brain metastases (BMs) in non-small cell lung cancer (NSCLC) patients, especially those with non-sensitive genetic mutations, is hindered by limited drug delivery through the blood-brain barrier (BBB). This retrospective study explores the efficacy of systemic treatments during brain metastasis to radiotherapy evaluation window in improving patient survival. METHODS: In this retrospective cohort study, we evaluated 209 NSCLC patients with non-sensitive mutations and BMs, treated between 2016 and 2023 at two tertiary medical centers (Chongqing University Cancer Hospital and Guangxi Medical University Cancer Hospital). The patients were divided into three groups, namely chemotherapy alone (C; n = 95), chemotherapy plus immune checkpoint inhibitors (ICIs) (C + I; n = 62), and chemotherapy with ICIs and antiangiogenic therapy (A) (C + I + A; n = 52). Statistical analyses were performed using R software, version 4.3.3. Categorical variables were compared using Fisher's exact test, and survival curves were estimated with the Kaplan-Meier method and compared via the log-rank test. Univariate and multivariate Cox regression models were used to assess factors associated with overall survival (OS). Bayesian model averaging (BMA) was employed to address model uncertainty and improve result robustness. Subgroup analyses evaluated treatment-related mortality risk. RESULTS: From an initial cohort of 658 NSCLC patients with BMs, 209 were analyzed with a median age of 59; the majority were male (80.9%) and diagnosed with adenocarcinoma (78.9%). Univariate analysis identified significant variables influencing outcomes, including BMs radiotherapy EQD2, BMs count, local thoracic treatment, BMs radiotherapy field, intracranial response, and systemic treatment post-BMs diagnosis. The C + I + A regimen significantly improved median OS to 23.6 months compared to 11.4 months with C and 16.2 months with C + I, with a hazard ratio (HR) of 0.60 (95% CI: 0.43-0.82; P < 0.0001). The two-year OS rate was highest in the C + I + A group at 38.5%, versus 10.5% in C and 20.4% in C + I (P < 0.001). Cox regression and BMA analyses confirmed the stability of BMA in providing HR estimates, yielding area under the curve (AUC) values of 0.785 for BMA and 0.793 for the Cox model, with no significant difference in predictive performance. Subgroup analysis revealed a 71% mortality risk reduction with C + I + A (HR: 0.29; 95% CI: 0.18-0.47; P < 0.0001), showing consistent benefits regardless of patient sex, BMs count, extracranial metastases presence, and local thoracic treatments. Treatment sequence analysis indicated a median OS of 33.4 months for patients starting with A, though not statistically significant (HR: 0.59; P = 0.36). The overall incidence of radiation-induced brain injury was low at 3.3%, with rates in the C, C + I, and C + I + A groups being 3.2%, 4.8%, and 1.9%, respectively (P = 0.683). CONCLUSION: Our study demonstrates the significant benefit of the C + I + A combination therapy in improving OS and reducing mortality risk in NSCLC patients with non-sensitive gene-mutated BMs. The sequential administration of A followed by ICIs shows a promising synergistic effect with cranial radiotherapy, highlighting the potential for optimized treatment sequencing. These findings emphasize the efficacy of tailored combination therapies in complex oncological care and suggest that our approach could lead to meaningful improvements in clinical outcomes for this challenging patient population.

Genetic Analysis of Melanoma Types Using Japanese Genomic Database.

OBJECTIVES: The purpose of this study is to compare genetic mutations, tumor mutation burden (TMB), and the effects of molecular targeted drugs and immune checkpoint inhibitors (ICIs) in head and neck mucosal melanoma (HNMUM) with those in skin melanoma (SKM) and ocular melanoma (OM). METHODS: Data were analyzed for 72 consecutive patients with HNMUM, including 366 with SKM and 31 with OM, registered at the Japan National Cancer Center, Center for Cancer Genomics and Advanced Therapeutics (C-CAT) between June 2019 and October 2023. Genetic alterations and TMB were determined by FoundationOne CDx next-generation sequencing. RESULTS: The top 10 mutations in HNMUM were RAD21 (47.2%), NBN (45.8%), MYC (40.3%), LYN (31.9%), NRAS (29.1%), IRF4 (23.6%), DAXX (22.2%), KIT (22.2%), NOTCH3 (20.8%), and DDR1 (19.4%), with 16.6 ± 0.8 (mean ± SEM) mutations/individual. In SKM, BRAF (p = 0.04) mutation was associated with a significantly better prognosis. The TMB values were 5.7 ± 2.1 (mean ± SEM) in HNMUM, 4.1 ± 0.2 in SKM, and 3.4 ± 0.9 in OM, with no significant differences among the three groups. The median survival time for patients with distant metastases was 803 (95% confidence interval: 539-NA) days for HNMUM, 1413 (831-2172) days for SKM, and 1138 (438-NA) days for OM. CONCLUSIONS: The top 10 mutations in HNMUM are closer to those in OM than those in SKM. There was no significant difference in TMB values or survival rates with regard to the therapeutic effect of ICIs among the diseases, which suggests that current treatment of HNMUM with ICIs is appropriate. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Genetic testing and human leukocyte antigen in patients with hypertrophic cardiomyopathy and connective tissue diseases.

Hypertrophic cardiomyopathy (HCM) is caused by myocardial hypertrophy, often due to mutations in cardiac sarcomere protein genes such as beta-myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC3). However, a significant proportion of HCM cases lack identified genetic mutations, and genotype-phenotype correlations remain unclear. Concurrently, potential associations between HCM and human leukocyte antigen (HLA) types, as well as connective tissue diseases, have been proposed. In this single-center study, we aimed to investigate the genetic and HLA profiles of patients with obstructive hypertrophic cardiomyopathy (HOCM) and connective tissue diseases, particularly focusing on the prevalence of genetic variants and HLA types. We conducted a detailed analysis of five patients with HOCM and connective tissue diseases and sarcoidosis, identifying rare variants in causative genes for HCM in two cases and observing specific HLA types that were relatively common. Notably, 15% of all HOCM cases presented with connective tissue diseases, mainly rheumatoid arthritis. These findings underscore the complexity of HCM etiology and suggest potential implications for both diagnostic strategies and therapeutic approaches in patients with concomitant inflammatory conditions.

Association between low incidence of TP53 mutations and reduced early relapse rates in Uygur DLBCL.

Diffuse large B-cell lymphoma (DLBCL) demonstrates significant heterogeneity, investigations into the distinctions in clinical and molecular characteristics between Chinese Uygur and Han DLBCL patients remain unexplored. We retrospectively reviewed 279 DLBCL patients (105 Uygur and 174 Han patients), of which 155 patients underwent genetic profiling by NGS. Compared with Han patient, Uygur patients have better clinical prognostic indicators, including a higher proportion of patients with 0-1 extranodal involvement and I/II Ann Arbor staging. Consistently, Uygur patients were significantly associated with lower risk of relapse (P = 0.06), with a one-year relapse rate of 5% vs 17% and two-year relapse rate of 19% vs 36% compared to Han patients. At the molecular level, TP53 (21.3%) was among the top frequently altered gene in the cohort. Notably, the Uygur patients exhibited a significantly lower frequency of TP53 alterations and higher frequency of ASXL3 alterations. Logistic regression analysis showed that the lowered frequency of TP53 and enrichment of ASXL3 in the Uygur patients were independent of other factors. However, only patients with TP53 mutations had higher relapse rate than those with wild type TP53 (one-year, 20% vs 10%; two-year, 51% vs 21%). Our findings highlight the notable contribution of a low TP53 mutation frequency in Uygur patients as a pivotal factor associated with the favorable prognosis of this population.

Current genetic models for studying congenital heart diseases: Advantages and disadvantages.

Congenital heart disease (CHD) encompasses a diverse range of structural and functional anomalies that affect the heart and the major blood vessels. Epidemiological studies have documented a global increase in CHD prevalence, which can be attributed to advancements in diagnostic technologies. Extensive research has identified a plethora of CHD-related genes, providing insights into the biochemical pathways and molecular mechanisms underlying this pathological state. In this review, we discuss the advantages and challenges of various In vitro and in vivo CHD models, including primates, canines, Xenopus frogs, rabbits, chicks, mice, Drosophila, zebrafish, and induced pluripotent stem cells (iPSCs). Primates are closely related to humans but are rare and expensive. Canine models are costly but structurally comparable to humans. Xenopus frogs are advantageous because of their generation of many embryos, ease of genetic modification, and cardiac similarity. Rabbits mimic human physiology but are challenging to genetically control. Chicks are inexpensive and simple to handle; however, cardiac events can vary among humans. Mice differ physiologically, while being evolutionarily close and well-resourced. Drosophila has genes similar to those of humans but different heart structures. Zebrafish have several advantages, including high gene conservation in humans and physiological cardiac similarities but limitations in cross-reactivity with mammalian antibodies, gene duplication, and limited embryonic stem cells for reverse genetic methods. iPSCs have the potential for gene editing, but face challenges in terms of 2D structure and genomic stability. CRISPR-Cas9 allows for genetic correction but requires high technical skills and resources. These models have provided valuable knowledge regarding cardiac development, disease simulation, and the verification of genetic factors. This review highlights the distinct features of various models with respect to their biological characteristics, vulnerability to developing specific heart diseases, approaches employed to induce particular conditions, and the comparability of these species to humans. Therefore, the selection of appropriate models is based on research objectives, ultimately leading to an enhanced comprehension of disease pathology and therapy.

Advances in Melanoma: From Genetic Insights to Therapeutic Innovations.

Advances in melanoma research have unveiled critical insights into its genetic and molecular landscape, leading to significant therapeutic innovations. This review explores the intricate interplay between genetic alterations, such as mutations in BRAF, NRAS, and KIT, and melanoma pathogenesis. The MAPK and PI3K/Akt/mTOR signaling pathways are highlighted for their roles in tumor growth and resistance mechanisms. Additionally, this review delves into the impact of epigenetic modifications, including DNA methylation and histone changes, on melanoma progression. The tumor microenvironment, characterized by immune cells, stromal cells, and soluble factors, plays a pivotal role in modulating tumor behavior and treatment responses. Emerging technologies like single-cell sequencing, CRISPR-Cas9, and AI-driven diagnostics are transforming melanoma research, offering precise and personalized approaches to treatment. Immunotherapy, particularly immune checkpoint inhibitors and personalized mRNA vaccines, has revolutionized melanoma therapy by enhancing the body's immune response. Despite these advances, resistance mechanisms remain a challenge, underscoring the need for combined therapies and ongoing research to achieve durable therapeutic responses. This comprehensive overview aims to highlight the current state of melanoma research and the transformative impacts of these advancements on clinical practice.

Influence of genetic mutations to atria vulnerability to atrial fibrillation: An in-silico 3D human atria study.

BACKGROUND AND OBJECTIVE: Personalized 3D computer models of atria have been extensively implemented in the last yearsas a tool to facilitate the understanding of the mechanisms underlying different forms of arrhythmia, such as atrial fibrillation (AF). Meanwhile, genetic mutations acting on potassium channel dynamics were demonstrated to induce fibrillatory episodes in asymptomatic patients. This research study aims at assessing the effects and the atrial susceptibility to AF of three gain-of-function mutations - namely, KCNH2 T895M, KCNH2 T436M, and KCNE3-V17M - associated with AF outbreaks, using highly detailed 3D atrial models with realistic wall thickness and heterogenous histological properties. METHODS: The 3D atrial model was generated by reconstructing segmented anatomical structures from CT scans of an AF patient. Modified versions of the Courtemanche human atrial myocyte model were used to reproduce the electrophysiological activity of the WT and of the three mutant cells. Ectopic foci (EF) were simulated in sixteen locations across the atrial mesh using an S1-S2 protocol with two S2 basic cycle lengths (BCL) and eleven coupling intervals in order to induce arrhythmias. RESULTS: The three genetic mutations at 3D level reduced the APD90. The KCNE3-V17M mutation provoked the highest shortening (55 % in RA and LA with respect to WT), followed by KCNH2 T895M (14 % in RA and 18 % LA with respect to WT)and KCNH2 T436M (7 % in RA and 9 % LA with respect to WT). The KCNE3-V17M mutation led to arrhythmia in 67 % of the cases simulated and in 94 % of ectopic foci considered, at S2 BCL equal to 100 ms. The KCNH2 T436M and KCNH2 T895M mutations increased the vulnerability to AF in a similar way, leading to arrhythmic episodes in 7 % of the simulated conditions, at S2 BCL set to 160 ms. Overall, 60 % of the arrhythmic events generated arise in the left atrium. Spiral waves, multiple rotors and disordered electrical pattern were elicited in the presence of the KCNE3-V17M mutation, exhibiting an instantaneous mean frequency of 7.6 Hz with a mean standard deviation of 1.12 Hz. The scroll waves induced in the presence of the KCNH2 T436M and KCNH2 T895M mutations showed steadiness and regularity with an instantaneous mean frequencies in the range of 4.9 - 5.1 Hz and a mean standard deviation within 0.19 - 0.53 Hz. CONCLUSIONS: The pro-arrhythmogenicity of the KCNE3-V17M, KCNH2 T895M and KCNH2 T436M mutations was studied and proved on personalized 3D cardiac models. The three genetic mutations were demonstrated to increase the predisposition of atrial tissue to the formation of AF-susceptible substrate in different ways based on their effects on electrophysiological properties of the atria.

Personalized Medicine in Pancreatic Cancer: The Promise of Biomarkers and Molecular Targeting with Dr. Michael J. Pishvaian.

Pancreatic cancer, with its alarming rising incidence, is predicted to become the second deadliest type of solid tumor by 2040, highlighting the urgent need for improved diagnostic and treatment strategies. Despite medical advancements, the five-year survival rate for pancreatic cancer remains about 14%, dropping further when metastasized. This review explores the promise of biomarkers for early detection, personalized treatment, and disease monitoring. Molecular classification of pancreatic cancer into subtypes based on genetic mutations, gene expression, and protein markers guides treatment decisions, potentially improving outcomes. A plethora of clinical trials investigating different strategies are currently ongoing. Targeted therapies, among which those against CLAUDIN 18.2 and inhibitors of Claudin 18.1, have shown promise. Next-generation sequencing (NGS) has emerged as a powerful tool for the comprehensive genomic analysis of pancreatic tumors, revealing unique genetic alterations that drive cancer progression. This allows oncologists to tailor therapies to target specific molecular abnormalities. However, challenges remain, including limited awareness and uptake of biomarker-guided therapies. Continued research into the molecular mechanisms of pancreatic cancer is essential for developing more effective treatments and improving patient survival rates.

The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease mainly characterized by the accumulation of ubiquitinated proteins in the affected motor neurons. At present, the accurate pathogenesis of ALS remains unclear and there are still no effective treatment measures for ALS. The potential pathogenesis of ALS mainly includes the misfolding of some pathogenic proteins, the genetic variation, mitochondrial dysfunction, autophagy disorders, neuroinflammation, the misregulation of RNA, the altered axonal transport, and gut microbial dysbiosis. Exploring the pathogenesis of ALS is a critical step in searching for the effective therapeutic approaches. The current studies suggested that the genetic variation, gut microbial dysbiosis, the activation of glial cells, and the transportation disorder of extracellular vesicles may play some important roles in the pathogenesis of ALS. This review conducts a systematic review of these current potential promising topics closely related to the pathogenesis of ALS; it aims to provide some new evidences and clues for searching the novel treatment measures of ALS.

Molecular landscape of borderline ovarian tumours: A systematic review.

Borderline ovarian tumours (BOTs) show intriguing characteristics distinguishing them from other ovarian tumours. The aim of the systematic review was to analyse the spectrum of molecular changes found in BOTs and discuss their significance in the context of the overall therapeutic approach. The systematic review included articles published between 2000 and 2023 in the databases: PubMed, EMBASE, and Cochrane. After a detailed analysis of the available publications, we qualified for the systematic review: 28 publications on proto-oncogenes: BRAF, KRAS, NRAS, ERBB2, and PIK3CA, 20 publications on tumour suppressor genes: BRCA1/2, ARID1A, CHEK2, PTEN, 4 on adhesion molecules: CADM1, 8 on proteins: B-catenin, claudin-1, and 5 on glycoproteins: E-Cadherin. In addition, in the further part of the systematic review, we included eight publications on microsatellite instability and three describing loss of heterozygosity in BOT. Molecular changes found in BOTs can vary on a case-by-case basis, identifying carcinogenic mutations through molecular analysis and developing targeted therapies represent significant advancements in the diagnosis and treatment of ovarian malignancies. Molecular studies have contributed significantly to our understanding of BOT pathogenesis, but substantial research is still required to elucidate the relationship between ovarian neoplasms and extraneous disease, identify accurate prognostic indicators, and develop targeted therapeutic approaches.

Molecular analysis of genetic mutations in non-small cell lung cancer in Morocco.

Non-small cell lung cancer (NSCLC) is a significant global health issue with diverse molecular profiles affecting treatment responses. Yet, NSCLC's molecular epidemiology in Morocco is largely unexplored. This study focuses on NSCLC genetic mutations, specifically in adenocarcinoma, among Moroccan patients to contribute to understanding NSCLC in this population. Ninety-four patients diagnosed with lung adenocarcinoma were analyzed. Formalin-fixed paraffin-embedded tissue samples were processed, and deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) was extracted using standardized protocols. Mutations were detected using the AmoyDx Pan Lung Cancer Polymerase Chain Reaction (PCR) Panel kit, and their frequencies were assessed through statistical analysis. Epidermal Growth Factor Receptor (EGFR) mutations were detected in 22.34% of patients, predominantly exon 19 deletions (66.66%) and exon 21 L858R mutations (23.80%). Anaplastic lymphoma kinase (ALK) gene fusion was observed in 3.19% of patients, and KRAS mutations in 1.06%. No mutations were found in other tested genes. A slightly higher mutation rate was noted in females (54.16%) compared to males (45.84%). The study reveals a distinct mutation profile in Moroccan NSCLC patients, with a notable prevalence of EGFR mutations, albeit lower than in some Asian populations. The significance of EGFR mutations in treatment response aligns with global findings, highlighting the importance of understanding regional molecular variations for personalized therapy. Despite limitations in sample size and clinical data, this study sheds light on the genetic landscape of NSCLC in Morocco. The observed mutation rates, particularly in EGFR, underscore the potential for targeted therapies in Moroccan NSCLC patients, emphasizing the need for further research to refine treatment strategies tailored to this population.