UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

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.

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.

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.

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.

OBJECTIVE: 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.
METHODS: 3 Laryngoscope, 2024.

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.

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.

Genetic mutations and chronic inflammation of the colon contribute to the development of colorectal cancer (CRC). Using a murine model of inflammation-induced colon tumorigenesis, we determined how genetic mutations alter colon tumor cell differentiation. Inflammation induced by enterotoxigenic Bacteroides fragilis (ETBF) colonization of multiple intestinal neoplasia (MinApcΔ716/+) mice triggers loss of heterozygosity of Apc causing colon tumor formation. Here, we report that the addition of BRAFV600E mutation (BRAFF-V600ELgr5tm1(Cre/ERT2)CleMinApcΔ716/+, BLM) or knocking out Msh2 (Msh2LoxP/LoxPVil1-creMinApcΔ716/+, MSH2KO) in the Min model altered colon tumor differentiation. Using single-cell RNA sequencing, we uncovered the differences between BLM, Min, and MSH2KO tumors at a single-cell resolution. BLM tumors showed an increase in differentiated tumor epithelial cell lineages and a reduction in the tumor stem cell population. Interestingly, the tumor stem cell population of BLM tumors had revival colon stem cell characteristics with low WNT signaling and an increase in RevCSC marker gene expression. In contrast, MSH2KO tumors were characterized by an increased tumor stem cell population that had higher WNT signaling activity compared to Min tumors. Furthermore, overall BLM tumors had higher expression of transcription factors that drive differentiation, such as Cdx2, than Min tumors. Using RNA velocity, we identified additional potential regulators of BLM tumor differentiation such as NDRG1. The role of CDX2 and NDRG1 as putative regulators for BLM tumor cell differentiation was verified using organoids derived from BLM tumors. Our results demonstrate the critical connections between genetic mutations and cell differentiation in inflammation-induced colon tumorigenesis. Understanding such roles will deepen our understanding of inflammation-associated colon cancer.

Cervical cancer is the fourth most common cancer in women. Advanced stage and metastatic disease are often associated with poor clinical outcomes. This substantiates the absolute necessity for high-throughput diagnostic and treatment platforms that are patient and tumour specific. Cervical cancer treatment constitutes multimodal intervention. Systemic treatments such as chemotherapy and/or focal radiotherapy are typically applied as neoadjuvant and/or adjuvant strategies. Cisplatin constitutes an integral part of standard cervical cancer treatment approaches. However, despite initial patient response, de novo or delayed/acquired treatment resistance is often reported, and toxicity is of concern. Chemotherapy resistance is associated with major alterations in genomic, metabolomic, epigenetic and proteomic landscapes. This results in imbalanced homeostasis associated with pro-oncogenic and proliferative survival, anti-apoptotic benefits, and enhanced DNA damage repair processes. Although significant developments in cancer diagnoses and treatment have been made over the last two decades, drug resistance remains a major obstacle to overcome.
Despite advances in treatment, the disease’s advanced stages and spread to other parts of the body often lead to poor outcomes. This highlights the urgent need for better diagnostic and treatment methods tailored to each patient and their specific tumour. Treatment for cervical cancer usually involves a combination of therapies. Chemotherapy and focused radiation therapy are commonly used before or after surgery to improve outcomes. However, some patients develop resistance to these treatments, either from the start or after initially responding to therapy. This resistance can make treatment less effective and increase the risk of side effects. Chemotherapy resistance is often linked to changes in the genes and proteins of cancer cells. These changes disrupt the normal balance within the cells, making them more prone to grow and survive, resist cell death, and repair DNA damage caused by treatment. Despite progress in cancer research and treatment, drug resistance remains a significant challenge. This review aims to explore how acquired genetic mutations contribute to drug resistance in cervical cancer. By understanding these mutations better, researchers and clinicians in low- to middle-income countries can develop more effective treatment strategies to improve outcomes for patients.