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Combining germline, tissue and liquid biopsy analysis by comprehensive genomic profiling to improve the yield of actionable variants in a real-world cancer cohort.

BACKGROUND: Comprehensive next-generation sequencing is widely used for precision oncology and precision prevention approaches. We aimed to determine the yield of actionable gene variants, the capacity to uncover hereditary predisposition and liquid biopsy appropriateness instead of, or in addition to, tumor tissue analysis, in a real-world cohort of cancer patients, who may benefit the most from comprehensive genomic profiling. METHODS: Seventy-eight matched germline/tumor tissue/liquid biopsy DNA and RNA samples were profiled using the Hereditary Cancer Panel (germline) and the TruSight Onc

Deciphering and targeting oncogenic pathways through integrated approaches and amino acid metabolism in hematologic malignancies.

Hematologic malignancies, including leukemia, lymphoma, and multiple myeloma, represent a diverse group of blood cancers driven by complex oncogenic pathways and genetic aberrations. Despite advances in treatment, resistance and relapse remain significant clinical challenges. This review presents an integrative approach to blood cancer therapy, highlighting the convergence of precision medicine, CRISPR-based gene editing, immunotherapy (including CAR-T cells and immune checkpoint inhibitors), and targeted modulation of amino acid metabolism. We investigate the molecular pathways driving tumour

Производимые микробиотой иммунные регуляционные метаболиты желчных кислот контролируют автонепроницаемость центральной нервной системы.

Микробиота комменсового кишечника играет определенную роль в патогенезе внекишечных аутоиммунных заболеваний, таких как множественный склероз (MS) с неизвестными механизмами. Деоксихоловая кислота (DCA) и литохолическая кислота (LCA) представляют собой вторичные метаболиты желчных кислот (BAM), получаемые из первичных желчных кислот кишечными микробиотами, которые играют ключевые функции по регулированию иммунной системы путем поощрения дифференциации клеток FOXP3+, регулируемой Т (Treg), за счет клеток TH17. Здесь мы показываем, что бактерии, выделяющие ферменты, ответственные за вторичное пр

SAE1 May Play a Pro-Carcinogenic Role in Pancreatic Adenocarcinoma: A Comprehensive Study Integrating Multiple Pieces of Evidence.

SAE1, a key factor in tumour development, has not been thoroughly examined in pancreatic adenocarcinoma (PAAD), a cancer with high incidence and poor prognosis. We conducted a comprehensive study, integrating mRNA data, immunohistochemistry, CRISPR-modified cell line analysis and single-cell RNA sequencing to assess SAE1's role in PAAD. We also used ChIP-Seq to explore SAE1's transcriptional regulation and analysed clinical data, drug sensitivity and molecular docking models. SAE1 mRNA was significantly overexpressed in PAAD, with a substantial impact on cell proliferation and migration. Funct

Exploring the association and causal effect between white blood cells and psoriasis using large-scale population data.

IntroductionPsoriasis is a chronic inflammatory disease of the skin. A few studies have shown that psoriasis is an immune-mediated disease in which multiple immune cells play crucial roles. However, the association between circulating immune cells and psoriasis remains elusive.MethodsTo explore the role of circulating immune cells in psoriasis, 361,322 individuals from the UK Biobank (UKB) and 3,971 patients with psoriasis from China were included to investigate the association between white blood cells and psoriasis via an observational study. Genome-wide association studies (GWAS) and Mendel

Genomic instability and genetic heterogeneity in aging: insights from clonal hematopoiesis (CHIP), monoclonal gammopathy (MGUS), and monoclonal B-cell lymphocytosis (MBL).

Aging is a multifaceted process characterized by a gradual decline in physiological function and increased susceptibility to a range of chronic diseases. Among the molecular and cellular mechanisms driving aging, genomic instability is a fundamental hallmark, contributing to increased mutation load and genetic heterogeneity within cellular populations. This review explores the role of genomic instability and genetic heterogeneity in aging in the hematopoietic system, with a particular focus on clonal hematopoiesis of indeterminate potential (CHIP), monoclonal gammopathy of undetermined signifi

MTAP-Null Tumors: A Comprehensive Review on Synthetic Vulnerabilities and Therapeutic Strategies.

Homozygous deletion of the 9p21.3 genomic locus spanning the CDKN2A/B and MTAP genes is an event affecting 15% of cancers. While CDKN2A is a well-established tumor suppressor gene, the role of MTAP in tumorigenesis varies across cancer types. MTAP codes for methylthioadenosine phosphorylase, a key enzyme in the methionine salvage pathway, and its loss has been associated with several downstream synthetic vulnerabilities. Despite multiple efforts to exploit MTAP loss for targeted therapies, none of these efforts have yielded substantial results in clinical trials. In this review, we consolidate

Epigenome-wide association study of depression symptomatology in elderly monozygotic twins.

Depression is a severe and debilitating mental disorder diagnosed by evaluation of affective, cognitive and physical depression symptoms. Severity of these symptoms strongly impacts individual's quality of life and is influenced by a combination of genetic and environmental factors. One of the molecular mechanisms allowing for an interplay between these factors is DNA methylation, an epigenetic modification playing a pivotal role in regulation of brain functioning across lifespan. The aim of this study was to investigate if there are DNA methylation signatures associated with depression sympto

Role of Chitinase 3-like-1 in Myelofibrosis via Fibroblast-Produced Extracellular Matrix Enhancement.

Cluster of differentiation 14+ monocytes produced spindle-shaped fibrocytes, similar to fibroblasts. Recent studies have reported that fibrocytes are crucial for the development and progression of primary myelofibrosis (MF); however, their functional role remains unclear. We compared monocytes and fibrocytes using RNA sequencing for gene expression profiles. We focused on chitinase 3-like-1 (CHI3L1), which causes inflammation, organ fibrosis, and extracellular tissue remodeling. We found higher CHI3L1 levels in patients with myeloproliferative neoplasm with MF than in those without MF. Further

Множественный склероз Полигенный риск не обогащается в Three Множественные семьи в сопоставлении с демографическими случаями.

Множественный склероз (MS) — сложное неврологическое и аутоиммунное заболевание с установленным генетическим компонентом. Семьи с множественными случаями MS встречаются редко, но это происходит. Мы гипотезуем, что многодетные семьи могут иметь повышенный полигенный риск для MS. В ходе этой работы мы определили, обогащается ли полигенный риск для НР в многодетных семьях по сравнению с когортой контроля за конкретными случаями. Используя результаты крупнейшего исследования, проведенного в рамках ассоциации по геному MS, мы рассчитали взвешенный показатель полигенного риска (wPRS) для MS. Мы прим

Artificial intelligence in cancer immunotherapy: current trends in predicting response and personalizing treatment.

Artificial intelligence (AI) can transform cancer immunotherapy by enabling more accurate prediction of treatment responses, the discovery of specific biomarkers, and the development of personalised treatment plans. Traditional single-marker biomarkers (PD-L1, TMB, MSI) lack consistency across tumour types and cannot be used to assess tumour heterogeneity or the dynamic tumour microenvironment (TME). This review synthesises developments in multimodal AI models that combine genomics, transcriptomics, radiomics, digital pathology (pathomics), circulating biomarkers, and clinical evidence to crea

Biochemical and Metabolical Pathways Associated with Microbiota-Derived Butyrate in Colorectal Cancer and Omega-3 Fatty Acids Implications: A Narrative Review.

Knowledge regarding the influence of the microbial community in cancer promotion or protection has expanded even more through the study of bacterial metabolic products and how they can modulate cancer risk, which represents an extremely challenging approach for the relationship between intestinal microbiota and colorectal cancer (CRC). This review discusses research progress on the effect of bacterial dysbiosis from a metabolic point of view, particularly on the biochemical mechanisms of butyrate, one of the main short chain fatty acids (SCFAs) with anti-inflammatory and anti-tumor properties

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… The third millennium can be considered so far as the golden age of microbiota research, as it brought extensive population-based studies, such as the Human Microbiome Project (started five years after the completion of the Human Genome Project) or the American Gut Project. …

Combination of the PI3K inhibitor Idelalisib with the conventional cytostatics cytarabine and dexamethasone leads to changes in pathway activation that induce anti-proliferative effects in B lymphoblastic leukaemia cell lines.

BackgroundThe introduction of combined conventional cytostatics and pathway-specific inhibitors has opened new treatment options for several cancer types including hematologic neoplasia such as leukaemias. As the detailed understanding of the combination-induced molecular effects is often lacking, the identification of combination-induced molecular mechanisms bears significant value for the further development of interventional approaches.MethodsCombined application of conventional cytostatic agents (cytarabine and dexamethasone) with the PI3K-inhibitor Idelalisib was analysed on cell-biologic

The role of B2M in cancer immunotherapy resistance: function, resistance mechanism, and reversal strategies.

Immunotherapy has emerged as a preeminent force in the domain of cancer therapeutics and achieved remarkable breakthroughs. Nevertheless, the high resistance has become the most substantial impediment restricting its clinical efficacy. Beta-2 microglobulin (B2M), the light chain of major histocompatibility complex (MHC) class I, plays an indispensable part by presenting tumor antigens to cytotoxic T lymphocytes (CTLs) for exerting anti-tumor effects. Accumulating evidence indicates that B2M mutation/defect is one of the key mechanisms underlying tumor immunotherapy resistance. Therefore, eluci

Epigenetic and Transcriptomic Regulation Landscape in HPV+ Cancers: Biological and Clinical Implications.

Human Papillomavirus (HPV) is an oncogenic virus that causes the highest number of viral-associated cancer cases and deaths worldwide, with more than 690,000 new cases per year and 342,000 deaths only for cervical cancer (CC). Although the incidence and mortality rates for CC are declining in countries where screening and vaccination programs have been implemented, other types of cancer in which HPV is involved, such as oropharyngeal cancer, are increasing, particularly in men. Mutational and transcriptional profiles of various HPV-associated neoplasms have been described, and accumulated evid

The causal relationship between multiple cardiovascular diseases and glioblastoma: A Mendelian randomization study.

Observational studies suggest an association between glioblastoma (GBM) and cardiovascular diseases (CVDs), but a causal relationship remains unestablished. This study aimed to investigate the causal link between multiple CVDs and GBM risk. The inverse variance weighted method indicated that all 18 CVDs had significant causal associations with GBM (P < .05). Genetically predicted CVDs were uniformly associated with a lower risk of GBM (odds ratio < 1), identifying them as potential protective factors. Sensitivity analyses confirmed the absence of significant heterogeneity or horizontal pleiotr

Идентификация сигнатуры, связанной с микроглией, в экспериментальном аутоиммунном энцефаломиелите.

Множественный склероз (MS) — хроническое нервно-воспалительное расстройство, характеризующееся демиелинизацией и иммунной диагностикой, и микроглией играет центральную роль в прогрессии заболеваний. Несмотря на это, конкретные микроглиальные генные сигнатуры, способствующие НР, по-прежнему недостаточно характеризуются. МЕТОДЫ: Мы использовали экспериментальную аутоиммунную модель мышьяка-энцефаломиэлита (EAE) и провели последовательность RNA для выявления дифференциально выраженных RNA (DEmRNA), длинных некодирующих RNA (DElncRNA), циркулярных RNA (DEcirRNA) и микроRNA (DEmiRNA) в микроглии. П

Association of coronary artery disease related single nucleotide-polymorphisms with extreme Prakriti types: Insights from a case control study.

BACKGROUND: Coronary artery disease has well-established genetic variants but identification of susceptible ones is needed. Ayurveda stratifies people phenotypically termed as "Prakriti" to assess the risk. OBJECTIVES: The present research was aimed to identify Prakriti stratified genetic risks for CAD. MATERIAL AND METHODS: Initially, literature search was done using bioinformatics and manual-curation, to identify susceptible SNPs. Further, global-screening-array was performed to evaluate association of these polymorphisms in Prakriti stratified 200 CAD patients and 100 healthy controls. Th

Воздействие причинно-следственных связей между распространенными заболеваниями и провокационными кишечными заболеваниями: исследование по изучению двухнаправленной менделианской случайности.

ЦЕЛИ: Исследования по изучению связей между различными заболеваниями и подстрекательскими кишечными заболеваниями (ИББ) часто ограничиваются путаницей и обратной причиной. Мы стремились оценить потенциальные причинно-следственные связи между широким кругом заболеваний и ИБД, включая болезнь Крона (КД) и язвительный колит (КЮ). МЕТОДЫ: Мы провели всеобъемлющий анализ 104 распространенных болезней и признаков БИ с использованием общего подхода, основанного на обобщенных кратких данных, с использованием метода ОР (МСУГ). Сводные статистические данные о заболеваниях, полученные в рамках общегеноми

New genomic and proteomic biomarker discovery in cancer: revolutionizing diagnosis and prognostication.

Cancer remains a major global health challenge, with substantial morbidity and mortality worldwide. Advances in genomic and proteomic biomarker discovery have transformed cancer diagnosis, prognosis, and treatment selection. The evolution from early serological markers such as carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA) to modern multi-omics approaches enabled by next-generation sequencing (NGS), mass spectrometry (MS), and advanced bioinformatics has revolutionized personalized medicine and targeted therapy, leading to improved outcomes. This review highlights the histo