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Randomized phase 2 study of valproic acid combined with simvastatin and gemcitabine/nab-paclitaxel-based regimens in untreated metastatic pancreatic adenocarcinoma patients: the VESPA trial study protocol.

BackgroundMetastatic pancreatic ductal adenocarcinoma (mPDAC) patients have very poor prognosis highlighting the urgent need of novel treatments. In this regard, repurposing non-oncology already-approved drugs might be an attractive strategy to offer more-effective treatment easily tested in clinical trials. Accumulating evidence suggests that epigenetic deregulation is a hallmark of cancer contributing to treatment resistance in several solid tumors, including PDAC. Histone deacetylase inhibitors (HDACi) are epigenetic drugs we have investigated preclinically and clinically as anticancer agen

Inhibition of Heat Shock-Induced H3K9ac Reduction Sensitizes Cancer Cells to Hyperthermia.

Heat stress, clinically known as hyperthermia, is a promising adjunctive modality in cancer treatment. However, the efficacy of hyperthermia as a monotherapy is limited and the underlying mechanism remains poorly understood. Targeting histone modifications is an emerging strategy for cancer therapy, but little is known regarding the role of heat stress in altering these modifications. Here, we report that heat shock inhibits H3K9 acetylation (H3K9ac) via histone deacetylase 6 (HDAC6) regulation. Heat shock inhibits the interaction between HDAC6 and heat shock protein 90 (HSP90), enhances nucle

Application of High Throughput Technologies in the Development of Acute Myeloid Leukemia Therapy: Challenges and Progress.

Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by extensive heterogeneity in genetics, response to therapy and long-term outcomes, making it a prototype example of development for personalized medicine. Given the accessibility to hematologic malignancy patient samples and recent advances in high-throughput technologies, large amounts of biological data that are clinically relevant for diagnosis, risk stratification and targeted drug development have been generated. Recent studies highlight the potential of implementing genomic-based and phenotypic-based screen

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… High-Throughput Technologies-Based Targeted Therapies The applications of genomics, epigenomics, transcriptomics, proteomics and metabolomics are attributed to recent advances in next generation genome sequencing, bioinformatics, proteomic analytic tools, along with high-throughput technologies. … Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 2013;368:2059–2074. doi: 10.1056/NEJMoa1301689. 6. Dohner H., Gaidzik V.I. Impact of genetic features on treatment decisions in AML. Hematol. Am. Soc. Hematol. Educ. …

Полигенная природа множественного склероза: генетические варианты, иммунологические модуляции и экологические связи.

Множественный склероз (MS) — изнуряющее воспалительное расстройство центральной нервной системы, характеризующееся обезвоживанием, — в значительной степени зависит от полигенных вариаций. Хотя конкретная причина НР остается неясной, считается, что она возникает в результате сложного взаимодействия генетических и экологических факторов. Последние исследования были сосредоточены на полигенном характере генетических изменений, связанных с риском НР. В настоящем обзоре подчеркивается важнейшая роль этих генетических вариантов в формировании восприимчивости к болезням и их развития. Специфические а

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… Epigenomics, another omics method, studies changes in DNA and histones that can affect gene expression while preserving the DNA sequence [ 259 ]. Ho et al. … In summary, integrating genetic data with transcriptomics, epigenomics, proteomics, metabolomics, and microbiomics can enhance our understanding of MS etiology. …

Beyond regulations at DNA levels: A review of epigenetic therapeutics targeting cancer stem cells.

In the past few years, the paramount role of cancer stem cells (CSCs), in terms of cancer initiation, proliferation, metastasis, invasion and chemoresistance, has been revealed by accumulating studies. However, this level of cellular plasticity cannot be entirely explained by genetic mutations. Research on epigenetic modifications as a complementary explanation for the properties of CSCs has been increasing over the past several years. Notably, therapeutic strategies are currently being developed in an effort to reverse aberrant epigenetic alterations using specific chemical inhibitors. In thi

Intravenous Vitamin C for Cancer Therapy - Identifying the Current Gaps in Our Knowledge.

The use of intravenous vitamin C (IVC) for cancer therapy has long been an area of intense controversy. Despite this, high dose IVC has been administered for decades by complementary health care practitioners and physicians, with little evidence base resulting in inconsistent clinical practice. In this review we pose a series of questions of relevance to both researchers and clinicians, and also patients themselves, in order to identify current gaps in our knowledge. These questions include: Do oncology patients have compromised vitamin C status? Is intravenous the optimal route of vitamin C a

Single-cell sequencing in molecular diagnostics: Transformative yet untapped potential.

Single-cell sequencing (SCS) techniques have the potential to offer precise insights into cellular diversity by revealing unique genetic and transcriptomic profiles at the single-cell level. This advanced technology has been used extensively in research, but it has still not translated to clinical diagnostics, despite its potential. SCS provides more accurate granular information about heterogeneous cell populations and the creation of personalized treatment strategies. However, the integration of SCS into clinical practice is challenging. This review discusses the potential of SCS technologie

Diverse antitumor effects of ascorbic acid on cancer cells and the tumor microenvironment.

Ascorbic acid has attracted substantial attention for its potential antitumor effects by acting as an antioxidant in vivo and as a cofactor in diverse enzymatic reactions. However, solid proof of its clinical efficacy against cancer and the mechanism behind its effect have not been established. Moreover, cancer forms cancer-specific microenvironments and interacts with various cells, such as cancer-associated fibroblasts (CAFs), to maintain cancer growth and progression; however, the effect of ascorbic acid on the cancer microenvironment is unclear. This review discusses the effects and mechan

The Hedgehog-GLI pathway in embryonic development and cancer: implications for pulmonary oncology therapy.

Transcriptional regulation and epigenetic mechanisms closely control gene expression through diverse physiological and pathophysiological processes. These include the development of germ layers and post-natal epithelial cell-tissue differentiation, as well as, involved with the induction, promotion and/or progression of human malignancies. Diverse studies have shed light on the molecular similarities and differences involved in the stages of embryological epithelial development and dedifferentiation processes in malignant tumors of epithelial origin, of which many focus on lung carcinomas. In

The Critical Role of Hypoxic Microenvironment and Epigenetic Deregulation in Esophageal Cancer Radioresistance.

Esophageal cancer (EC) is the seventh most common cancer worldwide and the sixth leading cause of death, according to Globocan 2018. Despite efforts made for therapeutic advances, EC remains highly lethal, portending a five-year overall survival of just 15-20%. Hence, the discovery of new molecular targets that might improve therapeutic efficacy is urgently needed. Due to high proliferative rates and also the limited oxygen and nutrient diffusion in tumors, the development of hypoxic regions and consequent activation of hypoxia-inducible factors (HIFs) are a common characteristic of solid tumo

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… Thus, the epigenome landscape is currently recognized as having an important role in the process of neoplastic transformation and progression [ 41 ]. … Epigenomics. 2015;7:791–811. doi: 10.2217/epi.15.24. 71. Ikeda S., Kitadate A., Abe F., Takahashi N., Tagawa H. Hypoxia-inducible KDM3A addiction in multiple myeloma. Blood Adv. 2018;2:323–334. doi: 10.1182/bloodadvances.2017008847. 72. …

Acute myeloid leukemia synchronous with multiple myeloma successfully treated by azacytidine/lenalidomide and daratumumab without a decrease in myeloid clone size.

Synchronous diagnosis of acute myeloid leukemia (AML) and symptomatic multiple myeloma (MM) is a rare situation that poses serious therapeutic difficulties. We report the case of a 68-year-old male which evolved simultaneously to symptomatic MM and AML. Both diseases first responded to treatment for 40 months after 7+3 induction and maintenance therapy of azacytidine + lenalidomide. MM relapsed first and was treated with azacytidine + daratumumab, which led an additional 15 months of progression-free survival. Little myeloid clonal size reduction over time was seen. This case shows that AML an

Correlation of long non-coding RNA expression with metastasis, drug resistance and clinical outcome in cancer.

The therapeutic response and clinical outcome of patients diagnosed with the same cancer type and that receive identical treatment is highly variable to reflect the genetic heterogeneity within tumor cells. Non-coding RNAs (ncRNAs) are recently discovered molecules that regulate eukaryotic gene expression and represent a significant advance towards a better understanding of the mechanisms that govern cellular growth. NcRNAs are essential for the proper regulation of cell proliferation and survival under physiologic conditions and are deregulated in many pathologies, e.g., human cancers. NcRNAs

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… Toxicol 2000 40 581 616 10836148 10.1146/annurev.pharmtox.40.1.581 31 Ivanov M Kacevska M Ingelman-Sundberg M 2012 Epigenomics and interindividual differences in drug response Clin Pharmacol Ther 2012 92 727 736 23093317 10.1038/clpt.2012.152 32 Shen DW Pouliot LM Hall MD Gottesman MM Cisplatin resistance … : a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes Pharmacol Rev 2012 64 706 721 22659329 10.1124/pr.111.005637 PMC3400836 33 Haenisch S Cascorbi I miRNAs as mediators of drug resistance Epigenomics 2012 4 369 381 22920178 10.2217/epi.12.39 34 Lipovich L Johnson …

Эпигенетика и метаболическая метаболическая дисфункция при многоразовом склерозе: обзор подходов к травяным лекарствам и текущих клинических испытаний.

Множественный склероз (MS) — сложная аутоиммунная болезнь, характеризующаяся воспалением, обезвоживанием и нейродегенерацией в центральной нервной системе (КНС). Хотя точные причины остаются неясными, недавние исследования подчеркивают важную роль эпигенетических изменений и митохондриальной дисфункции в начале и развитии болезни. Эпигенетические изменения, такие, как метилация ДНК, модификация гистона и регулирование микроРНК, влияют на генное выражение, не изменяя последовательности ДНК, что приводит к иммунной дисрегуляции и воспалению. Аналогичным образом, митохондриальная дисфункция, отме

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… Epigenetic Modifications in Multiple Sclerosis Epigenetic Modifications and Their Impact on Gene Expression Without Altering DNA Sequence The study of the epigenome, a collection of chemical substances that control how the entire genome functions, is known as epigenomics. … As a result, the creation of proteins in some body cells may be controlled by the epigenome. “Marking” the genome refers to the process of epigenomic chemicals attaching to DNA and having an impact on how it functions [ 28 ]. …

Long-Term Effects of Pediatric Acute Lymphoblastic Leukemia Chemotherapy: Can Recent Findings Inform Old Strategies?

During the last few decades, pediatric acute lymphoblastic leukemia (ALL) cure rates have improved significantly with rates exceeding 90%. Parallel to this remarkable improvement, there has been mounting interest in the long-term health of the survivors. Consequently, modified treatment protocols have been developed and resulted in the reduction of many adverse long-term consequences. Nevertheless, these are still substantial concerns that warrant further mitigation efforts. In the current review, pediatric-ALL survivors' late adverse events, including secondary malignant neoplasms (SMNs), car

Репрессии на цикле синергии со стороны HDAC/EZH2 H3K27-altered диффузная средняя глиома.

Diffuse midline glioma (DMG) — агрессивная хитрость под воздействием H3K27M онкохистоуна, приводящая к глобальному эпигенетическому регулированию и ограниченной эффективности одноагентной эпигенетической терапии. Ранее мы наблюдали клиническую выгоду от ингибитора HDAC/EZH2, но механистическая основа была неясной. Для принятия ответных мер в связи с наркотиками и проведения функциональных анализов использовалась группа культур ДИМ-глиомы стволовых клеток (ГНК) от опухолей головного мозга и спинного мозга, при этом репрезентативные модели были дополнительно проанализированы на предмет транскрип

Deep Learning Techniques to Characterize the RPS28P7 Pseudogene and the Metazoa-SRP Gene as Drug Potential Targets in Pancreatic Cancer Patients.

The molecular explanation about why some pancreatic cancer (PaCa) patients die early and others die later is poorly understood. This study aimed to discover potential novel markers and drug targets that could be useful to stratify and extend expected survival in prospective early-death patients. We deployed a deep learning algorithm and analyzed the gene copy number, gene expression, and protein expression data of death versus alive PaCa patients from the GDC cohort. The genes with higher relative amplification (copy number >4 times in the dead compared with the alive group) were EWSR1, FLT3,

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… Multi-omics analysis based on integrated genomics, epigenomics and transcriptomics in pancreatic cancer Epigenomics 2020 12 507 524 10.2217/epi-2019-0374 32048534 10. Kaubryte J. Lai A.G. …

Translational Bioinformatics Applied to the Study of Complex Diseases.

Translational Bioinformatics (TBI) is defined as the union of translational medicine and bioinformatics. It emerges as a major advance in science and technology by covering everything, from the most basic database discoveries, to the development of algorithms for molecular and cellular analysis, as well as their clinical applications. This technology makes it possible to access the knowledge of scientific evidence and apply it to clinical practice. This manuscript aims to highlight the role of TBI in the study of complex diseases, as well as its application to the understanding and treatment o

Harnessing Epigenetic Mechanisms to Overcome Immune Evasion in Cancer: The Current Strategies and Future Directions.

Combining epigenetic alterations with cancer immunotherapy offers a promising approach to improve therapeutic outcomes by targeting the complex biology of tumors. Epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) play a dual role in maintaining immune homeostasis and promoting cancer progression. Changes like hypomethylation in tumor cells can contribute to immune evasion and treatment resistance. Advances in epigenetic tools, particularly clustered regularly interspaced short palindromic repeat (CRISPR) and their associated protein (Cas9)-based

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… Epigenome-driven strategies for personalized cancer immunotherapy. Rocha GI, Gomes JE, Leite ML, da Cunha NB, Costa FF. Cancer Manag Res. 2023;15:1351–1367. doi: 10.2147/CMAR.S272031. 2. CAR-T cell therapy: current limitations and potential strategies. Sterner RC, Sterner RM. … Interpreting non-coding disease-associated human variants using single-cell epigenomics. Gaulton KJ, Preissl S, Ren B. Nat Rev Genet. 2023;24:516–534. doi: 10.1038/s41576-023-00598-6. 9. Oncogenic metabolic reprogramming in breast cancer: focus on signaling pathways and mitochondrial genes. …

Azacitidine regulates DNA methylation of GADD45γ in myelodysplastic syndromes.

BACKGROUND: Myelodysplastic syndrome (MDS) is a heterogeneous clonal disease originated from hematopoietic stem cells. Epigenetic studies had demonstrated that DNA methylation and histone acetylation were abnormal in MDS. Azacitidine is an effective drug in the treatment of demethylation. METHODS: RT-PCR was performed to determine GADD45γ in 15 MDS clinical samples. Myelodysplastic syndrome cell lines SKM-1 and HS-5 were transfected with GADD45γ eukaryotic expression vector and/or GADD45γ shRNA interference plasmid, and treated with azacitidine. Proliferation and apoptosis were examined by CC

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… Technological advances in epigenomics lead to a better understanding of inflammatory diseases, decitabine and H3K27me3 . Epigenomics . 2015 ; 7 ( 2 ): 133 ‐ 136 . 25942529 10.2217/epi.14.90 25 Jing Y , Shen X , Mei Q , Han W . …

Epigenetic profiling reveals key super-enhancer networks driving oncogenesis in HPV-positive HNSCC.

Human papillomavirus-positive (HPV+) head and neck squamous cell carcinoma (HNSCC) is a growing subset of cancer cases distinct from HPV-negative by fewer genetic mutations and prevalent epigenetic dysregulation. We mapped H3K27ac-marked super-enhancers (SEs) via ChIP-seq in HPV+ patient-derived xenografts (PDXs) and normal oropharyngeal mucosa, identifying tumor-specific SE domains (T-SEDs) enriched for transcription factors (TFs) including TP63, FOSL1, and JUND. These SE-associated TFs regulate key oncogenic pathways and are downregulated by BRD4 inhibition with JQ1, highlighting sensitivity

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… Integrating multi-omics approaches, including genomics, transcriptomics, and epigenomics, could provide deeper insights into the molecular landscape of HNSCC and identify new therapeutic targets. … EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling. Mol. Cell. 2015;60:307–318. doi: 10.1016/j.molcel.2015.09.002. 39. Sengupta S., George R.E. Super-Enhancer-Driven Transcriptional Dependencies in Cancer. …