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SETD2 and EZH2: Two epigenetic drivers of prostate cancer.

Prostate cancer is a prevalent malignancy among men, characterized by complex mechanisms underlying metastasis and treatment resistance. Epigenetic modifications play a crucial role in regulating prostate cancer progression, particularly involving histone methyltransferases such as SET-domain containing 2 (SETD2) and Enhancer of Zeste homolog 2 (EZH2). SETD2 contributes to chromatin stability by catalyzing the trimethylation of histone H3 lysine 36 (H3K36me3), and its downregulation is strongly correlated with increased invasiveness and epithelial-mesenchymal transition in prostate cancer. Con

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… Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair. Nature. 2015;518(7538):258–62. doi: 10.1038/nature14184. 81. Li H, Tu J, Zhao Z, Chen L, Qu Y, Li H. et al. … SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability. Cell Rep. 2014;7(6):2006–18. doi: 10.1016/j.celrep.2014.05.026. 84. Tonini T, D'Andrilli G, Fucito A, Gaspa L, Bagella L. …

Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial).

BACKGROUND: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy has been approved for TNBC and cytotoxic agents remain the mainstay of treatment. Ixazomib is a selective and reversible inhibitor of the proteasome, which has been mainly investigated in the treatment of multiple myeloma. In a preclinical study TNBC cells were treated with the first-generation proteasome inhibitor bortezomib in combination with cisplatin and synergistic efficacy was demonstrat

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… Activated FANCD2 [ 8 ] as well as BRCA1 regulate the DNA repair by homologous recombination [ 9 ] and are therefore critical for the function of the Fanconi anemia pathway [ 7 ]. In addition, FANCD2 interacts with the MRE11-NBS1-RAD50 complex in the repair of DNA crosslinks [ 7 ]. … Interplay between Fanconi anemia and homologous recombination pathways in genome integrity. EMBO J. 2016;35(9):909–923. doi: 10.15252/embj.201693860. 9. Moynahan ME, Jasin M. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. …

Journey of TRAIL from Bench to Bedside and its Potential Role in Immuno-Oncology.

Induction of apoptosis in cancer cells has increasingly been the focus of many therapeutic approaches in oncology field. Since its identification as a TNF family member, TRAIL (TNF-related apoptosis-inducing ligand) paved a new path in apoptosis inducing cancer therapies. Its selective ability to activate extrinsic and intrinsic cell death pathways in cancer cells only, independently from p53 mutations responsible for conventional therapeutics resistance, spotted TRAIL as a potent cancer apoptotic agent. Many recombinant preparations of TRAIL and death receptor targeting monoclonal antibodies

Molecular targeted therapy for anticancer treatment.

Since the initial clinical approval in the late 1990s and remarkable anticancer effects for certain types of cancer, molecular targeted therapy utilizing small molecule agents or therapeutic monoclonal antibodies acting as signal transduction inhibitors has served as a fundamental backbone in precision medicine for cancer treatment. These approaches are now used clinically as first-line therapy for various types of human cancers. Compared to conventional chemotherapy, targeted therapeutic agents have efficient anticancer effects with fewer side effects. However, the emergence of drug resistanc

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… of homologous recombination repair and ADP-ribosylation (PARylation) reversion mutations | Nausea, vomiting, diarrhea, constipation, red blood cell count decrease, photosensitivity, renal impairment, dysgeusia | 8 , 178 , 247 PARP | Niraparib (MK-4827) | Zejula (Tesaro) | Recurrent ovarian cancer (2017 … BReast CAncer gene 1 (BRCA1) and BRCA2 (BRCA1/2) are tumor-suppressor genes that play a key role in repair of double-strand DNA breaks via the conservative homologous recombination repair (HRR) process 175 , 177 . …

Декодирование связи между микроорганизмами и автоиммунизацией: многоаспектный обзор данных по конкретным патогенам, которые вызывают аутоиммунные заболевания.

Происхождение и прогрессирование аутоиммунных заболеваний (АИД) являются результатом совокупного воздействия генетической восприимчивости, дефектов иммунной реакции и экологических факторов. Среди них микроорганизмы, являющиеся ключевыми экологическими факторами, широко гипотезуют для того, чтобы сыграть свою роль в инициировании АИД, однако точная причинно-следственная связь еще не доказана. Цель этого обзора заключается в глубоком изучении ключевой роли конкретных микробных инфекций в инициировании АИД путем интеграции данных, полученных с помощью three - измерения: эпидемиологические исслед

Role of Bruton's tyrosine kinase in B cells and malignancies.

Bruton's tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK was initially shown to be defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) and is essential both for B cell development and function of mature B cells. Shortly after its discovery, BTK was placed in the signal transduction pathway downstream of the B cell antigen receptor (BCR). More recently, small-molecule inhibitors of this kinase have shown excellent anti-tumor a

Update on Classic and Novel Approaches in Metastatic Triple-Negative Breast Cancer Treatment: A Comprehensive Review.

Triple-negative breast cancer (TNBC) accounts for almost 15% of all diagnosed breast cancers and often presents high rates of relapses and metastases, with generally poor prognosis despite multiple lines of treatment. Immunotherapy has radically changed the approach of clinicians towards TNBC in the last two to three years, even if targeted and specific therapeutic options are still missing; this unmet need is further justified by the extreme molecular and clinical heterogeneity of this subtype of breast cancer and by the weak response to both single-agent and combined therapies. In March 2023

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… On the contrary, DSBs are considered among the most cytotoxic mechanisms of DNA damage, and a key role is played by homologous recombination and non-homologous end-joining (NHEJ) [ 71 , 72 ]. … Approximately 25% of patients with TNBC are carriers of breast cancer susceptibility gene 1 or 2 ( BRCA1/2 ) deleterious mutations, which are, in turn, essential components of homologous recombination repair (HRR) [ 75 ]. …

Усиление ремиэлизации в множестве склероза через M1 Muscarinic ацетилхолиновый рецептор.

Растет распространенность склероза (MS), однако по-прежнему требуется лечение, способное обратить вспять прогресс в развитии болезни. Одна из стратегий, которая продемонстрировала многообещающее изменение режима MS, заключается в воспрещении рецептора M1 — члена семейства мускаринических ацетилхолинов (mAChR). Считается, что антагонизм M1 mAChR является механизмом, с помощью которого Клемастин, развивающийся препарат, который был замечен в целях усиления миелинизации в исследованиях животных и клинических испытаниях этапа II, вызывает его эффект, стимулирующий миелинацию. Недавние исследования

Новые роли протеина CCN3 в заболеваниях, связанных с иммуном.

Протеины CCN представляют собой семейство внеклеточных матриц (ECM) белков, которые в настоящее время состоят из шести секретных белков (CCN1-6). Протеин CCN3, также известный как нефробластома с перевыраженным белком (NOV), является членом семейства CCN с множеством биологических функций, связанных с основными клеточными процессами, такими, как рост клеток, миграция и дифференциация. Недавно КХН3 стала одним из важнейших регуляторов различных заболеваний, включая иммунные заболевания, включая ревматологический артрит, остеоартрит и системный склероз. В ходе этого обзора мы кратко представим с

Genetic architecture of multiple myeloma: From somatic alterations to germline susceptibility and clinical implications.

Multiple myeloma (MM) is best understood as a dynamically evolving genomic ecosystem shaped by inherited susceptibility, early oncogenic events, and continuous selective pressures. We propose an evolutionary genomics framework integrating germline risk, disease initiation, clonal diversification, and therapeutic adaptation into a unified model of MM biology. Polygenic risk burden, rare predisposing variants, and alterations in DNA repair and telomere pathways create a permissive background that influences precursor states and immune interactions. Primary cytogenetic events, particularly immuno

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… recombination repair Pathogenic germline variants detected in MM cohorts Homologous recombination deficiency context [ 67 , 70 ] DDR ATM DNA damage signaling kinase Recurrent germline variants reported Genome stability regulation [ 70 ] DDR CHEK2 Checkpoint kinase Germline variants reported Cell-cycle … recombination repair | Pathogenic germline variants detected in MM cohorts | Homologous recombination deficiency context | [ 67 , 70 ] DDR | ATM | DNA damage signaling kinase | Recurrent germline variants reported | Genome stability regulation | [ 70 ] DDR | CHEK2 | Checkpoint kinase | Germline variants …

CD200 является мощным новым фактором роста в Мультимиломе, зависящим от сигнала рецептора IGF1.

CD200 — это иммунный контрольно-пропускной пункт, безошибочно выраженный в 70% недавно диагностированных пациентов с множественной миеломой (ММ) и связанный с плохим исходом. Выражение CD200 клетками опухоли препятствует иммунной реакции через взаимодействие с CD200R и участвует в устойчивости к иммунной терапии. Однако его роль в опухоли остается слабой. В этом исследовании мы показываем, что клетки MM, перевыражающие CD200, представляют собой значительное пролиферативное преимущество в свободных культурных сыворотках, средних и клоногенных анализах. Преимущество роста клеток, опосредованное

Precision in Action: The Role of Clustered Regularly Interspaced Short Palindromic Repeats/Cas in Gene Therapies.

Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated enzyme-CAS holds great promise for treating many uncured human diseases and illnesses by precisely correcting harmful point mutations and disrupting disease-causing genes. The recent Food and Drug Association (FDA) approval of the first CRISPR-based gene therapy for sickle cell anemia marks the beginning of a new era in gene editing. However, delivering CRISPR specifically into diseased cells in vivo is a significant challenge and an area of intense research. The identification of new CRISPR/Cas variants, particularly

Molecular and epigenetic regulatory mechanisms of normal stem cell radiosensitivity.

Ionizing radiation (IR) therapy is a major cancer treatment modality and an indispensable auxiliary treatment for primary and metastatic cancers, but invariably results in debilitating organ dysfunctions. IR-induced depletion of neural stem/progenitor cells in the subgranular zone of the dentate gyrus in the hippocampus where neurogenesis occurs is considered largely responsible for deficiencies such as learning, memory, and spatial information processing in patients subjected to cranial irradiation. Similarly, IR therapy-induced intestinal injuries such as diarrhea and malabsorption are commo

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… Biehs R DNA double-strand break resection occurs during non-homologous end joining in G1 but is distinct from resection during homologous recombination Mol. Cell 2017 65 671 684 e675 10.1016/j.molcel.2016.12.016 28132842 PMC5316416 3. … Mujoo K Differentiation of human induced pluripotent or embryonic stem cells decreases the DNA damage repair by homologous recombination Stem Cell Rep. 2017 9 1660 1674 10.1016/j.stemcr.2017.10.002 PMC5831054 29103969 60. …

First-in-human Study of AZD5153, A Small-molecule Inhibitor of Bromodomain Protein 4, in Patients with Relapsed/Refractory Malignant Solid Tumors and Lymphoma.

AZD5153, a reversible, bivalent inhibitor of the bromodomain and extraterminal family protein BRD4, has preclinical activity in multiple tumors. This first-in-human, phase I study investigated AZD5153 alone or with olaparib in patients with relapsed/refractory solid tumors or lymphoma. Adults with relapsed tumors intolerant of, or refractory to, prior therapies received escalating doses of oral AZD5153 once daily or twice daily continuously (21-day cycles), or AZD5153 once daily/twice daily continuously or intermittently plus olaparib 300 mg twice daily, until disease progression or unacceptab

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… In addition, BRD4 is involved in regulating the antitumor activity of natural killer cells ( 4 ), and in replication stress–induced DNA damage response (DDR; ref. 5 ) and homologous recombination–mediated DNA repair (HRR; ref. 6 ). … BET proteins regulate homologous recombination-mediated DNA repair: BRCAness and implications for cancer therapy. Int J Cancer 2019;144:755–66. 7. Aftimos P, Oliveira M, Punie K, Boni V, Hamilton E, Gucalp A, et al. …

The DNA damage response network in the treatment of head and neck squamous cell carcinoma.

BACKGROUND: We sought to determine whether DNA damage response (DDR)-related aberrations predict therapeutic benefit in cisplatin-treated head and neck squamous cell carcinoma (HNSCC) patients and how DDR pathways are modulated after treatment with olaparib alone or in combination with cisplatin or durvalumab. PATIENTS AND METHODS: Oxidative stress, abasic sites and DDR-related parameters, including endogenous DNA damage, DNA repair mechanisms and apoptosis rates, were evaluated in HNSCC cell lines and peripheral blood mononuclear cells from 46 healthy controls (HC) and 70 HNSCC patients at b

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… Homologous recombination in cancer development, treatment and development of drug resistance. Carcinogenesis. 2010;31:955–960. doi: 10.1093/carcin/bgq064. 17. Chakraborty A., Tapryal N., Venkova T. … Dysfunctional homologous recombination mediates genomic instability and progression in myeloma. Blood. 2009;113:2290–2297. doi: 10.1182/blood-2007-05-089193. 58. Sliwinski T., Walczak A., Przybylowska K. …

Премии победителей и резюме 32nd Ежегодный симпозиум Общества протеинов; Бостон, ОЭТ, июль 9-12, 2018.

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Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality Strategy.

BackgroundChromatin is dynamically remodeled to adapt to all DNA-related processes, including DNA damage responses (DDR). This adaptation requires DNA and histone epigenetic modifications, which are mediated by several types of enzymes; among them are lysine methyltransferases (KMTs).MethodsKMT inhibitors, chaetocin and tazemetostat (TZM), were used to study their role in the DDR induced by ionizing radiation or doxorubicin in two human sarcoma cells lines. The effect of these KMT inhibitors was tested by the analysis of chromatin epigenetic modifications, H4K16ac and H4K20me2. DDR was monitor

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… EZH2 inhibition sensitizes CARM1-high, homologous recombination proficient ovarian cancers to PARP inhibition. Cancer Cell 37 157.e6 – 167.e6 . 10.1016/j.ccell.2019.12.015 32004442 PMC7155421 Kategaya L. Perumal S. K. Hager J. H. Belmont L. D. ( 2019 ). … Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination. Nat. Struct. Mol. Biol. 20 317 – 325 . 10.1038/nsmb.2499 23377543 PMC3594358 Tewari K. S. Eskander R. N. Monk B. J. ( 2015 ). …

Targeting epigenetic methylation: emerging diagnosis and therapeutic strategies in cancer.

Epigenetics shapes all aspects of cancer occurrence and progression. Among them, chromatin methylation is a particularly important regulator of oncogenic processes. The dynamic shifts in methylation can influence the development or death of tumor cells. In the therapeutic context, effectively targeting and modulating DNA, RNA, and histone methylation brings promise for the early detection, prognostic assessment, and treatment of cancer. In particular, novel methylation inhibitors or modulators powerfully kill tumor cells or improve existing therapeutic strategies through different signaling pa

Выборочное конечное метилирование базы трона.

Активные ТРНК сильно модифицируются после расшифровки, особенно на позиции болтающихся 34 и положение 37 относительно 3- ...на стороне антикодона. :: 5-carboxy-methoxy изменение U34 (cmo5U34) присутствует в граф-отрицательных tRNA six аминокислоты (Ala, Ser, Pro, Tr, Leu и Val), four из которых (Ala, Ser, Pro и Tr) имеет окончательную группу метила для формирования 5-methoxy-carbonyl-methoxy-uridine (mcmo5U34) для более высокой точности считывания параметров. Молекулярная основа для селективной конечной метилации не понятна. Многие cmo5U34-tRNAs Они имеют важное значение для роста и не могут б

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… The strain was then deleted of the UGG tRNA Pro gene, using the λ Red recombinase of pKD46 ( 26 ) to catalyze homologous recombination at the proM locus with a proM-kan R PCR fragment amplified by primers proMKO-F and proMKO-R from pKD4. …

Circadian clock and cancer.

Circadian rhythms play a critical role in regulating physiological and behavioral processes, such as the sleep-wake cycle, hormone secretion, and metabolism. These rhythms are controlled by endogenous biological clocks, which are synchronized with environmental cues, primarily the light-dark cycle. Notably, disruption or reprogramming of circadian rhythms is closely associated with cancer initiation, progression, and treatment response. At the molecular level, the dysregulation of core clock genes can disturb normal cellular rhythms, leading to aberrant cell proliferation, impaired DNA repair,

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… Mechanistically, CRY1, a key circadian regulator of homologous recombination, orchestrates the temporal induction of DDR genes following DSBs, sequentially activating early sensors and downstream effectors to ensure repair fidelity [72] . … For example, in cell-cycle and apoptosis regulation, BMAL1 is recruited to DDSB through ATM-mediated phosphorylation at Ser183, subsequently recruiting CLOCK to acetylate histone H4, thereby promoting homologous recombination repair in a transcription-independent manner. …