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DNA Damaging Drugs

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MYCN Impact on High-Risk Neuroblastoma: From Diagnosis and Prognosis to Targeted Treatment.

Among childhood cancers, neuroblastoma is the most diffuse solid tumor and the deadliest in children. While to date, the pathology has become progressively manageable with a significant increase in 5-year survival for its less aggressive form, high-risk neuroblastoma (HR-NB) remains a major issue with poor outcome and little survivability of patients. The staging system has also been improved to better fit patient needs and to administer therapies in a more focused manner in consideration of pathology features. New and improved therapies have been developed; nevertheless, low efficacy and high

Euchromatic Histone Lysine Methyltransferase 2 Inhibition Enhances Carfilzomib Sensitivity and Overcomes Drug Resistance in Multiple Myeloma Cell Lines.

Proteasome inhibitors (PIs) are extensively used for the therapy of multiple myeloma. However, patients continuously relapse or are intrinsically resistant to this class of drugs. In addition, adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. Here, to identify compounds that can increase the efficacy of PIs, we performed a functional screening using a library of small-molecule inhibitors covering key signaling pathways. Among the best synthetic lethal interactions, the euchromatic histone-lysine N-methyltransferase 2 (EHMT2) inhibitor UNC0642 displayed a coope

Hallmarks of ribosomopathies.

Ribosomopathies are diseases caused by defects in ribosomal constituents or in factors with a role in ribosome assembly. Intriguingly, congenital ribosomopathies display a paradoxical transition from early symptoms due to cellular hypo-proliferation to an elevated cancer risk later in life. Another association between ribosome defects and cancer came into view after the recent discovery of somatic mutations in ribosomal proteins and rDNA copy number changes in a variety of tumor types, giving rise to somatic ribosomopathies. Despite these clear connections between ribosome defects and cancer,

Clinical relevance of extracellular vesicles in hematological neoplasms: from liquid biopsy to cell biopsy.

In the era of precision medicine, liquid biopsy is becoming increasingly important in oncology. It consists in the isolation and analysis of tumor-derived biomarkers, including extracellular vesicles (EVs), in body fluids. EVs are lipid bilayer-enclosed particles, heterogeneous in size and molecular composition, released from both normal and neoplastic cells. In tumor context, EVs are valuable carriers of cancer information; in fact, their amount, phenotype and molecular cargo, including proteins, lipids, metabolites and nucleic acids, mirror nature and origin of parental cells rendering EVs a

Update on current pancreatic treatments: from molecular pathways to treatment.

Pancreatic cancer is still diagnosed at a late stage although we have novel diagnostic tools. Pancreatic cancer chemotherapy treatment resistance is observed and therefore novel treatments are in need. Anti-cancer stem cell therapy, combination of chemotherapy and/or radiotherapy with immunotherapy, proteins/enzymes and gene therapy are currently under evaluation. Targeted treatment with tyrosine kinase inhibitors is also administered and novel inhibitors are also under evaluation. In the current review we present recent data from our search within the year 2018.

Epimutational profile of hematologic malignancies as attractive target for new epigenetic therapies.

In recent years, recurrent somatic mutations in epigenetic regulators have been identified in patients with hematological malignancies. Furthermore, chromosomal translocations in which the fusion protein partners are themselves epigenetic regulators or where epigenetic regulators are recruited/targeted by oncogenic fusion proteins have also been described. Evidence has accumulated showing that "epigenetic drugs" are likely to provide clinical benefits in several hematological malignancies, granting their approval for the treatment of myelodysplastic syndromes and cutaneous T-cell lymphomas. A

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… The BET family consists of four members that regulate transcription by RNA polymerase II (Pol II): BRD2, BRD3, BRD4, which are ubiquitously expressed, and BRDT, the expression of which is restricted to germ cells. … Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012;287:43137–43155. doi: 10.1074/jbc.M112.413047. 99. Garcia JS, Jain N, Godley LA. …

Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon?

Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most aggressive malignancies with a 5-year survival rate of <7%. Due to growing incidence, late diagnosis and insufficient treatment options, PDAC is predicted to soon become one of the leading causes of cancer-related death. Although intensified cytostatic combinations, particularly gemcitabine plus nab-paclitaxel and the folinic acid, fluorouracil, irinotecan, oxaliplatin (FOLFIRINOX) protocol, provide some improvement in efficacy and survival compared with gemcitabine alone, a breakthrough in the treatment of metastatic pancreat

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… BET bromodomains recruit CDK9, the catalytic subunit of P-TEFb, which catalyses the phosphorylation of serine 2 in the heptapeptide repeat sequence within the C-terminal domain of RNA polymerase II, a post-translational modification associated with transcriptional elongation. 66 Importantly, Dinaciclib …

Evolution of Molecular Targeted Cancer Therapy: Mechanisms of Drug Resistance and Novel Opportunities Identified by CRISPR-Cas9 Screening.

Molecular targeted therapy has revolutionized the landscape of cancer treatment due to better therapeutic responses and less systemic toxicity. However, therapeutic resistance is a major challenge in clinical settings that hinders continuous clinical benefits for cancer patients. In this regard, unraveling the mechanisms of drug resistance may identify new druggable genetic alterations for molecularly targeted therapies, thus contributing to improved therapeutic efficacies. The recent rapid development of novel methodologies including CRISPR-Cas9 screening technology and patient-derived models

Chemorefractory extranodal nasal-type natural-killer/T-cell lymphoma with great response to pembrolizumab in a young patient: a case report.

IntroductionExtranodal, natural-killer/T-cell lymphoma of nasal type is a rare but aggressive disease usually presenting as progressive necrotic lesions in the nasal cavity that responds poorly to chemotherapy. In this paper, we report a relapsing, chemorefractory case of extranodal natural-killer/T-cell lymphoma responding to checkpoint inhibitor immunotherapy with pembrolizumab.Case presentationA 32-year-old Hispanic woman with a history of recurrent sinusitis and preseptal abscess presented with a hoarse voice, swelling around the right eye, and diplopia. Laryngoscopy showed infiltrating ti

Tumor Whole-Genome Sequencing for Prediction of Venous Thromboembolism in Patients With Metastasized Solid Cancer.

BACKGROUND: International guidelines suggest prophylactic anticoagulation for patients with cancer at high risk of venous thromboembolism (VTE). Here, we evaluated whether tumor whole-genome sequencing data may improve the selection of high-risk patients. METHODS: In a pan-cancer cohort of 3087 patients, associations of candidate clinical predictors, the germline extended 297-single nucleotide polymorphism polygenic risk score, tumor mutational characteristics, and somatic tumor mutations with VTE were estimated by calculating hazard ratios (HRs). RESULTS: During 12-month follow-up, 237 (7.7

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… The 10 genes with the strongest association with VTE are shown in Table 3 , and included POLR2E (RNA Polymerase II Subunit E; HR, 3.34 [95% CI, 1.68–6.97]), PALM (Paralemmin; HR, 3.73 [95% CI, 1.74–7.99]), TBX22 (T-box Transcription Factor 22; HR, 2.47 [95% CI, 1.40–4.35]), and ELANE (Elastase, Neutrophil … Polymerase II Subunit E SLFN14 Schlafen Family Member 14 SNP single nucleotide polymorphism TBX22 T-box Transcription Factor 22 VTE venous thromboembolism WDR64 WD Repeat Domain 64 XKR3 XK Related 3 F.I. …

Exosomes derived from BMSCs ameliorate cyclophosphamide-induced testosterone deficiency by enhancing the autophagy of Leydig cells via the AMPK-mTOR signaling pathway.

Cyclophosphamide-induced testosterone deficiency (CPTD) during the treatment of cancers and autoimmune disorders severely influences the quality of life of patients. Currently, several guidelines recommend patients suffering from CPTD receive testosterone replacement therapy (TRT). However, TRT has many disadvantages underscoring the requirement for alternative, nontoxic treatment strategies. We previously reported bone marrow mesenchymal stem cells-derived exosomes (BMSCs-exos) could alleviate cyclophosphamide (CP)-induced spermatogenesis dysfunction, highlighting their role in the treatment

С-терминальный связывающий белок 2 - новый дезинфицирующий опухоль, направленный на MYC-IRF4 ось в множестве миеломы.

Клетки с множественной миеломой (MM) подвержены зависимости от MYC, а их непосредственные цели по трансактивации IRF4 направлены на распространение и выживание. MYC и IRF4 по-прежнему считаются "ненаркоманными", поскольку большинство мелких ингибиторов молекулярного происхождения страдают от низкой производительности, неоптимальных фармакокинетических свойств и нежелательных нецелевых эффектов. Косвенное подавление MYC/IRF4 проявляется в качестве терапевтической уязвимости MM. Здесь мы обнаружили неоцененную опухоль, впечатляющую роль связующего белка С-терминала 2 (CTBP2) в MM путем сильного

Effect of miRNA-19a on gastrointestinal motility in rats with functional dyspepsia.

The effect of microRNA (miRNA)-19a on gastrointestinal motility in rats with functional dyspepsia was investigated. Fifty adult Sprague-Dawley (SD) rats were randomly divided into 5 groups, 10 rats in each group, one group as the normal group, one group as the model group, and the other three groups were divided into negative control group, miRNA-19a mimic group and miRNA-19a inhibitor group. All rats were intraperitoneally injected with miRNA-19a scramble, miRNA-19a mimic and miRNA-19a inhibitor. Except the normal group, the functional dyspepsia model rat was established by proper clipping ta

A signal-seeking Phase 2 study of olaparib and durvalumab in advanced solid cancers with homologous recombination repair gene alterations.

PurposeTo determine the safety and efficacy of PARP plus PD-L1 inhibition (olaparib + durvalumab, O + D) in patients with advanced solid, predominantly rare cancers harbouring homologous recombination repair (HRR) defects.Patients and methodsIn total, 48 patients were treated with O + D, 16 with BRCA1/2 alterations (group 1) and 32 with other select HRR alterations (group 2). Overall, 32 (66%) patients had rare or less common cancers. The primary objective of this single-arm Phase II trial was a progression-free survival rate at 6 months (PFS6). Post hoc exploratory analyses were conducted on

Exploring the Potential of MicroRNA Let-7c as a Therapeutic for Prostate Cancer.

Prostate cancer (PCa) is one of the leading causes of mortality worldwide and often presents with aberrant microRNA (miRNA) expression. Identifying and understanding the unique expression profiles could aid in the detection and treatment of this disease. This review aims to identify miRNAs as potential therapeutic targets for PCa. Three bio-informatic searches were conducted to identify miRNAs that are reportedly implicated in the pathogenesis of PCa. Only hsa-Lethal-7 (let-7c), recognized for its role in PCa pathogenesis, was common to all three databases. Three further database searches were

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… Figure 1 miRNA Biogenesis The miRNA is translated by RNA polymerase II to form a pri-miRNA. The RNase III enzyme DROSHA cuts the single-stranded RNA/double-stranded RNA (ssRNA/dsRNA) junction to create a pre-miRNA. The pre-miRNA is transported to the cytoplasm via EXPORTIN 5/RAN-GTP. … Figure 1 miRNA Biogenesis The miRNA is translated by RNA polymerase II to form a pri-miRNA. The RNase III enzyme DROSHA cuts the single-stranded RNA/double-stranded RNA (ssRNA/dsRNA) junction to create a pre-miRNA. The pre-miRNA is transported to the cytoplasm via EXPORTIN 5/RAN-GTP. …

Структурная основа для селективного метилирования 5-carboxymethoxyuridine В модификацию tRNA.

Постранарные модификации tRNA широко сохранены во всех сферах жизни. Особенно те из них, которые происходят в антикодоне, часто модифицируют эффективность перевода. Производственные показатели 5-hydroxyuridine конкретно встречаются в бактериальных тРНК, где 5-methoxyuridine и 5-carboxymethoxyuridine , являются основными видами бактерий с положительной и отрицательной массой, соответственно. В некоторых видах тРНК, 5- Карбоксиметоксиуридин может быть дополнительно метилирован CMOM для образования метилэстера. В этом докладе мы представляем рентгеновскую кристаллическую структуру Escherichia col

Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 Modulates Aggressiveness of Ewing Sarcoma by Regulating the CD164-CXCR4 Axis.

Ewing sarcoma (EWS) is the second most common bone and soft tissue-associated malignancy in children and young adults. It is driven by the fusion oncogene EWS/FLI1 and characterized by rapid growth and early metastasis. We have previously discovered that the mRNA binding protein IGF2BP3 constitutes an important biomarker for EWS as high expression of IGF2BP3 in primary tumors predicts poor prognosis of EWS patients. We additionally demonstrated that IGF2BP3 enhances anchorage-independent growth and migration of EWS cells suggesting that IGF2BP3 might work as molecular driver and predictor of E

Application and mechanistic research of novel therapeutic strategies in cisplatin-resistant small cell lung cancer.

IntroductionSmall cell lung cancer (SCLC) initially responds well to cisplatin-based chemotherapy, but rapid development of drug resistance limits long-term efficacy and subsequent treatment options. Understanding the multifactorial mechanisms of cisplatin resistance is essential for improving patient outcomes. This review synthesizes recent preclinical and clinical advances, focusing on seven key resistance mechanisms and emerging therapeutic strategies, including immunotherapy, targeted therapy, and novel chemotherapeutic agents.DiscussionCisplatin resistance in SCLC arises through multiple

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… It binds to DNA, obstructing access to transcription factors and essential transcription machinery such as RNA polymerase II, thereby disrupting the transcription process, causing the buildup of DNA double-strand breaks, which ultimately leads to cell death [ 148 , 149 ]. …

miRNAs in the Regulation of Cancer Immune Response: Effect of miRNAs on Cancer Immunotherapy.

In the last few decades, carcinogenesis has been extensively explored and substantial research has identified immunogenic involvement in various types of cancers. As a result, immune checkpoint blockers and other immune-based therapies were developed as novel immunotherapeutic strategies. However, despite being a promising therapeutic option, immunotherapy has significant constraints such as a high cost of treatment, unpredictable toxicity, and clinical outcomes. miRNAs are non-coding, small RNAs actively involved in modulating the immune system's multiple signalling pathways by binding to the

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… MicroRNA Genes Are Transcribed by RNA Polymerase II. EMBO J. 2004;23:4051–4060. doi: 10.1038/sj.emboj.7600385. 27. Denli A.M., Tops B.B.J., Plasterk R.H.A., Ketting R.F., Hannon G.J. Processing of Primary MicroRNAs by the Microprocessor Complex. …