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Advances of DNA Damage Repair-Related Drugs and Combination With Immunotherapy in Tumor Treatment.

Cancer therapy has been an important and popular area in cancer research. With medical technology developing, the appearance of various targeted drugs and immunotherapy offer more choices to cancer treatment. With the increase in drug use, people have found more and more cases in which tumors are resistant to DNA damage repair (DDR)-based drugs. Recently, the concept of combination therapy has been brought up in cancer research. It takes advantages of combining two or more therapies with different mechanisms, aiming to benefit from the synergistic effects and finally rescue patients irresponsi

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… DNA Damage During the G0/G1 Phase Triggers RNA-Templated, Cockayne Syndrome B-Dependent Homologous Recombination. PNAS (2015) 112(27):E3495–504. doi: 10.1073/pnas.1507105112 9. Keung MYT, Wu Y, Vadgama JV. … PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers. J Clin Med (2019) 8(4):1–24. doi: 10.3390/jcm8040435 10. Newlands ES, Stevens MF, Wedge SR, Wheelhouse RT, Brock C. …

Therapeutic Targeting of DNA Damage Repair in the Era of Precision Oncology and Immune Checkpoint Inhibitors.

Cancer manifestation is a multistep process involving accumulation of various genetic and epigenetic changes that results in oncogenic "hallmarks of cancer" processes including genomic instability. Exploitation of aberrant DNA-damage response (DDR) mechanisms in cancer is in part a goal of many therapeutic strategies, and recent evidence supports the role of targeting DDR in modulating the tumor immune microenvironment to enhance immunotherapeutic response. Improved cancer profiling, including next-generation and whole-genome mutational sequencing of tumor tissue, as well as circulating nuclei

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… BRCAm: BRCA-mutated; DDR: DNA-damage response; DFS: disease-free survival; gBRCA: germline BRCA; HR: hazard ratio; HRD: homologous recombination-deficiency; HRR: homologous recombination response; LOH: loss of heterogeneity mCRPC: metastatic castration-resistant prostate cancer; MR: mismatch repair; … recombination-deficiency; HRR: homologous recombination response; ICI: immune checkpoint inhibitor; IO: immunotherapy; LA: locally advanced; LRC: locoregional control; MPR: major pathological response; MSS: microsatellite stable; NK: natural killer; ORR: objective response rate; OS: overall survival …

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.

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… Mutations or copy number abnormalities of genes involved in homologous recombination (HR) have been previously investigated in PAC tissue samples 29 . … In the study by Shahda S et al. 29 mutations or copy number abnormalities of genes involved in homologous recombination (HR) were investigated in tissue samples. …

Gene therapy: principles, challenges and use in clinical practice.

INTRODUCTION: Gene therapy is an emerging topic in medicine. The first products have already been licensed in the European Union for the treatment of immune deficiency, spinal muscular atrophy, hemophilia, retinal dystrophy, a rare neurotransmitter disorder and some hematological cancers, while many more are being assessed in preclinical and clinical trials. OBJECTIVE: The purpose of this review is to provide an overview of the core principles of gene therapy along with information on challenges and risks. Benefits, adverse effects and potential risks are illustrated based on the examples of

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… In stark contrast, HDR—the naturally occurring recombination mechanisms observed in mammalian cells—involves the use of the sister chromatide as a template for a “copy and paste” process known as homologous recombination. … However, for genome editing, a cell can be tricked, and a DNA donor repair template can be introduced into the cell that will be used for homologous recombination instead of the sister chromatide. …

Острый инфекционный мононуклеоз порождает стойкие, функциональные антитела EBNA-1 с высокой поперечной реактивностью до альфа-кристаллической бета.

Мы исследуем масштаб, специфичность и функциональные свойства ядерного антигена 1 (EBNA-1) вируса Эпштейн-Барр (EBV) у молодых людей в ходе первичной инфекции. Обнаружены специфические связующие антитела EBNA-1, а также антитела, способные к осаждению клеточного фагоцитоза (ADCP) и дополняющего антитела (ADCD). Эти антитела в первую очередь направлены против региона EBNA-1, который, как известно, вызывает перекрестные антитела для нескольких самопептидов. У лиц, имеющих по крайней мере один аллеле HLA-DRB1*15:01, отмечаются высшие связующие и ADCD антитела EBNA-1. Альфакристалллин бета (КРИАБ)

Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment.

Platinum-based chemotherapies, such as cisplatin, play a large role in cancer treatment. The development of resistance and treatment toxicity creates substantial barriers to disease control, yet. To enhance the therapeutic index of cisplatin-based chemotherapy, it is imperative to circumvent resistance and toxicity while optimizing tumor sensitization. One of the primary mechanisms by which cancer cells develop resistance to cisplatin is through upregulation of DNA repair pathways. In this review, we discuss the DNA damage response in the context of cisplatin-induced DNA damage. We describe th

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… The primary DNA repair pathways include homologous recombination (HR), nucleotide excision repair (NER), NHEJ, base excision repair (BER), and mismatch repair (MMR). When cells are defective in one of these pathways, DNA damage accumulates. … Homologous Recombination Cisplatin-induced ROS and stalling of the DNA replication fork can produce DNA DSBs that are primarily repaired through one of two mechanisms [ 32 ]. HR is the preferred pathway as it is highly precise and preserves the entire DNA sequence. …

How histone modifications influence cellular radiosensitivity: Pharmaceutically targeting epigenetic regulators as a promising avenue to overcome radioresistance.

Cancer remains the leading cause of mortality worldwide. Radiotherapy (RT), a cornerstone of oncological treatment for over a century, has achieved great success in various cancers. However, radioresistance remains the primary factor leading to the failure of radiotherapy. Histone modifications in cancer cells are known to play a pivotal role in regulating radiosensitivity by modulating chromatin structure, either by loosening or tightening it. Here, we provide a comprehensive summary of the link between aberrant histone modifications and radiation resistance across various cancer and normal t

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… Presently, DSBs are primarily repaired through the mechanisms of homologous recombination (HR) and non-homologous end joining (NHEJ). HR is contingent upon the appropriate cell cycle and exhibits a low repair efficiency, yet it is characterized by error-free repair. … This process involves Rad52, a known SUMO substrate, which likely facilitates homologous recombination by coordinating with SUMOylated chromatin components. …

Анализ ассоциации геномов показывает новый QTL CsPC1 для перикарпового цвета в огурце.

Огурчик - это важная дыня в мире с разными перикарными цветами. Однако потенциальные гены и основополагающий генетический механизм для такой важной черты огурца неизвестны. В этом исследовании на хромосоме был найден цвет колокольчика, контролирующего перикарп 3 генома огурцов. Результаты: В этом исследовании светло-зеленая линия G35 и темно-зеленая линия Q51 были пересечены для производства one Население F2. Таким образом, мы определили крупное цокольное поле CsPC1 (Перикарный цвет) 1). Далее мы нарисовали строку CsPC1 94-kb районная хромосома 3 который содержит 15 Гены. Среди этих генов Csa3

Тип 1 Диабет - Ассоциированные Автоантифиды, Сера и T-Cell Receptor Squences признают Myelin Basic Protein: Novel Peripheral Diabetic Neurophy-Multiple Sclerosis Connection.

(В тыс.1) Фон: Neuropaties - типичные осложнения типа 1 Диафиоз (T1D) и предыдущие исследования продемонстрировали сопутствующую демиелинизацию с использованием основного белка миелина (MBP). Пациенты T1D значительно повышают риск множественного склероза (MS) и наоборот. Причины неизвестны.2) Методы: Протеономический поиск с использованием BLAST использовался для выявления сходств между последовательностями T-клекторных (TCR) пациентов T1D и MS. LALIGN использовалась для изучения вопроса о том, T1D-related белки подражают MBP. Для проверки на перекрестную реактивность между исследователями имм

Targeting the DNA Damage Response for Cancer Therapy.

Over the course of long-term evolution, cells have developed intricate defense mechanisms in response to DNA damage; these mechanisms play a pivotal role in maintaining genomic stability. Defects in the DNA damage response pathways can give rise to various diseases, including cancer. The DNA damage response (DDR) system is instrumental in safeguarding genomic stability. The accumulation of DNA damage and the weakening of DDR function both promote the initiation and progression of tumors. Simultaneously, they offer opportunities and targets for cancer therapeutics. This article primarily elucid

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… Homologous Recombination (HR) HR is a relatively complex but highly accurate repair mechanism that relies on using a homologous template strand to synthesize a new one. It primarily occurs during the S and G2 phases of the cell cycle. … Pathways and assays for DNA double-strand break repair by homologous recombination Acta Biochim. Biophys. Sin. 2019 51 879 889 10.1093/abbs/gmz076 31294447 11. Lindahl T. Barnes D.E. Repair of endogenous DNA damage Cold Spring Harb. Symp. Quant. …

Short-chain acyl post-translational modifications in cancers: Mechanisms, roles, and therapeutic implications.

Post-translational modifications (PTMs) play a pivotal role in epigenetic regulation and are key pathways for modulating protein functionality. PTMs involve the covalent attachment of distinct chemical groups, such as succinyl, crotonyl, and lactyl, at specific protein sites, which alter protein structure, function, stability, and activity, ultimately influencing biological processes. Recently, metabolically derived short-chain acylation modifications (with acyl groups containing fewer than six carbon atoms) have been progressively identified, such as butyrylation, succinylation, crotonylation

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… These modifications can target both histones and non‐histones, affecting processes like DNA homologous recombination (HR) repair and non‐homologous end‐joining (NHEJ) repair, modulating genome stability, thereby regulating tumor malignant phenotypes and chemo/radiotherapy sensitivity (Figure 3 and Table … Abbreviations: 5‐FU, 5‐Fluorouracil; CBP: CREB‐binding protein; CDYL1, chromodomain Y‐like 1; DDR, DNA damage response; DNA‐PKcs, DNA‐dependent protein kinase catalytic subunit; GCN5, general control non‐depressible 5; H2A, histone H2A; H3, histone H3; HR, homologous recombination; Kcr, lysine crotonylation …

CRISPR-Cas: Converting A Bacterial Defence Mechanism into A State-of-the-Art Genetic Manipulation Tool.

Bacteriophages are pervasive viruses that infect bacteria, relying on their genetic machinery to replicate. In order to protect themselves from this kind of invader, bacteria developed an ingenious adaptive defence system, clustered regularly interspaced short palindromic repeats (CRISPR). Researchers soon realised that a specific type of CRISPR system, CRISPR-Cas9, could be modified into a simple and efficient genetic engineering technology, with several improvements over currently used systems. This discovery set in motion a revolution in genetics, with new and improved CRISPR systems being

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… Homologous recombination was the first precise gene-editing technique to be developed [ 5 ]. The sequences of the DNA fragment delivered to the cell were homologous to the sequences of a target location in the genome, thus providing a way to reduce non-specific binding. … A mechanism for the suppression of homologous recombination in G1 cells. Nature. 2015;528:422–426. doi: 10.1038/nature16142. 112. Lin S., Staahl B.T., Alla R.K., Doudna J.A. …

Biological and clinical aspects of HPV-related cancers.

Cancer-related diseases represent the second overall cause of death worldwide. Human papilloma virus (HPV) is an infectious agent which is mainly sexually transmitted and may lead to HPV-associated cancers in both men and women. Almost all cervical cancers are HPV-associated, however, an increasing number of head and neck cancers (HNCs), especially oropharyngeal cancer, can be linked to HPV infection. Moreover, anogenital cancers, including vaginal, vulvar, penial, and anal cancers, represent a subset of HPV-related cancers. Whereas testing and prevention of cervical cancer have significantly

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… As BRCA1 and RNF168 both promote homologous recombination repair (HRR) 63 , 64 , the high alteration rate of both suggests a HPV-mediated facilitated HRR in HPV-associated HNC cancers. … High-risk alphapapillomavirus oncogenes impair the homologous recombination pathway. J Virol. 2017;91:e01084–17. doi: 10.1128/JVI.01084-17. 70. Khanal S, Galloway DA. …

E3 ubiquitin ligases orchestrate chemo-resistance in gastrointestinal malignancies: from DNA damage response to therapeutic targeting.

Therapy resistance in gastrointestinal tumors remains a critical challenge in clinical oncology, severely compromising therapeutic efficacy and long-term patient survival. E3 ubiquitin ligases, as core enzymes involved in the protein ubiquitination process, have been demonstrated to play indispensable roles in regulating key biological processes in tumor cells, including DNA damage repair, cell cycle progression, apoptosis, cancer stem cell maintenance, and immune evasion. Additionally, E3 ligases are key regulators of resistance to multiple anticancer strategies, such as chemotherapy, radioth

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… E3 ligases regulate PARP inhibitor resistance PARP inhibitors (PARPis) represent a paradigm of synthetic lethality-based cancer therapy, particularly effective against homologous recombination-deficient (HRD) tumors harboring BRCA1/2 mutations ( 142 ). … In PARP inhibitor (PARPi) resistance, RNF126 and TRIP12 promote homologous recombination (HR) restoration through the regulation of BRCA1 and RAD51, thereby reducing PARPi sensitivity. …

Twenty-five years of type I interferon-based treatment: a critical analysis of its therapeutic use.

The clinical exploitation of type I interferon (IFN) as an antiviral and antineoplastic agent is based on the properties originally attributed to this cytokine family, with schedules reflecting only their antiviral and antiproliferative activities. Nevertheless, type I IFN has emerged as a central activator of the innate immunity. As current schedules of treatment for chronic hepatitis C and for hematological and solid tumors, based on the continuous administration of recombinant type I IFN or pegylated formulations, disregard viral resistance, host genetic variants predicting treatment outcom

Mechanisms and Clinical Applications of Genome Instability in Multiple Myeloma.

Ongoing genomic instability represents a hallmark of multiple myeloma (MM) cells, which manifests largely as whole chromosome- or translocation-based aneuploidy. Importantly, although it supports tumorigenesis, progression and, response to treatment in MM patients, it remains one of the least understood components of malignant transformation in terms of molecular basis. Therefore these aspects make the comprehension of genomic instability a pioneering strategy for novel therapeutic and clinical speculations to use in the management of MM patients. Here we will review mechanisms mediating genom

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… To handle this warning, cells employ several DSBs repair mechanisms: Non-Homologous end joining (NHEJ) and Homologous Recombination (HR) [ 44 ]. … Dysfunctional homologous recombination mediates genomic instability and progression in myeloma Blood 2009 113 10 2290 2297 10.1182/blood-2007-05-089193 2-s2.0-63849240546 19050310 PMC2652372 46 Herrero A. B. San Miguel J. Gutierrez N. C. Ricchetti M. …

Identification and characterization of a nuclear interacting partner of anaplastic lymphoma kinase (NIPA).

Anaplastic large-cell lymphoma is a subtype of non-Hodgkin lymphomas characterized by the expression of CD30. More than half of these lymphomas carry a chromosomal translocation t(2;5) leading to expression of the oncogenic tyrosine kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). NPM-ALK is capable of transforming fibroblasts and lymphocytes in vitro and of causing lymphomas in mice. Previously, we and others demonstrated phospholipase C-gamma and phosphatidylinositol 3-kinase as crucial downstream signaling mediators of NPM-ALK-induced oncogenicity. In this study, we used an ALK fu

An ERG channel inhibitor from the scorpion Buthus eupeus.

The isolation of the peptide inhibitor of M-type K(+) current, BeKm-1, from the venom of the Central Asian scorpion Buthus eupeus has been described previously (Fillipov A. K., Kozlov, S. A., Pluzhnikov, K. A., Grishin, E. V., and Brown, D. A. (1996) FEBS Lett. 384, 277-280). Here we report the cloning, expression, and selectivity of BeKm-1. A full-length cDNA of 365 nucleotides encoding the precursor of BeKm-1 was isolated using the rapid amplification of cDNA ends polymerase chain reaction technique from mRNA obtained from scorpion telsons. Sequence analysis of the cDNA revealed that the pre

The XPB subunit of repair/transcription factor TFIIH directly interacts with SUG1, a subunit of the 26S proteasome and putative transcription factor.

Mutations in the basal transcription initiation/DNA repair factor TFIIH are responsible for three human disorders: xeroderma pigmentosum (XP), cockayne syndrome (CS) and trichothiodystrophy (TTD). The non-repair features of CS and TTD are thought to be due to a partial inactivation of the transcription function of the complex. To search for proteins whose interaction with TFIIH subunits is disturbed by mutations in patients we used the yeast two-hybrid system and report the isolation of a novel XPB interacting protein, SUG1. The interaction was validated in vivo and in vitro in the following m

PARP Inhibitors and Haematological Malignancies-Friend or Foe?

Since their introduction several years ago, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have become the standard of care for breast and gynaecological cancers with BRCA gene mutations. Given that PARPi act by exploiting defective DNA repair mechanisms within tumour cells, they should be ideally suited to combatting haematological malignancies where these pathways are notoriously defective, even though BRCA mutations are rare. To date, despite promising results in vitro, few clinical trials in humans for haematological malignancies have been performed, and additional investigation is

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… Generally, cancers with high levels of genomic instability and replication stress due to DNA repair deficiencies (especially in homologous recombination repair [HRR]) are particularly responsive to PARPi by a process known as ‘synthetic lethality’ [ 28 , 29 ]. … TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes. J. Clin. Oncol. 2020;38:4274–4282. doi: 10.1200/JCO.20.02151. 35. Cancer Genome Atlas Research Network. …