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Mitochondrial Genetic and Epigenetic Regulations in Cancer: Therapeutic Potential.

Mitochondria are dynamic organelles managing crucial processes of cellular metabolism and bioenergetics. Enabling rapid cellular adaptation to altered endogenous and exogenous environments, mitochondria play an important role in many pathophysiological states, including cancer. Being under the control of mitochondrial and nuclear DNA (mtDNA and nDNA), mitochondria adjust their activity and biogenesis to cell demands. In cancer, numerous mutations in mtDNA have been detected, which do not inactivate mitochondrial functions but rather alter energy metabolism to support cancer cell growth. Increa

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… In the nucleus, an aberrant capacity for homologous recombination (HR) and nucleotide excision repair (NER) critically contributes to avoidance of apoptosis and leads to drug resistance; in mitochondria, mechanisms of DNA damage response (DDR) and repair still require more elucidation. … Mechanism of Homologous Recombination and Implications for Aging-Related Deletions in Mitochondrial DNA Microbiol. Mol. Biol. Rev. 2013 77 476 496 10.1128/MMBR.00007-13 24006472 PMC3811608 106. Pohjoismäki J.L.O. Goffart S. Taylor R.W. Turnbull D. Suomalainen-Wartiovaara A. Jacobs H.T. …

Strategies to Improve Sensitivity to Radiotherapy in Pediatric Solid Tumors.

The primary goal in the treatment of pediatric malignancies is to maintain effective cancer control while minimizing toxicities and late effects. Radiotherapy is a component of standard therapy against many pediatric cancers, but tumor cell DNA damage repair mechanisms and the hypoxic tumor microenvironment may limit the effectiveness of this modality. Additionally, irradiated cancer cells often acquire resistance to radiotherapy that permits cancer cell survival or stimulates tumor regrowth after treatment, further limiting the efficacy of radiotherapy. Various preclinical studies have invest

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… The DNA damage is repaired by base excision repair (BER), nucleotide excision repair (NER), non-homologous end joining (NHEJ), or homologous recombination (HR) [ 24 ]. If the damage is irreparable, the cell activates apoptosis to prevent propagation of damaged DNA. … These effects are believed to be due to the disruption of the homologous recombination repair pathway through p53 reactivation [ 74 ]. …

What's your poison? Impact of individual repair capacity on the outcomes of genotoxic therapies in cancer. Part II - information content and validity of biomarkers for individual repair capacity in the assessment of outcomes of anticancer therapy.

The individual variance in the efficiency of repair of damage induced by genotoxic therapies may be an important factor in the assessment of eligibility for different anticancer treatments, the outcomes of various treatments and the therapy-associated complications, including acute and delayed toxicity and acquired drug resistance. The second part of this paper analyses the currently available information about the possibilities of using experimentally obtained knowledge about individual repair capacity for the purposes of personalised medicine and healthcare.

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… recombination) and the synonymous Asp568Asp polymorphism in the gene LIG4 (non-homologous end joining); damage-related signaling: BRCA1 Pro871Leu (rs799719). … As XRCC2 protein functions in repair of double-strand breaks by homologous recombination, it could be expected that even subtle deficiencies in this repair pathway would have significant impact on repair of therapy-inflicted damage (31, 32) . …

Advances in CRISPR-Cas technology and its applications: revolutionising precision medicine.

CRISPR-Cas (Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated proteins) has undergone marked advancements since its discovery as an adaptive immune system in bacteria and archaea, emerged as a potent gene-editing tool after the successful engineering of its synthetic guide RNA (sgRNA) toward the targeting of specific DNA sequences with high accuracy. Besides its DNA editing ability, further-developed Cas variants can also edit the epigenome, rendering the CRISPR-Cas system a versatile tool for genome and epigenome manipulation and a pioneering force in precision medic

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… Manipulating viral genomes, especially for oncolytic herpes simplex viruses (oHSVs), has classically relied on laborious methods involving homologous recombination via bacterial artificial chromosomes (BACs). …

Dual Roles of NIX/BNIP3L in Tumors: Friend or Foe.

Cancer is one of the leading causes of disease-related death worldwide, and targeting key regulatory genes to induce programmed cell death in tumor cells has emerged as a crucial therapeutic strategy, following surgery, radiotherapy, and chemotherapy. As a mitochondrial outer membrane protein, NIX/BNIP3L can both mediate apoptosis to inhibit tumor cell growth and promote tumor cell survival by clearing intracellular reactive oxygen species (ROS) through mitophagy. Therefore, we summarize a brief overview of the structure and function of NIX/BNIP3L, as well as the mechanisms of NIX/BNIP3L gener

Molecularly Targeted Therapies in Oncology: Mechanisms, Resistance, and Combination Strategies.

Targeted therapies are reshaping oncology by enabling treatment selection based on actionable molecular alterations, improving precision, and reducing unnecessary toxicity. This review provides an up-to-date overview of current targeted treatment modalities and the medicinal chemistry principles that support their discovery and optimization. We synthesize evidence on small-molecule and biologic strategies spanning receptor and non-receptor kinases and their major signaling axes (PI3K-AKT-mTOR and RAS-RAF-MEK-ERK), apoptosis regulation (BCL-2 family), DNA repair via poly(ADP-ribose) polymerase

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… DSBs are repaired primarily through homologous recombination repair (HRR) or non-homologous end joining (NHEJ). HRR involves, among others, BRCA-family proteins (BRCA1/BRCA2); when these are mutated and lose their function, homologous recombination deficiency (HRD) arises. … Clinically, rucaparib has been used, among others, in BRCA-mutated ovarian cancer, and its antitumor activity relies on both catalytic PARP inhibition and synthetic lethality driven by the accumulation of DNA damage in homologous recombination (HR)-deficient cells [ 183 ]. …

Genetic Regulation of Tryptase Production and Clinical Impact: Hereditary Alpha Tryptasemia, Mastocytosis and Beyond.

Tryptase is a serine protease that is predominantly produced by tissue mast cells (MCs) and stored in secretory granules together with other pre-formed mediators. MC activation, degranulation and mediator release contribute to various immunological processes, but also to several specific diseases, such as IgE-dependent allergies and clonal MC disorders. Biologically active tryptase tetramers primarily derive from the two genes TPSB2 (encoding β-tryptase) and TPSAB1 (encoding either α- or β-tryptase). Based on the most common gene copy numbers, three genotypes, 0α:4β, 1α:3β and 2α:2β, were defi

Identifying novel genes and biological processes relevant to the development of cancer therapy-induced mucositis: An informative gene network analysis.

Mucositis is a complex, dose-limiting toxicity of chemotherapy or radiotherapy that leads to painful mouth ulcers, difficulty eating or swallowing, gastrointestinal distress, and reduced quality of life for patients with cancer. Mucositis is most common for those undergoing high-dose chemotherapy and hematopoietic stem cell transplantation and for those being treated for malignancies of the head and neck. Treatment and management of mucositis remain challenging. It is expected that multiple genes are involved in the formation, severity, and persistence of mucositis. We used Ingenuity Pathway A

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… BRCA1 has important roles in nucleotide excision repair, non-homologous end-joining, and homologous recombinational repair by interacting with components of these DNA repair mechanisms, and by regulating the expression of genes involved in these repair pathways [ 73 ]. …

Связанный с K27 ROR__t Уничтожение Nedd4 потенциалами Th17-посредованная автонепроницаемость.

СПРАВОЧНАЯ ИНФОРМАЦИЯ: Было продемонстрировано, что THCT E3 Ubriquitin ligase Nedd4 позитивно регулирует реакцию клеток Т, однако его роль в дифференциации клеток и автономном иммунитете Т неизвестна. Считается, что 17 клеток играют ключевую роль в развитии и патогенезе аутоиммунных заболеваний. Тем не менее, правила, регулирующие активацию РОРТ в ходе дифференциации клеток TH17 с помощью сигнала TCR, пока еще не уточнены. Эти неизведанные аспекты вдохновляют нас на изучение потенциальной роли Nedd4 в автоматическом иммунитете Th17.МЕТОДЫ: Мы провели оценку воздействия дефицита Nedd4 на развит

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… Targeted clones were confirmed by Southern blot for proper homologous recombination with single integration of the Neo-resistance cassette, which was flanked by two Frt sequences. The targeting vector was electroporated into C57BL/6 ES cells which were selected with G418 using standard protocols. …

Gene and cell therapy of human genetic diseases: Recent advances and future directions.

Disruptions in normal development and the emergence of health conditions often result from the malfunction of vital genes in the human body. Decades of scientific research have focused on techniques to modify or substitute defective genes with healthy alternatives, marking a new era in disease treatment, prevention and cure. Recent strides in science and technology have reshaped our understanding of disorders, medication development and treatment recommendations, with human gene and cell therapy at the forefront of this transformative shift. Its primary objective is the modification of genes o

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… These technologies create breaks in the DNA at targeted locations, which are then repaired through processes like homologous recombination (HR) or non‐homologous end‐joining (NHEJ), often with the assistance of donor DNA. 84 When comparing these genome editing techniques, notable distinctions emerge. …

Staying Abreast of New Biomarkers in Hematology/Oncology.

There has been an increasing number of approvals for targeted therapies in oncology in the past decade, changing the treatment paradigm for many solid tumors and hematologic malignancies. At JADPRO Live 2023, presenters provided an in-depth review of cancer biomarkers, including testing methodology, recommended therapies, and how advanced practitioners can integrate results into clinical decision-making.

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… BRCA1 and 2 are part of the homologous recombination repair pathway and two of many homologous recombination deficiency (HRR) genes. Loss of BRCA function allows cells to accumulate mutations and genomic rearrangements that lead to cancer. …

Molecular Targeting and Rational Chemotherapy in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a molecularly complex disease with multiple aberrant genetic pathways involved in its pathogenesis. Approximately one-third to one-half of patients with AML would relapse, and no standard therapy is established for relapsing and/or refractory AML (RR-AML) yet. It is unlikely that blockage of only one specific pathway will lead to prolonged remissions and cures in all fractions of the AML patients population. Nowadays, novel therapeutic agents with rational combination are being recognized which improve the cure rate for relapsed AML. These drugs and their metabo

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… Additionally, the homologous recombination (HR) repair or homology-directed repair (HDR) is a major pathway in DNA damage in which the damage is not necessarily removed, but tolerated by using homologous template sequences to synthesize the sequence complementary to the damaged area of the genome. … Abbreviations: AML, acute myeloid leukemia; NER, nucleotide excision repair; BER, base excision repair; HDR, homology-directed repair; FA, Fanconi anemia; HR, homologous recombination; DDR, DNA damage response; NHEJ, non-homologous end joining; SSBs, single-strand breaks; DSB, double-strand breaks; PARP …

The landscape and trajectory of global CRISPR therapeutics.

With the first regulatory approval in 2023 of a CRISPR-based therapy for sickle cell disease followed by the recent demonstration of an accelerated, personalized CRISPR treatment for congenital severe carbamoyl-phosphate synthetase 1 deficiency, CRISPR-Cas9 genome editing has progressed from a laboratory technology into a clinical reality in just over a decade. While enthusiasm for deploying CRISPR-Cas9 to treat a range of human genetic diseases continues to grow, broad clinical application remains constrained due to technical, regulatory, manufacturing and economic challenges. Here, scientist

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… Despite its precision, CRISPR-Cas9-mediated HDR remains inefficient in non-dividing or slowly dividing cell types, as homologous recombination is restricted to S/G2 phases of the cell cycle. 16 These intrinsic limitations of NHEJ- and HDR-mediated gene editing have catalyzed the development of next-generation …

m5C RNA methylation in cancer: from biological mechanism to clinical perspectives.

Cancer remains a significant global health threat, characterized by high morbidity and mortality rates. Despite advancements, numerous challenges persist in cancer treatment, underscoring the urgent need for novel therapeutic strategies. As a burgeoning area of cancer research, increasing evidence highlights the critical role of 5-methylcytosine (m5C) methylation in tumorigenesis, progression, and clinical application. In this review, we systematically review the biological mechanism and clinical translational potential of m5C RNA methylation in cancer and analyze in detail the dynamic interac

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… Yang H Wang Y Xiang Y Yadav T Ouyang J Phoon L Zhu X Shi Y Zou L Lan L FMRP promotes transcription-coupled homologous recombination via facilitating TET1-mediated m5C RNA modification demethylation Proc Natl Acad Sci U S A 2022 119 e2116251119 10.1073/pnas.2116251119 35290126 PMC8944906 Yang H, Wang … FMRP promotes transcription-coupled homologous recombination via facilitating TET1-mediated m5C RNA modification demethylation. Proc Natl Acad Sci U S A. 2022;119:e2116251119. 10.1073/pnas.2116251119. 35290126 10.1073/pnas.2116251119 PMC8944906 69. …

Influence of the TGF-β Superfamily on Osteoclasts/Osteoblasts Balance in Physiological and Pathological Bone Conditions.

The balance between bone forming cells (osteoblasts/osteocytes) and bone resorbing cells (osteoclasts) plays a crucial role in tissue homeostasis and bone repair. Several hormones, cytokines, and growth factors-in particular the members of the TGF-β superfamily such as the bone morphogenetic proteins-not only regulate the proliferation, differentiation, and functioning of these cells, but also coordinate the communication between them to ensure an appropriate response. Therefore, this review focuses on TGF-β superfamily and its influence on bone formation and repair, through the regulation of

Calpastatin phosphorylation regulates radiation-induced calpain activity in glioblastoma.

Glioblastoma (GBM) is an aggressive, malignant brain tumor that inevitably develops resistance to conventional chemotherapy and radiation treatments. In order to identify signaling pathways involved in the development of radiation resistance, we performed mass spectrometry-based phospho-proteomic profiling of GBM cell lines and normal human astrocytes before and after radiation treatment. We found radiation induced phosphorylation of a number of proteins including calpastatin, specifically in GBM stem cells (GSCs). Herein, we focused on calpastatin, an endogenous inhibitor of calpain proteases

Actinium-225-PSMA-617 treatment in a patient with advanced prostate cancer causes secondary myelofibrosis: a case report and literature review.

Advanced prostate cancer (PCa) is still an incurable disease. Still, the field of PSMA-targeted radioligand therapy is developing rapidly and is playing an increasingly important role in the treatment of advanced Pca in the future. As an α -particle emitter, Ac-225 shows a potent killing ability for tumor cells due to its short range and high energy deposition in the tumor micrometastasis focus. However, the secondary myelofibrosis (SMF) associated with Ac-225-PSMA-617 treatment is a significant concern. We present a case of metastatic castration-resistant prostate cancer (mCRPC) who developed

Протеин внешней мембраны LipL21 как потенциальный кандидат против Leptospira interrogans: An in silico provision.

Резюме Leptospirosis one Из наиболее распространенных зоонотических заболеваний, вызванных лептоспирами, характерными для которых являются мягкие фебрильные заболевания и серьезные многоорганические сбои. Обычные вакцины против «Лептоспира» имеют ряд недостатков, включая краткосрочный иммунитет и защиту на основе «серовара». В настоящем исследовании основное внимание уделяется определению наиболее эффективного внешнего мембранного белка (ОМП) в качестве потенциального антигена с использованием различных вычислительных подходов к обеспечению защиты от лептоспироза, поскольку они сохраняются в п

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A novel NKG2A alpaca nanobody targeting immune checkpoint blockade for the treatment of malignant melanoma.

Alpacas belong to the Camelidae family. Antibodies produced through alpaca immunization are called nanoantibodies. Compared to traditional antibodies, nanoantibodies have several characteristics, including smaller molecular weight, stable structure, high homology with human antibodies, and suitability for prokaryotic expression. Malignant melanoma (MM) is a severe and aggressive form of cancer that affects both humans and animals. It commonly arises in the mucous membranes of the skin, nose, mouth, anus, and digestive tract, as well as in the choroid of the eyes. Multiple factors contribute to