Targeting ATM enhances radiation sensitivity of colorectal cancer by Potentiating radiation-induced cell death and antitumor immunity.

Introduction: The efficacy of radiotherapy in colorectal cancer (CRC) is often limited by radiation resistance. Ataxia telangiectasia mutated (ATM) is well known for its role in repairing double-strand DNA breaks within the DNA damage response (DDR) pathway. However, whether ATM mediates other mechanisms contributing to radiation resistance remains insufficiently investigated.

[Effect of simplified formula of Jinfukang Oral Liquid on apoptosis of renal tubular epithelial cells induced by cisplatin].

In order to study the effect of the simplified formula of Jinfukang Oral Liquid(ALG-12) on renal tubular injury induced by cisplatin(DDP), 48 C57 mice were divided into control group, model group, DDP group, and DDP combined with low, medium, and high dose groups of ALG-12. The mice were administered for 16 days after the establishment of the subcutaneous Lewis lung cancer heterotopic transplant tumor model of mice. The pathological changes, serum creatinine(Scr), blood urea nitrogen(BUN), kidney injury molecule 1(Kim-1), neutrophil gelatinase-associated lipocalin(NGAL), malondialdehyde(MDA), and total superoxide dismutase(T-SOD) in renal tissue and the degree of renal tubular cell apoptosis were analyzed to investigate the effect of ALG-12 on renal injury induced by DDP treatment on non-small cell lung cancer(NSCLC).

Radiotherapy-resistant prostate cancer cells escape immune checkpoint blockade through the senescence-related ataxia telangiectasia and Rad3-related protein.

Background: The majority of patients with prostate cancer (PCa) exhibit intrinsic resistance to immune checkpoint blockade (ICB) following radiotherapy (RT). This resistance is generally attributed to the limited antigen presentation of heterogeneous cells within tumors. Here, we aimed to isolate and characterize these diverse subgroups of tumor post-RT to understand the molecular mechanisms of their resistance to ICB.

Clinical and genetic characterization of a progressive RBL2-associated neurodevelopmental disorder.

Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants.

High- and Moderate-Risk Variants Among Breast Cancer Patients and Healthy Donors Enrolled in Multigene Panel Testing in a Population of Central Russia.

Assessments of breast cancer (BC) risk in carriers of pathogenic variants identified by gene panel testing in different populations are highly in demand worldwide. We performed target sequencing of 78 genes involved in DNA repair in 860 females with BC and 520 age- and family history-matched controls from Central Russia. Among BC patients, 562/860 (65.

AZD1390, an Ataxia telangiectasia mutated inhibitor, enhances cisplatin mediated apoptosis in breast cancer cells.

Genomic instability is often caused by deficiencies in DNA damage repair pathways, making therapeutic targeting of DDR beneficial for cancer patients with specific DDR functions. ATM kinase plays a critical role in various cellular processes and its deficiency increases sensitivity to DDR-targeted agents in different cancers. Recent studies highlight ATM inhibition as a potential clinical target, with AZD1390 being a notable ATM inhibitor due to its potent and selective inhibition, ability to accumulate at DNA breaks.

Novel pathogenic ATM mutation with ataxia-telangiectasia in a Chinese family.

Ataxia-Telangiectasia (A-T) is a rare, autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, and increased cancer risk. Mutations in the ATM gene, which is essential for DNA damage repair, underlie this condition. This study reports a novel homozygous frameshift mutation (ATM_ex20 c.

USP14 inhibition by degrasyn induces YAP1 degradation and suppresses the progression of radioresistant esophageal cancer.

Background: Radiotherapy is a major modality for esophageal cancer (ESCA) treatment, yet radioresistance severely hampers its therapeutic efficacy. Ubiquitin-specific peptidase 14 (USP14) is a novel deubiquitinase and can mediate cancer cells' response to irradiation, although the underlying mechanism remains unclear, including in ESCA.

Methods: To evaluate the expression of USP14 in ESCA tissues or cells, we used RNA-Seq, immunoblotting, co-immunoprecipitation (Co-IP), ubiquitination, quantitative real-time polymerase chain reaction (qRT-PCR), and immunofluorescence assays in this investigation.

[The role of clonal hematopoiesis in the molecular diagnostics of solid tumors].

This review presents the latest molecular genetic diagnostic and clinical aspects related to clonal hematopoiesis of indeterminate potential (CHIP). CHIP belongs to the continuously expanding group of pre-cancerous conditions, increasingly recognized in routine patient care due to the development of molecular diagnostic tools and the increase in life expectancy. The incidence of CHIP mutations increases with age (1-2% in individuals aged 50 years, 15-45% in those aged 80 years).

Rubella virus vaccine-induced granulomas: a case in children with ataxia-telangiectasia.

Ataxia telangiectasia (AT) is a rare autosomal recessive primary immunodeficiency disorder (PID) resulting from a mutation in the ATM gene involved in DNA repair. We describe the case of a young girl with cutaneous granulomas that developed after childhood vaccinations. Immunohistochemistry revealed granulomas induced by the rubella virus vaccine.

Endoscopic innovations in diagnosis and management of pancreatic cancer: a narrative review and future directions.

Pancreatic cancer serves as the third leading cause of cancer-associated morbidity and mortality in the United States, with a 5-year survival rate of only 12% with an expected increase in incidence and mortality in the coming years. Pancreatic ductal adenocarcinomas constitute most pancreatic malignancies. Certain genetic syndromes, including Lynch syndrome, hereditary breast and ovarian cancer syndrome, hereditary pancreatitis, familial adenomatous polyposis, Peutz-Jeghers syndrome, familial pancreatic cancer mutation, and ataxia telangiectasia, confer a significantly higher risk.

MeCP2 deficiency leads to the γH2AX nano foci expansion after ionizing radiation.

DNA double-strand breaks (DSBs) trigger the recruitment of repair protein and promote signal transduction through posttranslational modifications such as phosphorylation. After DSB induction, ataxia telangiectasia mutated (ATM) phosphorylates H2AX on chromatin surrounds the mega-base pairs proximal to the DSBs. Advanced super-resolution microscopic technology has demonstrated the formation of γH2AX nano foci as a unit of nano domain comprised of multiple nucleosomes.

Cell cycle arrest via DNA Damage Response (DDR) pathway induced by extracellular self-DNA (esDNA) application in rice root.

Conspecific plant growth is inhibited by extracellular fragments in a concentration-dependent manner. Although several reports have addressed this self-DNA inhibition, the underlying mechanism remains unclear. In this investigation, we evaluated the progression of cell cycle of rice roots in responding to extracellular-self DNA (esDNA).

Upregulation of ISG15 induced by MAPT/tau accumulation represses autophagic flux by inhibiting HDAC6 activity: a vicious cycle in alzheimer disease.

Alzheimer disease (AD), a prevalent neurodegenerative condition in the elderly, is marked by a deficit in macroautophagy/autophagy, leading to intracellular MAPT/tau accumulation. While ISG15 (ISG15 ubiquitin like modifier) has been identified as a regulator of selective autophagy in ataxia telangiectasia (A-T), its role in AD remains unexplored. Our study reveals elevated ISG15 levels in the brains of patients with sporadic AD and AD models and .

Discovery of ART0380, a Potent and Selective ATR Kinase Inhibitor Undergoing Phase 2 Clinical Studies for the Treatment of Advanced or Metastatic Solid Cancers.

One of the hallmarks of cancer is high levels of DNA replication stress and defects in the DNA damage response (DDR) pathways, which are critical for maintaining genomic integrity. Ataxia telangiectasia and Rad3-related protein (ATR) is a key regulator of the DDR machinery and an attractive therapeutic target, with multiple ATR inhibitors holding significant promise in ongoing clinical studies. Herein, we describe the discovery and characterization of ART0380 (), a potent and selective ATR inhibitor with a compelling in vitro and in vivo pharmacological profile currently undergoing Phase 2 clinical studies in patients with advanced or metastatic solid tumors as monotherapy and in combination with DNA-damaging agents (NCT04657068 and NCT05798611).

Ataxia telangiectasia.

Ataxia telangiectasia (AT) is a rare neurocutaneous syndrome that results from biallelic pathogenic variants in the ataxia telangiectasia mutated (ATM) gene, named for its characteristic cerebellar ataxia in the early toddler years and variable oculocutaneous telangiectasias in the school age years. While its name only hints at neurologic and cutaneous manifestations, this multisystemic disorder also has important immunologic, oncologic, respiratory, and endocrinologic implications. This article will review the function of the ATM gene, the neurologic manifestations of AT, non-neurologic complications, mimickers of AT (including other disorders of defective DNA repair), and the realm of therapeutic research for AT.

Transcriptional and functional regulation of cell cycle and UV response by PPARβ in human skin epidermal cells.

Solar radiation is the main source of human exposure to UV rays, which is the major carcinogen in skin cancers by inducing DNA damage. Skin cells repair these damages by activating the DNA damage response (DDR) to safeguard genome integrity, thereby preventing skin cancers. Peroxisome proliferator-activated receptor beta (PPARβ), a druggable transcription factor, is involved in the development of UV-dependent skin cancers, although its role is not mechanistically elucidated.