Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “ATM”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1985

Effects of high hydrostatic pressure per se, 101 atm on eel metabolism.

Oxygen consumption (MO2) of confined eels was measured at atmospheric pressure, 1 atm, and at 101 atm of hydrostatic pressure per se (HP). The tolerance of the eels to hypoxia was studied at the two experimental pressures. At atmospheric pressure, when oxygen partial pressure (PWO2) fell below the critical pressure, Pc = 22.4 +/- 1.95 Torr, there was a linear PWO2-related decrease in MO2. At maximal hypoxia, the eels survived for several hours by their efficient anaerobic metabolism. At 101 atm of HP, as soon as the experimental pressure was attained, a linear PWO2-related decrease in MO2 was observed at PWO2 levels much higher than those considered as critical at atmospheric pressure. The relation MO2 = f (PWO2) was similar to that observed at 1 atm when PWO2 less than Pc, that is, when aerobic metabolism was insufficient to ensure the eels' energetic requirement. Moreover, the eels tolerated hypoxia much less well at 101 atm of HP than at 1 atm. In conclusion, the exposure of eels to 101 atm of HP induced a sharp decrease in aerobic metabolism; then, at 101 atm, the energetic requirements must be ensured by anaerobic processes which produced lactates in plasma whose values were similar to those observed at 1 atm when PWO2 less than Pc.

Anaerobiosis↗
PubMed2026

Germline ATM Testing in Hereditary Cancer Syndromes: Feedback from a Five-Year Center Cohort.

PURPOSE: Germline ATM pathogenic or likely pathogenic (P/LP) variants are increasingly recognized as clinically relevant in hereditary cancer predisposition, their integration into routine testing remains heterogeneous across countries. We describe the prevalence, tumor spectrum and relative risk associated with germline ATM P/LP variants in individuals with breast and pancreatic cancer. METHODS: We conducted a five-year retrospective (2019-2025) reanalysis of the ATM gene in 1,707 probands tested with hereditary breast and ovarian cancer (HBOC) or pancreatic cancer panels in our center. For all probands that underwent targeted ATM reanalysis, relative risks (RR) and odds ratios (OR) were calculated. Family-based segregation was performed when possible. RESULTS: Targeted ATM re-analysis identified 33 additional probands with P/LP variants, increasing diagnostic yield from 7.3% to 9.1% in HBOC and from 4.3% to 9.7% in pancreatic cancer. Among 22 breast-cancer probands, mean age at diagnosis was 47 years. Case-control comparison yielded OR 3.85 (95% CI 2.43-6.08; P=8.5×10-9) for breast cancer and OR 15.81 (95% CI 6.31-39.66; P=4.0×10-9) for pancreatic cancer. CONCLUSION: This work strengthens the role of ATM in cancer predisposition panels and supports its inclusion in French national hereditary cancer panel recommendations, together with implementation of appropriate surveillance and counseling for individuals harboring ATM P/LP variants.

ATM↗
PubMed2025

Genomic and Immune Landscape of Pancreatic Ductal Adenocarcinoma Associated with Germline Pathogenic Variants in ATM.

PURPOSE: Germline pathogenic variants (PV) in ATM increase the risk of pancreatic ductal adenocarcinoma (PDAC), but the underlying tumor biology of PDAC associated with germline PV in ATM has not been adequately explored. EXPERIMENTAL DESIGN: Whole-genome, whole-exome, and RNA sequencing were performed on PDAC tumors from 25 germline ATM PV carriers diagnosed at Mayo Clinic between 2007 and 2017. Somatic and copy-number alterations, mutational signatures, transcriptomic subtypes, and the immune landscape were evaluated. RESULTS: High-quality whole-exome and whole-genome sequencing were obtained from 21 and 15 tumors, respectively. Biallelic inactivation of ATM was observed in 87%, KRAS PV in 90%, CDKN2A homozygous loss in 60%, and TP53 alterations in <10% of these tumors. A predominant clock-like mutational signature was present in all samples. Whole-transcriptome analysis identified that the aberrantly differentiated endocrine exocrine subtype accounted for 18% of PDAC and was consistently associated with >5-year overall survival. In addition, a 28-gene expression-based signature associated with overall survival was identified and further validated in The Cancer Genome Atlas cohort. Immune landscape analysis through CODEX identified enriched CD4 T-helper cell/tumor interactions and reduced B7H3-high cell/tumor interactions in ATM PV carriers compared with noncarriers. CONCLUSIONS: The observed absence of TP53 PV and enrichment for CDKN2A alterations in ATM tumors, along with differences in the mutational signatures, transcriptomic subtypes and immune landscape, improve our understanding of the mechanistic pathways involved in PDAC development in germline ATM PV carriers and help identify potential targeted therapeutic strategies.

Humans↗
PubMed1992

Cardiovascular responses to upright tilt in man during acute exposure to 3 atm abs air.

To examine the effect of acute hyperbaric exposure on cardiovascular response to orthostasis, a passive 70 degrees head-up tilt (HUT) test was performed for 15 min in a simulated compressed-air hyperbaric environment of 3 atm abs at ambient temperature of 31 degrees C (thermoneutral) on 8 male subjects. Heart rate (HR), blood pressure, cardiac output (CO) by impedance cardiography, forearm blood flow (FBF) by the occlusion plethysmography, and laser-Doppler skin blood flow (BFLD) on the thigh were measured for 15 min before, during, and after HUT. Esophageal temperature and HR data were recorded continuously. An identical test was performed in a 29 degrees C (thermoneutral) normal atmospheric condition. None of the subjects showed signs of syncope during HUT in either environment. Baseline HR was significantly lower (P less than 0.05) at 3 atm abs, and the increase in HR (delta HR) during HUT was of the same magnitude (15 beats/min) at both atmospheric pressures. The reduction of systolic blood pressure (delta SBP) was identical in both environments. Thus, the chronotropic response to HUT (delta HR/delta SBP) was the same. A marked reduction in CO (P less than 0.05) was attributed to a reduction of stroke volume during HUT, and the reduction was greater (P less than 0.05) at 3 atm abs. There were no pressure-dependent changes during HUT in FBF, forearm vascular resistance, and BFLD except for a greater increase (P less than 0.05) in total peripheral resistance at 3 atm abs. These observations suggest that orthostatic tolerance was maintained in the presence of lower CO at 3 atm abs, probably by a greater vasoconstrictor response in the splanchnic areas. We conclude that the substantial bradycardia which occurred at 3 atm abs did not interfere with a normal response to orthostasis in humans because of a peripheral vasoconstriction caused by the elevated oxygen pressure and an enhanced increase in total peripheral resistance which occurred during HUT in 3 atm abs.

Adult↗
PubMed2024

The immediate-early protein 1 of human herpesvirus 6B interacts with NBS1 and inhibits ATM signaling.

Viral infection often trigger an ATM serine/threonine kinase (ATM)-dependent DNA damage response in host cells that suppresses viral replication. Viruses evolved different strategies to counteract this antiviral surveillance system. Here, we report that human herpesvirus 6B (HHV-6B) infection causes genomic instability by suppressing ATM signaling in host cells. Expression of immediate-early protein 1 (IE1) phenocopies this phenotype and blocks homology-directed double-strand break repair. Mechanistically, IE1 interacts with NBS1, and inhibits ATM signaling through two distinct domains. HHV-6B seems to efficiently inhibit ATM signaling as further depletion of either NBS1 or ATM do not significantly boost viral replication in infected cells. Interestingly, viral integration of HHV-6B into the host's telomeres is not strictly dependent on NBS1, challenging current models where integration occurs through homology-directed repair. Given that spontaneous IE1 expression has been detected in cells of subjects with inherited chromosomally-integrated form of HHV-6B (iciHHV-6B), a condition associated with several health conditions, our results raise the possibility of a link between genomic instability and the development of iciHHV-6-associated diseases.

Humans↗
PubMed1988

Identification of a tumor-associated target antigen, ATM-1, for a human T-cell clone with activated killer activity and its existence in sera of cancer patients.

Three human T-cell clones with activated killer activity (5B5, 5C1, and 7B5) which could lyse various tumor cell lines were established. The cytotoxic activity of these clones was decreased by incubation with anti-CD3 monoclonal antibody, suggesting that they recognized tumor cells by T-cell antigen receptor. A monoclonal antibody which blocked the cytotoxic activity of clone 5B5 was obtained. This antibody (N1977) blocked the binding and cytotoxic activity of clone 5B5 at the target cell level, suggesting that the antigen defined by N1977 antibody, designated as ATM-1, was a target molecule recognized by 5B5 cells. ATM-1 in the conditioned medium of a cancer cell line (NBT-2) and serum from a patient with lung cancer was characterized by following its immunoreactivity. On gel filtration, both the conditioned medium and the serum gave three peaks of ATM-1 immunoreactivity, corresponding to approximate molecular weights of 1,200,000, 700,000, and 120,000, respectively. They were chromatofocused at pH 4.0, 4.8, and 6.5, respectively. The high molecular weight forms were shown to be molecules with the disulfide-linked elementary glycoprotein with ATM-1 immunoreactivity and approximate molecular weight of 120,000. Most of the molecules with ATM-1 immunoreactivity bound to both concanavalin A and wheat germ agglutinin, and their binding activity to the antibodies was lost by treatment at 60 degrees C for 30 min. An assay of ATM-1 level in sera was performed by a sandwich enzyme immunoassay. The following positive percentages were obtained from preliminary clinical studies: breast cancer, 67% (8 of 12 cases); hepatocellular carcinoma, 83% (10 of 12 cases); gastric cancer, 58% (7 of 12 cases); lung cancer, 41% (5 of 12 cases); hematological malignancies, 0% (0 of 9 cases); systemic lupus erythematosus, 0% (0 of 8 cases); rheumatoid arthritis, 0% (0 of 8 cases).

Animals↗
PubMed2026

ATM Variants and Breast Cancer Risk in North Macedonia: Focus on the Regionally Enriched p.(Leu2492Arg) Variant.

BACKGROUND: Germline pathogenic variants (PVs) in the ataxia-telangiectasia mutated (ATM) gene are established moderate-risk factors for breast cancer (BC), however, population-specific variant spectra and the clinical significance of many missense variants remain incompletely characterized. AIMS: To evaluate the prevalence of ATM variants in a large cohort of patients with BC from North Macedonia and compare it with that in the general population, with a particular focus on the frequency of the p.(Leu2492Arg) variant and its distribution relative to global genomic datasets. STUDY DESIGN: Retrospective case&#x2013;control study. METHODS: ATM variants were analyzed in 1,211 patients with BC from North Macedonia using a targeted hereditary cancer gene panel. These findings were compared with those from 1,303 population-based controls analyzed by clinical exome or whole-exome sequencing. RESULTS: Pathogenic ATM variants were identified in 1.9% of BC cases and 0.4% of controls, indicating a significantly increased risk of BC [odds ratio (OR) = 5.02, p = 0.0006]. Most PVs were protein-truncating, with six recurrent variants accounting for over 70% of detections, suggesting regional enrichment. Carriers showed a significantly higher prevalence of human epidermal growth factor receptor 2-positive tumors (OR = 2.92, p = 0.0189). Variants of uncertain significance were observed at comparable frequencies in cases and controls. The p.(Leu2492Arg) missense variant was more frequently detected in cases than in controls (1.9% vs. 1.1%; OR = 1.78, p = 0.086) and exhibited a markedly higher allele frequency in this population than in global databases. CONCLUSION: These findings confirm ATM as a clinically relevant BC susceptibility gene in North Macedonia and highlight the population-specific enrichment of both PVs and the p.(Leu2492Arg) missense variant. The results emphasize the importance of using population-matched controls and regional genomic data for accurate risk assessment and variant interpretation.

Humans↗
PubMed1992

[Two cases of recurrent optic neuritis (OPN) and acute transverse myelopathy (ATM) with associated anticardiolipin antibodies].

We investigated anticardiolipin antibodies (aCL) by enzyme linked immunosorbent assay with adding aCL-cofactor in two cases of recurrent OPN and ATM patients. These two patients had similar clinical features with ATM and OPN during their clinical courses. They were supposed to be suffered with multiple sclerosis (MS), although cranial MRI was normal and oligoclonal IgG band (OCB) was consistently absent in the cerebrospinal fluid. Positive aCL is suggestive that this disease may be a disorder associated with aCL with different etiology and pathogenesis from other MS patients. Serologic testing for aCL with aCL-cofactor should be warranted for MS patients, especially for those showing OPN and ATM during the clinical course, because in orientals the incidence of ATM and OPN is relatively high among MS.

Acute Disease↗
PubMed2025

Crosstalk between chromatin state and ATM signalling in DNA damage-induced transcription stress.

The DNA Damage Response (DDR) is a highly regulated process that safeguards genomic integrity against DNA lesions. Increasing evidence supports a reciprocal relationship between damaged chromatin architecture and the signalling pathways that coordinate the DDR. However, the mechanisms underlying this interplay in response to transcription-blocking DNA lesions remain largely unexplored. Here, we show that stalling of RNA polymerase II (RNAPII) at such lesions induces local chromatin acetylation, mediated primarily by the histone acetyltransferase p300. The resulting chromatin relaxation stimulates the dissociation of mature co-transcriptional spliceosomes from nascent RNA and promotes RNA:DNA hybrid (R-loop) formation, leading to ATM activation. In turn, activated ATM modulates chromatin conformation by phosphorylating histone H2A.X and triggering p38MAPK/MSK1-dependent histone H3S10 phosphorylation. Our findings highlight the cross-regulation between chromatin state and ATM signalling as a key component of the cellular response to transcription stress.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1977

Effect of a novel adenosine deaminase inhibitor (co-vidarabine, co-V) upon the antiviral activity in vitro and in vivo of vidarabine (Vira-Atm) for DNA virus replication.

A new potent inhibitor of adenosine deaminase (co-vidarabine) was used in combination studies with adenine arabinoside (vidarabine, Vira-ATM) to protect this purine nucleoside from enzymatic deamination to the more weakly active metabolite, hypoxanthine arabinoside. Comparing the combination to vidarabine alone, a significant increase (10-fold) of the antiviral activity of the combined drugs was observed against herpes and vaccinia viruses in tissue culture and subcutaneously, against cranial herpesvirus infections in mice. Several other investigators have also recently reported several-fold enhancement of vidarabine activity by newly described deaminase inhibitors. They observed that plaque formation by several large DNA-containing viruses (herpes, vaccinia, varicella zoster) and an RNA-containing oncogenic virus was markedly prevented by the combination compared to vidarabine alone. In animals, enhanced protection (increased survivors) and/or highly significant increase in the life span of dying mice treated with the 2-drug combination, was also observed compared to vidarabine administered singly. These observations in animals clearly indicate that combination studies with vidarabine (Vira-ATM) and co-vidarabine (deaminase inhibitor) deserve serious consideration as future therapy for systemic virus infections in man including herpesvirus encephalitis.

Adenosine Deaminase Inhibitors↗
PubMedDate not supplied

Saturation curve in gases of high atomic number at pressures up to 8 atm. I. Krypton and xenon.

The saturation curve has been studied in xenon and in krypton up to a pressure of 8 atm. An empirical formula has been found that describes the fraction of current collected over a wide range of voltages, pressures, ionization intensities, and electrode spacings. This is of practical value in the design of ionography chambers. For krypton the collection fraction fKr = (1 + 0.25eta-1.74)-1, and for xenon fXe = (1 + 0.16eta-1.88)-1, where eta = Fp-0.7Vd-2q-1/2 with F = 3.61 X 10(-7) and 2.50 X 10(-7) for krypton and xenon, respectively. The ranges of the variables covered in the experiments were p = 1-8 atm, V = 5-25000 V, d = 0.3-1.3 cm, and q = 4 X 10(-9)-6 X 10(-8) A/cm3.

Atmospheric Pressure↗
PubMed1991

O2 pressures between 0.12 and 2.5 atm abs, circulatory function, and N2 elimination.

To study the effects of inhaled oxygen pressures on N2 elimination, 72, 2-h washouts were performed in 6 subjects at oxygen pressures of 0.12, 0.2, 1.0, 2.0, and 2.5 atm abs using a closed circuit system that supplied an O2-argon mixture and collected the N2 off-gassed. Hypoxia induced a significant (9.4%, P less than 0.05) increase in nitrogen eliminated as compared to normoxia. Pure oxygen breathing induced a small, insignificant (3.5%) decrease in nitrogen yields, but further increases in oxygen pressure induced significant decreases in nitrogen yields (-8.9% and -16.9% for 2.0 and 2.5 atm abs, respectively). Heart rate, cardiac output, skin perfusion and leg blood flow decreased, whereas mean arterial pressure increased with increasing oxygen pressure. We conclude, therefore, that perfusion-dependent N2 elimination decreases secondary to vasoconstriction induced by increasing oxygen pressures. Changes in inhaled oxygen pressures during different phases of compression-decompression may induce alterations in the rate of inert gas uptake and elimination. Although not currently quantifiable, such alterations would imply added uncertainties in the computation of decompression schedules. Oxygen breathing during decompression should be performed at the lowest possible ambient pressure compatible with freedom from pathogenic bubble formation.

Adult↗
PubMed2026

An IRAK1-snRNA axis activates ATM to promote accurate repair within transcriptionally active chromatin.

Genomic integrity in transcriptionally active regions is pivotal for suppressing oncogenic mutations, yet the mechanisms that govern precise homologous recombination (HR) repair within these regions remain elusive. Here, we report that the IRAK1-spliceosome axis operates with small nuclear RNA (snRNA) as a central hub, potently promoting accurate repair at DNA double-strand break (DSB) sites within active chromatin in human cancer cells. Mechanistically, IRAK1 phosphorylates spliceosomal serine/arginine (SR)-rich proteins to recruit snRNA to DSBs, inducing robust condensation of the MRE11-RAD50-NBS1 (MRN) complex near transcriptionally active regions to create an ATM activation platform. Collectively, our findings define a prevalent mechanism governing region-specific precise repair in transcriptionally active domains, where snRNA acts as a "transcription repair bridge" to link transcriptional processes to HR repair and ultimately preserves genomic stability. Inhibiting IRAK1 axis impairs HR repair in transcriptionally active regions, causing a marked increase in mutation rates specific to these regions and cancer-cell chemosensitivity.

Humans↗
PubMedDate not supplied

Saturation curve in gases of high atomic number at pressures up to 8 atm. Part II: Freon 13-B1, and mixtures of Freon with xenon and krypton.

The saturation curve has been studied in Freon 13-B1 (CF3Br) and in mixtures of Freon with xenon and krypton up to a pressure of 8 atm. The enhanced initial recombination due to the electron affinity of Freon has been evaluated and an empirical formula constructed that describes the fraction of current which escapes initial recombination over a wide range of voltages, pressures, and electrode spacings. After correction for this initial recombination, the general saturation curve for Freon and for mixtures of this gas with krypton and xenon has been derived and, again, convenient empirical formulae established which allow the current collection efficiency to be calculated for any given parameters within the range investigated. These formulae are of practical value in the design of image-forming ionization chambers.

Chlorofluorocarbons, Methane↗
PubMed1990

CO2 retention with minimal symptoms but severe dysfunction during wet simulated dives to 6.8 atm abs.

During wet dives in a hyperbaric chamber to 6.8 atm abs (690 kPa), air breathing subjects were experimentally exposed to external breathing resistance. Two of them were, unbeknownst to themselves, severely incapacitated. In the first incident the subject had been exercising for 25 min (end-tidal PCO2 60-65 mmHg, 7.3-8.0 kPa) when the breathing resistance was rapidly increased from low to very high (requiring pressure swings of 80 cmH2O, 8 kPa, peak to peak). He functioned normally (end-tidal PCO2 72 mmHg, 9.6 kPa) for about 100 s but 20 s later he was confused and irrational. After being extracted from the water (end-tidal PCO2 above 90 mmHg, 12 kPa), he lost consciousness for about 60 s. In the second incident the subject was exercising and breathing against a high resistance (pressure swings of 50-55 cmH2O, 5.0-5.6 kPa). His end-tidal PCO2 was high (65-68 mmHg, 8.7-9.3 kPa) throughout the exercise period, and after 24 min he reported mild dyspnea. A few seconds later he became confused. In other experiments both subjects voluntarily terminated experiments when the breathing resistance became overwhelming. These 2 subjects generally had high end-tidal PCO2 levels, but 1 other subject with end-tidal PCO2 levels in the same range never experienced any problems. These incidents indicate that severe hypercapnia does not necessarily correlate with dyspnea and that severe disturbances in mental function due to hypercapnia can develop suddenly when high breathing resistance is encountered in diving.

Blood Gas Monitoring, Transcutaneous↗
PubMed1989

Changes in regional cerebral blood flow and sucrose space after 3-4 weeks of hypobaric hypoxia (0.5 ATM).

In summary, we can come to a number of meaningful conclusions regarding chronic exposure to hypobaric hypoxia in rats (refer to Figure 1). First, despite an increased hematocrit, and thus increased oxygen carrying capacity, regional cerebral blood flow is elevated after 4 weeks of chronic hypobaric hypoxia. This elevation in blood flow occurs even though the rat hyperventilates to lower than normal arterial CO2 content which would ordinarily decrease cerebral blood flow. Second, although blood flow is increased in both chronic and acute hypoxia, the increases can not be through similar mechanisms since in the acute hypoxic condition there is also an increase in local blood volume that is absent in the chronic response. Third, the effect of chronic hypoxic exposure on cerebral blood flow persists for at least 4 hours after the animal is returned to normobaric normoxia. Fourth, sometime between 4 and 24 hours of recovery is necessary to reverse the effect of chronic hypoxia on cerebral blood flow. One day after having been returned to normobaric normoxia cerebral blood flow had returned to control. On the other hand, hematocrit was still elevated in these rats. Thus, the change in hematocrit does not seem to be associated in any mechanistic manner with the blood flow response.

Animals↗