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MedRxiv : the Preprint Server For... Feb 2024Bloom Syndrome (BSyn) is an autosomal recessive disorder caused by biallelic germline variants in which functions to maintain genomic stability. BSyn patients have poor...
BACKGROUND
Bloom Syndrome (BSyn) is an autosomal recessive disorder caused by biallelic germline variants in which functions to maintain genomic stability. BSyn patients have poor growth, immune defects, insulin resistance, and a significantly increased risk of malignancies, most commonly hematologic. The malignancy risk in carriers of pathogenic variants in ( variant carriers) remains understudied. Clonal hematopoiesis of indeterminate potential (CHIP) is defined by presence of somatic mutations in leukemia-related genes in blood of individuals without leukemia and is associated with increased risk of leukemia. We hypothesize that somatic mutations driving clonal expansion may be an underlying mechanism leading to increased cancer risk in BSyn patients and variant carriers.
METHODS
To determine whether or somatic variation is increased in BSyn patients or carriers, we performed and analyzed exome sequencing on BSyn and control trios.
RESULTS
We discovered that both BSyn patients and carriers had increased numbers of low-frequency, putative somatic variants in CHIP genes compared to controls. Furthermore, BLM variant carriers had increased numbers of somatic variants in DNA methylation genes compared to controls. There was no statistical difference in the numbers of variants in BSyn probands compared to control probands.
CONCLUSION
Our findings of increased CHIP in BSyn probands and carriers suggest that one or two germline pathogenic variants in could be sufficient to increase the risk of clonal hematopoiesis. These findings warrant further studies in larger cohorts to determine the significance of CHIP as a potential biomarker of aging, cancer, cardiovascular disease, morbidity and mortality.
PubMed: 38370823
DOI: 10.1101/2024.02.02.24302163 -
International Journal of Molecular... Apr 2024We explore the possibility that defects in genes associated with the response and repair of DNA double strand breaks predispose oral potentially malignant disorders... (Review)
Review
We explore the possibility that defects in genes associated with the response and repair of DNA double strand breaks predispose oral potentially malignant disorders (OPMD) to undergo malignant transformation to oral squamous cell carcinoma (OSCC). Defects in the homologous recombination/Fanconi anemia (HR/FA), but not in the non-homologous end joining, causes the DNA repair pathway to appear to be consistent with features of familial conditions that are predisposed to OSCC (FA, Bloom's syndrome, Ataxia Telangiectasia); this is true for OSCC that occurs in young patients, sometimes with little/no exposure to classical risk factors. Even in Dyskeratosis Congenita, a disorder of the telomerase complex that is also predisposed to OSCC, attempts at maintaining telomere length involve a pathway with shared HR genes. Defects in the HR/FA pathway therefore appear to be pivotal in conditions that are predisposed to OSCC. There is also some evidence that abnormalities in the HR/FA pathway are associated with malignant transformation of sporadic cases OPMD and OSCC. We provide data showing overexpression of HR/FA genes in a cell-cycle-dependent manner in a series of OPMD-derived immortal keratinocyte cell lines compared to their mortal counterparts. The observations in this study argue strongly for an important role of the HA/FA DNA repair pathway in the development of OSCC.
Topics: Humans; Mouth Neoplasms; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Fanconi Anemia; Head and Neck Neoplasms; DNA
PubMed: 38612901
DOI: 10.3390/ijms25074092 -
Biomedicine & Pharmacotherapy =... Dec 2023The high expression of BLM (Bloom syndrome) DNA helicase in tumors involves its strong association with cell expansion. Bisbenzylisoquinoline alkaloids own an antitumor...
The high expression of BLM (Bloom syndrome) DNA helicase in tumors involves its strong association with cell expansion. Bisbenzylisoquinoline alkaloids own an antitumor property and have developed as candidates for anticancer drugs. This paper aimed to study the antitumor effect of fangchinoline derivative HY-2 by targeting BLM DNA helicase, and then explore its inhibitory mechanism on proliferation of MDA-MB-435 breast cancer cells. We confirmed that the mRNA and protein levels of BLM DNA helicase in breast cancer were higher than those in normal tissues. HY-2 could inhibit the DNA binding, ATPase and DNA unwinding of BLM DNA helicase with enzymatic assay. HY-2 could also inhibit the DNA unwinding of DNA helicase in cells. In addition, HY-2 showed an inhibiting the MDA-MB-435, MDA-MB-231, MDA-MB-436 breast cancer cells expansion. The mRNA and protein levels of BLM DNA helicase in MDA-MB-435 cells increased after HY-2 treatment, which might contribute to HY-2 inhibiting the DNA binding, ATPase and DNA unwinding of BLM DNA helicase. The mechanism of HY-2 inhibition on BLM DNA helicase was further confirmed with the effect of HY-2 on the ultraviolet spectrogram of BLM DNA helicase and Molecular dynamics simulation of the interacting between HY-2 and BLM DNA helicase. Our study provided some valuable clues for the exploration of HY-2 in the living body and developing it as an anticancer drug.
Topics: Female; Humans; Antineoplastic Agents; Benzylisoquinolines; Breast Neoplasms; DNA; RecQ Helicases; RNA, Messenger; DNA Helicases
PubMed: 37988849
DOI: 10.1016/j.biopha.2023.115908 -
American Journal of Perinatology Oct 2023Both high altitude and trisomy 21 (T21) status can negatively impact respiratory outcomes. The objective of this study was to examine the association between altitude...
OBJECTIVE
Both high altitude and trisomy 21 (T21) status can negatively impact respiratory outcomes. The objective of this study was to examine the association between altitude and perinatal respiratory support in neonates with T21 compared with those without T21.
STUDY DESIGN
This retrospective cohort study used the United States all-county natality files that included live, singleton, in-hospital births from 2015 to 2019. Descriptive statistics for neonates with and without the primary outcome of sustained assisted ventilation (>6 hours) were compared using -tests and Chi-squared analyses. Multivariable logistic regression was used to determine the association between respiratory support and the presence of T21, and included an interaction term to determine whether the association between respiratory support and the presence of T21 was modified by elevation at delivery.
RESULTS
A total of 17,939,006 neonates, 4,059 (0.02%) with T21 and 17,934,947 (99.98%) without, were included in the study. The odds of requiring sustained respiratory support following delivery were 5.95 (95% confidence interval [CI]: 5.31, 6.66), 4.06 (95% CI: 2.39, 6.89), 2.36 (95% CI: 1.64, 3.40), and 5.04 (95% CI: 1.54, 16.54) times as high for neonates with T21 than without T21 when born at low, medium, high, and very high elevations, respectively. The odds of requiring immediate ventilation support following delivery were 5.01 (95% CI: 4.59, 5.46), 5.90 (95% CI: 4.16, 8.36), 2.86 (95% CI: 2.15, 3.80), and 12.08 (95% CI: 6.78, 21.51) times as high for neonates with T21 than without T21 when born at low, medium, high, and very high elevation, respectively.
CONCLUSION
Neonates with T21 have increased odds of requiring respiratory support following delivery when compared with neonates without T21 at all categories of altitude. However, the odds ratios did not increase monotonically with altitude which indicates additional research is critical in understanding the effects of altitude on neonates with T21.
KEY POINTS
· Neonates with T21 have an increased need for perinatal respiratory support at all altitudes.. · The odds of needing perinatal respiratory support did not increase monotonically with elevation.. · Additional research is critical to understanding the effects of altitude on neonates with T21..
Topics: Infant, Newborn; Pregnancy; Female; Humans; United States; Down Syndrome; Altitude; Retrospective Studies; Hospitals; Logistic Models
PubMed: 34674211
DOI: 10.1055/s-0041-1736594 -
Journal of Stroke and Cerebrovascular... Jan 2024Bloom syndrome is a chromosomal breakage disorder associated with immune deficiency, characterized by short stature, predisposition to early-onset cancer, and immune...
OBJECTIVE
Bloom syndrome is a chromosomal breakage disorder associated with immune deficiency, characterized by short stature, predisposition to early-onset cancer, and immune defects. Currently, there have been no reports of acute cerebral infarction in patients with Bloom syndrome. Here, we report a case of Bloom syndrome complicated by elevated antiphospholipid antibodies and acute cerebral infarction.
MATERIALS AND METHODS
A 23-year-old male with a known genetic diagnosis of Bloom syndrome was admitted to the Respiratory Department due to pulmonary aspergillosis. The patient experienced sudden dizziness, and subsequent cranial MRI revealed a newly developed infarction in the right cerebellar hemisphere.
RESULTS
Six days later, the patient presented with sudden right visual field loss, and a repeat cranial MRI showed new infarctions in the left occipital and temporal lobes. Positive lupus anticoagulant and prolonged activated partial thromboplastin time suggested elevated antiphospholipid antibodies causing thrombus formation. Unfortunately, anticoagulant treatment was not administered due to recurrent hemoptysis.
CONCLUSION
This study reports the first case of a Bloom syndrome patient with elevated antiphospholipid antibodies and acute cerebral infarction, suggesting that the immune and coagulation abnormalities caused by Bloom syndrome may contribute to the development of acute cerebral infarction.
Topics: Male; Humans; Young Adult; Adult; Antibodies, Antiphospholipid; Ischemic Stroke; Bloom Syndrome; Antiphospholipid Syndrome; Stroke; Brain Ischemia; Infarction; Cerebral Infarction
PubMed: 37988834
DOI: 10.1016/j.jstrokecerebrovasdis.2023.107490 -
Cell Death Discovery Nov 2023Ionizing radiation (IR) causes a wide variety of DNA lesions, of which DNA double-stranded breaks (DSBs) are the most deleterious. Homologous recombination (HR) is a...
Ionizing radiation (IR) causes a wide variety of DNA lesions, of which DNA double-stranded breaks (DSBs) are the most deleterious. Homologous recombination (HR) is a crucial route responsible for repairing DSBs. RecQ-mediated genome instability protein 1 (RMI1) is a member of an evolutionarily conserved Bloom syndrome complex, which prevents and resolves aberrant recombination products during HR, thereby promoting genome stability. However, little is known about the role of RMI1 in regulating the cellular response to IR. This study aimed to understand the cellular functions and molecular mechanisms by which RMI1 maintains genomic stability after IR exposure. Here, we showed IR upregulated the RMI1 protein level and induced RMI1 relocation to the DNA damage sites. We also demonstrated that the loss of RMI1 in cells resulted in enhanced levels of DNA damage, sustained cell cycle arrest, and impaired HR repair after IR, leading to reduced cell viability and elevated genome instability. Taken together, our results highlighted the direct roles of RMI1 in response to DNA damage induced by IR and implied that RMI1 might be a new genome safeguard molecule to radiation-induced damage.
PubMed: 38007566
DOI: 10.1038/s41420-023-01726-1 -
Harmful Algae Jan 2024Ciguatera Poisoning (CP) is a widespread and complex poisoning syndrome caused by the consumption of fish or invertebrates contaminated with a suite of potent...
Ciguatera Poisoning (CP) is a widespread and complex poisoning syndrome caused by the consumption of fish or invertebrates contaminated with a suite of potent neurotoxins collectively known as ciguatoxins (CTXs), which are produced by certain benthic dinoflagellates species in the genera Gambierdiscus and Fukuyoa. Due to the complex nature of this HAB problem, along with a poor understanding of toxin production and entry in the coral reef food web, the development of monitoring, management, and forecasting approaches for CP has lagged behind those available for other HAB syndromes. Over the past two decades, renewed research on the taxonomy, physiology, and toxicology of CP-causing dinoflagellates has advanced our understanding of the species diversity that exists within these genera, including identification of highly toxic species (so called "superbugs") that likely contribute disproportionately to ciguatoxins entering coral reef food webs. The recent development of approaches for molecular analysis of field samples now provide the means to investigate in situ community composition, enabling characterization of spatio-temporal species dynamics, linkages between toxic species abundance and toxin flux, and the risk of ciguatoxin prevalence in fish. In this study we used species-specific fluorescent in situ hybridization (FISH) probes to investigate Gambierdiscus species composition and dynamics in St. Thomas (USVI) and the Florida Keys (USA) over multiple years (2018-2020). Within each location, samples were collected seasonally from several sites comprising varying depths, habitats, and algal substrates to characterize community structure over small spatial scales and across different host macrophytes. This approach enabled the quantitative determination of communities over spatiotemporal gradients, as well as the selective enumeration of species known to exhibit high toxicity, such as Gambierdiscus silvae. The investigation found differing community structure between St. Thomas and Florida Keys sites, driven in part by differences in the distribution of toxin-producing species G. silvae and G. belizeanus, which were present throughout sampling sites in St. Thomas but scarce or absent in the Florida Keys. This finding is significant given the high toxicity of G. silvae, and may help explain differences in fish toxicity and CP incidence between St. Thomas and Florida. Intrasite comparisons along a depth gradient found higher concentrations of Gambierdiscus spp. at deeper locations. Among the macrophytes sampled, Dictyota may be a likely vector for toxin transfer based on their widespread distribution, apparent colonization by G. silvae, and palatability to at least some herbivore grazers. Given its ubiquity throughout both study regions and sites, this taxa may also serve as a refuge, accumulating high concentrations of Gambierdiscus and other benthic dinoflagellates, which in turn can serve as source populations for highly palatable and ephemeral habitats nearby, such as turf algae. These studies further demonstrate the successful application of FISH probes in examining biogeographic structuring of Gambierdiscus communities, targeting individual toxin-producing species, and characterizing species-level dynamics that are needed to describe and model ecological drivers of species abundance and toxicity.
Topics: Ciguatoxins; Florida; In Situ Hybridization, Fluorescence; United States Virgin Islands; Ciguatera Poisoning; Dinoflagellida
PubMed: 38212087
DOI: 10.1016/j.hal.2023.102562 -
MedEdPORTAL : the Journal of Teaching... 2023Acute radiation syndrome (ARS) is a high-risk, low-frequency diagnosis that can be fatal and is difficult to diagnose without an obvious history of ionizing radiation...
INTRODUCTION
Acute radiation syndrome (ARS) is a high-risk, low-frequency diagnosis that can be fatal and is difficult to diagnose without an obvious history of ionizing radiation exposure.
METHODS
Twenty-two emergency medicine residents and one pharmacy resident participated in an hour-long simulation session. To accommodate all learners, the simulation was conducted eight times over a block of scheduled time (two to four learners/session). Sessions included a prebriefing, pre/post questionnaires, the ARS case, and a debriefing. Learners evaluated and managed a 47-year-old male (manikin) with the hematopoietic and cutaneous subsyndromes of ARS who presented with hand pain/erythema/edema and underlying signs of infection 2 weeks after an unrecognized radiation exposure. Learners had to perform a history and physical, recognize/manage abnormal vitals, order/interpret labs, consult appropriate disciplines, and initiate supportive care.
RESULTS
There was a mean reported increase in ability to recognize signs and symptoms of ARS ( < .001) and appropriately manage a patient with this condition ( = .03) even after controlling for baseline confidence in ability to make and manage uncommon diagnoses, respectively. Learners rated this simulation as a valuable learning experience, effective in teaching them how to diagnose and treat ARS, and one they would recommend to other health care professionals.
DISCUSSION
This simulation aimed to teach the diagnosis and initial management of the hematopoietic and cutaneous subsyndromes of ARS. It should be used to increase awareness of the potential for ionizing radiation exposure under less obvious conditions and raise the index of suspicion for ARS in the undifferentiated patient.
Topics: Male; Humans; Middle Aged; Acute Radiation Syndrome; High Fidelity Simulation Training; Emergency Medicine; Simulation Training; Patient Simulation
PubMed: 37538304
DOI: 10.15766/mep_2374-8265.11331 -
Pharmacopsychiatry May 2024Up to now, it is unclear whether different medicinal (MC) strains are differently efficacious across different medical conditions. In this study, the effectiveness of...
BACKGROUND
Up to now, it is unclear whether different medicinal (MC) strains are differently efficacious across different medical conditions. In this study, the effectiveness of different MC strains was compared depending on the disease to be treated.
METHODS
This was an online survey conducted in Germany between June 2020 and August 2020. Patients were allowed to participate only if they received a -based treatment from pharmacies in the form of flowers prescribed by a physician.
RESULTS
The survey was completed by n=1,028 participants. Most participants (58%) have used MC for more than 1 year, on average, 5.9 different strains. (pure tetrahydrocannabinol to pure cannabidiol [THC:CBD]=22:<1) was the most frequently prescribed strain, followed by (THC:CBD=19:<1) and (THC:CBD=22:1). The most frequent conditions MC was prescribed for were different pain disorders, psychiatric and neurological diseases, and gastrointestinal symptoms. Overall, the mean patient-reported effectiveness was 80.1% (range, 0-100%). A regression model revealed no association between the patient-reported effectiveness and the variety. Furthermore, no influence of the disease on the choice of the MC strain was detected. On average, 2.1 side effects were reported (most commonly dry mouth (19.5%), increased appetite (17.1%), and tiredness (13.0%)). However, 29% of participants did not report any side effects. Only 398 participants (38.7%) indicated that costs for MC were covered by their health insurance.
CONCLUSIONS
Patients self-reported very good efficacy and tolerability of MC. There was no evidence suggesting that specific MC strains are superior depending on the disease to be treated.
Topics: Humans; Germany; Male; Medical Marijuana; Female; Adult; Middle Aged; Prospective Studies; Aged; Young Adult; Cannabidiol; Surveys and Questionnaires; Adolescent; Dronabinol; Cannabis; Treatment Outcome
PubMed: 38471525
DOI: 10.1055/a-2261-2269 -
Cell Reports. Medicine Jun 2024Descendants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant now account for almost all SARS-CoV-2 infections. The Omicron variant and...
Descendants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant now account for almost all SARS-CoV-2 infections. The Omicron variant and its sublineages have spike glycoproteins that are highly diverged from the pandemic founder and first-generation vaccine strain, resulting in significant evasion from monoclonal antibody therapeutics and vaccines. Understanding how commonly elicited antibodies can broaden to cross-neutralize escape variants is crucial. We isolate IGHV3-53, using "public" monoclonal antibodies (mAbs) from an individual 7 months post infection with the ancestral virus and identify antibodies that exhibit potent and broad cross-neutralization, extending to the BA.1, BA.2, and BA.4/BA.5 sublineages of Omicron. Deep mutational scanning reveals these mAbs' high resistance to viral escape. Structural analysis via cryoelectron microscopy of a representative broadly neutralizing antibody, CAB-A17, in complex with the Omicron BA.1 spike highlights the structural underpinnings of this broad neutralization. By reintroducing somatic hypermutations into a germline-reverted CAB-A17, we delineate the role of affinity maturation in the development of cross-neutralization by a public class of antibodies.
Topics: SARS-CoV-2; Humans; Antibodies, Viral; COVID-19; Spike Glycoprotein, Coronavirus; Antibodies, Neutralizing; Antibodies, Monoclonal; Cross Reactions; Cryoelectron Microscopy; Neutralization Tests
PubMed: 38761799
DOI: 10.1016/j.xcrm.2024.101577