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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 -
The World Journal of Men's Health Apr 2024Non-obstructive azoospermia (NOA) is a common, but complex problem, with multiple therapeutic options and a lack of clear guidelines. Hence, there is considerable...
Global Practice Patterns and Variations in the Medical and Surgical Management of Non-Obstructive Azoospermia: Results of a World-Wide Survey, Guidelines and Expert Recommendations.
PURPOSE
Non-obstructive azoospermia (NOA) is a common, but complex problem, with multiple therapeutic options and a lack of clear guidelines. Hence, there is considerable controversy and marked variation in the management of NOA. This survey evaluates contemporary global practices related to medical and surgical management for patients with NOA.
MATERIALS AND METHODS
A 56-question online survey covering various aspects of the evaluation and management of NOA was sent to specialists around the globe. This paper analyzes the results of the second half of the survey dealing with the management of NOA. Results have been compared to current guidelines, and expert recommendations have been provided using a Delphi process.
RESULTS
Participants from 49 countries submitted 336 valid responses. Hormonal therapy for 3 to 6 months was suggested before surgical sperm retrieval (SSR) by 29.6% and 23.6% of participants for normogonadotropic hypogonadism and hypergonadotropic hypogonadism respectively. The SSR rate was reported as 50.0% by 26.0% to 50.0% of participants. Interestingly, 46.0% reported successful SSR in <10% of men with Klinefelter syndrome and 41.3% routinely recommended preimplantation genetic testing. Varicocele repair prior to SSR is recommended by 57.7%. Half of the respondents (57.4%) reported using ultrasound to identify the most vascularized areas in the testis for SSR. One-third proceed directly to microdissection testicular sperm extraction (mTESE) in every case of NOA while others use a staged approach. After a failed conventional TESE, 23.8% wait for 3 months, while 33.1% wait for 6 months before proceeding to mTESE. The cut-off of follicle-stimulating hormone for positive SSR was reported to be 12-19 IU/mL by 22.5% of participants and 20-40 IU/mL by 27.8%, while 31.8% reported no upper limit.
CONCLUSIONS
This is the largest survey to date on the real-world medical and surgical management of NOA by reproductive experts. It demonstrates a diverse practice pattern and highlights the need for evidence-based international consensus guidelines.
PubMed: 38606867
DOI: 10.5534/wjmh.230339 -
Antioxidants (Basel, Switzerland) Feb 2024Obesity and metabolic dysfunction have been shown to be associated with overproduction of reactive oxygen species (ROS) in the gastrointestinal (GI) tract, which...
Obesity and metabolic dysfunction have been shown to be associated with overproduction of reactive oxygen species (ROS) in the gastrointestinal (GI) tract, which contributes to dysbiosis or imbalances in the gut microbiota. Recently, the reversal of dysbiosis has been observed as a result of dietary supplementation with antioxidative compounds including polyphenols. Likewise, dietary polyphenols have been associated with scavenging of GI ROS, leading to the hypothesis that radical scavenging in the GI tract is a potential mechanism for the reversal of dysbiosis. The objective of this study was to investigate the relationship between GI ROS, dietary antioxidants and beneficial gut bacterium . The results of this study demonstrated to be a discriminant microorganism between lean ( = 7) and obese ( = 7) mice. The relative abundance of was also found to have a significant negative correlation with extracellular ROS in the GI tract as measured using fluorescent probe hydroindocyanine green. The ability of the dietary antioxidants ascorbic acid, β-carotene and grape polyphenols to scavenge GI ROS was evaluated in tandem with their ability to support bloom in lean mice ( = 20). While the relationship between GI ROS and relative abundance of was conserved in lean mice, only grape polyphenols stimulated the bloom of . Analysis of fecal antioxidant capacity and differences in the bioavailability of the antioxidants of interest suggested that the poor bioavailability of grape polyphenols contributes to their superior radical scavenging activity and support of in comparison to the other compounds tested. These findings demonstrate the utility of the GI redox environment as a modifiable therapeutic target in the treatment of chronic inflammatory diseases like metabolic syndrome.
PubMed: 38539838
DOI: 10.3390/antiox13030304 -
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 -
Open Heart Mar 2024Coronary CT angiography (CCTA) permits both qualitative and quantitative analysis of atherosclerotic plaque and may be a suitable risk modifier in assessing patients at...
OBJECTIVE
Coronary CT angiography (CCTA) permits both qualitative and quantitative analysis of atherosclerotic plaque and may be a suitable risk modifier in assessing patients at intermediate risk of atherosclerotic cardiovascular disease. We sought to determine the association of plaque components with long-term major adverse cardiovascular events (MACEs) in asymptomatic intermediate-risk patients, compared with conventional coronary artery calcium (CAC) score.
METHODS
100 intermediate-risk patients underwent double-blinded CCTA. Follow-up was conducted at 10 years and data were cross-referenced with the National Death Index. The primary outcome was MACE, which was a composite of death, acute coronary syndrome (ACS), revascularisation and stroke.
RESULTS
The median time from CCTA to follow-up was 9.5 years. 83 patients completed follow-up interview and mortality data were available on all 100 patients. MACE occurred in 17 (20.5%) patients, which included 2 (2%) deaths, 8 (10%) ACS, 3 (4%) strokes and 5 (6%) revascularisation procedures. 47 (57%) patients had mixed plaque, which was predictive of MACE (OR 4.68 (95% CI 1.19 to 18.5) p=0.028). The burden of non-calcified and mixed plaque, defined by non-calcified plaque segment stenosis score, was also a predictor of long-term MACE (OR 1.59 (95% CI 1.18 to 2.13) p=0.002). Neither calcified plaque (OR 3.92 (95% CI 0.80 to 19.3)) nor CAC score (OR 1.01 (95% CI 0.999 to 1.02)) was associated with long-term MACE.
CONCLUSION
The presence and burden of mixed plaque on CCTA is associated with an increased risk of long-term MACE among asymptomatic intermediate-risk patients and is a superior predictor to CAC score.
Topics: Humans; Plaque, Atherosclerotic; Computed Tomography Angiography; Prognosis; Coronary Angiography; Tomography, X-Ray Computed; Atherosclerosis; Acute Coronary Syndrome
PubMed: 38458771
DOI: 10.1136/openhrt-2024-002609 -
Translational Oncology May 2024Cancer management in Africa faces diverse challenges due to limited resources, health system challenges, and other matters. Identifying hereditary cancer syndromic cases...
Cancer management in Africa faces diverse challenges due to limited resources, health system challenges, and other matters. Identifying hereditary cancer syndromic cases is crucial to improve clinical management and preventive care in these settings. This study aims to explore the clinicopathological features and genetic factors associated with hereditary cancer in Tunisia, a North African country with a rising cancer burden MATERIALS AND METHODS: Clinicopathological features and personal/family history of cancer were explored in 521 patients. Genetic analysis using Sanger and next-generation sequencing was performed for a set of patients RESULTS: Hereditary breast and ovarian cancer syndrome was the most frequent cluster in which 36 BRCA mutations were identified. We described a subgroup of patients with likely ''breast cancer-only syndrome'' among this cluster. Two cases of Li-Fraumeni syndrome with distinct TP53 mutations namely c.638G>A and c.733G>A have been identified. Genetic investigation also allowed the identification of a new BLM homozygous mutation (c.3254dupT) in one patient with multiple primary cancers. Phenotype-genotype correlation suggests the diagnosis of Bloom syndrome. A recurrent MUTYH mutation (c.1143_1144dup) was identified in three patients with different phenotypes CONCLUSION: Our study calls for comprehensive genetic education and the implementation of genetic screening in Tunisia and other African countries health systems, to reduce the burden of hereditary diseases and improve cancer outcomes in resource-stratified settings.
PubMed: 38387387
DOI: 10.1016/j.tranon.2024.101912 -
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 -
Virus Evolution 2024In March 2023, the Chinese CDC publicly released raw metagenomic sequencing data for environmental samples collected in early 2020 from the Huanan Seafood Market. Prior...
In March 2023, the Chinese CDC publicly released raw metagenomic sequencing data for environmental samples collected in early 2020 from the Huanan Seafood Market. Prior to that data release, some scientists had suggested that these samples could be informative for establishing if animals such as raccoon dogs had been infected with severe acute respiratory syndrome virus 2 (SARS-CoV-2). However, no one had analyzed how much SARS-CoV-2 was actually present in the metagenomic sequencing data. After the raw data became available, I fully analyzed the abundance of both viral and animal genetic material in the samples. That analysis, which was published in , found that the SARS-CoV-2 content of most samples was very low and that the abundance of SARS-CoV-2 was most strongly associated with animals such as largemouth bass that are not plausible candidates for having been infected. Based on these results, I concluded that the metagenomic content of the samples was not informative for determining if any non-human animals in the market had been infected with SARS-CoV-2. One of the authors of an earlier study of these samples, Florence Débarre, recently submitted a response to my paper. Here, I reply in turn to explain why it is important to quantify the abundance of viral material before drawing conclusions from metagenomic sequencing. I also report new analyses of other animal coronaviruses in the samples and show that material from some other animal coronaviruses is much more abundant than SARS-CoV-2 in samples collected on the date when most wildlife stall sampling was performed. I further show that material from some of these animal coronaviruses is associated with the animals they probably infect but that no such association exists for SARS-CoV-2. Overall, these new analyses further emphasize the importance of quantifying the actual amount of viral material in metagenomic samples and underscore why the environmental samples from the Huanan Seafood Market are not informative for determining if any non-human animals were infected with SARS-CoV-2.
PubMed: 38361815
DOI: 10.1093/ve/vead089 -
JACC. Case Reports Feb 2024We present a 19-year-old male athlete, without cardiovascular risk factors, with anterior ST-segment elevation myocardial infarction caused by left anterior descending...
We present a 19-year-old male athlete, without cardiovascular risk factors, with anterior ST-segment elevation myocardial infarction caused by left anterior descending artery spontaneous coronary artery dissection. Symptoms began during a swim practice, and patient endorsed using C4 Ripped (Cellucor), a preworkout supplement to enhance athletic performance. We hypothesize that this was the major contributor to presentation. The patient showed improvement after 4 days.
PubMed: 38361558
DOI: 10.1016/j.jaccas.2023.102189 -
Nature Communications Feb 2024Replication fork reversal, a critical protective mechanism against replication stress in higher eukaryotic cells, is orchestrated via a series of coordinated enzymatic...
Replication fork reversal, a critical protective mechanism against replication stress in higher eukaryotic cells, is orchestrated via a series of coordinated enzymatic reactions. The Bloom syndrome gene product, BLM, a member of the highly conserved RecQ helicase family, is implicated in this process, yet its precise regulation and role remain poorly understood. In this study, we demonstrate that the GCFC domain-containing protein TFIP11 forms a complex with the BLM helicase. TFIP11 exhibits a preference for binding to DNA substrates that mimic the structure generated at stalled replication forks. Loss of either TFIP11 or BLM leads to the accumulation of the other protein at stalled forks. This abnormal accumulation, in turn, impairs RAD51-mediated fork reversal and slowing, sensitizes cells to replication stress-inducing agents, and enhances chromosomal instability. These findings reveal a previously unidentified regulatory mechanism that modulates the activities of BLM and RAD51 at stalled forks, thereby impacting genome integrity.
Topics: Humans; DNA Replication; DNA Damage Tolerance; RecQ Helicases; DNA; Proteins; Genomic Instability; Rad51 Recombinase; RNA Splicing Factors
PubMed: 38341452
DOI: 10.1038/s41467-024-45684-3