Zhangstevenson9593

Germline pathogenic variants in BRCA1 confer a high risk of developing breast and ovarian cancer. The BRCA1 exon 11 (formally exon 10) is one of the largest exons and codes for the nuclear localization signals of the corresponding gene product. This exon can be partially or entirely skipped during pre-mRNA splicing, leading to three major in-frame isoforms that are detectable in most cell types and tissue, and in normal and cancer settings. However, it is unclear whether the splicing imbalance of this exon is associated with cancer risk. Here we identify a common genetic variant in intron 10, rs5820483 (NC_000017.11g.43095106_43095108dup), which is associated with exon 11 isoform expression and alternative splicing, and with the risk of breast cancer, but not ovarian cancer, in BRCA1 pathogenic variant carriers. The identification of this genetic effect was confirmed by analogous observations in mouse cells and tissue in which a loxP sequence was inserted in the syntenic intronic region. The prediction that the rs5820483 minor allele variant would create a binding site for the splicing silencer hnRNP A1 was confirmed by pull-down assays. Our data suggest that perturbation of BRCA1 exon 11 splicing modifies the breast cancer risk conferred by pathogenic variants of this gene.

The enormous increase in COVID-19-associated mucormycosis (CAM) in India lacks an explanation. Zinc supplementation during COVID-19 management is speculated as a contributor to mucormycosis. We conducted an experimental and clinical study to explore the association of zinc and mucormycosis.

We inoculated pure isolates of Rhizopus arrhizus obtained from subjects with CAM on dichloran rose Bengal chloramphenicol (DRBC) agar enriched with (three different concentrations) and without zinc. At 24h, we counted the viable colonies and measured the dry weight of colonies at 24, 48 and 72h. We also compared the clinical features and serum zinc levels in 29 CAM cases and 28 COVID-19 subjects without mucormycosis (controls).

We tested eight isolates of R arrhizus and noted a visible increase in growth in zinc-enriched media. A viable count percentage showed a significantly increased growth in four of the eight isolates in zinc-augmented DRBC agar. A time- and concentration-dependent increase in the mean fungal biomass with zinc was observed in all three isolates tested. We enrolled 29 cases of CAM and 28 controls. The mean serum zinc concentration was below the reference range in all the subjects and was not significantly different between the cases and controls.

Half of the R arrhizus isolates grew better with zinc enrichment in vitro. However, our study does not conclusively support the hypothesis that zinc supplementation contributed to the pathogenesis of mucormycosis. More data, both in vitro and in vivo, may resolve the role of zinc in the pathogenesis of CAM.

Half of the R arrhizus isolates grew better with zinc enrichment in vitro. However, our study does not conclusively support the hypothesis that zinc supplementation contributed to the pathogenesis of mucormycosis. More data, both in vitro and in vivo, may resolve the role of zinc in the pathogenesis of CAM.

Endomyocardial biopsy (EMB) is costly and discomforting yet remains a key component of surveillance after pediatric heart transplantation (HT). Donor-derived cell-free DNA (dd-cfDNA) has been histologically validated with high negative predictive value, offering an alternative to surveillance EMB (sEMB).

We implemented an alternative surveillance protocol using commercially available dd-cfDNA assays in place of sEMB after pediatric HT. Recipients ≧7months post-HT with reassuring clinical assessment were referred for dd-cfDNA. When not elevated above the manufacturers' threshold, sEMB was deferred. Subsequent clinical status and results of follow-up EMB were analyzed.

Over 17months, 58 recipients [34% female, median age at HT 3.1years (IQR 0.6-10.6)] had dd-cfDNA assessed per protocol. Median age was 14.8years (8.4-18.3) and time from HT 6.0years (2.2-11.2). Forty-seven (81%) had non-elevated dd-cfDNA and 11 (19%) were elevated. During a median of 8.7months (4.2-15), all are alive without allograft loss/new dysfunction. Among those with non-elevated dd-cfDNA, 24 (51%) had subsequent sEMB at 12.1months (6.9-12.9) with 23showing no acute rejection (AR) grade 0R/pAMR0 (n=16); 1R(1A)/pAMR0 (n=7). One had AR (grade 2R(3A)/pAMR0) on follow-up sEMB after decreased immunosuppression following a diagnosis of PTLD. All 11 with elevated dd-cfDNA had reflex EMB at 19days (12-32) with AR in 4 grade 1R(1B-2)/pAMR0 (n=3); 1R(1B)/pAMR2 (n=1).

dd-cfDNA assessment in place of selected, per-protocol EMB decreased surveillance EMB by 81% in our pediatric HT recipient cohort with no short-term adverse outcomes. Individual center approach to surveillance EMB will influence the utility of these findings.

dd-cfDNA assessment in place of selected, per-protocol EMB decreased surveillance EMB by 81% in our pediatric HT recipient cohort with no short-term adverse outcomes. Individual center approach to surveillance EMB will influence the utility of these findings.The seven xeroderma pigmentosum proteins (XPps), XPA-XPG, coordinate the nucleotide excision repair (NER) pathway, promoting the excision of DNA lesions caused by exposition to ionizing radiation, majorly from ultraviolet light. Significant efforts are made to investigate NER since mutations in any of the seven XPps may cause the xeroderma pigmentosum and trichothiodystrophy diseases. However, these proteins collaborate with other pivotal players in all known NER steps to accurately exert their purposes. Therefore, in the old and ever-evolving field of DNA repair, it is imperative to reexamine and describe their structures to understand NER properly. This work provides an up-to-date review of the protein structural aspects of the closest partners that directly interact and influence XPps RAD23B, CETN2, DDB1, RPA (RPA70, 32, and 14), p8 (GTF2H5), and ERCC1. Structurally and functionally vital domains, regions, and critical residues are reexamined, providing structural lessons and perspectives about these indispensable proteins in the NER and other DNA repair pathways. JAK inhibitor By gathering all data related to the major human xeroderma pigmentosum-interacting proteins, this review will aid newcomers on the subject and guide structural and functional future studies.

Alcohol-based hand rub (ABHR) is widely used for hand disinfection in the health care sector. ABHR is, however, known to cause discomfort when applied on damaged skin emphasizing the unmet need for alternative and better tolerated types of disinfectants. Active chlorine hand disinfectants (ACHDs) are potential new candidates; however, the effect on the skin barrier function compared to ABHR remains to be assessed.

In Study A, the forearm skin of healthy adults was repeatedly exposed to ACHD and ABHR. Skin barrier function was assessed by measurement of transepidermal water loss, electrical conductance, pH, and erythema at baseline and at follow-up after 2 days, and subjective discomfort was likewise assessed. Study B was performed in the same way; however, in order to induce an experimental irritant contact dermatitis, sodium lauryl sulfate patch tests were applied to forearms before exposure to ACHD and ABHR.

In both studies, the skin barrier function was unaffected after repetitive exposure to ACHD and ABHR, and with no significant differences between the products. Subjective discomfort was reported as sporadic or very mild in relation to both products.

Our results illustrate that use of ACHD does not affect the skin barrier function negatively, neither in intact skin nor in skin with experimentally induced contact dermatitis. Future studies should include real-life evaluation of skin barrier function and subjective discomfort following ACHD use in individuals with and without hand eczema.

Our results illustrate that use of ACHD does not affect the skin barrier function negatively, neither in intact skin nor in skin with experimentally induced contact dermatitis. Future studies should include real-life evaluation of skin barrier function and subjective discomfort following ACHD use in individuals with and without hand eczema.

Erythropoietic protoporphyria (EPP) is a rare disorder of heme biosynthesis hallmarked by early-onset photosensitivity and mainly due to defective ferrochelatase activity leading to increased erythrocyte protoporphyrin IX (PPIX) levels. Evidence regarding the relationship between erythrocyte PPIX concentration and photosensitivity is limited.

To investigate the relationship between free erythrocyte PPIX (FEP) concentration; routine laboratory tests, particularly iron metabolism biomarkers; and ultraviolet (UV) A/visible light phototesting findings, 20 genetically confirmed EPP and one XLPP treatment-naive patients were included in our study. They underwent UVA and visible light phototesting. On the same day, blood samples were collected for measurement of FEP, serum iron, transferrin, transferrin saturation, and ferritin, 25-hydroxyvitamin D, and liver enzyme levels.

Median FEP concentration at the time of phototesting was 57.50 (IQR 34.58-102.70)μg/g of Hb. UVA and visible light phototesting were positive in 9 (42.9%) and 8 (38.1%) patients, respectively. Median FEP concentration was significantly higher in UVA phototest-positive patients than in those negative (64.37 [IQR 57.45-121.82] vs 45.35 [IQR 24.53-74.61]μg/g of Hb, respectively; P=.04486). Similarly, UVA photosensitive individuals had significantly lower median serum iron levels (61.5 [IQR 33.5-84]μg/dL vs 109 [IQR 63.25-154]μg/dL, respectively; P=.01862) and transferrin saturation values (15.005 [IQR 7.0775-18.41] % vs 29.645 [IQR 17.8225-34.3575] %; P=.0109) than those negative.

Our study demonstrates that UVA phototest positivity is associated with higher FEP concentration and lower transferrin saturation and serum iron concentration in EPP.

Our study demonstrates that UVA phototest positivity is associated with higher FEP concentration and lower transferrin saturation and serum iron concentration in EPP.Idiopathic hypereosinophilic syndrome with cardiac involvement is characterized by endocardial fibrosis and thrombosis. Here, we report a case of mitral valve prosthetic dysfunction in a patient with idiopathic hypereosinophilic syndrome and review related cases in the literature. Valve replacement with a 27-mm St. Jude bioprosthetic mitral valve improved his symptoms and hypereosinophilia. A 4-year follow-up revealed that the prosthetic valve was intact without thrombosis. Because mechanical prosthesis implantation yields poor surgical outcomes, bioprosthesis is the preferred choice for patients with idiopathic hypereosinophilic syndrome. Medications for controlling eosinophilia may improve the long-term outcomes of valve replacement surgeries.A 61-year-old female patient with chest pain was diagnosed with localized pericardial effusion, resistance to medical therapy. Cardiac magnetic resonance imaging revealed a massive aneurysm originating from coronary veins, which was successfully removed.

In the still ongoing COVID-19 pandemic, one of the main prevention strategy remain to be the use of protective face masks. Changes in skin characteristics and dermatological problems related to wearing different types of masks have been observed. The aim of this study was to compare the short-term effects of cotton versus medical masks on skin biophysical parameters in general population.

Twenty-eight human volunteers were enrolled and divided in cotton mask and medical mask wearing groups. We measured four skin biophysical parameters trans-epidermal water loss (TEWL), stratum corneum hydration (SCH), skin pH, and erythema index (EI) before and 3h after wearing masks on both uncovered and mask-wearing face area.

TEWL increased after 3h on exposed skin in cotton mask group and slightly decreased in medical mask group There was an increase in SCH after 3h of wearing protective face masks in both groups. pH of the covered skin slightly decreased while EI increased after 3h in both groups; changes were not statistically significant.