Faculty Bibliography

The intricate network of protein-chaperone interactions is crucial for maintaining cellular function. Recent discoveries have unveiled the existence of specialized chaperone assemblies, known as epichaperomes, which serve as scaffolding platforms that orchestrate the reconfiguration of protein-protein interaction networks, thereby enhancing cellular adaptability and proliferation. This study explores the structural and regulatory aspects of epichaperomes, with a particular focus on the role of post-translational modifications (PTMs) in their formation and function. A key finding is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 within an intrinsically disordered region, as critical determinants of epichaperome assembly. Our data demonstrate that phosphorylation of these serine residues enhances HSP90's interactions with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Moreover, we establish a direct link between epichaperome function and cellular physiology, particularly in contexts where robust proliferation and adaptive behavior are essential, such as in cancer and pluripotent stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone assemblies in diseases characterized by epichaperome dysregulation, thereby bridging the gap between fundamental research and precision medicine.

BACKGROUND:Lipid metabolism has essential roles in skin barrier formation and the regulation of skin inflammation. Lipid homeostasis regulates skin melanogenesis, although the underlying mechanism remains largely unknown. Sterol regulatory element binding protein 1 (SREBP-1) is a key transcription factor essential for cellular lipid metabolism. Loss-of-function variants in SREBF1 are responsible for autosomal-dominant ichthyosis follicularis, alopecia and photophobia syndrome, emphasizing the significance of lipid homeostasis in skin keratinization. OBJECTIVES/OBJECTIVE:To identify the genetic basis of a new entity featuring diffuse skin hyperpigmentation with congenital cataracts, and to unravel the underlying mechanism for the pathogenesis of the SREBF1 variant. METHODS:Whole-exome sequencing was performed to identify underlying genetic variants. Quantitative polymerase chain reaction, Western blot and immunofluorescence staining were used to assess the expression and the subcellular localization of the SREBF1 variant. The transcriptional activity of mutant SREBP-1 was determined by a luciferase reporter assay. A transgenic zebrafish model was constructed. RESULTS:Two unrelated patients presented with generalized skin hyperpigmentation with skin xerosis, congenital cataracts and extracutaneous symptoms. We identified a de novo nonsense variant c.1289C>A (p.Ser430*) in SREBF1 in both patients. The variant encoded a truncated protein that showed preferential nucleus localization, in contrast to wild-type SREBP-1 which - in sterol-sufficient conditions - is mainly localized in the cytoplasm. The luciferase reporter assay revealed that the p.Ser430* mutant exhibited enhanced transcriptional activity. Cultured patient primary melanocytes showed increased melanin synthesis vs. those from healthy controls. At 35 days postfertilization, the p.Ser430* transgenic zebrafish model exhibited more black spots, along with upregulated expression of melanogenic genes. CONCLUSIONS:We demonstrated that a gain-of-function variant of SREBF1 causes a previously undescribed disorder characterized by generalized skin hyperpigmentation and congenital cataracts. Our study reveals the involvement of SREBP-1 in melanogenesis and lens development, and paves the way for the development of novel therapeutic targets for skin dyspigmentation or cataracts.

This review aims to present a detailed analysis of the most common developmental and acquired dental abnormalities, including caries, resorptive lesions, and congenital anomalies of teeth number, size, form, and structure. This review highlights how diagnostic imaging can aid in the accurate identification and management of these conditions.

Analyses of women dermatology literature authorship from 2018 to 2022 reveal a slight increase in total female authors, female first authors, and female senior authors with no substantial immediate impact of COVID-19 on current trends, encouraging future examination of long-term effects and ongoing promotion of systemic initiatives to support gender equity.

BACKGROUND:Optimal duration and choice of antiplatelet therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention remain controversial. METHODS AND RESULTS/RESULTS:Digital databases (PubMed, Cochrane, and Embase) were queried to select all randomized controlled trials on a post-percutaneous coronary intervention population with acute coronary syndrome. Dual-antiplatelet therapy (DAPT) with aspirin and clopidogrel for 12 months was compared with 4 major strategies: high-potency, high- to low-potency, low-dose, and short-duration DAPT. A network meta-analysis was performed to compare the safety and efficacy of different antiplatelet strategies. This study was the second updated manuscript under the International Prospective Register of Systematic Review registration (CRD42021286552). Thirty-two randomized controlled trials comprising 103 459 (51 750 experimental, 51 709 control) patients were included. Compared with DAPT with aspirin and clopidogrel for 12 months, high- to low-potency DAPT (risk ratio [RR], 0.69 [95% CI, 0.52-0.92]) and aspirin+prasugrel containing DAPT for 12 months (RR, 0.84 [95% CI, 0.72-0.98]) had a significantly lower, whereas DAPT for 1 month followed by clopidogrel only (RR, 1.59 [95% CI, 1.06-2.39]) had a higher, incidence of major adverse cardiovascular events at 1 year (median follow-up). Prasugrel (RR, 1.35 [95% CI, 1.09-1.66]) and ticagrelor (RR, 1.38 [95% CI, 1.17-1.62]) containing DAPT for 12 months had significantly higher rates, whereas high- to low-potency DAPT (RR, 0.85 [95% CI, 0.63-1.15]) had no significant risk of major bleeding. CONCLUSIONS:Aspirin and ticagrelor for 3 months, followed by aspirin and clopidogrel for the remaining duration, can be considered the optimal strategy for treating post-percutaneous coronary intervention patients with acute coronary syndrome because of a significantly reduced risk of major adverse cardiovascular events without increasing the risk of bleeding.

BACKGROUND:New York (NY) State implemented a new cystic fibrosis (CF) newborn screen (NBS) algorithm in December 2017 with improvement in positive predictive value and unanticipated increased identification of infants with cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS). Repeat sweat testing is recommended in infants with CRMS. During the COVID-19 pandemic infants with CRMS were lost to follow up. With this quality improvement (QI) initiative, we aimed to perform repeat sweat testing in 25% of infants lost to follow up. We also describe consensus recommendations for CRMS from the NY CF NBS Consortium. METHODS:Our QI team identified the primary drivers contributing to absent follow up, outreached to families, and created a questionnaire to evaluate parental understanding of CRMS using QI-based strategies. RESULTS:Of 350 infants diagnosed with CRMS during the study period, 179 (51.1%) infants were lost to follow up. A total of 31 (17.3%) were scheduled for repeat sweat tests and followed up at CF Centers. Families reported high satisfaction with the CRMS knowledge questionnaire. CONCLUSIONS:With this QI-based approach, we effectively recaptured infants with CRMS previously lost to follow up during the COVID-19 pandemic. Ongoing concerns about infection risk and lack of understanding on the part of families and pediatricians likely contributed to patients with CRMS lost to follow up. Consensus recommendations for CRMS include annual visits with repeat sweat testing until 2-6 years of age and education for adolescents about clinical and reproductive implications of CRMS.

Interferons (IFNs) play a crucial role in the regulation and evolution of host-virus interactions. Here, we conducted a genome-wide arrayed CRISPR knockout screen in the presence and absence of IFN to identify human genes that influence Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. We then performed an integrated analysis of genes interacting with SARS-CoV-2, drawing from a selection of 67 large-scale studies, including our own. We identified 28 genes of high relevance in both human genetic studies of Coronavirus Disease 2019 (COVID-19) patients and functional genetic screens in cell culture, with many related to the IFN pathway. Among these was the IFN-stimulated gene PLSCR1. PLSCR1 did not require IFN induction to restrict SARS-CoV-2 and did not contribute to IFN signaling. Instead, PLSCR1 specifically restricted spike-mediated SARS-CoV-2 entry. The PLSCR1-mediated restriction was alleviated by TMPRSS2 overexpression, suggesting that PLSCR1 primarily restricts the endocytic entry route. In addition, recent SARS-CoV-2 variants have adapted to circumvent the PLSCR1 barrier via currently undetermined mechanisms. Finally, we investigate the functional effects of PLSCR1 variants present in humans and discuss an association between PLSCR1 and severe COVID-19 reported recently.

BACKGROUND/UNASSIGNED:The ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) demonstrated greater health status benefits with an initial invasive strategy, as compared with a conservative one, for patients with chronic coronary disease and moderate or severe ischemia. Whether these benefits vary globally is important to understand to support global adoption of the results. METHODS/UNASSIGNED:We analyzed participants' disease-specific health status using the validated 7-item Seattle Angina Questionnaire (SAQ: >5-point differences are clinically important) at baseline and over 1-year follow-up across 37 countries in 6 international regions. The average effect of initial invasive versus conservative strategies on 1-year SAQ scores was estimated using Bayesian proportional odds regression and compared across regions. RESULTS/UNASSIGNED:Considerable regional variation in baseline health status was observed among 4617 participants (mean age=64.4±9.5 years, 24% women), with the mean SAQ summary scores of 67.4±19.5 in Eastern Europe participants (17% of the total), 71.4±15.4 in Asia-Pacific (18%), 74.9±16.7 in Central and South America (10%), 75.5±19.5 in Western Europe (26%), and 78.6±19.2 in North America (28%). One-year improvements in SAQ scores were greater in regions with lower baseline scores with initial invasive management (17.7±20.9 in Eastern Europe and 11.4±19.3 in North America), but similar in the conservative arm. Adjusting for baseline SAQ scores, similar health status benefits of an initial invasive strategy on 1-year SAQ scores were observed (ranging from 2.38 points [95% CI, 0.04-4.50] in North America to 4.66 points [95% CI, 2.46-6.94] in Eastern Europe), with an 88.3% probability that the difference in benefit across regions was <5 points. CONCLUSIONS/UNASSIGNED:In patients with chronic coronary disease and moderate or severe ischemia, initial invasive management was associated with a consistent health status benefit across regions, with modest regional variability, supporting the international generalizability of health status benefits from invasive management of chronic coronary disease. REGISTRATION/UNASSIGNED:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

There is a paucity of information on racial and ethnic disparities relating to barriers to care in healthcare access and utilization in patients with cutaneous malignancies. We conducted a cross-sectional analysis of adults with melanoma, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) in the National Institutes of Health (NIH) All of Us Research Program collected between May 2018 and July 2022. Participants included adults (aged 18 or older) with cutaneous malignancy who completed the Health Care Access and Utilization survey. We identified 5,817 adults who were diagnosed with BCC (67%), cSCC (28.9%), and melanoma (23.9%). Non-Hispanic Black (NHB) and Hispanic patients were more likely than non-Hispanic White (NHW) patients to delay a primary care visit due to cost (p = 0.005 and p = 0.015, respectively). NHB patients were also more likely to delay care due to lack of transportation (p < 0.001). NHB and Hispanic patients were more likely to place importance on seeing a provider from the same background (NHB p < 0.002; Hispanic p = 0.002) and also were more likely to report never being able to see such a provider (NHB p < 0.001; Hispanic p = 0.002). Medicaid/Medicare patients, non-college graduates, and those with lower incomes also faced increased barriers to care, including delays due to cost and transportation issues. People of color with cutaneous malignancies are more likely to delay care in seeing primary care providers due to cost or transportation issues. This study provides important insights on disproportionate healthcare usage among racial/ethnic groups that may help mitigate healthcare disparities.