Faculty Bibliography

Arrhythmogenic cardiomyopathy (ACM) is a familial disease, with approximately 60% of patients displaying a pathogenic variant. The majority of genes linked to ACM code for components of the desmosomes: plakophilin-2 (PKP2), desmoglein-2 (DSG2) and desmocollin-2 (DSC2), plakoglobin (JUP) and desmoplakin (DSP). Genetic variants involving the desmosomes are known to cause dysfunction of cell-to-cell adhesions and intercellular gap junctions. In turn, this may result in failure to mechanically hold together the cardiomyocytes, fibrofatty myocardial replacement, cardiac conduction delay and ventricular arrhythmias. It is becoming clearer that pathogenic variants in desmosomal genes such as PKP2 are not only responsible for a mechanical dysfunction of the intercalated disc (ID), but are also the cause of various pro-arrhythmic mechanisms. In this review, we discuss in detail the different molecular interactions associated with desmosomal pathogenic variants, and their contribution to various ACM phenotypes.

Ire1 is an endoplasmic reticulum (ER) transmembrane RNase that cleaves substrate mRNAs to help cells adapt to ER stress. Because there are cell types with physiological ER stress, loss of Ire1 results in metabolic and developmental defects in diverse organisms. In Drosophila, Ire1 mutants show developmental defects at early larval stages and in pupal eye photoreceptor differentiation. These Drosophila studies relied on a single Ire1 loss of function allele with a Piggybac insertion in the coding sequence. Here, we report that an Ire1 allele with a specific impairment in the RNase domain, H890A, unmasks previously unrecognized Ire1 phenotypes in Drosophila eye pigmentation. Specifically, we found that the adult eye pigmentation is altered, and the pigment granules are compromised in Ire1^H890A homozygous mosaic eyes. Furthermore, the Ire1^H890A mutant eyes had dramatically reduced Rhodopsin-1 protein levels. Drosophila eye pigment granules are most notably associated with late endosome/lysosomal defects. Our results indicate that the loss of Ire1, which would impair ER homeostasis, also results in altered adult eye pigmentation.

BACKGROUND:Limited research has addressed the obesity-COVID-19 severity association in paediatric patients. OBJECTIVE:To determine whether obesity is an independent risk factor for COVID-19 severity in paediatric patients and whether age modifies this association. METHODS:SARS-CoV-2-positive patients at NYU Langone Health from 1 March 2020 to 3 January 2021 aged 0-21 years with available anthropometric measurements: weight, length/height and/or body mass index (BMI). Modified log-Poisson models were utilized for the analysis. Main outcomes were 1) hospitalization and 2) critical illness (intensive care unit [ICU] admission). RESULTS:One hundred and fifteen of four hundred and ninety-four (23.3%) patients had obesity. Obesity was an independent risk factor for critical illness (adjusted risk ratio [ARR] 2.02, 95% CI 1.17 to 3.48). This association was modified by age, with obesity related to a greater risk for critical illness in adolescents (13-21 years) [ARR 3.09, 95% CI 1.48 to 6.47], but not in children (0-12 years). Obesity was not an independent risk factor for hospitalization for any age. CONCLUSION/CONCLUSIONS:Obesity was an independent risk factor for critical illness in paediatric patients, and this association was modified by age, with obesity related to a greater risk for critical illness in adolescents, but not in children. These findings are crucial for patient risk stratification and care.

The field of cardio-oncology has emerged in response to the increased risk of cardiovascular disease (CVD) in patients with cancer. However, recent studies suggest a more complicated CVD-cancer relationship, wherein development of CVD, either prior to or following a cancer diagnosis, can also lead to increased risk of cancer and worse outcomes for patients. In this review, we describe the current evidence base, across epidemiological as well as preclinical studies, which supports the emerging concept of 'reverse-cardio oncology', or CVD-induced acceleration of cancer pathogenesis.

Hand injuries often result in significant functional impairments and are rarely completely restored. The spontaneous regeneration of injured appendages, which occurs in salamanders and newts, for example, has been reported in human fingertips after distal amputation, but this type of regeneration is rare in mammals and is incompletely understood. Here, we study fingertip regeneration by amputating murine digit tips, either distally to initiate regeneration, or proximally, causing fibrosis. Using an unbiased microarray analysis, we found that digit tip regeneration is significantly associated with hair follicle differentiation, Wnt, and sonic hedgehog (SHH) signaling pathways. Viral over-expression and genetic knockouts showed the functional significance of these pathways during regeneration. Using transgenic reporter mice, we demonstrated that, while both canonical Wnt and HH signaling were limited to epidermal tissues, downstream hedgehog signaling (through Gli) occurred in mesenchymal tissues. These findings reveal a mechanism for epidermal/mesenchyme interactions, governed by canonical hedgehog signaling, during digit regeneration. Further research into these pathways could lead to improved therapeutic outcomes after hand injuries in humans.

Psychological stress (PS) is associated with systemic inflammation and accelerates inflammatory disease progression (e.g., atherosclerosis). The mechanisms underlying stress-mediated inflammation and future health risk are poorly understood. Monocytes are key in sustaining systemic inflammation, and recent studies demonstrate that they maintain the memory of inflammatory insults, leading to a heightened inflammatory response upon rechallenge. We show that PS induces remodeling of the chromatin landscape and transcriptomic reprogramming of monocytes, skewing them to a primed hyperinflammatory phenotype. Monocytes from stressed mice and humans exhibit a characteristic inflammatory transcriptomic signature and are hyperresponsive upon stimulation with Toll-like receptor ligands. RNA and ATAC sequencing reveal that monocytes from stressed mice and humans exhibit activation of metabolic pathways (mTOR and PI3K) and reduced chromatin accessibility at mitochondrial respiration-associated loci. Collectively, our findings suggest that PS primes the reprogramming of myeloid cells to a hyperresponsive inflammatory state, which may explain how PS confers inflammatory disease risk.

Tissue repair and healing remain among the most complicated processes that occur during postnatal life. Humans and other large organisms heal by forming fibrotic scar tissue with diminished function, while smaller organisms respond with scarless tissue regeneration and functional restoration. Well-established scaling principles reveal that organism size exponentially correlates with peak tissue forces during movement, and evolutionary responses have compensated by strengthening organ-level mechanical properties. How these adaptations may affect tissue injury has not been previously examined in large animals and humans. Here, we show that blocking mechanotransduction signaling through the focal adhesion kinase pathway in large animals significantly accelerates wound healing and enhances regeneration of skin with secondary structures such as hair follicles. In human cells, we demonstrate that mechanical forces shift fibroblasts toward pro-fibrotic phenotypes driven by ERK-YAP activation, leading to myofibroblast differentiation and excessive collagen production. Disruption of mechanical signaling specifically abrogates these responses and instead promotes regenerative fibroblast clusters characterized by AKT-EGR1.

Purpose: Because of the COVID-19 pandemic, the Radiation Oncology Education Collaborative Study Group (ROECSG) hosted its annual international symposium using a virtual format in May 2020. This report details the experience of hosting a virtual meeting and presents attendee feedback on the platform. Approach/Methods: The ROECSG symposium was hosted virtually on May 15, 2020. A postsymposium survey was distributed electronically to assess attendee demographics, participation, and experience. Attendee preference and experience were queried using 3-point and 5-point Likert-type scales, respectively. Symplur LLC was used to generate analytics for the conference hashtag (#ROECSG). Results/Outcomes: The survey was distributed to all 286 registrants, with a response rate of 67% (191 responses). Seventeen nonattendee responses were omitted from this analysis, for a total of 174 included respondents. Eighty-two attendees (47%) were present for the entire symposium. A preference for a virtual symposium was expressed by 78 respondents (45%), whereas 44 (25%) had no preference and 52 (30%) preferred an in-person meeting. A total of 150 respondents (86%) rated the symposium as "extremely" well organized. Respondents who had not attended a prior in-person ROECSG symposium were more likely to prefer the virtual format (P =.03). Seventy-eight respondents (45%) reported a preference for the virtual platform for reviewing scholarly work, and 103 (59%) reported a preference for an in-person platform for networking. On the day of the symposium, #ROECSG had 408 tweets and 432,504 impressions. Discussion/Significance: The 2020 ROECSG symposium was well received and can serve as a framework for future virtual meetings. Although the virtual setting may facilitate sharing research, networking aspects are more limited. Effort is needed to develop hybrid virtual and in-person meetings that meet the needs of participants in both settings. Social media is a significant avenue for dissemination and discussion of information and may be valuable in the virtual setting. Keywords: Education, Virtual platform, Research scholarship
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Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of NF2 patients with vestibular schwannoma (VS). To assess the pharmacokinetics, pharmacodynamics and potential mechanisms of treatment resistance, we performed a pre-surgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for VS or meningiomas. Eligible patients with meningioma or VS requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately prior to and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and post-operative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/ml and 9.4 ng/ml, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared to control tissues from untreated patients (p=0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited anti-tumor effect of everolimus observed in clinical studies for NF2 patients and will inform the design of future pre-clinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.