Atypical Warfarin-Induced Calciphylaxis Outside a Typical Presentation of End-Stage Renal Disease on Hemodialysis.

We present a case report highlighting a 47-year-old woman who developed warfarin-induced calciphylaxis. She initially developed bilateral leg wounds secondary to restraint straps from helicopter transportation to a higher level of care for treatment of critical aortic stenosis. She was started on warfarin following surgical implantation of a mechanical aortic valve. After her wounds failed to heal, a punch biopsy of the wounds demonstrated ulceration, altered vasculature, and soft tissue calcification. The pathology confirmed the clinical concern for calciphylaxis, which is most often diagnosed in patients with a history of end-stage renal disease on hemodialysis. However, our patient did not demonstrate evidence of renal disease prior to the onset of calciphylaxis. Her wounds began to heal after treatment with sodium thiosulfate and changing her anticoagulation from warfarin to rivaroxaban.

Case Report of COVID-19 mRNA Vaccine-Associated Myocarditis.

INTRODUCTION: We present a case report highlighting a single patient out of 3 who developed myocarditis within days after receiving Pfizer and Moderna COVID-19 mRNA vaccines. CASE PRESENTATION: A 19-year-old male was admitted to our hospitalist service with substernal chest pain that was sharp, constant, and varied with position. He had received his second dose of the Pfizer-BioNTech COVID-19 vaccine (Pfizer vaccine) 2 days prior. Electrocardiogram was consistent with pericarditis. He had persistently elevated troponins and globally reduced systolic function by echocardiogram, which was consistent with myocarditis. He received colchicine, ibuprofen, and proton pump inhibitors with a resolution of symptoms. After 32 days, follow-up echocardiogram had returned to normal, and his symptoms had resolved completely. DISCUSSION: Given the onset of symptoms after the second dose of vaccine and our review of similar cases in the literature, it seems likely the patient's myopericarditis was caused by the vaccine. Rare complications of new vaccines given to millions of people are rapidly identified by the Vaccine Adverse Event Reporting System. CONCLUSIONS: The identification of myopericarditis as a complication of mRNA vaccines will need further study to understand the pathophysiology, incidence, and prevalence in specific age groups and biological sexes.

Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11.

PURPOSE: Growth differentiation factor 11 (GDF11) is a key signaling protein required for proper development of many organ systems. Only one prior study has associated an inherited GDF11 variant with a dominant human disease in a family with variable craniofacial and vertebral abnormalities. Here, we expand the phenotypic spectrum associated with GDF11 variants and document the nature of the variants. METHODS: We present a cohort of six probands with de novo and inherited nonsense/frameshift (4/6 patients) and missense (2/6) variants in GDF11. We generated gdf11 mutant zebrafish to model loss of gdf11 phenotypes and used an overexpression screen in Drosophila to test variant functionality. RESULTS: Patients with variants in GDF11 presented with craniofacial (5/6), vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6), and connective tissue abnormalities (3/6). gdf11 mutant zebrafish show craniofacial abnormalities and body segmentation defects that match some patient phenotypes. Expression of the patients' variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) allele whereas the missense variants in our cohort are partial LOF variants. CONCLUSION: GDF11 is needed for human development, particularly neuronal development, and LOF GDF11 alleles can affect the development of numerous organs and tissues.

MET-GRB2 Signaling-Associated Complexes Correlate with Oncogenic MET Signaling and Sensitivity to MET Kinase Inhibitors.

Purpose: Targeting MET in cancer is hampered by lack of diagnostics that accurately reflect high MET signaling and dependence. We hypothesized that assays reflecting MET signaling associated protein complexes could redefine tumors dependent on MET and could add additional precision beyond genomic assessments.Experimental Design: We used biochemical approaches, cellular viability studies, and proximity ligation assays to assess MET dependence. We examined MET signaling complexes in lung cancer patient specimens (N = 406) and patient-derived xenograft (PDX) models of solid tumors (N = 308). We evaluated response to crizotinib in a MET-amplified cohort of PDX models of lung cancer (N = 6) and provide a case report of a lung cancer patient harboring a Δexon14 MET splice variant.Results: We found the interaction of MET with the adaptor protein GRB2 is necessary for oncogenic survival signaling by MET. MET-GRB2 complexes were identified only within MET-amplified PDX models and patient specimens but exhibit substantial variability. Lack of MET-GRB2 complexes was associated with lack of response to MET TKI in cell lines and PDX models. Presence of MET-GRB2 complexes can further subtype tumors with Δexon14 MET splice variants. Presence of these complexes correlated with response to crizotinib in one patient with Δexon14 MET lacking MET gene amplification.Conclusions: Proximity assays measuring MET-GRB2 signaling complexes provide novel insights into MET-mediated signaling and could complement current clinical genomics-based assay platforms. Clin Cancer Res; 23(22); 7084-96. ©2017 AACR.