Shriya Deshmukh

Sima Khazaei1, Nicolas De Jay1,2, Shriya Deshmukh3, Liam D. Hendrikse4,5,6, Wajih Jawhar1,7, Carol C.L. Chen1, Leonie G. Mikael8, Damien Faury8, Dylan M. Marchione9, Joel Lanoix10, Éric Bonneil10, Takeaki Ishii7,11, Siddhant U. Jain12, Kateryna Rossokhata1, Tianna S. Sihota1, Robert Eveleigh13, Véronique Lisi1, Ashot S. Harutyunyan8, Sungmi Jung14, Jason Karamchandani15, Brendan C. Dickson16, Robert Turcotte17, Jay S. Wunder18,19, Pierre Thibault10,20, Peter W. Lewis12, Benjamin A. Garcia9, Stephen C. Mack21, Michael D. Taylor4,5,6, Livia Garzia7,17, Claudia L. Kleinman1,2, and Nada Jabado1,3,8 ReseaRch aRticle

Background: With few evidence-based disease-modifying therapies being available for patients with progressive multiple sclerosis (PMS), how can neurologists best care for their patients? Little is known about the perspectives of patients with respect to the role they would like their neurologist to play in their care. We hereby report an update to our abstract presented at the Canadian Neurological Sciences Federation’s annual congress in 2016. Methods: Patients with PMS having an Expanded Disability Status Scale (EDSS) score of 6 or more were invited to participate. Semi-structured interviews were conducted with patients and their caregivers, and written questionnaires were completed by all participants. Collected data was subjected to thematic coding. Results: We have now interviewed a total of 18 patients (compared to 10 in 2016) and have reached thematic saturation. The majority of patients identified the neurologist as a useful figure in their care. Three main reasons were iden...

A high percentage of pediatric gliomas and bone tumors reportedly harbor missense mutations at glycine 34 in genes encoding histone variant H3.3. We find that these H3.3 G34 mutations directly alter the enhancer chromatin landscape of mesenchymal stem cells by impeding methylation at lysine 36 on histone H3 (H3K36) by SETD2, but not by the NSD1/2 enzymes. The reduction of H3K36 methylation by G34 mutations promotes an aberrant gain of PRC2-mediated H3K27me2/3 and loss of H3K27ac at active enhancers containing SETD2 activity. This altered histone modification profile promotes a unique gene expression profile that supports enhanced tumor development in vivo. Our findings are mirrored in G34W-containing giant cell tumors of bone where patient-derived stromal cells exhibit gene expression profiles associated with early osteoblastic differentiation. Overall, we demonstrate that H3.3 G34 oncohistones selectively promote PRC2 activity by interfering with SETD2-mediated H3K36 methylation. W...

Background: Patients with advanced, disabling multiple sclerosis (MS) have few effective treatment options. Little is known about the role that patients and their care providers want their neurologist to fill in this situation. Objective: To better understand the role that patients with disabling MS and their care providers want their neurologist to have in their care. Methods: In this exploratory qualitative study, we conducted semi-structured interviews with 29 participants (19 patients with severe disability due to MS and 10 care providers). Interview transcripts were analyzed using inductive thematic analysis. Results: Participants identified three main roles for their neurologist: a source of hope for therapeutic advances, an educator about the disease and its management, and a source of support. Conclusion: Despite sustaining a level of disability that may be refractory to standard medical therapy, patients with disabling MS and care providers continue to value certain roles o...

Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival. T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3's plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, promoting HLH and SPTCL. Our findings highlight HLH-SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH-SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.

ABSTRACTPolycomb group (PcG) proteins are essential for development and are frequently misregulated in human cancers. Polycomb Repressive Complexes (PRC1, PRC2) function in a collaborative epigenetic cross-talk with H3K27me3 to initiate and maintain transcriptional silencing. Diffuse intrinsic pontine gliomas (DIPGs) have extremely low H3K27me3 levels mediated by H3 K27M oncohistone. Posterior fossa type A (PFA) ependymomas also exhibit very low H3K27 methylation but lack the K27M oncohistone. Instead, PFA tumors express high levels of EZHIP (Enhancer of Zeste Homologs Inhibitory Protein, also termed CXORF67). We find that a highly conserved sequence within the C-terminus of EZHIP is necessary and sufficient to inhibit the catalytic activity of PRC2 in vitro and in vivo. Our biochemical experiments indicate that EZHIP directly interacts with the active site of the EZH2 subunit in a mechanism that is remarkably similar to the K27M oncohistone. Furthermore, expression of H3 K27M or EZ...