Biology subjects

Lim, S. T.

Publications and source records attributed to Lim, S. T..

3 recordsLinked to original sources

bioRxiv2020

Correspondence: Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma

Recurrent GNAQ mutation encoding p.T96S in natural-killer/T cell lymphoma (NKTCL) was recently reported in 8.7% (11/127) of NKTCL patients. At the time of publication, this phenomenon was not observed in preceding genomic studies of NKTCL. We suspected that p.T96S was a false-positive somatic call due to misaligned sequencing reads that originated from the highly similar GNAQ-pseudogene (GNAQP) chr2q21.1 locus. Linkage disequilibrium analysis also revealed that GNAQP has high frequencies of co-occurring polymorphic mismatches which led to the preferential misalignment of sequencing reads to the GNAQ chr9q21.2 locus instead. This correspondence implicates our interpretation of true-positive somatic variants and many other studies which could be affected by similar suboptimal interpretation of somatic mutations.

genomics↗

bioRxiv2019

Islet macrophages drive islet remodeling and compensatory hyperinsulinemia in the early diabetes

{beta}-cells respond to peripheral insulin resistance by increasing circulating insulin in early type-2 diabetes (T2D). Islet remodeling supports this compensation but the drivers of this process remain poorly understood. Infiltrating macrophages have been implicated in late stage T2D but relatively little is known on islet resident macrophages, especially in early T2D. We hypothesize that islet resident macrophages contribute to islet vascular remodeling and hyperinsulinemia, the failure of which results in a rapid progression to T2D. Using genetic and diet-induced models of compensatory hyperinsulinemia we show that its depletion significantly compromises islet remodeling in terms of size, vascular density and insulin secretion capacity. Depletion of islet macrophages reduces VEGF-A secretion from both human and mouse islets ex vivo and the impact of reduced VEGF-A functionally translates to delayed re-vascularization upon transplantation in vivo. Hence, we show a new role of islet resident macrophages in the context of early T2D and suggest that there is considerable utility in harnessing islet macrophages to promote islet remodeling and islet insulin secretion capacity.\n\nHighlightsO_LIThe compensatory hyperinsulinemic phase of type-2 diabetes is accompanied with significant pancreatic islet remodeling.\nC_LIO_LIBona fide islet resident macrophages are increased during the diabetic compensation phase by largely in situ proliferation.\nC_LIO_LIAblating macrophages severely compromises the islet remodeling process and exacerbates glycemic control in vivo.\nC_LIO_LIMouse and human islet macrophages contribute VEGF-A to the islet environment.\nC_LIO_LISpecific removal of islet macrophages delays islet vascularization in compensatory hyperinsulinemic mice.\nC_LI

molecular biology↗

bioRxiv2018

Whole-Genome Genomics Correlates of Response To Anti-PD1 Therapy in Relapsed/Refractory Natural Killer/T Cell Lymphoma

AbstractThis study aims to identify recurrent genetic alterations in relapsed or refractory (RR) natural-killer/T-cell lymphoma (NKTL) patients who have achieved complete response (CR) with programmed cell death 1 (PD-1) blockade therapy. Seven of the eleven patients treated with pembrolizumab achieved CR while the remaining four had progressive disease (PD). Using whole genome sequencing (WGS), we found recurrent clonal structural rearrangements (SR) of the PD-L1 gene in four of the seven (57%) CR patients pretreated tumors. These PD-L1 SRs consist of inter-chromosomal translocations, tandem duplication and micro-inversion that disrupted the suppressive function of PD-L1 3UTR. Interestingly, recurrent JAK3-activating (p.A573V) mutations were also validated in two CR patients tumors that did not harbor the PD-L1 SR. Importantly, these mutations were absent in the four PD cases. With immunohistochemistry (IHC), PD-L1 positivity could not discriminate patients who archived CR (range: 6%-100%) from patients who had PD (range: 35%-90%). PD-1 blockade with pembrolizumab is a potent strategy for RR NKTL patients and genomic screening could potentially accompany PD-L1 IHC positivity to better select patients for anti-PD-1 therapy.

genomics↗