Biology subjects

Fung, K.-M.

Publications and source records attributed to Fung, K.-M..

5 recordsLinked to original sources

bioRxiv2025

Atorvastatin suppresses cardiac fibrosis and dysfunction induced by HIV and certain antiretroviral drugs in mice by blocking platelet TGFβ1

Cardiovascular disease (CVD) both atherosclerosis-related and heart failure with preserved ejection fraction (HFpEF) and linked to cardiac fibrosis, contributes to morbidity and mortality in people with HIV (PWH) receiving antiretroviral therapy (ART). In the REPRIEVE trial, pitavastatin reduced atherosclerotic CVD risk to a magnitude inconsistent with pitavastatins impact solely on LDL-cholesterol and inflammation. We hypothesized that HFpEF in PWH relates to HIV-induced fibrosis mediated by platelet TGF{beta}1, that it is accelerated by certain contemporary ART, and may also be inhibited by statins. ART drugs used in REPRIEVE, including a nucleoside/nucleotide, integrase inhibitor-based regimen (tenofovir (TDF), emtricitabine (FTC), and dolutegravir (DTG)), and the protease inhibitors ritonavir (RTV) and darunavir (DRV), and the impact of atorvastatin, were examined in two HIV mouse models: transgenic Tg26 mice and HIV-PDX mice engrafted with HIV-infected T cells. Tg26 and HIV-PDX mice had higher cardiac fibrosis than littermate controls without HIV (p<0.05). Administration of TDF-FTC-DTG or RTV, but not DRV, resulted in a further [~]2-fold increase in fibrosis (p<0.01). Higher cardiac fibrosis with intracardiac fat accumulation correlated with reduced diastolic function. Mice depleted of platelet TGF{beta}1 (TGF{beta}1Platelet-{Delta}Tg26), or treated with atorvastatin, were partially protected from HIV- and ART-induced cardiac fibrosis, steatosis, and diastolic dysfunction. Atorvastatin effects occurred independently of changes in inflammatory cytokines and total cholesterol. They correlated with reduced platelet activation and TGF{beta}1 signaling in cardiac endothelial cells, fibroblasts, and macrophages undergoing mesenchymal transition. These results indicate that certain ART regimens accelerate HIV-associated CVD characterized by HFpEF via platelet TGF{beta}1-dependent processes and mitigated by atorvastatin. They enhance understanding of the pleiotropic effects of statins in HIV/ART CVD and suggest a mechanism that might be targeted by antiplatelet agents or inhibition of TGF{beta} signaling. Key PointsO_LIContemporary ART regimens induce release of platelet TGF{beta}1 and are associated with cardiac fibrosis and diastolic dysfunction with ectopic fat deposition in HIV-infected mice. C_LIO_LIDepleting platelet TGF{beta}1 and/or treating with atorvastatin therapy suppresses HIV-ART-induced cardiac fibrosis, suggesting use of anti-platelet strategies to prevent heart failure among PWH. C_LI

biochemistry↗

bioRxiv2025

Real-Time Viability Assessment of Ex Vivo Mouse Kidneys for Transplant Applications Using Dynamic Optical Coherence Tomography

Kidney transplantation remains the preferred treatment for patients with end-stage kidney disease. However, the ongoing shortage of donor organs continues to limit the availability of transplant treatments. Existing evaluation methods, such as the kidney donor profile index (KDPI) and pre-transplant donor biopsy (PTDB), have various limitations, including low discriminative power, invasiveness, and sampling errors, which reduce their effectiveness in organ quality assessment and contribute to the risk of unnecessary organ discard. In this study, we explored the dynamic optical coherence tomography (DOCT) as a real-time, non-invasive approach to monitor the viability of ex vivo mouse kidneys during static cold storage over 48 hours. The dynamic metrics logarithmic intensity variance (LIV), early OCT correlation decay speed (OCDSe), and late OCT correlation decay speed (OCDSl) were extracted from OCT signal fluctuations to quantify temporal and spatial tissue activity and deterioration. Our results demonstrate that DOCT provides complementary functional information to morphological assessment offered by conventional OCT imaging, showing potential to improve pre-transplant organ evaluation and clinic decision-making.

bioengineering↗

bioRxiv2022

Activation of ERK by altered RNA splicing in cancer

Many cancers carry change-of-function mutations affecting RNA splicing factors, however, less is known about the functional consequences of upregulated RNA splicing factors in cancer. Here, we demonstrate that SMNDC1, a poorly studied splicing factor, which we found to be upregulated in multiple carcinomas and associated with poor patient prognosis, promotes cell proliferation, clonal expansion, and tumor growth by promoting the retention of G-rich exons, which otherwise would be excluded or retained at a lower rate after RNA splicing in normal cells. Inclusion of exon 4 (E4) of MAPK3 (ERK1), which encodes both kinase phosphorylation sites (Thr202/Tyr204), was among the promoted exons by SMNDC1. Forced exclusion of MAPK3-E4 using anti-sense oligos inhibited the ERK1 phosphorylation, expression of target genes and decreased tumor cell growth. These data support that cancer cells exploit a "splicing switch" to promote ERK kinase activity and offer a druggable alternative to block oncogenic signaling and altered RNA splicing in cancer cells SIGNIFICANCEERK signaling promotes tumor growth and survival. Exon 4 of MAPK3 (ERK1) encodes the activation phosphorylation sites of ERK1 kinase. Aberrant RNA splicing induced by SMNDC1 in cancer cells increases the retention of exon 4 during mRNA splicing, unleashes the kinase activity. SMNDC1 potentializes as a cancer therapeutic target.

cancer biology↗

bioRxiv2021

A protocol for the reduction of applied torque on parent vessel duringelastase-induced aneurysm formation using rabbit animal models

Endovascular therapies for intracranial aneurysms requires animal models for testing the safety and effectiveness prior to translation to the clinic. Rabbits combined with the elastase and right common carotid artery (RCCA) ligation methods is currently a widely used animal model for endovascular device testing. However, the injection of elastase utilizing angiocatheters may potentially exerts adverse torque to the parent vessel and the optimal aneurysm creation period has not been well investigated. In this study, we present a modification to the elastase/RCCA-ligation method by replacing the angio-catheter with a butterfly catheter. Formation of saccular aneurysms was introduced in New Zealand white rabbits (n = 6), and were maintained for 2, 4 and 6 weeks. The formed aneurysms exhibited an elongated geometry and were stable during the study period. We found that the modification in the animal surgery procedure provides improved manipulation of the surgical area, prolonged injection of elastase, and effective degradation of the vascular elastic lamina. Compared to the traditional elastase/RCCA-ligation method, the present technique can more effectively reduce unwanted injury to the parent vessel and, therefore, improved stability of the vasculature for testing the efficacy of newly developed endovascular embolization devices.

bioengineering↗

bioRxiv2018

A Tumor Suppressor-Regulated Cell Cycle Derived Gene Signature Is Prognostic Of Recurrence Risk In Prostate Cancer

BackgroundThe clinical behavior of prostate cancer (PCa) is variable, and while the majority of cases remain indolent, 10% of patients progress to deadly forms of the disease. Current clinical predictors used at the time of diagnosis have limitations to accurately establish progression risk. Here we describe the development of a tumor suppressor regulated, cell-cycle gene expression based prognostic signature for PCa, and validate its independent contribution to risk stratification in several radical prostatectomy (RP) patient cohorts.\n\nMethodsWe used RNA interference experiments in PCa cell lines to identify a gene expression based gene signature associated with Tmeff2, an androgen regulated, tumor suppressor gene whose expression shows remarkable heterogeneity in PCa. Gene expression was confirmed by qRT-PCR. Correlation of the signature with disease outcome (time to recurrence) was retrospectively evaluated in four geographically different cohorts of patients that underwent RP (834 samples), using multivariate logistical regression analysis. Multivariate analysis were adjusted for standard clinicopathological variables. Performance of the signature was compared to previously described gene expression based signatures using the SIgCheck software.\n\nResultsLow levels of Tmeff2 mRNA significantly (p<0.0001) correlated with reduced disease-free survival (DFS) in patients from the Memorial Sloan Kettering Cancer Center (MSKCC) dataset. We identified a panel of 11 TMEFF2 regulated cell cycle related genes (TMCC11), with strong prognostic value. TMCC11 expression was significantly associated with time to recurrence after prostatectomy in four geographically different patient cohorts (2.9[≤]HR[≥]4.1; p[≤]0.002), served as an independent indicator of poor prognosis in the four RP cohorts (1.96[≤]HR[≥]4.28; p[≤]0.032) and improved the prognostic value of standard clinicopathological markers. The prognostic ability of TMCC11 panel exceeded previously published oncogenic gene signatures (p=0.00017).\n\nConclusionsThis study provides evidence that the TMCC11 gene signature is a robust independent prognostic marker for PCa, reveals the value of using highly heterogeneously expressed genes, like Tmeff2, as guides to discover prognostic indicators, and suggests the possibility that low Tmeff2 expression marks a distinct subclass of PCa.

cancer biology↗