Biology subjects

Yuen, J. G.

Publications and source records attributed to Yuen, J. G..

4 recordsLinked to original sources

bioRxiv2023

Development of Gemcitabine-Modified miRNA Mimics as Cancer Therapeutics for Pancreatic Ductal Adenocarcinoma

Pancreatic cancer, including its most common subtype, pancreatic adenocarcinoma (PDAC), has the lowest five-year survival rate among patients with pancreatic cancer in the United States. Despite advancements in anticancer treatment, the overall median survival for patients with PDAC has not dramatically improved. Therefore, there is an urgent need to develop new strategies of treatment to address this issue. Non-coding RNAs, including microRNAs (miRNAs), have been found to have major roles in carcinogenesis and the subsequent treatment of various cancer types like PDAC. In this study, we developed a treatment strategy by modifying tumor suppressor miRNAs, hsa-miRNA-15a (miR-15a) and hsa-miRNA-194-1 (miR-194), with the nucleoside analog chemotherapeutic gemcitabine (Gem) to create Gem-modified mimics of miR-15a (Gem-miR-15a) and miR-194 (Gem-miR-194). In a panel of PDAC cell lines, we found that Gem-miR-15a and Gem-miR-194 induce cell cycle arrest and apoptosis, and these mimics are potent inhibitors with IC50 values up to several hundred fold less than their native counterparts or Gem alone. Furthermore, we found that Gem-miR-15a and Gem-miR-194 retained miRNA function by downregulating the expression of several key targets including WEE1, CHK1, BMI1, and YAP1 for Gem-miR-15a, and FOXA1 for Gem-miR-194. We also found that our Gem-modified miRNA mimics exhibit an enhanced efficacy compared to Gem alone in patient-derived PDAC organoids. Furthermore, we observed that Gem-miR-15a significantly inhibits PDAC tumor growth in vivo without observing any noticeable signs of toxicity. Overall, our results demonstrate the therapeutic potential of Gem-modified miRNAs as a treatment strategy for PDAC. One Sentence SummaryYuen and Hwang et. al. have developed a potent therapeutic strategy for patients with pancreatic cancer by modifying microRNAs with gemcitabine.

cancer biology↗

bioRxiv2022

Development of a 5-FU Modified miR-129 Mimic as a Therapeutic for Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related deaths in the United States with non-small cell lung cancer (NSCLC) accounting for most cases. Despite advances in cancer therapeutics, the 5-year survival rate has remained poor due to several contributing factors, including its resistance to therapeutics. Therefore, there is a pressing need to develop therapeutics that can overcome resistance. Non-coding RNAs, including microRNAs (miRNAs), have been found to contribute to cancer resistance and therapeutics by modulating the expression of several targets involving multiple key mechanisms. In this study, we investigated the therapeutic potential of miR-129 modified with 5-fluorouracil (5-FU) in NSCLC. Our results show that 5-FU modified miR-129 (5-FU-miR-129) inhibits proliferation, induces apoptosis, and retains function as a miRNA in NSCLC cell lines A549 and Calu-1. Notably, we observed that 5-FU-miR-129 was able to overcome resistance to tyrosine kinase inhibitors and chemotherapy in cell lines resistant to erlotinib or 5-FU. Furthermore, we observed that the inhibitory effect of 5-FU-miR-129 can also be achieved in NSCLC cells under vehicle-free conditions. Finally, 5-FU-miR-129 inhibited NSCLC tumor growth and extended survival in vivo without toxic side effects. Altogether, our results demonstrate the potential of 5-FU-miR-129 as a highly potent cancer therapeutic in NSCLC.

cancer biology↗

bioRxiv2022

Development of 5-FU-modified tumor suppressor microRNAs as a platform for novel microRNA-based cancer therapeutics

MicroRNA (miRNAs) are pleiotropic post-transcriptional modulators of gene expression. Its inherently pleiotropic nature make miRNAs strong candidates for the development of cancer therapeutics, yet despite its potential, there remains a challenge to deliver nucleic acid-based therapies into cancer cells. We developed a novel approach to modify miRNAs by replacing the uracil bases with 5-fluorouracil (5-FU) in the guide strand of tumor suppressor miRNAs, thereby combining the therapeutic effect of 5-FU with tumor suppressive effect of miRNAs to create a potent, multi-targeted therapeutic molecule without altering its native RNA interference (RNAi) function. To demonstrate the general applicability of this approach to other tumor suppressive miRNAs, we screened a panel of 12 novel miRNA mimetics in several cancer types including leukemia, breast, gastric, lung, and pancreatic cancer. Our results show that 5-FU-modified miRNA mimetics have increased potency (low nM range) in inhibiting cancer cell proliferation and that these mimetics can be delivered into cancer cells without delivery vehicle both in vitro and in vivo, thus representing significant advancements in the development of therapeutic miRNAs for cancer. This work demonstrates the potential of fluoropyrimidine modifications that can be broadly applicable and may serve as a platform technology for future miRNA and nucleic acid-based therapeutics.

cancer biology↗

bioRxiv2021

Dry heat sterilization as a method to recycle N95 respirator masks: the importance of fit

In times of crisis, including the current COVID-19 pandemic, the supply chain of filtering facepiece respirators, such as N95 respirators, are disrupted. To combat shortages of N95 respirators, many institutions were forced to decontaminate and reuse respirators. While several reports have evaluated the impact on filtration as a measurement of preservation of respirator function after decontamination, the equally important fact of maintaining proper fit to the users face has been understudied. In the current study, we demonstrate the complete inactivation of SARS-CoV-2 and preservation of fit test performance of N95 respirators following treatment with dry heat. We apply scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM/EDS), X-ray diffraction (XRD) measurements, Raman spectroscopy, and contact angle measurements to analyze filter material changes as a consequence of different decontamination treatments. We further compared the integrity of the respirator after autoclaving versus dry heat treatment via quantitative fit testing and found that autoclaving, but not dry heat, causes the fit of the respirator onto the users face to fail, thereby rendering the decontaminated respirator unusable. Our findings highlight the importance to account for both efficacy of disinfection and mask fit when reprocessing respirators to for clinical redeployment.

scientific communication and education↗