Medical Specialties Commons^™

Gsk-J4 Inhibition Of Kdm6b Histone Demethylase Blocks Adhesion Of Mantle Cell Lymphoma Cells To Stromal Cells By Modulating Nf-Κb Signaling, Laia Sadeghi, Anthony P H Wright

Faculty, Staff and Student Publications

Multiple signaling pathways facilitate the survival and drug resistance of malignant B-cells by regulating their migration and adhesion to microenvironmental niches. NF-κB pathways are commonly dysregulated in mantle cell lymphoma (MCL), but the exact underlying mechanisms are not well understood. Here, using a co-culture model system, we show that the adhesion of MCL cells to stromal cells is associated with elevated levels of KDM6B histone demethylase mRNA in adherent cells. The inhibition of KDM6B activity, using either a selective inhibitor (GSK-J4) or siRNA-mediated knockdown, reduces MCL adhesion to stromal cells. We showed that KDM6B is required both for the removal …

Examination Of Fully Automated Mammographic Density Measures Using Libra And Breast Cancer Risk In A Cohort Of 21,000 Non-Hispanic White Women, Laurel A Habel, Stacey E Alexeeff, Ninah Achacoso, Vignesh A Arasu, Aimilia Gastounioti, Lawrence Gerstley, Robert J Klein, Rhea Y Liang, Jafi A Lipson, Walter Mankowski, Laurie R Margolies, Joseph H Rothstein, Daniel L Rubin, Li Shen, Adriana Sistig, Xiaoyu Song, Marvella A Villaseñor, Mark Westley, Alice S Whittemore, Martin J Yaffe, Pei Wang, Despina Kontos, Weiva Sieh

Faculty, Staff and Student Publications

BACKGROUND: Breast density is strongly associated with breast cancer risk. Fully automated quantitative density assessment methods have recently been developed that could facilitate large-scale studies, although data on associations with long-term breast cancer risk are limited. We examined LIBRA assessments and breast cancer risk and compared results to prior assessments using Cumulus, an established computer-assisted method requiring manual thresholding.

METHODS: We conducted a cohort study among 21,150 non-Hispanic white female participants of the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California who were 40-74 years at enrollment, followed for up to 10 years, and had archived …

Sars-Cov-2 Infection In Unvaccinated High-Risk Pregnant Women In The Bronx, Ny, Usa Is Associated With Decreased Apgar Scores And Placental Villous Infarcts, Sandra E. Reznik, Patricia M. Vuguin, Alexa Cohen, Rasha Khoury, Olivier Loudig, Ridin Balakrishnan, Susan A. Fineberg, Francine Hughes, Malini Harigopal, Maureen J. Charron

School of Medicine Faculty Publications

Babies born to severe acute respiratory syndrome corona virus-2 (SARS-CoV-2)-infected mothers are at greater risk for perinatal morbidity and more likely to receive a neurodevelopmental diagnosis in the first year of life. However, the effect of maternal infection on placental function and neonatal outcomes varies depending upon the patient population. We set out to test our hypothesis that maternal SARS-CoV-2 infection in our underserved, socioeconomically disadvantaged, mostly unvaccinated, predominantly African American and Latina population in the Bronx, NY would have effects evident at birth. Under IRB approval, 56 SARS-CoV-2-positive patients infected during the “first wave” of the pandemic with alpha …

Refractive Outcomes Of Phacoemulsification Wtih Endocyclophotocoagulation Vs. Phacoemulsification Alone, Truman Silvasi

Conference Presentation Abstracts

No abstract provided.

Richter Syndrome And The Retina, Sahal Saleh

Conference Presentation Abstracts

No abstract provided.

"Reducing Heart Failure Readmission Rates Through Implementation Of Heart Failure Diuretic", Caley Tatrn, Yvonne Weideman, Venkatraman Srinivasan

Doctor of Nursing Practice (DNP) Manuscripts

Background and significance: heart disease was the number one cause of death in the United States in 2021, with 696, 962 deaths (Leading Causes of Death, 2022). There are about 6.2 million individuals in the U.S. total with heart failure (Kilgore et al., 2017). About one-quarter of patients with heart failure are readmitted within thirty days of discharge, while one-quarter of hospital readmissions are preventable. Between 2010-2017, over seven million patients were admitted for heart failure in the United States. Eighteen percent had a readmission within thirty days and thirty-one percent had a readmission within ninety days (Khan et …

Ex Vivo Drug Sensitivity Imaging-Based Platform For Primary Acute Lymphoblastic Leukemia Cells, Lauren Rowland, Brandon Smart, Anthony Brown, Gino M Dettorre, Yoshihiro Gocho, Jeremy Hunt, Wenjian Yang, Satoshi Yoshimura, Noemi Reyes, Guoqing Du, August John, Dylan Maxwell, Wendy Stock, Steven Kornblau, Mary V Relling, Hiroto Inaba, Ching-Hon Pui, Jean-Pierre Bourquin, Seth E Karol, Charles G Mullighan, William E Evans, Jun J Yang, Kristine R Crews

Faculty, Staff and Student Publications

Resistance of acute lymphoblastic leukemia (ALL) cells to chemotherapy, whether present at diagnosis or acquired during treatment, is a major cause of treatment failure. Primary ALL cells are accessible for drug sensitivity testing at the time of new diagnosis or at relapse, but there are major limitations with current methods for determining drug sensitivity ex vivo. Here, we describe a functional precision medicine method using a fluorescence imaging platform to test drug sensitivity profiles of primary ALL cells. Leukemia cells are co-cultured with mesenchymal stromal cells and tested with a panel of 40 anti-leukemia drugs to determine individual patterns of …

Recognition Of And Response To Obstetric Emergencies: Developing A Virtual Competency-Based Orientation Program, Susan Morrison

Student Scholarly Projects

In order to improve outcomes in the perinatal setting, the development of a Virtual Competency-Based Orientation Program (CBO) toolkit is vital. Two toolkits, namely the Alliance for Innovation on Maternal Health (AIM) and the California Maternal Quality Care Collaborative (CMQCC), have been identified as effective in enhancing perinatal outcomes. AIM is a national initiative focused on improving maternal health outcomes, promoting safer birth practices, and saving lives through the implementation of best practices. CMQCC is a multi-stakeholder organization in California committed to eliminating preventable morbidity, mortality, and racial disparities in maternity care. Both AIM and CMQCC CBO toolkits incorporate research, …

Dosimetric Comparison Of Glioblastoma Radiotherapy Treatment Plans On A Low-Field Mri-Guided Linear Accelerator Compared To Conventional C-Arm Linear Accelerator, Emily J. Moats

Masters Projects

Introduction

MRI-guided radiation therapy has proven to provide many benefits such as real-time tracking, dose escalation, and the ability to perform online adaptive therapy. The objective of this study is to compare curative treatment plans for glioblastoma tumors on a low-field MR-guided linac vs a C-Arm linac and evaluate if they are comparable in terms of coverage, organ at risk sparing, delivery time, and deliverability.

Methods

This is a retrospective study that consisted of 15 previously treated patients who received radiation therapy for glioblastoma on a C-Arm linac. The CT simulation data that was used for the original treated plans …

Overview Of Iron Deficiency And Iron Deficiency Anemia In Women And Girls Of Reproductive Age, Richard J. Derman, Anmol Patted

Global Health Articles

Over 50% of pregnant women are anemic and the majority of these are iron deficient. Micronutrient deficiency, the symptom of heavy menstrual bleeding in nonpregnant individuals, and loss of blood associated with pregnancy and obstetric delivery contribute to iron deficiency (ID). Poor outcomes with low maternal iron can affect not only the pregnancy but can also have major bearings on the offspring. Correction of ID and iron deficiency anemia (IDA) in pregnant and prepregnant populations with single-dose intravenous iron supplementation may offer improved outcomes. A harmonization process that incorporates all major randomized controlled trials studying the use of single-dose IV …

Glycemic Markers And Insulin-Related Parameters In The Progression Of Diabetes And Lower Extremities Complications: A Pilot Study In Mexican Americans From Starr County, Peter Elvin, Garrett Edwards, Walid Fakhouri, Craig Hanis, Cláudia Cristina Biguetti

School of Podiatric Medicine Publications

No abstract provided.

The At-Hook Is An Evolutionarily Conserved Auto-Regulatory Domain Of Swi/Snf Required For Cell Lineage Priming, Dhurjhoti Saha, Solomon Hailu, Arjan Hada, Junwoo Lee, Jie Luo, Jeff A Ranish, Yuan-Chi Lin, Kyle Feola, Jim Persinger, Abhinav Jain, Bin Liu, Yue Lu, Payel Sen, Blaine Bartholomew

Faculty, Staff and Student Publications

The SWI/SNF ATP-dependent chromatin remodeler is a master regulator of the epigenome, controlling pluripotency and differentiation. Towards the C-terminus of the catalytic subunit of SWI/SNF is a motif called the AT-hook that is evolutionary conserved. The AT-hook is present in many chromatin modifiers and generally thought to help anchor them to DNA. We observe however that the AT-hook regulates the intrinsic DNA-stimulated ATPase activity aside from promoting SWI/SNF recruitment to DNA or nucleosomes by increasing the reaction velocity a factor of 13 with no accompanying change in substrate affinity (K

Evidenced-Based Practice Competency Assessment For Competency-Based Orientation Protocol To Improve Competency Level Among Medical-Surgical Nurses, Maryann Ornelas

Student Scholarly Projects

Practice Problem: Within a 12-month period, high incidences of severe post-spinal surgical complications resulted in a host of concerns in this clinical site when patients either returned to the operating room for spine revision or increased the length of stay.

PICOT: The PICOT question that guided this project was: "In Medical Surgical (Med-Surg) nurses (P), how would a Competency-Based Orientation (CBO) protocol with the inclusions of four critical elements of postoperative spinal care [POSC] (I) compared to the usual postoperative practice (C) enhance competency level in Med-Surg nurses when delivering postoperative practice at an inpatient setting (O) over 10 weeks …

Shp2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors To Re-Treatment With Targeted Therapy, Alexander Drilon, Manish R Sharma, Melissa L Johnson, Timothy A Yap, Shirish Gadgeel, Dale Nepert, Gang Feng, Micaela B Reddy, Allison S Harney, Mohamed Elsayed, Adam W Cook, Christina E Wong, Ronald J Hinklin, Yutong Jiang, Eric N Brown, Nickolas A Neitzel, Ellen R Laird, Wen-I Wu, Anurag Singh, Ping Wei, Keith A Ching, John J Gaudino, Patrice A Lee, Dylan P Hartley, S Michael Rothenberg

Faculty, Staff and Student Publications

Rationally targeted therapies have transformed cancer treatment, but many patients develop resistance through bypass signaling pathway activation. PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers. Activity in this setting was confirmed in diverse tumor models. Patients with ALK fusion–positive lung cancer, BRAF^V600E-mutant colorectal cancer, KRAS^G12D-mutant ovarian cancer, and ROS1 fusion–positive pancreatic cancer who previously developed targeted therapy resistance were treated with PF-07284892 on the first dose level of a first-in-human clinical trial. After progression on PF-07284892 monotherapy, a novel study design allowed the addition …

Innate Immune System In The Context Of Radiation Therapy For Cancer, Boopathi Ettickan, Robert Den, Chellappagounder Thangavel

Department of Radiation Oncology Faculty Papers

Radiation therapy (RT) remains an integral component of modern oncology care, with most cancer patients receiving radiation as a part of their treatment plan. The main goal of ionizing RT is to control the local tumor burden by inducing DNA damage and apoptosis within the tumor cells. The advancement in RT, including intensity-modulated RT (IMRT), stereotactic body RT (SBRT), image-guided RT, and proton therapy, have increased the efficacy of RT, equipping clinicians with techniques to ensure precise and safe administration of radiation doses to tumor cells. In this review, we present the technological advancement in various types of RT methods …

Csf1r Regulates Schizophrenia-Related Stress Response And Vascular Association Of Microglia/Macrophages, Ling Yan, Yanli Li, Fengmei Fan, Mengzhuang Gou, Fangling Xuan, Wei Feng, Keerthana Chithanathan, Wei Li, Junchao Huang, Hongna Li, Wenjin Chen, Baopeng Tian, Zhiren Wang, Shuping Tan, Alexander Zharkovsky, L Elliot Hong, Yunlong Tan, Li Tian

Faculty, Staff and Student Publications

BACKGROUND: Microglia are known to regulate stress and anxiety in both humans and animal models. Psychosocial stress is the most common risk factor for the development of schizophrenia. However, how microglia/brain macrophages contribute to schizophrenia is not well established. We hypothesized that effector molecules expressed in microglia/macrophages were involved in schizophrenia via regulating stress susceptibility.

METHODS: We recruited a cohort of first episode schizophrenia (FES) patients (n = 51) and age- and sex-paired healthy controls (HCs) (n = 46) with evaluated stress perception. We performed blood RNA-sequencing (RNA-seq) and brain magnetic resonance imaging, and measured plasma level of colony stimulating …

An Ontology-Based Approach For Harmonization And Cross-Cohort Query Of Alzheimer’S Disease Data Resources, Xubing Hao, Xiaojin Li, Guo-Qiang Zhang, Cui Tao, Paul E Schulz, Licong Cui

Faculty, Staff and Student Publications

BACKGROUND: In the United States, the National Alzheimer's Coordinating Center (NACC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) are two major data sharing resources for Alzheimer's Disease (AD) research. NACC and ADNI strive to make their data more FAIR (findable, interoperable, accessible and reusable) for the broader research community. However, there is limited work harmonizing and supporting cross-cohort interoperability of the two resources.

METHOD: In this paper, we leverage an ontology-based approach to harmonize data elements in the two resources and develop a web-based query system to search patient cohorts across the two resources. We first mapped data elements across …

Proteomic Profiling Across Breast Cancer Cell Lines And Models, Marian Kalocsay, Matthew J Berberich, Robert A Everley, Maulik K Nariya, Mirra Chung, Benjamin Gaudio, Chiara Victor, Gary A Bradshaw, Robyn J Eisert, Marc Hafner, Peter K Sorger, Caitlin E Mills, Kartik Subramanian

Faculty, Staff and Student Publications

We performed quantitative proteomics on 60 human-derived breast cancer cell line models to a depth of ~13,000 proteins. The resulting high-throughput datasets were assessed for quality and reproducibility. We used the datasets to identify and characterize the subtypes of breast cancer and showed that they conform to known transcriptional subtypes, revealing that molecular subtypes are preserved even in under-sampled protein feature sets. All datasets are freely available as public resources on the LINCS portal. We anticipate that these datasets, either in isolation or in combination with complimentary measurements such as genomics, transcriptomics and phosphoproteomics, can be mined for the purpose …

Spatial Transcriptomics Of Intraductal Papillary Mucinous Neoplasms Of The Pancreas Identifies Nkx6-2 As A Driver Of Gastric Differentiation And Indolent Biological Potential, Marta Sans, Yuki Makino, Jimin Min, Kimal I Rajapakshe, Michele Yip-Schneider, C Max Schmidt, Mark W Hurd, Jared K Burks, Javier A Gomez, Fredrik I Thege, Johannes F Fahrmann, Robert A Wolff, Michael P Kim, Paola A Guerrero, Anirban Maitra

Faculty, Staff and Student Publications

Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most common subtype of IPMNs harbor a gastric foveolar-type epithelium, and these low-grade mucinous neoplasms are harbingers of IPMNs with high-grade dysplasia and cancer. The molecular underpinning of gastric differentiation in IPMNs is unknown, although identifying drivers of this indolent phenotype might enable opportunities for intercepting progression to high-grade IPMN and cancer. We conducted spatial transcriptomics on a cohort of IPMNs, followed by orthogonal and cross species validation studies, which established the transcription factor NKX6-2 as a key determinant of gastric …

Multiomics Analyses Reveal Dars1-As1/Ybx1-Controlled Posttranscriptional Circuits Promoting Glioblastoma Tumorigenesis/Radioresistance, Caishang Zheng, Yanjun Wei, Qiang Zhang, Ming Sun, Yunfei Wang, Jiakai Hou, Peng Zhang, Xiangdong Lv, Dan Su, Yujie Jiang, Joy Gumin, Nidhi Sahni, Baoli Hu, Wenyi Wang, Xi Chen, Daniel J Mcgrail, Chaolin Zhang, Suyun Huang, Han Xu, Junjie Chen, Frederick F Lang, Jian Hu, Yiwen Chen

Faculty, Staff and Student Publications

The glioblastoma (GBM) stem cell-like cells (GSCs) are critical for tumorigenesis/therapeutic resistance of GBM. Mounting evidence supports tumor-promoting function of long noncoding RNAs (lncRNAs), but their role in GSCs remains poorly understood. By combining CRISPRi screen with orthogonal multiomics approaches, we identified a lncRNA DARS1-AS1-controlled posttranscriptional circuitry that promoted the malignant properties of GBM cells/GSCs. Depleting DARS1-AS1 inhibited the proliferation of GBM cells/GSCs and self-renewal of GSCs, prolonging survival in orthotopic GBM models. DARS1-AS1 depletion also impaired the homologous recombination (HR)-mediated double-strand break (DSB) repair and enhanced the radiosensitivity of GBM cells/GSCs. Mechanistically, DARS1-AS1 interacted with YBX1 to promote …

Reduced Racial Disparity As A Result Of Survival Improvement In Prostate Cancer, Baoyi Zhang, Jianrong Li, Mabel Tang, Chao Cheng

Faculty, Staff and Students Publications

Prostate cancer is a cancer type associated with a high level of racial and socioeconomic disparities as reported by many previous studies. However, the changes in these disparities in the past two decades have not been systematically studied. In this study, we investigated the Surveillance Epidemiology End Results (SEER) data for prostate cancer patients diagnosed during 2004-2018. African Americans and Asians showed significantly better and worse cancer-specific survival (CSS), respectively, compared to non-Hispanic white individuals after adjusting for confounding factors such as age and cancer stage. Importantly, the data indicated that racial disparities fluctuated and reached the highest level during …

Dna-Encoded Chemical Libraries Yield Non-Covalent And Non-Peptidic Sars-Cov-2 Main Protease Inhibitors, Ravikumar Jimmidi, Srinivas Chamakuri, Shuo Lu, Melek Nihan Ucisik, Peng-Jen Chen, Kurt M Bohren, Seyed Arad Moghadasi, Leroy Versteeg, Christina Nnabuife, Jian-Yuan Li, Xuan Qin, Ying-Chu Chen, John C Faver, Pranavanand Nyshadham, Kiran L Sharma, Banumathi Sankaran, Allison Judge, Zhifeng Yu, Feng Li, Jeroen Pollet, Reuben S Harris, Martin M Matzuk, Timothy Palzkill, Damian W Young

Faculty, Staff and Students Publications

The development of SARS-CoV-2 main protease (Mpro) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate Mpro inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of Mpro. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using Mpro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of Mpro with low nanomolar Ki values. Furthermore, these compounds demonstrate efficacy against mutant forms of Mpro that …

The Co-Delivery Of Adenovirus-Based Immune Checkpoint Vaccine Elicits A Potent Anti-Tumor Effect In Renal Carcinoma, Nan Jiang, Yanyan Zheng, Jiage Ding, Jiawei Wang, Fei Zhu, Meng Wang, Navid Sobhani, Praveen Neeli, Gang Wang, Hailong Li, Junnian Zheng, Dafei Chai

Faculty, Staff and Students Publications

Immune-based checkpoint therapy has made significant progress in cancer treatment, but its therapeutic effect is limited. A replication-defective adenovirus (Ad) vaccine encoding tumor antigen carbonic anhydrase IX (CAIX) combined with Ad-encoding immune checkpoint PD-L1 was developed to treat renal carcinoma. Three tumor models, subcutaneous, lung metastasis and orthotopic tumor were established, and Ad vaccines were used to immunize them and evaluate the vaccine's therapeutic effect. Compared to the single Ad vaccine group, the subcutaneous tumor growth was significantly reduced in Ad-CAIX/Ad-PD-L1 combination group. Co-immunization of Ad-CAIX/Ad-PD-L1 enhanced the induction and maturation of CD11c

My Happy Baby Is Back: Zero Balancing, Craniosacral Therapy And A Baby’S Journey To Becoming Mobile, Veronica Quarry

Journal of Transformative Touch

Alison began receiving ZB and CST at 13 months of age due to gross motor delays: at that age she was only able to sit somewhat rigidly. After the first session, Alison changed` from being very unhappy and seemingly frustrated to being happy and more calm. Within one month of weekly sessions, Alison was able to be on her tummy, began to crawl, became more agile in seated play, was squatting and standing and took her first steps.

Racial And Ethnic Disparities In Antifibrotic Therapy In Idiopathic Pulmonary Fibrosis, Joy Zhao, Joseph Fares, Gautam George, Arlene Maheu, Giorgos Loizidis, Jesse Roman, Daniel Kramer, Michael Li, Ross Summer

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

BACKGROUND AND OBJECTIVE: Racial disparities have been documented in care of many respiratory diseases but little is known about the impact of race on the treatment of interstitial lung diseases. The purpose of this study was to determine how race and ethnicity influence treatment of idiopathic pulmonary fibrosis.

METHODS: Adults with idiopathic pulmonary fibrosis (>18 years) were identified using TriNetX database and paired-wised comparisons were performed for antifibrotic treatment among White, Black, Hispanic and Asian patients. Mortality of treated and untreated IPF patients was compared after propensity score matching for age, sex, nicotine dependence, oxygen dependence and predicted FVC. …

Transmission Of Yellow Fever Vaccine Virus Through Blood Transfusion And Organ Transplantation In The Usa In 2021: Report Of An Investigation, Carolyn V. Gould, Rebecca J. Free, Julu Bhatnagar, Raymond A. Soto, Tricia L. Royer, Warren R. Maley, Sean Moss, Matthew A. Berk, Rebecca Craig-Shapiro, Rosy Priya L. Kodiyanplakkal, Lars F. Westblade, Thangamani Muthukumar, Yoram A. Puius, Amresh Raina, Azam Hadi, Kymberly A. Gyure, Danielle Trief, Marcus Pereira, Matthew J. Kuehnert, Vennus Ballen, Debra A. Kessler, Kimberly Dailey, Charles Omura, Thuy Doan, Steve Miller, Michael R. Wilson, Jennifer A. Lehman, Jana M. Ritter, Elizabeth Lee, Luciana Silva-Flannery, Sarah Reagan-Steiner, Jason O. Velez, Janeen J. Laven, Kelly A. Fitzpatrick, Amanda Panella, Emily H. Davis, Holly R. Hughes, Aaron C. Brault, Kirsten St George, Amy B. Dean, Joel Ackelsberg, Sridhar V. Basavaraju, Charles Y. Chiu, J. Erin Staples

Department of Medicine Faculty Papers

BACKGROUND: In 2021, four patients who had received solid organ transplants in the USA developed encephalitis beginning 2-6 weeks after transplantation from a common organ donor. We describe an investigation into the cause of encephalitis in these patients.

METHODS: From Nov 7, 2021, to Feb 24, 2022, we conducted a public health investigation involving 15 agencies and medical centres in the USA. We tested various specimens (blood, cerebrospinal fluid, intraocular fluid, serum, and tissues) from the organ donor and recipients by serology, RT-PCR, immunohistochemistry, metagenomic next-generation sequencing, and host gene expression, and conducted a traceback of blood transfusions received by …

Combined Crispri And Proteomics Screening Reveal A Cohesin-Ctcf-Bound Allele Contributing To Increased Expression Of Ruvbl1 And Prostate Cancer Progression, Yijun Tian, Dandan Dong, Zixian Wang, Lang Wu, Jong Y Park, Gong-Hong Wei, Liang Wang

Faculty, Staff and Student Publications

Genome-wide association studies along with expression quantitative trait locus (eQTL) mapping have identified hundreds of single-nucleotide polymorphisms (SNPs) and their target genes in prostate cancer (PCa), yet functional characterization of these risk loci remains challenging. To screen for potential regulatory SNPs, we designed a CRISPRi library containing 9,133 guide RNAs (gRNAs) to cover 2,166 candidate SNP loci implicated in PCa and identified 117 SNPs that could regulate 90 genes for PCa cell growth advantage. Among these, rs60464856 was covered by multiple gRNAs significantly depleted in screening (FDR < 0.05). Pooled SNP association analysis in the PRACTICAL and FinnGen cohorts showed significantly higher PCa risk for the rs60464856 G allele (p value = 1.2 × 10

Genotype Error Due To Low-Coverage Sequencing Induces Uncertainty In Polygenic Scoring, Ella Petter, Yi Ding, Kangcheng Hou, Arjun Bhattacharya, Alexander Gusev, Noah Zaitlen, Bogdan Pasaniuc

Faculty, Staff and Student Publications

Polygenic scores (PGSs) have emerged as a standard approach to predict phenotypes from genotype data in a wide array of applications from socio-genomics to personalized medicine. Traditional PGSs assume genotype data to be error-free, ignoring possible errors and uncertainties introduced from genotyping, sequencing, and/or imputation. In this work, we investigate the effects of genotyping error due to low coverage sequencing on PGS estimation. We leverage SNP array and low-coverage whole-genome sequencing data (lcWGS, median coverage 0.04×) of 802 individuals from the Dana-Farber PROFILE cohort to show that PGS error correlates with sequencing depth (p = 1.2 × 10

Moving The Pendulum For Glioblastoma Treatment: One Injection At A Time, Xizi Wu, Christopher Alvarez-Breckenridge

Faculty, Staff and Student Publications

Despite advances, glioblastoma is characterized by exceptionally high rates of recurrence and resistance to therapy. This commentary remarks on the recently published article by Maruyama et al, which reports the PMDA review of G47Δ injection for malignant glioma, in which the efficacy and safety results of G47Δ were evaluated and approval conditions clarified.

Facs-Based Genome-Wide Crispr Screens Define Key Regulators Of Dna Damage Signaling Pathways, Min Huang, Fuwen Yao, Litong Nie, Chao Wang, Dan Su, Huimin Zhang, Siting Li, Mengfan Tang, Xu Feng, Bin Yu, Zhen Chen, Shimin Wang, Ling Yin, Lisha Mou, Traver Hart, Junjie Chen

Faculty, Staff and Student Publications

DNA damage-activated signaling pathways are critical for coordinating multiple cellular processes, which must be tightly regulated to maintain genome stability. To provide a comprehensive and unbiased perspective of DNA damage response (DDR) signaling pathways, we performed 30 fluorescence-activated cell sorting (FACS)-based genome-wide CRISPR screens in human cell lines with antibodies recognizing distinct endogenous DNA damage signaling proteins to identify critical regulators involved in DDR. We discovered that proteasome-mediated processing is an early and prerequisite event for cells to trigger camptothecin- and etoposide-induced DDR signaling. Furthermore, we identified PRMT1 and PRMT5 as modulators that regulate ATM protein level. Moreover, we discovered …