Medical Specialties Commons^™

In Vivo Characterization Of Glutamine Metabolism Identifies Therapeutic Targets In Clear Cell Renal Cell Carcinoma, Akash K Kaushik, Amy Tarangelo, Lindsey K Boroughs, Mukundan Ragavan, Yuanyuan Zhang, Cheng-Yang Wu, Xiangyi Li, Kristen Ahumada, Jui-Chung Chiang, Vanina T Tcheuyap, Faeze Saatchi, Quyen N Do, Cissy Yong, Tracy Rosales, Christina Stevens, Aparna D Rao, Brandon Faubert, Panayotis Pachnis, Lauren G Zacharias, Hieu Vu, Feng Cai, Thomas P Mathews, Giannicola Genovese, Barbara S Slusher, Payal Kapur, Xiankai Sun, Matthew Merritt, James Brugarolas, Ralph J Deberardinis

Faculty, Staff and Student Publications

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with …

Protocol For Mathematical Prediction Of Patient Response And Survival To Immune Checkpoint Inhibitor Immunotherapy, Joseph D Butner, Maguy Farhat, Vittorio Cristini, Caroline Chung, Zhihui Wang

Faculty, Staff and Student Publications

This protocol describes the application of a mechanistic mathematical model of immune checkpoint inhibitor (ICI) immunotherapy to patient tumor imaging data for predicting solid tumor response and patient survival under ICI intervention. We describe steps for data collection and processing, data pipelines, and approaches to increase precision. The protocol is highly predictive as early as the first restaging after treatment start and can be used with standard-of-care imaging measures. For complete details on the use and execution of this protocol, please refer to Butner et al. (2020)

Processing And Cryopreservation Of Human Ureter Tissues For Single-Cell And Spatial Transcriptomics Assays, Emily E Fink, Surbhi Sona, Byron H Lee, Angela H Ting

Faculty, Staff and Student Publications

Characterizing the cellular heterogeneity of human ureter tissues using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics provides a detailed atlas of cell types, signaling networks, and potential cell-cell cross talk underlying developmental and regenerative pathways. We describe an optimized protocol for generating, cryopreserving, and thawing single-cell suspensions from ureter tissues isolated post-cystectomy for scRNA-seq. In addition, we describe an optimized protocol for cryopreserving human ureter tissues for 10x Genomics Visium spatial gene expression platform. For complete details on the use and execution of this protocol, please refer to Fink et al. (2022).

Isolation, Culture, And Immunophenotypic Analysis Of Bone Marrow Hspcs From Patients With Myelodysplastic Syndromes, Irene Ganan-Gomez, Karen Clise-Dwyer, Simona Colla

Faculty, Staff and Student Publications

Drug testing assays in hematopoietic stem and progenitor cells (HSPCs) are fundamental in biological studies of myelodysplastic syndromes (MDS) but have historically entailed a technical challenge. This protocol allows the efficient isolation of MDS HSPCs from bone marrow mononuclear cell fractions and their culturing with the support of stromal cells for improved maintenance during drug testing. Lastly, specific steps are given to quantify surviving cells and assess changes in the HSPC hierarchies.

For complete details on the use and execution of this protocol, please refer to Ganan-Gomez et al. (2022).

Egfr Is A Master Switch Between Immunosuppressive And Immunoactive Tumor Microenvironment In Inflammatory Breast Cancer, Xiaoping Wang, Takashi Semba, Ganiraju C Manyam, Jing Wang, Shan Shao, Francois Bertucci, Pascal Finetti, Savitri Krishnamurthy, Lan Thi Hanh Phi, Troy Pearson, Steven J Van Laere, Jared K Burks, Evan N Cohen, James M Reuben, Fei Yang, Hu Min, Nicholas Navin, Van Ngu Trinh, Toshiaki Iwase, Harsh Batra, Yichao Shen, Xiang Zhang, Debu Tripathy, Naoto T Ueno

Faculty, Staff and Student Publications

Inflammatory breast cancer (IBC), the most aggressive breast cancer subtype, is driven by an immunosuppressive tumor microenvironment (TME). Current treatments for IBC have limited efficacy. In a clinical trial (NCT01036087), an anti-EGFR antibody combined with neoadjuvant chemotherapy produced the highest pathological complete response rate ever reported in patients with IBC having triple-negative receptor status. We determined the molecular and immunological mechanisms behind this superior clinical outcome. Using novel humanized IBC mouse models, we discovered that EGFR-targeted therapy remodels the IBC TME by increasing cytotoxic T cells and reducing immunosuppressive regulatory T cells and M2 macrophages. These changes were due to …

Frequency And Burden Of Neurological Manifestations Upon Hospital Presentation In Covid-19 Patients: Findings From A Large Brazilian Cohort, Milena Soriano Marcolino, Fernando Anschau, Luciane Kopittke, Magda Carvalho Pires, Izabela Guimarães Barbosa, Daniella Nunes Pereira, Lucas Emanuel Ferreira Ramos, Luís Fernando Israel Assunção, André Soares De Moura Costa, Matheus Carvalho Alves Nogueira, Helena Duani, Karina Paula Medeiros Prado Martins, Leila Beltrami Moreira, Carla Thais Cândida Alves Da Silva, Neimy Ramos De Oliveira, Patricia Klarmann Ziegelmann, Milton Henriques Guimarães-Júnior, Mauro Oscar Soares De Souza Lima, Rubia Laura Oliveira Aguiar, Luanna Silva Monteiro Menezes, Talita Fischer Oliveira, Maíra Dias Souza, Bárbara Lopes Farace, Christiane Corrêa Rodrigues Cimini, Amanda De Oliveira Maurílio, Silvana Mangeon Mereilles Guimarães, Silvia Ferreira Araújo, Guilherme Fagundes Nascimento, Daniel Vitório Silveira, Karen Brasil Ruschel, Thainara Conceição De Oliveira, Alexandre Vargas Schwarzbold, Luiz Antônio Nasi, Maiara Anschau Floriani, Veridiana Baldon Dos Santos, Carolina Marques Ramos, Joice Coutinho De Alvarenga, Ana Luiza Bahia Alves Scotton, Euler Roberto Fernandes Manenti, Gabriela Petry Crestani, Joanna D'Arc Lyra Batista, Daniela Ponce, Juliana Machado-Rugolo, Adriana Falangola Benjamin Bezerra, Petrônio José De Lima Martelli, Heloisa Reniers Vianna, Luís César De Castro, Cássia Regina Gotler Medeiros, Giovanna Grunewald Vietta, Elayne Crestani Pereira, José Miguel Chatkin, Mariana Frizzo De Godoy, Polianna Delfino-Pereira, Antonio Lucio Teixeira

Faculty, Staff and Student Publications

BACKGROUND: Scientific data regarding the prevalence of COVID-19 neurological manifestations and prognosis in Latin America countries is still lacking. Therefore, the study aims to understand neurological manifestations of SARS-CoV 2 infection and outcomes in the Brazilian population.

METHODS: This study is part of the Brazilian COVID-19 Registry, a multicentric cohort, including data from 37 hospitals. For the present analysis, patients were grouped according to the presence of reported symptoms (i.e., headache; anosmia and ageusia; syncope and dizziness) vs. clinically-diagnosed neurological manifestations (clinically-defined neurological syndrome: neurological signs or diagnoses captured by clinical evaluation) and matched with patients without neurological manifestations by …

The Challenges And Opportunities Of Scrna-Seq In Covid-19 Research And Clinical Translation, Wendao Liu, Xiaohua Ye, Zhiqiang An, Zhongming Zhao

Faculty, Staff and Student Publications

The application of single-cell RNA sequencing in COVID-19 research has greatly improved our understanding of COVID-19 pathogenesis and immunological characteristics. In this commentary, we discuss the current challenges, limitations, and perspectives in harnessing the power of single-cell RNA sequencing to accelerate both basic research and therapeutic development for COVID-19 and other emerging infectious diseases.

Outcomes In Patients With Poor-Risk Cytogenetics With Or Without Tp53 Mutations Treated With Venetoclax And Azacitidine, Daniel A Pollyea, Keith W Pratz, Andrew H Wei, Vinod Pullarkat, Brian A Jonas, Christian Recher, Sunil Babu, Andre C Schuh, Monique Dail, Yan Sun, Jalaja Potluri, Brenda Chyla, Courtney D Dinardo

Faculty, Staff and Student Publications

PURPOSE: To evaluate efficacy and safety of venetoclax + azacitidine in treatment-naïve patients with acute myeloid leukemia harboring poor-risk cytogenetics and TP53mut or TP53wt.

PATIENTS AND METHODS: We analyzed data from a phase III study (NCT02993523) comparing venetoclax (400 mg orally days 1-28) + azacitidine (75 mg/m2 days 1-7) or placebo + azacitidine, and from a phase Ib study (NCT02203773) of venetoclax + azacitidine. Patients were ineligible for intensive therapy. TP53 status was analyzed centrally; cytogenetic studies were performed locally.

RESULTS: Patients (n = 127) with poor-risk cytogenetics receiving venetoclax + azacitidine (TP53wt = 50; TP53mut = 54) were compared …

3d Imaging Analysis On An Organoid-Based Platform Guides Personalized Treatment In Pancreatic Ductal Adenocarcinoma, Ya'an Kang, Jenying Deng, Jianhua Ling, Xinqun Li, Yi-Ju Chiang, Eugene J Koay, Huamin Wang, Jared K Burks, Paul J Chiao, Mark W Hurd, Manoop S Bhutani, Jeffrey H Lee, Brian R Weston, Anirban Maitra, Naruhiko Ikoma, Ching-Wei D Tzeng, Jeffrey E Lee, Ronald A Depinho, Robert A Wolff, Shubham Pant, Florencia Mcallister, Matthew Hg Katz, Jason B Fleming, Michael P Kim

Faculty, Staff and Student Publications

BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with unpredictable responses to chemotherapy. Approaches to assay patient tumors before treatment and identify effective treatment regimens based on tumor sensitivities are lacking. We developed an organoid-based platform (OBP) to visually quantify patient-derived organoid (PDO) responses to drug treatments and associated tumor-stroma modulation for personalized PDAC therapy.METHODSWe retrospectively quantified apoptotic responses and tumor-stroma cell proportions in PDOs via 3D immunofluorescence imaging through annexin A5, α-smooth muscle actin (α-SMA), and cytokeratin 19 (CK-19) levels. Simultaneously, an ex vivo organoid drug sensitivity assay (ODSA) was used to measure responses to standard-of-care …

Detection Of Stroke With Retinal Microvascular Density And Self-Supervised Learning Using Oct-A And Fundus Imaging, Samiksha Pachade, Ivan Coronado, Rania Abdelkhaleq, Juntao Yan, Sergio Salazar-Marioni, Amanda Jagolino, Charles Green, Mozhdeh Bahrainian, Roomasa Channa, Sunil A Sheth, Luca Giancardo

Faculty, Staff and Student Publications

Acute cerebral stroke is a leading cause of disability and death, which could be reduced with a prompt diagnosis during patient transportation to the hospital. A portable retina imaging system could enable this by measuring vascular information and blood perfusion in the retina and, due to the homology between retinal and cerebral vessels, infer if a cerebral stroke is underway. However, the feasibility of this strategy, the imaging features, and retina imaging modalities to do this are not clear. In this work, we show initial evidence of the feasibility of this approach by training machine learning models using feature engineering …

Hypermethylation Of Nc886 In Hpv-Positive Oropharyngeal Cancer And Its Clinical Implications: An Epigenome-Wide Association Study, Yifan Xu, Ziqiao Wang, Peng Wei, Richa Gairola, Karl T Kelsey, Andrew G Sikora, Guojun Li, Jian Gu

Faculty, Staff and Student Publications

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased rapidly in the United States, driven by rising human papillomavirus (HPV) infections in the U.S. population. HPV-positive OPSCC patients have a better prognosis than HPV-negative patients. To gain insights into the unique biology of HPV(+) OPSCC that may contribute to its clinical behaviors, we performed a multi-stage epigenome-wide methylation profiling of leukocyte and tumor DNA in OPSCC patients and compared the methylation levels of CpG sites between HPV(+) and HPV(-) OPSCC patients. We identified and validated a significantly differentially methylated region (DMR) of 1,355 bp encompassing non-coding RNA 886 ( …

Consensus Opinion From An International Group Of Experts On Measurable Residual Disease In Hairy Cell Leukemia, Farhad Ravandi, Robert J Kreitman, Enrico Tiacci, Leslie Andritsos, Versha Banerji, Jacqueline C Barrientos, Seema A Bhat, James S Blachly, Alessandro Broccoli, Timothy Call, Dai Chihara, Claire Dearden, Judit Demeter, Sasha Dietrich, Monica Else, Narendranath Epperla, Brunangelo Falini, Francesco Forconi, Douglas E Gladstone, Alessandro Gozzetti, Sunil Iyengar, James B Johnston, Jeffrey Jorgensen, Gunnar Juliusson, Francesco Lauria, Gerard Lozanski, Sameer A Parikh, Jae H Park, Aaron Polliack, Graeme Quest, Tadeusz Robak, Kerry A Rogers, Alan Saven, John F Seymour, Tamar Tadmor, Martin S Tallman, Constantine S Tam, Philip A Thompson, Xavier Troussard, Clive S Zent, Thorsten Zenz, Pier Luigi Zinzani, Bernhard Wörmann, Kanti Rai, Michael Grever

Faculty, Staff and Student Publications

A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in patients with hairy cell leukemia (HCL). However, due to the indolent nature of the disease as well as reports suggesting long-term survival in patients treated with a single course of a nucleoside analog albeit without evidence of cure, the merits of detection of MRD and attempts to eradicate it have been debated. Studies utilizing novel strategies in the relapse setting have demonstrated the utility of achieving CR with undetectable MRD (uMRD) in prolonging the …

Using Patient Flow Analysis With Real-Time Patient Tracking To Optimize Radiation Oncology Consultation Visits, Shane Mesko, Julius Weng, Prajnan Das, Albert C Koong, Joseph M Herman, Dorothy Elrod-Joplin, Ashley Kerr, Thomas Aloia, John Frenzel, Katy E French, Wendi Martinez, Iris Recinos, Abdulaziz Alshaikh, Utpala Daftary, Amy C Moreno, Quynh-Nhu Nguyen

Faculty, Staff and Student Publications

PURPOSE: Clinical efficiency is a key component of the value-based care model and a driver of patient satisfaction. The purpose of this study was to identify and address inefficiencies at a high-volume radiation oncology clinic.

METHODS AND MATERIALS: Patient flow analysis (PFA) was used to create process maps and optimize the workflow of consultation visits in a gastrointestinal radiation oncology clinic at a large academic cancer center. Metrics such as cycle times, waiting times, and rooming times were assessed by using a real-time patient status function in the electronic medical record for 556 consults and compared between before vs after …

Defining Cellular Population Dynamics At Single-Cell Resolution During Prostate Cancer Progression, Alexandre A Germanos, Sonali Arora, Ye Zheng, Erica T Goddard, Ilsa M Coleman, Anson T Ku, Scott Wilkinson, Hanbing Song, Nicholas J Brady, Robert A Amezquita, Michael Zager, Annalysa Long, Yu Chi Yang, Jason H Bielas, Raphael Gottardo, David S Rickman, Franklin W Huang, Cyrus M Ghajar, Peter S Nelson, Adam G Sowalsky, Manu Setty, Andrew C Hsieh

Faculty, Staff and Student Publications

Advanced prostate malignancies are a leading cause of cancer-related deaths in men, in large part due to our incomplete understanding of cellular drivers of disease progression. We investigate prostate cancer cell dynamics at single-cell resolution from disease onset to the development of androgen independence in an in vivo murine model. We observe an expansion of a castration-resistant intermediate luminal cell type that correlates with treatment resistance and poor prognosis in human patients. Moreover, transformed epithelial cells and associated fibroblasts create a microenvironment conducive to pro-tumorigenic immune infiltration, which is partially androgen responsive. Androgen-independent prostate cancer leads to significant diversification of …

Mir21 Modulates The Hippo Signaling Pathway Via Interference With Pp2a Bβ To Inhibit Trophoblast Invasion And Cause Preeclampsia, Mingyu Hu, Yangxi Zheng, Jiujiang Liao, Li Wen, Juan Cheng, Jiayu Huang, Biao Huang, Li Lin, Yao Long, Yue Wu, Xuan Ye, Yong Fu, Hongbo Qi, Philip N Baker, Chao Tong

Faculty, Staff and Student Publications

Preeclampsia (PE) is a pregnancy-specific disorder attributed to deficient extravillous trophoblast (EVT) invasion into the uterus, but the mechanism of EVT invasion remains unclear. In this study, we found significantly elevated expression of microRNA 21 (miR21), which negatively regulates trophoblast invasion and migration, in preeclamptic placentae. Whole-genome RNA sequencing revealed that PPP2R2B, which encodes PP2A Bβ, and the Hippo pathway are downstream targets of miR21. The effects of miR21 on trophoblast mobility were abolished in LATS1T1079A/S909A and YAP-5SA mutants. Moreover, we found that PP2A Bβ dephosphorylates LATS1 via direct protein-protein interactions and thus modulates the phosphorylation and subcellular distribution …

Egfr-Phosphorylated Gdh1 Harmonizes With Rsk2 To Drive Creb Activation And Tumor Metastasis In Egfr-Activated Lung Cancer, Jihoon Kang, Jaemoo Chun, Jung Seok Hwang, Chaoyun Pan, Jie Li, Austin C Boese, Isabelle Young, Courteney M Malin, Yibin Kang, Don L Gibbons, Gabriel Sica, Haian Fu, Suresh S Ramalingam, Lingtao Jin, Sumin Kang

Faculty, Staff and Student Publications

The cancer metastasis process involves dysregulated oncogenic kinase signaling, but how this orchestrates metabolic networks and signal cascades to promote metastasis is largely unclear. Here we report that inhibition of glutamate dehydrogenase 1 (GDH1) and ribosomal S6 kinase 2 (RSK2) synergistically attenuates cell invasion, anoikis resistance, and immune escape in lung cancer and more evidently in tumors harboring epidermal growth factor receptor (EGFR)-activating or EGFR inhibitor-resistant mutations. Mechanistically, GDH1 is activated by EGFR through phosphorylation at tyrosine 135 and, together with RSK2, enhances the cAMP response element-binding protein (CREB) activity via CaMKIV signaling, thereby promoting metastasis. Co-targeting RSK2 and GDH1 …

Histopathological Tumour Response Scoring In Resected Pancreatic Cancer Following Neoadjuvant Therapy: International Interobserver Study (Isgpp-1), Boris V Janssen, Stijn Van Roessel, Susan Van Dieren, Onno De Boer, Volkan Adsay, Olca Basturk, Lodewijk Brosens, Fiona Campbell, Deyali Chatterjee, Angela Chou, Claudio Doglioni, Irene Esposito, Roger Feakins, Talia L Fuchs, Noriyoshi Fukushima, Anthony J Gill, Seung-Mo Hong, Ralph H Hruban, Jeffrey Kaplan, Alyssa Krasinkas, Claudio Luchini, Chanjuan Shi, Aatur Singhi, Elizabeth Thompson, Marie-Louise F Velthuysen, Marc G Besselink, Joanne Verheij, Huamin Wang, Caroline Verbeke, Arantza Fariña

Faculty, Staff and Student Publications

Background: Most tumour response scoring systems for resected pancreatic cancer after neoadjuvant therapy score tumour regression. However, whether treatment-induced changes, including tumour regression, can be identified reliably on haematoxylin and eosin-stained slides remains unclear. Moreover, no large study of the interobserver agreement of current tumour response scoring systems for pancreatic cancer exists. This study aimed to investigate whether gastrointestinal/pancreatic pathologists can reliably identify treatment effect on tumour by histology, and to determine the interobserver agreement for current tumour response scoring systems.

Methods: Overall, 23 gastrointestinal/pancreatic pathologists reviewed digital haematoxylin and eosin-stained slides of pancreatic cancer or treated tumour bed. The …

Issues In Melanoma Detection: Semisupervised Deep Learning Algorithm Development Via A Combination Of Human And Artificial Intelligence, Xinyuan Zhang, Ziqian Xie, Yang Xiang, Imran Baig, Mena Kozman, Carly Stender, Luca Giancardo, Cui Tao

Faculty, Staff and Student Publications

BACKGROUND: Automatic skin lesion recognition has shown to be effective in increasing access to reliable dermatology evaluation; however, most existing algorithms rely solely on images. Many diagnostic rules, including the 3-point checklist, are not considered by artificial intelligence algorithms, which comprise human knowledge and reflect the diagnosis process of human experts.

OBJECTIVE: In this paper, we aimed to develop a semisupervised model that can not only integrate the dermoscopic features and scoring rule from the 3-point checklist but also automate the feature-annotation process.

METHODS: We first trained the semisupervised model on a small, annotated data set with disease and dermoscopic …

Gabapentin Disrupts Binding Of Perlecan To The Α 2Δ1 Voltage Sensitive Calcium Channel Subunit And Impairs Skeletal Mechanosensation, Perla C Reyes Fernandez, Christian S Wright, Adrianna N Masterson, Xin Yi, Tristen V Tellman, Andrei Bonteanu, Katie Rust, Megan L Noonan, Kenneth E White, Karl J Lewis, Uma Sankar, Julia M Hum, Gregory Bix, Danielle Wu, Alexander G Robling, Rajesh Sardar, Mary C Farach-Carson, William R Thompson

Faculty, Staff and Student Publications

Our understanding of how osteocytes, the principal mechanosensors within bone, sense and perceive force remains unclear. Previous work identified "tethering elements" (TEs) spanning the pericellular space of osteocytes and transmitting mechanical information into biochemical signals. While we identified the heparan sulfate proteoglycan perlecan (PLN) as a component of these TEs, PLN must attach to the cell surface to induce biochemical responses. As voltage-sensitive calcium channels (VSCCs) are critical for bone mechanotransduction, we hypothesized that PLN binds the extracellular α2δ1 subunit of VSCCs to couple the bone matrix to the osteocyte membrane. Here, we showed co-localization of PLN and α2δ1 along …

Mapping Single-Cell Transcriptomes In The Intra-Tumoral And Associated Territories Of Kidney Cancer, Ruoyan Li, John R Ferdinand, Kevin W Loudon, Georgina S Bowyer, Sean Laidlaw, Francesc Muyas, Lira Mamanova, Joana B Neves, Liam Bolt, Eirini S Fasouli, Andrew R J Lawson, Matthew D Young, Yvette Hooks, Thomas R W Oliver, Timothy M Butler, James N Armitage, Tev Aho, Antony C P Riddick, Vincent Gnanapragasam, Sarah J Welsh, Kerstin B Meyer, Anne Y Warren, Maxine G B Tran, Grant D Stewart, Isidro Cortés-Ciriano, Sam Behjati, Menna R Clatworthy, Peter J Campbell, Sarah A Teichmann, Thomas J Mitchell

Faculty, Staff and Student Publications

Tumor behavior is intricately dependent on the oncogenic properties of cancer cells and their multi-cellular interactions. To understand these dependencies within the wider microenvironment, we studied over 270,000 single-cell transcriptomes and 100 microdissected whole exomes from 12 patients with kidney tumors, prior to validation using spatial transcriptomics. Tissues were sampled from multiple regions of the tumor core, the tumor-normal interface, normal surrounding tissues, and peripheral blood. We find that the tissue-type location of CD8+ T cell clonotypes largely defines their exhaustion state with intra-tumoral spatial heterogeneity that is not well explained by somatic heterogeneity. De novo mutation calling from single-cell …

A Text-Based Smoking Cessation Intervention For Sexual And Gender Minority Groups: Protocol For A Feasibility Trial, Irene Tami-Maury, Rebecca Klaff, Allison Hussin, Nathan Grant Smith, Shine Chang, Lorna Mcneill, Lorraine R Reitzel, Sanjay Shete, Lorien C Abroms

Faculty, Staff and Student Publications

BACKGROUND: Smoking among sexual and gender minority (SGM) groups, which include lesbian, gay, bisexual, transgender, and queer individuals, has been reported to be highly prevalent. This is attributed to several factors, including minority-specific stress and targeted tobacco marketing. Therefore, this population is at an increased risk for tobacco-related diseases. SMS text messaging programs have been found to be effective for smoking cessation and appeal to traditionally hard-to-reach populations over other interventions. It has also been suggested that targeted and tailored interventions could be more effective among SGM smokers because they can be designed to assure a safe, validating health care …

High-Frequency Ultrasound In Patients With Seronegative Rheumatoid Arthritis, Junkui Wang, Miao Wang, Qinghua Qi, Zhibin Wu, Jianguo Wen

Faculty, Staff and Student Publications

This study aimed to investigate the value of high-frequency ultrasound (HFUS) in differentiation of the seronegative rheumatoid arthritis (SNRA) and osteoarthritis (OA) and in the diagnosis of SNRA. 83 patients diagnosed with SNRA (SNRA group) and 40 diagnosed with OA (OA group) who received HFUS were retrospectively analyzed. The grayscale (GS) scores, power Doppler (PD) scores, and bone erosion (BE)scores were recorded, and added up to calculate the total scores of US variables. The correlations of the total scores of US variables with the 28-joint disease activity score (DAS28), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were analyzed. The …

Efficacy Of Cabozantinib In Metastatic Mit Family Translocation Renal Cell Carcinomas, Jonathan Thouvenin, Omar Alhalabi, Maria Carlo, Lucia Carril-Ajuria, Laure Hirsch, Nieves Martinez-Chanza, Sylvie Négrier, Luca Campedel, Dylan Martini, Delphine Borchiellini, Jad Chahoud, Massimo Lodi, Philippe Barthélémy, Elshad Hasanov, Andrew W Hahn, Thierry Gil, Srinivas R Viswanathan, Ziad Bakouny, Pavlos Msaouel, Mehmet Asim Bilen, Toni K Choueiri, Laurence Albiges, Nizar M Tannir, Gabriel G Malouf

Faculty, Staff and Student Publications

Background: MiT family translocation renal cell carcinoma (TRCC) is a rare and aggressive subgroup of renal cell carcinoma harboring high expression of c-MET. While TRCC response rates to VEGF receptor tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a VEGFR, MET, and AXL inhibitor) in this subgroup is unclear.

Methods: We performed a multicenter, retrospective, international cohort study of patients with TRCC treated with cabozantinib. The main objectives were to estimate response rate according to RECIST 1.1 and to analyze progression-free survival (PFS) and overall survival (OS).

Results: Fifty-two patients with metastatic TRCC treated in …

Inhibition Of The Phosphatidylinositol-3 Kinase Pathway Using Bimiralisib In Loss-Of-Function Notch1-Mutant Head And Neck Cancer, Faye M Johnson, Filip Janku, Mohamed A Gouda, Hai T Tran, Jitesh D Kawedia, Debora Schmitz, Hendrik Streefkerk, J Jack Lee, Clark R Andersen, Defeng Deng, Seema Rawal, Pooja A Shah, Adel K El-Naggar, Jason M Johnson, Mitchell J Frederick

Faculty, Staff and Student Publications

BACKGROUND: PI3K/mTOR inhibition leads to apoptosis of NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC) cells. We tested the efficacy of the PI3K/mTOR inhibitor bimiralisib in patients with NOTCH1-mutant HNSCC.

METHODS: Patients with recurrent/metastatic NOTCH1-mutant HNSCC who had progressed during chemotherapy and immunotherapy received bimiralisib until unacceptable toxicity or progression. To assess whether NOTCH1 mutations can be detected in blood, we measured circulating tumor DNA (ctDNA). To assess activated NOTCH1 protein levels, we quantitated cleaved NOTCH1 (cl-NOTCH) by immunohistochemistry.

RESULTS: Eight patients were treated, and 6 were evaluable for response. The objective response rate was 17%. For all 8 patients, …

Consistency Of Efficacy Results Across Various Clinical Measures And Statistical Methods In The Lecanemab Phase 2 Trial Of Early Alzheimer’S Disease, Shobha Dhadda, Michio Kanekiyo, David Li, Chad J Swanson, Michael Irizarry, Scott Berry, Lynn D Kramer, Donald A Berry

Faculty, Staff and Student Publications

BACKGROUND: Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils and slowed clinical decline in an 18-month phase 2 proof-of-concept study (Study 201; ClinicalTrials.gov NCT01767311) in 856 subjects with early Alzheimer's disease (AD). In this trial, subjects were randomized to five lecanemab dose regimens or placebo. The primary efficacy endpoint was change from baseline in the Alzheimer's Disease Composite Score (ADCOMS) at 12 months with Bayesian analyses. The key secondary endpoints were ADCOMS at 18 months and Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) …

G-Rich Motifs Within Phosphorothioate-Based Antisense Oligonucleotides (Asos) Drive Activation Of Fxn Expression Through Indirect Effects, Feng Wang, Ezequiel Calvo-Roitberg, Julia M Rembetsy-Brown, Minggang Fang, Jacquelyn Sousa, Zachary J Kartje, Pranathi Meda Krishnamurthy, Jonathan Lee, Michael R Green, Athma A Pai, Jonathan K Watts

Faculty, Staff and Student Publications

Friedreich's ataxia is an incurable disease caused by frataxin (FXN) protein deficiency, which is mostly induced by GAA repeat expansion in intron 1 of the FXN gene. Here, we identified antisense oligonucleotides (ASOs), complementary to two regions within the first intron of FXN pre-mRNA, which could increase FXN mRNA by ∼2-fold in patient fibroblasts. The increase in FXN mRNA was confirmed by the identification of multiple overlapping FXN-activating ASOs at each region, two independent RNA quantification assays, and normalization by multiple housekeeping genes. Experiments on cells with the ASO-binding sites deleted indicate that the ASO-induced FXN activation was driven by …

Clinical Trial Development In Tp53-Mutated Locally Advanced And Recurrent And/Or Metastatic Head And Neck Squamous Cell Carcinoma, Cristina P Rodriguez, Hyunseok Kang, Jessica L Geiger, Barbara Burtness, Christine H Chung, Curtis R Pickering, Carole Fakhry, Quynh Thu Le, Sue S Yom, Thomas J Galloway, Erica Golemis, Alice Li, Jeffrey Shoop, Stuart Wong, Ranee Mehra, Heath Skinner, Nabil F Saba, Elsa R Flores, Jeffrey N Myers, James M Ford, Rachel Karchin, Robert L Ferris, Charles Kunos, Jean M Lynn, Shakun Malik

Faculty, Staff and Student Publications

TP53 mutation is the most frequent genetic event in head and neck squamous cell carcinoma (HNSCC), found in more than 80% of patients with human papillomavirus-negative disease. As mutations in the TP53 gene are associated with worse outcomes in HNSCC, novel therapeutic approaches are needed for patients with TP53-mutated tumors. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issues of identifying and developing clinical trials for patients with TP53 mutations. Subcommittees, or breakout groups, were tasked with developing clinical studies in both the locally advanced and recurrent and/or metastatic (R/M) disease settings as well as …

Potential Probiotic Properties Of Exopolysaccharide-Producing Lacticaseibacillus Paracasei Eps Da-Bacs And Prebiotic Activity Of Its Exopolysaccharide, Min-Gyu Lee, Huijin Joeng, Jaein Shin, Suin Kim, Chaeeun Lee, Youngbo Song, Byung-Hoo Lee, Hyoung-Geun Park, Tae-Ho Lee, Hai-Hua Jiang, Young-Sun Han, Bong-Gyeong Lee, Ho-Jin Lee, Min-Ju Park, Yun-Ju Jun, Young-Seo Park

Faculty, Staff and Student Publications

Exopolysaccharide (EPS)-producing Lacticaseibacillus paracasei EPS DA-BACS was isolated from healthy human feces and its probiotic properties, as well as the structure and prebiotic activity of the EPS from this strain were examined. EPS from L. paracasei EPS DA-BACS had a ropy phenotype, which is known to have potential health benefits and is identified as loosely cell-bounded glucomannan-type EPS with a molecular size of 3.7 × 106 Da. EPS promoted the acid tolerance of L. paracasei EPS DA-BACS and provided cells with tolerance to gastrointestinal stress. The purified EPS showed growth inhibitory activity against Clostridium difficile. L. paracasei EPS DA-BACS cells …

Targeting Tmem205 Mediated Drug Resistance In Ovarian Clear Cell Carcinoma Using Oncolytic Virus, Uksha Saini, Brentley Q Smith, Kalpana Deepa Priya Dorayappan, Ji Young Yoo, G Larry Maxwell, Balveen Kaur, Ikuo Konishi, David O'Malley, David E Cohn, Karuppaiyah Selvendiran

Faculty, Staff and Student Publications

BACKGROUND: Ovarian clear cell carcinoma (OCCC) accounts for approximately 8-10% of epithelial ovarian cancers in the United States. Although it is rare, OCCC usually presents with treatment challenges and the overall prognosis is far worse than high grade serous ovarian cancer HGSOC. The objective of this study was to examine the therapeutic relevance of combining oncolytic virus with cisplatin for ovarian cancer clear cell carcinoma (OCCC).

RESULTS: We identified that TMEM205, a recently discovered transmembrane protein, contributes to chemoresistance in OCCC cells via the exosomal pathway. Mechanistically, TMEM205 undergoes ligand-independent constitutive endocytosis and co-localizes with Rab11 to contribute to the …

A Gbd 2019 Study Of Health And Sustainable Development Goal Gains And Forecasts To 2030 In Spain, Jeffrey V Lazarus, Alberto Ortiz, Stefanos Tyrovolas, Esteve Fernández, Danielle Guy, Trenton M White, Rui Ma, Simon I Hay, Mohsen Naghavi, Joan B Soriano, Gbd 2019 Spain Collaborators

Faculty, Staff and Student Publications

This study aimed to report mortality, risk factors, and burden of diseases in Spain. The Global Burden of Disease, Injuries, and Risk Factors 2019 estimates the burden due to 369 diseases, injuries, and impairments and 87 risk factors and risk factor combinations. Here, we detail the updated Spain 1990-2019 burden of disease estimates and project certain metrics up to 2030. In 2019, leading causes of death were ischaemic heart disease, stroke, chronic obstructive pulmonary disease, Alzheimer's disease, and lung cancer. Main causes of disability adjusted life years (DALYs) were ischaemic heart disease, diabetes, lung cancer, low back pain, and stroke. …