Genetic Phenomena Commons^™

Dedifferentiated Liposarcomas Treated With Immune Checkpoint Blockade: The Md Anderson Experience, Madeline B Torres, Cheuk Hong Leung, Marianne Zoghbi, Rossana Lazcano, Davis Ingram, Khalida Wani, Emily Z Keung, M Alejandra Zarzour, Christopher P Scally, Kelly K Hunt, Anthony Conley, Andrew J Bishop, B Ashleigh Guadagnolo, Ahsan Farooqi, Devarati Mitra, Alison K Yoder, Michael S Nakazawa, Dejka Araujo, Andrew Livingston, Ravin Ratan, Shreyaskumar Patel, Vinod Ravi, Alexander J Lazar, Christina L Roland, Neeta Somaiah, Elise F Nassif Haddad

Faculty, Staff and Student Publications

Background: Dedifferentiated liposarcoma (DDLPS) is one of the most common types of soft tissue sarcoma (STS) characterized by liposarcomatous differentiation and a predilection for the retroperitoneum. Despite the growing number of histology-specific immune checkpoint blockade (ICB) trials in STS, it is still difficult to identify the radiographic objective response rate (ORR) for DDLPS in the real world setting. This study aimed to evaluate the ORR and survival of patients with DDLPS treated with ICB at a single center.

Methods: We conducted a retrospective study of 31 patients with pathologically confirmed DDLPS treated with ICB at MD Anderson Cancer Center between …

Inhibition Of Nitric Oxide Synthase Transforms Carotid Occlusion-Mediated Benign Oligemia Into De Novo Large Cerebral Infarction, Ha Kim, Jinyong Chung, Jeong Wook Kang, Dawid Schellingerhout, Soo Ji Lee, Hee Jeong Jang, Inyeong Park, Taesu Kim, Dong-Seok Gwak, Ji Sung Lee, Sung-Ha Hong, Kang-Hoon Je, Hee-Joon Bae, Joohon Sung, Eng H Lo, James Faber, Cenk Ayata, Dong-Eog Kim

Faculty, Staff and Student Publications

No abstract provided.

Heterologous Prime-Pull Mucosal Vaccination With An Adjuvanted Rbd Vaccine Elicits Robust Iga Production And Protects Against Sars-Cov-2, Allyson H Hirsch, Calder R Ellsworth, William A Lewis, Ryan Craig, Amy E Meyer, Jonatan Maldonado, Frania Ramirez Lopez, Syamala Rani Thimmiraju, James B Mclachlan, Xuebin Qin, Nicholas J Maness, Jeroen Pollet, Ulrich Strych, Maria Elena Bottazzi, Peter J Hotez, Lisa A Morici

Faculty, Staff and Students Publications

Despite the efficacy of approved severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in preventing severe disease and death, breakthrough infections continue to occur in vaccinated individuals, contributing to further viral mutation and spread. These limitations may be attributable to the poor induction of mucosal immunity by parenteral vaccination. Mucosal adjuvants, such as T-vant, can enhance vaccine-induced immune responses through the generation of antigen-specific antibodies and T cells in the respiratory tract. In this study, we evaluated the protective efficacy of adjuvanted SARS-CoV-2 receptor binding domain (RBD) subunit vaccines administered by homologous and heterologous routes. Immunized mice were challenged with …

Monoallelic Expression Can Govern Penetrance Of Inborn Errors Of Immunity, O'Jay Stewart, Conor Gruber, Haley E Randolph, Roosheel Patel, Meredith Ramba, Enrica Calzoni, Lei Haley Huang, Jay Levy, Sofija Buta, Angelica Lee, Christos Sazeides, Zoe Prue, David P Hoytema Van Konijnenburg, Ivan K Chinn, Luis A Pedroza, James R Lupski, Erica G Schmitt, Megan A Cooper, Anne Puel, Xiao Peng, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Satoshi Okada, Marta Martin-Fernandez, Jordan S Orange, Jean-Laurent Casanova, Joshua D Milner, Dusan Bogunovic

Faculty, Staff and Students Publications

Inborn errors of immunity (IEIs) are genetic disorders that underlie susceptibility to infection, autoimmunity, autoinflammation, allergy and/or malignancy1. Incomplete penetrance is common among IEIs despite their monogenic basis2. Here we investigate the contribution of autosomal random monoallelic expression (aRMAE), a somatic commitment to the expression of one allele3,4, to phenotypic variability observed in families with IEIs. Using a clonal primary T cell system to assess aRMAE status of genes in healthy individuals, we find that 4.30% of IEI genes and 5.20% of all genes undergo aRMAE. Perturbing H3K27me3 and DNA methylation alters …

Mixed-Methods Evaluation And Behavior Change Interventions To Improve Hand Hygiene Resources And Practices Among Healthcare Workers In Polyclinics And Health Centers In Belize, 2023, Anh N Ly, Kelsey Mcdavid, Christina Craig, Rosalva Blanco, Vickie Romero, Melissa Diaz-Musa, Francis Morey, Russell Manzanero, Gerhaldine Morazan, Makenzie Towery, Anna Impellitteri, Matthew Lozier, Kristy O Murray

Faculty, Staff and Students Publications

Background: Hand hygiene (HH) is an effective public health measure to prevent the spread of infections in healthcare settings. A previous study in Belize showed gaps in HH practices in hospitals and large polyclinics; however, there are limited national data assessing access to and use of HH resources in smaller outpatient primary care facilities, especially in rural areas.

Methods: In February 2023, facility assessments were conducted at 26 health centers and polyclinics in Belize to assess the availability of HH resources. Of these, 12 pilot healthcare facilities (HCF) were selected for additional evaluation, which included observation of HH practices, hand …

Predicting Kidney Graft Function And Failure Among Kidney Transplant Recipients, Yi Yao, Brad C Astor, Wei Yang, Tom Greene, Liang Li

Faculty, Staff and Student Publications

Background: Graft loss is a major health concern for kidney transplant (KTx) recipients. It is of clinical interest to develop a prognostic model for both graft function, quantified by estimated glomerular filtration rate (eGFR), and the risk of graft failure. Additionally, the model should be dynamic in the sense that it adapts to accumulating longitudinal information, including time-varying at-risk population, predictor-outcome association, and clinical history. Finally, the model should also properly account for the competing risk by death with a functioning graft. A model with the features above is not yet available in the literature and is the focus of …

Nos Inhibition Sensitizes Metaplastic Breast Cancer To Pi3k Inhibition And Taxane Therapy Via C-Jun Repression, Tejaswini Reddy, Akshjot Puri, Liliana Guzman-Rojas, Christoforos Thomas, Wei Qian, Jianying Zhou, Hong Zhao, Bijan Mahboubi, Adrian Oo, Young-Jae Cho, Baek Kim, Jose Thaiparambil, Roberto Rosato, Karina Ortega Martinez, Maria Florencia Chervo, Camila Ayerbe, Noah Giese, David Wink, Stephen Lockett, Stephen Wong, Jeffrey Chang, Savitri Krishnamurthy, Clinton Yam, Stacy Moulder, Helen Piwnica-Worms, Funda Meric-Bernstam, Jenny Chang

Faculty, Staff and Student Publications

Metaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor efficacy of taxane. We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane. Mechanistically, NOS blockade leads to a decrease in the S-nitrosylation of c-Jun NH

Parp Inhibition Radiosensitizes Brca1 Wildtype And Mutated Breast Cancer To Proton Therapy, Mariam Ben Kacem, Scott J Bright, Emma Moran, David B Flint, David K J Martinus, Broderick X Turner, Ilsa Qureshi, Rishab Kolachina, Mandira Manandhar, Poliana C Marinello, Simona F Shaitelman, Gabriel O Sawakuchi

Faculty, Staff and Student Publications

Aggressive breast cancers often fail or acquire resistance to radiotherapy. To develop new strategies to improve the outcome of aggressive breast cancer patients, we studied how PARP inhibition radiosensitizes breast cancer models to proton therapy, which is a radiotherapy modality that generates more DNA damage in the tumor than standard radiotherapy using photons. Two human BRCA1-mutated breast cancer cell lines and their isogenic BRCA1-recovered pairs were treated with a PARP inhibitor and irradiated with photons or protons. Protons (9.9 and 3.85 keV/µm) induced higher cell kill independent of BRCA1 status. PARP inhibition amplified the cell kill effect to both photons …

High Peripheral T Cell Diversity Is Associated With Lower Risk Of Toxicity And Superior Response To Dual Immune Checkpoint Inhibitor Therapy In Patients With Metastatic Nsclc, Mehmet Altan, Ruoxing Li, Ziyi Li, Runzhe Chen, Ajay Sheshadri, Hai T Tran, Latasha Little, Joshua Baguley, Jefferson Sinson, Natalie Vokes, Saumil Gandhi, Mara B Antonoff, Stephen G Swisher, Greg Lizee, Alexandre Reuben, John V Heymach, Jianjun Zhang

Faculty, Staff and Student Publications

INTRODUCTION: Despite significant successes, immune checkpoint blockade fails to achieve clinical responses in a significant proportion of patients, predictive markers for responses are imperfect and immune-related adverse events (irAEs) are unpredictable. We used T-cell receptor (TCR) sequencing to systematically analyze prospectively collected patient blood samples from a randomized clinical trial of dual immune checkpoint inhibitor therapy to evaluate changes in the T-cell repertoire and their association with response and irAEs.

METHODS: Patients with immunotherapy-naïve metastatic non-small cell lung cancer (NSCLC) were treated with ipilimumab and nivolumab according to trial protocol (LONESTAR, NCT03391869). Blood samples were systematically obtained at baseline (n=107), …

Inhibition Of Microrna-660-5p Decreases Breast Cancer Progression Through Direct Targeting Of Tmem41b, Valeria Villarreal-García, José Roberto Estupiñan-Jiménez, Vianey Gonzalez-Villasana, Pablo E Vivas-Mejía, Marienid Flores-Colón, Irma Estefanía Ancira-Moreno, Patricio Adrián Zapata-Morín, Claudia Altamirano-Torres, José Manuel Vázquez-Guillen, Cristina Rodríguez-Padilla, Recep Bayraktar, Mohamed H Rashed, Cristina Ivan, Gabriel Lopez-Berestein, Diana Reséndez-Pérez

Faculty, Staff and Student Publications

Background: Breast cancer is the most prevalent cancer among women worldwide. Most breast cancer-related deaths result from metastasis and drug resistance. Novel therapies are imperative for targeting metastatic and drug-resistant breast cancer cells. Accumulating evidence suggests that dysregulated microRNAs (miRNAs) promote breast cancer progression, metastasis, and drug resistance. Compared with healthy breast tissue, miR-660-5p is notably overexpressed in breast cancer tumor tissues. However, the downstream effectors of miR-660-5p in breast cancer cells have not been fully elucidated. Our aim was to investigate the role of miR-660-5p in breast cancer cell proliferation, migration, invasion, and angiogenesis and to identify its potential …

Results Of The Simultaneous Combination Of Ponatinib And Blinatumomab In Philadelphia Chromosome-Positive All, Hagop Kantarjian, Nicholas J Short, Fadi G Haddad, Nitin Jain, Xuelin Huang, Guillermo Montalban-Bravo, Rashmi Kanagal-Shamanna, Tapan M Kadia, Naval Daver, Kelly Chien, Yesid Alvarado, Guillermo Garcia-Manero, Ghayas C Issa, Rebecca Garris, Cedric Nasnas, Lewis Nasr, Farhad Ravandi, Elias Jabbour

Faculty, Staff and Student Publications

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In this analysis, we update our experience with the chemotherapy-free regimen of blinatumomab and ponatinib in 60 patients with newly diagnosed Philadelphia chromosome (Ph)-positive ALL. At a median follow-up of 24 months, the complete molecular response rate …

Protocol For Culturing Patient-Derived Organoids Of Cervical Cancer, Rui Wang, Timothy Harris, Dalissa Negrón-Figueroa, David Lo, Allison Judge, D'Shaunique Walters, Bo Jiang, Lauren E Colbert

Faculty, Staff and Student Publications

Herein, we present a protocol for culturing patient-derived organoids (PDOs) of cervical cancer that includes workflows for tumor biopsy/resection tissue and cytobrush-sampled cells. We describe steps for PDO culture initiation, including rinsing, gentle dissociation, Lymphoprep separation, and cell assessment, as well as seeding cells from surgical and cytobrush tissue digestion. We then provide guidance on PDO maintenance and passage and techniques for producing conditioned medium. Overall, this protocol serves as a valuable guide for establishing and maintaining cervical cancer PDOs. For complete details on the use and execution of this protocol, please refer to Colbert et al.

Age-Related Tfeb Downregulation In Proximal Tubules Causes Systemic Metabolic Disorders And Occasional Apolipoprotein A4-Related Amyloidosis, Jun Nakamura, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Atsushi Takahashi, Jun Matsuda, Satoshi Minami, Shinsuke Sakai, Hiroaki Yonishi, Shihomi Maeda, Sho Matsui, Hideaki Kawai, Isao Matsui, Tadashi Yamamuro, Ryuya Edahiro, Seiji Takashima, Akira Takasawa, Yukinori Okada, Tamotsu Yoshimori, Andrea Ballabio, Yoshitaka Isaka

Duncan NRI Faculty and Staff Publications

With the aging of society, the incidence of chronic kidney disease (CKD), a common cause of death, has been increasing. Transcription factor EB (TFEB), the master transcriptional regulator of the autophagy/lysosomal pathway, is regarded as a promising candidate for preventing various age-related diseases. However, whether TFEB in the proximal tubules plays a significant role in elderly patients with CKD remains unknown. First, we found that nuclear TFEB localization in proximal tubular epithelial cells (PTECs) declined with age in both mice and humans. Next, we generated PTEC-specific Tfeb-deficient mice and bred them for up to 24 months. We found that TFEB …

Deuterated Water Labeling In Ibrutinib-Treated Patients With Cll: Leukemia Cell Kinetics Correlate With Ighv, Zap-70, And Mrd, Ekaterina Kim, Shih-Shih Chen, Mariela Sivina, Hyunsoo Hwang, Xuelin Huang, Alessandra Ferrajoli, Nitin Jain, William G Wierda, Dominik Wodarz, Nicholas Chiorazzi, Jan A Burger

Faculty, Staff and Student Publications

Deuterated (“heavy”) water labeling in patients with chronic lymphocytic leukemia (CLL) demonstrates that IGHV unmutated and ZAP-70+ patients have higher blood and tissue CLL death rates on ibrutinib therapy, resulting in lower measurable residual disease levels with long-term ibrutinib treatment. This trial was registered at www.clinicaltrials.gov as #NCT01752426.

Enhancer Reprogramming Underlies Therapeutic Utility Of A Smarca2 Degrader In Smarca4 Mutant Cancer, Sasikumar Kotagiri, Nicholas Blazanin, Yuanxin Xi, Yanyan Han, Md Qudratullah, Xiaobing Liang, Yawen Wang, Poonam Pandey, Hira Mazhar, Truong Nguyen Lam, Anand Kamal Singh, Jing Wang, Yonathan Lissanu

Faculty, Staff and Student Publications

Genomic studies have identified frequent mutations in subunits of the SWI/SNF (switch/sucrose non-fermenting) chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer (NSCLC). Genetic evidence indicates that the paralog SMARCA2 is synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. Here, we utilized structure-activity relationship (SAR) studies to develop YD23, a potent and selective proteolysis targeting chimera (PROTAC) targeting SMARCA2. Mechanistically, we show that SMARCA2 degradation induces reprogramming of the enhancer landscape in SMARCA4-mutant cells with loss of chromatin accessibility at enhancers of genes …

Transcriptomic Clustering Of Chronic Lymphocytic Leukemia: Molecular Subtypes Based On Bruton’S Tyrosine Kinase Expression Levels, Gorkem Kismali, Ganiraju Manyam, Nitin Jain, Cristina Ivan, Betty Lamothe, Mary L Ayres, Lakesla R Iles, William G Wierda, Varsha Gandhi

Faculty, Staff and Student Publications

Historically, CLL prognostication relied on disease burden, reflected in clinical stage. Later, chromosome abnormalities and genomics suggested several CLL subtypes which were aligned with response to therapy. Gene expression profiling data identified pathways associated with CLL progression. We hypothesized that transcriptome and proteome may identify functional omics associated with CLL nosology. As a test cohort, we utilized publicly available treatment-naïve CLL transcriptomics data (n = 130) and did consensus clustering that identified BTK-expression-based clusters. The BTK-High and BTK-Low clusters were validated in public and our in-house databases (n = >550 CLL patients). To associate with functional relevance, we took samples …

Utility Of Colposcopy For The Screening And Management Of Cervical Cancer In Africa: A Cross-Sectional Analysis Of Providers’ Training And Practices, Joël Fokom Domgue, Issimouha Dille, Freddy Gnangnon, Sharon Kapambwe, Celine Bouchard, Nomonde Mbatani, Elodie Gauroy, Nathalie Ledaga Ambounda, Robert Yu, Fatoumata Sidibe, Joseph Kamgno, Bangaly Traore, Pierre-Marie Tebeu, Gregory Halle-Ekane, Mohenou Isidore Diomande, Jean-Marie Dangou, Fabrice Lecuru, Isaac Adewole, Marie Plante, Partha Basu, Sanjay Shete

Faculty, Staff and Student Publications

Introduction: Cervical cancer is a public health issue in Africa with devastating socioeconomic consequences due to the lack of organized screening programs. The success of screening programs depends on the appropriate investigation and management of women who test positive for screening. Colposcopic assessment following positive screening results is a noteworthy issue in Africa. This study aimed to assess the utilization of colposcopy by providers in the region.

Methods: A cross-sectional study was conducted in 2021-2022 among healthcare providers involved in cervical cancer prevention activities in Africa. They were invited to report prior colposcopy training, whether they performed colposcopy and the …

Automated Segmentation Of Mri White Matter Hyperintensities In 8421 Patients With Acute Ischemic Stroke, Hosung Kim, Wi-Sun Ryu, Dawid Schellingerhout, Jonghyeok Park, Jinyong Chung, Sang-Wuk Jeong, Dong-Seok Gwak, Beom Joon Kim, Joon-Tae Kim, Keun-Sik Hong, Kyung Bok Lee, Tai Hwan Park, Jong-Moo Park, Kyusik Kang, Yong-Jin Cho, Byung-Chul Lee, Kyung-Ho Yu, Mi Sun Oh, Soo Joo Lee, Jae-Kwan Cha, Dae-Hyun Kim, Jun Lee, Man Seok Park, Hee-Joon Bae, Dong-Eog Kim

Faculty, Staff and Student Publications

Background and purpose: To date, only a few small studies have attempted deep learning-based automatic segmentation of white matter hyperintensity (WMH) lesions in patients with cerebral infarction; this issue is complicated because stroke-related lesions can obscure WMH borders. We developed and validated deep learning algorithms to segment WMH lesions accurately in patients with cerebral infarction using multisite data sets involving 8421 patients with acute ischemic stroke.

Materials and methods: We included 8421 patients with stroke from 9 centers in Korea. 2D UNet and squeeze-and-excitation (SE)-UNet models were trained using 2408 FLAIR MRIs from 3 hospitals and validated using 6013 FLAIR …

Additional Expression Of T-Cell Engager In Clinically Tested Oncolytic Adeno-Immunotherapy Redirects Tumor-Infiltrated, Irrelevant T Cells Against Cancer Cells To Enhance Antitumor Immunity, Daisuke Morita, Amanda Rosewell Shaw, Greyson Biegert, Caroline Porter, Mae Woods, Spyridoula Vasileiou, Bora Lim, Masataka Suzuki

Faculty, Staff and Student Publications

Background: Oncolytic adenoviruses (OAds) are the most clinically tested viral vectors for solid tumors. However, most clinically tested "Armed" OAds show limited antitumor effects in patients with various solid tumors even with increased dosages and multiple injections. We developed a binary oncolytic/helper-dependent adenovirus system (CAdVEC), in which tumors are coinfected with an OAd and a non-replicating helper-dependent Ad (HDAd). We recently demonstrated that a single low-dose CAdVEC expressing interleukin-12, programmed death-ligand 1 blocker, and HSV thymidine kinase safety switch (CAdTrio) induces significant antitumor effects in patients, including complete response. Similar to previous OAd studies, all patients primarily amplified Ad-specific T …

Clonal Landscape And Clinical Outcomes Of Telomere Biology Disorders: Somatic Rescue And Cancer Mutations, Fernanda Gutierrez-Rodrigues, Emma M Groarke, Natthakan Thongon, Juan Jose Rodriguez-Sevilla, Luiz Fernando B Catto, Marena R Niewisch, Ruba Shalhoub, Lisa J Mcreynolds, Diego V Clé, Bhavisha A Patel, Xiaoyang Ma, Dalton Hironaka, Flávia S Donaires, Nina Spitofsky, Barbara A Santana, Tsung-Po Lai, Lemlem Alemu, Sachiko Kajigaya, Ivana Darden, Weiyin Zhou, Paul V Browne, Subrata Paul, Justin Lack, David J Young, Courtney D Dinardo, Abraham Aviv, Feiyang Ma, Michel Michels De Oliveira, Ana Paula De Azambuja, Cynthia E Dunbar, Malgorzata Olszewska, Emmanuel Olivier, Eirini P Papapetrou, Neelam Giri, Blanche P Alter, Carmem Bonfim, Colin O Wu, Guillermo Garcia-Manero, Sharon A Savage, Neal S Young, Simona Colla, Rodrigo T Calado

Faculty, Staff and Student Publications

Telomere biology disorders (TBDs), caused by pathogenic germ line variants in telomere-related genes, present with multiorgan disease and a predisposition to cancer. Clonal hematopoiesis (CH) as a marker of cancer development and survival in TBDs is poorly understood. Here, we characterized the clonal landscape of a large cohort of 207 patients with TBD with a broad range of age and phenotype. CH occurred predominantly in symptomatic patients and in signature genes typically associated with cancers: PPM1D, POT1, TERT promoter (TERTp), U2AF1S34, and/or TP53. Chromosome 1q gain (Chr1q+) was the commonest karyotypic abnormality. Clinically, multiorgan involvement and CH in TERTp, TP53, …

Integrative Multi-Omics Analysis Uncovers Tumor-Immune-Gut Axis Influencing Immunotherapy Outcomes In Ovarian Cancer, Spencer R Rosario, Mark D Long, Shanmuga Chilakapati, Eduardo Cortes Gomez, Sebastiano Battaglia, Prashant K Singh, Jianmin Wang, Katy Wang, Kristopher Attwood, Suzanne M Hess, A J Robert Mcgray, Kunle Odunsi, Brahm H Segal, Gyorgy Paragh, Song Liu, Jennifer A Wargo, Emese Zsiros

Faculty, Staff and Student Publications

Recurrent ovarian cancer patients, especially those resistant to platinum, lack effective curative treatments. To address this, we conducted a phase 2 clinical trial (NCT02853318) combining pembrolizumab with bevacizumab, to increase T cell infiltration into the tumor, and oral cyclophosphamide, to reduce the number of regulatory T cells. The trial accrued 40 heavily pretreated recurrent ovarian cancer patients. The primary endpoint, progression free survival, was extended to a median of 10.2 months. The secondary endpoints demonstrated an objective response rate of 47.5%, and disease control in 30% of patients for over a year while maintaining a good quality of life. We …

Trajectory, Interactions, And Predictors Of Higher Symptom Burden During Induction Therapy For Multiple Myeloma, Mona Kamal, Qiuling Shi, Shu-En Shen, Charles Cleeland, Xin Shelley Wang

Faculty, Staff and Student Publications

Background: Patients with multiple myeloma (MM) experience disabling symptoms that are difficult to manage and may persist after induction therapy. Monitoring disease-related and induction therapy-induced symptoms and identifying patients at greater risk for high symptom burden are unmet clinical needs. The objective of this study was to examine the trajectories of symptom severity over time and identify predictors of high symptom burden during MM induction therapy.

Methodology: Eligible patients with MM rated their symptoms by completing the MD Anderson Symptom Inventory MM module repeatedly during 16 weeks of induction therapy. Group-based trajectory modeling identified patient groups with persistently high-severity (versus …

Diet And Immune Effects Trial (Diet)- A Randomized, Double-Blinded Dietary Intervention Study In Patients With Melanoma Receiving Immunotherapy, Rachel M Farias, Yan Jiang, Erma J Levy, Cindy Hwang, Jian Wang, Elizabeth M Burton, Lorenzo Cohen, Nadim Ajami, Jennifer A Wargo, Carrie R Daniel, Jennifer L Mcquade

Faculty, Staff and Student Publications

Background: Gut microbiome modulation is a promising strategy for enhancing the response to immune checkpoint blockade (ICB). Fecal microbiota transplant studies have shown positive signals of improved outcomes in both ICB-naïve and refractory melanoma patients; however, this strategy is challenging to scale. Diet is a key determinant of the gut microbiota, and we have previously shown that (a) habitual high dietary fiber intake is associated with an improved response to ICB and (b) fiber manipulation in mice impacts antitumor immunity. We recently demonstrated the feasibility of a controlled high-fiber dietary intervention (HFDI) conducted in melanoma survivors with excellent compliance and …

Individualized Functional Magnetic Resonance Imaging Neuromodulation Enhances Visuospatial Perception: A Proof-Of-Concept Study, Anthony Allam, Vincent Allam, Sandy Reddy, Eric M Rohren, Sameer A Sheth, Emmanouil Froudarakis, T Dorina Papageorgiou

Duncan NRI Faculty and Staff Publications

This proof-of-concept study uses individualized functional magnetic resonance imaging neuromodulation (iNM) to explore the mechanisms that enhance BOLD signals in visuospatial perception (VP) networks that are crucial for navigation. Healthy participants (n = 8) performed a VP up- and down-direction discrimination task at full and subthreshold coherence through peripheral vision, and superimposed direction through visual imagery (VI) at central space under iNM and control conditions. iNM targets individualized anatomical and functional middle- and medial-superior temporal (MST) networks that control VP. We found that iNM engaged selective exteroceptive and interoceptive attention (SEIA) and motor planning (MP) networks. Specifically, iNM increased …

Private-Sector Readmissions For Inpatient Surgery In Veterans Health Administration Hospitals, Mary Vaughan Sarrazin, Yubo Gao, Carly A Jacobs, Michael A Jacobs, Susanne Schmidt, Heather Davila, Katherine Hadlandsmyth, Andrea L Strayer, John Cashy, George Wehby, Paula K Shireman, Daniel E Hall

Faculty, Staff and Student Publications

Importance: The Veterans Health Administration (VHA) reports multiple indicators of hospital surgical performance, including hospital risk-standardized 30-day readmission rates (RSRRs). Currently, most routinely reported measures do not include readmissions that occur outside VHA hospitals. The impact of readmissions outside the VHA on hospital RSRR is not known.

Objective: To measure the impact of including non-VHA readmissions on VHA hospital performance rankings for 30-day readmission.

Design, setting, and participants: This retrospective cohort study included patients aged at least 65 years from 2013 to 2019 from the Veterans Affairs Surgical Quality Improvement Program linked to patient-level data from the VHA and Medicare. …

Myeloid Activation Clears Ascites And Reveals Il27-Dependent Regression Of Metastatic Ovarian Cancer, Brennah Murphy, Taito Miyamoto, Bryan S Manning, Gauri Mirji, Alessio Ugolini, Toshitha Kannan, Kohei Hamada, Yanfang P Zhu, Daniel T Claiborne, Lu Huang, Rugang Zhang, Yulia Nefedova, Andrew Kossenkov, Filippo Veglia, Rahul Shinde, Nan Zhang

Faculty, Staff and Student Publications

Patients with metastatic ovarian cancer (OvCa) have a 5-year survival rate of < 30% due to the persisting dissemination of chemoresistant cells in the peritoneal fluid and the immunosuppressive microenvironment in the peritoneal cavity. Here, we report that intraperitoneal administration of β-glucan and IFNγ (BI) induced robust tumor regression in clinically relevant models of metastatic OvCa. BI induced tumor regression by controlling fluid tumor burden and activating localized antitumor immunity. β-glucan alone cleared ascites and eliminated fluid tumor cells by inducing intraperitoneal clotting in the fluid and Dectin-1-Syk-dependent NETosis in the omentum. In omentum tumors, BI expanded a novel subset of immunostimulatory IL27+ macrophages and neutralizing IL27 impaired BI efficacy in vivo. Moreover, BI directly induced IL27 secretion in macrophages where single agent treatment did not. Finally, BI extended mouse survival in a chemoresistant model and significantly improved chemotherapy response in a chemo-sensitive model. In summary, we propose a new therapeutic strategy for the treatment of metastatic OvCa.

Nuclear Expression Of Dynamin 2 Is Associated With Tumor Aggressiveness In Bladder Cancer Patients: A Bioinformatics And Experimental Approach, Mahdieh Razmi, Leili Saeednejad Zanjani, Mandana Rahimi, Roya Sajed, Sadegh Safaei, Zahra Madjd, Roya Ghods

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Dynamin 2 (DNM2) is aberrantly expressed in different malignancies and exerts a function in tumor progression.

AIMS: This study, for the first time, aimed to evaluate the clinical and prognostic value of DNM2 in the pathophysiology of bladder cancer using bioinformatics analysis and experimental evaluation.

METHODS AND RESULTS: We analyzed gene expression of DNM2 in bladder tumor by GEPIA2 and GENT2 platforms. Cluster subnetworks were recognized from the protein-protein interaction (PPI) network using the MCODE plugin to screen the key genes. Subsequently, the pathway enrichment analysis was evaluated. Then, the immunohistochemical examination was conducted on 209 paraffin-embedded bladder cancer …

Prevalence, Diagnostic Features, And Medical Outcomes Of Females With Turner Syndrome With A Trisomy X Cell Line (45, X/47, Xxx): Results From The Insights Registry, Natalia Klamut, Samantha Bothwell, Alexandra E Carl, Vaneeta Bamba, Jennifer R Law, Wendy J Brickman, Karen O Klein, Roopa Kanakatti Shankar, Catherina T Pinnaro, Patricia Y Fechner, Siddharth K Prakash, Iris Gutmark-Little, Susan Howell, Nicole Tartaglia, Marybel Good, Kelly C Ranallo, Shanlee M Davis

Faculty, Staff and Student Publications

Turner syndrome (TS) is defined by partial or complete absence of a sex chromosome. Little is known about the phenotype of individuals with TS mosaic with trisomy X (45,X/47,XXX or 45,X/46,XX/47,XXX) (~3% of TS). We compared the diagnostic, perinatal, medical, and neurodevelopmental comorbidities of mosaic 45,X/47,XXX (n = 35, 9.4%) with nonmosaic 45,X (n = 142) and mosaic 45,X/46,XX (n = 66). Females with 45,X/47,XXX had fewer neonatal concerns and lower prevalence of several TS-related diagnoses compared with 45,X; however the prevalence of neurodevelopmental and psychiatric diagnoses were not different. Compared to females with 45,X/46,XX, the 45,X/47,XXX group was significantly …

Impact Of Prenatal Genomics On Clinical Genetics Practice, Roni Zemet, Ignatia B Van Den Veyver

Duncan NRI Faculty and Staff Publications

Genetic testing for prenatal diagnosis in the pre-genomic era primarily focused on detecting common fetal aneuploidies, using methods that combine maternal factors and imaging findings. The genomic era, ushered in by the emergence of new technologies like chromosomal microarray analysis and next-generation sequencing, has transformed prenatal diagnosis. These new tools enable screening and testing for a broad spectrum of genetic conditions, from chromosomal to monogenic disorders, and significantly enhance diagnostic precision and efficacy. This chapter reviews the transition from traditional karyotyping to comprehensive sequencing-based genomic analyses. We discuss both the clinical utility and the challenges of integrating prenatal exome and …

Association Of Late Eating With Colorectal Adenomas: A Cross-Sectional Study, Darbaz Adnan, Edena R Khoshaba, Mostafa Abel-Reheem, Jonathan Q Trinh, Yin Cao, Faraz Bishehsari

Faculty, Staff and Student Publications

Purpose: Colorectal cancer (CRC) is linked to lifestyle exposures. However, changes in the CRC rates among younger populations remain poorly understood and suggest the existence of yet unidentified factor(s) that may contribute to colon carcinogenesis. Here, we investigated the potential role of time of eating in the risk of pre-cancerous colonic neoplasms (tubular adenoma: TA).

Methods: We enrolled 663 participants undergoing screening colonoscopies. Data on food timing, dietary intake, sleep/wake patterns, and chronotype were collected through structured questionnaires. Late eating was defined as the consumption of food or snack within a 3-hour window of sleep onset for at least four …