Medical Specialties Commons^™

Precision Fetal Cardiology Detects Cyanotic Congenital Heart Disease Using Maternal Saliva Metabolome And Artificial Intelligence, Ray Bahado-Singh, Nadia Ashrafi, Amin Ibrahim, Buket Aydas, Ali Yilmaz, Perry Friedman, Stewart F Graham, Onur Turkoglu

Faculty, Staff and Students Publications

Prenatal sonographic diagnosis of congenital heart disease (CHD) can lead to improved morbidity and mortality. However, the diagnostic accuracy of ultrasound, the sole prenatal screening tool, remains limited. Failed prenatal or early newborn detection of cyanotic CHD (CCHD) can have disastrous consequences. We therefore sought to use a Precision Fetal Cardiology based approach combining metabolomic profiling of maternal saliva and machine learning, a major branch of artificial intelligence (AI), for the prenatal detection of isolated, non-syndromic cyanotic CHD. Metabolomic analyses using Ultra-High Performance Liquid Chromatography/Mass Spectrometry identified 468 metabolites in the saliva. Six different AI platforms were utilized for the …

Dna Methylation Profile In Buffy Coat Identifies Methylation Differences Between Cirrhosis With And Without Hepatocellular Carcinoma, Hyeyeun Lim, Hashem B El-Serag, Michelle Luster, Megan L Grove, Jinyoung Byun, Yuri Jung, Younghun Han, Eric Boerwinkle, Christopher I Amos, Aaron P Thrift

Faculty, Staff and Students Publications

Background/Objectives: Cirrhosis is the precursor to most cases of hepatocellular carcinoma (HCC). Understanding the mechanisms leading to the transition from cirrhosis to HCC and identifying key biomarkers is crucial to developing effective screening strategies and reducing HCC-related mortality. DNA methylation is associated with gene inactivation and plays an important role in physiological and pathological processes; however, its role in cirrhosis progression to HCC is unknown.

Methods: We performed genome-wide DNA methylation profiling using Illumina Infinium MethylationEPI BeadChip in pre-diagnostic samples from 22 cirrhosis patients who subsequently developed HCC and 22 cirrhosis patients who remained HCC-free during an average 4-year follow-up. …

Foxr2 Targets Lhx6+/Dlx+ Neural Lineages To Drive Central Nervous System Neuroblastoma, Selin Jessa, Antonella De Cola, Bhavyaa Chandarana, Michael Mcnicholas, Steven Hébert, Adam Ptack, Damien Faury, Jessica W Tsai, Andrey Korshunov, Timothy N Phoenix, Benjamin Ellezam, David T W Jones, Michael D Taylor, Pratiti Bandopadhayay, Manav Pathania, Nada Jabado, Claudia L Kleinman

Faculty, Staff and Students Publications

Central nervous system neuroblastoma with forkhead box R2 (FOXR2) activation (NB-FOXR2) is a high-grade tumor of the brain hemispheres and a newly identified molecular entity. Tumors express dual neuronal and glial markers, leading to frequent misdiagnoses, and limited information exists on the role of FOXR2 in their genesis. To identify their cellular origins, we profiled the transcriptomes of NB-FOXR2 tumors at the bulk and single-cell levels and integrated these profiles with large single-cell references of the normal brain. NB-FOXR2 tumors mapped to LHX6+/DLX+ lineages derived from the medial ganglionic eminence, a progenitor domain in the ventral telencephalon. In vivo prenatal …

Spatial Distribution Of Tumor Cells In Clear Cell Renal Cell Carcinoma Is Associated With Metastasis And A Matrisome Gene Expression Signature, Prahlad Bhat, Pheroze Tamboli, Kanishka Sircar, Kasthuri Kannan

Faculty, Staff and Student Publications

Background/Objectives: Predicting the behavior of clear cell renal cell carcinoma (ccRCC) is challenging using standard-of-care histopathologic examination. Indeed, pathologic RCC tumor grading, based on nuclear morphology, performs poorly in predicting outcomes of patients with International Society of Urological Pathology/World Health Organization grade 2 and 3 tumors, which account for most ccRCCs.

Methods: We applied spatial point process modeling of H&E-stained images of patients with grade 2 and grade 3 ccRCCs (n = 72) to find optimum separation into two groups.

Results: One group was associated with greater spatial randomness and clinical metastasis (p < 0.01). Notably, spatial analysis outperformed standard pathologic grading in predicting clinical metastasis. Moreover, cell-to-cell interaction distances in the metastasis-associated group were significantly greater than those in the other patient group and were also greater than expected by the random distribution of cells. Differential gene expression between the two spatially defined groups of patients revealed a matrisome signature, consistent with the extracellular matrix's crucial role in tumor invasion. The top differentially expressed genes (with a fold change > 3) stratified a larger, multi-institutional …

Anti-Ctla-4 Generates Greater Memory Response Than Anti-Pd-1 Via Tcf-1, Stephen Mok, Huey Liu, Didem Ağaç Çobanoğlu, Nana-Ama A S Anang, James J Mancuso, E John Wherry, James P Allison

Faculty, Staff and Student Publications

The effects of T cell differentiation arising from immune checkpoint inhibition targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on the immunological memory response remain unclear. Our investigation into the effects of anti-CTLA-4 and anti-PD-1 on memory T cell formation in mice reveals that memory T cells generated by anti-CTLA-4 exhibit greater expansion, cytokine production, and antitumor activity than those from anti-PD-1. Notably, anti-CTLA-4 preserves more T cell factor-1 (TCF-1)+ T cells during priming, while anti-PD-1 leads to more thymocyte selection-associated high mobility group box (TOX)+ T cells. Experiments using conditional

Pre-Emptive Treatment For Cytomegalovirus Viraemia To Prevent Cytomegalovirus Disease In Solid Organ Transplant Recipients, Robin Wm Vernooij, Mini Michael, Julia Mt Colombijn, Daniel S Owers, Angela C Webster, Giovanni Fm Strippoli, Elisabeth M Hodson

Faculty, Staff and Students Publications

Background: Cytomegalovirus (CMV) is a significant cause of morbidity and death in solid organ transplant recipients. Pre-emptive treatment of patients with CMV viraemia using antiviral agents has been suggested as an alternative to routine prophylaxis to prevent CMV disease. This is an update of a Cochrane review first published in 2006 and updated in 2013.

Objectives: To determine the benefits and harms of pre-emptive treatment of CMV viraemia to prevent CMV disease and death (any cause) and the indirect effects of CMV infection (acute rejection, graft loss, opportunistic infections) in solid organ transplant recipients.

Search methods: The Cochrane Kidney and …

Surgical Outcomes And Associated Morbidity Of Active And Expectant Management Of Second-Trimester Placenta Accreta Spectrum (Pas), Jessian L Munoz, Rachel Counts, Amanda E Lacue, Kayla E Ireland, Patrick S Ramsey, Kristyn Brandi

Faculty, Staff and Students Publications

Background and Objectives: Management of second-trimester placenta accreta spectrum (PAS) is currently center-dependent with minimal evidence-based practices. This study aims to analyze outcomes of hysterectomy as second-trimester active management (AM) versus cesarean hysterectomy as expectant management (EM) in cases of PAS with intraoperative and postoperative outcomes. Materials and Methods: This study is a retrospective case-control study of patients with a pathology-confirmed diagnosis of PAS managed at a single center over 16 years (2005–2020). All cases were diagnosed during the first or second trimester by ultrasonography and managed by the same multidisciplinary team with delivery within the second trimester. Results: …

Zongertinib (Bi 1810631), An Irreversible Her2 Tki, Spares Egfr Signaling And Improves Therapeutic Response In Preclinical Models And Patients With Her2-Driven Cancers, Birgit Wilding, Lydia Woelflingseder, Anke Baum, Krzysztof Chylinski, Gintautas Vainorius, Neil Gibson, Irene C Waizenegger, Daniel Gerlach, Martin Augsten, Fiona Spreitzer, Yukina Shirai, Masachika Ikegami, Sylvia Tilandyová, Dirk Scharn, Mark A Pearson, Johannes Popow, Anna C Obenauf, Noboru Yamamoto, Shunsuke Kondo, Frans L Opdam, Annemarie Bruining, Shinji Kohsaka, Norbert Kraut, John V Heymach, Flavio Solca, Ralph A Neumüller

Faculty, Staff and Student Publications

Mutations in ERBB2 (encoding HER2) occur in 2% to 4% of non-small cell lung cancer (NSCLC) and confer poor prognosis. ERBB-targeting tyrosine kinase inhibitors, approved for treating other HER2-dependent cancers, are ineffective in HER2-mutant NSCLC due to dose-limiting toxicities or suboptimal potency. We report the discovery of zongertinib (BI 1810631), a covalent HER2 inhibitor. Zongertinib potently and selectively blocks HER2, while sparing EGFR, and inhibits the growth of cells dependent on HER2 oncogenic driver events, including HER2-dependent human cancer cells resistant to trastuzumab deruxtecan. Zongertinib displays potent antitumor activity in HER2-dependent human NSCLC xenograft models and enhances the activities of …

Neutrophil Extracellular Traps Promote Pre-Metastatic Niche Formation In The Omentum By Expanding Innate-Like B Cells That Express Il-10, Wonjae Lee, Song Yi Ko, Hironari Akasaka, Melanie Weigert, Ernst Lengyel, Honami Naora

Faculty, Staff and Student Publications

Disseminated cancer cells in the peritoneal fluid often colonize omental fat-associated lymphoid clusters but the mechanisms are unclear. Here, we identify that innate-like B cells accumulate in the omentum of mice and women with early-stage ovarian cancer concomitantly with the extrusion of chromatin fibers by neutrophils called neutrophil extracellular traps (NETs). Studies using genetically modified NET-deficient mice, pharmacologic inhibition of NETs, and adoptive B cell transfer show that NETs induce expression of the chemoattractant CXCL13 in the pre-metastatic omentum, stimulating recruitment of peritoneal innate-like B cells that in turn promote expansion of regulatory T cells and omental metastasis through producing …

Integrating Priorities At The Intersection Of Cancer And Neuroscience, William L Hwang, Ella N Perrault, Alexander Birbrair, Brandi J Mattson, David H Gutmann, Donald J Mabbott, Edna Cukierman, Elizabeth A Repasky, Erica K Sloan, Hui Zong, Ihsan Ekin Demir, Jami L Saloman, Jeremy C Borniger, Jian Hu, Jorg Dietrich, Joshua J Breunig, Kaan Çifcibaşı, Khalil Ali Ahmad Kasm, Manuel Valiente, Max Wintermark, Munjal M Acharya, Nicole N Scheff, Nisha J D'Silva, Paola D Vermeer, Richard J Wong, Sebastien Talbot, Shawn L Hervey-Jumper, Timothy C Wang, Yi Ye, Yuan Pan, Yuri L Bunimovich, Moran Amit

Faculty, Staff and Student Publications

Cancer neuroscience is a rapidly growing multidisciplinary field that conceptualizes tumors as tissues fully integrated into the nervous system. Recognizing the complexity and challenges in this field is of fundamental importance to achieving the goal of translational impact for cancer patients. Our commentary highlights key scientific priorities, optimal training settings, and roadblocks to translating scientific findings to the clinic in this emerging field, aiming to formulate a transformative and cohesive path forward.

Nerves At Play: The Peripheral Nervous System In Extracranial Malignancies, Paola D Vermeer, Anthony C Restaino, Jeffrey L Barr, Dan Yaniv, Moran Amit

Faculty, Staff and Student Publications

The exponential growth of the cancer neuroscience field has shown that the host's immune, vascular, and nervous systems communicate with and influence each other in the tumor microenvironment, dictating the cancer malignant phenotype. Unraveling the nervous system's contributions toward this phenotype brings us closer to cancer cures. In this review, we summarize the peripheral nervous system's contributions to cancer. We highlight the effects of nerve recruitment and tumor innervation, the neuro-immune axis, glial cell activity, and neural regulation on cancer development and progression. We also discuss harnessing the neural control of peripheral cancers as a potential therapeutic approach in oncology. …

Combined Kras Inhibition And Immune Therapy Generates Durable Complete Responses In An Autochthonous Pdac Model, Yonghong Liu, Jincheng Han, Wen-Hao Hsu, Kyle A Labella, Pingna Deng, Xiaoying Shang, Paulino Tallón De Lara, Li Cai, Shan Jiang, Ronald A Depinho

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy. In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. Here, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor for myeloid cells, antagonistic anti-LAG3 antibody for T cells, and agonistic anti-41BB antibody for dendritic cells. This combination elicited robust anti-tumor regression in iKPC mice bearing large autochthonous tumors. While untreated mice succumbed within 3 weeks, sustained treatment led to durable complete tumor regression and prolonged survival in …

Identification And Characterization Of A Novel Pavlovskyella (Acari: Argasidae) From Chile, Parasite Of The Culpeo Fox (Lycalopex Culpaeus), Sebastián Muñoz-Leal, Alexander R Kneubehl, Karen Ardiles, Catalina Parragué-Migone, Ignacio Troncoso-Toro, Pablo Oyarzún-Ruiz, Job E Lopez

Faculty, Staff and Students Publications

Soft ticks (Argasidae) of the subgenus Pavlovskyella Pospelova-Shtrom are worldwide distributed parasites of medical importance. However, the systematics of the subgenus are currently under debate because genetic data shows that the group is paraphyletic. Meanwhile, species of Pavlovskyella continue to be discovered. In this study a novel species of the subgenus is described from specimens collected on a fox in central Chile. The larva of this new species differentiates from other Pavlovskyella spp. by having the following combination of characters: subpyriform dorsal plate; 15 pairs of setae, 7 anterolateral, 3 central, and 5 posterolateral, and hypostome with denticles in the …

Lipid Nanoparticles Deliver Dna-Encoded Biologics And Induce Potent Protective Immunity, Dafei Chai, Junhao Wang, Jing Ming Lim, Xiaohui Xie, Xinfang Yu, Dan Zhao, Perry Ayn Mayson Maza, Yifei Wang, Dana Cyril-Remirez, Ken H Young, Yong Li

Faculty, Staff and Students Publications

Lipid nanoparticles (LNPs) for mRNA delivery have advanced significantly, but LNP-mediated DNA delivery still faces clinical challenges. This study compared various LNP formulations for delivering DNA-encoded biologics, assessing their expression efficacy and the protective immunity generated by LNP-encapsulated DNA in different models. The LNP formulation used in Moderna's Spikevax mRNA vaccine (LNP-M) demonstrated a stable nanoparticle structure, high expression efficiency, and low toxicity. Notably, a DNA vaccine encoding the spike protein, delivered via LNP-M, induced stronger antigen-specific antibody and T cell immune responses compared to electroporation. Single-cell RNA sequencing (scRNA-seq) analysis revealed that the LNP-M/pSpike vaccine enhanced CD80 activation signaling …

Infiltrating Plasma Cells Maintain Glioblastoma Stem Cells Through Igg-Tumor Binding, Jiancheng Gao, Danling Gu, Kailin Yang, Junxia Zhang, Qiankun Lin, Wei Yuan, Xu Zhu, Deobrat Dixit, Ryan C Gimple, Hao You, Qian Zhang, Zhumei Shi, Xiao Fan, Qiulian Wu, Chenfei Lu, Zhangchun Cheng, Daqi Li, Linjie Zhao, Bin Xue, Zhu Zhu, Zhe Zhu, Hui Yang, Ningwei Zhao, Wei Gao, Yingmei Lu, Junfei Shao, Chuandong Cheng, Dapeng Hao, Shuo Yang, Yun Chen, Xiaoming Wang, Chunsheng Kang, Jing Ji, Jianghong Man, Sameer Agnihotri, Qianghu Wang, Fan Lin, Xu Qian, Stephen C Mack, Zhibin Hu, Chaojun Li, Michael D Taylor, Yan Li, Nu Zhang, Jeremy N Rich, Yongping You, Xiuxing Wang

Faculty, Staff and Students Publications

Glioblastoma is a highly aggressive primary brain tumor with glioblastoma stem cells (GSCs) enforcing the intra-tumoral hierarchy. Plasma cells (PCs) are critical effectors of the B-lineage immune system, but their roles in glioblastoma remain largely unexplored. Here, we leverage single-cell RNA and B cell receptor sequencing of tumor-infiltrating B-lineage cells and reveal that PCs are aberrantly enriched in the glioblastoma-infiltrating B-lineage population, experience low level of somatic hypermutation, and are associated with poor prognosis. PCs secrete immunoglobulin G (IgG), which stimulates GSC proliferation via the IgG-FcγRIIA-AKT-mTOR axis. Disruption of IgG-FcγRIIA paracrine communication inhibits GSC proliferation and self-renewal. Glioblastoma-infiltrating PCs are …

Neurocognitive Outcomes And Functional Independence In Adult Survivors Of Childhood Medulloblastoma Diagnosed Over 3 Decades, Chiara Papini, Sedigheh Mirzaei, Mengqi Xing, Ingrid Tonning Olsson, Ralph Salloum, Peter M K De Blank, Katharine R Lange, Tricia Z King, Deokumar Srivastava, Wendy M Leisenring, Rebecca M Howell, Kevin C Oeffinger, Leslie L Robison, Gregory T Armstrong, Kevin R Krull, Tara M Brinkman

Faculty, Staff and Student Publications

Background: Treatment of childhood medulloblastoma has evolved to reduce neurotoxicity while improving survival. However, the impact of evolving therapies on late neurocognitive outcomes and adult functional independence remains unknown.

Methods: Adult survivors of childhood medulloblastoma (n = 505; median [minimum-maximum] age, 29 [18-46] years) and sibling controls (n = 727; 32 [18-58] years) from the Childhood Cancer Survivor Study completed surveys assessing neurocognitive problems and chronic health conditions (CHCs). Treatment exposures were categorized as historical (craniospinal irradiation [CSI] ≥ 30 Gy, no chemotherapy), standard-risk (CSI > 0 to < 30 Gy + chemotherapy) and high-risk (CSI ≥ 30 Gy + chemotherapy) therapy. Latent class analysis identified patterns of functional independence using employment, independent living, assistance with routine/personal care needs, driver's license, and marital/partner status. Multivariable models estimated the risk of neurocognitive impairment in survivors versus siblings and by treatment exposure group, and associations between neurocognitive impairment, CHCs, and functional independence.

Results: Survivors in each treatment exposure group had a 4- to 5-fold elevated …

Is Modulation Of Immune Checkpoints On Glioblastoma-Infiltrating Myeloid Cells A Viable Therapeutic Strategy?, Ruochen Du, Jianzhong Zhang, Rimas V Lukas, Shashwat Tripathi, Jared T Ahrendsen, Michael A Curran, Crismita Dmello, Peng Zhang, Roger Stupp, Ganesh Rao, Amy B Heimberger

Faculty, Staff and Students Publications

The field of immunology has traditionally focused on immune checkpoint modulation of adaptive immune cells. However, many malignancies such as glioblastoma are mostly devoid of T cells and rather are enriched with immunosuppressive myeloid cells of the innate immune system. While some immune checkpoint targets are shared between adaptive and innate immunity, myeloid-specific checkpoints could also serve as potential therapeutics. To better understand the impact of immune checkpoint blockade on myeloid cells, we systematically summarize the current literature focusing on the direct immunological effects of PD-L1/PD-1, CD24/Siglec-10, collagen/LAIR-1, CX3CL1/CX3CR1, and CXCL10/CXCR3. By synthesizing the molecular mechanisms and the translational implications, …

Conformational Switching Of Arp5 Subunit Regulates Ino80 Chromatin Remodeling, Shagun Shukla, Somnath Paul, Jeison Garcia, Yuan Zhong, Sara Sanz Juste, Karissa Beauchemin, Blaine Bartholomew

Faculty, Staff and Student Publications

The INO80 chromatin remodeler is a versatile enzyme capable of several functions, including spacing nucleosomes equal distances apart, precise positioning of nucleosomes based on DNA shape/sequence and exchanging histone dimers. Within INO80, the Arp5 subunit plays a central role in INO80 remodeling, evidenced by its interactions with the histone octamer, nucleosomal and extranucleosomal DNA, and its necessity in linking INO80's ATPase activity to nucleosome movement. We find two distinct regions of Arp5 binding near the acidic pocket of nucleosomes. One region has an arginine anchor that binds nucleosomes and is vital for INO80 mobilizing nucleosomes. The other region has a …

Pharmacological Or Genetic Inhibition Of Ltcc Promotes Cardiomyocyte Proliferation Through Inhibition Of Calcineurin Activity, Lynn A C Devilée, Abou Bakr M Salama, Jessica M Miller, Janice D Reid, Qinghui Ou, Nourhan M Baraka, Kamal Abou Farraj, Madiha Jamal, Yibing Nong, Todd K Rosengart, Douglas Andres, Jonathan Satin, Tamer M A Mohamed, James E Hudson, Riham R E Abouleisa

Faculty, Staff and Students Publications

Cardiomyocytes (CMs) lost during ischemic cardiac injury cannot be replaced due to their limited proliferative capacity. Calcium is an important signal transducer that regulates key cellular processes, but its role in regulating CM proliferation is incompletely understood. Here we show a robust pathway for new calcium signaling-based cardiac regenerative strategies. A drug screen targeting proteins involved in CM calcium cycling in human embryonic stem cell-derived cardiac organoids (hCOs) revealed that only the inhibition of L-Type Calcium Channel (LTCC) induced the CM cell cycle. Furthermore, overexpression of Ras-related associated with Diabetes (RRAD), an endogenous inhibitor of LTCC, induced CM cell cycle …

Hyperleukocytosis In A Neuroblastoma Patient After Treatment With Natural Killer T Cells Expressing A Gd2-Specific Chimeric Antigen Receptor And Il-15, Gengwen Tian, Amy N Courtney, Hangjin Yu, Saleh Bhar, Xin Xu, Gabriel A Barragán, Claudia Martinez Amador, Nisha Ghatwai, Michael S Wood, Deborah Schady, Antonino Montalbano, Shantan Reddy, Aoife M Roche, David De La Cerda, Donald Williams Parsons, Erica J Di Pierro, Frederic D Bushman, Andras Heczey, Leonid S Metelitsa

Faculty, Staff and Students Publications

The ability of immune cells to expand numerically after infusion distinguishes adoptive immunotherapies from traditional drugs, providing unique therapeutic advantages as well as the potential for unmanageable toxicities. Here, we describe a case of lethal hyperleukocytosis in a patient with neuroblastoma treated on phase 1 clinical trial (NCT03294954) with autologous natural killer T cells (NKTs) expressing a GD2-specific chimeric antigen receptor and cytokine interleukin 15 (GD2-CAR.15). This patient was the first to be treated on dose level (DL) 5 and the first patient whose product was restimulated with K562-derived artificial antigen-presenting cells (aAPCs) instead of autologous peripheral blood mononuclear cells …

Integrating Ctla-4/Pd-1 Blockade Into Cervical Cancer Management: Results Of Compassion-16, Jeffrey A How, Amir A Jazaeri

Faculty, Staff and Student Publications

Although there is anti-tumor efficacy of dual CTLA-4/PD-1 blockade in advanced/recurrent cervical cancer, it is unclear whether combination with chemotherapy is synergistic. In COMPASSION-16, Wu et al. demonstrated improved survival outcomes of cadolinimab plus chemotherapy compared to chemotherapy alone for first-line systemic therapy for advanced/recurrent cervical cancer, suggesting a potential role of bispecific CTLA-4/PD-1 inhibitors in the frontline setting.

Pembrolizumab Plus Chemotherapy In Frontline Treatment Of Advanced Ovarian Cancer: Clinical And Translational Results From A Phase 2 Trial, Jeffrey A How, Minghao Dang, Sanghoon Lee, Bryan Fellman, Shannon N Westin, Anil K Sood, Nicole D Fleming, Aaron Shafer, Ying Yuan, Jinsong Liu, Li Zhao, Joseph Celestino, Richard Hajek, Margaret B Morgan, Edwin R Parra, Caddie D Laberiano Fernandez, Claudio A Arrechedera, Luisa Maren Solis Soto, Kathleen M Schmeler, Alpa Nick, Karen H Lu, Robert Coleman, Linghua Wang, Amir A Jazaeri

Faculty, Staff and Student Publications

Background: The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood.

Methods: In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, …

Sitravatinib In Combination With Nivolumab Plus Ipilimumab In Patients With Advanced Clear Cell Renal Cell Carcinoma: A Phase 1 Trial, Pavlos Msaouel, Kai Yu, Ying Yuan, Jianfeng Chen, Xinmiao Yan, Menuka Karki, Fei Duan, Rahul A Sheth, Priya Rao, Kanishka Sircar, Amishi Y Shah, Amado J Zurita, Giannicola Genovese, Min Li, Chih-Chen Yeh, Minghao Dang, Guangchun Han, Yanshuo Chu, Max Hallin, Peter Olson, Rui Yang, Daniela Slavin, Hirak Der-Torossian, Curtis D Chin, Nizar M Tannir, Linghua Wang, Jianjun Gao

Faculty, Staff and Student Publications

We conducted a phase I trial to determine the optimal dose of triplet therapy with the tyrosine kinase inhibitor sitravatinib plus nivolumab plus ipilimumab in 22 previously untreated patients with advanced clear cell renal cell carcinoma. The primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), 1-year survival probability, and sitravatinib pharmacokinetics. Sitravatinib dose of 35 mg daily plus nivolumab 3 mg/kg and ipilimumab 1 mg/kg resulted in high frequency of immune-related adverse events. Subsequent dose reduction of ipilimumab to 0.7 mg/kg allowed safe …

Superstable Lipid Vacuoles Endow Cartilage With Its Shape And Biomechanics, Raul Ramos, Kim T Pham, Richard C Prince, Leith B Leiser-Miller, Maneeshi S Prasad, Xiaojie Wang, Rachel C Nordberg, Benjamin J Bielajew, Jerry C Hu, Kosuke Yamaga, Ji Won Oh, Tao Peng, Rupsa Datta, Aksana Astrowskaja, Axel A Almet, John T Burns, Yuchen Liu, Christian Fernando Guerrero-Juarez, Bryant Q Tran, Yi-Lin Chu, Anh M Nguyen, Tsai-Ching Hsi, Norman T-L Lim, Sandra Schoeniger, Ruiqi Liu, Yun-Ling Pai, Chella K Vadivel, Sandy Ingleby, Andrew E Mckechnie, Frank Van Breukelen, Kyle L Hoehn, John J Rasweiler, Michinori Kohara, William J Loughry, Scott H Weldy, Raymond Cosper, Chao-Chun Yang, Sung-Jan Lin, Kimberly L Cooper, Sharlene E Santana, Jeffrey E Bradley, Michael A Kiebish, Michelle Digman, David E James, Amy E Merrill, Qing Nie, Thomas F Schilling, Aliaksandr A Astrowski, Eric O Potma, Martín I García-Castro, Kyriacos A Athanasiou, Richard R Behringer, Maksim V Plikus

Faculty, Staff and Student Publications

Conventionally, the size, shape, and biomechanics of cartilages are determined by their voluminous extracellular matrix. By contrast, we found that multiple murine cartilages consist of lipid-filled cells called lipochondrocytes. Despite resembling adipocytes, lipochondrocytes were molecularly distinct and produced lipids exclusively through de novo lipogenesis. Consequently, lipochondrocytes grew uniform lipid droplets that resisted systemic lipid surges and did not enlarge upon obesity. Lipochondrocytes also lacked lipid mobilization factors, which enabled exceptional vacuole stability and protected cartilage from shrinking upon starvation. Lipid droplets modulated lipocartilage biomechanics by decreasing the tissue's stiffness, strength, and resilience. Lipochondrocytes were found in multiple mammals, including humans, …

Peripheral Extracellular Vesicles For Diagnosis And Prognosis Of Resectable Lung Cancer: The Lucex Study Protocol, Jorge Rodríguez-Sanz, Nadia Muñoz-González, José Pablo Cubero, Pablo Ordoñez, Victoria Gil, Raquel Langarita, Myriam Ruiz, Marta Forner, Marta Marín-Oto, Elisabet Vera, Pedro Baptista, Francesca Polverino, Juan Antonio Domingo, Javier García-Tirado, José María Marin, David Sanz-Rubio

Faculty, Staff and Students Publications

Background/Objectives: Lung cancer is the primary cause of cancer-related deaths. Most patients are typically diagnosed at advanced stages. Low-dose computed tomography (LDCT) has been proven to reduce lung cancer mortality, but screening programs using LDCT are associated with a high number of false positives and unnecessary thoracotomies. It is therefore imperative that a certain diagnosis is refined, especially in cases of solitary pulmonary nodules that are difficult to technically access for an accurate preoperative diagnosis. Extracellular vesicles (EVs) involved in intercellular communication may be an innovative biomarker for diagnosis and therapeutic strategies in lung cancer, regarding their ability to carry …

Molecular Dynamics At Immune Synapse Lipid Rafts Influence The Cytolytic Behavior Of Car T Cells, Ahmed Z Gad, Jessica S Morris, Lea Godret-Miertschin, Melisa J Montalvo, Sybrina S Kerr, Harrison Berger, Jessica C H Lee, Amr M Saadeldin, Mohammad H Abu-Arja, Shuo Xu, Spyridoula Vasileiou, Rebecca M Brock, Kristen Fousek, Mohamed F Sheha, Madhuwanti Srinivasan, Yongshuai Li, Arash Saeedi, Kandice R Levental, Ann M Leen, Maksim Mamonkin, Alexandre Carisey, Navin Varadarajan, Meenakshi Hegde, Sujith K Joseph, Ilya Levental, Malini Mukherjee, Nabil Ahmed

Faculty, Staff and Students Publications

Chimeric antigen receptor T cells (CART) targeting CD19 through CD28.ζ signaling induce rapid lysis of leukemic blasts, contrasting with persistent tumor control exhibited by 4-1BB.ζ-CART. We reasoned that molecular dynamics at the CART immune synapse (CARIS) could explain differences in their tumor rejection kinetics. We observed that CD28.ζ-CART engaged in brief highly lethal CARIS and mastered serial killing, whereas 4-1BB.ζ-CART formed lengthy CARIS and relied on robust expansion and cooperative killing. We analyzed CARIS membrane lipid rafts (mLRs) and found that, upon tumor engagement, CD28.ζ-CAR molecules rapidly but transiently translocated into mLRs, mobilizing the microtubular organizing center and lytic granules …

Functional Characterization Of Qt Interval Associated Scn5a Enhancer Variants Identify Combined Additive Effects, Lavanya Gunamalai, Parul Singh, Brian Berg, Leilei Shi, Ernesto Sanchez, Alexa Smith, Ghislain Breton, Mark T Bedford, Darius Balciunas, Ashish Kapoor

Faculty, Staff and Student Publications

Several empirical and theoretical studies suggest the presence of multiple enhancers per gene that collectively regulate gene expression, and that common sequence variation impacting on the activities of these enhancers is a major source of inter-individual gene expression variability. However, for the vast majority of genes, enhancers and the underlying regulatory variation remains unknown. Even for the genes with well-characterized enhancers, the nature of the combined effects from multiple enhancers and their variants, when known, on gene expression regulation remains unexplored. Here, we have evaluated the combined effects from five SCN5A enhancers and their regulatory variants that are known to …

A Phase Ia Study Of A Novel Anti-Her2 Antibody-Drug Conjugate Gq1001 In Patients With Previously Treated Her2 Positive Advanced Solid Tumors, Chenfei Zhou, Bin Wang, Christina Teng, Hui Yang, Sarina A Piha-Paul, Gary Richardson, Ashanya Malalasekera, Yajun Sun, Wei Wang, Jieqiong Liu, Yan Shi, Xianbao Zhan, Charlotte Lemech

Faculty, Staff and Student Publications

Background: A novel anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate (ADC) GQ1001 was assessed in patients with previously treated HER2 positive advanced solid tumors in a global multi-center phase Ia dose escalation trial.

Methods: In this phase Ia trial, a modified 3 + 3 study design was adopted during dose escalation phase. Eligible patients were enrolled, and GQ1001 monotherapy was administered intravenously every 3 weeks. The starting dose was 1.2 mg/kg, followed by 2.4, 3.6, 4.8, 6.0, 7.2 and 8.4 mg/kg. Extra patients were enrolled into 6.0, 7.2, and 8.4 mg/kg cohorts as dose expansion phase. The primary …

Alleviation Of Liver Fibrosis By Inhibiting A Non-Canonical Atf4-Regulated Enhancer Program In Hepatic Stellate Cells, Li-Xian Yang, Chuangye Qi, Si Lu, Xiang-Shi Ye, Parnaz Merikhian, Du-Yu Zhang, Tao Yao, Jiang-Sha Zhao, Ying Wu, Yongshi Jia, Bo Shan, Jinghai Chen, Xiaozhou Mou, Jia You, Wenbo Li, Yu-Xiong Feng

Faculty, Staff and Student Publications

Liver fibrosis is a critical liver disease that can progress to more severe manifestations, such as cirrhosis, yet no effective targeted therapies are available. Here, we identify that ATF4, a master transcription factor in ER stress response, promotes liver fibrosis by facilitating a stress response-independent epigenetic program in hepatic stellate cells (HSCs). Unlike its canonical role in regulating UPR genes during ER stress, ATF4 activates epithelial-mesenchymal transition (EMT) gene transcription under fibrogenic conditions. HSC-specific depletion of ATF4 suppresses liver fibrosis in vivo. Mechanistically, TGFβ resets ATF4 to orchestrate a unique enhancer program for the transcriptional activation of pro-fibrotic EMT genes. …

A Β-Hydroxybutyrate Shunt Pathway Generates Anti-Obesity Ketone Metabolites, Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L Li, Xuchao Lyu, Wei Wei, Alan Sheng-Hwa Tung, Steffen H Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine P Ward, Lichao Liu, Katrin J Svensson, Emily L Goldberg, Christopher D Gardner, Jonathan P Little, Steven M Banik, Yong Xu, Jonathan Z Long

Children’s Nutrition Research Center Staff Publications

β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit …