Digital Commons Network^™

Beyond The Global Brain Differences: Intraindividual Variability Differences In 1q211 Distal And 15q112 Bp1-Bp2 Deletion Carriers, Rune Boen, Tobias Kaufmann, Dennis Van Der Meer, Oleksandr Frei, Ingrid Agartz, David Ames, Micael Andersson, Nicola J Armstrong, Eric Artiges, Joshua R Atkins, Jochen Bauer, Francesco Benedetti, Dorret I Boomsma, Henry Brodaty, Katharina Brosch, Randy L Buckner, Murray J Cairns, Vince Calhoun, Svenja Caspers, Sven Cichon, Aiden P Corvin, Benedicto Crespo-Facorro, Udo Dannlowski, Friederike S David, Eco J C De Geus, Greig I De Zubicaray, Sylvane Desrivières, Joanne L Doherty, Gary Donohoe, Stefan Ehrlich, Else Eising, Thomas Espeseth, Simon E Fisher, Andreas J Forstner, Lidia Fortaner-Uyà, Vincent Frouin, Masaki Fukunaga, Tian Ge, David C Glahn, Janik Goltermann, Hans J Grabe, Melissa J Green, Nynke A Groenewold, Dominik Grotegerd, Gøril Rolfseng Grøntvedt, Tim Hahn, Ryota Hashimoto, Jayne Y Hehir-Kwa, Frans A Henskens, Avram J Holmes, Asta K Håberg, Jan Haavik, Sebastien Jacquemont, Andreas Jansen, Christiane Jockwitz, Erik G Jönsson, Masataka Kikuchi, Tilo Kircher, Kuldeep Kumar, Stephanie Le Hellard, Costin Leu, David E Linden, Jingyu Liu, Robert Loughnan, Karen A Mather, Katie L Mcmahon, Allan F Mcrae, Sarah E Medland, Susanne Meinert, Clara A Moreau, Derek W Morris, Bryan J Mowry, Thomas W Mühleisen, Igor Nenadić, Markus M Nöthen, Lars Nyberg, Roel A Ophoff, Michael J Owen, Christos Pantelis, Marco Paolini, Tomas Paus, Zdenka Pausova, Karin Persson, Yann Quidé, Tiago Reis Marques, Perminder S Sachdev, Sigrid B Sando, Ulrich Schall, Rodney J Scott, Geir Selbæk, Elena Shumskaya, Ana I Silva, Sanjay M Sisodiya, Frederike Stein, Dan J Stein, Benjamin Straube, Fabian Streit, Lachlan T Strike, Alexander Teumer, Lea Teutenberg, Anbupalam Thalamuthu, Paul A Tooney, Diana Tordesillas-Gutierrez, Julian N Trollor, Dennis Van 'T Ent, Marianne B M Van Den Bree, Neeltje E M Van Haren, Javier Vázquez-Bourgon, Henry Völzke, Wei Wen, Katharina Wittfeld, Christopher R K Ching, Lars T Westlye, Paul M Thompson, Carrie E Bearden, Kaja K Selmer, Dag Alnæs, Ole A Andreassen, Ida E Sønderby, Enigma-Cnv Working Group

Faculty, Staff and Student Publications

Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure.

Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., …

Armc5 Controls The Degradation Of Most Pol Ii Subunits, And Armc5 Mutation Increases Neural Tube Defect Risks In Mice And Humans, Hongyu Luo, Linjiang Lao, Kit Sing Au, Hope Northrup, Xiao He, Diane Forget, Marie-Soleil Gauthier, Benoit Coulombe, Isabelle Bourdeau, Wei Shi, Lucia Gagliardi, Maria Candida Barisson Villares Fragoso, Junzheng Peng, Jiangping Wu

Faculty, Staff and Student Publications

BACKGROUND: Neural tube defects (NTDs) are caused by genetic and environmental factors. ARMC5 is part of a novel ubiquitin ligase specific for POLR2A, the largest subunit of RNA polymerase II (Pol II).

RESULTS: We find that ARMC5 knockout mice have increased incidence of NTDs, such as spina bifida and exencephaly. Surprisingly, the absence of ARMC5 causes the accumulation of not only POLR2A but also most of the other 11 Pol II subunits, indicating that the degradation of the whole Pol II complex is compromised. The enlarged Pol II pool does not lead to generalized Pol II stalling or a generalized …

Small Needle-Knife Versus Extracorporeal Shock Wave Therapy For The Treatment Of Plantar Fasciitis: A Systematic Review And Meta-Analysis, Chaoqun Feng, Junjie Yao, Yizhou Xie, Min Zhao, Youpeng Hu, Ziang Hu, Ruoyan Li, Haoyang Wu, Yuanxin Ge, Fei Yang, Xiaohong Fan

Faculty, Staff and Student Publications

BACKGROUND: Plantar fasciitis (PF) is the most common cause of chronic heel pain among adults. Extracorporeal shock wave therapy (ESWT) is the recommended in the current guidelines, and the small needle-knife yields acceptable clinical effects for musculoskeletal pain.

OBJECTIVE: To systematically compare the efficacy of the small needle-knife versus ESWT for the treatment of PF.

METHODS: The present review was registered in the International Prospective Register of Systematic Reviews (i.e., "PROSPERO", CRD42023448813). Two of the authors searched electronic databases for randomized controlled trials (RCTs) comparing the small needle-knife versus ESWT for the treatment of PF, and collected outcomes including curative …

Increased Iron Uptake By Splenic Hematopoietic Stem Cells Promotes Tet2-Dependent Erythroid Regeneration, Yu-Jung Tseng, Yuki Kageyama, Rebecca L Murdaugh, Ayumi Kitano, Jong Hwan Kim, Kevin A Hoegenauer, Jonathan Tiessen, Mackenzie H Smith, Hidetaka Uryu, Koichi Takahashi, James F Martin, Md Abul Hassan Samee, Daisuke Nakada

Faculty, Staff and Student Publications

Hematopoietic stem cells (HSCs) are capable of regenerating the blood system, but the instructive cues that direct HSCs to regenerate particular lineages lost to the injury remain elusive. Here, we show that iron is increasingly taken up by HSCs during anemia and induces erythroid gene expression and regeneration in a Tet2-dependent manner. Lineage tracing of HSCs reveals that HSCs respond to hemolytic anemia by increasing erythroid output. The number of HSCs in the spleen, but not bone marrow, increases upon anemia and these HSCs exhibit enhanced proliferation, erythroid differentiation, iron uptake, and TET2 protein expression. Increased iron in HSCs promotes …

Large Scale Plasma Proteomics Identifies Novel Proteins And Protein Networks Associated With Heart Failure Development, Amil M Shah, Peder L Myhre, Victoria Arthur, Pranav Dorbala, Humaira Rasheed, Leo F Buckley, Brian Claggett, Guning Liu, Jianzhong Ma, Ngoc Quynh Nguyen, Kunihiro Matsushita, Chiadi Ndumele, Adrienne Tin, Kristian Hveem, Christian Jonasson, Håvard Dalen, Eric Boerwinkle, Ron C Hoogeveen, Christie Ballantyne, Josef Coresh, Torbjørn Omland, Bing Yu

Faculty, Staff and Student Publications

Heart failure (HF) causes substantial morbidity and mortality but its pathobiology is incompletely understood. The proteome is a promising intermediate phenotype for discovery of novel mechanisms. We measured 4877 plasma proteins in 13,900 HF-free individuals across three analysis sets with diverse age, geography, and HF ascertainment to identify circulating proteins and protein networks associated with HF development. Parallel analyses in Atherosclerosis Risk in Communities study participants in mid-life and late-life and in Trøndelag Health Study participants identified 37 proteins consistently associated with incident HF independent of traditional risk factors. Mendelian randomization supported causal effects of 10 on HF, HF risk …

Akt Enhances The Vulnerability Of Cancer Cells To Vcp/P97 Inhibition-Mediated Paraptosis, Dong Min Lee, In Young Kim, Hong Jae Lee, Min Ji Seo, Mi-Young Cho, Hae In Lee, Gyesoon Yoon, Jae-Hoon Ji, Seok Soon Park, Seong-Yun Jeong, Eun Kyung Choi, Yong Hyeon Choi, Chae-Ok Yun, Mirae Yeo, Eunhee Kim, Kyeong Sook Choi

Faculty, Staff and Student Publications

Valosin-containing protein (VCP)/p97, an AAA+ ATPase critical for maintaining proteostasis, emerges as a promising target for cancer therapy. This study reveals that targeting VCP selectively eliminates breast cancer cells while sparing non-transformed cells by inducing paraptosis, a non-apoptotic cell death mechanism characterized by endoplasmic reticulum and mitochondria dilation. Intriguingly, oncogenic HRas sensitizes non-transformed cells to VCP inhibition-mediated paraptosis. The susceptibility of cancer cells to VCP inhibition is attributed to the non-attenuation and recovery of protein synthesis under proteotoxic stress. Mechanistically, mTORC2/Akt activation and eIF3d-dependent translation contribute to translational rebound and amplification of proteotoxic stress. Furthermore, the ATF4/DDIT4 axis augments VCP …

Fecal Pharmacokinetics And Gut Microbiome Effects Of Oral Omadacycline Versus Vancomycin In Healthy Volunteers, Jinhee Jo, Chenlin Hu, Khurshida Begum, Weiqun Wang, Thanh M Le, Samantha Agyapong, Blake M Hanson, Hossaena Ayele, Chris Lancaster, M Jahangir Alam, Anne J Gonzales-Luna, Kevin W Garey

Faculty, Staff and Student Publications

BACKGROUND: Clostridioides difficile infection (CDI) is a common healthcare-associated infection with limited treatment options. Omadacycline, an aminomethylcycline tetracycline, has potent in vitro activity against C difficile and a low propensity to cause CDI in clinical trials. We aimed to assess fecal pharmacokinetics and gut microbiome effects of oral omadacycline compared to oral vancomycin in healthy adults.

METHODS: This was a phase 1, nonblinded, randomized clinical trial conducted in healthy volunteers aged 18-40 years. Subjects received a 10-day course of omadacycline or vancomycin. Stool samples were collected at baseline, daily during therapy, and at follow-up visits. Omadacycline and vancomycin stool concentrations …

Targeting Innate Immunity In Glioma Therapy, Andrew G Gillard, Dong Ho Shin, Lethan A Hampton, Andres Lopez-Rivas, Akhila Parthasarathy, Juan Fueyo, Candelaria Gomez-Manzano

Faculty, Staff and Student Publications

Currently, there is a lack of effective therapies for the majority of glioblastomas (GBMs), the most common and malignant primary brain tumor. While immunotherapies have shown promise in treating various types of cancers, they have had limited success in improving the overall survival of GBM patients. Therefore, advancing GBM treatment requires a deeper understanding of the molecular and cellular mechanisms that cause resistance to immunotherapy. Further insights into the innate immune response are crucial for developing more potent treatments for brain tumors. Our review provides a brief overview of innate immunity. In addition, we provide a discussion of current therapies …

Fbpp: Software To Design Pcr Primers And Probes For Nucleic Acid Base Detection Of Foodborne Pathogens, Mohamed A Soliman, Mohamed S Azab, Hala A Hussein, Mohamed M Roushdy, Mohamed N Abu El-Naga

Faculty, Staff and Student Publications

Foodborne pathogens can be found in various foods, and it is important to detect foodborne pathogens to provide a safe food supply and to prevent foodborne diseases. The nucleic acid base detection method is one of the most rapid and widely used methods in the detection of foodborne pathogens; it depends on hybridizing the target nucleic acid sequence to a synthetic oligonucleotide (probes or primers) that is complementary to the target sequence. Designing primers and probes for this method is a preliminary and critical step. However, new bioinformatics tools are needed to automate, specific and improve the design sets to …

Mendelian Randomization With Incomplete Measurements On The Exposure In The Hispanic Community Health Study/Study Of Latinos, Yilun Li, Kin Yau Wong, Annie Green Howard, Penny Gordon-Larsen, Heather M Highland, Mariaelisa Graff, Kari E North, Carolina G Downie, Christy L Avery, Bing Yu, Kristin L Young, Victoria L Buchanan, Robert Kaplan, Lifang Hou, Brian Thomas Joyce, Qibin Qi, Tamar Sofer, Jee-Young Moon, Dan-Yu Lin

Faculty, Staff and Student Publications

Mendelian randomization has been widely used to assess the causal effect of a heritable exposure variable on an outcome of interest, using genetic variants as instrumental variables. In practice, data on the exposure variable can be incomplete due to high cost of measurement and technical limits of detection. In this paper, we propose a valid and efficient method to handle both unmeasured and undetectable values of the exposure variable in one-sample Mendelian randomization analysis with individual-level data. We estimate the causal effect of the exposure variable on the outcome using maximum likelihood estimation and develop an expectation maximization algorithm for …

Multiplex Immunofluorescence Captures Progressive Immune Exhaustion With Advancing Penile Squamous Cell Cancer Stage, Filip Ionescu, Jonathan Nguyen, Carlos Moran Segura, Mahati Paravathaneni, G Daniel Grass, Peter Johnstone, Niki M Zacharias, Curtis A Pettaway, Xin Lu, Youngchul Kim, Junmin Whiting, Jasreman Dhillon, Steven A Eschrich, Juskaran Chadha, Keerthi Gullapalli, Gabriel Roman Souza, Hiroko Miyagi, Brandon J Manley, Philippe E Spiess, Jad Chahoud

Faculty, Staff and Student Publications

Penile squamous cell carcinoma (PSCC) is a rare and deadly malignancy. Therapeutic advances have been stifled by a poor understanding of disease biology. Specifically, the immune microenvironment is an underexplored component in PSCC and the activity of immune checkpoint inhibitors observed in a subset of patients suggests immune escape may play an important role in tumorigenesis. Herein, we explored for the first time the immune microenvironment of 57 men with PSCC and how it varies with the presence of human papillomavirus (HPV) infection and across tumor stages using multiplex immunofluorescence of key immune cell markers. We observed an increase in …

Covid-19 Convalescent Plasma Therapy Decreases Inflammatory Cytokines: A Randomized Controlled Trial, Feben Habtehyimer, Xianming Zhu, Andrew D Redd, Kelly A Gebo, Alison G Abraham, Eshan U Patel, Oliver Laeyendecker, Thomas J Gniadek, Reinaldo E Fernandez, Owen R Baker, Malathi Ram, Edward R Cachay, Judith S Currier, Yuriko Fukuta, Jonathan M Gerber, Sonya L Heath, Barry Meisenberg, Moises A Huaman, Adam C Levine, Aarthi Shenoy, Shweta Anjan, Janis E Blair, Daniel Cruser, Donald N Forthal, Laura L Hammitt, Seble Kassaye, Giselle S Mosnaim, Bela Patel, James H Paxton, Jay S Raval, Catherine G Sutcliffe, Matthew Abinante, Kevin S Oei, Valerie Cluzet, Marie Elena Cordisco, Benjamin Greenblatt, William Rausch, David Shade, Amy L Gawad, Sabra L Klein, Andrew Pekosz, Shmuel Shoham, Arturo Casadevall, Evan M Bloch, Daniel Hanley, Aaron A R Tobian, David J Sullivan

Faculty, Staff and Student Publications

This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

Reactivation Of The G1 Enhancer Landscape Underlies Core Circuitry Addiction To Swi/Snf, Katerina Cermakova, Ling Tao, Milan Dejmek, Michal Sala, Matthew D Montierth, Yuen San Chan, Ivanshi Patel, Courtney Chambers, Mario Loeza Cabrera, Dane Hoffman, Ronald J Parchem, Wenyi Wang, Radim Nencka, Eveline Barbieri, H Courtney Hodges

Faculty, Staff and Student Publications

Several cancer core regulatory circuitries (CRCs) depend on the sustained generation of DNA accessibility by SWI/SNF chromatin remodelers. However, the window when SWI/SNF is acutely essential in these settings has not been identified. Here we used neuroblastoma (NB) cells to model and dissect the relationship between cell-cycle progression and SWI/SNF ATPase activity. We find that SWI/SNF inactivation impairs coordinated occupancy of non-pioneer CRC members at enhancers within 1 hour, rapidly breaking their autoregulation. By precisely timing inhibitor treatment following synchronization, we show that SWI/SNF is dispensable for survival in S and G2/M, but becomes acutely essential only during G1 phase. …

Luminescence And Excited-State Reactivity In A Heteroleptic Tricyanido Fe(Iii) Complex, Yating Ye, Pablo Garrido-Barros, Joël Wellauer, Carlos M Cruz, Rodrigue Lescouëzec, Oliver S Wenger, Juan Manuel Herrera, Juan-Ramón Jiménez

Faculty, Staff and Student Publications

Harnessing sunlight via photosensitizing molecules is key for novel optical applications and solar-to-chemical energy conversion. Exploiting abundant metals such as iron is attractive but becomes challenging due to typically fast nonradiative relaxation processes. In this work, we report on the luminescence and excited-state reactivity of the heteroleptic [FeIII(pzTp)(CN)3]− complex (pzTp = tetrakis(pyrazolyl)borate), which incorporates a σ-donating trispyrazolyl chelate ligand and three monodentate σ-donating and π-accepting cyanide ligands. Contrary to the nonemissive [Fe(CN)6]3–, a broad emission band centered at 600 nm at room temperature has been recorded for the heteroleptic analogue attributed to the radiative deactivation from a 2LMCT excited state …

Delineating The Mechanism Of Fragility At Bcl6 Breakpoint Region Associated With Translocations In Diffuse Large B Cell Lymphoma, Vidya Gopalakrishnan, Urbi Roy, Shikha Srivastava, Khyati M Kariya, Shivangi Sharma, Saniya M Javedakar, Bibha Choudhary, Sathees C Raghavan

Faculty, Staff and Student Publications

BCL6 translocation is one of the most common chromosomal translocations in cancer and results in its enhanced expression in germinal center B cells. It involves the fusion of BCL6 with any of its twenty-six Ig and non-Ig translocation partners associated with diffuse large B cell lymphoma (DLBCL). Despite being discovered long back, the mechanism of BCL6 fragility is largely unknown. Analysis of the translocation breakpoints in 5' UTR of BCL6 reveals the clustering of most of the breakpoints around a region termed Cluster II. In silico analysis of the breakpoint cluster sequence identified sequence motifs that could potentially fold into …

Shaping The Future Of Global Access To Safe, Effective, Appropriate And Quality Health Products, Raffaella Ravinetto, Rodrigo Henriquez, Prashant N Srinivas, Hazel Bradley, Renier Coetzee, Theresa J Ochoa, Jean Claude Semuto Ngabonziza, Jean-Baptiste Mazarati, Wim Van Damme, Remco Van De Pas, Nico Vandaele, Els Torreele

Faculty, Staff and Student Publications

No abstract provided.

Effects Of Kras Genetic Interactions On Outcomes In Cancers Of The Lung, Pancreas, And Colorectum, Isabella N Grabski, John V Heymach, Kenneth L Kehl, Scott Kopetz, Ken S Lau, Gregory J Riely, Deborah Schrag, Rona Yaeger, Rafael A Irizarry, Kevin M Haigis

Faculty, Staff and Student Publications

Background: KRAS is among the most commonly mutated oncogenes in cancer, and previous studies have shown associations with survival in many cancer contexts. Evidence from both clinical observations and mouse experiments further suggests that these associations are allele- and tissue-specific. These findings motivate using clinical data to understand gene interactions and clinical covariates within different alleles and tissues.

Methods: We analyze genomic and clinical data from the AACR Project GENIE Biopharma Collaborative for samples from lung, colorectal, and pancreatic cancers. For each of these cancer types, we report epidemiological associations for different KRAS alleles, apply principal component analysis (PCA) to …

Synthetic Oct-A Blood Vessel Maps Using Fundus Images And Generative Adversarial Networks, Ashanul Haque, Mohd Wajid Ali Khan, Khalaf M Alenezi, Raoudha Soury, Muhammad S Khan, Shahzaib Ahamad, Md Mushtaque, Dinesh Gupta

Faculty, Staff and Student Publications

The design and development of new small-molecule glycation inhibitors are essential for preventing various chronic diseases, including diabetes mellitus, immunoinflammation, cardiovascular, and neurodegenerative diseases. 4-Thiazolidinone or thiazolidine-4-one is a well-known heterocyclic compound with the potential to inhibit the formation of advanced glycation end products. In the present work, we report the synthesis and characterization of four new 5-arylidene 3-cyclopropyl-2-(phenylimino)thiazolidin-4-one (1–4) compounds and their human serum albumin glycation inhibitory activity. One of the compounds 5-(2H-1,3-benzodioxol-5-ylmethylidene)-3-cyclopropyl-2-(phenylimino)-1,3-thiazolidin-4-one (3) showed potent inhibition in the synthesis of initial, intermediary, and final products of glycation reactions. Besides, conformational …

Modeling Methyl-Sensitive Transcription Factor Motifs With An Expanded Epigenetic Alphabet, Coby Viner, Charles A Ishak, James Johnson, Nicolas J Walker, Hui Shi, Marcela K Sjöberg-Herrera, Shu Yi Shen, Santana M Lardo, David J Adams, Anne C Ferguson-Smith, Daniel D De Carvalho, Sarah J Hainer, Timothy L Bailey, Michael M Hoffman

Faculty, Staff and Student Publications

BACKGROUND: Transcription factors bind DNA in specific sequence contexts. In addition to distinguishing one nucleobase from another, some transcription factors can distinguish between unmodified and modified bases. Current models of transcription factor binding tend not to take DNA modifications into account, while the recent few that do often have limitations. This makes a comprehensive and accurate profiling of transcription factor affinities difficult.

RESULTS: Here, we develop methods to identify transcription factor binding sites in modified DNA. Our models expand the standard A/C/G/T DNA alphabet to include cytosine modifications. We develop Cytomod to create modified genomic sequences and we also enhance …

Low-Level Resource Partitioning Supports Coexistence Among Functionally Redundant Bacteria During Successional Dynamics, Xiaoqian Annie Yu, Craig Mclean, Jan-Hendrik Hehemann, David Angeles-Albores, Fuqing Wu, Artur Muszyński, Christopher H Corzett, Parastoo Azadi, Elizabeth B Kujawinski, Eric J Alm, Martin F Polz

Faculty, Staff and Student Publications

Members of microbial communities can substantially overlap in substrate use. However, what enables functionally redundant microorganisms to coassemble or even stably coexist remains poorly understood. Here, we show that during unstable successional dynamics on complex, natural organic matter, functionally redundant bacteria can coexist by partitioning low-concentration substrates even though they compete for one simple, dominant substrate. We allowed ocean microbial communities to self-assemble on leachates of the brown seaweed Fucus vesiculosus and then analyzed the competition among 10 taxonomically diverse isolates representing two distinct stages of the succession. All, but two isolates, exhibited an average of 90% ± 6% pairwise …

Product Attributes Of Car T-Cell Therapy Differentially Associate With Efficacy And Toxicity In Second-Line Large B-Cell Lymphoma (Zuma-7), Simone Filosto, Saran Vardhanabhuti, Miguel A Canales, Xavier Poiré, Lazaros J Lekakis, Sven De Vos, Craig A Portell, Zixing Wang, Christina To, Marco Schupp, Soumya Poddar, Tan Trinh, Carmen M Warren, Ethan G Aguilar, Justin Budka, Paul Cheng, Justin Chou, Adrian Bot, Rhine R Shen, Jason R Westin

Faculty, Staff and Student Publications

Treatment resistance and toxicities remain a risk following chimeric antigen receptor (CAR) T-cell therapy. Herein, we report pharmacokinetics, pharmacodynamics, and product and apheresis attributes associated with outcomes among patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) in ZUMA-7. Axi-cel peak expansion associated with clinical response and toxicity, but not response durability. In apheresis material and final product, a naive T-cell phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved response durability, event-free survival, progression-free survival, and a lower number of prior therapies. This phenotype was not associated with high-grade cytokine release syndrome (CRS) or neurologic events. …

Gut Epithelial Interleukin-17 Receptor A Signaling Can Modulate Distant Tumors Growth Through Microbial Regulation, Vidhi Chandra, Le Li, Olivereen Le Roux, Yu Zhang, Rian M Howell, Dhwani N Rupani, Seyda Baydogan, Haiyan D Miller, Erick Riquelme, Joseph Petrosino, Michael P Kim, Krishna P L Bhat, James R White, Jay K Kolls, Yuliya Pylayeva-Gupta, Florencia Mcallister

Faculty, Staff and Student Publications

Microbes influence cancer initiation, progression and therapy responsiveness. IL-17 signaling contributes to gut barrier immunity by regulating microbes but also drives tumor growth. A knowledge gap remains regarding the influence of enteric IL-17-IL-17RA signaling and their microbial regulation on the behavior of distant tumors. We demonstrate that gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA induces growth of pancreatic and brain tumors due to excessive development of Th17, primary source of IL-17 in human and mouse pancreatic ductal adenocarcinoma, as well as B cells that circulate to distant tumors. Microbial dependent IL-17 signaling increases DUOX2 signaling in …

Comparison Of Energy Budget Of Cockroach Nymph (Hemimetabolous) And Hornworm (Holometabolous) Under Food Restriction, Charles J Green, Chen Hou

Faculty, Staff and Student Publications

Animals with different life histories budget their intake energy differently when food availability is low. It has been shown previously that hornworm (larva of Manduca sexta), a holometabolous insect species with a short development stage, prioritizes growth at the price of metabolism under food restriction, but it is unclear how hemimetabolous insect species with a relatively long development period budget their intake energy under food scarcity. Here, we use orange head cockroaches (Eublaberus posticus) to investigate this question. We found that for both species under food restriction, rates of metabolism and growth were suppressed, but the degree …

Drmref: Comprehensive Reference Map Of Drug Resistance Mechanisms In Human Cancer, Xiaona Liu, Jiahao Yi, Tina Li, Jianguo Wen, Kexin Huang, Jiajia Liu, Grant Wang, Pora Kim, Qianqian Song, Xiaobo Zhou

Faculty, Staff and Student Publications

Drug resistance poses a significant challenge in cancer treatment. Despite the initial effectiveness of therapies such as chemotherapy, targeted therapy and immunotherapy, many patients eventually develop resistance. To gain deep insights into the underlying mechanisms, single-cell profiling has been performed to interrogate drug resistance at cell level. Herein, we have built the DRMref database (https://ccsm.uth.edu/DRMref/) to provide comprehensive characterization of drug resistance using single-cell data from drug treatment settings. The current version of DRMref includes 42 single-cell datasets from 30 studies, covering 382 samples, 13 major cancer types, 26 cancer subtypes, 35 treatment regimens and 42 drugs. All datasets in …

Current And Future Therapeutic Strategies For High-Grade Gliomas Leveraging The Interplay Between Epigenetic Regulators And Kinase Signaling Networks, Lea M Stitzlein, Jack T Adams, Erin N Stitzlein, Richard W Dudley, Joya Chandra

Faculty, Staff and Student Publications

Targeted therapies, including small molecule inhibitors directed against aberrant kinase signaling and chromatin regulators, are emerging treatment options for high-grade gliomas (HGG). However, when translating these inhibitors into the clinic, their efficacy is generally limited to partial and transient responses. Recent studies in models of high-grade gliomas reveal a convergence of epigenetic regulators and kinase signaling networks that often cooperate to promote malignant properties and drug resistance. This review examines the interplay between five well-characterized groups of chromatin regulators, including the histone deacetylase (HDAC) family, bromodomain and extraterminal (BET)-containing proteins, protein arginine methyltransferase (PRMT) family, Enhancer of zeste homolog 2 …

Ageannomo: A Knowledgebase Of Multi-Omics Annotation For Animal Aging, Kexin Huang, Xi Liu, Zhaocan Zhang, Tiangang Wang, Haixia Xu, Qingxuan Li, Yuhao Jia, Liyu Huang, Pora Kim, Xiaobo Zhou

Faculty, Staff and Student Publications

Aging entails gradual functional decline influenced by interconnected factors. Multiple hallmarks proposed as common and conserved underlying denominators of aging on the molecular, cellular and systemic levels across multiple species. Thus, understanding the function of aging hallmarks and their relationships across species can facilitate the translation of anti-aging drug development from model organisms to humans. Here, we built AgeAnnoMO (https://relab.xidian.edu.cn/AgeAnnoMO/#/), a knowledgebase of multi-omics annotation for animal aging. AgeAnnoMO encompasses an extensive collection of 136 datasets from eight modalities, encompassing 8596 samples from 50 representative species, making it a comprehensive resource for aging and longevity research. AgeAnnoMO characterizes …

Sirtuin 2 Inhibition Modulates Chromatin Landscapes Genome-Wide To Induce Senescence In Atrx-Deficient Malignant Glioma, Prit Benny Malgulwar, Carla Danussi, Sharvari Dharmaiah, William Johnson, Anand Singh, Kunal Rai, Arvind Rao, Jason T Huse

Faculty, Staff and Student Publications

BACKGROUND: Functional inactivation of ATRX characterizes large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped.

METHODS: We utilized integrated multiomics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanism(s).

RESULTS: CMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (SIRT2) as a central mediator …

Fusionpdb:: A Knowledgebase Of Human Fusion Proteins, Himansu Kumar, Lin-Ya Tang, Chengyuan Yang, Pora Kim

Faculty, Staff and Student Publications

Tumorigenic functions due to the formation of fusion genes have been targeted for cancer therapeutics (i.e. kinase inhibitors). However, many fusion proteins involved in various cellular processes have not been studied for targeted therapeutics. This is because the lack of complete fusion protein sequences and their whole 3D structures has made it challenging to develop new therapeutic strategies. To fill these critical gaps, we developed a computational pipeline and a resource of human fusion proteins named FusionPDB, available at https://compbio.uth.edu/FusionPDB. FusionPDB is organized into four levels: 43K fusion protein sequences (14.7K in-frame fusion genes, Level 1), over 2300 + 1267 …

Surgical Management Of Choanal Atresia: Two Classic Cases And Review Of The Literature, Philipp Karschnia, Jorg Dietrich, Francesco Bruno, Antonio Dono, Stephanie T Juenger, Nico Teske, Jacob S Young, Tommaso Sciortino, Levin Häni, Martin Van Den Bent, Michael Weller, Michael A Vogelbaum, Ramin A Morshed, Alexander F Haddad, Annette M Molinaro, Nitin Tandon, Juergen Beck, Oliver Schnell, Lorenzo Bello, Shawn Hervey-Jumper, Niklas Thon, Stefan J Grau, Yoshua Esquenazi, Roberta Rudà, Susan M Chang, Mitchel S Berger, Daniel P Cahill, Joerg-Christian Tonn

Faculty, Staff and Student Publications

BACKGROUND: Resection of the contrast-enhancing (CE) tumor represents the standard of care in newly diagnosed glioblastoma. However, some tumors ultimately diagnosed as glioblastoma lack contrast enhancement and have a 'low-grade appearance' on imaging (non-CE glioblastoma). We aimed to (a) volumetrically define the value of non-CE tumor resection in the absence of contrast enhancement, and to (b) delineate outcome differences between glioblastoma patients with and without contrast enhancement.

METHODS: The RANO resect group retrospectively compiled a global, eight-center cohort of patients with newly diagnosed glioblastoma per WHO 2021 classification. The associations between postoperative tumor volumes and outcome were analyzed. Propensity score-matched …

Development Of A Rabbit Human Glioblastoma Model For Testing Of Endovascular Selective Intra-Arterial Infusion (Esia) Of Novel Stem Cell-Based Therapeutics, Peter Kan, Visish M Srinivasan, Joy Gumin, Roberto Garcia, Stephen R Chen, Jeremiah N Johnson, Dalis E Collins, Melissa M Chen, Daniel Ledbetter, Jason Huse, Zean Aaron Evan Luna, Ariadna Robledo, Viren Vasandani, Abhijit Rao, Sanjay K Singh, Elizabeth J Shpall, Juan Fueyo, Candelaria Gomez-Manzano, Frederick F Lang

Faculty, Staff and Student Publications

BACKGROUND: Endovascular selective intra-arterial (ESIA) infusion of cellular oncotherapeutics is a rapidly evolving strategy for treating glioblastoma. Evaluation of ESIA infusion requires a unique animal model. Our goal was to create a rabbit human GBM model to test IA infusions of cellular therapies and to test its usefulness by employing clinical-grade microcatheters and infusion methods to deliver mesenchymal stem cells loaded with an oncolytic adenovirus, Delta-24-RGD (MSC-D24).

METHODS: Rabbits were immunosuppressed with mycophenolate mofetil, dexamethasone, and tacrolimus. They underwent stereotactic xenoimplantation of human GBM cell lines (U87, MDA-GSC-17, and MDA-GSC-8-11) into the right frontal lobe. Tumor formation was confirmed on …