Digital Commons Network^™

Crispr-Cas9 And Cas12a Target Site Richness Reflects Genomic Diversity In Natural Populations Of Anopheles Gambiae And Aedes Aegypti Mosquitoes, Travis C Collier, Yoosook Lee, Derrick K Mathias, Víctor López Del Amo

Faculty, Staff and Student Publications

Due to limitations in conventional disease vector control strategies including the rise of insecticide resistance in natural populations of mosquitoes, genetic control strategies using CRISPR gene drive systems have been under serious consideration. The identification of CRISPR target sites in mosquito populations is a key aspect for developing efficient genetic vector control strategies. While genome-wide Cas9 target sites have been explored in mosquitoes, a precise evaluation of target sites focused on coding sequence (CDS) is lacking. Additionally, target site polymorphisms have not been characterized for other nucleases such as Cas12a, which require a different DNA recognition site (PAM) and would …

Biophysics Of Protein-Lipid Interactions, Paula A Bender, Vasanthi Jayaraman

Faculty, Staff and Student Publications

The biological phenomenon of protein-lipid interactions in cell membranes underlies the diversity of peripheral membrane protein function and physical properties of the membrane. To summarize novel findings in the field, this research highlight focuses on recent publications in Biophysical Journal.

Antitumor Activity Of A Pyrrolobenzodiazepine Antibody-Drug Conjugate Targeting Lgr5 In Preclinical Models Of Neuroblastoma, Jianghua Tu, Yukimatsu Toh, Adela M Aldana, Jake J Wen, Ling Wu, Joan Jacob, Li Li, Sheng Pan, Kendra S Carmon, Qingyun J Liu

Faculty, Staff and Student Publications

Neuroblastoma (NB) is a cancer of the peripheral nervous system found in children under 15 years of age. It is the most frequently diagnosed cancer during infancy, accounting for ~12% of all cancer-related deaths in children. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a membrane receptor that is associated with the primary tumor formation and metastasis of cancers in the gastrointestinal system. Remarkably, high levels of LGR5 are found in NB tumor cells, and high LGR5 expression is strongly correlated with poor survival. Antibody-drug conjugates (ADCs) are monoclonal antibodies that are covalently linked to cell-killing cytotoxins to deliver the payloads …

Learning To Express Reward Prediction Error-Like Dopaminergic Activity Requires Plastic Representations Of Time, Ian Cone, Claudia Clopath, Harel Z Shouval

Faculty, Staff and Student Publications

The dominant theoretical framework to account for reinforcement learning in the brain is temporal difference learning (TD) learning, whereby certain units signal reward prediction errors (RPE). The TD algorithm has been traditionally mapped onto the dopaminergic system, as firing properties of dopamine neurons can resemble RPEs. However, certain predictions of TD learning are inconsistent with experimental results, and previous implementations of the algorithm have made unscalable assumptions regarding stimulus-specific fixed temporal bases. We propose an alternate framework to describe dopamine signaling in the brain, FLEX (Flexibly Learned Errors in Expected Reward). In FLEX, dopamine release is similar, but not identical …

Emerging Biomedical And Clinical Applications Of 3d-Printed Poly(Lactic Acid)-Based Devices And Delivery Systems, Allan John R Barcena, Prashanth Ravi, Suprateek Kundu, Karthik Tappa

Faculty, Staff and Student Publications

Poly(lactic acid) (PLA) is widely used in the field of medicine due to its biocompatibility, versatility, and cost-effectiveness. Three-dimensional (3D) printing or the systematic deposition of PLA in layers has enabled the fabrication of customized scaffolds for various biomedical and clinical applications. In tissue engineering and regenerative medicine, 3D-printed PLA has been mostly used to generate bone tissue scaffolds, typically in combination with different polymers and ceramics. PLA's versatility has also allowed the development of drug-eluting constructs for the controlled release of various agents, such as antibiotics, antivirals, anti-hypertensives, chemotherapeutics, hormones, and vitamins. Additionally, 3D-printed PLA has recently been used …

Emergent Emm4 Group A Streptococcus Evidences A Survival Strategy During Interaction With Immune Effector Cells, Chioma M Odo, Luis A Vega, Piyali Mukherjee, Sruti Debroy, Anthony R Flores, Samuel A Shelburne

Faculty, Staff and Student Publications

The major gram-positive pathogen group A Streptococcus (GAS) is a model organism for studying microbial epidemics as it causes waves of infections. Since 1980, several GAS epidemics have been ascribed to the emergence of clones producing increased amounts of key virulence factors such as streptolysin O (SLO). Herein, we sought to identify mechanisms underlying our recently identified temporal clonal emergence among emm4 GAS, given that emergent strains did not produce augmented levels of virulence factors relative to historic isolates. By creating and analyzing isoallelic strains, we determined that a conserved mutation in a previously undescribed gene encoding a putative carbonic …

Clonal Hematopoiesis Driven By Mutated Dnmt3a Promotes Inflammatory Bone Loss, Hui Wang, Kimon Divaris, Bohu Pan, Xiaofei Li, Jong-Hyung Lim, Gundappa Saha, Marko Barovic, Danai Giannakou, Jonathan M Korostoff, Yu Bing, Souvik Sen, Kevin Moss, Di Wu, James D Beck, Christie M Ballantyne, Pradeep Natarajan, Kari E North, Mihai G Netea, Triantafyllos Chavakis, George Hajishengallis

Faculty, Staff and Student Publications

Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3a

The Multifaceted Role Of Neutrophils In Nsclc In The Era Of Immune Checkpoint Inhibitors, Shucheng Miao, Bertha Leticia Rodriguez, Don L Gibbons

Faculty, Staff and Student Publications

Lung cancer is the most common cause of cancer-related death in both males and females in the U.S. and non-small-cell lung cancer (NSCLC) accounts for 85%. Although the use of first- or second-line immune checkpoint inhibitors (ICIs) exhibits remarkable clinical benefits, resistance to ICIs develops over time and dampens the efficacy of ICIs in patients. Tumor-associated neutrophils (TANs) have an important role in modulating the tumor microenvironment (TME) and tumor immune response. The major challenge in the field is to characterize the TANs in NSCLC TME and understand the link between TAN-related immunosuppression with ICI treatment response. In this review, …

Tsg-6+ Cancer-Associated Fibroblasts Modulate Myeloid Cell Responses And Impair Anti-Tumor Response To Immune Checkpoint Therapy In Pancreatic Cancer, Swetha Anandhan, Shelley Herbrich, Sangeeta Goswami, Baoxiang Guan, Yulong Chen, Marc Daniel Macaluso, Sonali Jindal, Seanu Meena Natarajan, Samuel W Andrewes, Liangwen Xiong, Ashwat Nagarajan, Sreyashi Basu, Derek Ng Tang, Jielin Liu, Jimin Min, Anirban Maitra, Padmanee Sharma

Faculty, Staff and Student Publications

Resistance to immune checkpoint therapy (ICT) presents a growing clinical challenge. The tumor microenvironment (TME) and its components, namely tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), play a pivotal role in ICT resistance; however, the underlying mechanisms remain under investigation. In this study, we identify expression of TNF-Stimulated Factor 6 (TSG-6) in ICT-resistant pancreatic tumors, compared to ICT-sensitive melanoma tumors, both in mouse and human. TSG-6 is expressed by CAFs within the TME, where suppressive macrophages expressing Arg1, Mafb, and Mrc1, along with TSG-6 ligand Cd44, predominate. Furthermore, TSG-6 expressing CAFs co-localize with the CD44 expressing macrophages in the TME. …

Leukocyte Immunoglobulin-Like Receptor B1 (Lilrb1) Protects Human Multiple Myeloma Cells From Ferroptosis By Maintaining Cholesterol Homeostasis, Miao Xian, Qiang Wang, Liuling Xiao, Ling Zhong, Wei Xiong, Lingqun Ye, Pan Su, Chuanchao Zhang, Yabo Li, Robert Z Orlowski, Fenghuang Zhan, Siddhartha Ganguly, Youli Zu, Jianfei Qian, Qing Yi

Faculty, Staff and Student Publications

Multiple myeloma (MM) is a hematologic malignancy characterized by uncontrolled proliferation of plasma cells in the bone marrow. MM patients with aggressive progression have poor survival, emphasizing the urgent need for identifying new therapeutic targets. Here, we show that the leukocyte immunoglobulin-like receptor B1 (LILRB1), a transmembrane receptor conducting negative immune response, is a top-ranked gene associated with poor prognosis in MM patients. LILRB1 deficiency inhibits MM progression in vivo by enhancing the ferroptosis of MM cells. Mechanistic studies reveal that LILRB1 forms a complex with the low-density lipoprotein receptor (LDLR) and LDLR adapter protein 1 (LDLRAP1) to facilitate LDL/cholesterol …

Rna 2′-O-Methylation Promotes Persistent R-Loop Formation And Aid-Mediated Igh Class Switch Recombination, Muzaffer Ahmad Kassab, Yibin Chen, Xin Wang, Bo He, Eric J Brown, Xiaochun Yu

Faculty, Staff and Student Publications

BACKGROUND: RNA-DNA hybrids or R-loops are associated with deleterious genomic instability and protective immunoglobulin class switch recombination (CSR). However, the underlying phenomenon regulating the two contrasting functions of R-loops is unknown. Notably, the underlying mechanism that protects R-loops from classic RNase H-mediated digestion thereby promoting persistence of CSR-associated R-loops during CSR remains elusive.

RESULTS: Here, we report that during CSR, R-loops formed at the immunoglobulin heavy (IgH) chain are modified by ribose 2'-O-methylation (2'-OMe). Moreover, we find that 2'-O-methyltransferase fibrillarin (FBL) interacts with activation-induced cytidine deaminase (AID) associated snoRNA aSNORD1C to facilitate the 2'-OMe. Moreover, deleting AID C-terminal tail impairs …

Genes Related To Frontonasal Malformations Are Regulated By Mir-338-5p, Mir-653-5p, And Mir-374-5p In O9-1 Cells, Chihiro Iwaya, Sunny Yu, Junichi Iwata

Faculty, Staff and Student Publications

Frontonasal malformations are caused by a failure in the growth of the frontonasal prominence during development. Although genetic studies have identified genes that are crucial for frontonasal development, it remains largely unknown how these genes are regulated during this process. Here, we show that microRNAs, which are short non-coding RNAs capable of targeting their target mRNAs for degradation or silencing their expression, play a crucial role in the regulation of genes related to frontonasal development in mice. Using the Mouse Genome Informatics (MGI) database, we curated a total of 25 mouse genes related to frontonasal malformations, including frontonasal hypoplasia, frontonasal …

Impact Of Isotype On The Mechanism Of Action Of Agonist Anti-Ox40 Antibodies In Cancer: Implications For Therapeutic Combinations, Jane E Willoughby, Lang Dou, Sabyasachi Bhattacharya, Heather Jackson, Laura Seestaller-Wehr, David Kilian, Laura Bover, Kui S Voo, Kerry L Cox, Tom Murray, Mel John, Hong Shi, Paul Bojczuk, Junping Jing, Heather Niederer, Andrew J Shepherd, Laura Hook, Stephanie Hopley, Tatyana Inzhelevskaya, Chris A Penfold, C Ian Mockridge, Vikki English, Sara J Brett, Roopa Srinivasan, Christopher Hopson, James Smothers, Axel Hoos, Elaine Paul, Stephen L Martin, Peter J Morley, Niranjan Yanamandra, Mark S Cragg

Faculty, Staff and Student Publications

BACKGROUND: OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer.

METHODS: Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in …

Context-Dependent T-Box Transcription Factor Family: From Biology To Targeted Therapy, Siwen Li, Xiangyuan Luo, Mengyu Sun, Yijun Wang, Zerui Zhang, Junqing Jiang, Dian Hu, Jiaqian Zhang, Zhangfan Wu, Yufei Wang, Wenjie Huang, Limin Xia

Faculty, Staff and Student Publications

T-BOX factors belong to an evolutionarily conserved family of transcription factors. T-BOX factors not only play key roles in growth and development but are also involved in immunity, cancer initiation, and progression. Moreover, the same T-BOX molecule exhibits different or even opposite effects in various developmental processes and tumor microenvironments. Understanding the multiple roles of context-dependent T-BOX factors in malignancies is vital for uncovering the potential of T-BOX-targeted cancer therapy. We summarize the physiological roles of T-BOX factors in different developmental processes and their pathological roles observed when their expression is dysregulated. We also discuss their regulatory roles in tumor …

Antitumor Effects Of Resveratrol Opposing Mechanisms Of Helicobacter Pylori In Gastric Cancer, Daniela Trautmann, Francesca Suazo, Keila Torres, Layla Simón

Faculty, Staff and Student Publications

Gastric cancer is an aggressive and multifactorial disease. Helicobacter pylori (H. pylori) is identified as a significant etiological factor in gastric cancer. Although only a fraction of patients infected with H. pylori progresses to gastric cancer, bacterial infection is critical in the pathology and development of this malignancy. The pathogenic mechanisms of this bacterium involve the disruption of the gastric epithelial barrier and the induction of chronic inflammation, oxidative stress, angiogenesis and metastasis. Adherence molecules, virulence (CagA and VacA) and colonization (urease) factors are important in its pathogenicity. On the other hand, resveratrol is a natural polyphenol with …

Protein Sumoylation Promotes Camp-Independent Epac1 Activation, Wenli Yang, Fang C Mei, Wei Lin, Mark A White, Li Li, Yue Li, Sheng Pan, Xiaodong Cheng

Faculty, Staff and Student Publications

Protein SUMOylation is a prevalent stress-response posttranslational modification crucial for maintaining cellular homeostasis. Herein, we report that protein SUMOylation modulates cellular signaling mediated by cAMP, an ancient and universal stress-response second messenger. We identify K561 as a primary SUMOylation site in exchange protein directly activated by cAMP (EPAC1) via site-specific mapping of SUMOylation using mass spectrometry. Sequence and site-directed mutagenesis analyses reveal that a functional SUMO-interacting motif in EPAC1 is required for the binding of SUMO-conjugating enzyme UBC9, formation of EPAC1 nuclear condensate, and EPAC1 cellular SUMOylation. Heat shock-induced SUMO modification of EPAC1 promotes Rap1/2 activation in a cAMP-independent manner. …

Genetically Engineering Glycolysis In T Cells Increases Their Antitumor Function, Raphaëlle Toledano Zur, Orna Atar, Tilda Barliya, Shiran Hoogi, Ifat Abramovich, Eyal Gottlieb, Noga Ron-Harel, Cyrille J Cohen

Faculty, Staff and Student Publications

BACKGROUND: T cells play a central role in the antitumor response. However, they often face numerous hurdles in the tumor microenvironment, including the scarcity of available essential metabolites such as glucose and amino acids. Moreover, cancer cells can monopolize these resources to thrive and proliferate by upregulating metabolite transporters and maintaining a high metabolic rate, thereby outcompeting T cells.

METHODS: Herein, we sought to improve T-cell antitumor function in the tumor vicinity by enhancing their glycolytic capacity to better compete with tumor cells. To achieve this, we engineered human T cells to express a key glycolysis enzyme, phosphofructokinase, in conjunction …

Baseline Data Collections Of Lipopolysaccharide Content In 414 Herbal Extracts And Its Role In Innate Immune Activation, Vindy Tjendana Tjhin, Masataka Oda, Masashi Yamashita, Tomoko Iwaki, Yasuko Fujita, Koji Wakame, Hiroyuki Inagawa, Gen-Ichiro Soma

Faculty, Staff and Student Publications

Some herbal extracts contain relatively high amounts of lipopolysaccharide (LPS). Because orally administered LPS activates innate immunity without inducing inflammation, it plays a role as an active ingredient in herbal extracts. However, the LPS content in herbal extracts remains extensively unevaluated. This study aimed to create a database of LPS content in herbal extracts; therefore, the LPS content of 414 herbal extracts was measured and the macrophage activation potential was evaluated. The LPS content of these hot water extracts was determined using the kinetic-turbidimetric method. The LPS concentration ranged from a few ng/g to hundreds of μg/g (Standard Escherichia coli …

Influence Of Knot Strength On The Mechanical Performance Of A Biodegradable Gillnet, Louis Le Gué, Esther Savina, Mael Arhant, Peter Davies, Nicolas Dumergue, Benoit Vincent

Faculty, Staff and Student Publications

Ghost fishing is a global issue that can be addressed using fishing gear materials that do not persist in the marine environment. However, for these alternatives to be widely adopted, they must meet the same mechanical specifications as current commercial materials while degrading without any negative impact. The objective of this study was to compare a conventional gillnet made of polyamide 6 (PA6) with an alternative made of poly(butylene succinate-co-adipate-co-terephthalate) (PBSAT) at three different scales: monofilament, knot, and net. While the PBSAT monofilament's strength was half that of the conventional PA6 net, knot and net losses were even more significant. …

The Protective Efficacy Of A Sars-Cov-2 Vaccine Candidate B1351v Against Several Variant Challenges In K18-Hace2 Mice, Jie Yang, Huifen Fan, Anna Yang, Wenhui Wang, Xin Wan, Fengjie Lin, Dongsheng Yang, Jie Wu, Kaiwen Wang, Wei Li, Qian Cai, Lei You, Deqin Pang, Jia Lu, Changfu Guo, Jinrong Shi, Yan Sun, Xinguo Li, Kai Duan, Shuo Shen, Shengli Meng, Jing Guo, Zejun Wang

Faculty, Staff and Student Publications

The emergence of SARS-CoV-2 variants of concern (VOCs) with increased transmissibility and partial resistance to neutralization by antibodies has been observed globally. There is an urgent need for an effective vaccine to combat these variants. Our study demonstrated that the B.1.351 variant inactivated vaccine candidate (B.1.351V) generated strong binding and neutralizing antibody responses in BALB/c mice against the B.1.351 virus and other SARS-CoV-2 variants after two doses within 28 days. Immunized K18-hACE2 mice also exhibited elevated levels of live virus-neutralizing antibodies against various SARS-CoV-2 viruses. Following infection with these viruses, K18-hACE2 mice displayed a stable body weight, a high survival …

Controlled Delivery Of Rosuvastatin Or Rapamycin Through Electrospun Bismuth Nanoparticle-Infused Perivascular Wraps Promotes Arteriovenous Fistula Maturation, Allan John R Barcena, Joy Vanessa D Perez, Marvin R Bernardino, Erin Marie D San Valentin, Jossana A Damasco, Carleigh Klusman, Benjamin Martin, Karem A Court, Biana Godin, Gino Canlas, Natalie Fowlkes, Richard R Bouchard, Jizhong Cheng, Steven Y Huang, Marites P Melancon

Faculty, Staff and Student Publications

In the context of arteriovenous fistula (AVF) failure, local delivery enables the release of higher concentrations of drugs that can suppress neointimal hyperplasia (NIH) while reducing systemic adverse effects. However, the radiolucency of polymeric delivery systems hinders long-term in vivo surveillance of safety and efficacy. We hypothesize that using a radiopaque perivascular wrap to deliver anti-NIH drugs could enhance AVF maturation. Through electrospinning, we fabricated multifunctional perivascular polycaprolactone (PCL) wraps loaded with bismuth nanoparticles (BiNPs) for enhanced radiologic visibility and drugs that can attenuate NIH—rosuvastatin (Rosu) and rapamycin (Rapa). The following groups were tested onto the AVFs of a total …

Improving Laboratory Animal Genetic Reporting: Lag-R Guidelines, Lydia Teboul, James Amos-Landgraf, Fernando J Benavides, Marie-Christine Birling, Steve D M Brown, Elizabeth Bryda, Rosie Bunton-Stasyshyn, Hsian-Jean Chin, Martina Crispo, Fabien Delerue, Michael Dobbie, Craig L Franklin, Ernst-Martin Fuchtbauer, Xiang Gao, Christelle Golzio, Rebecca Haffner, Yann Hérault, Martin Hrabe De Angelis, Kevin C Kent Lloyd, Terry R Magnuson, Lluis Montoliu, Stephen A Murray, Ki-Hoan Nam, Lauryl M J Nutter, Eric Pailhoux, Fernando Pardo Manuel De Villena, Kevin Peterson, Laura Reinholdt, Radislav Sedlacek, Je Kyung Seong, Toshihiko Shiroishi, Cynthia Smith, Toru Takeo, Louise Tinsley, Jean-Luc Vilotte, Søren Warming, Sara Wells, C Bruce Whitelaw, Atsushi Yoshiki, Asian Mouse Mutagenesis Resource Association, Celphedia Infrastructure, Infrafrontier Consortium, International Mammalian Genome Society, International Mouse Phenotyping Consortium, International Society For Transgenic Technologies, Mutant Mouse Resource And Research Centers, Phenomics Australia, Rrrc- Rat Resource And Research Center, Guillaume Pavlovic

Faculty, Staff and Student Publications

The biomedical research community addresses reproducibility challenges in animal studies through standardized nomenclature, improved experimental design, transparent reporting, data sharing, and centralized repositories. The ARRIVE guidelines outline documentation standards for laboratory animals in experiments, but genetic information is often incomplete. To remedy this, we propose the Laboratory Animal Genetic Reporting (LAG-R) framework. LAG-R aims to document animals' genetic makeup in scientific publications, providing essential details for replication and appropriate model use. While verifying complete genetic compositions may be impractical, better reporting and validation efforts enhance reliability of research. LAG-R standardization will bolster reproducibility, peer review, and overall scientific rigor.

The Use Of Apparent Diffusion Coefficient Values For Differentiating Bevacizumab-Related Cytotoxicity From Tumor Recurrence And Radiation Necrosis In Glioblastoma, Kamand Khalaj, Michael A Jacobs, Jay-Jiguang Zhu, Yoshua Esquenazi, Sigmund Hsu, Nitin Tandon, Alireza Akhbardeh, Xu Zhang, Roy Riascos, Arash Kamali

Faculty, Staff and Student Publications

OBJECTIVES: Glioblastomas (GBM) are the most common primary invasive neoplasms of the brain. Distinguishing between lesion recurrence and different types of treatment related changes in patients with GBM remains challenging using conventional MRI imaging techniques. Therefore, accurate and precise differentiation between true progression or pseudoresponse is crucial in deciding on the appropriate course of treatment. This retrospective study investigated the potential of apparent diffusion coefficient (ADC) map values derived from diffusion-weighted imaging (DWI) as a noninvasive method to increase diagnostic accuracy in treatment response.

METHODS: A cohort of 21 glioblastoma patients (mean age: 59.2 ± 11.8, 12 Male, 9 Female) …

Post-Immunotherapy Ctla-4 Ig Treatment Improves Antitumor Efficacy, Stephen Mok, Didem Ağaç Çobanoğlu, Huey Liu, James J Mancuso, James P Allison

Faculty, Staff and Student Publications

Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4 Ig), an inhibitor of T cell costimulation through CD28, reverses irAEs in animal models. However, concerns exist about potentially compromising antitumor response of ICT. In mouse tumor models, we administered CTLA-4 Ig 1) concomitantly with ICT or 2) after ICT completion. Concomitant treatment reduced antitumor efficacy, while post-ICT administration improved efficacy without affecting frequency and function of CD8 T cells. The improved response was independent of the ICT used, whether …

Inhibition Of Malt1 And Bcl2 Induces Synergistic Antitumor Activity In Models Of B-Cell Lymphoma, Joshua P Plotnik, Adam E Richardson, Haopeng Yang, Estela Rojas, Velitchka Bontcheva, Colleen Dowell, Sydney Parsons, Ashley Wilson, Vida Ravanmehr, Christine Will, Paul Jung, Haizhong Zhu, Sarathy Karunan Partha, Sanjay C Panchal, Raghuveer Singh Mali, Frederick J Kohlhapp, Ryan A Mcclure, Cyril Y Ramathal, Mariam D George, Manisha Jhala, Nathaniel L Elsen, Wei Qiu, Russell A Judge, Chin Pan, Anthony Mastracchio, Jared Henderson, Jonathan A Meulbroek, Michael R Green, William N Pappano

Faculty, Staff and Student Publications

The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 …

Assessment Of Patient-Derived Xenograft Growth And Antitumor Activity: The Nci Pdxnet Consensus Recommendations, Funda Meric-Bernstam, Michael W Lloyd, Soner Koc, Yvonne A Evrard, Lisa M Mcshane, Michael T Lewis, Kurt W Evans, Dali Li, Lawrence Rubinstein, Alana Welm, Dennis A Dean, Anuj Srivastava, Jeffrey W Grover, Min J Ha, Huiqin Chen, Xuelin Huang, Kaushik Varadarajan, Jing Wang, Jack A Roth, Bryan Welm, Ramaswamy Govinden, Li Ding, Salma Kaochar, Nicholas Mitsiades, Luis Carvajal-Carmona, Meenhard Herylyn, Michael A Davies, Geoffrey I Shapiro, Ryan Fields, Jose G Trevino, Joshua C Harrell, Nci Pdxnet Consortium, James H Doroshow, Jeffrey H Chuang, Jeffrey A Moscow

Faculty, Staff and Student Publications

Although patient-derived xenografts (PDX) are commonly used for preclinical modeling in cancer research, a standard approach to in vivo tumor growth analysis and assessment of antitumor activity is lacking, complicating the comparison of different studies and determination of whether a PDX experiment has produced evidence needed to consider a new therapy promising. We present consensus recommendations for assessment of PDX growth and antitumor activity, providing public access to a suite of tools for in vivo growth analyses. We expect that harmonizing PDX study design and analysis and assessing a suite of analytical tools will enhance information exchange and facilitate identification …

Ultrapotent Broadly Neutralizing Human-Llama Bispecific Antibodies Against Hiv-1, Jianliang Xu, Tongqing Zhou, Krisha Mckee, Baoshan Zhang, Cuiping Liu, Alexandra F Nazzari, Amarendra Pegu, Chen-Hsiang Shen, Jordan E Becker, Michael F Bender, Payton Chan, Anita Changela, Ridhi Chaudhary, Xuejun Chen, Tal Einav, Young Do Kwon, Bob C Lin, Mark K Louder, Jonah S Merriam, Nicholas C Morano, Sijy O'Dell, Adam S Olia, Reda Rawi, Ryan S Roark, Tyler Stephens, I-Ting Teng, Emily Tourtellott-Fogt, Shuishu Wang, Eun Sung Yang, Lawrence Shapiro, Yaroslav Tsybovsky, Nicole A Doria-Rose, Rafael Casellas, Peter D Kwong

Faculty, Staff and Student Publications

Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV‐1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion‐stabilized HIV‐1 envelope (Env) trimer, BG505 DS‐SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4‐binding site (CD4bs) of vulnerability. Two of the vaccine‐elicited CD4bs‐targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a‐hinge region and human IgG1‐constant region (G36×3‐IgG2a and R27×3‐IgG2a), neutralized 96% of a multiclade 208‐strain panel at geometric mean IC80s of 0.314 and 0.033 µg mL−1, respectively. Cryo‐EM …

Targeting Of Cyp2e1 By Mirnas In Alcohol-Induced Intestine Injury, Hyejin Mun, Sungyul Lee, Suyoung Choi, Ji-Hoon Jeong, Seungbeom Ko, Yoo Lim Chun, Benjamin Deaton, Clay T Yeager, Audrey Boyette, Juliana Palmera, London Newman, Ping Zhou, Soona Shin, Dong-Chan Kim, Cari A Sagum, Mark T Bedford, Young-Kook Kim, Jaeyul Kwon, Junyang Jung, Jeong Ho Chang, Je-Hyun Yoon

Faculty, Staff and Student Publications

Although binge alcohol-induced gut leakage has been studied extensively in the context of reactive oxygen species-mediated signaling, it was recently revealed that post-transcriptional regulation plays an essential role as well. Ethanol (EtOH)-inducible cytochrome P450-2E1 (CYP2E1), a key enzyme in EtOH metabolism, promotes alcohol-induced hepatic steatosis and inflammatory liver disease, at least in part by mediating changes in intestinal permeability. For instance, gut leakage and elevated intestinal permeability to endotoxins have been shown to be regulated by enhancing CYP2E1 mRNA and CYP2E1 protein levels. Although it is understood that EtOH promotes CYP2E1 induction and activation, the mechanisms that regulate CYP2E1 expression …

Fc Engineering By Monoclonal Mammalian Cell Display For Improved Affinity And Selectivity Towards Fcγrs, Zening Wang, Minhyo Kang, Afshin Ebrahimpour, Chuan Chen, Xin Ge

Faculty, Staff and Student Publications

Fc optimization can significantly enhance therapeutic efficacy of monoclonal antibodies. However, existing Fc engineering approaches are sub-optimal with noted limitations, such as inappropriate glycosylation, polyclonal libraries, and utilizing fragment but not full-length IgG display. Applying cell cycle arrested recombinase-mediated cassette exchange, this study constructed high-quality monoclonal Fc libraries in CHO cells, displayed full-length IgG on cell surface, and preformed ratiometric fluorescence activated cell sorting (FACS) with the antigen and individual FcγRs. Identified Fc variants were quantitatively evaluated by flow cytometry, ELISA, kinetic and steady-state binding affinity measurements, and cytotoxicity assays. An error-prone Fc library focusing on the hinge-CH2 region was …

Epigenetic Regulation Of Heart Failure, Manisha Deogharia, Priyatansh Gurha

Faculty, Staff and Student Publications

Purpose of review: The studies on chromatin-modifying enzymes and how they respond to different stimuli within the cell have revolutionized our understanding of epigenetics. In this review, we provide an overview of the recent studies on epigenetic mechanisms implicated in heart failure.

Recent findings: We focus on the major mechanisms and the conceptual advances in epigenetics as evidenced by studies in humans and mouse models of heart failure. The significance of epigenetic modifications and the enzymes that catalyze them is also discussed. New findings from the studies of histone lysine demethylases demonstrate their significance in regulating fetal gene expression, as …