Digital Commons Network^™

Author Correction: Histone H2a Lys130 Acetylation Epigenetically Regulates Androgen Production In Prostate Cancer, Thanh Nguyen, Dhivya Sridaran, Surbhi Chouhan, Cody Weimholt, Audrey Wilson, Jingqin Luo, Tiandao Li, John Koomen, Bin Fang, Nagireddy Putluri, Arun Sreekumar, Felix Y Feng, Kiran Mahajan, Nupam P Mahajan

Faculty, Staff and Students Publications

No abstract provided.

Adjunctive Diagnostic Studies Completed Following Detection Of Candidemia In Children: Secondary Analysis Of Observed Practice From A Multicenter Cohort Study Conducted By The Pediatric Fungal Network, Rachel L Wattier, Robert F T Bucayu, Craig L K Boge, Rachael K Ross, Inci Yildirim, Theoklis E Zaoutis, Debra L Palazzi, Surabhi B Vora, Elio Castagnola, Martha Avilés-Robles, Lara Danziger-Isakov, Alison C Tribble, Tanvi S Sharma, Antonio C Arrieta, Gabriela Maron, David M Berman, Dwight E Yin, Lillian Sung, Michael Green, Emmanuel Roilides, Kiran Belani, José Romero, Pere Soler-Palacin, Eduardo López-Medina, Dawn Nolt, Ibrahim Zaid Bin Hussain, William J Muller, Sarmistha B Hauger, Natasha Halasa, Daniel Dulek, Alice Pong, Blanca E Gonzalez, Mark J Abzug, Fabianne Carlesse, Anna R Huppler, Sujatha Rajan, Catherine Aftandilian, Monica I Ardura, Arunaloke Chakrabarti, Benjamin Hanisch, Christine M Salvatore, Lena Klingspor, Elizabeth D Knackstedt, Irja Lutsar, Maria E Santolaya, Sydney Shuster, Sarah K Johnson, William J Steinbach, Brian T Fisher

Faculty, Staff and Students Publications

BACKGROUND: Adjunctive diagnostic studies (aDS) are recommended to identify occult dissemination in patients with candidemia. Patterns of evaluation with aDS across pediatric settings are unknown.

METHODS: Candidemia episodes were included in a secondary analysis of a multicenter comparative effectiveness study that prospectively enrolled participants age 120 days to 17 years with invasive candidiasis (predominantly candidemia) from 2014 to 2017. Ophthalmologic examination (OE), abdominal imaging (AbdImg), echocardiogram, neuroimaging, and lumbar puncture (LP) were performed per clinician discretion. Adjunctive diagnostic studies performance and positive results were determined per episode, within 30 days from candidemia onset. Associations of aDS performance with episode characteristics …

Differential Effects Of Pancreatic Cancer-Derived Extracellular Vesicles Driving A Suppressive Environment, Anurag Purushothaman, Jacqueline Oliva-Ramírez, Warapen Treekitkarnmongkol, Deivendran Sankaran, Mark W Hurd, Nagireddy Putluri, Anirban Maitra, Cara Haymaker, Subrata Sen

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) cells display extensive crosstalk with their surrounding environment to regulate tumor growth, immune evasion, and metastasis. Recent advances have attributed many of these interactions to intercellular communication mediated by small extracellular vesicles (sEVs), involving cancer-associated fibroblasts (CAF). To explore the impact of sEVs on monocyte lineage transition as well as the expression of checkpoint receptors and activation markers, peripheral blood monocytes from healthy subjects were exposed to PDAC-derived sEVs. Additionally, to analyze the role of sEV-associated HA in immune regulation and tissue-resident fibroblasts, monocytes and pancreatic stellate cells were cultured in the presence of PDAC sEVs …

Tmem27 Suppresses Tumor Development By Promoting Ret Ubiquitination, Positioning, And Degradation, Qianjin Guo, Zi-Ming Cheng, Hector Gonzalez-Cantú, Matthew Rotondi, Gabriela Huelgas-Morales, Purushoth Ethiraj, Zhijun Qiu, Jonathan Lefkowitz, Wan Song, Bethany N Landry, Hector Lopez, Cynthia M Estrada-Zuniga, Shivi Goyal, Mohammad Aasif Khan, Timothy J Walker, Exing Wang, Faqian Li, Yanli Ding, Lois M Mulligan, Ricardo C T Aguiar, Patricia L M Dahia

Faculty, Staff and Student Publications

The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell …

Axl-Initiated Paracrine Activation Of Pstat3 Enhances Mesenchymal And Vasculogenic Supportive Features Of Tumor-Associated Macrophages, Chia-Nung Hung, Meizhen Chen, Daniel T Dearmond, Cheryl H-L Chiu, Catherine A Limboy, Xi Tan, Meena Kusi, Chih-Wei Chou, Li-Ling Lin, Zhao Zhang, Chiou-Miin Wang, Chun-Liang Chen, Kohzoh Mitsuya, Pawel A Osmulski, Maria E Gaczynska, Nameer B Kirma, Ratna K Vadlamudi, Don L Gibbons, Steve Warner, Andrew J Brenner, Daruka Mahadevan, Joel E Michalek, Tim H-M Huang, Josephine A Taverna

Faculty, Staff and Student Publications

Tumor-associated macrophages (TAMs) are integral to the development of complex tumor microenvironments (TMEs) and can execute disparate cellular programs in response to extracellular cues. However, upstream signaling processes underpinning this phenotypic plasticity remain to be elucidated. Here, we report that concordant AXL-STAT3 signaling in TAMs is triggered by lung cancer cells or cancer-associated fibroblasts in the cytokine milieu. This paracrine action drives TAM differentiation toward a tumor-promoting "M2-like" phenotype with upregulation of CD163 and putative mesenchymal markers, contributing to TAM heterogeneity and diverse cellular functions. One of the upregulated markers, CD44, mediated by AXL-IL-11-pSTAT3 signaling cascade, enhances macrophage ability to …

A Peptide-Binding Domain Shared With An Antarctic Bacterium Facilitates, Cameron J Lloyd, Shuaiqi Guo, Brett Kinrade, Hossein Zahiri, Robert Eves, Syed Khalid Ali, Fitnat Yildiz, Ilja K Voets, Peter L Davies, Karl E Klose

Faculty, Staff and Student Publications

No abstract provided.

Setd2 Safeguards The Genome Against Isochromosome Formation, Frank M Mason, Emily S Kounlavong, Anteneh T Tebeje, Rashmi Dahiya, Tiffany Guess, Abid Khan, Logan Vlach, Stephen R Norris, Courtney A Lovejoy, Ruhee Dere, Brian D Strahl, Ryoma Ohi, Peter Ly, Cheryl Lyn Walker, W Kimryn Rathmell

Faculty, Staff and Students Publications

Isochromosomes are mirror-imaged chromosomes with simultaneous duplication and deletion of genetic material which may contain two centromeres to create isodicentric chromosomes. Although isochromosomes commonly occur in cancer and developmental disorders and promote genome instability, mechanisms that prevent isochromosomes are not well understood. We show here that the tumor suppressor and methyltransferase SETD2 is essential to prevent these errors. Using cellular and cytogenetic approaches, we demonstrate that loss of SETD2 or its epigenetic mark, histone H3 lysine 36 trimethylation (H3K36me3), results in the formation of isochromosomes as well as isodicentric and acentric chromosomes. These defects arise during DNA replication and are …

In Vivo Crispr/Cas9 Screening Identifies Pbrm1 As A Regulator Of Myeloid Leukemia Development In Mice, Bin E Li, Grace Y Li, Wenqing Cai, Qian Zhu, Davide Seruggia, Yuko Fujiwara, Christopher R Vakoc, Stuart H Orkin

Faculty, Staff and Students Publications

CRISPR/Cas9 screening approaches are powerful tool for identifying in vivo cancer dependencies. Hematopoietic malignancies are genetically complex disorders in which the sequential acquisition of somatic mutations generates clonal diversity. Over time, additional cooperating mutations may drive disease progression. Using an in vivo pooled gene editing screen of epigenetic factors in primary murine hematopoietic stem and progenitor cells (HSPCs), we sought to uncover unrecognized genes that contribute to leukemia progression. We, first, modeled myeloid leukemia in mice by functionally abrogating both Tet2 and Tet3 in HSPCs, followed by transplantation. We, then, performed pooled CRISPR/Cas9 editing of genes encoding epigenetic factors and …

Using Artificial Intelligence To Learn Optimal Regimen Plan For Alzheimer’S Disease, Kritib Bhattarai, Sivaraman Rajaganapathy, Trisha Das, Yejin Kim, Yongbin Chen, Alzheimer’S Disease Neuroimaging Initiative, Australian Imaging Biomarkers And Lifestyle Flagship Study Of Ageing, Qiying Dai, Xiaoyang Li, Xiaoqian Jiang, Nansu Zong

Faculty, Staff and Student Publications

BACKGROUND: Alzheimer's disease (AD) is a progressive neurological disorder with no specific curative medications. Sophisticated clinical skills are crucial to optimize treatment regimens given the multiple coexisting comorbidities in the patient population.

OBJECTIVE: Here, we propose a study to leverage reinforcement learning (RL) to learn the clinicians' decisions for AD patients based on the longitude data from electronic health records.

METHODS: In this study, we selected 1736 patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We focused on the two most frequent concomitant diseases-depression, and hypertension, thus creating 5 data cohorts (ie, Whole Data, AD, AD-Hypertension, AD-Depression, and AD-Depression-Hypertension). …

Dopamine Signaling From Ganglion Cells Directs Layer-Specific Angiogenesis In The Retina, Justine H Liang, Viktor Akhanov, Anthony Ho, Mohamed Tawfik, Shane P D'Souza, Morven A Cameron, Richard A Lang, Melanie A Samuel

Faculty, Staff and Students Publications

During central nervous system (CNS) development, a precisely patterned vasculature emerges to support CNS function. How neurons control angiogenesis is not well understood. Here, we show that the neuromodulator dopamine restricts vascular development in the retina via temporally limited production by an unexpected neuron subset. Our genetic and pharmacological experiments demonstrate that elevating dopamine levels inhibits tip-cell sprouting and vessel growth, whereas reducing dopamine production by all retina neurons increases growth. Dopamine production by canonical dopaminergic amacrine interneurons is dispensable for these events. Instead, we found that temporally restricted dopamine production by retinal ganglion cells (RGCs) modulates vascular development. RGCs …

Novel Genetic And Phenotypic Expansion In Gosr2-Related Progressive Myoclonus Epilepsy, Lea Hentrich, Mered Parnes, Timothy Edward Lotze, Rohini Coorg, Tom J De Koning, Kha M Nguyen, Calvin K Yip, Heinz Jungbluth, Anne Koy, Hormos Salimi Dafsari

Faculty, Staff and Students Publications

Biallelic variants in the Golgi SNAP receptor complex member 2 gene (GOSR2) have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report two novel patients from unrelated families with a GOSR2-related disorder and novel genetic and clinical findings. The first patient, a male compound heterozygous for the GOSR2 splice site variant c.336+1G>A and the novel c.364G>A,p.Glu122Lys missense variant showed global developmental delay and seizures at the age of 2 years, followed by myoclonus at the age …

Blockade Of Interferon Signaling Decreases Gut Barrier Integrity And Promotes Severe West Nile Virus Disease, Shih-Ching Lin, Fang R Zhao, Hana Janova, Adrian Gervais, Summer Rucknagel, Kristy O Murray, Jean-Laurent Casanova, Michael S Diamond

Faculty, Staff and Students Publications

The determinants of severe disease caused by West Nile virus (WNV) and why only ~1% of individuals progress to encephalitis remain poorly understood. Here, we use human and mouse enteroids, and a mouse model of pathogenesis, to explore the capacity of WNV to directly infect gastrointestinal (GI) tract cells and contribute to disease severity. At baseline, WNV poorly infects human and mouse enteroid cultures and enterocytes in mice. However, when STAT1 or type I interferon (IFN) responses are absent, GI tract cells become infected, and this is associated with augmented GI tract and blood-brain barrier (BBB) permeability, accumulation of gut-derived …

Transcriptomic Analysis Of Stem Cells From Chorionic Villi Uncovers The Impact Of Chromosomes 2, 6 And 22 In The Clinical Manifestations Of Down Syndrome, Salvatore Vaiasicca, Gianmarco Melone, David W James, Marcos Quintela, Alessandra Preziuso, Richard H Finnell, Robert Steven Conlan, Lewis W Francis, Bruna Corradetti

Faculty, Staff and Students Publications

BACKGROUND: Down syndrome (DS) clinical multisystem condition is generally considered the result of a genetic imbalance generated by the extra copy of chromosome 21. Recent discoveries, however, demonstrate that the molecular mechanisms activated in DS compared to euploid individuals are more complex than previously thought. Here, we utilize mesenchymal stem cells from chorionic villi (CV) to uncover the role of comprehensive functional genomics-based understanding of DS complexity.

METHODS: Next-generation sequencing coupled with bioinformatic analysis was performed on CV obtained from women carrying fetuses with DS (DS-CV) to reveal specific genome-wide transcriptional changes compared to their euploid counterparts. Functional assays were …

Overrepresented And Under Discussed: From Conceptual Analysis To Practical Implications For Crossover Among Black Girls, Karen M. Kolivoski, Alexandra Miller, Macon Stewart, Sherri Y. Simmons-Horton

Journal of Family Strengths

Crossover youth are young people who have experiences of maltreatment and exhibit delinquency, which may or may not come to the formal attention of the child welfare and juvenile justice systems. Black youth are overrepresented among the crossover youth population, and evidence suggests that Black girls who experience crossover are particularly in need of specialized attention. Black girls’ experiences within child welfare, juvenile justice, and related systems are unique given the intersection of race and gender in light of issues such as discrimination, disparate treatment, and abuse undergone while in the care of agencies touted to protect them. Guided by …

Social Vulnerability Of The People Exposed To Wildfires In Us West Coast States, Arash Modaresi Rad, John T Abatzoglou, Erica Fleishman, Miranda H Mockrin, Volker C Radeloff, Yavar Pourmohamad, Megan Cattau, J Michael Johnson, Philip Higuera, Nicholas J Nauslar, Mojtaba Sadegh

Faculty, Staff and Student Publications

Understanding of the vulnerability of populations exposed to wildfires is limited. We used an index from the U.S. Centers for Disease Control and Prevention to assess the social vulnerability of populations exposed to wildfire from 2000-2021 in California, Oregon, and Washington, which accounted for 90% of exposures in the western United States. The number of people exposed to fire from 2000-2010 to 2011-2021 increased substantially, with the largest increase, nearly 250%, for people with high social vulnerability. In Oregon and Washington, a higher percentage of exposed people were highly vulnerable (>40%) than in California (~8%). Increased social vulnerability of …

Applications Of Degradable Hydrogels In Novel Approaches To Disease Treatment And New Modes Of Drug Delivery, Bo Hu, Jinyuan Gao, Yu Lu, Yuji Wang

Faculty, Staff and Student Publications

Hydrogels are particularly suitable materials for loading drug delivery agents; their high water content provides a biocompatible environment for most biomolecules, and their cross-linked nature protects the loaded agents from damage. During delivery, the delivered substance usually needs to be released gradually over time, which can be achieved by degradable cross-linked chains. In recent years, biodegradable hydrogels have become a promising technology in new methods of disease treatment and drug delivery methods due to their many advantageous properties. This review briefly discusses the degradation mechanisms of different types of biodegradable hydrogel systems and introduces the specific applications of degradable hydrogels …

Comparative Genomics Analysis Of Three Conserved Plasmid Families In The Western Hemisphere Soft Tick-Borne Relapsing Fever Borreliae Provides Insight Into Variation In Genome Structure And Antigenic Variation Systems, Alexander R Kneubehl, Job E Lopez

Faculty, Staff and Students Publications

Borrelia spirochetes, causative agents of Lyme disease and relapsing fever (RF), have uniquely complex genomes, consisting of a linear chromosome and both circular and linear plasmids. The plasmids harbor genes important for the vector-host life cycle of these tick-borne bacteria. The role of plasmids from Lyme disease causing spirochetes is more refined compared to RF Borrelia because of limited plasmid-resolved genome assemblies for the latter. We recently addressed this limitation and found that three linear plasmid families (F6, F27, and F28) were syntenic across all the RF Borrelia species that we examined. Given this conservation, we further investigated the three …

Ms 106 Guide To Ferid Murad, Md, Phd Papers (1959-1996), Ferid Murad (1936-2023)

Manuscript Finding Aids

The Ferid Murad, MD papers consists of fifiteen handwritten notebooks documenting Dr. Ferid Murad's research. The notebooks include research data presented in tables and charts, as well as Dr. Murad's notes. The notebooks span the years 1959-1970. In addition, the collection includes a small number of printed materials from organizations of which Dr. Murad was a part. Notably, there are manuals from his internship and residency at Massachusetts General Hospital, dating around 1965. See more at MS 106.

Response Patterns And Impact Of Mrd In Patients With Idh1/2-Mutated Aml Treated With Venetoclax And Hypomethylating Agents, Danielle Hammond, Sanam Loghavi, Sa A Wang, Marina Y Konopleva, Tapan M Kadia, Naval G Daver, Maro Ohanian, Ghayas C Issa, Yesid Alvarado, Nicholas J Short, Koji Sasaki, Naveen Pemmaraju, Guillermo Montalban-Bravo, Curtis A Lachowiez, Abhishek Maiti, Guillermo Garcia-Manero, Elias J Jabbour, Gautam Borthakur, Farhad Ravandi, Koichi Takahashi, Sherry R Pierce, Hagop M Kantarjian, Courtney D Dinardo

Faculty, Staff and Student Publications

No abstract provided.

Boosting Glycolysis To Combat Fragile Bone In Type 1 Diabetes, Zixue Jin, Brendan Lee

Faculty, Staff and Students Publications

Individuals with type 1 diabetes (T1D) have an increased risk of osteoporosis and fracture. In this issue of Cell Chemical Biology, Ji et al.1 show that impaired glucose metabolism in the bone-forming osteoblast drives diabetic osteoporosis in Akita mice, a mouse model of T1D.

Researching The Future: Scenarios To Explore The Future Of Human Genome Editing, Cynthia Selin, Lauren Lambert, Stephanie Morain, John P Nelson, Dorit Barlevy, Mahmud Farooque, Haley Manley, Christopher T Scott

Center for Medical Ethics and Health Policy Staff Publications

Background: Forward-looking, democratically oriented governance is needed to ensure that human genome editing serves rather than undercuts public values. Scientific, policy, and ethics communities have recognized this necessity but have demonstrated limited understanding of how to fulfill it. The field of bioethics has long attempted to grapple with the unintended consequences of emerging technologies, but too often such foresight has lacked adequate scientific grounding, overemphasized regulation to the exclusion of examining underlying values, and failed to adequately engage the public.

Methods: This research investigates the application of scenario planning, a tool developed in the high-stakes, uncertainty-ridden world of corporate strategy, …

Systematic Investigation Of The Homology Sequences Around The Human Fusion Gene Breakpoints In Pan-Cancer – Bioinformatics Study For A Potential Link To Mmej, Pora Kim, Himansu Kumar, Chengyuan Yang, Ruihan Luo, Jiajia Liu, Xiaobo Zhou

Faculty, Staff and Student Publications

Microhomology-mediated end joining (MMEJ), an error-prone DNA damage repair mechanism, frequently leads to chromosomal rearrangements due to its ability to engage in promiscuous end joining of genomic instability and also leads to increasing mutational load at the sequences flanking the breakpoints (BPs). In this study, we systematically investigated the homology sequences around the genomic breakpoint area of human fusion genes, which were formed by the chromosomal rearrangements initiated by DNA double-strand breakage. Since the RNA-seq data is the typical data set to check the fusion genes, for the known exon junction fusion breakpoints identified from RNA-seq data, we have to …

Critical Functions Of Extracellular Matrix In Brain Metastasis Seeding, Arseniy E Yuzhalin, Dihua Yu

Faculty, Staff and Student Publications

Human brain is characterized by extremely sparse extracellular matrix (ECM). Despite its low abundance, the significance of brain ECM in both physiological and pathological conditions should not be underestimated. Brain metastasis is a serious complication of cancer, and recent findings highlighted the contribution of ECM in brain metastasis development. In this review, we provide a comprehensive outlook on how ECM proteins promote brain metastasis seeding. In particular, we discuss (1) disruption of the blood-brain barrier in brain metastasis; (2) role of ECM in modulating brain metastasis dormancy; (3) regulation of brain metastasis seeding by ECM-activated integrin signaling; (4) functions of …

Systematic Investigation Of The Homology Sequences Around The Human Fusion Gene Breakpoints In Pan-Cancer - Bioinformatics Study For A Potential Link To Mmej, Pora Kim, Himansu Kumar, Chengyuan Yang, Ruihan Luo, Jiajia Liu, Xiaobo Zhou

Faculty, Staff and Student Publications

Microhomology-mediated end joining (MMEJ), an error-prone DNA damage repair mechanism, frequently leads to chromosomal rearrangements due to its ability to engage in promiscuous end joining of genomic instability and also leads to increasing mutational load at the sequences flanking the breakpoints (BPs). In this study, we systematically investigated the homology sequences around the genomic breakpoint area of human fusion genes, which were formed by the chromosomal rearrangements initiated by DNA double-strand breakage. Since the RNA-seq data is the typical data set to check the fusion genes, for the known exon junction fusion breakpoints identified from RNA-seq data, we have to …

Cumulative Incidence Of Physical And Sexual Dating Violence: Insights From A Long-Term Longitudinal Study, Jeff R Temple, Elizabeth Baumler, Leila Wood, Kelli Sargent Franco, Melissa Peskin, Christie Shumate

Faculty, Staff and Student Publications

Decades of inquiry on intimate partner violence show consistent results: violence is woefully common and psychologically and economically costly. Policy to prevent and effectively intervene upon such violence hinges upon comprehensive understanding of this phenomenon at a population level. The current study prospectively estimates the cumulative incidence of sexual and physical dating violence (DV) victimization/perpetration over a 12-year timeframe (2010–2021) using diverse participants assessed annually from age 15 to 26. Data are from Waves 1–13 of an ongoing longitudinal study. Since 2010 (except for 2018 and 2019), participants were assessed on past-year physical and sexual DV victimization and perpetration. Participants …

Polygenic Risk And Chemotherapy-Related Subsequent Malignancies In Childhood Cancer Survivors: A Childhood Cancer Survivor Study And St Jude Lifetime Cohort Study Report, Cindy Im, Noha Sharafeldin, Yan Yuan, Zhaoming Wang, Yadav Sapkota, Zhanni Lu, Logan G Spector, Rebecca M Howell, Michael A Arnold, Melissa M Hudson, Kirsten K Ness, Leslie L Robison, Smita Bhatia, Gregory T Armstrong, Joseph P Neglia, Yutaka Yasui, Lucie M Turcotte

Faculty, Staff and Student Publications

Purpose: Chemotherapeutic exposures are associated with subsequent malignant neoplasm (SMN) risk. The role of genetic susceptibility in chemotherapy-related SMNs should be defined as use of radiation therapy (RT) decreases.

Patients and methods: SMNs among long-term childhood cancer survivors of European (EUR; N = 9,895) and African (AFR; N = 718) genetic ancestry from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study were evaluated. An externally validated 179-variant polygenic risk score (PRS) associated with pleiotropic adult cancer risk from the UK Biobank Study (N > 400,000) was computed for each survivor. SMN cumulative incidence comparing top and bottom PRS …

Nlrp3 Selectively Drives Il-1Β Secretion By Pseudomonas Aeruginosa Infected Neutrophils And Regulates Corneal Disease Severity, Martin S Minns, Karl Liboro, Tatiane S Lima, Serena Abbondante, Brandon A Miller, Michaela E Marshall, Jolynn Tran Chau, Alicia Roistacher, Arne Rietsch, George R Dubyak, Eric Pearlman

Faculty, Staff and Student Publications

Macrophages infected with Gram-negative bacteria expressing Type III secretion system (T3SS) activate the NLRC4 inflammasome, resulting in Gasdermin D (GSDMD)-dependent, but GSDME independent IL-1β secretion and pyroptosis. Here we examine inflammasome signaling in neutrophils infected with Pseudomonas aeruginosa strain PAO1 that expresses the T3SS effectors ExoS and ExoT. IL-1β secretion by neutrophils requires the T3SS needle and translocon proteins and GSDMD. In macrophages, PAO1 and mutants lacking ExoS and ExoT (ΔexoST) require NLRC4 for IL-1β secretion. While IL-1β release from ΔexoST infected neutrophils is also NLRC4-dependent, infection with PAO1 is instead NLRP3-dependent and driven by the ADP ribosyl transferase activity …

Chronic Cough Relief By Allosteric Modulation Of P2x3 Without Taste Disturbance, Chang-Run Guo, Zhong-Zhe Zhang, Xing Zhou, Meng-Yang Sun, Tian-Tian Li, Yun-Tao Lei, Yu-Hao Gao, Qing-Quan Li, Chen-Xi Yue, Yu Gao, Yi-Yu Lin, Cui-Yun Hao, Chang-Zhu Li, Peng Cao, Michael X Zhu, Ming-Qiang Rong, Wen-Hui Wang, Ye Yu

Faculty, Staff and Student Publications

P2X receptors are cation channels that sense extracellular ATP. Many therapeutic candidates targeting P2X receptors have begun clinical trials or acquired approval for the treatment of refractory chronic cough (RCC) and other disorders. However, the present negative allosteric modulation of P2X receptors is primarily limited to the central pocket or the site below the left flipper domain. Here, we uncover a mechanism of allosteric regulation of P2X3 in the inner pocket of the head domain (IP-HD), and show that the antitussive effects of quercetin and PSFL2915 (our nM-affinity P2X3 inhibitor optimized based on quercetin) on male mice and guinea pigs …

Standardized Definitions For Efficacy End Points In Neoadjuvant Breast Cancer Clinical Trials: Neosteep, Jennifer K Litton, Meredith M Regan, Lajos Pusztai, Hope S Rugo, Sara M Tolaney, Elizabeth Garrett-Mayer, Laleh Amiri-Kordestani, Reva K Basho, Ana F Best, Jean-Francois Boileau, Carsten Denkert, Jared C Foster, Nadia Harbeck, Heather A Jacene, Tari A King, Ginny Mason, Ciara C O'Sullivan, Tatiana M Prowell, Andrea L Richardson, Karla A Sepulveda, Mary Lou Smith, Judy A Tjoe, Gulisa Turashvili, Wendy A Woodward, Lynn Pearson Butler, Elena I Schwartz, Larissa A Korde

Faculty, Staff and Student Publications

PURPOSE: The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points.

METHODS: The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes-both pathologic and time-to-event survival end points-particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at …

A Proteogenomics Data-Driven Knowledge Base Of Human Cancer, Yuxing Liao, Sara R Savage, Yongchao Dou, Zhiao Shi, Xinpei Yi, Wen Jiang, Jonathan T Lei, Bing Zhang

Faculty, Staff and Students Publications

By combining mass-spectrometry-based proteomics and phosphoproteomics with genomics, epi-genomics, and transcriptomics, proteogenomics provides comprehensive molecular characterization of cancer. Using this approach, the Clinical Proteomic Tumor Analysis Consortium (CPTAC) has characterized over 1,000 primary tumors spanning 10 cancer types, many with matched normal tissues. Here, we present LinkedOmicsKB, a proteogenomics data-driven knowledge base that makes consistently processed and systematically precomputed CPTAC pan-cancer proteogenomics data available to the public through ∼40,000 gene-, protein-, mutation-, and phenotype-centric web pages. Visualization techniques facilitate efficient exploration and reasoning of complex, interconnected data. Using three case studies, we illustrate the practical utility of LinkedOmicsKB in providing …