Medical Specialties Commons^™

Sars-Cov-2 Omicron: Viral Evolution, Immune Evasion, And Alternative Durable Therapeutic Strategies, Hailong Guo, Sha Ha, Jason W Botten, Kai Xu, Ningyan Zhang, Zhiqiang An, William R Strohl, John W Shiver, Tong-Ming Fu

Faculty, Staff and Student Publications

Since the SARS-CoV-2 Omicron virus has gained dominance worldwide, its continual evolution with unpredictable mutations and patterns has revoked all authorized immunotherapeutics. Rapid viral evolution has also necessitated several rounds of vaccine updates in order to provide adequate immune protection. It remains imperative to understand how Omicron evolves into different subvariants and causes immune escape as this could help reevaluate the current intervention strategies mostly implemented in the clinics as emergency measures to counter the pandemic and, importantly, develop new solutions. Here, we provide a review focusing on the major events of Omicron viral evolution, including the features of spike …

Efficient Gene Knockout And Genetic Interaction Screening Using The In4mer Crispr/Cas12a Multiplex Knockout Platform, Nazanin Esmaeili Anvar, Chenchu Lin, Xingdi Ma, Lori L Wilson, Ryan Steger, Annabel K Sangree, Medina Colic, Sidney H Wang, John G Doench, Traver Hart

Faculty, Staff and Student Publications

Genetic interactions mediate the emergence of phenotype from genotype, but technologies for combinatorial genetic perturbation in mammalian cells are challenging to scale. Here, we identify background-independent paralog synthetic lethals from previous CRISPR genetic interaction screens, and find that the Cas12a platform provides superior sensitivity and assay replicability. We develop the in4mer Cas12a platform that uses arrays of four independent guide RNAs targeting the same or different genes. We construct a genome-scale library, Inzolia, that is ~30% smaller than a typical CRISPR/Cas9 library while also targeting ~4000 paralog pairs. Screens in cancer cells demonstrate discrimination of core and context-dependent essential genes …

Utility Of Clinical Next Generation Sequencing Tests In Kit/Pdgfra/Sdh Wild-Type Gastrointestinal Stromal Tumors, Ryan A Denu, Cissimol P Joseph, Elizabeth S Urquiola, Precious S Byrd, Richard K Yang, Ravin Ratan, Maria Alejandra Zarzour, Anthony P Conley, Dejka M Araujo, Vinod Ravi, Elise F Nassif Haddad, Michael S Nakazawa, Shreyaskumar Patel, Wei-Lien Wang, Alexander J Lazar, Neeta Somaiah

Faculty, Staff and Student Publications

Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack alterations in KIT, PDGFRA, and SDH. We aimed to further characterize the clinical and genomic characteristics of these so-called "triple-negative" GISTs.

Methods: We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify "triple-negative" patients.

Results: Of …

The Impact Of Family Functioning Factors On Smartphone Addiction And Phubbing Among Muslim Adolescents In Thailand, Yejin Kim, Wanchai Dhammasaccakarn, Kasetchai Laeheem, Idsaratt Rinthaisong

Faculty, Staff and Student Publications

BACKGROUND: While there is research on protective factors against smartphone addiction (SA) and phubbing, which impact adolescents' physical, psychological, interpersonal, and academic well-being, focused studies on these issues among Thai Muslim students in Southern Thailand remain scarce.

OBJECTIVES: To bridge this gap, this research aimed to explore the influence of five family functioning factors-discipline, communication and problem-solving (CPS), relationship, emotional status, and family support-guided by family systems theory and the McMaster Model, on SA and phubbing.

METHODS: Data from 825 Thai Muslim adolescent secondary school students (Female N = 459 (55.7%), M

RESULTS: Significant connections were identified between family functioning …

New Insights Into Macrophage Polarization And Its Prognostic Role In Patients With Colorectal Cancer Liver Metastasis, Isha Khanduri, Harufumi Maki, Anuj Verma, Riham Katkhuda, Gayathri Anandappa, Renganayaki Pandurengan, Shanyu Zhang, Alicia Mejia, Zhimin Tong, Luisa M Solis Soto, Akshaya Jadhav, Ignacio I Wistuba, David Menter, Scott Kopetz, Edwin R Parra, Jean-Nicolas Vauthey, Dipen M Maru

Faculty, Staff and Student Publications

Background: As liver metastasis is the most common cause of mortality in patients with colorectal cancer, studying colorectal cancer liver metastasis (CLM) microenvironment is essential for improved understanding of tumor biology and to identify novel therapeutic targets.

Methods: We used a multiplex immunofluorescence platform to study tumor associated macrophage (TAM) polarization and adaptive T cell subtypes in tumor samples from 105 CLM patients (49 without and 56 with preoperative chemotherapy).

Results: CLM exhibited M2 macrophage polarization, and helper T cells were the prevalent adaptive T cell subtype. The density of total, M2 and TGFβ-expressing macrophages, and regulatory T cells was …

Chromosomal 3q Amplicon Encodes Essential Regulators Of Secretory Vesicles That Drive Secretory Addiction In Cancer, Xiaochao Tan, Shike Wang, Guan-Yu Xiao, Chao Wu, Xin Liu, Biyao Zhou, Jiang Yu, Dzifa Yawa Duose, Yuanxin Xi, Jing Wang, Kunika Gupta, Apar Pataer, Jack A Roth, Michael P Kim, Fengju Chen, Chad J Creighton, William K Russell, Jonathan M Kurie

Faculty, Staff and Student Publications

Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identify a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase Secretory Pathway Ca2+ Transporting 1 (ATP2C1). We show that GOLIM4 recruits ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate calcium-dependent cargo loading and Golgi membrane bending and vesicle scission. GOLIM4 depletion disrupts the protein complex, resulting in a secretory blockade that inhibits the progression of 3q-amplified malignancies. In addition to its role …

The Swi/Snf Atp-Dependent Chromatin Remodeling Complex In Cell Lineage Priming And Early Development, Dhurjhoti Saha, Srinivas Animireddy, Blaine Bartholomew

Faculty, Staff and Student Publications

ATP dependent chromatin remodelers have pivotal roles in transcription, DNA replication and repair, and maintaining genome integrity. SWI/SNF remodelers were first discovered in yeast genetic screens for factors involved in mating type switching or for using alternative energy sources therefore termed SWI/SNF complex (short for SWItch/Sucrose NonFermentable). The SWI/SNF complexes utilize energy from ATP hydrolysis to disrupt histone-DNA interactions and shift, eject, or reposition nucleosomes making the underlying DNA more accessible to specific transcription factors and other regulatory proteins. In development, SWI/SNF orchestrates the precise activation and repression of genes at different stages, safe guards the formation of specific cell …

Evolution Of Chromosome-Arm Aberrations In Breast Cancer Through Genetic Network Rewiring, Elena Kuzmin, Toby M Baker, Tom Lesluyes, Jean Monlong, Kento T Abe, Paula P Coelho, Michael Schwartz, Joseph Del Corpo, Dongmei Zou, Genevieve Morin, Alain Pacis, Yang Yang, Constanza Martinez, Jarrett Barber, Hellen Kuasne, Rui Li, Mathieu Bourgey, Anne-Marie Fortier, Peter G Davison, Atilla Omeroglu, Marie-Christine Guiot, Quaid Morris, Claudia L Kleinman, Sidong Huang, Anne-Claude Gingras, Jiannis Ragoussis, Guillaume Bourque, Peter Van Loo, Morag Park

Faculty, Staff and Student Publications

The basal breast cancer subtype is enriched for triple-negative breast cancer (TNBC) and displays consistent large chromosomal deletions. Here, we characterize evolution and maintenance of chromosome 4p (chr4p) loss in basal breast cancer. Analysis of The Cancer Genome Atlas data shows recurrent deletion of chr4p in basal breast cancer. Phylogenetic analysis of a panel of 23 primary tumor/patient-derived xenograft basal breast cancers reveals early evolution of chr4p deletion. Mechanistically we show that chr4p loss is associated with enhanced proliferation. Gene function studies identify an unknown gene, C4orf19, within chr4p, which suppresses proliferation when overexpressed-a member of the PDCD10-GCKIII kinase module …

Associations Between Stress, Health Behaviors, And Quality Of Life In Young Couples During The Transition To Survivorship: Protocol For A Measurement Burst Study, Dalnim Cho, Michael Roth, Susan K Peterson, Kristofer Jennings, Seokhun Kim, Shiao-Pei Weathers, Sairah Ahmed, J Andrew Livingston, Carlos Barcenas, Y Nancy You, Kathrin Milbury

Faculty, Staff and Student Publications

BACKGROUND: Cancer is a life-threatening, stressful event, particularly for young adults due to delays and disruptions in their developmental transitions. Cancer treatment can also cause adverse long-term effects, chronic conditions, psychological issues, and decreased quality of life (QoL) among young adults. Despite numerous health benefits of health behaviors (eg, physical activity, healthy eating, no smoking, no alcohol use, and quality sleep), young adult cancer survivors report poor health behavior profiles. Determining the associations of stress (either cancer-specific or day-to-day stress), health behaviors, and QoL as young adult survivors transition to survivorship is key to understanding and enhancing these survivors' health. …

Six-Year Follow-Up And Subgroup Analyses Of A Phase 2 Trial Of Venetoclax For Del(17p) Chronic Lymphocytic Leukemia, Stephan Stilgenbauer, Eugen Tausch, Andrew W Roberts, Matthew S Davids, Barbara Eichhorst, Michael Hallek, Peter Hillmen, Christof Schneider, Johannes Schetelig, Sebastian Böttcher, Arnon P Kater, Yanwen Jiang, Michelle Boyer, Relja Popovic, Majd T Ghanim, Michael Moran, Wendy J Sinai, Xifeng Wang, Nabanita Mukherjee, Brenda Chyla, William G Wierda, John F Seymour

Faculty, Staff and Student Publications

Chromosome 17p deletion (del[17p]) is associated with poor prognosis in patients with chronic lymphocytic leukemia (CLL). Venetoclax is approved for treatment of previously untreated and relapsed/refractory (R/R) CLL, including patients with del(17p), based on the open-label, multicenter, phase 2 M13-982 trial (NCT01889186). Here, we detail the 6-year follow-up analysis for M13-982. A total of 158 patients with previously untreated (n = 5) or R/R (n = 153) del(17p) CLL received 400 mg venetoclax daily after initial ramp-up until progressive disease. After a median follow-up of 70 months, the best objective response rate (ORR) was 77% (21% complete remission …

Association Between Antenatal Vaginal Bleeding And Adverse Perinatal Outcomes In Placenta Accreta Spectrum, J Connor Mulhall, Kayla E Ireland, John J Byrne, Patrick S Ramsey, Georgia A Mccann, Jessian L Munoz

Faculty, Staff and Student Publications

Background and Objectives: Placenta accreta spectrum (PAS) disorders are placental conditions associated with significant maternal morbidity and mortality. While antenatal vaginal bleeding in the setting of PAS is common, the implications of this on overall outcomes remain unknown. Our primary objective was to identify the implications of antenatal vaginal bleeding in the setting of suspected PAS on both maternal and fetal outcomes. Materials and Methods: We performed a case-control study of patients referred to our PAS center of excellence delivered by cesarean hysterectomy from 2012 to 2022. Subsequently, antenatal vaginal bleeding episodes were quantified, and components of maternal …

Th2 Cells Are Associated With Tumor Recurrence Following Radiation, Mohamed K Abdelhakiem, Riyue Bao, Phillip M Pifer, David Molkentine, Jessica Molkentine, Andrew Hefner, Beth Beadle, John V Heymach, Jason J Luke, Robert L Ferris, Curtis R Pickering, Jing H Wang, Ravi B Patel, Heath D Skinner

Faculty, Staff and Student Publications

The curative treatment of multiple solid tumors, including head and neck squamous cell carcinoma (HNSCC), utilizes radiation. The outcomes for HPV/p16-negative HNSCC are significantly worse than HPV/p16-positive tumors, with increased radiation resistance leading to worse locoregional recurrence (LRR) and ultimately death. This study analyzed the relationship between immune function and outcomes following radiation in HPV/p16-negative tumors to identify mechanisms of radiation resistance and prognostic immune biomarkers. A discovery cohort of 94 patients with HNSCC treated uniformly with surgery and adjuvant radiation and a validation cohort of 97 similarly treated patients were utilized. Tumor immune infiltrates were derived from RNAseq gene …

Mapping Of Alzheimer’S Disease Related Data Elements And The Nih Common Data Elements, Xubing Hao, Rashmie Abeysinghe, Fengbo Zheng, Paul E Schulz, The Alzheimer’S Disease Neuroimaging Initiative, Licong Cui

Faculty, Staff and Student Publications

Background

Alzheimer’s Disease (AD) is a devastating disease that destroys memory and other cognitive functions. There has been an increasing research effort to prevent and treat AD. In the US, two major data sharing resources for AD research are the National Alzheimer’s Coordinating Center (NACC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI); Additionally, the National Institutes of Health (NIH) Common Data Elements (CDE) Repository has been developed to facilitate data sharing and improve the interoperability among data sets in various disease research areas.

Method

To better understand how AD-related data elements in these resources are interoperable with each other, we …

A Tetravalent Nanovaccine That Inhibits Growth Of Hpv-Associated Head And Neck Carcinoma Via Dendritic And T Cell Activation, Romano Josi, Daniel E Speiser, Simone De Brot, Anne-Cathrine Vogt, Eva M Sevick-Muraca, Genrich V Tolstonog, Martin F Bachmann, Mona O Mohsen

Faculty, Staff and Student Publications

The global incidence of human papillomavirus (HPV) associated head and neck carcinoma is on the rise, in response to this a tetravalent therapeutic vaccine named Qβ-HPVag was developed. This vaccine, utilizing virus-like particles (VLPs) loaded with toll-like receptor ligands and chemically coupled to four HPV16-derived peptides, demonstrated strong anti-tumor effects in a murine head and neck cancer model. Qβ-HPVag impeded tumor progression, increased infiltration of HPV-specific T cells, and significantly improved survival. The vaccine`s efficacy was associated with immune repolarization in the tumor microenvironment, characterized by expanded activated dendritic cell subsets (cDC1, cDC2, DC3). Notably, mice responding to treatment exhibited …

Transposable Elements Regulate Thymus Development And Function, Jean-David Larouche, Céline M Laumont, Assya Trofimov, Krystel Vincent, Leslie Hesnard, Sylvie Brochu, Caroline Côté, Juliette F Humeau, Éric Bonneil, Joel Lanoix, Chantal Durette, Patrick Gendron, Jean-Philippe Laverdure, Ellen R Richie, Sébastien Lemieux, Pierre Thibault, Claude Perreault

Faculty, Staff and Student Publications

Transposable elements (TEs) are repetitive sequences representing ~45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTECs). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multiomic analyses of TEs in human and mouse thymic cells to elucidate their role in T-cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: …

Human Dna Polymerase Θ Does Not Harbor Intrinsic Nuclease Activity, Denisse Carvajal-Maldonado, Karl Zahn, Ryan Jensen, Richard D Wood, Sylvie Doublié

Faculty, Staff and Student Publications

No abstract provided.

Sequential Requirements For Distinct Polθ Domains During Theta-Mediated End Joining, Carel Fijen, Lea Drogalis Beckham, Dante Terino, Yuzhen Li, Dale A Ramsden, Richard D Wood, Sylvie Doublié, Eli Rothenberg

Faculty, Staff and Student Publications

DNA polymerase θ (Polθ) plays a central role in a DNA double-strand break repair pathway termed theta-mediated end joining (TMEJ). TMEJ functions by pairing short-sequence "microhomologies" (MHs) in single-stranded DNA at each end of a break and subsequently initiating DNA synthesis. It is not known how the Polθ helicase domain (HD) and polymerase domain (PD) operate to bring together MHs and facilitate repair. To resolve these transient processes in real time, we utilized in vitro single-molecule FRET approaches and biochemical analyses. We find that the Polθ-HD mediates the initial capture of two ssDNA strands, bringing them in close proximity. The …

Cdk8/Cdk19 Promotes Mitochondrial Fission Through Drp1 Phosphorylation And Can Phenotypically Suppress Pink1 Deficiency In Drosophila, Jenny Zhe Liao, Hyung-Lok Chung, Claire Shih, Kenneth Kin Lam Wong, Debdeep Dutta, Zelha Nil, Catherine Grace Burns, Oguz Kanca, Ye-Jin Park, Zhongyuan Zuo, Paul C Marcogliese, Katherine Sew, Hugo J Bellen, Esther M Verheyen

Faculty, Staff and Students Publications

Cdk8 in Drosophila is the orthologue of vertebrate CDK8 and CDK19. These proteins have been shown to modulate transcriptional control by RNA polymerase II. We found that neuronal loss of Cdk8 severely reduces fly lifespan and causes bang sensitivity. Remarkably, these defects can be rescued by expression of human CDK19, found in the cytoplasm of neurons, suggesting a non-nuclear function of CDK19/Cdk8. Here we show that Cdk8 plays a critical role in the cytoplasm, with its loss causing elongated mitochondria in both muscles and neurons. We find that endogenous GFP-tagged Cdk8 can be found in both the cytoplasm and nucleus. …

Improved Data Quality And Statistical Power Of Trial-Level Event-Related Potentials With Bayesian Random-Shift Gaussian Processes, Dustin Pluta, Beniamino Hadj-Amar, Meng Li, Yongxiang Zhao, Francesco Versace, Marina Vannucci

Faculty, Staff and Student Publications

Studies of cognitive processes via electroencephalogram (EEG) recordings often analyze group-level event-related potentials (ERPs) averaged over multiple subjects and trials. This averaging procedure can obscure scientifically relevant variability across subjects and trials, but has been necessary due to the difficulties posed by inference of trial-level ERPs. We introduce the Bayesian Random Phase-Amplitude Gaussian Process (RPAGP) model, for inference of trial-level amplitude, latency, and ERP waveforms. We apply RPAGP to data from a study of ERP responses to emotionally arousing images. The model estimates of trial-specific signals are shown to greatly improve statistical power in detecting significant differences in experimental conditions …

High-Performance Cementitious Composites Containing Nanostructured Carbon Additives Made From Charred Coal Fines, Yuan Gao, Viet Hung Pham, Jennifer Weidman, Ki-Joong Kim, Richard E Spaulding, Congjun Wang, Christopher S Matranga

Faculty, Staff and Student Publications

Carbon-based nanomaterials, such as carbon nanoplatelets, graphene oxide, and carbon quantum dots, have many possible end-use applications due to their ability to impart unique mechanical, electrical, thermal, and optical properties to cement composites. Despite this potential, these materials are rarely used in the construction industry due to high material costs and limited data on performance and durability. In this study, domestic coal is used to fabricate low-cost carbon nanomaterials that can be used economically in cement formulations. A range of chemical and physical processing approaches are employed to control the size, morphology, and chemical functionalization of the carbon nanomaterial, which …

Brafv600e-Mutant Metastatic Nsclc: Disease Overview And Treatment Landscape, David Planchard, Rachel E Sanborn, Marcelo V Negrao, Aria Vaishnavi, Egbert F Smit

Faculty, Staff and Student Publications

In this review, we cover the current understanding of BRAF mutations and associated clinical characteristics in patients with metastatic NSCLC, approved and emerging treatment options, BRAF sequencing approaches, and unmet needs. The BRAFV600E mutation confers constitutive activity of the MAPK pathway, leading to enhanced growth, proliferation, and survival of tumor cells. Testing for BRAF mutations enables patients to be treated with therapies that directly target BRAFV600E and the MAPK pathway, but BRAF testing lags behind other oncogene testing in metastatic NSCLC. Additional therapies targeting BRAFV600E mutations provide options for patients with metastatic NSCLC. Emerging therapies and combinations under investigation could …

Revolutionizing Diabetic Foot Ulcer Care: The Senotherapeutic Approach, Guiqin Zhang, Priyadarshani Nadeeshika Samarawickrama, Li Gui, Yuan Ma, Mei Cao, Hong Zhu, Wei Li, Honglin Yang, Kecheng Li, Yang Yang, Enfang Zhu, Wen Li, Yonghan He

Faculty, Staff and Student Publications

Diabetic foot ulcers (DFUs) are a prevalent and profoundly debilitating complication that afflicts individuals with diabetes mellitus (DM). These ulcers are associated with substantial morbidity, recurrence rates, disability, and mortality, imposing substantial economic, psychological, and medical burdens. Timely detection and intervention can mitigate the morbidity and disparities linked to DFU. Nevertheless, current therapeutic approaches for DFU continue to grapple with multifaceted limitations. A growing body of evidence emphasizes the crucial role of cellular senescence in the pathogenesis of chronic wounds. Interventions that try to delay cellular senescence, eliminate senescent cells (SnCs), or suppress the senescence-associated secretory phenotype (SASP) have shown …

Self-Assembled Sting-Activating Coordination Nanoparticles For Cancer Immunotherapy And Vaccine Applications, Xiaoqi Sun, Xuehui Huang, Kyung Soo Park, Xingwu Zhou, Andrew A Kennedy, Carla D Pretto, Qi Wu, Ziye Wan, Yao Xu, Wang Gong, Jonathan Z Sexton, Andrew W Tai, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

The cGAS-STING pathway plays a crucial role in innate immune activation against cancer and infections, and STING agonists based on cyclic dinucleotides (CDN) have garnered attention for their potential use in cancer immunotherapy and vaccines. However, the limited drug-like properties of CDN necessitate an efficient delivery system to the immune system. To address these challenges, we developed an immunostimulatory delivery system for STING agonists. Here, we have examined aqueous coordination interactions between CDN and metal ions and report that CDN mixed with Zn2+ and Mn2+ formed distinctive crystal structures. Further pharmaceutical engineering led to the development of a functional coordination …

Microbiome And Cancer Immunotherapies, Haoyan Chen, Laurence Zitvogel, Zhi Peng, Xiaochen Yin, Florencia Mcallister

Faculty, Staff and Student Publications

Here, we present 3 different perspectives on how the microbiome has impacted cancer patients, treatment, and clinical studies. We hear about the challenges of implementing microbiome analyses into the clinics, the impact these analyses might have on patients' care, and treatment in the future, specifically for gastric cancer treatment. These are a few of the many voices that are highlighting the role of the microbiome in cancer development, treatment, and clinical outcomes.

Jennifer A Wargo, Nadim J Ajami, And Carrie R Daniel-Macdougall, Jennifer A Wargo, Nadim J Ajami, Carrie R Daniel-Macdougall

Faculty, Staff and Student Publications

Dr. Jennifer A. Wargo, Dr. Nadim J. Ajami, and Dr. Carrie R. Daniel-MacDougall describe their academic and clinical work on the role of the microbiome to determine response to immunotherapies and discuss current challenges and potential needs to integrate their findings into clinical practice.

Multilocus Pathogenic Variants Contribute To Intrafamilial Clinical Heterogeneity: A Retrospective Study Of Sibling Pairs With Neurodevelopmental Disorders, Tugce Bozkurt-Yozgatli, Davut Pehlivan, Richard A Gibbs, Ugur Sezerman, Jennifer E Posey, James R Lupski, Zeynep Coban-Akdemir

Faculty, Staff and Students Publications

BACKGROUND: Multilocus pathogenic variants (MPVs) are genetic changes that affect multiple gene loci or regions of the genome, collectively leading to multiple molecular diagnoses. MPVs may also contribute to intrafamilial phenotypic variability between affected individuals within a nuclear family. In this study, we aim to gain further insights into the influence of MPVs on a disease manifestation in individual research subjects and explore the complexities of the human genome within a familial context.

METHODS: We conducted a systematic reanalysis of exome sequencing data and runs of homozygosity (ROH) regions of 47 sibling pairs previously diagnosed with various neurodevelopmental disorders (NDD). …

Multi-Omics Analysis Reveals Immune Features Associated With Immunotherapy Benefit In Patients With Squamous Cell Lung Cancer From Phase Iii Lung-Map S1400i Trial, Edwin Roger Parra, Jiexin Zhang, Dzifa Yawa Duose, Edgar Gonzalez-Kozlova, Mary W Redman, Hong Chen, Ganiraju C Manyam, Gayatri Kumar, Jianhua Zhang, Xingzhi Song, Rossana Lazcano, Mario L Marques-Piubelli, Caddie Laberiano-Fernandez, Frank Rojas, Baili Zhang, Len Taing, Aashna Jhaveri, Jacob Geisberg, Jennifer Altreuter, Franziska Michor, James Provencher, Joyce Yu, Ethan Cerami, Radim Moravec, Kasthuri Kannan, Rajyalakshmi Luthra, Gheath Alatrash, Hsin-Hui Huang, Hui Xie, Manishkumar Patel, Kai Nie, Jocelyn Harris, Kimberly Argueta, James Lindsay, Roshni Biswas, Stephen Van Nostrand, Seunghee Kim-Schulze, Jhanelle E Gray, Roy S Herbst, Ignacio I Wistuba, Scott Gettinger, Karen Kelly, Lyudmila Bazhenova, Sacha Gnjatic, J Jack Lee, Jianjun Zhang, Cara Haymaker

Faculty, Staff and Student Publications

PURPOSE: Identifying molecular and immune features to guide immune checkpoint inhibitor (ICI)-based regimens remains an unmet clinical need.

EXPERIMENTAL DESIGN: Tissue and longitudinal blood specimens from phase III trial S1400I in patients with metastatic squamous non-small cell carcinoma (SqNSCLC) treated with nivolumab monotherapy (nivo) or nivolumab plus ipilimumab (nivo+ipi) were subjected to multi-omics analyses including multiplex immunofluorescence (mIF), nCounter PanCancer Immune Profiling Panel, whole-exome sequencing, and Olink.

RESULTS: Higher immune scores from immune gene expression profiling or immune cell infiltration by mIF were associated with response to ICIs and improved survival, except regulatory T cells, which were associated with worse …

Safety Profile And Adverse Event Management For Futibatinib, An Irreversible Fgfr1-4 Inhibitor: Pooled Safety Analysis Of 469 Patients, Funda Meric-Bernstam, Antoine Hollebecque, Junji Furuse, Do-Youn Oh, John A Bridgewater, Masashi Shimura, Bailey Anderson, Nanae Hangai, Volker Wacheck, Lipika Goyal

Faculty, Staff and Student Publications

PURPOSE: Futibatinib, a covalently-binding inhibitor of fibroblast growth factor receptor (FGFR)1-4 gained approval for the treatment of refractory, advanced intrahepatic cholangiocarcinoma (iCCA) harboring an FGFR2 fusion/other rearrangement. An integrated analysis was performed to evaluate safety and provide guidance on the management of futibatinib-associated adverse events (AEs) in patients with unresectable/metastatic tumors, including iCCA.

PATIENTS AND METHODS: Data from three global phase I or II studies of futibatinib (NCT02052778; JapicCTI-142552) were pooled. AEs were graded per NCI CTCAE v4.03, where applicable. Safety was analyzed for patients receiving any futibatinib starting dose (overall population) and in those receiving the approved starting dose …

Vhl Governs M6a Modification And Pik3r3 Mrna Stability In Clear Cell Renal Cell Carcinomas, Hyemin Lee, Li Zhuang, Boyi Gan

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N6-Methyladenosine (m6A), a prevalent posttranscriptional modification, plays an important role in cancer progression. Clear cell renal cell carcinoma (ccRCC) is chiefly associated with the loss of the von Hippel-Lindau (VHL) gene, encoding a component of the E3 ubiquitin ligase complex. In this issue of the JCI, Zhang and colleagues unveiled a function of VHL beyond its canonical role as an E3 ubiquitin ligase in regulating hypoxia-inducible factors (HIFs). It also governed m6A modification by orchestrating the assembly of m6A writer proteins METTL3 and METTL14, thereby stabilizing PIK3R3 mRNA. Mechanistically, PIK3R3 contributed to p85 ubiquitination, which restrained PI3K/AKT signaling and consequently …

Sensitivity Analysis With Iterative Outlier Detection For Systematic Reviews And Meta-Analyses, Zhuo Meng, Jingshen Wang, Lifeng Lin, Chong Wu

Faculty, Staff and Student Publications

Meta-analysis is a widely used tool for synthesizing results from multiple studies. The collected studies are deemed heterogeneous when they do not share a common underlying effect size; thus, the factors attributable to the heterogeneity need to be carefully considered. A critical problem in meta-analyses and systematic reviews is that outlying studies are frequently included, which can lead to invalid conclusions and affect the robustness of decision-making. Outliers may be caused by several factors such as study selection criteria, low study quality, small-study effects, and so on. Although outlier detection is well-studied in the statistical community, limited attention has been …