Genetic Phenomena Commons^™

Aging-Related Biomarker Discovery In The Era Of Immune Checkpoint Inhibitors For Cancer Patients, Abdullah Al-Danakh, Mohammed Safi, Yuli Jian, Linlin Yang, Xinqing Zhu, Qiwei Chen, Kangkang Yang, Shujing Wang, Jianjun Zhang, Deyong Yang

Faculty, Staff and Student Publications

Older patients with cancer, particularly those over 75 years of age, often experience poorer clinical outcomes compared to younger patients. This can be attributed to age-related comorbidities, weakened immune function, and reduced tolerance to treatment-related adverse effects. In the immune checkpoint inhibitors (ICI) era, age has emerged as an influential factor impacting the discovery of predictive biomarkers for ICI treatment. These age-linked changes in the immune system can influence the composition and functionality of tumor-infiltrating immune cells (TIICs) that play a crucial role in the cancer response. Older patients may have lower levels of TIICs infiltration due to age-related immune …

Research Hot Spots And Trends In Endocrine-Related Adverse Events Caused By Immune Checkpoint Inhibitors: A Bibliometric Analysis And Visualization Research, Jun Zhao, Guangwei Liu, Xue Yang, Chuanzhou Zhang, Bing Han, Man Jiang

Faculty, Staff and Student Publications

Background: In recent years, with the widespread use of immune checkpoint inhibitors (ICIs) in cancer treatment, the toxicity associated with immunotherapy of ICIs has attracted more attention from scholars. Endocrine toxicity is the most likely immune-related adverse events (irAEs) and is often irreversible, posing a significant clinical treatment challenge.

Methods: In this study, bibliometric methods were used to analyze relevant literature in screening endocrine-related adverse events caused by ICIs in the Web of Science core collection database (WoSCC) and to summarize the status, research hot spots, and future trends in this field.

Results: 321 countries, 297 institutions, 365 authors, and …

Traf4-Mediated Nonproteolytic Ubiquitination Of Androgen Receptor Promotes Castration-Resistant Prostate Cancer, Yosi Gilad, Ortal Shimon, Sang Jun Han, David M Lonard, Bert W O'Malley

Faculty, Staff and Students Publications

Steroid receptor coactivators (SRCs) are master regulators of transcription that play key roles in human physiology and pathology. SRCs are particularly important for the regulation of the immune system with major roles in lymphocyte fate determination and function, macrophage activity, regulation of nuclear factor κB (NF-κB) transcriptional activity and other immune system biology. The three members of the p160 SRC family comprise a network of immune-regulatory proteins that can function independently or act in synergy with each other, and compensate for - or moderate - the activity of other SRCs. Recent evidence indicates that the SRCs are key participants in …

Psychological Distress And Mental Health Care Utilization Among Hispanic/Latino Survivors Of Adolescent And Young Adult Cancer, Eunju Choi, Amy M Berkman, Christabel K Cheung, Andrea C Betts, John M Salsman, Clark R Andersen, Carol Yesenia Ochoa-Dominguez, Kimberly Miller, Joel Milam, Ashna Shah, Susan K Peterson, Qian Lu, J Andrew Livingston, Michelle A T Hildebrandt, Susan K Parsons, David Freyer, Michael E Roth

Faculty, Staff and Student Publications

Purpose: Survivors of adolescent and young adult (AYA) cancer experience psychological distress and insufficient access to mental health care. Few studies have investigated racial/ethnic disparities in psychological health outcomes in this population. This study compared psychological distress, mental health care use, and inability to afford mental health care between Hispanic/Latino survivors of AYA cancer and Hispanic/Latino controls.

Methods: The National Health Interview Survey data (2010-2018) were analyzed to identify Hispanic/Latino survivors of AYA cancer and Hispanic/Latino age- and sex-matched non-cancer controls. Sociodemographic, chronic health, modifiable factors, and psychological outcomes were compared using chi-square tests. Logistic regression models with survey weights …

Development And Validation Of Age-Specific Risk Prediction Models For Primary Ovarian Insufficiency In Long-Term Survivors Of Childhood Cancer: A Report From The Childhood Cancer Survivor Study And St Jude Lifetime Cohort, Cindy Im, Zhe Lu, Sogol Mostoufi-Moab, Angela Delaney, Lin Yu, Jessica L Baedke, Yutong Han, Yadav Sapkota, Yutaka Yasui, Eric J Chow, Rebecca M Howell, Smita Bhatia, Melissa M Hudson, Kirsten K Ness, Gregory T Armstrong, Paul C Nathan, Yan Yuan

Faculty, Staff and Student Publications

BACKGROUND: Female survivors of childhood cancer are at risk for primary ovarian insufficiency (POI), defined as the cessation of gonadal function before the age of 40 years. We aimed to develop and validate models to predict age-specific POI risk among long-term survivors of childhood cancer.

METHODS: To develop models to predict age-specific POI risk for the ages of 21-40 years, we used data from the Childhood Cancer Survivor Study (CCSS). Female survivors aged 18 years or older at their latest follow-up, with self-reported menstrual history information and free of subsequent malignant neoplasms within 5 years of diagnosis, were included. We …

Inhibition Of The Proline Metabolism Rate-Limiting Enzyme P5cs Allows Proliferation Of Glutamine-Restricted Cancer Cells, Samantha J Linder, Tiziano Bernasocchi, Bárbara Martínez-Pastor, Kelly D Sullivan, Matthew D Galbraith, Caroline A Lewis, Christina M Ferrer, Ruben Boon, Giorgia G Silveira, Hyo Min Cho, Charles Vidoudez, Stuti Shroff, Joao P Oliveira-Costa, Kenneth N Ross, Rami Massri, Yusuke Matoba, Eugene Kim, Bo R Rueda, Shannon L Stott, Eyal Gottlieb, Joaquin M Espinosa, Raul Mostoslavsky

Faculty, Staff and Student Publications

Glutamine is a critical metabolite for rapidly proliferating cells as it is used for the synthesis of key metabolites necessary for cell growth and proliferation. Glutamine metabolism has been proposed as a therapeutic target in cancer and several chemical inhibitors are in development or in clinical trials. How cells subsist when glutamine is limiting is poorly understood. Here, using an unbiased screen, we identify ALDH18A1, which encodes P5CS, the rate-limiting enzyme in the proline biosynthetic pathway, as a gene that cells can downregulate in response to glutamine starvation. Notably, P5CS downregulation promotes de novo glutamine synthesis, highlighting a previously unrecognized …

Larotrectinib Efficacy And Safety In Adult Patients With Tropomyosin Receptor Kinase Fusion Sarcomas, Shivaani Kummar, Lin Shen, David S Hong, Ray Mcdermott, Vicki L Keedy, Michela Casanova, George D Demetri, Afshin Dowlati, Soledad Gallego Melcón, Ulrik N Lassen, Serge Leyvraz, Tianshu Liu, Victor Moreno, Jyoti Patel, Tejas Patil, Atrayee Basu Mallick, Nuno Sousa, Makoto Tahara, David S Ziegler, Ricarda Norenberg, Pierre Arvis, Nicoletta Brega, Alexander Drilon, Daniel S W Tan

Faculty, Staff and Student Publications

Background: Larotrectinib, a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor, has demonstrated efficacy in adult and pediatric patients with various solid tumors harboring NTRK gene fusions. This subset analysis focuses on the efficacy and safety of larotrectinib in an expanded cohort of adult patients with TRK fusion sarcomas.

Methods: Patients (≥18 years old) with sarcomas harboring NTRK gene fusions were identified from three clinical trials. Patients received larotrectinib 100 mg orally twice daily. Response was investigator-assessed per RECIST v1.1. Data cutoff was July 20, 2021.

Results: At the data cutoff, 36 adult patients with TRK fusion sarcomas had initiated …

Droid: Dose-Ranging Approach To Optimizing Dose In Oncology Drug Development, Beibei Guo, Ying Yuan

Faculty, Staff and Student Publications

In the era of targeted therapy, there has been increasing concern about the development of oncology drugs based on the "more is better" paradigm, developed decades ago for chemotherapy. Recently, the US Food and Drug Administration (FDA) initiated Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development. To accommodate this paradigm shifting, we propose a dose-ranging approach to optimizing dose (DROID) for oncology trials with targeted drugs. DROID leverages the well-established dose-ranging study framework, which has been routinely used to develop non-oncology drugs for decades, and bridges it with established oncology dose-finding designs to …

Alpha Particle-Emitting Radiopharmaceuticals As Cancer Therapy: Biological Basis, Current Status, And Future Outlook For Therapeutics Discovery, Ryan P Coll, Scott J Bright, David K J Martinus, Dimitra K Georgiou, Gabriel O Sawakuchi, H Charles Manning

Faculty, Staff and Student Publications

Critical advances in radionuclide therapy have led to encouraging new options for cancer treatment through the pairing of clinically useful radiation-emitting radionuclides and innovative pharmaceutical discovery. Of the various subatomic particles used in therapeutic radiopharmaceuticals, alpha (α) particles show great promise owing to their relatively large size, delivered energy, finite pathlength, and resulting ionization density. This review discusses the therapeutic benefits of α-emitting radiopharmaceuticals and their pairing with appropriate diagnostics, resulting in innovative "theranostic" platforms. Herein, the current landscape of α particle-emitting radionuclides is described with an emphasis on their use in theranostic development for cancer treatment. Commonly studied radionuclides …

Loss Of Adar1 In Macrophages In Combination With Interferon Gamma Suppresses Tumor Growth By Remodeling The Tumor Microenvironment, Weiwei Lin, Yikai Luo, Jie Wu, Haowan Zhang, Ge Jin, Chahua Guo, Hang Zhou, Han Liang, Xiaoyan Xu

Faculty, Staff and Student Publications

Background: ADAR1, the major enzyme for RNA editing, has emerged as a tumor-intrinsic key determinant for cancer immunotherapy efficacy through modulating interferon-mediated innate immunity. However, the role of ADAR1 in innate immune cells such as macrophages remains unknown.

Methods: We first analyzed publicly accessible patient-derived single-cell RNA-sequencing and perturbed RNA sequencing data to elucidate the ADAR1 expression and function in macrophages. Subsequently, we evaluated the combined effects of ADAR1 conditional knockout in macrophages and interferon (IFN)-γ treatment on tumor growth in three distinct disease mouse models: LLC for lung cancer, B16-F10 for melanoma, and MC38 for colon cancer. To gain …

Prevalence And Implications Of Significance Testing For Baseline Covariate Imbalance In Randomised Cancer Clinical Trials: The Table 1 Fallacy, Alexander D Sherry, Pavlos Msaouel, Zachary R Mccaw, Joseph Abi Jaoude, Eric J Hsu, Ramez Kouzy, Roshal Patel, Yumeng Yang, Timothy A Lin, Cullen M Taniguchi, Claus Rödel, Emmanouil Fokas, Chad Tang, Clifton David Fuller, Bruce Minsky, Tomer Meirson, Ryan Sun, Ethan B Ludmir

Faculty, Staff and Student Publications

Background: The 'Table 1 Fallacy' refers to the unsound use of significance testing for comparing the distributions of baseline variables between randomised groups to draw erroneous conclusions about balance or imbalance. We performed a cross-sectional study of the Table 1 Fallacy in phase III oncology trials.

Methods: From ClinicalTrials.gov, 1877 randomised trials were screened. Multivariable logistic regressions evaluated predictors of the Table 1 Fallacy.

Results: A total of 765 randomised controlled trials involving 553,405 patients were analysed. The Table 1 Fallacy was observed in 25% of trials (188 of 765), with 3% of comparisons deemed significant (59 of 2353), approximating …

Supportive Care For Dual Caregivers Who Care For Their Partner With Cancer And Their Young Children, Sujin Ann-Yi, Kathrin Milbury, Morgan Jones, Victoria Necroto, Meagan Whisenant, Yisheng Li, Eduardo Bruera

Faculty, Staff and Student Publications

Purpose: Advanced cancer patients and their spouses who parent minor children report parenting concerns and increased psychological distress. This single-arm trial examined the feasibility and initial evidence for efficacy of a novel parent support program.

Methods: Patients with a metastatic solid malignancy and their spouses completed self-reported assessments of psychological distress (HADS), parenting concerns (PCQ) and efficacy (CaPSE) at baseline. Both patients and spouses jointly attended the first two sessions addressing illness communication and family routines. Spouses individually attended two additional sessions focusing on caregiver support and death preparedness. All four sessions were delivered via videoconference by a licensed psychological …

Model-Informed Drug Development Of Autologous Car-T Cell Therapy: Strategies To Optimize Car-T Cell Exposure Leveraging Cell Kinetic/Dynamic Modeling, Anna M Mc Laughlin, Peter A Milligan, Cassian Yee, Martin Bergstrand

Faculty, Staff and Student Publications

Autologous Chimeric antigen receptor (CAR-T) cell therapy has been highly successful in the treatment of aggressive hematological malignancies and is also being evaluated for the treatment of solid tumors as well as other therapeutic areas. A challenge, however, is that up to 60% of patients do not sustain a long-term response. Low CAR-T cell exposure has been suggested as an underlying factor for a poor prognosis. CAR-T cell therapy is a novel therapeutic modality with unique kinetic and dynamic properties. Importantly, "clear" dose-exposure relationships do not seem to exist for any of the currently approved CAR-T cell products. In other …

Next-Generation Chimeric Antigen Receptors For T- And Natural Killer-Cell Therapies Against Cancer, Ye Li, Katayoun Rezvani, Hind Rafei

Faculty, Staff and Student Publications

Adoptive cellular therapy using chimeric antigen receptor (CAR) T cells has led to a paradigm shift in the treatment of various hematologic malignancies. However, the broad application of this approach for myeloid malignancies and solid cancers has been limited by the paucity and heterogeneity of target antigen expression, and lack of bona fide tumor-specific antigens that can be targeted without cross-reactivity against normal tissues. This may lead to unwanted on-target off-tumor toxicities that could undermine the desired antitumor effect. Recent advances in synthetic biology and genetic engineering have enabled reprogramming of immune effector cells to enhance their selectivity toward tumors, …

The Influence Of Obesity On Outcomes With Immune Checkpoint Blockade: Clinical Evidence And Potential Biological Mechanisms, Andrew W Hahn, Neha Venkatesh, Pavlos Msaouel, Jennifer L Mcquade

Faculty, Staff and Student Publications

Immune checkpoint blockade (ICB) is a mainstay of treatment for advanced cancer, yet tumor response and host toxicity are heterogenous in those patients who receive ICB. There is growing interest in understanding how host factors interact with tumor intrinsic properties and the tumor microenvironment to influence the therapeutic index with ICB. Obesity, defined by body mass index, is a host factor associated with improved outcomes in select cancers when treated with ICB. While the biological mechanism for this obesity paradox is not fully understood, pre-clinical and translational studies suggest obesity may potentially impact tumor metabolism, inflammation, and angiogenesis. Herein, we …

Novobiocin Blocks Nucleic Acid Binding To Polθ And Inhibits Stimulation Of Its Atpase Activity, Aleem Syed, Frantisek Filandr, Jeffrey Patterson-Fortin, Albino Bacolla, Ramya Ravindranathan, Jia Zhou, Drew T Mcdonald, Mohammed E Albuhluli, Amy Verway-Cohen, Joseph A Newman, Miaw-Sheue Tsai, Darin E Jones, David C Schriemer, Alan D D'Andrea, John A Tainer

Faculty, Staff and Student Publications

Polymerase theta (Polθ) acts in DNA replication and repair, and its inhibition is synthetic lethal in BRCA1 and BRCA2-deficient tumor cells. Novobiocin (NVB) is a first-in-class inhibitor of the Polθ ATPase activity, and it is currently being tested in clinical trials as an anti-cancer drug. Here, we investigated the molecular mechanism of NVB-mediated Polθ inhibition. Using hydrogen deuterium exchange-mass spectrometry (HX-MS), biophysical, biochemical, computational and cellular assays, we found NVB is a non-competitive inhibitor of ATP hydrolysis. NVB sugar group deletion resulted in decreased potency and reduced HX-MS interactions, supporting a specific NVB binding orientation. Collective results revealed that NVB …

Dendritic Cells As Shepherds Of T Cell Immunity In Cancer, Mikael J Pittet, Mauro Di Pilato, Christopher Garris, Thorsten R Mempel

Faculty, Staff and Student Publications

In cancer patients, dendritic cells (DCs) in tumor-draining lymph nodes can present antigens to naive T cells in ways that break immunological tolerance. The clonally expanded progeny of primed T cells are further regulated by DCs at tumor sites. Intratumoral DCs can both provide survival signals to and drive effector differentiation of incoming T cells, thereby locally enhancing antitumor immunity; however, the paucity of intratumoral DCs or their expression of immunoregulatory molecules often limits antitumor T cell responses. Here, we review the current understanding of DC-T cell interactions at both priming and effector sites of immune responses. We place emerging …

Enzyme-Mediated Depletion Of Methylthioadenosine Restores T Cell Function In Mtap-Deficient Tumors And Reverses Immunotherapy Resistance, Donjeta Gjuka, Elio Adib, Kendra Garrison, Jianfeng Chen, Yuxue Zhang, Wenjiao Li, Daniel Boutz, Candice Lamb, Yuri Tanno, Amin Nassar, Talal El Zarif, Neil Kale, Mehrdad Rakaee, Tarek H Mouhieddine, Sarah Abou Alaiwi, Alexander Gusev, Thomas Rogers, Jianjun Gao, George Georgiou, David J Kwiatkowski, Everett Stone

Faculty, Staff and Student Publications

Chromosomal region 9p21 containing tumor suppressors CDKN2A/B and methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic deletions in cancer. 9p21 loss is correlated with reduced tumor-infiltrating lymphocytes (TILs) and resistance to immune checkpoint inhibitor (ICI) therapy. Previously thought to be caused by CDKN2A/B loss, we now show that it is loss of MTAP that leads to poor outcomes on ICI therapy and reduced TIL density. MTAP loss causes accumulation of methylthioadenosine (MTA) both intracellularly and extracellularly and profoundly impairs T cell function via the inhibition of protein arginine methyltransferase 5 (PRMT5) and by adenosine receptor agonism. Administration of …

Cancer Germline Predisposing Variants And Late Mortality From Subsequent Malignant Neoplasms Among Long-Term Childhood Cancer Survivors: A Report From The St Jude Lifetime Cohort And The Childhood Cancer Survivor Study, Cheng Chen, Na Qin, Mingjuan Wang, Qian Dong, Saima Sultana Tithi, Yawei Hui, Wenan Chen, Gang Wu, Dennis Kennetz, Michael N Edmonson, Michael C Rusch, Andrew Thrasher, John Easton, Heather L Mulder, Nan Song, Noel-Marie Plonski, Kyla Shelton, Cindy Im, Matthew J Ehrhardt, Kim E Nichols, Wendy M Leisenring, Kayla L Stratton, Rebecca Howell, Yutaka Yasui, Smita Bhatia, Gregory T Armstrong, Kirsten K Ness, Melissa M Hudson, Jinghui Zhang, Hui Wang, Deo Kumar Srivastava, Leslie L Robison, Zhaoming Wang

Faculty, Staff and Student Publications

Background: Carriers of cancer predisposing variants are at an increased risk of developing subsequent malignant neoplasms among those who have survived childhood cancer. We aimed to investigate whether cancer predisposing variants contribute to the risk of subsequent malignant neoplasm-related late mortality (5 years or more after diagnosis).

Methods: In this analysis, data were included from two retrospective cohort studies, St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS), with prospective follow-up of patients who were alive for at least 5 years after diagnosis with childhood cancer (ie, long-term childhood cancer survivors) with corresponding germline whole genome or …

Trends In Radiation Dose To The Contralateral Breast During Breast Cancer Radiation Therapy, Gordon P Watt, Susan A Smith, Rebecca M Howell, Angélica Pérez-Andújar, Ann S Reiner, Laura Cerviño, Beryl Mccormick, Daniela Hess, Julia A Knight, Kathleen E Malone, Esther M John, Leslie Bernstein, Charles F Lynch, Lene Mellemkjær, Roy E Shore, Xiaolin Liang, Meghan Woods, John D Boice, Lawrence T Dauer, Jonine L Bernstein

Faculty, Staff and Student Publications

Over 4 million survivors of breast cancer live in the United States, 35% of whom were treated before 2009. Approximately half of patients with breast cancer receive radiation therapy, which exposes the untreated contralateral breast to radiation and increases the risk of a subsequent contralateral breast cancer (CBC). Radiation oncology has strived to reduce unwanted radiation dose, but it is unknown whether a corresponding decline in actual dose received to the untreated contralateral breast has occurred. The purpose of this study was to evaluate trends in unwanted contralateral breast radiation dose to inform risk assessment of second primary cancer in …

Single-Cell Dissection Of Tumor Microenvironmental Response And Resistance To Cancer Therapy, Yikai Luo, Han Liang

Faculty, Staff and Student Publications

Cancer treatment strategies have evolved significantly over the years, with chemotherapy, targeted therapy, and immunotherapy as major pillars. Each modality leads to unique treatment outcomes by interacting with the tumor microenvironment (TME), which imposes a fundamental selective pressure on cancer progression. The advent of single-cell profiling technologies has revolutionized our understanding of the intricate and heterogeneous nature of the TME at an unprecedented resolution. This review delves into the commonalities and differential manifestations of how cancer therapies reshape the microenvironment in diverse cancer types. We highlight how groundbreaking immune checkpoint blockade (ICB) strategies alone or in combination with tumor-targeting treatments …

National Survey On The Availability Of Oncology Palliative Care Services At Tertiary General And Cancer Hospitals In China, Xiaomei Li, Xin Shelley Wang, Haili Huang, Miao Liu, Yinan Wu, Jiaojiao Qiu, Boran Zhang, Linhong Cui, David Hui

Faculty, Staff and Student Publications

Background: This nationwide survey studied the level of palliative care (PC) access for Chinese patients with cancer among cancer care providers either in tertiary general hospitals or cancer hospitals in China.

Methods: Using a probability-proportionate-to-size method, we identified local tertiary general hospitals with oncology departments to match cancer hospitals at the same geographic area. A PC program leader or a designee at each hospital reported available PC services, including staffing, inpatient and outpatient services, education, and research, with most questions adapted from a previous national survey on PC. The primary outcome was availability of a PC service.

Results: Most responders …

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 …

Deep Learning Integrates Histopathology And Proteogenomics At A Pan-Cancer Level, Joshua M Wang, Runyu Hong, Elizabeth G Demicco, Jimin Tan, Rossana Lazcano, Andre L Moreira, Yize Li, Anna Calinawan, Narges Razavian, Tobias Schraink, Michael A Gillette, Gilbert S Omenn, Eunkyung An, Henry Rodriguez, Aristotelis Tsirigos, Kelly V Ruggles, Li Ding, Ana I Robles, D R Mani, Karin D Rodland, Alexander J Lazar, Wenke Liu, David Fenyö, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Student Publications

We introduce a pioneering approach that integrates pathology imaging with transcriptomics and proteomics to identify predictive histology features associated with critical clinical outcomes in cancer. We utilize 2,755 H&E-stained histopathological slides from 657 patients across 6 cancer types from CPTAC. Our models effectively recapitulate distinctions readily made by human pathologists: tumor vs. normal (AUROC = 0.995) and tissue-of-origin (AUROC = 0.979). We further investigate predictive power on tasks not normally performed from H&E alone, including TP53 prediction and pathologic stage. Importantly, we describe predictive morphologies not previously utilized in a clinical setting. The incorporation of transcriptomics and proteomics identifies pathway-level …

Neurocognitive Outcomes In Adult Survivors Of Neuroblastoma: A Report From The Childhood Cancer Survivor Study, Caroline Hesko, Wei Liu, Deo K Srivastava, Tara M Brinkman, Lisa Diller, Todd M Gibson, Kevin C Oeffinger, Wendy M Leisenring, Rebecca Howell, Gregory T Armstrong, Kevin R Krull, Tara O Henderson

Faculty, Staff and Student Publications

Background: Despite survival improvements, there is a paucity of data on neurocognitive outcomes in neuroblastoma survivors. This study addresses this literature gap.

Methods: Neurocognitive impairments in survivors were compared to sibling controls from the Childhood Cancer Survivor Study (CCSS) using the CCSS Neurocognitive Questionnaire. Impaired emotional regulation, organization, task efficiency, and memory defined as scores ≥90th percentile of sibling norms. Modified Poisson regression models evaluated associations with treatment exposures, era of diagnosis, and chronic conditions. Analyses were stratified by age at diagnosis (≤1 and >1 year) as proxy for lower versus higher risk disease.

Results: Survivors (N = 837; median …

Global Impact Of Somatic Structural Variation On The Cancer Proteome, Fengju Chen, Yiqun Zhang, Darshan S Chandrashekar, Sooryanarayana Varambally, Chad J Creighton

Faculty, Staff and Students Publications

Both proteome and transcriptome data can help assess the relevance of non-coding somatic mutations in cancer. Here, we combine mass spectrometry-based proteomics data with whole genome sequencing data across 1307 human tumors spanning various tissues to determine the extent somatic structural variant (SV) breakpoint patterns impact protein expression of nearby genes. We find that about 25% of the hundreds of genes with SV-associated cis-regulatory alterations at the mRNA level are similarly associated at the protein level. SVs associated with enhancer hijacking, retrotransposon translocation, altered DNA methylation, or fusion transcripts are implicated in protein over-expression. SVs combined with altered protein levels …

Going Circular: History, Present, And Future Of Circrnas In Cancer, Giuseppina Pisignano, David C Michael, Tanvi H Visal, Radu Pirlog, Michael Ladomery, George A Calin

Faculty, Staff and Student Publications

To date, thousands of highly abundant and conserved single-stranded RNA molecules shaped into ring structures (circRNAs) have been identified. CircRNAs are multifunctional molecules that have been shown to regulate gene expression transcriptionally and post-transcriptionally and exhibit distinct tissue- and development-specific expression patterns associated with a variety of normal and disease conditions, including cancer pathogenesis. Over the past years, due to their intrinsic stability and resistance to ribonucleases, particular attention has been drawn to their use as reliable diagnostic and prognostic biomarkers in cancer diagnosis, treatment, and prevention. However, there are some critical caveats to their utility in the clinic. Their …

Oral Delivery Of Rnai For Cancer Therapy, Humayra Afrin, Renu Geetha Bai, Raj Kumar, Sheikh Shafin Ahmad, Sandeep K Agarwal, Md Nurunnabi

Faculty, Staff and Students Publications

Cancer is a major health concern worldwide and is still in a continuous surge of seeking for effective treatments. Since the discovery of RNAi and their mechanism of action, it has shown promises in targeted therapy for various diseases including cancer. The ability of RNAi to selectively silence the carcinogenic gene makes them ideal as cancer therapeutics. Oral delivery is the ideal route of administration of drug administration because of its patients' compliance and convenience. However, orally administered RNAi, for instance, siRNA, must cross various extracellular and intracellular biological barriers before it reaches the site of action. It is very …

Ras Gtpases And Interleaflet Coupling In The Plasma Membrane, Junchen Liu, Neha Arora, Yong Zhou

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RAS genes are frequently mutated in cancer. The primary signaling compartment of wild-type and constitutively active oncogenic mutant RAS proteins is the inner leaflet of the plasma membrane (PM). Thus, a better understanding of the unique environment of the PM inner leaflet is important to shed further light on RAS function. Over the past few decades, an integrated approach of superresolution imaging, molecular dynamic simulations, and biophysical assays has yielded new insights into the capacity of RAS proteins to sort lipids with specific headgroups and acyl chains, to assemble signaling nanoclusters on the inner PM. RAS proteins also sense and …

The Y Of Cancer Sex Differences, Jiexi Li, Ronald A Depinho

Faculty, Staff and Student Publications

No abstract provided.