Medicine and Health Sciences Commons^™

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 …

Author Correction: Distinct Molecular And Immune Hallmarks Of Inflammatory Arthritis Induced By Immune Checkpoint Inhibitors For Cancer Therapy, Sang T Kim, Yanshuo Chu, Mercy Misoi, Maria E Suarez-Almazor, Jean H Tayar, Huifang Lu, Maryam Buni, Jordan Kramer, Emma Rodriguez, Zulekha Hussain, Sattva S Neelapu, Jennifer Wang, Amishi Y Shah, Nizar M Tannir, Matthew T Campbell, Don L Gibbons, Tina Cascone, Charles Lu, George R Blumenschein, Mehmet Altan, Bora Lim, Vincente Valero, Monica E Loghin, Janet Tu, Shannon N Westin, Aung Naing, Guillermo Garcia-Manero, Noha Abdel-Wahab, Hussein A Tawbi, Patrick Hwu, Isabella C Glitza Oliva, Michael A Davies, Sapna P Patel, Jun Zou, Andrew Futreal, Adi Diab, Linghua Wang, Roza Nurieva

Faculty, Staff and Student Publications

No abstract provided.

Genomic Determinants Of Response And Resistance To Inotuzumab Ozogamicin In B-Cell All, Yaqi Zhao, Nicholas J Short, Hagop M Kantarjian, Ti-Cheng Chang, Pankaj S Ghate, Chunxu Qu, Walid Macaron, Nitin Jain, Beenu Thakral, Aaron H Phillips, Joseph Khoury, Guillermo Garcia-Manero, Wenchao Zhang, Yiping Fan, Hui Yang, Rebecca S Garris, Lewis F Nasr, Richard W Kriwacki, Kathryn G Roberts, Marina Konopleva, Elias J Jabbour, Charles G Mullighan

Faculty, Staff and Student Publications

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO-treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of the response and resistance to InO. Pre- and post-InO-treated patient samples were analyzed by whole genome, exome, and/or transcriptome sequencing. Acquired CD22 mutations were observed in 11% (3/27) of post-InO-relapsed tumor samples, but not in refractory samples (0/16). There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included epitope loss (protein truncation and destabilization) and epitope alteration. Two CD22 mutant cases were post-InO …

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 …

Calcitriol Unleashed: A Rare Culprit In Hypercalcemia Associated With Rare Primary Pancreatic Lymphoma - A Case Report, Dania Kaur, Abhinav Vyas, Sowmya Sagireddy, Rabia Qazi, Sarah Elsayed, Jyoti Verma, Prutha Pathak, Rachna Valvani

Journal of Community Hospital Internal Medicine Perspectives

Hypercalcemia of Malignancy is a complicated condition often linked to parathyroid hormone, parathyroid hormone-related peptide, or bone metastasis. This report presents a unique case of calcitriol-mediated hypercalcemia in an 89-year-old female with primary pancreatic lymphoma, highlighting the rarity and complexity of this presentation. Initially, the patient's condition was thought to be related to sarcoidosis, but the recurrence of hypercalcemia led to the discovery of pancreatic B-cell lymphoma as the underlying cause. It also emphasizes the need to explore new treatment options. Interestingly, it demonstrates the successful use of cinacalcet in treating calcitriol-induced hypercalcemia in malignancies, which could be a potential …

Immunotherapy Induced Adrenal Insufficiency: An Underdiagnosed Cause Of Persistent Hypotension In Cancer, Nina H. Cheng, Hannah Lee, Divya Balchander, Remy Mimms, Mahesh Krishnamurthy

Journal of Community Hospital Internal Medicine Perspectives

Endocrinopathies following immunotherapy have infrequently been documented in the literature. Adrenal insufficiency is a rare consequence of pembrolizumab immunotherapy, with incidence reported to be between 0.98 and 1.3%. We present the case of a 34-year-old female with triple negative breast cancer on chemotherapy who presented with generalized weakness with tachycardia, tachypnea and hypotension unresponsive to fluids. Despite initial improvement with intravenous hydrocortisone and midodrine, the patient continued to be symptomatically hypotensive following discharge and required re-admission. AM cortisol level was found to be < 0.5 ug/dl and ACTH was

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 …

Loss Of The Dna Repair Gene Rnase H2 Identifies A Unique Subset Of Ddr-Deficient Leiomyosarcomas, Michael S Nakazawa, Ian M Silverman, Victoria Rimkunas, Artur Veloso, Dominik Glodzik, Adrienne Johnson, Toshiro K Ohsumi, Shreyaskumar R Patel, Anthony P Conley, Christina L Roland, Pamela T Soliman, Hannah C Beird, Chia-Chin Wu, Davis R Ingram, Rossana Lazcano, Dawon Song, Khalida M Wani, Alexander J Lazar, Timothy A Yap, Wei-Lien Wang, J Andrew Livingston

Faculty, Staff and Student Publications

Targeting the DNA damage response (DDR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS), and loss of RNase H2, a DDR pathway member, is a potentially actionable alteration for DDR-targeted treatments. Therefore, we designed a protein- and genomic-based RNase H2 screening assay to determine its prevalence and prognostic significance. Using a selective RNase H2 antibody on a pan-tumor microarray (TMA), RNase H2 loss was more common in LMS (11.5%, 9/78) than across all tumors (3.8%, 32/843). In a separate LMS cohort, RNase H2 deficiency was confirmed in uterine LMS (U-LMS, 21%, 23/108) and soft-tissue LMS (ST-LMS; 30%, 39/102). In …

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 …

Prognostic Value Of The 1-Min Sit-To-Stand Test To Predict Post-Operative Complications In Patients With Lung Cancer Elected For Lung Resection, Kirsten Quadflieg, Rachael Higgins, Eva Arents, Heleen Demeyer, Maarten Criel, Marc Daenen, David Ruttens, Michiel Thomeer, Dieter Stevens, Andrew Maiorana, Martijn A. Spruit, Vinicius Cavalheri, Chris Burtin

Research outputs 2022 to 2026

No abstract provided.

Use Of Cobalt(Iii) And Copper(Ii) Complexes With Thiosemicarbazone Ligands And Berberine Chloride As Anti-Cancer Agents Against Triple Negative Breast Cancer, Duaa Rashad Alajroush

Chemistry & Biochemistry Theses & Dissertations

It is a worrying fact that chemotherapeutic options for treating triple negative breast cancer are limited in nature, including the use of inorganic pharmaceuticals such as cisplatin and its analogues. It has been reported that cisplatin has undesirable side effects when used as a chemotherapeutic drug. As such, there is a need to use non-platinum-containing complexes as chemotherapeutic agents. Based on that issue, it has been reported by our research group and others that cobalt- and copper-containing complexes have shown great potential in anti-cancer properties when compared to cisplatin. In this research project, the cytotoxic effects of the following complexes: …

Exercise And Diet Support In Breast And Prostate Cancer Survivors: Findings From Focus Groups, Jack Dalla Via, Christopher R. Andrew, Brenton J. Baguley, Nina Stewart, Jonathan M. Hodgson, Joshua R. Lewis, Mandy Stanley, Mary A. Kennedy

Research outputs 2022 to 2026

Purpose: Cancer survival is improving, making optimal management of long-term treatment-related adverse effects increasingly important. Exercise and a healthy diet are beneficial and regularly recommended in cancer survivorship guidelines; however, few cancer survivors meet these recommendations so there is a need to explore why. This study aimed to understand experiences receiving exercise and diet support among Australian breast and prostate cancer survivors during and following treatment, and to explore what support they would like to receive. Methods: Adults who completed active treatment for breast or prostate cancer were recruited via a private cancer care centre. Using a qualitative descriptive study …

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 …

Effect Of Medicaid Expansion On Cancer Treatment And Survival Among Medicaid Beneficiaries And The Uninsured, Kristin M Primm, Hui Zhao, Naomi N Adjei, Charlotte C Sun, Alen Haas, Larissa A Meyer, Shine Chang

Faculty, Staff and Student Publications

BACKGROUND: The Affordable Care Act expanded Medicaid coverage for people with low income in the United States. Expanded insurance coverage could promote more timely access to cancer treatment, which could improve overall survival (OS), yet the long-term effects of Medicaid expansion (ME) remain unknown. We evaluated whether ME was associated with improved timely treatment initiation (TTI) and 3-year OS among patients with breast, cervical, colon, and lung cancers who were affected by the policy.

METHODS: Medicaid-insured or uninsured patients aged 40-64 with stage I-III breast, cervical, colon, or non-small cell lung cancer within the National Cancer Database (NCDB). A difference-in-differences …

A Deep Catalogue Of Protein-Coding Variation In 983,578 Individuals, Kathie Y Sun, Xiaodong Bai, Siying Chen, Suying Bao, Chuanyi Zhang, Manav Kapoor, Joshua Backman, Tyler Joseph, Evan Maxwell, George Mitra, Alexander Gorovits, Adam Mansfield, Boris Boutkov, Sujit Gokhale, Lukas Habegger, Anthony Marcketta, Adam E Locke, Liron Ganel, Alicia Hawes, Michael D Kessler, Deepika Sharma, Jeffrey Staples, Jonas Bovijn, Sahar Gelfman, Alessandro Di Gioia, Veera M Rajagopal, Alexander Lopez, Jennifer Rico Varela, Jesús Alegre-Díaz, Jaime Berumen, Roberto Tapia-Conyer, Pablo Kuri-Morales, Jason Torres, Jonathan Emberson, Rory Collins, Regeneron Genetics Center, Rgc-Me Cohort Partners; Michael Cantor, Michael Cantor, Timothy Thornton, Hyun Min Kang, John D Overton, Alan R Shuldiner, M Laura Cremona, Mona Nafde, Aris Baras, Gonçalo Abecasis, Jonathan Marchini, Jeffrey G Reid, William Salerno, Suganthi Balasubramanian

Faculty, Staff and Student Publications

Rare coding variants that substantially affect function provide insights into the biology of a gene1-3. However, ascertaining the frequency of such variants requires large sample sizes4-8. Here we present a catalogue of human protein-coding variation, derived from exome sequencing of 983,578 individuals across diverse populations. In total, 23% of the Regeneron Genetics Center Million Exome (RGC-ME) data come from individuals of African, East Asian, Indigenous American, Middle Eastern and South Asian ancestry. The catalogue includes more than 10.4 million missense and 1.1 million predicted loss-of-function (pLOF) variants. We identify individuals with rare biallelic pLOF variants in 4,848 genes, 1,751 of …

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 …

Change In Trust In Us Government Health Agencies For Cancer Information In The Covid-19 Era, Onyema G Chido-Amajuoyi, Rajesh Talluri, Henry K Onyeaka, Itunu Sokale, Gideon T Dosunmu, Noelle Loconte, Sanjay Shete

Faculty, Staff and Student Publications

This cross-sectional study assesses changes in levels of public trust in US government health agencies providing cancer information.

Machine Learning Identifies Prognostic Subtypes Of The Tumor Microenvironment Of Nsclc, Duo Yu, Michael J Kane, Eugene J Koay, Ignacio I Wistuba, Brian P Hobbs

Faculty, Staff and Student Publications

The tumor microenvironment (TME) plays a fundamental role in tumorigenesis, tumor progression, and anti-cancer immunity potential of emerging cancer therapeutics. Understanding inter-patient TME heterogeneity, however, remains a challenge to efficient drug development. This article applies recent advances in machine learning (ML) for survival analysis to a retrospective study of NSCLC patients who received definitive surgical resection and immune pathology following surgery. ML methods are compared for their effectiveness in identifying prognostic subtypes. Six survival models, including Cox regression and five survival machine learning methods, were calibrated and applied to predict survival for NSCLC patients based on PD-L1 expression, CD3 expression, …

Mutation Order In Acute Myeloid Leukemia Identifies Uncommon Patterns Of Evolution And Illuminates Phenotypic Heterogeneity, Matthew Schwede, Katharina Jahn, Jack Kuipers, Linde A Miles, Robert L Bowman, Troy Robinson, Ken Furudate, Hidetaka Uryu, Tomoyuki Tanaka, Yuya Sasaki, Asiri Ediriwickrema, Brooks Benard, Andrew J Gentles, Ross Levine, Niko Beerenwinkel, Koichi Takahashi, Ravindra Majeti

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) has a poor prognosis and a heterogeneous mutation landscape. Although common mutations are well-studied, little research has characterized how the sequence of mutations relates to clinical features. Using published, single-cell DNA sequencing data from three institutions, we compared clonal evolution patterns in AML to patient characteristics, disease phenotype, and outcomes. Mutation trees, which represent the order of select mutations, were created for 207 patients from targeted panel sequencing data using 1 639 162 cells, 823 mutations, and 275 samples. In 224 distinct orderings of mutated genes, mutations related to DNA methylation typically preceded those related to …

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 …

Ceramide-Mediated Orchestration Of Oxidative Stress Response Through Filopodia-Derived Small Extracellular Vesicles, Zainuddin Quadri, Ahmed Elsherbini, Simone M. Crivelli, Salim S. El-Amouri, Priyanka Tripathi, Zhihui Zhu, Xiaojia Ren, Liping Zhang, Stefka D. Spassieva, Mariana N. Nikolova‑Karakashian, Erhard Bieberich

Markey Cancer Center Faculty Publications

Extracellular vesicles (EVs) are shed from the plasma membrane, but the regulation and function of these EVs remain unclear. We found that oxidative stress induced by H 2 O 2 in Hela cells stimulated filopodia formation and the secretion of EVs. EVs were small (150 nm) and labeled for CD44, indicating that they were derived from filopodia. Filopodia-derived small EVs (sEVs) were enriched with the sphingolipid ceramide, consistent with increased ceramide in the plasma membrane of filopo- dia. Ceramide was colocalized with neutral sphingomyelinase 2 (nSMase2) and acid sphingomyelinase (ASM), two sphingomyelinases generating ceramide at the plasma membrane. Inhibition of …

Soxb1 Transcription Factors Are Essential For Initiating And Maintaining Neural Plate Border Gene Expression, Elizabeth Schock, Joshua R. York, Austin P. Li, Ashlyn Y. Tu, Carole Labonne

Markey Cancer Center Faculty Publications

SoxB1 transcription factors (Sox2/3) are well known for their role in early neural fate specification in the embryo, but little is known about functional roles for SoxB1 factors in non-neural ectodermal cell types, such as the neural plate border (NPB). Using Xenopus laevis, we set out to determine whether SoxB1 transcription factors have a regulatory function in NPB formation. Here, we show that SoxB1 factors are necessary for NPB formation, and that prolonged SoxB1 factor activity blocks the transition from a NPB to a neural crest state. Using ChIP-seq, we demonstrate that Sox3 is enriched upstream of NPB genes in …

14-3-3Ζ Suppresses Rankl Signaling By Destabilizing Traf6, R. Ayyasamy, S. Fan, P. Czernik, B. Lecka-Czernik, Somsubhra Chattopadhyay, R. Chakravarti

Markey Cancer Center Faculty Publications

Macrophages are essential regulators of inflammation and bone loss. Receptor activator of nuclear factor-κβ ligand (RANKL), a pro-inflammatory cytokine, is responsible for macrophage differentiation to osteoclasts and bone loss. We recently showed that 14-3-3ζ-knockout (Ywhaz^KO) rats exhibit increased bone loss in the inflammatory arthritis model. 14-3-3ζ is a cytosolic adaptor protein that actively participates in many signaling transductions. However, the role of 14-3-3ζ in RANKL signaling or bone remodeling is unknown. We investigated how 14-3-3ζ affects osteoclast activity by evaluating its role in RANKL signaling. We utilized 14-3-3ζ-deficient primary bone marrow–derived macrophages obtained from wildtype and Ywhaz^{KO …}

Discussions Of Cancer Survivorship Care Needs: Are There Rural Versus Urban Inequities?, Tyrone F. Borders, Lindsey R. Hammerslag

Markey Cancer Center Faculty Publications

Background: Rural cancer survivors may face greater challenges receiving survivorship care than urban cancer survivors.

Purpose: To test for rural versus urban inequities and identify other correlates of discussions about cancer survivorship care with healthcare professionals.

Methods: Data are from the 2017 Medical Expenditure Panel Survey (MEPS), which included a cancer survivorship supplement. Adult survivors were asked if they discussed with a healthcare professional 5 components of survivorship care: need for follow-up services, lifestyle/health recommendations, emotional/social needs, long-term side effects, and a summary of treatments received. The Behavioral Model of Health Services guided the inclusion of predisposing, enabling, and need …

Diffuse Reflectance Spectroscopy For Optical Characterizations Of Orthotopic Head And Neck Cancer Models In Vivo, Pranto Soumik Saha, Jing Yan, Caigang Zhu

Markey Cancer Center Faculty Publications

We demonstrated an easy-to-build, portable diffuse reflectance spectroscopy device along with a Monte Carlo inverse model to quantify tissue absorption and scattering-based parameters of orthotopic head and neck cancer models in vivo. Both tissue-mimicking phantom studies and animal studies were conducted to verify the optical spectroscopy system and Monte Carlo inverse model for the accurate extraction of tissue optical properties. For the first time, we reported the tissue absorption and scattering coefficients of mouse normal tongue tissues and tongue tumor tissues. Our in vivo animal studies showed reduced total hemoglobin concentration, lower tissue vascular oxygen saturation, and increased tissue scattering …

A Probabilistic Approach To Estimate The Temporal Order Of Pathway Mutations Accounting For Intra-Tumor Heterogeneity, Menghan Wang, Yanqi Xie, Jinpeng Liu, Austin Li, Li Chen, Arnold Stromberg, Susanne Arnold, Chunming Liu, Chi Wang

Markey Cancer Center Faculty Publications

The development of cancer involves the accumulation of somatic mutations in several essential biological pathways. Delineating the temporal order of pathway mutations during tumori- genesis is crucial for comprehending the biological mechanisms underlying cancer development and identifying potential targets for therapeutic intervention. Several computational and statistical methods have been introduced for estimating the order of somatic mutations based on mutation profile data from a cohort of patients. However, one major issue of current methods is that they do not take into account intra-tumor heterogeneity (ITH), which limits their ability to accurately discern the order of pathway mutations. To address this …

Response To Replication Stress And Maintenance Of Genome Stability By Wrn, The Werner Syndrome Protein, David K. Orren, Amrita Machwe

Markey Cancer Center Faculty Publications

Werner syndrome (WS) is an autosomal recessive disease caused by loss of function of WRN. WS is a segmental progeroid disease and shows early onset or increased frequency of many characteristics of normal aging. WRN possesses helicase, annealing, strand exchange, and exonuclease activities and acts on a variety of DNA substrates, even complex replication and re- combination intermediates. Here, we review the genetics, biochemistry, and probably physiological functions of the WRN protein. Although its precise role is unclear, evidence suggests WRN plays a role in pathways that respond to replication stress and maintain genome stability particularly in telomeric regions.

Lurbinectedin In Small Cell Lung Cancer: Real-World Experience Of A Multicentre National Early Access Programme, Marliese Alexander, Jennifer Rogers, Sagun Parakh, Paul Mitchell, Timothy D. Clay, Steven Kao, Brett G.M. Hughes, Malinda Itchins, Benjamin Y. Kong, Nick Pavlakis, Benjamin J. Solomon, Thomas John

Research outputs 2022 to 2026

Background and Aims: Lurbinectedin is a novel oncogenic transcription inhibitor active in several cancers, including small cell lung cancer (SCLC). We aimed to describe the first Australian experience of the clinical efficacy and tolerability of lurbinectedin for the treatment of SCLC after progression on platinum-containing therapy. Methods: Multicentre real-world study of individuals with SCLC initiating lurbinectedin monotherapy (3.2 mg/m2 three-weekly) on an early access programme between May 2020 and December 2021. Key outcomes were clinical utilisation, efficacy and tolerability. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan–Meier method. Outcome data were collected within the AUstralian Registry …

Management Of Malignant Pleural Effusion And Trapped Lung: A Survey Of Respiratory Physicians And Thoracic Surgeons In Australasia, Calvin Sidhu, Gavin Wright, Carolyn J. Peddle-Mcintyre, Ai Ling Tan, Yun Chor Gary Lee

Research outputs 2022 to 2026

Background:

Malignant pleural effusions (MPEs) are common, and a third of them have underlying trapped lung (TL). Management of MPE and TL is suspected to be heterogeneous. Understanding current practices in Australasia is important in guiding policies and future research.

Aims:

Electronic survey of Australia-New Zealand respiratory physicians, thoracic surgeons and their respective trainees to determine practice of MPE and TL management.

Results:

Of the 132 respondents, 56% were respiratory physicians, 23% were surgeons and 20% were trainees. Many respondents defined TL as >25% or any level of incomplete lung expansion; 75% would use large-volume thoracentesis to determine whether TL …