Medicine and Health Sciences Commons^™

Bayesian Hierarchical Random-Effects Meta-Analysis And Design Of Phase I Clinical Trials, Ruitao Lin, Haolun Shi, Guosheng Yin, Peter F Thall, Ying Yuan, Christopher R Flowers

Faculty, Staff and Student Publications

We propose a curve-free random-effects meta-analysis approach to combining data from multiple phase I clinical trials to identify an optimal dose. Our method accounts for between-study heterogeneity that may stem from different study designs, patient populations, or tumor types. We also develop a meta-analytic-predictive (MAP) method based on a power prior that incorporates data from multiple historical studies into the design and conduct of a new phase I trial. Performances of the proposed methods for data analysis and trial design are evaluated by extensive simulation studies. The proposed random-effects meta-analysis method provides more reliable dose selection than comparators that rely …

Development Of A Distributed International Patient Data Registry For Hairy Cell Leukemia, Leslie A Andritsos, Mirela Anghelina, Jasmine Neal, James S Blachly, Puneet Mathur, Omkar Lele, Claire Dearden, Sunil Iyengar, Matthew Cross, Clive S Zent, Kerry A Rogers, Narendranath Epperla, Gerard Lozanski, Christopher C Oakes, Eric Kraut, Amy S Ruppert, Qiuhong Zhao, Seema A Bhat, Francesco Forconi, Versha Banerji, Sasanka Handunnetti, Constantine S Tam, John F Seymour, Monica Else, Robert J Kreitman, Alan Saven, Timothy Call, Sameer A Parikh, Farhad Ravandi, James B Johnston, Enrico Tiacci, Xavier Troussard, Martin S Tallman, Sascha Dietrich, Tamar Tadmor, Alessandro Gozzetti, Pier Luigi Zinzani, Tadeusz Robak, Graeme Quest, Judit Demeter, Kanti Rai, Soledad A Fernandez, Michael Grever

Faculty, Staff and Student Publications

Hairy cell leukemia (HCL) is a rare lymphoproliferative disorder, comprising only 2% of all leukemias. The Hairy Cell Leukemia Foundation (HCLF) has developed a patient data registry to enable investigators to better study the clinical features, treatment outcomes, and complications of patients with HCL. This system utilizes a centralized registry architecture. Patients are enrolled at HCL Centers of Excellence (COE) or via a web-based portal. All data are de-identified, which reduces regulatory burden and increases opportunities for data access and re-use. To date, 579 patients have been enrolled in the registry. Efforts are underway to engage additional COE's to expand …

Prognostic Impact Of Breslow Thickness In Acral Melanoma: A Retrospective Analysis, Xiaoting Wei, Yu Chen, Hong Yao, Di Wu, Hang Li, Rui Zhang, Zhihong Chi, Chuanliang Cui, Xue Bai, Lili Mao, Zhonghui Qi, Ke Li, Shijie Lan, Lizhu Chen, Rui Guo, Xinyu Yao, Bin Lian, Yan Kong, Jie Dai, Bixia Tang, Xuan Wang, Jeffrey E Gershenwald, Charles M Balch, Jun Guo, Lu Si

Faculty, Staff and Student Publications

Background: Evidence for the prognostic importance of tumor thickness in acral melanoma (AM) patients is limited.

Objective: The objective of the study was to determine the prognostic impact of Breslow thickness in AM.

Methods: This multicenter study enrolled patients diagnosed with localized AM between January 1, 2000 and December 31, 2017. Melanoma-specific survival (MSS) in different tumor thickness strata (T1-T4: ≤1, >1-2, >2-4, >4 mm, respectively) was estimated by the Kaplan-Meier method. Comparisons were performed by the log-rank test and multivariable Cox regression.

Results: A total of 853 patients with clinical N0 (cN0) AM were included in the analysis. The …

Neoadjuvant Chemo-Immunotherapy For Lung Cancer: How Much Is Too Much?, Nathaniel Deboever, Jianjun Zhang

Faculty, Staff and Student Publications

No abstract provided.

Neoadjuvant Chemotherapy Is Associated With Altered Immune Cell Infiltration And An Anti-Tumorigenic Microenvironment In Resected Pancreatic Cancer, Andressa Dias Costa, Sara A Väyrynen, Akhil Chawla, Jinming Zhang, Juha P Väyrynen, Mai Chan Lau, Hannah L Williams, Chen Yuan, Vicente Morales-Oyarvide, Dalia Elganainy, Harshabad Singh, James M Cleary, Kimberly Perez, Kimmie Ng, William Freed-Pastor, Joseph D Mancias, Stephanie K Dougan, Jiping Wang, Douglas A Rubinson, Richard F Dunne, Margaret M Kozak, Lauren Brais, Emma Reilly, Thomas Clancy, David C Linehan, Daniel T Chang, Aram F Hezel, Albert C Koong, Andrew J Aguirre, Brian M Wolpin, Jonathan A Nowak

Faculty, Staff and Student Publications

PURPOSE: Neoadjuvant chemotherapy is increasingly administered to patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC), yet its impact on the tumor immune microenvironment is incompletely understood.

DESIGN: We employed quantitative, spatially resolved multiplex immunofluorescence and digital image analysis to identify T-cell subpopulations, macrophage polarization states, and myeloid cell subpopulations in a multi-institution cohort of up-front resected primary tumors (n = 299) and in a comparative set of resected tumors after FOLFIRINOX-based neoadjuvant therapy (n = 36) or up-front surgery (n = 30). Multivariable-adjusted Cox proportional hazards models were used to evaluate associations between the immune microenvironment and patient …

Direct Cd32 T-Cell Cytotoxicity: Implications For Breast Cancer Prognosis And Treatment, Giuseppe Sconocchia, Giulia Lanzilli, Valeriana Cesarini, Domenico A Silvestris, Katayoun Rezvani, Roberto Arriga, Sara Caratelli, Ken Chen, Jinzhuang Dou, Carlo Cenciarelli, Gabriele Toietta, Silvia Baldari, Tommaso Sconocchia, Francesca De Paolis, Anna Aureli, Giandomenica Iezzi, Maria Irno Consalvo, Francesco Buccisano, Maria I Del Principe, Luca Maurillo, Adriano Venditti, Alessio Ottaviani, Giulio C Spagnoli

Faculty, Staff and Student Publications

The FcγRII (CD32) ligands are IgFc fragments and pentraxins. The existence of additional ligands is unknown. We engineered T cells with human chimeric receptors resulting from the fusion between CD32 extracellular portion and transmembrane CD8α linked to CD28/ζ chain intracellular moiety (CD32-CR). Transduced T cells recognized three breast cancer (BC) and one colon cancer cell line among 15 tested in the absence of targeting antibodies. Sensitive BC cell conjugation with CD32-CR T cells induced CD32 polarization and down-regulation, CD107a release, mutual elimination, and proinflammatory cytokine production unaffected by human IgGs but enhanced by cetuximab. CD32-CR T cells protected immunodeficient mice …

Statistical Process Control To Monitor Use Of A Web-Based Autoplanning Tool, Hunter Mehrens, Raphael Douglas, Mary Gronberg, Kelly Nealon, Joy Zhang, Laurence Court

Faculty, Staff and Student Publications

PURPOSE: To investigate the use of statistical process control (SPC) for quality assurance of an integrated web-based autoplanning tool, Radiation Planning Assistant (RPA).

METHODS: Automatically generated plans were downloaded and imported into two treatment planning systems (TPSs), RayStation and Eclipse, in which they were recalculated using fixed monitor units. The recalculated plans were then uploaded back to the RPA, and the mean dose differences for each contour between the original RPA and the TPSs plans were calculated. SPC was used to characterize the RPA plans in terms of two comparisons: RayStation TPS versus RPA and Eclipse TPS versus RPA for …

Reorganization Of The Functional Connectome From Rest To A Visual Perception Task In Schizophrenia And Bipolar Disorder, Philipp Riedel, Junghee Lee, Christopher G Watson, Amy M Jimenez, Eric A Reavis, Michael F Green

Faculty, Staff and Student Publications

Functional connectome organization is altered in schizophrenia (SZ) and bipolar disorder (BD). However, it remains unclear whether network reorganization during a task relative to rest is also altered in these disorders. This study examined connectome organization in patients with SZ (N = 43) and BD (N = 42) versus healthy controls (HC; N = 39) using fMRI data during a visual object-perception task and at rest. Graph analyses were conducted for the whole-brain network using indices selected a priori: three reflecting network segregation (clustering coefficient, local efficiency, modularity), two reflecting integration (characteristic path length, global efficiency). Group differences were limited …

A Cross-National Comparison Of The Linkages Between Family Structure Histories And Early Adolescent Substance Use, Haley Stritzel, Michael Green, Robert Crosnoe

Faculty, Staff and Student Publications

Family structure can influence adolescent health with cascading implications into adulthood. Life course theory emphasizes how this phenomenon is dynamic across time, contextualized in policy systems, and grounded in processes of selection and socialization. This study used data from the U.S. (National Longitudinal Survey of Youth 1979 Child and Young Adults, n = 6,236) and U.K. (Millennium Cohort Study, n = 11,095) to examine associations between a single mother family structure between ages 0-14 and early adolescent substance use at age 14 across time and place, using inverse probability of treatment weighting to explore how results varied by selection into …

Radiomics In Abdominopelvic Solid-Organ Oncologic Imaging: Current Status, Xiaoyang Liu, Mohamed G Elbanan, Antonio Luna, Masoom A Haider, Andrew D Smith, Carl F Sabottke, Bradley M Spieler, Baris Turkbey, David Fuentes, Ahmed Moawad, Serageldin Kamel, Natally Horvat, Khaled M Elsayes

Faculty, Staff and Student Publications

Radiomics is the process of extraction of high-throughput quantitative imaging features from medical images. These features represent noninvasive quantitative biomarkers that go beyond the traditional imaging features visible to the human eye. This article first reviews the steps of the radiomics pipeline, including image acquisition, ROI selection and image segmentation, image preprocessing, feature extraction, feature selection, and model development and application. Current evidence for the application of radiomics in abdominopelvic solid-organ cancers is then reviewed. Applications including diagnosis, subtype determination, treatment response assessment, and outcome prediction are explored within the context of hepatobiliary and pancreatic cancer, renal cell carcinoma, prostate …

Characterizing Treatment Resistance In Muscle Invasive Bladder Cancer Using The Chicken Egg Chorioallantoic Membrane Patient-Derived Xenograft Model, Hugo Villanueva, Gabrielle A Wells, Malachi T Miller, Mariana Villanueva, Ravi Pathak, Patricia Castro, Michael M Ittmann, Andrew G Sikora, Seth P Lerner

Faculty, Staff and Student Publications

BACKGROUND: Non-metastatic muscle invasive urothelial bladder cancer (MIBC) has a poor prognosis and standard of care (SOC) includes neoadjuvant cisplatin-based chemotherapy (NAC) combined with cystectomy. Patients receiving NAC have at best

METHODS: We optimized engraftment conditions for primary MIBC tumors using the CAM-PDX model and tested concordance between cisplatin-based chemotherapy response of patients to matching PDX tumors using tumor growth coupled with immunohistochemistry markers of proliferation and apoptosis. We also tested select kinase inhibitor response on chemotherapy-resistant bladder cancers on the CAM-PDX using tumor growth measurements and immuno-detection of proliferation marker, Ki-67.

RESULTS: Our results show primary, NAC-resistant, MIBC tumors …

Single-Cell Crispr Immune Screens Reveal Immunological Roles Of Tumor Intrinsic Factors, Jiakai Hou, Shaoheng Liang, Chunyu Xu, Yanjun Wei, Yunfei Wang, Yukun Tan, Nidhi Sahni, Daniel J Mcgrail, Chantale Bernatchez, Michael Davies, Yumei Li, Rui Chen, S Stephen Yi, Yiwen Chen, Cassian Yee, Ken Chen, Weiyi Peng

Faculty, Staff and Student Publications

Genetic screens are widely exploited to develop novel therapeutic approaches for cancer treatment. With recent advances in single-cell technology, single-cell CRISPR screen (scCRISPR) platforms provide opportunities for target validation and mechanistic studies in a high-throughput manner. Here, we aim to establish scCRISPR platforms which are suitable for immune-related screens involving multiple cell types. We integrated two scCRISPR platforms, namely Perturb-seq and CROP-seq, with both in vitro and in vivo immune screens. By leveraging previously generated resources, we optimized experimental conditions and data analysis pipelines to achieve better consistency between results from high-throughput and individual validations. Furthermore, we evaluated the performance …

Discovery And Systematic Characterization Of Risk Variants And Genes For Coronary Artery Disease In Over A Million Participants, Krishna G Aragam, Tao Jiang, Anuj Goel, Stavroula Kanoni, Brooke N Wolford, Deepak S Atri, Elle M Weeks, Minxian Wang, George Hindy, Wei Zhou, Christopher Grace, Carolina Roselli, Nicholas A Marston, Frederick K Kamanu, Ida Surakka, Loreto Muñoz Venegas, Paul Sherliker, Satoshi Koyama, Kazuyoshi Ishigaki, Bjørn O Åsvold, Michael R Brown, Ben Brumpton, Paul S De Vries, Olga Giannakopoulou, Panagiota Giardoglou, Daniel F Gudbjartsson, Ulrich Güldener, Syed M Ijlal Haider, Anna Helgadottir, Maysson Ibrahim, Adnan Kastrati, Thorsten Kessler, Theodosios Kyriakou, Tomasz Konopka, Ling Li, Lijiang Ma, Thomas Meitinger, Sören Mucha, Matthias Munz, Federico Murgia, Jonas B Nielsen, Markus M Nöthen, Shichao Pang, Tobias Reinberger, Gavin Schnitzler, Damian Smedley, Gudmar Thorleifsson, Moritz Von Scheidt, Jacob C Ulirsch, Biobank Japan, Epic-Cvd, David O Arnar, Noël P Burtt, Maria C Costanzo, Jason Flannick, Kaoru Ito, Dong-Keun Jang, Yoichiro Kamatani, Amit V Khera, Issei Komuro, Iftikhar J Kullo, Luca A Lotta, Christopher P Nelson, Robert Roberts, Gudmundur Thorgeirsson, Unnur Thorsteinsdottir, Thomas R Webb, Aris Baras, Johan L M Björkegren, Eric Boerwinkle, George Dedoussis, Hilma Holm, Kristian Hveem, Olle Melander, Alanna C Morrison, Marju Orho-Melander, Loukianos S Rallidis, Arno Ruusalepp, Marc S Sabatine, Kari Stefansson, Pierre Zalloua, Patrick T Ellinor, Martin Farrall, John Danesh, Christian T Ruff, Hilary K Finucane, Jemma C Hopewell, Robert Clarke, Rajat M Gupta, Jeanette Erdmann, Nilesh J Samani, Heribert Schunkert, Hugh Watkins, Cristen J Willer, Panos Deloukas, Sekar Kathiresan, Adam S Butterworth, Cardiogramplusc4d Consortium

Faculty, Staff and Student Publications

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in …

Tceal1 Loss-Of-Function Results In An X-Linked Dominant Neurodevelopmental Syndrome And Drives The Neurological Disease Trait In Xq222 Deletions, Hadia Hijazi, Linda M Reis, Davut Pehlivan, Jonathan A Bernstein, Michael Muriello, Erin Syverson, Devon Bonner, Mehrdad A Estiar, Ziv Gan-Or, Guy A Rouleau, Ekaterina Lyulcheva, Lynn Greenhalgh, Marine Tessarech, Estelle Colin, Agnès Guichet, Dominique Bonneau, R H Van Jaarsveld, A M A Lachmeijer, Lyse Ruaud, Jonathan Levy, Anne-Claude Tabet, Rafal Ploski, Małgorzata Rydzanicz, Łukasz Kępczyński, Katarzyna Połatyńska, Yidan Li, Jawid M Fatih, Dana Marafi, Jill A Rosenfeld, Zeynep Coban-Akdemir, Weimin Bi, Richard A Gibbs, Grace M Hobson, Jill V Hunter, Claudia M B Carvalho, Jennifer E Posey, Elena V Semina, James R Lupski

Faculty, Staff and Student Publications

An Xq22.2 region upstream of PLP1 has been proposed to underly a neurological disease trait when deleted in 46,XX females. Deletion mapping revealed that heterozygous deletions encompassing the smallest region of overlap (SRO) spanning six Xq22.2 genes (BEX3, RAB40A, TCEAL4, TCEAL3, TCEAL1, and MORF4L2) associate with an early-onset neurological disease trait (EONDT) consisting of hypotonia, intellectual disability, neurobehavioral abnormalities, and dysmorphic facial features. None of the genes within the SRO have been associated with monogenic disease in OMIM. Through local and international collaborations facilitated by GeneMatcher and Matchmaker Exchange, we have identified and herein report seven de novo variants involving …

Targeting The Mtor Pathway For The Prevention Of Er-Negative Breast Cancer, Abhijit Mazumdar, William M Tahaney, Jamal L Hill, Yun Zhang, Sumankalai Ramachandran, Jitesh Kawedia, Jing Qian, Alejandro Contreras, Michelle I Savage, Lana A Vornik, Shizuko Sei, Altaf Mohammed, Powel H Brown

Faculty, Staff and Student Publications

Our results show that everolimus delays mammary tumor formation in multiple mouse models, suggesting that mTOR inhibitors will be useful for the prevention of ER-negative and triple-negative breast cancer in humans. See related Spotlight, p. 787.

Genome Protection By Dna Polymerase Θ, Richard D Wood, Sylvie Doublié

Faculty, Staff and Student Publications

DNA polymerase θ (Pol θ) is a DNA repair enzyme widely conserved in animals and plants. Pol θ uses short DNA sequence homologies to initiate repair of double-strand breaks by theta-mediated end joining. The DNA polymerase domain of Pol θ is at the C terminus and is connected to an N-terminal DNA helicase-like domain by a central linker. Pol θ is crucial for maintenance of damaged genomes during development, protects DNA against extensive deletions, and limits loss of heterozygosity. The cost of using Pol θ for genome protection is that a few nucleotides are usually deleted or added at the …

Hdac2 In Primary Sensory Neurons Constitutively Restrains Chronic Pain By Repressing Α2Δ-1 Expression And Associated Nmda Receptor Activity, Jixiang Zhang, Shao-Rui Chen, Meng-Hua Zhou, Daozhong Jin, Hong Chen, Li Wang, Ronald A Depinho, Hui-Lin Pan

Faculty, Staff and Student Publications

α2δ-1 (encoded by the Cacna2d1 gene) is a newly discovered NMDA receptor-interacting protein and is the therapeutic target of gabapentinoids (e.g., gabapentin and pregabalin) frequently used for treating patients with neuropathic pain. Nerve injury causes sustained α2δ-1 upregulation in the dorsal root ganglion (DRG), which promotes NMDA receptor synaptic trafficking and activation in the spinal dorsal horn, a hallmark of chronic neuropathic pain. However, little is known about how nerve injury initiates and maintains the high expression level of α2δ-1 to sustain chronic pain. Here, we show that nerve injury caused histone hyperacetylation and diminished enrichment of histone deacetylase-2 (HDAC2), …

Hippo-Yap Signaling Maintains Sinoatrial Node Homeostasis, Mingjie Zheng, Rich G Li, Jia Song, Xiaolei Zhao, Li Tang, Shannon Erhardt, Wen Chen, Bao H Nguyen, Xiao Li, Min Li, Jianxin Wang, Sylvia M Evans, Vincent M Christoffels, Na Li, Jun Wang

Faculty, Staff and Student Publications

BACKGROUND: The sinoatrial node (SAN) functions as the pacemaker of the heart, initiating rhythmic heartbeats. Despite its importance, the SAN is one of the most poorly understood cardiac entities because of its small size and complex composition and function. The Hippo signaling pathway is a molecular signaling pathway fundamental to heart development and regeneration. Although abnormalities of the Hippo pathway are associated with cardiac arrhythmias in human patients, the role of this pathway in the SAN is unknown.

METHODS: We investigated key regulators of the Hippo pathway in SAN pacemaker cells by conditionally inactivating the Hippo signaling kinases

RESULTS: We …

Optimal Construction Of A Functional Interaction Network From Pooled Library Crispr Fitness Screens, Veronica Gheorghe, Traver Hart

Faculty, Staff and Student Publications

BACKGROUND: Functional interaction networks, where edges connect genes likely to operate in the same biological process or pathway, can be inferred from CRISPR knockout screens in cancer cell lines. Genes with similar knockout fitness profiles across a sufficiently diverse set of cell line screens are likely to be co-functional, and these "coessentiality" networks are increasingly powerful predictors of gene function and biological modularity. While several such networks have been published, most use different algorithms for each step of the network construction process.

RESULTS: In this study, we identify an optimal measure of functional interaction and test all combinations of options …

Genetic And Small-Molecule Modulation Of Stat3 In A Mouse Model Of Crohn's Disease, Prema Robinson, Emily Magness, Kelsey Montoya, Nikita Engineer, Thomas K Eckols, Emma Rodriguez, David J Tweardy

Faculty, Staff and Student Publications

Crohn's disease (CD), is an inflammatory bowel disease that can affect any part of the gastro-intestinal tract (GI) and is associated with an increased risk of gastro-intestinal cancer. In the current study, we determined the role of genetic and small-molecule modulation of STAT3 in a mouse model of CD. STAT3 has 2 isoforms (α, β) which are expressed in most cells in a 4:1 ratio (α: β). STAT3α has pro-inflammatory and anti-apoptotic functions, while STAT3β has contrasting roles. We used an animal model of CD consisting of intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid and examined the severity of CD in …

The Fate Of Early Perichondrial Cells In Developing Bones, Yuki Matsushita, Angel Ka Yan Chu, Chiaki Tsutsumi-Arai, Shion Orikasa, Mizuki Nagata, Sunny Y Wong, Joshua D Welch, Wanida Ono, Noriaki Ono

Faculty, Staff and Student Publications

In endochondral bone development, bone-forming osteoblasts and bone marrow stromal cells have dual origins in the fetal cartilage and its surrounding perichondrium. However, how early perichondrial cells distinctively contribute to developing bones remain unidentified. Here we show using in vivo cell-lineage analyses that Dlx5+ fetal perichondrial cells marked by Dlx5-creER do not generate cartilage but sustainably contribute to cortical bone and marrow stromal compartments in a manner complementary to fetal chondrocyte derivatives under the regulation of Hedgehog signaling. Postnatally, Dlx5+ fetal perichondrial cell derivatives preferentially populate the diaphyseal marrow stroma with a dormant adipocyte-biased state and are refractory to parathyroid …

Inactivation Of Lats1/2 Drives Luminal-Basal Plasticity To Initiate Basal-Like Mammary Carcinomas, Joseph G Kern, Andrew M Tilston-Lunel, Anthony Federico, Boting Ning, Amy Mueller, Grace B Peppler, Eleni Stampouloglou, Nan Cheng, Randy L Johnson, Marc E Lenburg, Jennifer E Beane, Stefano Monti, Xaralabos Varelas

Faculty, Staff and Student Publications

Basal-like breast cancers, an aggressive breast cancer subtype that has poor treatment options, are thought to arise from luminal mammary epithelial cells that undergo basal plasticity through poorly understood mechanisms. Using genetic mouse models and ex vivo primary organoid cultures, we show that conditional co-deletion of the LATS1 and LATS2 kinases, key effectors of Hippo pathway signaling, in mature mammary luminal epithelial cells promotes the development of Krt14 and Sox9-expressing basal-like carcinomas that metastasize over time. Genetic co-deletion experiments revealed that phenotypes resulting from the loss of LATS1/2 activity are dependent on the transcriptional regulators YAP/TAZ. Gene expression analyses of …

Interventions For Preventing And Ameliorating Cognitive Deficits In Adults Treated With Cranial Irradiation, Matthew A Kirkman, Julia Day, Karin Gehring, Karolis Zienius, David Grosshans, Martin Taphoorn, Jing Li, Paul D Brown

Faculty, Staff and Student Publications

BACKGROUND: Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of pharmacological and non-pharmacological treatment of cognitive deficits in this population is unclear. This is an updated version of the original Cochrane Review published in Issue 12, 2014.

OBJECTIVES: To assess the effectiveness of interventions for preventing or ameliorating cognitive deficits in adults treated with cranial irradiation.

SEARCH METHODS: For this review update we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE via Ovid, Embase via Ovid, and PsycInfo via Ovid to 12 …

Oxphos Promotes Apoptotic Resistance And Cellular Persistence In Th17 Cells In The Periphery And Tumor Microenvironment, Hanna S Hong, Nneka E Mbah, Mengrou Shan, Kristen Loesel, Lin Lin, Peter Sajjakulnukit, Luis O Correa, Anthony Andren, Jason Lin, Atsushi Hayashi, Brian Magnuson, Judy Chen, Zhaoheng Li, Yuying Xie, Li Zhang, Daniel R Goldstein, Shannon A Carty, Yu Leo Lei, Anthony W Opipari, Rafael J Argüello, Ilona Kryczek, Nobuhiko Kamada, Weiping Zou, Luigi Franchi, Costas A Lyssiotis

Faculty, Staff and Student Publications

T cell proliferation and cytokine production are bioenergetically and biosynthetically costly. The inability to meet these metabolic demands results in altered differentiation, accompanied by impaired effector function, and attrition of the immune response. Interleukin-17-producing CD4 T cells (TH17s) are mediators of host defense, autoimmunity, and antitumor immunity in the setting of adoptive T cell therapy. TH17s are long-lived cells that require mitochondrial oxidative phosphorylation (OXPHOS) for effector function in vivo. Considering that TH17s polarized under standardized culture conditions are predominately glycolytic, little is known about how OXPHOS regulates TH17 processes, such as their ability to persist and thus contribute to …

A Retrospective Comparative Study Of Sodium Fluoride Na18f-Pet/Ct And 68ga-Psma-11 Pet/Ct In The Bone Metastases Of Prostate Cancer Using A Volumetric 3-D Radiomic Analysis, Kalevi Kairemo, Aki Kangasmäki, Srinivasan Cheenu Kappadath, Timo Joensuu, Homer A Macapinlac

Faculty, Staff and Student Publications

Bone is the most common metastatic site in prostate cancer (PCa). 68Ga-PSMA-11 (or gozetotide) and sodium fluoride-18 (Na18F) are rather new radiopharmaceuticals for assessing PCa-associated bone metastases. Gozetotide uptake reflects cell membrane enzyme activity and the sodium fluoride uptake measures bone mineralization in advanced PCa. Here, we aim to characterize this difference and possibly provide a new method for patient selection in targeted therapies. Methods: The study consisted of 14 patients with advanced PCa (M group > 5 lesions), who had had routine PET/CT both with PSMA and NaF over consecutive days, and 12 PCa patients with no skeletal metastases (N). …

Coating Formulation Change Leads To Inferior Performance Of Long-Lasting Insecticidal Nets In Papua New Guinea, Nakei Bubun, Evodia Anetul, Melanie Koinari, Timothy W Freeman, Stephan Karl

Faculty, Staff and Student Publications

BACKGROUND: Long-lasting insecticidal nets (LLINs) play a key role in reducing malaria transmission in endemic countries. In a previous study, the authors demonstrated a substantial decrease in the bioefficacy of LLINs for malaria prevention delivered to Papua New Guinea (PNG) between 2013 and 2019. This coincided with a rise in malaria cases in the country. The present study was aimed at determining the underlying cause of the reduced bioefficacy observed in these LLINs. The main hypothesis was that a change in the coating formulation of the respective LLIN product was responsible, and had led to significantly altered product properties and …

The Innate Immune System In Cardiovascular Diseases And Its Role In Doxorubicin-Induced Cardiotoxicity, Anchit Bhagat, Pradeep Shrestha, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Innate immune cells are the early responders to infection and tissue damage. They play a critical role in the initiation and resolution of inflammation in response to insult as well as tissue repair. Following ischemic or non-ischemic cardiac injury, a strong inflammatory response plays a critical role in the removal of cell debris and tissue remodeling. However, persistent inflammation could be detrimental to the heart. Studies suggest that cardiac inflammation and tissue repair needs to be tightly regulated such that the timely resolution of the inflammation may prevent adverse cardiac damage. This involves the recognition of damage; activation and release …

Genomic Profiling For Clinical Decision Making In Myeloid Neoplasms And Acute Leukemia, Eric J Duncavage, Adam Bagg, Robert P Hasserjian, Courtney D Dinardo, Lucy A Godley, Ilaria Iacobucci, Siddhartha Jaiswal, Luca Malcovati, Alessandro M Vannucchi, Keyur P Patel, Daniel A Arber, Maria E Arcila, Rafael Bejar, Nancy Berliner, Michael J Borowitz, Susan Branford, Anna L Brown, Catherine A Cargo, Hartmut Döhner, Brunangelo Falini, Guillermo Garcia-Manero, Torsten Haferlach, Eva Hellström-Lindberg, Annette S Kim, Jeffery M Klco, Rami Komrokji, Mignon Lee-Cheun Loh, Sanam Loghavi, Charles G Mullighan, Seishi Ogawa, Attilio Orazi, Elli Papaemmanuil, Andreas Reiter, David M Ross, Michael Savona, Akiko Shimamura, Radek C Skoda, Francesc Solé, Richard M Stone, Ayalew Tefferi, Matthew J Walter, David Wu, Benjamin L Ebert, Mario Cazzola

Faculty, Staff and Student Publications

Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome …

Spatially Aware Dimension Reduction For Spatial Transcriptomics, Lulu Shang, Xiang Zhou

Faculty, Staff and Student Publications

Spatial transcriptomics are a collection of genomic technologies that have enabled transcriptomic profiling on tissues with spatial localization information. Analyzing spatial transcriptomic data is computationally challenging, as the data collected from various spatial transcriptomic technologies are often noisy and display substantial spatial correlation across tissue locations. Here, we develop a spatially-aware dimension reduction method, SpatialPCA, that can extract a low dimensional representation of the spatial transcriptomics data with biological signal and preserved spatial correlation structure, thus unlocking many existing computational tools previously developed in single-cell RNAseq studies for tailored analysis of spatial transcriptomics. We illustrate the benefits of SpatialPCA for …

Triple Blockade Of Ido-1, Pd-L1 And Mek As A Potential Therapeutic Strategy In Nsclc, Carminia Maria Della Corte, Vincenza Ciaramella, Kavya Ramkumar, Giovanni Vicidomini, Alfonso Fiorelli, Valerio Nardone, Salvatore Cappabianca, Immacolata Cozzolino, Federica Zito Marino, Gaetano Di Guida, Qi Wang, Robert Cardnell, Carl Michael Gay, Davide Ciardiello, Erika Martinelli, Teresa Troiani, Giulia Martini, Stefania Napolitano, Jing Wang, Lauren Averett Byers, Fortunato Ciardiello, Floriana Morgillo

Faculty, Staff and Student Publications

BACKGROUND: Despite the recent progress in the treatment and outcome of Non Small Cell Lung Cancer (NSCLC), immunotherapy has still significant limitations reporting a significant proportion of patients not benefiting from therapy, even in patients with high PD-L1 expression. We have previously demonstrated that the combined inhibition of MEK and PD-L1 in NSCLC patients derived three dimensional cultures exerted significant synergistic effect in terms of immune-dependent cancer cell death. However, subsequent experiments analyzing the expression of Indoleamine 2,3-dioxygenase-1 (Ido-1) gene expression demonstrated that Ido-1 resulted unaffected by the MEK inhibition and even increased after the combined inhibition of MEK and …