Genetic Phenomena Commons^™

Recurrent Hgnet-Mn1 Altered (Astroblastoma Mn1-Altered) Of The Foramen Magnum: Case Report And Molecular Classification, Sricharan Gopakumar, Malcolm F Mcdonald, Himanshu Sharma, Claudio E Tatsui, Gregory N Fuller, Ganesh Rao

Faculty, Staff and Student Publications

Background: Astroblastoma is a rare primary brain tumor of unclear origin, often occurring in young patients less than 30-years-old. It typically arises supratentorially and is diagnosed based on histological features including vascular hyalinization and perivascular pseudorosettes. Recent molecular characterization of primary CNS high-grade neuroepithelial tumors with meningioma I alteration (HGNET-MN1) found that HGNET-MN1 and tumors with morphological signatures of astroblastoma clustered together. Further analysis revealed such astroblastomas have MN1 alteration and the 2021 WHO classification of tumors of the CNS now recognizes astroblastoma MN1-altered as a new entity.

Case description: Here, we present the case of …

Re-Thinking Therapeutic Development For Cns Metastatic Disease, Chantal Saberian, Michael A Davies

Faculty, Staff and Student Publications

There has been unprecedented progress in the development of systemic therapies for patients with metastatic melanoma over the last decade. There is now tremendous potential and momentum to further and markedly reduce the impact of this disease. However, developing more effective treatments for metastases to the CNS remains a critical challenge for patients with melanoma. Melanoma patients with active CNS metastases have largely been excluded from both early-phase and registration trials for all currently approved targeted and immune therapies for this disease. While this exclusion has generally been justified in clinical research due to concerns about poor prognosis, lack of …

Behavioural Immune Landscapes Of Inflammation, Georgiana Crainiciuc, Miguel Palomino-Segura, Miguel Molina-Moreno, Jon Sicilia, David G Aragones, Jackson Liang Yao Li, Rodrigo Madurga, José M Adrover, Alejandra Aroca-Crevillén, Sandra Martin-Salamanca, Alfonso Serrano Del Valle, Sandra D Castillo, Heidi C E Welch, Oliver Soehnlein, Mariona Graupera, Fátima Sánchez-Cabo, Alexander Zarbock, Thomas E Smithgall, Mauro Di Pilato, Thorsten R Mempel, Pierre-Louis Tharaux, Santiago F González, Angel Ayuso-Sacido, Lai Guan Ng, Gabriel F Calvo, Iván González-Díaz, Fernando Díaz-De-María, Andrés Hidalgo

Faculty, Staff and Student Publications

Transcriptional and proteomic profiling of individual cells have revolutionized interpretation of biological phenomena by providing cellular landscapes of healthy and diseased tissues1,2. These approaches, however, do not describe dynamic scenarios in which cells continuously change their biochemical properties and downstream 'behavioural' outputs3-5. Here we used 4D live imaging to record tens to hundreds of morpho-kinetic parameters describing the dynamics of individual leukocytes at sites of active inflammation. By analysing more than 100,000 reconstructions of cell shapes and tracks over time, we obtained behavioural descriptors of individual cells and used these high-dimensional datasets to build behavioural landscapes. These landscapes recognized leukocyte …

Prediction Of Early (4-Week) Mortality In Acute Myeloid Leukemia With Intensive Chemotherapy, Koji Sasaki, Tapan Kadia, Kebede Begna, Courtney D Dinardo, Gautam Borthakur, Nicholas J Short, Nitin Jain, Naval Daver, Elias Jabbour, Guillermo Garcia-Manero, Guillermo Montalban Bravo, Lucia Masarova, Sherry Pierce, Marina Konopleva, Farhad Ravandi, Ayalew Tefferi, Hagop Kantarjian

Faculty, Staff and Student Publications

The progress with intensive chemotherapy and supportive care measures has improved survival in patients with newly diagnosed acute myeloid leukemia (AML). Given the recent development of effective low intensity therapies, an optimal decision on the therapy intensity may improve survival through the avoidance of early mortality. We reviewed the outcome of 3728 patients with newly diagnosed AML who received intensive chemotherapy between August 1980 and May 2020. Intensive chemotherapy was defined as a cumulative cytarabine dose ≥ 700 mg/m2 during induction therapy. We divided the whole cohort into a training and validation group at a 3:1 ratio. The population was …

The Current Status And Shortcomings Of Stereotactic Radiosurgery, Hunter Mehrens, Trang Nguyen, Sharbacha Edward, Shannon Hartzell, Mallory Glenn, Daniela Branco, Nadia Hernandez, Paola Alvarez, Andrea Molineu, Paige Taylor, Stephen Kry

Faculty, Staff and Student Publications

Background: Stereotactic radiosurgery (SRS) is a common treatment for intracranial lesions. This work explores the state of SRS treatment delivery to characterize current treatment accuracy based on treatment parameters.

Methods: NCI clinical trials involving SRS rely on an end-to-end treatment delivery on a patient surrogate (credentialing phantom) from the Imaging and Radiation Oncology Core (IROC) to test their treatment accuracy. The results of 1072 SRS phantom irradiations between 2012 and 2020 were retrospectively analyzed. Univariate analysis and random forest models were used to associate irradiation conditions with phantom performance. The following categories were evaluated in terms of how they predicted …

A Phase I, Open-Label, Dose-Escalation Study Of The Ox40 Agonist Ivuxolimab In Patients With Locally Advanced Or Metastatic Cancers, Adi Diab, Omid Hamid, John A Thompson, Willeke Ros, Ferry A L M Eskens, Toshihiko Doi, Siwen Hu-Lieskovan, Samuel J Klempner, Bishu Ganguly, Catherine Fleener, Xiao Wang, Tenshang Joh, Ken Liao, Shahram Salek-Ardakani, Carrie Turich Taylor, Jeffrey Chou, Anthony B El-Khoueiry

Faculty, Staff and Student Publications

PURPOSE: Stimulation of effector T cells is an appealing immunotherapeutic approach in oncology. OX40 (CD134) is a costimulatory receptor expressed on activated CD4

PATIENTS AND METHODS: Adult patients (

RESULTS: The most common all-causality adverse events were fatigue (46.2%), nausea (28.8%), and decreased appetite (25.0%). Of 31 treatment-related adverse events, 30 (96.8%) were grade ≤2. No dose-limiting toxicities occurred. Ivuxolimab exposure increased in a dose-proportionate manner from 0.3 to 10 mg/kg. Full peripheral blood target engagement occurred at ≥0.3 mg/kg. Three (5.8%) patients achieved a partial response, and disease control was achieved in 56% of patients. Increased CD4

CONCLUSIONS: Ivuxolimab …

Epithelial Morphogenesis In The Drosophila Egg Chamber Requires Parvin And Ilk, Athina Keramidioti, Evgenia Golegou, Eleni Psarra, Nikolaos Paschalidis, Konstantina Kalodimou, Shinya Yamamoto, Christos Delidakis, Katerina M Vakaloglou, Christos G Zervas

Duncan NRI Faculty and Staff Publications

Integrins are the major family of transmembrane proteins that mediate cell-matrix adhesion and have a critical role in epithelial morphogenesis. Integrin function largely depends on the indirect connection of the integrin cytoplasmic tail to the actin cytoskeleton through an intracellular protein network, the integrin adhesome. What is currently unknown is the role of individual integrin adhesome components in epithelia dynamic reorganization. Drosophila egg chamber consists of the oocyte encircled by a monolayer of somatic follicle epithelial cells that undergo specific cell shape changes. Egg chamber morphogenesis depends on a developmental array of cell-cell and cell-matrix signalling events. Recent elegant work …

An Asian Case Of Combined 17Α-Hydroxylase/17,20-Lyase Deficiency Due To Homozygous Pr96q Mutation: A Case Report And Review Of The Literature, Qian Liao, Rufei Shen, Mingyu Liao, Chenxi Ran, Ling Zhou, Yuling Zhang, Guiliang Peng, Zheng Sun, Hongting Zheng, Min Long

Center on Aging Staff Publications

Background: Combined 17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a very rare form of congenital adrenal hyperplasia (CAH) caused by mutations in the CYP17A1 gene. Almost 100 different mutations of the CYP17A1 gene have been reported, including p.R96Q mutation, but no case of p.R96Q mutation has been described in Asian populations.

Case presentation: We describe a 22-year-old female patient of 46,XY karyotype, who presented with pseudohermaphrodism, primary amenorrhea, underdeveloped secondary sexual characteristics, delayed epiphyseal healing, hypertension, and hypokalemia. The diagnosis of 17-OHD was reached by measurement of steroid hormones and abdominal CT scan and confirmed by genetic sequencing, which revealed a homozygous p.R96Q …

Advancements In The Quest To Map, Monitor, And Manipulate Neural Circuitry, Jessica L Swanson, Pey-Shyuan Chin, Juan M Romero, Snigdha Srivastava, Joshua Ortiz-Guzman, Patrick J Hunt, Benjamin R Arenkiel

Duncan NRI Faculty and Staff Publications

Neural circuits and the cells that comprise them represent the functional units of the brain. Circuits relay and process sensory information, maintain homeostasis, drive behaviors, and facilitate cognitive functions such as learning and memory. Creating a functionally-precise map of the mammalian brain requires anatomically tracing neural circuits, monitoring their activity patterns, and manipulating their activity to infer function. Advancements in cell-type-specific genetic tools allow interrogation of neural circuits with increased precision. This review provides a broad overview of recombination-based and activity-driven genetic targeting approaches, contemporary viral tracing strategies, electrophysiological recording methods, newly developed calcium, and voltage indicators, and neurotransmitter/neuropeptide biosensors …

Functional Studies Of Genetic Variants Associated With Human Diseases In Notch Signaling-Related Genes Using Drosophila, Sheng-An Yang, Jose L Salazar, David Li-Kroeger, Shinya Yamamoto

Duncan NRI Faculty and Staff Publications

Rare variants in the many genes related to Notch signaling cause diverse Mendelian diseases that affect myriad organ systems. In addition, genome- and exome-wide association studies have linked common and rare variants in Notch-related genes to common diseases and phenotypic traits. Moreover, somatic mutations in these genes have been observed in many types of cancer, some of which are classified as oncogenic and others as tumor suppressive. While functional characterization of some of these variants has been performed through experimental studies, the number of ‘variants of unknown significance’ identified in patients with diverse conditions keeps increasing as high-throughput sequencing technologies …

Comparison Of Treadmill Gait Between A Pediatric-Aged Individual With Syngap1-Related Intellectual Disability And A Fraternal Twin, Charles S Layne, Christopher A Malaya, David R Young, Berhard Suter, Jimmy L Holder

Duncan NRI Faculty and Staff Publications

SYNGAP1-related Intellectual Disability (SYNGAP1-ID) is a rare neurodevelopmental condition characterized by profound intellectual disability, gross motor delays, and behavioral issues. Ataxia and gait difficulties are often observed but have not yet been characterized by laboratory-based kinematic analyses. This investigation identified gait characteristics of an individual with SYNGAP1-ID and compared these with a neurotypical fraternal twin. Lower limb kinematics were collected with a 12-camera motion capture system while both participants walked on a motorized treadmill. Kinematic data were separated into strides, and stride times calculated. Sagittal plane hip, knee, and ankle joints were filtered and temporally normalized …

Quantification Of Behavioral Deficits In Developing Mice With Dystonic Behaviors., Meike E Van Der Heijden, Jason S Gill, Alejandro G Rey Hipolito, Luis E Salazar Leon, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Converging evidence from structural imaging studies in patients, the function of dystonia-causing genes, and the comorbidity of neuronal and behavioral defects all suggest that pediatric-onset dystonia is a neurodevelopmental disorder. However, to fully appreciate the contribution of altered development to dystonia, a mechanistic understanding of how networks become dysfunctional is required for early-onset dystonia. One current hurdle is that many dystonia animal models are ideally suited for studying adult phenotypes, as the neurodevelopmental features can be subtle or are complicated by broad developmental deficits. Furthermore, most assays that are used to measure dystonia are not suited for developing postnatal mice. …

Emerging Roles Of Alternative Cleavage And Polyadenylation (Apa) In Human Disease, Prakash Dharmalingam, Rajasekaran Mahalingam, Hari Krishna Yalamanchili, Tingting Weng, Harry Karmouty-Quintana, Ashrith Guha, Rajarajan A Thandavarayan

Duncan NRI Faculty and Staff Publications

In the messenger RNA (mRNA) maturation process, the 3'-end of pre-mRNA is cleaved and a poly(A) sequence is added, this is an important determinant of mRNA stability and its cellular functions. More than 60%-70% of human genes have three or more polyadenylation (APA) sites and can be cleaved at different sites, generating mRNA transcripts of varying lengths. This phenomenon is termed as alternative cleavage and polyadenylation (APA) and it plays role in key biological processes like gene regulation, cell proliferation, senescence, and also in various human diseases. Loss of regulatory microRNA binding sites and interactions with RNA-binding proteins leading to …

A Novel Group Of Genes That Cause Endocrine Resistance In Breast Cancer Identified By Dynamic Gene Expression Analysis, Arvand Asghari, Katherine Wall, Michael Gill, Natascha Del Vecchio, Farnaz Allahbakhsh, Jacky Wu, Nan Deng, W Jim Zheng, Hulin Wu, Michihisa Umetani, Vahed Maroufy

Faculty, Staff and Student Publications

Breast cancer (BC) is the most common type of cancer diagnosed in women. Among female cancer deaths, BC is the second leading cause of death worldwide. For estrogen receptor-positive (ER-positive) breast cancers, endocrine therapy is an effective therapeutic approach. However, in many cases, an ER-positive tumor becomes unresponsive to endocrine therapy, and tumor regrowth occurs after treatment. While some genetic mutations contribute to resistance in some patients, the underlying causes of resistance to endocrine therapy are mostly undetermined. In this study, we utilized a recently developed statistical approach to investigate the dynamic behavior of gene expression during the development of …

Urinary T Cells Are Detected In Patients With Immune Checkpoint Inhibitor-Associated Immune Nephritis That Are Clonotypically Identical To Kidney T Cell Infiltrates, Shailbala Singh, Leticia C Clemente, Edwin R Parra, Amanda Tchakarov, Chao Yang, Yisheng Li, James P Long, Cassian Yee, Jamie S Lin

Faculty, Staff and Student Publications

Acute kidney injury (AKI) occurs in ~20% of patients receiving immune checkpoint inhibitor (ICI) therapy; however, only 2-5% will develop ICI-mediated immune nephritis. Conventional tests are nonspecific in diagnosing disease pathology and invasive procedures (i.e. kidney biopsy) may not be feasible. In other autoimmune renal diseases, urinary immune cells correlated with the pathology or were predictive of disease activity. Corresponding evidence and analysis are absent for ICI-mediated immune nephritis. We report the first investigation analyzing immune cell profiles of matched kidney biopsies and urine of patients with ICI-AKI. We demonstrated the presence of urinary T cells in patients with immune …

Donor Selection For Kir Alloreactivity Is Associated With Superior Survival In Haploidentical Transplant With Ptcy, Jun Zou, Piyanuch Kongtim, Samer A Srour, Uri Greenbaum, Johannes Schetelig, Falk Heidenreich, Henning Baldauf, Brandt Moore, Supawee Saengboon, Yudith Carmazzi, Gabriela Rondon, Qing Ma, Katayoun Rezvani, Elizabeth J Shpall, Richard E Champlin, Stefan O Ciurea, Kai Cao

Faculty, Staff and Student Publications

With the continuous increase in the use of haploidentical donors for transplantation, the selection of donors becomes increasingly important. Haploidentical donors have been selected primarily based on clinical characteristics, while the effects of killer cell immunoglobulin-like receptors (KIRs) on outcomes of haploidentical-hematopoietic stem cell transplantation (haplo-HSCT) with post-transplant cyclophosphamide (PTCy) remain inconclusive. The present study aimed to thoroughly evaluate the effect of KIRs and binding ligands assessed by various models, in addition to other patient/donor variables, on clinical outcomes in haplo-HSCT. In a cohort of 354 patients undergoing their first haplo-HSCT, we found that a higher Count Functional inhibitory KIR …

A Multicenter Study Of Icu Resource Utilization In Pediatric, Adolescent And Young Adult Patients Post Car-T Therapy, Dristhi Ragoonanan, Saleh Bhar, Gopi Mohan, Fernando Beltramo, Sajad J Khazal, Caitlin Hurley, Clark Andersen, Steven Margossian, Sattva S Neelapu, Elizabeth Shpall, Cristina Gutierrez, Priti Tewari, Basirat Shoberu, Aimee Talleur, David Mccall, Cesar Nunez, Branko Cuglievan, Francesco Paolo Tambaro, Demetrios Petropoulos, Hisham Abdel-Azim, Kris M Mahadeo

Faculty, Staff and Student Publications

Tisagenlecleucel is associated with remarkable outcomes in treating patients up to the age of 25 years with refractory B-cell acute lymphoblastic leukemia (ALL). Yet, due to unique and potentially life-threatening complications, access remains limited to higher-resource and certified centers. Reports of inequity and related disparities in care are emerging. In this multicenter study of ALL patients admitted for anti-leukemia therapy, who required pediatric intensive care (ICU) support (n = 205), patients receiving tisagenlecleucel (n = 39) were compared to those receiving conventional chemotherapy (n = 166). The median time to ICU transfer was 6 (0-43) versus 1 (0-116) days, respectively …

Immune Checkpoint Inhibitor-Related Gastrointestinal Toxicity In Patients With Malignancy Involving The Luminal Gastrointestinal Tract And Its Impact On Cancer Outcomes, Kevin Yu, Antony Mathew, Fiyinfoluwa Abraham, Rajan Amin, Miho Kono, Michael Overman, Dan Zhao, Anam Khan, Muhammad A Khan, Anusha S Thomas, Yinghong Wang

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitors (ICI) are known to cause immune-related adverse events (irAE) with the gastrointestinal (GI) tract among the most affected. Our knowledge of GI irAE in patients with luminal GI malignancies is poor. We aimed to characterize the incidence, clinical features, treatment, and outcomes of these GI irAEs.

Methods: This was a retrospective study of patients with malignancies involving the luminal GI tract and GI irAEs at MD Anderson Cancer Center from January 2010 to June 2020. Clinical data were collected and analyzed.

Results: Eighteen patients with luminal GI tract malignancies treated with ICIs had evidence of GI …

Update On Mri In Evaluation And Treatment Of Endometrial Cancer, Ekta Maheshwari, Stephanie Nougaret, Erica B Stein, Gaiane M Rauch, Ken-Pin Hwang, R Jason Stafford, Ann H Klopp, Pamela T Soliman, Katherine E Maturen, Andrea G Rockall, Susanna I Lee, Elizabeth A Sadowski, Aradhana M Venkatesan

Faculty, Staff and Student Publications

Endometrial cancer is the second most common gynecologic cancer worldwide and the most common gynecologic cancer in the United States, with an increasing incidence in high-income countries. Although the International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial cancer is a surgical staging system, contemporary published evidence-based data and expert opinions recommend MRI for treatment planning as it provides critical diagnostic information on tumor size and depth, extent of myometrial and cervical invasion, extrauterine extent, and lymph node status, all of which are essential in choosing the most appropriate therapy. Multiparametric MRI using a combination of T2-weighted sequences, …

Highlights From The 7th Oncological Pathology Conference 'Pathological Anatomy In The Context Of The National Cancer Law: An Overview Of The Latin American Experience', 15, 22 And 23 July 2022, Trujillo, Peru, Caddie Laberiano-Fernández, Joan Moreno Luján, Bruno De Carvalho Dornelas, Magali Franco Benites, Patricia Gutiérrez Quispe, Valeria Aguilar Vásquez, Andric Guerrero Espinoza, Elsa Guerra Guerra, Gabriela Gil-Arroyo Álvarez, Juan Astigueta-Pérez, Maria Teresa Garcia De Dávila, Sandro Casavilca Zambrano, Tatiana Vidaurre Rojas, Alejandro Mariños, Emmanuel S González, Rossana Lazcano, Ricardo R Lastra, Isabel Alvarado-Cabrero, Henry Guerra Miller, Ricardo H Bardales, Milagros Abad-Licham

Faculty, Staff and Student Publications

The seventh session of the Oncological Pathology Conference (JoPaO) entitled 'Pathological Anatomy in the context of the National Cancer Law: An overview of the Latin American experience', was held virtually on July 15, 22 and 23. Peru was the headquarters for this event, where 17 national and international professors of high academic standing participated. They interacted in a multidisciplinary context through talks with national panellists and the general public. The recent promulgation of the 'National Cancer Law' fosters the development of discussion forums to analyse the national realities and uphold continuous learning about experiences in other Latin American countries with …

Electroacupuncture Ameliorates Inflammatory Response Induced By Retinal Ischemia-Reperfusion Injury And Protects The Retina Through The Dor-Bdnf/Trkb Pathway, Runjie Guo, Yongjie Zhang, Yue Geng, Ping Chen, Tiantian Fu, Yong Xia, Ren Zhang, Yuan Zhu, Jingling Jin, Nange Jin, Hong Xu, Xuesong Tian

Faculty, Staff and Student Publications

Objectives: Retinal ischemia-reperfusion injury (RIRI) is the common pathological basis of many ophthalmic diseases in the later stages, and inflammation is the primary damage mechanism of RIRI. Our study aimed to assess whether electroacupuncture (EA) has a protective effect against RIRI and to elucidate its related mechanisms.

Methods: A high-intraocular pressure (HIOP) model was used to simulate RIRI in Wistar rats. EA was applied to the EA1 group [Jingming (BL1) + Shuigou (GV26)] and the EA2 group [Jingming (BL1) + Hegu (LI4)] respectively for 30 min starting immediately after the onset of reperfusion and repeated (30 min/time) at 12 h …

Use Of Specific Duodenal Dose Constraints During Treatment Planning Reduces Toxicity After Definitive Paraaortic Radiation Therapy For Cervical Cancer, David S Lakomy, Juliana Wu, Bhavana V Chapman, Zhiqian Henry Yu, Belinda Lee, Ann H Klopp, Anuja Jhingran, Patricia J Eifel, Lilie L Lin

Faculty, Staff and Student Publications

Purpose: This study aimed to validate the safety of paraaortic nodal (PAN) radiation therapy (RT) for patients with cervical cancer when the duodenal dose is limited to V55 < 15 cm3 and V60 < 2 cm3.

Methods and materials: A total of 97 patients who were treated with RT for cervical cancer between 2010 and 2018 received at least 56 Gy to grossly involved PANs. Patients were treated with concurrent chemoradiation (n = 88; 91%), with 93% of patients (n = 90) receiving intensity modulated RT to the initial PAN field and 98% (n = 95) receiving intensity modulated RT to a sequential PAN boost. The V55 < 15 cm3 and V60 < 2 cm3 criteria were implemented in 2014. Normal tissues were contoured on computed tomography (CT) simulation data sets, and the duodenum was contoured from the gastric outlet to the duodenojejunal flexure. Sixty-six patients (68%) had a resimulation scan after approximately 20 fractions. Composite duodenal doses were calculated using the initial CT scan for 50 patients (52%) and the resimulation CT scan for 47 patients (48%) depending on the anatomic changes throughout treatment.

Results: …

Clinical Characteristics And Outcomes Of Castleman Disease: A Multicenter Consortium Study Of 428 Patients With 15-Year Follow-Up, Wanying Liu, Qingqing Cai, Tiantian Yu, Paolo Strati, Frederick B Hagemeister, Qiongli Zhai, Mingzhi Zhang, Ling Li, Xiaosheng Fang, Jianyong Li, Ruifang Sun, Shanxiang Zhang, Hanjin Yang, Zhaoming Wang, Wenbian Qian, Noriko Iwaki, Yasuharu Sato, Eric Oksenhendler, Zijun Y Xu-Monette, Ken H Young, Li Yu

Faculty, Staff and Student Publications

Castleman disease (CD) has been reported as a group of poorly understood lymphoproliferative disorders, including unicentric CD (UCD) and idiopathic multicentric CD (iMCD) which are human immunodeficiency virus (HIV) negative and human herpes virus 8 (HHV-8) negative. The clinical and independent prognostic factors of CD remain poorly elucidated. We retrospectively collected the clinical information of 428 patients with HIV and HHV-8 negative CD from 12 large medical centers with 15-year follow-up. We analyzed the clinicopathologic features of 428 patients (248 with UCD and 180 with iMCD) with a median age of 41 years. The histology subtypes were hyaline-vascular (HV) histopathology …

Targetable Vulnerability Of Deregulated Foxm1/Plk1 Signaling Axis In Diffuse Large B Cell Lymphoma, Fang Yu, Hua He, Loretta J Nastoupil, Zijun Y Xu-Monette, Ky Pham, Yong Liang, Guang Chen, Nathan H Fowler, C Cameron Yin, Dongfeng Tan, Yaling Yang, Shimin Hu, Ken H Young, Lan V Pham, M James You

Faculty, Staff and Student Publications

FOXM1 is a transcription factor that controls cell cycle regulation, cell proliferation, and differentiation. Overexpression of FOXM1 has been implicated in various cancer types. However, the activation status and functional significance of FOXM1 in diffuse large B cell lymphoma (DLBCL) have not been well investigated. Using proteomic approaches, we discovered that the protein expression levels of FOXM1 and PLK1 were positively correlated in DLBCL cell lines and primary DLBCL. Expression levels of FOXM1 and PLK1 mRNAs were also significantly higher in DLBCL than in normal human B cells and could predict poor prognosis of DLBCL, particularly in patients with germinal …

Quaking But Not Parkin Is The Major Tumor Suppressor In 6q Deleted Region In Glioblastoma, Fatma Betul Aksoy Yasar, Takashi Shingu, Daniel B Zamler, Mohammad Fayyad Zaman, Derek Lin Chien, Qiang Zhang, Jiangong Ren, Jian Hu

Faculty, Staff and Student Publications

Glioblastoma (GBM) is a high-grade, aggressive brain tumor with dismal median survival time of 15 months. Chromosome 6q (Ch6q) is a hotspot of genomic alterations, which is commonly deleted or hyper-methylated in GBM. Two neighboring genes in this region, QKI and PRKN have been appointed as tumor suppressors in GBM. While a genetically modified mouse model (GEMM) of GBM has been successfully generated with Qk deletion in the central nervous system (CNS), in vivo genetic evidence supporting the tumor suppressor function of Prkn has not been established. In the present study, we generated a mouse model with Prkn-null allele …

Disruption Of Growth Hormone Receptor Signaling Abrogates Hepatocellular Carcinoma Development, Abedul Haque, Vishal Sahu, Jamie Lynne Lombardo, Lianchun Xiao, Bhawana George, Robert A Wolff, Jeffrey S Morris, Asif Rashid, John J Kopchick, Ahmed O Kaseb, Hesham M Amin

Faculty, Staff and Student Publications

Introduction: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancers. It is an aggressive neoplasm with dismal outcome because most of the patients present with an advanced-stage disease, which precludes curative surgical options. Therefore, these patients require systemic therapies that typically induce small improvements in overall survival. Hence, it is crucial to identify new and promising therapeutic targets for HCC to improve the current outcome. The liver is a key organ in the signaling cascade triggered by the growth hormone receptor (GHR). Previous studies have shown that GHR signaling stimulates the proliferation and regeneration of liver cells …

Blockade Of Growth Hormone Receptor Signaling By Using Pegvisomant: A Functional Therapeutic Strategy In Hepatocellular Carcinoma, Ahmed O Kaseb, Abedul Haque, Deeksha Vishwamitra, Manal M Hassan, Lianchun Xiao, Bhawana George, Vishal Sahu, Yehia I Mohamed, Roberto Carmagnani Pestana, Jamie Lynne Lombardo, Rony Avritscher, James C Yao, Robert A Wolff, Asif Rashid, Jeffrey S Morris, Hesham M Amin

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC) is an aggressive neoplasm with poor clinical outcome because most patients present at an advanced stage, at which point curative surgical options, such as tumor excision or liver transplantation, are not feasible. Therefore, the majority of HCC patients require systemic therapy. Nonetheless, the currently approved systemic therapies have limited effects, particularly in patients with advanced and resistant disease. Hence, there is a critical need to identify new molecular targets and effective systemic therapies to improve HCC outcome. The liver is a major target of the growth hormone receptor (GHR) signaling, and accumulating evidence suggests that GHR signaling …

Editorial: The Role Of The Igf Axis In Tumorigenesis And Cancer Treatment: From Genes To Metabolites, Guo Mengzhe, Xie Shanshan, Zhao Di, Wu Shihua

Faculty, Staff and Student Publications

No abstract provided.

Distal-Less Homeobox Genes Dlx5/6 Regulate Müllerian Duct Regression, Rachel D Mullen, Brice Bellessort, Giovanni Levi, Richard R Behringer

Faculty, Staff and Student Publications

Dlx5 and Dlx6 encode distal-less homeodomain transcription factors that are present in the genome as a linked pair at a single locus. Dlx5 and Dlx6 have redundant roles in craniofacial, skeletal, and uterine development. Previously, we performed a transcriptome comparison for anti-Müllerian hormone (AMH)-induced genes expressed in the Müllerian duct mesenchyme of male and female mouse embryos. In that study, we found that Dlx5 transcripts were nearly seven-fold higher in males compared to females and Dlx6 transcripts were found only in males, suggesting they may be AMH-induced genes. Therefore, we investigated the role of Dlx5 and Dlx6 during AMH-induced Müllerian …

Doxorubicin-Induced Cardiotoxicity Is Mediated By Neutrophils Through Release Of Neutrophil Elastase, Anchit Bhagat, Pradeep Shrestha, Prince Jeyabal, Zhanglong Peng, Stephanie S Watowich, Eugenie S Kleinerman

Faculty, Staff and Student Publications

The mechanisms by which Doxorubicin (Dox) causes acute and late cardiotoxicity are not completely understood. One understudied area is the innate immune response, and in particular the role of neutrophils in Dox-induced cardiotoxicity. Here, using echocardiography, flow cytometry and immunofluorescence staining, we demonstrated increased infiltration of neutrophils that correlated with decreased heart function, disruption of vascular structures and increased collagen deposition in the heart after Dox treatment. Depleting neutrophils protected the heart from Dox-induced cardiotoxicity and changes in vascular structure. Furthermore, our data using neutrophil elastase (NE) knock-out mice and the NE inhibitor AZD9668 suggest that neutrophils cause this damage …