Neoplasms Commons^™

Validation Of Metabolic Alterations In Microscale Cell Culture Lysates Using Hydrophilic Interaction Liquid Chromatography (Hilic)-Tandem Mass Spectrometry-Based Metabolomics, Venugopal Gunda, Fang Yu, Pankaj K. Singh

Journal Articles: Eppley Institute

By standard convention, in order to increase the efficacy of metabolite detection from cell culture lysates, metabolite extracts from a large quantity of cells are utilized for multiple reaction monitoring-based metabolomic studies. Metabolomics from a small number of cell extracts offers a potential economical alternative to increased cell numbers, in turn increasing the utility of cell culture-based metabolomics. However, the effect of reduced cell numbers on targeted metabolomic profiling is relatively unstudied. Considering the limited knowledge available of the feasibility and accuracy of microscale cell culture metabolomics, the present study analyzes differences in metabolomic profiles of different cell numbers of …

Evaluating Human Cell Survival And Dna Damage After Exposure To Various Amounts Of Chlorine Dioxide And Exploring Its Use As A Potential Cancer Chemotherapy Agent, Niuska Mariana Alvarez Fuenmayor

SURF - Summer Undergraduate Research Fellowship Projects

Chlorine Dioxide (ClO₂) is a synthetic, green-yellowish gas with a chlorine-like, irritating odor that is used for the treatment of drinking water and food preservation. The aim of this study was to evaluate the genotoxic potential of the chlorine dioxide in mammalian cells and to determine what dose of ClO₂ is tolerable by normal cells and cells with aberrant DNA repair genes. Human and mouse embryonic cells were treated with various ClO₂ dilutions ranging from 2.5 mM to 25 mM. The cell viability and metabolic activity was determined via MTT, a colorimetric assay. Human HEK293 cells …

Tmsb4y Is A Candidate Tumor Suppressor On The Y Chromosome And Is Deleted In Male Breast Cancer., Hong Yuen Wong, Grace M Wang, Sarah Croessmann, Daniel J Zabransky, Anita Aggarwal, Min-Ling Liu, + 10 More

Pathology Faculty Publications

Male breast cancer comprises less than 1% of breast cancer diagnoses. Although estrogen exposure has been causally linked to the development of female breast cancers, the etiology of male breast cancer is unclear. Here, we show via fluorescence in situ hybridization (FISH) and droplet digital PCR (ddPCR) that the Y chromosome was clonally lost at a frequency of ~16% (5/31) in two independent cohorts of male breast cancer patients. We also show somatic loss of the Y chromosome gene TMSB4Y in a male breast tumor, confirming prior reports of loss at this locus in male breast cancers. To further understand …

Leveraging Global Gene Expression Patterns To Predict Expression Of Unmeasured Genes, James Rudd, René A. Zelaya, Eugene Demidenko, Ellen L. Goode, Casey S. Greene S. Greene, Jennifer A. Doherty

Dartmouth Scholarship

BackgroundLarge collections of paraffin-embedded tissue represent a rich resource to test hypotheses based on gene expression patterns; however, measurement of genome-wide expression is cost-prohibitive on a large scale. Using the known expression correlation structure within a given disease type (in this case, high grade serous ovarian cancer; HGSC), we sought to identify reduced sets of directly measured (DM) genes which could accurately predict the expression of a maximized number of unmeasured genes.

‘Much Clearer With Pictures’: Using Community-Based Participatory Research To Design And Test A Picture Option Grid For Underserved Patients With Breast Cancer, Marie-Anne Durand, Shama Alam, Stuart W. Grande, Glyn Elwyn

Dartmouth Scholarship

Women of low socioeconomic status (SES) diagnosed with early stage breast cancer experience decision-making, treatment and outcome disparities. Evidence suggests that decision aids can benefit underserved patients, when tailored to their needs. Our aim was to develop and test the usability, acceptability and accessibility of a pictorial encounter decision aid targeted at women of low SES diagnosed with early stage breast cancer.

Silibinin-Mediated Metabolic Reprogramming Attenuates Pancreatic Cancer-Induced Cachexia And Tumor Growth., Surendra K. Shukla, Aneesha Dasgupta, Kamiya Mehla, Venugopal Gunda, Enza Vernucci, Joshua J. Souchek, Gennifer Goode, Ryan King, Anusha Mishra, Ibha Rai, Sangeetha Nagarajan, Nina V. Chaika, Fang Yu, Surendra K. Shukla

Journal Articles: Eppley Institute

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic …

Cyclin-Dependent Kinase Inhibitor P1446a Induces Apoptosis In A Jnk/P38 Mapk-Dependent Manner In Chronic Lymphocytic Leukemia B-Cells, Cody Paiva, J. Claire Godbersen, Ryan S. Soderquist, Taylor Rowland, Sumner Kilmarx

Dartmouth Scholarship

CDK (cyclin-dependent kinase) inhibitors have shown remarkable activity in CLL, where its efficacy has been linked to inhibition of the transcriptional CDKs (7 and 9) and deregulation of RNA polymerase and short-lived pro-survival proteins such as MCL1. Furthermore, ER (endoplasmic reticulum) stress has been implicated in CDK inhibition in CLL. Here we conducted a pre-clinical study of a novel orally active kinase inhibitor P1446A in CLL B-cells. P1446A inhibited CDKs at nanomolar concentrations and induced rapid apoptosis of CLL cells in vitro, irrespective of chromosomal abnormalities or IGHV mutational status. Apoptosis preceded inactivation of RNA polymerase, and was accompanied by …

Does The Expression Of Ki-67, P16 And Cox-2 At Initial Diagnosis Of Breast Atypia Or Usual Ductal Hyperplasia Predict A Second Clinically Significant Event?, Judy A. Tjoe, Philippe Gascard, Jianxin Zhao, Gary F. Neitzel, Maharaj Singh, Brittany Last, James Marx, Thea Tlsty, Sanjay Kansra

Journal of Patient-Centered Research and Reviews

Background: Women diagnosed with atypical ductal hyperplasia (ADH) or atypical lobular hyperplasia (ALH) have a fivefold increased risk of developing breast cancer. Because ADH/ALH can be precursors or predictive markers of a subsequent clinically significant event (SCSE), i.e. atypia, in situ or invasive carcinoma, the clinical outcome for these patients ranges anywhere from remission to invasive malignancy. Currently we cannot predict which atypical breast lesion is likely to be associated with future cancer, resulting in aggressive management and, possibly, overtreatment. Kerlikowske et al. reported that a combination of three biomarkers (cell cycle regulator p16INK4a, proliferation antigen Ki-67 and stress response …

In Vitro Growth Suppression Of Renal Carcinoma Cells By Curcumin, Santhi D. Konduri, Madhavi Latha Yadav Bangaru, Phu Thanh Do, Shenglin Chen, Jeffrey Woodliff, Sanjay Kansra

Journal of Patient-Centered Research and Reviews

Purpose

Malignant clear cell renal carcinoma (ccRCC) is an aggressive tumor highly resistant to chemotherapy and radiation. Current therapeutic approaches to management of ccRCC have not significantly improved patient survival, therefore novel therapies are needed. Activated NFκB and STAT3 expression is associated with ccRCC pathogenesis. The dietary polyphenol curcumin is a well-documented antitumor agent and a known inhibitor of NFκB and STAT3 activation. Given the lack of effective therapies that block ccRCC progression, our objective was to examine whether curcumin could suppress the growth and migration of ccRCC cells, and whether this suppression was mediated via inhibition of NFκB and …

In Vitro Growth Suppression Of Renal Carcinoma Cells By Curcumin, Santhi Konduri, Madhavi Latha Yadav Bangaru, Phu Thanh Do, Shenglin Chen, Jeffrey Woodliff, Sanjay Kansra

Journal of Patient-Centered Research and Reviews

Background: Malignant clear cell renal carcinoma (ccRCC) is an aggressive tumor that is highly resistant to chemotherapy and radiation. Current therapeutic approaches to management of ccRCC have not significantly improved patient survival, therefore novel therapies are needed. The von Hippel-Lindau tumor suppressor gene is frequently mutated in ccRCC resulting in unregulated transcriptional activity of hypoxia-inducible factors (HIF) 1α and 2α. HIF-mediated transcription leads to increased growth factor expression and growth factor receptor (GFR)-mediated signaling. NFκB and STAT3 are phosphorylated in response to GFR activation and modulate gene expression, which promotes cell growth and invasion. Activated NFκB and STAT3 expression is …

Microrna Molecular Profiling From Matched Tumor And Bio-Fluids In Bladder Cancer, David A. Armstrong, Benjamin B. Green, John D. Seigne, Alan R. Schned, Carmen Marsit

Dartmouth Scholarship

MicroRNAs have been identified as potential cancer biomarkers due to their presence and stability in many body fluids including urine and plasma, but the relationship of the pattern of expression of these messengers across various biological media has not been addressed and could provide important information in order to translate these biomarkers for epidemiologic or clinical use. We analyzed microRNA of matched FFPE-tumor tissue, plasma, urine exosomes (n = 16) and WBCs (n = 11) from patients with bladder cancer, using Nanostring miRNA assays and droplet digital PCR for validation. Pearson correlations were used to compare expression between …

Mice Null For The Deubiquitinase Usp18 Spontaneously Develop Leiomyosarcomas, Fadzai Chinyengetere, David J. Sekula, Yun Lu, Andrew J. Giustini, Aarti Sanglikar, Masanori Kawakami, Tian Ma

Dartmouth Scholarship

USP18 (ubiquitin-specific protease 18) removes ubiquitin-like modifier interferon stimulated gene 15 (ISG15) from conjugated proteins. USP18 null mice in a FVB/N background develop tumors as early as 2 months of age. These tumors are leiomyosarcomas and thus represent a new murine model for this disease.

Active Yap Promotes Pancreatic Cancer Cell Motility, Invasion And Tumorigenesis In A Mitotic Phosphorylation-Dependent Manner Through Lpar3., Shuping Yang, Lin Zhang, Vinee Purohit, Surendra K. Shukla, Xingcheng Chen, Fang Yu, Kai Fu, Yuanhong Chen, Joyce C. Solheim, Surendra K. Shukla, Wei Song, Jixin Dong

Journal Articles: Eppley Institute

The transcriptional co-activator Yes-associated protein, YAP, is a main effector in the Hippo tumor suppressor pathway. We recently defined a mechanism for positive regulation of YAP through CDK1-mediated mitotic phosphorylation. Here, we show that active YAP promotes pancreatic cancer cell migration, invasion and anchorage-independent growth in a mitotic phosphorylation-dependent manner. Mitotic phosphorylation is essential for YAP-driven tumorigenesis in animals. YAP reduction significantly impairs cell migration and invasion. Immunohistochemistry shows significant upregulation and nuclear localization of YAP in metastases when compared with primary tumors and normal tissue in human. Mitotic phosphorylation of YAP controls a unique transcriptional program in pancreatic cells. …

‘The Thing Is Not Knowing’: Patients' Perspectives On Surveillance Of An Indeterminate Pulmonary Nodule, Renda Soylemez Wiener, Michael K. Gould, Steven Woloshin, Lisa M. Schwartz, Jack Clark

Dartmouth Scholarship

Background: The hundreds of thousands of patients found to have a potentially malignant pulmonary nodule each year are faced with tremendous uncertainty regarding what the nodule is and how it should be evaluated.

Objective: To explore patients' responses to the detection and evaluation of a pulmonary nodule.

Invariant Characteristics Of Carcinogenesis., Simon Sherman, Nirosha Rathnayake, Tengiz Mdzinarishvili

Journal Articles: Eppley Institute

Carcinogenic modeling is aimed at mathematical descriptions of cancer development in aging. In this work, we assumed that a small fraction of individuals in the population is susceptible to cancer, while the rest of the population is resistant to cancer. For individuals susceptible to cancer we adopted methods of conditional survival analyses. We performed computational experiments using data on pancreatic, stomach, gallbladder, colon and rectum, liver, and esophagus cancers from the gastrointestinal system collected for men and women in the SEER registries during 1975-2009. In these experiments, we estimated the time period effects, the birth cohort effects, the age effects …

Muc16-Mediated Activation Of Mtor And C-Myc Reprograms Pancreatic Cancer Metabolism., Surendra K. Shukla, Venugopal Gunda, Jaime Abrego, Dhanya Haridas, Anusha Mishra, Joshua J. Souchek, Nina V. Chaika, Fang Yu, Aaron R. Sasson, A Lazenby, Surinder K. Batra, Pankaj K. Singh

Journal Articles: Eppley Institute

MUC16, a transmembrane mucin, facilitates pancreatic adenocarcinoma progression and metastasis. In the current studies, we observed that MUC16 knockdown pancreatic cancer cells exhibit reduced glucose uptake and lactate secretion along with reduced migration and invasion potential, which can be restored by supplementing the culture media with lactate, an end product of aerobic glycolysis. MUC16 knockdown leads to inhibition of mTOR activity and reduced expression of its downstream target c-MYC, a key player in cellular growth, proliferation and metabolism. Ectopic expression of c-MYC in MUC16 knockdown pancreatic cancer cells restores the altered cellular physiology. Our LC-MS/MS based metabolomics studies indicate global …

Microrna-587 Antagonizes 5-Fu-Induced Apoptosis And Confers Drug Resistance By Regulating Ppp2r1b Expression In Colorectal Cancer., Yinbo Zhang, Geoffrey Talmon, Jing Wang

Journal Articles: Eppley Institute

Drug resistance is one of the major hurdles for cancer treatment. However, the underlying mechanisms are still largely unknown and therapeutic options remain limited. In this study, we show that microRNA (miR)-587 confers resistance to 5-fluorouracil (5-FU)-induced apoptosis in vitro and reduces the potency of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. Further studies indicate that miR-587 modulates drug resistance through downregulation of expression of PPP2R1B, a regulatory subunit of the PP2A complex, which negatively regulates AKT activation. Knockdown of PPP2R1B expression increases AKT phosphorylation, which leads to elevated XIAP expression and enhanced …

Yap1 Expression Predicts Sensitivity To Dual Akt/P70s6k Inhibition In Ovarian And Uterine Malignancies, Rebecca A. Previs

Dissertations and Theses (Open Access)

Purpose: The PI3K/AKT/P70S6K pathway is an attractive therapeutic target in ovarian and uterine malignancies due to its high rate of dysregulation and key roles in tumor growth. Here, we examined the biological effects of MSC2363318A, which is a novel inhibitor of AKT1, AKT3, and P70S6K.

Experimental Design: Orthotopic murine models of ovarian and uterine cancer were utilized to study the effect of MSC2363318A on survival and regression. Moreover, in vitro experiments (MTT, Western blot analysis, plasmid transfection, and reverse phase protein array [RPPA]) were carried out to characterize underlying mechanisms and potential biomarkers of response.

Results: MSC2363318A decreased tumor growth …

Health-Related Quality Of Life In Children With Cancer, Tha'er Ghandi Almomani

Theses and Dissertations (ETD)

Health-related quality of life is an important phenomenon to measure in children undergoing treatment for cancer. However, the effects of different treatment modalities and cancer related factors over the duration of treatment have not been explored. To assess the effects of different child-, cancer-, and treatment-related factors, we analyzed a large sample of children undergoing curative treatment for 5 different childhood cancer diagnoses. These diagnostic groups were Hodgkin Lymphoma (HL), Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Osteosarcoma (OS), and Melanoma. We analyzed a sample of 710 patients across the five diagnostic groups over four time-points in treatment. These …

Numerical Chromosomal Instability Mediates Susceptibility To Radiation Treatment, Samuel F. Bakhoum, Lilian Kabeche, Matthew D. Wood, Christopher D. Laucius

Dartmouth Scholarship

The exquisite sensitivity of mitotic cancer cells to ionizing radiation (IR) underlies an important rationale for the widely used fractionated radiation therapy. However, the mechanism for this cell cycle-dependent vulnerability is unknown. Here we show that treatment with IR leads to mitotic chromosome segregation errors in vivo and long-lasting aneuploidy in tumour-derived cell lines. These mitotic errors generate an abundance of micronuclei that predispose chromosomes to subsequent catastrophic pulverization thereby independently amplifying radiation-induced genome damage. Experimentally suppressing whole-chromosome missegregation reduces downstream chromosomal defects and significantly increases the viability of irradiated mitotic cells. Further, orthotopically transplanted human glioblastoma tumours in which …