Diseases Commons^™

Translation Initiation Complex Eif4f Is A Therapeutic Target For Dual Mtor Kinase Inhibitors In Non-Hodgkin Lymphoma., Christos Demosthenous, Jing Jing Han, Mary J Stenson, Matthew J Maurer, Linda E Wellik, Brian Link, Kristen Hege, Ahmet Dogan, Eduardo Sotomayor, Thomas Witzig, Mamta Gupta

Medicine Faculty Publications

Deregulated mRNA translation has been implicated in disease development and in part is controlled by a eukaryotic initiation complex eIF4F (composed of eIF4E, eIF4G and eIF4A). We demonstrate here that the cap bound fraction from lymphoma cells was enriched with eIF4G and eIF4E indicating that lymphoma cells exist in an activated translational state. Moreover, 77% (110/142) of diffuse large B cell lymphoma tumors expressed eIF4E and this was associated with an inferior event free survival. Over-expression of wild-type eIF4E (eIF4E(WT)) but not cap-mutant eIF4E (eIF4E(cap mutant)) increased the activation of the eIF4F complex. Treatment with the active-site dual mTOR inhibitor …

The Emerging Role Of Ng2 In Pediatric Diffuse Intrinsic Pontine Glioma., Sridevi Yadavilli, Joseph Scafidi, Oren J. Becher, Amanda M. Saratsis, Rebecca L. Hiner, Madhuri Kambhampati, Santi Mariarita, Tobey J. Macdonald, Kari-Elise Codispoti, Suresh N. Magge, Jyoti K. Jaiswal, Roger J. Packer, Javad Nazarian

Neurology Faculty Publications

Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis and are poorly understood brain cancers. Receptor tyrosine kinases stabilized by neuron-glial antigen 2 (NG2) protein are known to induce gliomagenesis. Here, we investigated NG2 expression in a cohort of DIPG specimens (n= 50). We demonstrate NG2 expression in the majority of DIPG specimens tested and determine that tumors harboring histone 3.3 mutation express the highest NG2 levels. We further demonstrate that microRNA 129-2 (miR129-2) is downregulated and hypermethylated in human DIPGs, resulting in the increased expression of NG2. Treatment with 5-Azacytidine, a methyltransferase inhibitor, results in NG2 downregulation in DIPG …

Integrative Analysis Of Survival-Associated Gene Sets In Breast Cancer, Frederick S. Varn, Matthew H. Ung, Shao Ke Lou, Chao Cheng

Dartmouth Scholarship

Patient gene expression information has recently become a clinical feature used to evaluate breast cancer prognosis. The emergence of prognostic gene sets that take advantage of these data has led to a rich library of information that can be used to characterize the molecular nature of a patient’s cancer. Identifying robust gene sets that are consistently predictive of a patient’s clinical outcome has become one of the main challenges in the field. We inputted our previously established BASE algorithm with patient gene expression data and gene sets from MSigDB to develop the gene set activity score (GSAS), a metric that …

Anti-Tumoral Effects Of Mir-3189-3p In Glioblastoma, Duane Jeansonne, Mariacristina Deluca, Luis Marrero, Adam Lassak, Marco Pacifici, Dorota Wyczechowska, Anna Wilk, Krzysztof Reiss, Francesca Peruzzi

School of Medicine Faculty Publications

Glioblastoma is one of the most aggressive brain tumors. We have previously found up-regulation of growth differentiation factor 15 (GDF15) in glioblastoma cells treated with the anticancer agent fenofibrate. Sequence analysis of GDF15 revealed the presence of a microRNA, miR-3189, in the single intron. We then asked whether miR-3189 was expressed in clinical samples and whether it was functional in glioblastoma cells. We found that expression of miR-3189-3p was down-regulated in astrocytoma and glioblastoma clinical samples compared with control brain tissue. In vitro, the functionality of miR-3189-3p was tested by RNA-binding protein immunoprecipitation, and miR-3189-3p coimmunoprecipitated with Argonaute 2 together …

Breast Cancer Screening: Early Detection Is Not Enough, Judy A. Tjoe

Journal of Patient-Centered Research and Reviews

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The Clinical Breast Examination: A Useful Screening Tool?, Jennifer Lo

Journal of Patient-Centered Research and Reviews

The standardization of the clinical breast examination as a screening tool for breast cancer has been a topic of controversy. Current recommendations vary significantly from organization to organization without consensus. There currently does not seem to be sufficient evidence regarding overall survival benefit of the clinical breast exam. However, as adjunct screening with mammography, it may help find earlier breast cancers and the up to 5–10% of cancers missed by mammography. The most appropriate standardized protocol may be that the clinical breast exam can be performed at the discretion of the provider and patient, with more inclination toward use in …

What Are The Recommended Timing And Screening Modalities For Women At Higher Risk Of Developing Breast Cancer? A Clin-Iq, Summer Jatala, Shawn Fitzgerald, Pamela Tietze, Kalyanakrishnan Ramakrisnan, Laine H. Mccarthy, Elizabeth Wickersham

Journal of Patient-Centered Research and Reviews

Early detection of breast cancer is desirable to prevent progression to advanced disease. This subject has been one of significant study and debate for women at normal risk, and recommendations continue to evolve. However, with regard to women at high risk, the recommendations from various health care professional organizations, including the U.S. Preventive Services Task Force, are different and also inconsistent concerning when to begin screening and which modalities should be used. We review several randomized controlled trials and consensus opinions regarding when to begin screening for breast cancer and how to best screen women at high risk. Specifically, we …

Active Immunotherapy And Adoptive Cell Transfer As An Effective Cancer Treatment, Philip Jay Cynamon

The Science Journal of the Lander College of Arts and Sciences

There are many ways to fight cancer using the body’s own immune system. Some methods include the administration of vaccines while others involve stimulatory factors injected near tumors. One promising method is enlisting the help of T cells. To fight cancer effectively, T cells must be able to recognize cancerous antigens and the environment in which these T cells reside must be conducive to their function, survival, and proliferation. This paper discusses a method of providing such an environment called adoptive cell transfer, as well as the elements that effect this protocol and the ways in which the environment can …

The Relationship Between Cancer Incidence, Stage, And Poverty In The United States, Francis P. Boscoe, Kevin A. Henry, Recinda L. Sherman, Christopher J. Johnson

Epidemiology & Biostatistics Faculty Scholarship

We extend a prior analysis on the relation between poverty and cancer incidence in a sample of 2.90 million cancers diagnosed in 16 U.S. states plus Los Angeles over the 2005-2009 period by additionally considering stage at diagnosis. Recognizing that higher relative disparities are often found among less-common cancer sites, our analysis incorporated both relative and absolute measures of disparities. Fourteen of the 21 cancer sites analyzed were found to have significant variation by stage; in each instance, diagnosis at distant stage was more likely among residents of high-poverty areas. If the incidence rates found in the lowest-poverty areas for …

Reciprocal Interaction Of Wnt And Rxr-Alpha Pathways In Hepatocyte Development And Hepatocellular Carcinoma, J. Li, M. Chanrion, E. Sawey, T. Wang, E. Chow, A. Tward, Y. Su, W. Xue, R. Lucito, L. Zender, +3 Additional Authors

Journal Articles

Genomic analysis of human hepatocellular carcinoma (HCC) is potentially confounded by the differentiation state of the hepatic cell-of-origin. Here we integrated genomic analysis of mouse HCC (with defined cell-of-origin) along with normal development. We found a major shift in expression of Wnt and RXR-alpha pathway genes (up and down, respectively) coincident with the transition from hepatoblasts to hepatocytes. A combined Wnt and RXR-alpha gene signature categorized HCCs into two subtypes (high Wnt, low RXR-alpha and low Wnt, high RXR-alpha), which matched cell-of-origin in mouse models and the differentiation state of human HCC. Suppression of RXR-alpha levels in hepatocytes increased Wnt …

Gentamicin Differentially Alters Cellular Metabolism Of Cochlear Hair Cells As Revealed By Nad(P)H Fluorescence Lifetime Imaging, Lyandysha V. Zholudeva, Kristina G. Ward, Michael G. Nichols, Heather Jensen Smith

Journal Articles: Eppley Institute

Aminoglycoside antibiotics are implicated as culprits of hearing loss in more than 120,000 individuals annually. Research has shown that the sensory cells, but not supporting cells, of the cochlea are readily damaged and/or lost after use of such antibiotics. High-frequency outer hair cells (OHCs) show a greater sensitivity to antibiotics than high- and low-frequency inner hair cells (IHCs). We hypothesize that variations in mitochondrial metabolism account for differences in susceptibility. Fluorescence lifetime microscopy was used to quantify changes in NAD(P)H in sensory and supporting cells from explanted murine cochleae exposed to mitochondrial uncouplers, inhibitors, and an ototoxic antibiotic, gentamicin (GM). …

Medically Inoperable Peripheral Lung Cancer Treated With Stereotactic Body Radiation Therapy, K. D. Kelley, D. L. Benninghoff, J. S. Stein, J. Z. Li, R. T. Byrnes, L. Potters, J. P. Knisely, H. D. Zinkin

Journal Articles

BACKGROUND: Lung cancer is the most frequent cause of cancer-related death in North America. There is wide variation between patients who are medically inoperable and those managed surgically. The use of stereotactic body radiotherapy (SBRT) has narrowed the gap in survival rates between operative and non-operative management for those with early stage disease. This retrospective study reports outcomes for the treatment of peripheral non-small cell lung carcinoma (NSCLC) with SBRT from a single community practice. METHODS: Sixty-seven consecutive patients (pts) with inoperable, untreated peripheral lung tumors were treated from 2010 through 2012 and included in this study. Stereotactic targeting was …

Humoral Immune Response Against Nontargeted Tumor Antigens After Treatment With Sipuleucel-T And Its Association With Improved Clinical Outcome, D. Guhathakurta, N. A. Sheikh, L. Q. Fan, H. Kandadi, T. C. Meagher, S. J. Hall, J. B. Whitmore, M. W. Frohlich, J. B. Trager, C. G. Drake, +7 Additional Authors

Journal Articles

PURPOSE: Antitumor activity of cancer immunotherapies may elicit immune responses to nontargeted (secondary) tumor antigens, or antigen spread. We evaluated humoral antigen spread after treatment with sipuleucel-T, an immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), designed to target prostatic acid phosphatase (PAP; primary antigen). EXPERIMENTAL DESIGN: Serum samples from patients with mCRPC enrolled in the placebo-controlled phase III IMPACT study (evaluable n = 142) were used to assess humoral antigen spread after treatment with sipuleucel-T. Immunoglobulin G (IgG) responses to self-antigens (including tumor antigens) were surveyed using protein microarrays and confirmed using Luminex xMAP. IgG responses …

A Quantitative Proteomics-Based Signature Of Platinum Sensitivity In Ovarian Cancer Cell Lines, G. Fan, K. O. Wrzeszczynski, C. Fu, G. Su, D. J. Pappin, R. Lucito, N. K. Tonks

Journal Articles

Although DNA encodes the molecular instructions that underlie the control of cell function, it is the proteins that are primarily responsible for implementing those instructions. Therefore quantitative analyses of the proteome would be expected to yield insights into important candidates for the detection and treatment of disease. We present an iTRAQ (isobaric tag for relative and absolute quantification)-based proteomic analysis of ten ovarian cancer cell lines and two normal ovarian surface epithelial cell lines. We profiled the abundance of 2659 cellular proteins of which 1273 were common to all 12 cell lines. Of the 1273, 75 proteins exhibited elevated expression …

Early Toxicity In Patients Treated With Postoperative Proton Therapy For Locally Advanced Breast Cancer, J. J. Cuaron, B. Chon, H. Tsai, A. Goenka, D. Deblois, A. Ho, S. Powell, E. Hug, O. Cahlon

Journal Articles

PURPOSE: To report dosimetry and early toxicity data in breast cancer patients treated with postoperative proton radiation therapy. METHODS AND MATERIALS: From March 2013 to April 2014, 30 patients with nonmetastatic breast cancer and no history of prior radiation were treated with proton therapy at a single proton center. Patient characteristics and dosimetry were obtained through chart review. Patients were seen weekly while on treatment, at 1 month after radiation therapy completion, and at 3- to 6-month intervals thereafter. Toxicity was scored using Common Terminology Criteria for Adverse Events version 4.0. Frequencies of toxicities were tabulated. RESULTS: Median dose delivered …

Clinical Significance Of A Point Mutation In Dna Polymerase Beta (Polb) Gene In Gastric Cancer., Xiaohui Tan, Hongyi Wang, Guangbin Luo, Shuyang Ren, Wenmei Li, Jiantao Cui, Harindarpal S. Gill, Sidney W. Fu, Youyong Lu

Medicine Faculty Publications

Gastric cancer (GC) is a major cause of global cancer mortality. Genetic variations in DNA repair genes can modulate DNA repair capability and, consequently, have been associated with risk of developing cancer. We have previously identified a T to C point mutation at nucleotide 889 (T889C) in DNA polymerase beta (POLB) gene, a key enzyme involved in base excision repair in primary GCs. The purpose of this study was to evaluate the mutation and expression of POLB in a larger cohort and to identify possible prognostic roles of the POLB alterations in GC. Primary GC specimens and their matched normal …

May Circulating Micrornas Be Gastric Cancer Diagnostic Biomarkers?, Xiaoling Wu, Xiaohui (Jane) Tan, Sidney W. Fu

Medicine Faculty Publications

Gastric cancer (GC) is the third leading cause of cancer-related deaths. More than 80% of the diagnosis was made at the advanced stages of the disease, highlighting the urgent demand for novel biomarkers that can be used for early detection. Recently, a number of studies suggest that circulating microRNAs (miRNAs) could be potential biomarkers for GC diagnosis. Cancer-related circulating miRNAs, as well as tissue miRNAs, provide a hopeful prospect of detecting GC at early stages, and the prospective participation of miRNAs in biomarker development will enhance the sensitivity and specificity of diagnostic tests for GC. As miRNAs in blood are …

A Coding Variant In Tmc8 (Ever2) Is Associated With High Risk Hpv Infection And Head And Neck Cancer Risk, Caihua Liang, Karl T. Kelsey, Michael D. Mcclean, Brock C. Christensen, Carmen J. Marsit

Dartmouth Scholarship

HPV infection is a causal agent in many epithelial cancers, yet our understanding of genetic susceptibility to HPV infection and resultant cancer risk is limited. Epidermodysplasia Verruciformis is a rare condition of extreme susceptibility to cutaneous HPV infection primarily attributable to mutations in TMC6 and TMC8. Genetic variation in the TMC6/TMC8 region has been linked to beta-type HPV infection and squamous cell carcinoma of the skin, cervical cancer, HPV persistence and progression to cervical cancer. Here, we have tested the hypothesis that the common TMC8 SNP rs7208422 is associated with high-risk HPV infection and risk of head and neck …

Short-Term Effects On The Fetus And Long-Term Outcome On Children Exposed To Maternal Chemotherapy, Yocheved Kramer

The Science Journal of the Lander College of Arts and Sciences

Ethical questions with regard to treatment arise when pregnant women are diagnosed with cancer. Does the health of the mother or the health of the fetus take priority? However, research suggests that concern over transplacental transfer should not deter those seeking treatments since avoidance of favorable transfer drugs can allow chemotherapy to be a viable option if properly administered. Doctors highly contraindicate the use of chemotherapeutic drugs in the first trimester due to high risks such as teratogenesis and fetal death. However, they reassure that treatment can be given in the final two trimesters. It presents minimal consequences as long …

Transposon Based Gene Therapy As A Treatment For Cancer, Jacob Stauber

The Science Journal of the Lander College of Arts and Sciences

Gene therapy is the use of genes to treat or prevent diseases. Diseases such as cancer, which are difficult to treat using conventional methods, can be treated using gene therapy. The transport of the therapeutic transgene can be accomplished using viral or non-viral methods. However, widespread use of viral vectors is limited due to its high cost of manufacture and safety concern. Non-viral vectors are limited in their effectiveness. The use of transposons such as the Sleeping Beauty transposon system can effectively deliver the transgene with less concern than viral vectors. This review discusses the various vectors and treatment strategies …

Is Proton Beam Therapy More Effective Than Intensity-Modulated Radiotherapy In Prostate Cancer Treatment?, Daniel Zelefsky

The Science Journal of the Lander College of Arts and Sciences

Prostate cancer is the most common form of cancer found in American males. Breaking technological advances in prostate cancer treatment continue to develop to help fight this disease, one such is proton beam therapy. Proton beam therapy is theorized to spare even more healthy tissue than photon radiotherapy because it delivers a majority of its radiation during the Bragg peak. Since this technology is substantially costlier than any other form of radiation therapy, physicians are assessing its effectiveness and determining if it is worth the cost. Currently, there is no significant difference seen in patient quality of life between recipients …

Epigenetics As A Cure For Cancer, Sara Rivka Margolis

The Science Journal of the Lander College of Arts and Sciences

Epigenetics is an emerging research topic that is being tested as a potential cure for cancer. Epigenetics is a non-genetic influence that shapes the phenotype. Epigenetics effects gene expression, but does not cause any changes in the DNA. DNA methylation patterns is one such epigenetic change in the cell that has huge potential for cancer treatment. Scientists have observed that many cancerous genes express signs of either hypermethylation or hypomethylation. The key for the treatment is that epigenetic changes are reversible, which opens the door to potential drugs to cure cancer and other diseases.

Chemoenzymatic Studies To Enhance The Chemical Space Of Natural Products, Jhong-Min Chen

Theses and Dissertations--Pharmacy

Natural products provide some of the most potent anticancer agents and offer a template for new drug design or improvement with the advantage of an enormous chemical space. The overall goal of this thesis research is to enhance the chemical space of two natural products in order to generate novel drugs with better in vivo bioactivities than the original natural products.

Polycarcin V (PV) is a gilvocarcin-type antitumor agent with similar structure and comparable bioactivity with the principle compound of this group, gilvocarcin V (GV). Modest modifications of the polyketide-derived tetracyclic core of GV had been accomplished, but the most …

Clinical And Pathologic Significance Of Integrin Α6Β4 Expression In Human Malignancies, Rachel L. Stewart

Theses and Dissertations--Clinical and Translational Science

Integrins are cellular adhesion molecules that bind cells to the extracellular matrix. The integrin α6β4, a receptor for laminins, is predominantly expressed on epithelial cells where it is present at the basal surface adjacent to the basement membrane. This integrin plays a critical role in maintaining normal cellular functions, yet has also been implicated in promoting invasion and metastasis in human malignancies. While overexpression of the integrin α6β4 has been detected in select human cancers, the clinical significance of integrin α6β4 expression in a number of malignancies has not been determined. The purpose of this study was to examine integrin …

The Influence Of Matrix Stiffness On Extracellular Matrix Protein Expression In 3d Encapsulated Mammary Fibroblasts, Kathryn Woods

PCOM Biomedical Studies Student Scholarship

A disease that transcends all races is breast cancer, the second leading cause of death among women with cancer. One factor, which participates in breast tumor progression, is the extracellular matrix (ECM), an acellular, protein-rich entity, which drives several cell, processes shown to promote tumorigenesis. Specifically, abnormal expression patterns and cross-linking of matrix fibers induces a more dense tissue structure, which has been reported to drive breast cancer progression. Alterations in ECM expression and cross-linking are in part due to carcinoma-associated fibroblasts (CAFs), activated fibroblasts which deposit copious ECM in the breast tumor environment. The goal of this study is …

Synthesis And Evaluation Of The Diarylthiourea Analogs As Novel Anti-Cancer Agents, Shengquan Liu, Maggie C. Louie, Vanishree Rajagopalan, Guangyan Zhou, Esmerelda Ponce, Tran Nguyen, Linda Green

Faculty Publications & Research of the TUC College of Osteopathic Medicine

No abstract provided.

Killing Adherent And Nonadherent Cancer Cells With The Plasma Pencil, Mounir Laroussi, Soheila Mohades, Nazir Barekzi

Electrical & Computer Engineering Faculty Publications

The application of low temperature plasmas in biology and medicine may lead to a paradigm shift in the way various diseases can be treated without serious side effects. Low temperature plasmas generated in gas mixtures that contain oxygen or air produce several chemically reactive species that have important biological implications when they interact with eukaryotic or prokaryotic cells. Here, a review of the effects of low temperature plasma generated by the plasma pencil on different cancerous cells is presented. Results indicate that plasma consistently shows a delayed killing effect that is dose dependent. In addition, there is some evidence that …

Is Collagenase Clostridium Histolyticum A Safe And Effective Treatment For Adult Patients With Dupuytren’S Contracture?, Heather N. Bailey

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this selective EBM review is to determine whether or not collagenase clostridium histolyticum is a safe and effective treatment for adult patients with Dupuytren’s contracture.

STUDY DESIGN: Review of two double-blind, placebo-controlled randomized controlled trials and one cross-sectional study. All of these studies are published in English between 2009-2013.

DATA SOURCES: Two double-blind, placebo-controlled randomized controlled trials and one cross-sectional study found using PubMed.

OUTCOMES MEASURED: Each randomized controlled trial measured the ability to meet the primary end point and all secondary endpoints, percent decrease in degree of contracture, increase in range of motion, patient satisfaction, …

Will The Addition Of Oxaliplatin To 5-Fluorouracil (5fu), And Leucovorin Improve Disease Free Survival Of Patients With Stage Iii Colon Cancer Who Had Surgical Resection Of The Tumor?, Sarah Cotter

PCOM Physician Assistant Studies Student Scholarship

Objective: The objective of this selective EBM review is to determine whether or not the addition of oxaliplatin to 5FU and leucovorin will improve disease free survival of patients with stage III colon cancer who had surgical resection of the tumor.

Study Design: Review of three published, double blind randomized control trials in the English language in 2004, 2007, and 2009.

Outcomes Measured: The outcome is disease free survival of colon cancer. It is measured using periodic patient follow-up. History and PE, neuro assessment, liver and kidney function tests, CEA test, CBC, and imaging studies such as colonoscopy or barium …

Is Tamoxifen Prophylaxis Effective In Reducing The Incidence Of Breast Cancer In Women Who Are At High Risk?, Maria Deveau

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this EBM review is to determine whether or not Tamoxifen prophylaxis is effective in reducing the incidence of breast cancer in woman who are at high risk.

STUDY DESIGN: Review of three English language primary studies published from 2005 to 2007.

DATA SOURCE: Three double-blind randomized control trials found using the PubMed and Cochrane database.

OUTCOME MEASURED: The primary outcome by all three studies included incidence of breast cancer.

RESULTS: Three double- blind randomized controlled trials were included in this review. Study by Powles et al showed statistically significant reduction in the incidents of breast cancer …