Diseases Commons^™

Atm Signaling To Tsc2: Mechanisms And Implications For Cancer Therapy, Angela Alexander

Dissertations and Theses (Open Access)

Ataxia telangiectasia mutated (ATM) is a critical component of the cellular response to DNA damage, where it acts as a damage sensor, and signals to a large network of proteins which execute the important tasks involved in responding to the damage, namely inducing cell cycle checkpoints, inducing DNA repair, modulating transcriptional responses, and regulating cell death pathways if the damage cannot be repaired faithfully. We have now discovered that an additional novel component of this ATM-dependent damage response involves induction of autophagy in response to oxidative stress. In contrast to DNA damage-induced ATM activation however, oxidative stress induced ATM, occurs …

Insights Into P53-Dependent Apoptotic Signaling And Cell Fate Vis-A-Vis Functional Cooperation Among Bcl-Xl, Cytoplasmic P53, And Puma, John C. Fisher

Theses and Dissertations (ETD)

Following DNA damage, nuclear p53 induces the expression of PUMA (p53 upregulated modulator of apoptosis), a BH3‑only protein that binds and inhibits the anti‑apoptotic BCL‑2 repertoire, including BCL‑xL. Structural investigations of PUMA and the BCL‑xL×PUMA BH3 domain complex by X‑ray crystallography and nuclear magnetic resonance (NMR) spectroscopy reveal a novel, PUMA‑induced, domain‑swapped dimerization of BCL‑xL that requires a π‑stacking interaction between PUMA W71 and BCL‑xL H113. PUMA is an intrinsically disordered protein, but upon interaction with BCL‑xL, PUMA W71 and the PUMA BH3 domain residues fold into an alpha helix and subtly remodel BCL‑xL to trigger its dimerization. Wild type …

The Effects Of Curcumin On Body Composition Of Patients With Advanced Pancreatic Cancer, Henrique A. Parsons Md

Dissertations and Theses (Open Access)

Cachexia is very common among patients with advanced pancreatic cancer and is a marker of poor prognosis. Weight loss in cachexia is due to both adipose and muscle compartments, and sarcopenia (severe muscle depletion) is associated with worse outcomes. Curcumin has shown a myriad of biological effects, including anti-cancer and anti-inflammatory. The ability of curcumin to attenuate cachexia and muscle loss has been tested in animal models, with conflicting results so far. The hypothesis of this study was that patients with advanced pancreatic cancer treated with curcumin for two months have less fat and muscle loss as compared to matched …

Cancer Management Is A Multidisciplinary Team Work, Ahmed Nadeem Abbasi

Department of Radiation Oncology

No abstract provided.

Renal Thrombotic Microangiopathy In Mice With Combined Deletion Of Endocytic Recycling Regulators Ehd3 And Ehd4., Manju George, Mark A. Rainey, Mayumi Naramura, Kirk W. Foster, Melissa S. Holzapfel, Laura L. Willoughby, Guoguang Ying, Rasna M. Goswami, Channabasavaiah B. Gurumurthy, Vimla Band, Simon C. Satchell, Hamid Band

Journal Articles: Eppley Institute

Eps15 Homology Domain-containing 3 (EHD3), a member of the EHD protein family that regulates endocytic recycling, is the first protein reported to be specifically expressed in the glomerular endothelium in the kidney; therefore we generated Ehd3(-/-) mice and assessed renal development and pathology. Ehd3(-/-) animals showed no overt defects, and exhibited no proteinuria or glomerular pathology. However, as the expression of EHD4, a related family member, was elevated in the glomerular endothelium of Ehd3(-/-) mice and suggested functional compensation, we generated and analyzed Ehd3(-/-); Ehd4(-/-) mice. These mice were smaller, possessed smaller and paler kidneys, were proteinuric and died between …

A Survey Of Oxidative Paracatalytic Reactions Catalyzed By Enzymes That Generate Carbanionic Intermediates: Implications For Ros Production, Cancer Etiology, And Neurodegenerative Diseases, Victoria Bunik, John Schloss, John T. Pinto, Natalia Dudareva, Arthur J L Cooper

NYMC Faculty Publications

Enzymes that generate carbanionic intermediates often catalyze paracatalytic reactions with O2 and other electrophiles not considered “normal” reactants. For example, pyridoxal 5′-phosphate (PLP)—containing pig kidney dopa decarboxylase oxidizes dopamine with molecular O2 to 3,4-dihydroxyphenylacetaldehyde at about 1% of the rate at which it catalyzes nonoxidative dopa decarboxylation. The mutant Y332F enzyme, however, catalyzes stoichiometric conversion of dopa to 3,4-dihydroxyphenylacetaldehyde, suggesting that even minor structural changes may alter or initiate paracatalytic reactions catalyzed by certain enzymes. Carbanions generated by several thiamine diphosphate (ThDP)—dependent enzymes react with different electrophiles, transforming some xenobiotics and endogenous compounds into potentially biologically hazardous products. The detrimental …

The Roles Of Conserved And Nonconserved Cysteinyl Residues In The Oligomerization And Function Of Mammalian Prestin, Benjamin Currall, Danielle Rossino, Heather Jensen Smith, Richard Hallworth

Journal Articles: Eppley Institute

The creation of several prestin knockout and knockin mouse lines has demonstrated the importance of the intrinsic outer hair cell membrane protein prestin to mammalian hearing. However, the structure of prestin remains largely unknown, with even its major features in dispute. Several studies have suggested that prestin forms homo-oligomers that may be stabilized by disulfide bonds. Our phylogenetic analysis of prestin sequences across chordate classes suggested that the cysteinyl residues could be divided into three groups, depending on the extent of their conservation between prestin orthologs and paralogs or homologs. An alanine scan functional analysis was performed of all nine …

Microrna-183 Family Expression In Hair Cell Development And Requirement Of Micrornas For Hair Cell Maintenance And Survival, Michael D. Weston, Marsha L. Pierce, Heather Jensen Smith, Bernd Fritzsch, Sonia Rocha-Sanchez, Kirk W. Beisel, Garrett A. Soukup

Journal Articles: Eppley Institute

MicroRNAs (miRNAs) post-transcriptionally repress complementary target gene expression and can contribute to cell differentiation. The coordinate expression of miRNA-183 family members (miR-183, miR-96, and miR-182) has been demonstrated in sensory cells of the mouse inner ear and other vertebrate sensory organs. To further examine hair cell miRNA expression in the mouse inner ear, we have analyzed miR-183 family expression in wild type animals and various mutants with defects in neurosensory development. miR-183 family member expression follows neurosensory cell specification, exhibits longitudinal (basal-apical) gradients in maturating cochlear hair cells, and is maintained in sensory neurons and most hair cells into adulthood. …

Current Review Of In Nivo Gbm Rodent Models: Emphasis On The Cns-1 Tumour Model, Valerie L. Jacobs, Pablo A. Valdes, William F. Hickey, Joyce A. De Leo

Dartmouth Scholarship

GBM (glioblastoma multiforme) is a highly aggressive brain tumour with very poor prognosis despite multi-modalities of treatment. Furthermore, recent failure of targeted therapy for these tumours highlights the need of appropriate rodent models for preclinical studies. In this review, we highlight the most commonly used rodent models (U251, U86, GL261, C6, 9L and CNS-1) with a focus on the pathological and genetic similarities to the human disease. We end with a comprehensive review of the CNS-1 rodent model.

Cd151 Reinforces Vascular Stability By Balancing Endothelial Cell Adhesion And Cytoskeletal Tension, Feng Zhang

Theses and Dissertations (ETD)

Tetraspanin CD151 is highly expressed in endothelial cells and regulates pathological angiogenesis. However, the mechanism by which CD151 promotes vascular morphogenesis and whether CD151 engages other vascular functions are unclear. We observed that CD151 is required for the maintenance of endothelial capillary-like structures formed in vitro and the integrity of lung endothelial cell-cell contacts in vivo. As a master regulator of endothelial cell-matrix and cell-cell adhesions, CD151 is needed for the optimal functions of various cell adhesion proteins such as integrin, cadherin, and CD44. The loss of CD151 elevates the cellular intrinsic contraction by upregulating RhoA signaling and downregulating of …

Development Of A Lung Cancer-Specific Model For Support Group Interest, Laura Testerman

Loma Linda University Electronic Theses, Dissertations & Projects

Despite high levels of both emotional and physical distress and desire for utilization of support group services, lung cancer patients rarely participate in these supportive services. Lung cancer survivors’ interest in and use of supportive psychosocial services remains poorly understood, and Internet-based services may be of particular benefit to this population. The Behavioral Model for Vulnerable Populations, which emphasizes Predisposing (i.e., demographic as well as attitudes about support services), Enabling (i.e., accessibility of services), and Illness (i.e., need for services based on health) factors, was applied to the prediction of survivors’ behavioral intention to participate in face-to-face support groups (F2F) …

Harnessing The Effect Of Adoptively Transferred Tumor-Reactive T Cells On Endogenous (Host-Derived) Antitumor Immunity, Yolanda Nesbeth, Jose R. Conejo-Garcia

Dartmouth Scholarship

Adoptive T cell transfer therapy, the ex vivo activation, expansion, and subsequent administration of tumor-reactive T cells, is already the most effective therapy against certain types of cancer. However, recent evidence in animal models and clinical trials suggests that host conditioning interventions tailored for some of the most aggressive and frequent epithelial cancers will be needed to maximize the benefit of this approach. Similarly, the subsets, stage of differentiation, and ex vivo expansion procedure of tumor-reactive T cells to be adoptively transferred influence their in vivo effectiveness and may need to be adapted for different types of cancer and host …

The Relationship Between The Level Of Support Group Participation And Psychosocial Factors In Prostate Cancer Patients Treated With Proton Therapy, Carol A. L. Davis

Loma Linda University Electronic Theses, Dissertations & Projects

Background. The role of support groups for cancer patients is known to be beneficial in helping people adjust to the disease, and cope with the myriad of effects that cancer has on quality of life. Although many people express interest in attending such support groups, few attend regularly. It is unclear what characteristics distinguish those who use such services from those who do not, especially among proton therapy patients.

Objective. To examine demographic and psychosocial characteristics associated with the Brotherhood of the Balloon (BOB) prostate cancer support group membership, a unique treatment-focused group originating at Loma Linda University Medical Center …

Improving Quantitative Treatment Response Monitoring With Deformable Image Registration, Blake A. Cannon

Dissertations and Theses (Open Access)

Quantitative imaging with 18F-FDG PET/CT has the potential to provide an in vivo assessment of response to radiotherapy (RT). However, comparing tissue tracer uptake in longitudinal studies is often confounded by variations in patient setup and potential treatment induced gross anatomic changes. These variations make true response monitoring for the same anatomic volume a challenge, not only for tumors, but also for normal organs-at-risk (OAR). The central hypothesis of this study is that more accurate image registration will lead to improved quantitation of tissue response to RT with 18F-FDG PET/CT. Employing an in-house developed “demons” based deformable image registration algorithm, …

Modeling Sporadic Tumor Formation Driven By Telomere Dysfunction In The Gastrointestinal Tract, Suzanne S. Chan

Dissertations and Theses (Open Access)

Colorectal cancer is a complex disease that is thought to arise when cells accumulate mutations that allow for uncontrolled growth. There are several recognized mechanisms for generating such mutations in sporadic colon cancer; one of which is chromosomal instability (CIN). One hypothesized driver of CIN in cancer is the improper repair of dysfunctional telomeres. Telomeres comprise the linear ends of chromosomes and play a dual role in cancer. Its length is maintained by the ribonucleoprotein, telomerase, which is not a normally expressed in somatic cells and as cells divide, telomeres continuously shorten. Critically shortened telomeres are considered dysfunctional as they …

Characterizing Accuracy Of Total Hemoglobin Recovery Using Contrast-Detail Analysis In 3d Image-Guided Near Infrared Spectroscopy With The Boundary Element Method, Hamid R. Ghadyani, Subhadra Srinivasan, Brian W. Pogue, Keith D. Paulsen

Dartmouth Scholarship

The quantification of total hemoglobin concentration (HbT) obtained from multi-modality image-guided near infrared spectroscopy (IG-NIRS) was characterized using the boundary element method (BEM) for 3D image reconstruction. Multi-modality IG-NIRS systems use a priori information to guide the reconstruction process. While this has been shown to improve resolution, the effect on quantitative accuracy is unclear. Here, through systematic contrast-detail analysis, the fidelity of IG-NIRS in quantifying HbT was examined using 3D simulations. These simulations show that HbT could be recovered for medium sized (20mm in 100mm total diameter) spherical inclusions with an average error of 15%, for the physiologically …

Lung Carcinoma: Its Profile And Changing Trends, Saad Siddiqui, Mohammed Usman Ali, Mahrukh Ayesha Ali, Noreen Shah, Shagufta Nasreen

Section of Pulmonary & Critical Care

BACKGROUND: Lung Carcinoma is the leading causes of morbidity and mortality worldwide with an incidence of 1.3 million cases per year. This study was undertaken to determine prevalence of various histological types of lung carcinoma and to analyse their changing trends with time.

METHODS: This is a retrospective analytical study. A total of 330 cases of lung carcinoma were analysed from 2003 to 2008. Cases from Khyber Pakhtunkhwa and Federally Administered Tribal Area (FATA) were included in this study. Furthermore, only cases of lung carcinoma were considered while other malignancies were excluded.

RESULTS: Squamous Cell carcinoma was found in 42.7% …

Breast Cancer Dna Methylation Profiles Are Associated With Tumor Size And Alcohol And Folate Intake, Brock C. Christensen, Karl T. Kelsey, Shichun Zheng, E. Andres Houseman, Carmen J. Marsit, Margaret R. Wrensch, Joseph L. Wiemels, Heather H. Nelson, Margaret R. Karagas

Dartmouth Scholarship

Although tumor size and lymph node involvement are the current cornerstones of breast cancer prognosis, they have not been extensively explored in relation to tumor methylation attributes in conjunction with other tumor and patient dietary and hormonal characteristics. Using primary breast tumors from 162 (AJCC stage I-IV) women from the Kaiser Division of Research Pathways Study and the Illumina GoldenGate methylation bead-array platform, we measured 1,413 autosomal CpG loci associated with 773 cancer-related genes and validated select CpG loci with Sequenom EpiTYPER. Tumor grade, size, estrogen and progesterone receptor status, and triple negative status were significantly (Q-values <0.05) associated with altered methylation of 209, 74, 183, 69, and 130 loci, respectively. Unsupervised clustering, using a recursively partitioned mixture model (RPMM), of all autosomal CpG loci revealed eight distinct methylation classes. Methylation class membership was significantly associated with patient race (P<0.02) and tumor size (P<0.001) in univariate tests. Using multinomial logistic regression to adjust for potential confounders, patient age and tumor size, as well as known disease risk factors of alcohol intake and total dietary folate, were all significantly (P<0.0001) associated with methylation class membership. Breast cancer prognostic characteristics and risk-related exposures appear to be associated with gene-specific tumor methylation, as well as overall methylation patterns.

Notch1 Functions As A Tumor Suppressor In A Model Of K-Ras–Induced Pancreatic Ductal Adenocarcinoma, Linda Hanlon, Jacqueline L Avila, Renée M Demarest, Scott Troutman, Megan Allen, Francesca Ratti, Anil K Rustgi, Ben Z Stanger, Fred Radtke, Volkan Adsay, Fenella Long, Anthony J Capobianco, Joseph L Kissil

Rowan-Virtua School of Osteopathic Medicine Departmental Research

K-ras is the most commonly mutated oncogene in pancreatic cancer and its activation in murine models is sufficient to recapitulate the spectrum of lesions seen in human pancreatic ductal adenocarcinoma (PDAC). Recent studies suggest that Notch receptor signaling becomes reactivated in a subset of PDACs, leading to the hypothesis that Notch1 functions as an oncogene in this setting. To determine whether Notch1 is required for K-ras-induced tumorigenesis, we used a mouse model in which an oncogenic allele of K-ras is activated and Notch1 is deleted simultaneously in the pancreas. Unexpectedly, the loss of Notch1 in this model resulted in increased …

Tamoxifen: Mechanisms Of Resistance, Cyrus Mccoy Adams

Theses and Dissertations (ETD)

The role of estrogen in breast cancer has been recognized for decades. The selective estrogen receptor modulator tamoxifen was the first targeted therapy for the treatment of breast cancer. It was also the first drug approved by the FDA for the reduction of breast cancer risk. While tamoxifen has extended the lives of countless patients with breast cancer, resistance to tamoxifen remains a significant clinical problem. Work over the last two decades has greatly enhanced our understanding of the molecular mechanisms by which breast cancer cells may become resistant to tamoxifen treatment. Here I review our current understanding of the …

Evaluating The Impact Of The Guatemalan Nursing Program On Staff, Organizational, And Clinical Outcomes, Sara Williamson Day

Theses and Dissertations (ETD)

There is great disparity between the outcome of childhood cancer in developed and developing countries. Nurses, who comprise the largest group of health care professionals globally, are essential to successful treatment. Pediatric oncology education is generally unavailable for nurses in developing countries. This lack of education is likely to contribute to the disparity in survival rates, as undereducated nurses are unable to meet the demands of pediatric cancer care. A second critical problem in developing countries is the workload of the nurse, with a patient nurse ratio reported as high as 30 patients per one nurse.

In 2006, the quality …

The Use Of Preclinical Models To Improve The Treatment Of Retinoblastoma, Katie Marie Nemeth

Theses and Dissertations (ETD)

Rodent models play an essential role in the development of new chemotherapeutics and dosing regimes. It is often difficult to carryout a clinical study for pediatric cancers due to the small patient population. Retinoblastoma, a pediatric cancer of the eye, is one example of a pediatric cancer that can benefit from preclinical studies. Over the years various retinoblastoma rodent models have been developed used to test various combination of broad-spectrum systemic chemotherapy. It was found form these studies that the combination of topotecan and carboplatin was effective. However both drugs cause myelosuppression and therefore administrating both of these drugs systemically …

Pain Management In Nursing Home Residents With Cancer And Dementia With And Without Hospice Services, Todd Bryant Monroe

Theses and Dissertations (ETD)

Aims: We sought to identify differences in pain management between two groups; nursing home residents with malignant cancer and dementia with and without hospice services.

Methods: Decedent records from 2003-2009 were assessed for diagnosis of dementia and cause of death as cancer. Ten malignant cancer diagnoses were determined a priori from the CDC 2004 data on the top 10 malignant cancers for all races and genders. Fifty-five decedents from 10 nursing homes were included in the final sample. Four instruments were used: Minimum Data Set (MDS) a standardized assessment tool required of most U.S. nursing homes. A large …

Growing Burden Of Neurological Diseases In Pakistan � Need For A National Health Survey, Mohammad Wasay, Shaukat Ali

Department of Medicine

No abstract provided.

Proliferation Of Aneuploid Human Cells Is Limited By A P53-Dependent Mechanism, Sarah L. Thompson, Duane A. Compton

Dartmouth Scholarship

Most solid tumors are aneuploid, and it has been proposed that aneuploidy is the consequence of an elevated rate of chromosome missegregation in a process called chromosomal instability (CIN). However, the relationship of aneuploidy and CIN is unclear because the proliferation of cultured diploid cells is compromised by chromosome missegregation. The mechanism for this intolerance of nondiploid genomes is unknown. In this study, we show that in otherwise diploid human cells, chromosome missegregation causes a cell cycle delay with nuclear accumulation of the tumor suppressor p53 and the cyclin kinase inhibitor p21. Deletion of the p53 gene permits the accumulation …

Pregnancy Associated Breast Cancer: An Analysis Of Fetal Treatment Risk, Melissa Barnett

The Science Journal of the Lander College of Arts and Sciences

There are several viable treatment options for patients with PABC considered un-harmful to fetal development. Trastusumab, or Herceptin, targets HER2 protein and successfully combats aggressive breast cancer. In standard doses, it appears to be safe to the fetus even when administered during the first trimester. A likely side effect of Herceptin is anhydramnios, which can be monitored for throughout the stages of a pregnancy (Shrim et al. 2008). Anthracyclines, commonly used in chemotherapy, appear to be non-toxic, and have been used to successfully cure PABC patients in their second and third trimester. However, first trimester spontaneous abortions are documented to …

Regulation Of Apoptotic Effects Of Erythrocarpine E, A New Cytotoxic Limonoid Extracted From Chisocheton Erythrocarpus., Norliza Shah Jehan Muttiah

Student Works (2010-2019)

The aim of this study is to determine the cytotoxic and apoptotic effects of erythrocarpine E (CEB4), a new limonoid extracted from Chisocheton erythrocarpus. MTT assay, Live/Dead® Viability/Cytotoxicity assay, cell cycle analysis, annexin V analysis, PARP cleavage analysis, DNA fragmentation assay, sandwich ELISA assay and Western blot analysis were performed on five CEB4 treated cancer cell lines; HSC4COX2- and HSC2 (oral), CaSki (cervical), HepG2 (liver), MCF7 (breast) and NHBE (normal human bronchial epithelial cell line). CEB4 treated HSC4COX2-, HSC2, CaSki, HepG2 and MCF7 cells demonstrated a cytotoxic effect and inhibited cell proliferation in a dose and time dependent manner. CEB4 …

Cyclin D1 Amplification In Tongue And Buccal Mucosa Squamous Cell Carcinoma., Haydar M. Mahdey

Student Works (2010-2019)

Introduction Oral cancer is a significant health problem worldwide with almost 300,000 new cases are diagnosed each year. Despite the numerous studies done, and even with the best treatment option utilized, more than 50% of patients with oral cancer will experience relapse. In search for better options for prognostication, researches are now focusing on the molecular biology of cancer, for instance in search of reliable tumor markers. Among the markers reported in the literatures, Cyclin D1 is actively studied protein. Cyclin D1 regulates the cell cycle progression by forming a complex with different cyclin dependant kinase. Dysregulation of cyclin D1 …

The Neighborhood Cancer Center, Gregory R. Harper Md, Phd, Debbie Salas-Lopez Md, Mph, Keith J. Weinhold Mha, Elliot J. Sussman Md, Mba

Administration & Leadership

No abstract provided.

Inadequate Health Numeracy Affects Cancer Screening Practices In Vulnerable Populations, Sherrine Eid Mph, Dorothy Faulkner Phd

Administration & Leadership

No abstract provided.