Medicine and Health Sciences Commons^™

Regulation Of Cellular Protein Phosphatase-1 (Pp1) By Phosphorylation Of The Cpi-17 Family, C-Kinase-Activated Pp1 Inhibitors., Masumi Eto

Department of Molecular Physiology and Biophysics Faculty Papers

The regulatory circuit controlling cellular protein phosphatase-1 (PP1), an abundant group of Ser/Thr phosphatases, involves phosphorylation of PP1-specific inhibitor proteins. Malfunctions of these inhibitor proteins have been linked to a variety of diseases, including cardiovascular disease and cancer. Upon phosphorylation at Thr(38), the 17-kDa PP1 inhibitor protein, CPI-17, selectively inhibits a specific form of PP1, myosin light chain phosphatase, which transduces multiple kinase signals into the phosphorylation of myosin II and other proteins. Here, the mechanisms underlying PP1 inhibition and the kinase/PP1 cross-talk mediated by CPI-17 and its related proteins, PHI, KEPI, and GBPI, are discussed.

Giant Synovial Cell Sarcoma Of The Thorax In A 46-Year-Old Man: A Case Report., Saulat Hasnain Fatimi, Taimur Saleem

Department of Surgery

Background:Although synovial cell sarcoma is a common tumor of the extremities, its occurrence in the thorax has been less frequently documented. Case Presentation: A 46-year-old Pakistani man presented with a 2 month history of progressively increasing cough and left lower chest pain. Initial evaluation was done using a chest x-ray, the Patient was found to have a large mass involving the lower portion of the left chest. A computed tomography scan was performed next which showed a large mass involving the left chest wall with invasion into the pericardium and left hemidiaphragm. En bloc surgical resection of the tumor …

Initial Tumor Metabolic Parameters (Maximum Suv And Metabolic Volume) Predict Death From Lung Cancer And Rapid Suv Decline Is Associated With Local Control, Maria Werner-Wasik, Edward Pequignot, Terry Hyslop, Brian Shulli, Ying Xiao, Mitchell Machtay, Amy Taylor, Walter Curran, Rita Axelrod

Department of Radiation Oncology Faculty Papers

Factors associated with local failure and death from lung cancer were evaluated based on post-treatment FDG-PET imaging in patients (pts) with non-small cell lung cancer (NSCLC).

PET-CT scans were obtained 6-8 weeks after thoracic RT and approximately every 3 months thereafter.

Mepe/Of45 Protects Cells From Dna Damage Induced Killing Via Stabilizing Chk1., Shuang Liu, Hongyan Wang, Xiang Wang, Lin Lu, Ning Gao, Peter S N Rowe, Baocheng Hu, Ya Wang

Department of Radiation Oncology Faculty Papers

Matrix extracellular phosphoglycoprotein/osteoblast factor 45 (MEPE/OF45) was cloned in 2000 with functions related to bone metabolism. We identified MEPE/OF45 for the first time as a new co-factor of CHK1 in mammalian cells to protect cells from DNA damage induced killing. We demonstrate here that MEPE/OF45 directly interacts with CHK1. Knocking down MEPE/OF45 decreases CHK1 levels and sensitizes the cells to DNA damage inducers such as ionizing radiation (IR) or camptothicin (CPT)-induced killing. Over-expressing wild-type MEPE/OF45, but not the mutant MEPE/OF45 (depleted the key domain to interact with CHK1) increases CHK1 levels in the cells and increases the resistance of the …

No Association Of Obesity And Type 2 Diabetes Mellitus Related Genetic Variants With Colon Cancer, Cheryl L. Thompson, Sarah J. Plummer, Thomas C. Tucker, Graham Casey, Li Li

Markey Cancer Center Faculty Publications

Background: Obesity and type 2 diabetes mellitus (T2D) are known risk factors for colon cancer. Recent reports from a number of genome wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with obesity and T2D. Here we tested the hypothesis that these SNPs may also be associated with risk of colon cancer.

Methods: We genotyped nine SNPs reported in GWAS of obesity and/or T2D, including SNPs in HHEX, KCNJ11, SLC30A8, FTO, CDKN2, CDKAL1, TCF2, and the rs9300039 SNP in an intergenic region, in 561 colon cancer cases and 721 population controls.

Results: None of these SNPs were …

Stromal Caveolin-1 Levels Predict Early Ductal Carcinoma In Situ Progression To Invasive Breast Carcinoma, A. K. Witkiewicz, A. Dasgupta, G. F. Schwartz, Kh H. Nguyen, H. R. Rui, M. P. Lisanti

Department of Cancer Biology Faculty Papers

With the increased use of screening mammography, the incidence of ductal carcinoma in situ (DCIS) has increased substantially and it currently accounts for 20-30% of newly diagnosed breast carcinomas in United States. Breast conserving therapy with or without radiotherapy is the accepted treatment for most cases of DCIS. However, the local recurrence rate with such therapy rages from 10 to 40% with half of these patients developing invasive carcinoma. Tamoxifen, used as an adjuvant systemic therapy for DCIS, does not increase overall survival and data on reduction of local recurrence rates are conflicting.

The current classification for DCIS based on …

Expression And Function Of Hypoxia Inducible Factor-1 Alpha In Human Melanoma Under Non-Hypoxic Conditions, Caroline N. Mills, Sandeep S. Joshi, Richard M. Niles

Biochemistry and Microbiology

Background

Hypoxia inducible factor-1 alpha (HIF-1α) protein is rapidly degraded under normoxic conditions. When oxygen tensions fall HIF-1α protein stabilizes and transactivates genes involved in adaptation to hypoxic conditions. We have examined the normoxic expression of HIF-1α RNA and protein in normal human melanocytes and a series of human melanoma cell lines isolated from radial growth phase (RGP), vertical growth phase (VGP) and metastatic (MET) melanomas.

Results

HIF-1α mRNA and protein was increased in RGP vs melanocytes, VGP vs RGP and MET vs VGP melanoma cell lines. We also detected expression of a HIF-1α mRNA splice variant that lacks part …

Doxorubicin Loaded Polymeric Nanoparticulate Delivery System To Overcome Drug Resistance In Osteosarcoma, Michiro Susa, Arun K. Iyer, Keinosuke Ryu, Francis J. Hornicek, Henry Mankin, Mansoor M. Amiji, Zhenfeng Duan

Pharmaceutical Sciences Faculty Publications

Background: Drug resistance is a primary hindrance for the efficiency of chemotherapy against osteosarcoma. Although chemotherapy has improved the prognosis of osteosarcoma patients dramatically after introduction of neo-adjuvant therapy in the early 1980's, the outcome has since reached plateau at approximately 70% for 5 year survival. The remaining 30% of the patients eventually develop resistance to multiple types of chemotherapy. In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) tumor cells, we explored the possibility of loading doxorubicin onto biocompatible, lipid-modified dextran-based polymeric nanoparticles and evaluated the …

Solution Structure Of The Inhibitory Phosphorylation Domain Of Myosin Phosphatase Targeting Subunit 1., Shunsuke Mori, Ryou Iwaoka, Masumi Eto, Shin-Ya Ohki

Department of Molecular Physiology and Biophysics Faculty Papers

Cell motility, such as smooth muscle contraction and cell migration, is controlled by the reversible phosphorylation of the regulatory light chain of myosin II and other cytoskeletal proteins. Mounting evidence suggests that in smooth muscle cells and other types of cells in vertebrates, myosin phosphatase (MP) plays an important role in controlling the phosphorylation of myosin II as well as other cytoskeletal proteins, including ezrin, moesin, and radixin.1 MP is a holoenzyme consisting of a catalytic subunit of a type-1 Ser/Thr phosphatase (PP1C) delta isoform, a myosin phosphatase targeting subunit 1 (MYPT1), and an accessory subunit M21. In this ternary …

Ppar Agonists Down-Regulate The Expression Of Atp10c Mrna During Adipogenesis, A Peretich, Maria Cekanova Ms, Rndr, Phd, S Hurst, Sj Baek, Madhu Dahr

Faculty Publications and Other Works -- Biochemistry, Cellular and Molecular Biology

No abstract provided.

Malignant Phyllodes Tumour As An Intracystic Growth With Osteosarcomatous Differentiation, Shaista Afzal Saeed, Imrana Masroor

Department of Radiology

Phyllodes tumour is an uncommon fibro epithelial tumour of breast that often presents clinically as a rapidly enlarging lump. On mammography it appears as a soft tissue density well circumscribed mass. Ultrasound shows it to be a solid hypoechoic mass with small cystic spaces. A case of malignant phyllodes tumour with an atypical appearance of intracystic tumour on sonography is reported with pertinent imaging features and histopathological diagnostic criteria. The tumour had undergone osteosarcomatous differentiation.

Imrt Commissioning: Multiple Institution Planning And Dosimetry Comparisons, A Report From Aapm Task Group 119., Gary A Ezzell, Jay W Burmeister, Nesrin Dogan, Thomas J Losasso, James G Mechalakos, Dimitris Mihailidis, Andrea Molineu, Jatinder R Palta, Chester R Ramsey, Bill J Salter, Jie Shi, Ping Xia, Ning J Yue, Ying Xiao, Phd

Department of Radiation Oncology Faculty Papers

AAPM Task Group 119 has produced quantitative confidence limits as baseline expectation values for IMRT commissioning. A set of test cases was developed to assess the overall accuracy of planning and delivery of IMRT treatments. Each test uses contours of targets and avoidance structures drawn within rectangular phantoms. These tests were planned, delivered, measured, and analyzed by nine facilities using a variety of IMRT planning and delivery systems. Each facility had passed the Radiological Physics Center credentialing tests for IMRT. The agreement between the planned and measured doses was determined using ion chamber dosimetry in high and low dose regions, …

Wnt Pathway Reprogramming During Human Embryonal Carcinoma Differentiation And Potential For Therapeutic Targeting, Grace E. Snow, Allison C. Kasper, Alexander M. Busch, Elisabeth Schwarz, Katherine E. Ewings, Thomas Bee, Michael J. Spinella, Ethan Dmitrovsky, Sarah J. Freemantle

Dartmouth Scholarship

Testicular germ cell tumors (TGCTs) are classified as seminonas or non-seminomas of which a major subset is embryonal carcinoma (EC) that can differentiate into diverse tissues. The pluripotent nature of human ECs resembles that of embryonic stem (ES) cells. Many Wnt signalling species are regulated during differentiation of TGCT-derived EC cells. This study comprehensively investigated expression profiles of Wnt signalling components regulated during induced differentiation of EC cells and explored the role of key components in maintaining pluripotency.

Ethnic Disparities In Cervical Cancer Survival Among Texas Women, Ann L. Coker, Christopher P. Desimone, Katherine S. Eggleston, Arica L. White, Melanie Williams

CRVAW Faculty Journal Articles

Objective: The aim of this work was to determine whether minority women are more likely to die of cervical cancer. A population-based cohort study was performed using Texas Cancer Registry (TCR) data from 1998 to 2002.

Methods: A total of 5,166 women with cervical cancer were identified during 1998–2002 through the TCR. Measures of socioeconomic status (SES) and urbanization were created using census block group-level data. Multilevel logistic regression was used to calculate the odds of dying from cervical cancer by race, and Cox proportional hazards modeling was used for cervical cancer-specific survival analysis.

Results: After adjusting for age, SES, …

The Effects Of Field-Of-View And Patient Size On Ct Numbers From Cone-Beam Computed Tomography., Katrina Y T Seet, Arvand Barghi, Slav Yartsev, Jacob Van Dyk

Oncology Publications

Cone-beam computed tomography (CBCT) is used for patient alignment before treatment and is ideal for use in adaptive radiotherapy to account for tumor shrinkage, organ deformation and weight loss. However, CBCT images are prone to artifacts such as streaking and cupping effects, reducing image quality and CT number accuracy. Our goal was to determine the optimum combination of cone-beam imaging options to increase the accuracy of image CT numbers. Several phantoms with and without inserts of known relative electron densities were imaged using the Varian on-board imaging system. It was found that CT numbers are most influenced by the selection …

What Factors Predict Outcome At Relapse After Previous Esophagectomy And Adjuvant Therapy In High-Risk Esophageal Cancer?, Edward Yu, Patricia Tai, Richard Malthaner, Larry Stitt, George Rodrigues, Rashid Dar, Brian Yaremko, Jawaid Younus, Michael Sanatani, Mark Vincent, Brian Dingle, Dalilah Fortin, Richard Inculet

Oncology Presentations

Management of patients who have disease relapse after completion of surgery and adjuvant chemo-radiation (CRT) is controversial.

Some oncologists would advocate intensive therapeutic intervention due to promising experience on treatment for recurrence disease while others would recommend palliative support due to the concerns for poor patient outcome post disease recurrence.

In Addition, it is not clear if patient outcome is improved post adjuvant CRT when patients at risk have resection margin involvement and if time interval to recurrence can affect patient survival post relapse.

The present study was conducted to determine what factors will affect patient outcome at relapse after …

Determination Of Complication Rate Of Picc Lines In Oncological Patients, Ghulam Haider, Shiyam Kumar, Basit Salam, Nehal Masood, Asim Jamal, Yasmeen Abdul Rasheed

Department of Radiation Oncology

OBJECTIVE: To determine the complication rate of (PICCs) peripherally inserted central catheters in cancer patients with a 1 year prospective cohort study.

METHODS: All PICCs inserted in adult cancer patients in Radiology Department of The Aga Khan University Hospital were followed prospectively till removed or patient expired and pattern of complications noted.

RESULTS: One hundred and fourty six PICCs were inserted over a period of 1 year and followed for a total of 3329 catheter-days; median placement, 14 days: range 3-218 days. Of these 67 (32.8%) PICCs were complicated and removed earlier, for a rate of 14.4/1000 PICC-days. Patients with …

Effects Of Genistein Following Fractionated Lung Irradiation In Mice., Andrea E Para, Andrea Bezjak, Ivan W T Yeung, Jacob Van Dyk, Richard P Hill

Oncology Publications

BACKGROUND AND PURPOSE: This study investigated protection of lung injury by genistein following fractionated doses of radiation and its effect on tumor response.

MATERIAL AND METHODS: C3H/HeJ mice were irradiated (100 kVp X-rays) with 9 fractions of 3.1 Gy over 30 days (approximately equivalent to 10 Gy single dose) and were maintained on a genistein diet ( approximately 10mg/kg). Damage was assessed over 28 weeks in lung cells by a cytokinesis block micronucleus (MN) assay and by changes in breathing rate and histology. Tumor protection was assessed using a colony assay to determine cell survival following in situ irradiation of …

In Reply To Dr. Hurkmans Et Al., Ying Xiao, Phd, Lech S. Papiez, Phd, James M. Galvin, Dsc

Department of Radiation Oncology Faculty Papers

No abstract provided.

A Generalized Beta Model For The Age Distribution Of Cancers: Application To Pancreatic And Kidney Cancer., Tengiz Mdzinarishvili, Michael X. Gleason, Leo Kinarsky, Simon Sherman

Journal Articles: Eppley Institute

The relationships between cancer incidence rates and the age of patients at cancer diagnosis are a quantitative basis for modeling age distributions of cancer. The obtained model parameters are needed to build rigorous statistical and biological models of cancer development. In this work, a new mathematical model, called the Generalized Beta (GB) model is proposed. Confidence intervals for parameters of this model are derived from a regression analysis. The GB model was used to approximate the incidence rates of the first primary, microscopically confirmed cases of pancreatic cancer (PC) and kidney cancer (KC) that served as a test bed for …

Expression Of Cpi-17 In Smooth Muscle During Embryonic Development And In Neointimal Lesion Formation., Jee In Kim, Garbo D Young, Li Jin, Avril V Somlyo, Masumi Eto

Department of Molecular Physiology and Biophysics Faculty Papers

Ca(2+) sensitivity of smooth muscle (SM) contraction is determined by CPI-17, an inhibitor protein for myosin light chain phosphatase (MLCP). CPI-17 is highly expressed in mature SM cells, but the expression level varies under pathological conditions. Here, we determined the expression of CPI-17 in embryonic SM tissues and arterial neointimal lesions using immunohistochemistry. As seen in adult animals, the predominant expression of CPI-17 was detected at SM tissues on mouse embryonic sections, whereas MLCP was ubiquitously expressed. Compared with SM alpha-actin, CPI-17 expression doubled in arterial SM from embryonic day E10 to E14. Like SM alpha-actin and other SM marker …

Genomic Biomarkers For Molecular Imaging: Predicting The Future., Mathew L. Thakur

Department of Radiation Oncology Faculty Papers

Over the past few decades, great strides have been made in anatomical imaging of disease that has led to their diagnosis with minimal invasion. Despite these advances, diseases such as cancer continue to take one human life every minute in the United States. Complimentary approaches that pertain directly to the genesis of the disease might contribute to its early diagnosis and subsequent management. In cancer, an array of molecular abnormalities leading to the modulations in expression of key proteins important in the cellular signaling pathways and cell proliferation has been identified. These specific disease fingerprints, biomarkers, are overexpressed on malignant …

Knowledge, Attitude And Preventive Practices For Breast Cancer Among Health Care Professionals At Aga Khan Hospital Karachi, Shiyam Kumar, Ayesha Mallick Imam, Nauman Fazal Manzoor, Nehal Masood

Department of Radiation Oncology

OBJECTIVE: To assess the knowledge and practice of risk factors, symptoms and screening for breast cancer among health care professionals.

METHODS: A cross sectional study was carried out at The Aga Khan University Hospital from January 2008 to March 2008. A total of 336 health care workers including consultants (48), fellows (17), residents (76), medical officers (14), interns (37), nurses (94) and fourth and final year medical students (50) were requested to fill a questionnaire designed to assess the knowledge about the risk factors, signs and symptoms, screening tools, breast self examination (BSE) and treatment.

RESULTS: More than two third …

Clinical Presentation And Outcomes Of Patients With Biliary Malignancies: The Aga Khan University Experience., Shiyam Kumar, Nehal Masood, Asim Jamal Shaikh Dr, Azmina T. Valimuhammad, Ghulam H, Amar Lal, Najeeb Niamatullah

Department of Medicine

No abstract provided.

A Real-Time Prostate Cancer Detection Technique Using Needle Insertion Force And Patient-Specific Criteria During Percutaneous Intervention, Kaiguo Yan, T. Podder, L. Li, J. Joseph, D. R. Rubens, E. M. Messing, L. Liao, Y. Yu

Department of Radiation Oncology Faculty Papers

In this article, the authors present a novel real-time cancer detection technique by using needle insertion forces in conjunction with patient-specific criteria during percutaneous interventions. Needle insertion experiments and pathological analysis were performed for developing a computer-aided detection (CAD) model. Backward stepwise regression method was performed to identify the statistically significant patient-specific factors. A baseline force model was then developed using these significant factors. The threshold force model that estimated the lower bound of the cancerous tissue forces was formulated by adding an adjustable classifier to the baseline force model. Trade-off between sensitivity and specificity was obtained by varying the …

Clinical And Translational Implications Of The Caveolin Gene Family: Lessons From Mouse Models And Human Genetic Disorders., Isabelle Mercier, Jean-Francois Jasmin, Stephanos Pavlides, Carlo Minetti, Neal Flomenberg, Richard G Pestell, Philippe G Frank, Federica Sotgia, Michael P Lisanti

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Here we review the clinical and translational implications of the caveolin gene family for understanding the pathogenesis of human diseases, including breast and prostate cancers, pulmonary hypertension, cardiomyopathy, diabetes, and muscular dystrophy. Detailed phenotypic analysis of caveolin knockout mice has served to highlight the crucial role of a caveolin deficiency in the pathogenesis of many human disease processes. Mutations in the human caveolin genes are associated with a number of established genetic disorders (such as breast cancer, lipodystrophy, muscular dystrophy, and cardiomyopathy), making the caveolins important and novel targets for drug development. The implementation of new strategies for caveolin replacement …

Addressing Cervical Cancer In Central Appalachia, Baretta R. Casey, Richard A. Crosby, Wallace Bates, Tonya D. Godsey, Mark B. Dignan

Center of Excellence in Rural Health Presentations

Rural women, particularly those residing in Appalachia, have some of the nation’s highest cervical cancer mortality rates. With support from federal and private grants, the University of Kentucky Center for Excellence in Rural Health-Hazard is attempting to address this issue. Eastern Kentucky-based researchers are surveying 18- to 26-year-old female community health center patients and college students about their risk factors for the disease, and then offering them free Gardasil, a vaccine against the virus that causes most cervical cancer cases.

Discovery And Scoring Of Protein Interaction Subnetworks Discriminative Of Late Stage Human Colon Cancer, Rod K. Nibbe, Sanford Markowitz, Lois Myeroff, Rob M. Ewing, Mark R. Chance

Faculty Scholarship

We used a systems biology approach to identify and score protein interaction subnetworks whose activity patterns are discriminative of late stage human colorectal cancer (CRC) versus control in colonic tissue. We conducted two gel-based proteomics experiments to identify significantly changing proteins between normal and late stage tumor tissues obtained from an adequately sized cohort of human patients. A total of 67 proteins identified by these experiments was used to seed a search for proteinprotein interaction subnetworks. A scoring scheme based on mutual information, calculated using gene expression data as a proxy for subnetwork activity, was developed to score the targets …

A Case Of Finger Clubbing Associated With Nasopharyngeal Carcinoma In A Young Girl, And Review Of Pathophysiology, Nasir Ali, Ahmed Nadeem Abbasi, Farook Karsan, Raheel Hashmi, Quratul-Ain Badar, Asim Jamal Sheikh

Department of Radiation Oncology

Hypertrophic osteoarthropathy is characterized by clubbing of the digital tips and periosteal reaction of long bones. Most of the cases are associated with malignancy or other conditions such as congenital heart disease, liver cirrhosis, pulmonary fibrosis, biliary atresia and gastrointestinal polyps. Hypertrophic osteoarthropathy associated with malignancy is rare in children. A few cases of hypertrophic osteoarthropathy in children with nasopharyngeal carcinoma have been reported. This is a case of hypertrophic osteoarthropathy associated with nasopharyngeal carcinoma with lung and bone metastasis in a 16 year old girl. In this case, lung metastases progressed after intensive chemotherapy and hypertrophic osteoarthropathy (Clubbing) persisted.

Y27632, A Rho-Activated Kinase Inhibitor, Normalizes Dysregulation In Alpha1-Adrenergic Receptor-Induced Contraction Of Lyon Hypertensive Rat Artery Smooth Muscle., Maria Regina Freitas, Masumi Eto, Jason A Kirkbride, Christa Schott, Jean Sassard, Jean-Claude Stoclet

Department of Molecular Physiology and Biophysics Faculty Papers

RhoA-activated kinase (ROK) is involved in the disorders of smooth muscle contraction found in hypertension model animals and patients. We examined whether the alpha1-adrenergic receptor agonist-induced ROK signal is perturbed in resistance small mesentery artery (SMA) of Lyon genetically hypertensive (LH) rats, using a ROK antagonist, Y27632. Smooth muscle strips of SMA and aorta were isolated from LH and Lyon normotensive (LN) rats. After Ca(2+)-depletion and pre-treatment with phenylephrine (PE), smooth muscle contraction was induced by serial additions of CaCl(2). In LH SMA Ca(2+) permeated cells to a lesser extent as compared with LN SMA, while CaCl(2)-induced contraction of LH …