The role of SRC family kinase activation in prostate cancer growth and lymph node metastasis

Aberrant expression and/or activation of Src Family of non-receptor protein tyrosine kinases (SFKs) occur frequently during progressive stages of multiple types of human malignancies, including prostate cancer. Two SFKs, Src and Lyn, are expressed and implicated in prostate cancer progression. Work in this dissertation investigated the specific roles of Src and Lyn in the prostate tumor progression, and the effects of SFK inhibition on prostate tumor growth and lymph node metastasis in pre-clinical mouse models. ^ Firstly, using a pharmacological inhibitor of SFKs in clinical trials, dasatinib, I demonstrated that SFK inhibition affects both cellular migration and proliferation in vitro. Systemic administration of dasatinib reduced primary tumor growth, as well as development of lymph node metastases, in both androgen-sensitive and -resistant orthotopic prostate cancer mouse models. Immunohistochemical analysis of the primary tumors revealed that dasatinib treatment decreased SFK phosphorylation but not expression, resulting in decreased cellular proliferation and increased apoptosis. For this analysis of immunohistochemical stained tissues, I developed a novel method of quantifying immunohistochemical stain intensity that greatly reduced the inherent bias in analyzing staining intensity. ^ To determine if Src and Lyn played overlapping or distinct roles in prostate cancer tumor growth and progression, Src expression alone was inhibited by small-interfering RNA. The resulting stable cell lines were decreased in migration, but not substantially affected in proliferation rates. In contrast, an analogous strategy targeting Lyn led to stable cell lines in which proliferation rates were significantly reduced. ^ Lastly, I tested the efficacy of a novel SFK inhibitor (KX2-391) targeting peptide substrate-binding domain, on prostate cancer growth and lymph node metastasis in vivo. I demonstrated that KX2-391 has similar effects as dasatinib, an ATP-competitive small molecular inhibitor, on both the primary tumor growth and development of lymph node metastasis in vivo, work that contributed to the first-in-man Phase I clinical trial of KX2-391. ^ In summary, studies in this dissertation provide the first demonstration that Src and Lyn activities affect different cellular functions required for prostate tumor growth and metastasis, and SFK inhibitors effectively reduce primary tumor growth and lymph node metastasis. Therefore, I conclude that SFKs are promising therapeutic targets for treatment of human prostate cancer. ^

Evaluation of Knowledge Regarding Diagnostic Strategies for Genetic Diseases in Select Residents

Genetics education for physicians has been a popular publication topic in the United States and in Europe for over 20 years. Decreasing numbers of medical genetics professionals and an increasing volume of genetic information has created a dire need for increased genetics training in medical school and in clinical practice. This study aimed to assess how well pediatrics-focused primary care physicians apply their general genetics knowledge to clinical genetic testing using scenario-based questions. We chose to specifically focus on knowledge of the diagnostic applicability of Chromosomal Microarray (CMA) technology in pediatrics because of its recent recommendation by the International Standard Cytogenomic Array (ISCA) Consortium as a first-tier genetic test for individuals with developmental disabilities and/or congenital anomalies. Proficiency in ordering baseline genetic testing was evaluated for eighty-one respondents from four pediatrics-focused residencies (categorical pediatrics, pediatric neurology, internal medicine/pediatrics, and family practice) at two large residency programs in Houston, Texas. Similar to other studies, we found an overall deficit of genetic testing knowledge, especially among family practice residents. Interestingly, residents who elected to complete a genetics rotation in medical school scored significantly better than expected, as well as better than residents who did not elect to complete a genetics rotation. We suspect that the insufficient knowledge among physicians regarding a baseline genetics work-up is leading to redundant (i.e. concurrent karyotype and CMA) and incorrect (i.e. ordering CMA to detect achondroplasia) genetic testing and is contributing to rising health care costs in the United States. Our results provide specific teaching points upon which medical schools can focus education about clinical genetic testing and suggest that increased collaboration between primary care physicians and genetics professionals could benefit patient health care overall.

Does prior receipt of a rifamycin antibiotic increase the risk of acquiring an infection due to a rifamycin-resistant strain of Clostridium difficile?

Objectives. To examine the association between prior rifamycin exposure and later development of C. difficile infection (CDI) caused by a rifamycin-resistant strain of C. difficile , and to compare patient characteristics between rifamycin-resistant strains of C. difficile infection and rifamycin-susceptible strains of C. difficile infection. ^ Methods. A case-control study was performed in a large university-affiliated hospital in Houston, Texas. Study subjects were patients with C. difficile infection acquired at the hospital with culture-positive isolates of C. difficile with which in vitro rifaximin and rifampin susceptibility has been tested. Prior use of rifamycin, demographic and clinical characteristics was compared between case and control groups using univariate statistics. ^ Results. A total of 49 C. difficile strains met the study inclusion criteria for rifamycin-resistant case isolates, and a total of 98 rifamycin-susceptible C. difficile strains were matched to case isolates. Of 49 case isolates, 12 (4%) were resistant to rifampin alone, 12 (4%) were resistant to rifaximin alone, and 25 (9%) were resistant to both rifampin and rifaximin. There was no significant association between prior rifamycin use and rifamycin-resistant CDI. Cases and controls did not differ according to demographic characteristics, length of hospital stay, known risk factors of CDI, type of CDI-onset, and pre-infection medical co-morbidities. Our results on 37 rifaximin-resistant isolates (MIC ≥32 &mgr;g/ml) showed more than half of isolates had a rifaximin MIC ≥256 &mgr;g/ml, and out of these isolates, 19 isolates had MICs ≥1024 &mgr;g/ml. ^ Conclusions. Using a large series of rifamycin-non-susceptible isolates, no patient characteristics were independently associated with rifamycin-resistant CDI. This data suggests that factors beyond previous use of rifamycin antibiotics are primary risk factors for rifamycin-resistant C. difficile. ^

Texas Medical Center --- Its Origins

This document details the people and institutions who were instrumental in the establishment and development of the Texas Medical Center (TMC). Biographical information about the founders, role the M. D. Anderson Foundation, and opening of the main institutions in the early 1950s is detailed. A copy of a speech given in 1958 by W. B. Bates, one of the trustees of the M. D. Anderson Foundation, on the history and development of the TMC is significant because he was one of the founders of the TMC. This document was commissioned by the Houston Chamber of Commerce in 1971 as the Texas Medical Center began a new phase of expansion with the pending addition of The University of Texas Medical School at Houston. It includes information about each of the 21 institutions which comprised the TMC at that time.

William Osler: Original Papers 1881-1897

Part 1: 1881-1888 On Some Points in the Etiology and Pathology of Ulcerative Endocarditis, 1881 On Certain Parasites in the Blood of the Frog, 1883 The Third Corpuscle of the Blood, 1883 On the Use of Arsenic in Certain Forms of Anaemia, 1886 Antifebrin, 1887 Case of Arterio-Venous Aneurism of the Axillary Artery and Vein of Fourteen Year's Duration, 1887 Typhilitis and Appendicitis, 1888 Part 2: 1889-1892 Annual Address - License to Practice 1889 Case of Syphiloma of the Cord of the Cauda Equina-Death From Diffuse Central Myelitis, 1889 On a Case of Simple Idiopathic Muscular Atrophy, Involving the Face and the Scapulo-Humeral Muscles, 1889 Note on Intra-Thoracic Growths Developing from the Thyroid Gland, 1889 On the Value of Laveran's Organisms in the Diagnosis of Malaria, 1889 On the Form of Convulsive Tic Associated with Corprolalia, Etc., 1890 A Case of Sensory Aphasia Word-blindness with Hemianopsia, 1891 Rudolf Virchow: The Man and the Student, 1891 The Healing of Tuberculosis, 1892 The Cold-Bath Treatment of Typhoid Fever, 1892 Part 3: 1893 Remarks on the Varieties of Chronic Chorea, and a Report Upon Two Families of the Hereditary Form, With One Autopsy, 1893 Note on Arsenical Neuritis Following the use of Fowler's Solution, 1893 Note on a Remarkable House Epidemic of Typhoid Fever, 1893 Cases of Sub-Phrenic Abscess, 1893 On Sporadic Cretinism in America, 1893 Notes on Tuberculosis in Children, 1893 Part 4: 1849-1895 Parotitis in Pneumonia, Case of Pericarditis Treated by Incision and Drainage, 1894 The Army Surgeon, 1894 Introductory Remarks to Course of Clinical Demonstrations on Typhoid Fever, 1894 Cancer of the Stomach with Very Rapid Course, 1895 Case of Sporadic Cretinism (Infantile Myxcedema) Treated Successfully with Thyroid Extract, 1895 Visible Contractile Tumour of the Pylorus Following Ulcer of the Stomach, 1895 On the Association of Enormous Heart Hypertrophy, Chronic Proliferative Peritonitis, and Recurring Ascites, with Adherent Pericardium, 1895 Teaching and Thinking the Two Functions of a Medical School, 1895 The Practical Value of Laveran's Discoveries, 1895 Part 5 1896 Addison's Disease, 1896 On Six Cases of Addison's Disease, 1896 Hemiplegia in Typhoid Fever Thomas Dover (of Dover's Powder) Physician and Buccaneer, 1896 John Keats The Apothecary Poet, 1896 On The Classification of the Tics or Habit Movements, 1896 The Cerebral Complication of Raynaud's Disease, 1896 Part 6: 1897 On Certain Features in the Prognosis of Pneumonia, 1897 Clinical Lecture on Mitral Stenosis - Sudden Death - Ball Thrombus in the Left Auricle, 1897 The Diagnosis of Malarial Fever, 1897 The Functions of a State Faculty (President's Address), 1897 A Clinical Lecture on The Ball-Valve Gall-Stone in the Common Duct, 1897 Pneumonia (Review of Cases studied), 1897 Internal Medicine as a Vocation, 1897 Back Notes

αvβ8 Integrin Interacts with RhoGDI1 to Regulate Rac1 and Cdc42 Activation and Drive Glioblastoma Cell Invasion

As an interface between the circulatory and central nervous systems, the neurovascular unit is vital to the development and survival of tumors. The malignant brain cancer glioblastoma multiforme (GBM) displays invasive growth behaviors that are major impediments to surgical resection and targeted therapies. Adhesion and signaling pathways that drive GBM cell invasion remain largely uncharacterized. Here we have utilized human GBM cell lines, primary patient samples, and pre-clinical mouse models to demonstrate that integrin αvβ8 is a major driver of GBM cell invasion. β8 integrin is overexpressed in many human GBM cells, with higher integrin expression correlating with increased invasion and diminished patient survival. Silencing β8 integrin in human GBM cells leads to impaired tumor cell invasion due to hyperactivation of the Rho GTPases Rac1 and Cdc42. β8 integrin associates with Rho GDP Dissociation Inhibitor 1 (RhoGDI1), an intracellular signaling effector that sequesters Rho GTPases in their inactive GDP-bound states. Silencing RhoGDI1 expression or uncoupling αvβ8 integrin-RhoGDI1 protein interactions blocks GBM cell invasion due to Rho GTPase hyperactivation. These data reveal for the first time that αvβ8 integrin, via interactions with RhoGDI1, suppresses activation of Rho proteins to promote GBM cell invasiveness. Hence, targeting the αvβ8 integrin-RhoGDI1 signaling axis may be an effective strategy for blocking GBM cell invasion.

Left, right and interval bivariate censored data: Evaluating screening mammography in the presence of lead -time bias, length bias and over-detection

Of the large clinical trials evaluating screening mammography efficacy, none included women ages 75 and older. Recommendations on an upper age limit at which to discontinue screening are based on indirect evidence and are not consistent. Screening mammography is evaluated using observational data from the SEER-Medicare linked database. Measuring the benefit of screening mammography is difficult due to the impact of lead-time bias, length bias and over-detection. The underlying conceptual model divides the disease into two stages: pre-clinical (T0) and symptomatic (T1) breast cancer. Treating the time in these phases as a pair of dependent bivariate observations, (t0,t1), estimates are derived to describe the distribution of this random vector. To quantify the effect of screening mammography, statistical inference is made about the mammography parameters that correspond to the marginal distribution of the symptomatic phase duration (T1). This shows the hazard ratio of death from breast cancer comparing women with screen-detected tumors to those detected at their symptom onset is 0.36 (0.30, 0.42), indicating a benefit among the screen-detected cases. ^

The multidisciplinary management of hip fractures in older patients

Acknowledgements The authors would like to thank our colleagues for valuable discussion and feedback on the article. These include Jane Thompson (Physiotherapy), Janet Christie (Occupational Therapy), Denise Donald (Discharge Coordinator) and James Duff (Orthogeriatric Specialist Nurse). Miss Riemen is supported by Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative (Grant no. WT 085664) and through Clinical Research Fellowship Number 105424/Z/14/Z.

A systematic review of the cost-effectiveness of non-surgical obesity interventions in men

Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Competencias y contenidos comunes de salud pública del Grado en Medicina en las universidades españolas

Objetivo: Consensuar las competencias profesionales de salud pública que deben adquirir los estudiantes en el Grado en Medicina y los contenidos fundamentales que debe incluir la materia de salud pública según el criterio de un grupo de docentes de salud pública del Grado en Medicina de distintas universidades españolas. Métodos: Se organizó una 2 ª Reunión del Foro de Profesorado Universitario de Salud Pública en la Universidad Rey Juan Carlos (Madrid, 11-12 de diciembre de 2014), en la que participaron 24 docentes de 19 universidades españolas con Grado en Medicina que fueron distribuidos en tres grupos durante tres sesiones de trabajo. En la primera sesión, se identificaron y clasificaron las competencias propias del Grado; en la segunda, se propusieron contenidos de salud pública para las competencias identificadas; en la tercera, se organizaron los contenidos en bloques temáticos. Los resultados se discutieron hasta alcanzar acuerdos, en distintas sesiones plenarias. Resultados: El mayor número de competencias identificadas corresponde a actividades de las funciones «Valorar las necesidades de salud de la población» y «Desarrollar políticas de salud». El programa final incluye contenidos básicos organizados en cinco bloques: Concepto de salud, salud pública y sus condicionantes; Epidemiología e investigación en salud; Condicionantes y problemas de salud; Estrategias, intervenciones y políticas; y Sistemas de salud, gestión clínica y sanitaria. Conclusiones: Las competencias y los contenidos comunes consensuados en este Foro constituyen una base para actualizar y mejorar la formación en salud pública de los futuros profesionales de la medicina.

Student lecture notes on anatomy and surgery, and medical notes, of Lyman Spalding, 1795

Contains notes taken by Harvard student Lyman Spalding (1775-1821) from lectures on anatomy and surgery delivered by Harvard Professor John Warren (1753-1815) in 1795, as well a section entitled “Medical Observations,” which includes entries on “Vernal Debility,” or diseases occurring in the spring, and lung function. It is unclear if these are Spalding’s own writings or transcriptions from a published work. There is also text transcribed from “Elementa Medicinae,” published in 1780 by Scottish physician John Brown.

Medical Curriculum Change at Queen's-affiliated Medical Colleges: 1881 – 1910

This study explores the curriculum at Queen’s-affiliated medical colleges, specifically The Royal College of Physicians and Surgeons, Kingston, the Kingston Women’s Medical College, and Queen’s Medical College, from 1881 to 1910, using the textbooks prescribed by these institutions as primary sources. The central question encompasses what factors primarily motivated the curriculum at Queen’s-affiliated medical colleges to change. Within the historiographical scholarship on Queen’s College, this question has not yet been addressed and, to my knowledge, this is the first medical education history to specifically address textbooks as part of a medical school curriculum. During this period, these institutions experienced reorganizational shifts, such as the reunification of Queen’s Medical College with The Royal College of Physicians and Surgeons, Kingston, as well as the introduction and subsequent exclusion of female students. Within this context, this study examines how the forces of scientific innovation and co-education impacted the curriculum during the period under study, as measured by textbook change, specifically in the courses of obstetrics and gynaecology, the theory and practice of medicine, and surgery. To what degree was curriculum in these courses responsive to scientific inventions and discoveries, changing therapeutic practices, and possible gender biases? From 1881 to 1910, innovations such as x-ray and anaesthesia became commonplace within medical practice. Some technologies gained acceptance in the curriculum, while others fell out of favour. This study tracks these scientific discoveries through the textbooks used at Queen’s-affiliated medical colleges in order to demonstrate how the evolving nature of medicine was represented in the curriculum. To address how gender influenced the curriculum, textbooks from the Kingston Women’s Medical College and The Royal College of Physicians and Surgeons, Kingston, were compared. For two out of the three examined courses, it was found that sections of textbooks discussing various topics at the Kingston Women’s Medical College contained significantly more detail than their corresponding sections within The Royal College’s textbooks. It was speculated that the instructors preferred to teach their female students through textbooks, rather than lectures.

Medical faculty and students, 1865

Standing in front of the class (from left) are Abram Sager, Alonzo Palmer, Corydon Ford, Moses Gunn, and Silas Douglas (source: Not Just Any Medical School by Horace W. Davenport). On verso: March 1865. Dr. J. Ballard, then at 20 ... Gift of Dr. Elmer Belt, Los Angeles, Calif.

A supplement to area health education centers : a directory of Federal, State, local and private decentralized health professional education programs /

Mode of access: Internet.

The education of physicians for primary care /

Mode of access: Internet.