tbuckley/cabot-search huggingface dataset:
Sensitization to the Lysosomal Cell Death Pathway upon Immortalization and Transformation
Authors: Nicole Fehrenbacher, Mads Gyrd-Hansen, Birgit Poulsen, Ute Felbor, Tuula Kallunki, Marianne Boes, Ekkehard Weber, Marcel Leist, Marja Jäättelä
Journal: Cancer Research (2004)

Abstract Tumorigenesis is associated with several changes that alter the cellular susceptibility to programmed cell death. Here, we show that immortalization and transformation sensitize cells in particular to the cysteine cathepsin-mediated lysosomal death pathway. Spontaneous immortalization increased the susceptibility of wild-type murine embryonic fibroblasts (MEFs) to tumor necrosis factor (TNF)-mediated cytotoxicity &amp;gt;1000-fold, whereas immortalized MEFs deficient for lysosomal cysteine protease cathepsin B (CathB) retained the resistant phenotype of primary cells. This effect was specific for cysteine cathepsins, because also lack of cathepsin L (a lysosomal cysteine protease), but not that of cathepsin D (a lysosomal aspartyl protease) or caspase-3 (the major executioner protease in classic apoptosis) inhibited the immortalization-associated sensitization of MEFs to TNF. Oncogene-driven transformation of immortalized MEFs was associated with a dramatic increase in cathepsin expression and additional sensitization to the cysteine cathepsin-mediated death pathway. Importantly, exogenous expression of CathB partially reversed the resistant phenotype of immortalized CathB-deficient MEFs, and the inhibition of CathB activity by pharmacological inhibitors or RNA interference attenuated TNF-induced cytotoxicity in immortalized and transformed wild-type cells. Thus, tumorigenesis-associated changes in lysosomes may counteract cancer progression and enhance therapeutic responses by sensitizing cells to programmed cell death.
Potential Gene Therapy for Lecithin-Cholesterol Acyltransferase (LCAT)–Deficient and Hypoalphalipoproteinemic Patients With Adenovirus-Mediated Transfer of Human LCAT Gene
Authors: Sandrine Se´guret-Mace´, Martine Latta-Mahieu, Graciela Castro, Ge´rald Luc, Jean-Charles Fruchart, Edward Rubin, Patrice Dene`fle, Nicolas Duverger
Journal: Circulation (1996)

Background Overexpression of human lecithin-cholesterol acyltransferase (LCAT) in transgenic mice results in an increase of the antiatherogenic HDLs. Methods and Results To investigate the potential use of LCAT for gene therapy, a recombinant adenovirus was constructed in which the human LCAT cDNA was expressed under the control of the human cytomegalovirus immediate/early promoter followed by a chimeric intron (AdCMV human LCAT). Human apolipoprotein (apo) A-I transgenic mice infected with AdCMV human LCAT by intravenous injection accumulated reactive LCAT in the plasma. LCAT activity was increased 201-fold in the plasma of mice infected with 1×10 9 pfu AdCMV human LCAT, from 45±2 to 9068±812 nmol·mL −1 ·h −1 , in comparison with basal LCAT activity measured in control mice, 5 days after injection. Plasma HDL cholesterol levels rose from 117±12 to 797±48 mg/dL, and plasma human apo A-I concentrations increased from 247±14 to 616±17 mg/dL, in AdCMV human LCAT–infected mice compared with control mice. HDL particles were larger and had a different electrophoretic mobility. Studies of cholesterol efflux by incubation of serum with cholesterol-loaded Fu5AH cells showed that serum from AdCMV human LCAT–infected mice promoted a significantly higher efflux than did that of the controls. Conclusions These data establish the potential of this approach for treatment of subjects with LCAT gene defects as well as patients with low plasma levels of apo A-I and HDL cholesterol.
Lisinopril lowers cardiac adrenergic drive and increases beta-receptor density in the failing human heart.
Authors: E M Gilbert, A Sandoval, P Larrabee, D G Renlund, J B O'Connell, M R Bristow
Journal: Circulation (1993)

BACKGROUND In subjects with heart failure, angiotensin converting enzyme inhibitors exhibit mild systemic antiadrenergic effects, as deduced from treatment-related lowering of systemic venous norepinephrine levels. The effects of angiotensin converting enzyme inhibitors on cardiac adrenergic drive in subjects with heart failure has not previously been investigated. METHODS AND RESULTS In a placebo-controlled, double-blind crossover study of 14 patients, we measured cardiac and systemic adrenergic drive, myocardial and lymphocyte beta-adrenergic receptors, and hemodynamic changes at baseline and after 12 weeks of therapy. Relative to placebo, lisinopril therapy was associated with only minimal, statistically insignificant changes in hemodynamics, a significant increase in myocardial beta-receptor density, no significant (P &lt; .05) changes in cardiac or systemic adrenergic drive, and no detectable change in lymphocyte beta-receptor density. When subjects were rank ordered into groups with the highest and lowest coronary sinus norepinephrine levels, those with the highest norepinephrine levels exhibited significant decreases in central venous norepinephrine, coronary sinus norepinephrine, and an increase in myocardial beta-receptor density relative to changes in placebo or relative to baseline values. Subjects with lower cardiac adrenergic drive exhibited no significant changes in coronary sinus or systemic norepinephrine levels or in myocardial beta-receptor density. CONCLUSIONS The angiotensin converting enzyme inhibitor lisinopril lowered cardiac adrenergic drive and increased beta-receptor density in subjects with increased cardiac adrenergic drive but had no effects on these parameters in subjects with normal cardiac adrenergic drive. These data suggest that cardiac antiadrenergic properties contribute to the efficacy of angiotensin converting enzyme inhibitor in subjects with heart failure.
Exercise and Intermittent Claudication
Authors: JOSEPH S. ALPERT, O. ANDRÉE LARSEN, NIELS A. LASSEN
Journal: Circulation (1969)

Nineteen patients with obliterative arteriosclerotic disease of the legs and suffering from intermittent claudication were studied before and during a 6 months' training program. The maximal walking distance and the calf muscle blood flow during walking (xenon-133 clearance technique) was recorded at monthly intervals. A significant correlation was established between improvement in maximal walking distance and a change on exercise toward more normal (that is, more adequate) blood flow in the calf. In particular, it was found that calf muscle blood flow during walking was increased by physical training. The data suggest that functional factors (for example, better coordination of the working muscles or a decrease of in-between-step intra-muscular pressure) as well as anatomic factors (increase in number or diameter of collateral vessels, or both) are involved in increasing collateral efficiency.
Internal Medicine 1976: Consequences of Subspecialization and Technology
Authors: ROBERT G. PETERSDORF
Journal: Annals of Internal Medicine (1976)

Editorials1 January 1976Internal Medicine 1976: Consequences of Subspecialization and TechnologyROBERT G. PETERSDORF, M.D., F.A.C.P.ROBERT G. PETERSDORF, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-84-1-92 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptAll of medicine, including internal medicine, is undergoing future shock. Gone are the days when the internist was the master clinician and consultant, practicing without constraints by local, state, or federal governments, ignorant of the costs of diagnostic studies and therapy, free to bill his patient what he wished or to give care free—a healer, confessor, and miracle worker to his patients and a high priest to his peers. The internist of the present, and indeed of the future, is questioning his very existence; he finds himself being supplanted as a consultant by the organsystem oriented subspecialist, and his role...References1. PETERSDORF R: Internal medicine and family practice: contreversies, conflicts and compromise. N Engl J Med 293:326-332, 1975 CrossrefMedlineGoogle Scholar2. PETERSDORF R: Primary care: the academic perspective. J Med Educ, in press Google Scholar3. PETERSDORF R: Health manpower: numbers, distribution quality. Ann Intern Med 82:694-701, 1975 LinkGoogle Scholar4. YOUNG L: Changes in the postdoctoral education of internists. Ann Intern Med 83:728-730, 1975 LinkGoogle Scholar5. BEESON P: Some good features of the British National Health Service. J Med Educ 49:43-49, 1974 MedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: ROBERT G. PETERSDORF, M.D., F.A.C.P.Affiliations: Department of Medicine University of Washington School of Medicine Seattle, Washington PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byThe Diagnostic Yield of Upper Endoscopy Procedures in Children- Is it Cost Effective?The Literature of American Internal Medicine: A Historical ViewW. BRUCE FYE, M.A., M.D.Hierarchical organization, integrations in biology and cancer, balance loss, and a question on modernismA National Study of Internal Medicine and Its Specialties: II. Primary Care in Internal MedicineROBERT C. MENDENHALL, M.S., ALVIN R. TARLOV, M.D., ROGER A. GIRARD, Ph.D., JANET K. MICHEL, M.S., STEPHEN E. RADECKI, M.A.The Super-specialistsA case for the view that there are too few gastroenterologistsThe Physician as a Double AgentManpower in GastroenterologyThe general internist an academic viewpointPsychiatry and TechnologyGraduate Medical Education 1976? Will Internal Medicine Meet the Challenge?PHILIP R. LEE, M.D.Reading in Internal MedicineRUSSELL M. WILDER, M.D., F.A.C.P. 1 January 1976Volume 84, Issue 1Page: 92-94KeywordsForecastingShockSub-specialty care ePublished: 1 December 2008 Issue Published: 1 January 1976 PDF downloadLoading ...
The Burden of Treatment Failure in Type 2 Diabetes
Authors: Denise G. Simons-Morton, Saul Genuth, Robert P. Byington, Hertzel C. Gerstein, William T. Friedewald
Journal: Diabetes Care (2005)

In the July 2004 issue of Diabetes Care, Brown et al. (1) conclude by stating, “our results strongly suggest that the recommended [HbA1c] threshold for [treatment] action should be 7.0% or lower” and “an even stronger signal would be provided by a treatment threshold of 6.0%, which has proved widely …
Abstract 4045: Restoring miR-15a/16 in the NZB mouse model of chronic lymphocytic leukemia reduces disease and enhances drug sensitivity
Authors: Erica Salerno, Yao Yuan, Frederick D. Coffman, Brian J. Scaglione, Brian D. Brown, Desiree Bonci, Elizabeth S. Raveche
Journal: Cancer Research (2010)

Abstract Alterations in the human 13q14 genomic region containing the microRNAS, mir-15a and mir-16-1 are present in a majority of human chronic lymphocytic leukemia (CLL). We have previously found the development of CLL in the New Zealand Black (NZB) murine model to be associated with a point mutation in the primary mir-15a/16-1 region, as well as a decrease in both mature miR-16 and miR-15a levels. Addition of exogenous miR-15a and miR-16 led to an accumulation of cells in G1 in both normal B cell and NZB-derived malignant B-1 cell lines. However, the NZB line had a significantly greater G1 accumulation, suggesting a restoration of cell cycle control upon exogenous miR-15a/16 addition. Our experiments demonstrated a reduction in protein levels of cyclin D1, a miR-15a/16 target and cell cycle regulator of G1/S transition, in the NZB cell line following miR-15a/16 addition. These miRNAs were shown to directly target the cyclin D1 3′UTR using a GFP lentiviral sensor. In vivo restoration of NZB with a miR-16-producing lentiviral vector resulted in the depletion of endogenous-transduced malignant aneuploid B-1 cells. In addition, experimentally increasing miR-16 in either a drug-resistant malignant NZB B-1 cell line or ex vivo splenic NZB B-1 cells augmented apoptosis induction by the following agents: genistein, a soy isoflavone tyrosine kinase inhibitor; nutlin, an MDM2 antagonist; and 2-fluoroadenine-9-B-D-arabinofuranoside, a purine nucleotide analog. Our data support a role for miR-16 in apoptosis induction, either alone, or in synergy with chemotherapeutic agents to increase their efficacy in murine CLL cells. This research was funded in part by the NJCCR pre-doctoral fellowship awarded to E.S. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4045.
Mortality in the British rubber industries 1966-76
Authors: R D Smith
Journal: BMJ (1980)

Nor do I agree with him that money, fame, and power are the usual motives behind such forgeries.There is, however, a long tradition among scientists of faking results in order to establish a pet theory, and those like Cyril Burt who have followed it include Haekel, Mendel, Kammering, Blondlot, Dubois, and (I believe) Teilhard de Chardin.To my mind, Malcolm Bowden's book Ape Man: Fact or Fallacy ?4 has irrevocably implicated Teilhard not only in the Piltdown forgery, but also in manufacturing evidence concerning Pekin and Java Man.Teilhard's motive was to establish the rather potty theory of evolution spelled out in "The Phenomenon of Man."The esteem that this book was held in and his own continuing high reputation must make him a candidate for the title of "Faker of the Century.
An Evaluation of the 24-Hour RAIU Test Performed with an Anger Camera and a Pinhole Collimator
Authors: JOHN R. PRINCE, WALTER G. DUKSTEIN, WILLIAM E. WHITE, DELORES SULLIVAN
Journal: Clinical Nuclear Medicine (1979)

RAIU measurements obtained with a conventional thyroid uptake probe have been compared with those obtained with an Anger camera and a pinhole collimator. Although the field distribution for the pinhole collimator deviates markedly from the IAEA recommendations, the group data from the comparative measurements in this series were identical, with a confidence level of only 99%. However, in several cases the data from differing measurement regimes for individuals varied markedly.
Increase in alcohol sales in Scotland is driven by low prices and rising affluence
Authors: B. Christie
Journal: BMJ (2011)

The amount of alcohol sold in Scotland is enough to allow every adult to exceed the sensible drinking guidelines every week of the year.

A report from health improvement agency NHS Health Scotland shows that since 1994 sales of pure alcohol per adult per year increased by 11% to 11.9 litres in 2009. This is 21% more than the 9.8 litres of alcohol sold per person in 2009 in England and Wales.

An analysis of sales trends shows that this has been driven by increasing sales of wine, which have doubled in Scotland since 1994, and by …
VRC 004: Safety and Immunogenicity of a Multiclade HIV-1 DNA Vaccine in Healthy Uninfected Adults (VRC-HIVDNA009-00-VP)
Authors: J.E. Martin, M.E. Enama, R.A. Koup, R.T. Bailer, Z. Moodie, M. Roederer, G.J. Nabel, B.S. Graham
Journal: Journal of Allergy and Clinical Immunology (2005)
ELECTROENCEPHALOGRAPHIC CHANGES IN PROFESSIONAL BOXERS
Authors: Ewald W. Busse
Journal: JAMA (1952)

Since the days of the Roman gladiators, men have fought each other and other persons have watched. The sport of boxing, as it exists today, is largely the product of psychological forces that have not changed in essence for 2,000 years. It is the feeling of many persons that in spite of periodic criticism and the efforts to ban prize fighting, the sport will persist. Since it appears unlikely that athletic contests requiring physical contact will ever cease, the physician should attempt to safeguard the physical and mental health of the participants. Much has been accomplished to protect the athlete in such sports as football and ice hockey, but protective measures for the amateur and professional pugilist have not kept pace. Jokl<sup>1</sup>in his monograph (1941), which is concerned with the medical aspects of boxing, recognized and deplored this situation, and he collected a wide variety of case material
P08.18 * FRACTIONATED STEREOTACTIC RADIOSURGERY FOR PATIENTS WITH SKULL BASE METASTASES INVOLVING THE ANTERIOR VISUAL PATHWAY
Authors: G. Minniti, V. Esposito, E. Clarke, R. M. Enrici
Journal: Neuro-Oncology (2014)

BACKGROUND: The base of the skull is a less common site of metastases; however, they represent a clinical challenge as growing lesions in such area that compress optic nerve, chiasm, and nerves involved in the extraocular movement have been associated with serious morbidity. We have analyzed the tumor control, survival outcomes, and toxicity after stereotactic radiosurgery (SRS) for skull base metastases from systemic cancer involving the anterior visual pathway. PATIENTS AND METHODS: We have analyzed 34 patients (23 females and 11 males, median age 59 years) who underwent multi-fraction SRS for a skull base metastasis compressing or in close proximity of optic nerves and chiasm. All metastases were treated with frameless LINAC-based multi-fraction SRS in 5 daily fractions of 5 Gy. Local control, distant failure, and overall survival were estimated using the Kaplan-Meier method calculated from the time of SRS. Prognostic variables were assessed using log-rank and Cox regression analyses. RESULTS: At a median follow-up 13 (range, 2-36.5 months) months, twenty-five patients had died and 9 were alive. The 1-year and 2-year local control rates were 89% and 72%, and respective actuarial survival rates were 63% and 30%. Four patients recurred with a median time to progression of 12 months (range, 6-27 months), and 17 patients had new brain metastases at distant brain sites. The 1-year and 2-year distant failure rates were 50% and 77%, respectively. On multivariate analysis, a Karnofsky performance status (KPS) >70 and the absence of extracranial metastases were prognostic factors associated with lower distant failure rates and longer survival. After multi-fraction SRS, 15 (51%) out of 29 patients had a clinical improvement of their preexisting cranial deficits. No patients developed radiation-induced optic neuropathy during the follow-up. CONCLUSIONS: Multi-fraction SRS (5 x 5 Gy) is a safe treatment option associated with good local control and improved cranial nerve symptoms for patients with a skull base metastasis involving the anterior visual pathway.
RECONSTITUTION OF ANTIPHAGE ANTIBODIES FROM L AND H POLYPEPTIDE CHAINS AND THE FORMATION OF INTERSPECIES MOLECULAR HYBRIDS
Authors: M. Fougereau, D. E. Olins, G. M. Edelman
Journal: The Journal of Experimental Medicine (1964)

Reconstitution of phage-neutralizing activity was observed after admixture of separated L and H polypeptide chains of purified antibodies obtained from single sheep or guinea pigs and directed against f1 and f2 phages. Hybrid mixtures of complementary chains of antiphage antibodies and gamma-globulins of the same animal showed less activity than the homologous mixtures of chains from antibodies of the same specificity. 7S interspecies molecular hybrids could be formed between L or H chains of sheep gamma-globulins and the complementary chains of guinea pig gamma-globulins. In contrast to the results obtained within a single animal species, mixtures of L or H chains of antiphage antibodies from one species with the complementary chains of antibodies to the same phage from the other species showed slight or negligible potentiation of neutralizing activity.
Marihuana and Tidal Volume
Authors: Conrad J. Schwarz
Journal: JAMA (1973)

<h3>To the Editor.—</h3> As with many other clinical features of cannabis that were submerged until recently, the observation that regular use might have a cumulative effect requiring a period of abstinence for the symptoms to clear (222:35, 1972) goes back many years. Rosenthal translates from original manuscripts the medieval Moslem recorder Az-Zarkashi as stating the following of a certain Shayk Ali al-Hariri, a 13th century religious leader: This Hariri was very hard on habitual users of hashish. One of his followers sent a messenger to him to upbraid him (for his attitude). The Shaykh said to the messenger: "If the man mentioned is one of my followers, so that I have to oblige him, let him give up hashish for 40 days until his body is free from it, and 40 more days until he is rested from it, after having become free; then let him come to me so
Shaving for head lice is unnecessary and distressing
Authors: Christine M Brenton
Journal: BMJ (2005)

Timing of tracheostomy in adult patients Potential ramifications are alarmingEditor-In their systematic review and meta-analysis Griffiths et al conclude that tracheostomies should be performed earlier in critically ill patients. 1As ear, nose, and throat surgeons we find the potential ramifications quite alarming, primarily as undertaking this major operation is not without potential morbidity in patients who are already systemically unwell. 2 3 These patients are often anaemic and have coagulopathies and sepsis among other comorbidities-points that we thought the authors had not discussed, and factors that have implications for the surgical procedure.In our experience, many patients listed for tracheostomy from intensive care units are extubated or sometimes die while waiting for their procedure; if tracheostomy were performed immediately these patients would be subjected to unnecessary procedures.The postoperative sequelae of tracheostomy are a slow weaning process before patients can be decannulated, followed by potential tracheal stenosis. 4hese patients may be able to leave intensive care earlier, but Griffiths et al do not say how long they then remain inpatients before discharge because of problems with rehabilitation with a tracheostomy tube in situ.Interestingly, although duration of ventilation and stay in the intensive care unit were shortened by an earlier tracheostomy, mortality was not altered and inpatient stay was likely to have been lengthened. 5he authors divided timing of tracheostomy into two groups, demarcated by seven days after intubation, making an artificial separation that seems invalid.It would have been more interesting to see whether increasing number of days have a proportional relation to the duration of ventilation and stay in intensive care on a linear scale.We advise great caution in interpreting the findings of Griffiths et al and about its impact on the delivery of the tracheostomy service in hospitals.
909 14-3-3ζ IS OVEREXPRESSED IN HEPATOCELLULAR CARCINOMA AND ITS SUPPRESSION INHIBITS TUMOR GROWTH AND ENHANCES CHEMOSENSITIVITY
Authors: S.K. Yoon, J.E. Choi, S.W. Lee, M.J. Song, S.H. Bae, J.Y. Choi, J.M. Yang, Y.S. Lee, C.D. Lee, K.W. Chung
Journal: Journal of Hepatology (2010)
Progression of Idiopathic Pulmonary Fibrosis
Authors: Rony M Abou Jawde, Feyrouz Al-Ashkar
Journal: New England Journal of Medicine (2004)

A 75-year-old man with idiopathic pulmonary fibrosis was admitted because of progressive shortness of breath. He stated that he had not had new cough, fever, chest pain, palpitations, orthopnea, or paroxysmal nocturnal dyspnea. His home oxygen requirement had increased from 3 liters per minute to 6 liters per minute, administered by nasal cannula. The patient had received the diagnosis of idiopathic pulmonary fibrosis in 1998 on the basis of clinical and radiographic findings (Panel A). His disease had progressed despite corticosteroid and interferon gamma therapy. Repeated computed tomography showed marked progression of fibrotic changes (Panel B). Broad areas of honeycomb . . .