tbuckley/cabot-search huggingface dataset:
PD09-06: Phase II Trial of RAD001 (Everolimus), an mTOR Inhibitor, with Weekly Cisplatin and Paclitaxel in Patients with HER2−Negative Metastatic Breast Cancer (MBC).
Authors: IA Mayer, J Means-Powell, VG Abramson, Y Shyr, JM Balko, MG Kuba, HM Gharavi, L Schlabach, CL Arteaga, JA Pietenpol
Journal: Cancer Research (2011)

Abstract Background: In basal-like breast cancers, drugs that either negatively modulate p63 and/or activate p73, such as cisplatin and paclitaxel, promote p73-dependent apoptosis. Further, the serine threonine kinase mTOR negatively regulates p73. Inhibition of mTOR with RAD001 upregulates p73, and results in p73-mediated apoptosis. Therefore, we conducted a phase II trial in patients with HER2−negative MBC to explore safety, tolerability and anti-tumor activity of the combination of paclitaxel, cisplatin and RAD001. Materials and Methods: We initiated an open-label, phase II multi-institutional study of weekly cisplatin (25 mg/m2), paclitaxel (80 mg/m2) and daily RAD001 (5 mg), given on a 28-day cycle. Treatment was continued until unacceptable toxicity or progression of disease. All toxicities were documented using the NCICTCv.4. Disease was assessed every 2 months. Results: A total of 55 patients were enrolled. Median age was 55 years; 62% of patients had prior chemotherapy with a median of 3 previous regimens in the metastatic setting. Sixty-three percent of patients had triple-negative disease, 81% patients had visceral disease, and 35% had bone metastases. Twenty-one patients are still on study. The most common toxicities are summarized in the table below. Neutropenia was the main cause for dose reductions, mainly after cycle 3. Only 1 patient developed febrile neutropenia. Of the 44 patients assessed for best response (RECIST) thus far, 11 had partial response, 21 stable disease, 9 disease progression, and 3 were not evaluable. Thirty eight patients have discontinued treatment so far; 30 due to disease progression, 5 due to toxicity, and 3 withdrew consent. Current median time to progression on the evaluable patients is 6 months. Discussion: The combination of RAD001, cisplatin and paclitaxel was overall very well tolerated despite cumulative pancytopenia. Significant antitumor activity in this heavily pre-treated patient population was seen. All patients’ primary diagnostic and/or metastatic tumor biopsies are currently being analyzed for the presence of PIK3CA and AKT1 mutations, and immunohistochemical expression of p53, p63, p73, and PTEN. Microarrays are being generated to determine whether time to progression is superior in patients with basal-like breast cancers. Microarrays will be mined to identify a pretreatment profile that mirrors a low p63/high p73 gene expression signature. Correlation of mutational analysis and gene signatures with clinical benefit will be presented at the meeting Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-06.
JOINT AFFECTIONS IN NERVOUS DISEASE.
Authors: LEWELLYS F. BARKER
Journal: JAMA (1907)

America has the honor of having first seriously directed the attention of the medical world to the intimate relation between disease of the joints and of the nervous system. Since Dr. John Keasley Mitchell<sup>1</sup>wrote his suggestive articles in 1831 and 1833 our knowledge of this relation has made remarkable progress. If we leave out of consideration the atrophic joints and limbs of the cerebral and spinal palsies of children and the joint changes in acromegaly the most important joint affections in nervous disease fall into the following groups: The intermittent joint effusions (hydrops articulorum intermittens). The arthropathies of tabes and dementia paralytica (arthropathia tabetica). The syringomyelic arthropathies (arthropathia syringomyelica). The painful joints of the psychoneurotics (arthral-algia psychoneurotica). <h3>THE REGULARLY INTERMITTENT JOINT EFFUSIONS</h3><h3>(Hydrops Articulorum Intermittens).</h3> This remarkable affection early described by Moore<sup>2</sup>has been carefully studied in this country by Kennedy,<sup>3</sup>Barnes,<sup>4</sup>Brackett and Cotton
Diagnosis of Non-Hodgkin??s Lymphoma Intracerebral Mass Lesions Usefulness of Tc-99m Pertechnetate and Ga-67 Citrate Brain Scans
Authors: BERNARD L. ZIDAR, MUSTAFA ADATEPE, FRANK HRYSCHKO, ROBERT J. HARTSOCK, LAIBE KESSLER, THOMAS A. LYONS
Journal: Clinical Nuclear Medicine (1982)

This paper summarizes the clinical and diagnostic features of five reports of patients with intracerebral, non-Hodgkin's lymphoma. In three patients the brain lesion was the only evidence of lymphoma, while two patients also had concomitant systemic involvement. Four patients had diffuse histiocytic lymphoma and one had a mixed type of malignant lymphoma. In all patients, Tc-99m and Ga-67 brain scans disclosed discrete areas of increased radionuclide uptake consistent with a mass. In each case, brain blood perfusion studies were normal and brain computerized tomographic (CT) scans and cerebral angiograms produced variable nondiagnostic patterns. Craniotomies in four patients provided histologic confirmation of the non-Hodgkin's lymphoma in the areas of abnormality. The remaining patient had systemic histiocytic lymphoma with concomitant brain lesions that responded to irradiation. The combined use of the above noninvasive modalities in correlation with clinical findings may result in more accurate prebiopsy diagnoses of intracerebral lymphoma.
HMG-CoA Reductase Inhibitors Reduce Senescence and Increase Proliferation of Endothelial Progenitor Cells via Regulation of Cell Cycle Regulatory Genes
Authors: Birgit Assmus, Carmen Urbich, Alexandra Aicher, Wolf K. Hofmann, Judith Haendeler, Lothar Rössig, Ioakim Spyridopoulos, Andreas M. Zeiher, Stefanie Dimmeler
Journal: Circulation Research (2003)

Endothelial progenitor cells (EPCs) play an important role in postnatal neovascularization of ischemic tissue. Ex vivo expansion of EPCs might be useful for potential clinical cell therapy of myocardial ischemia. However, cultivation of primary cells leads to cellular aging (senescence), thereby severely limiting the proliferative capacity. Therefore, we investigated whether statins might be able to prevent senescence of EPCs. EPCs were isolated from peripheral blood and characterized. After ex vivo cultivation, EPCs became senescent as determined by acidic β-galactosidase staining. Atorvastatin or mevastatin dose-dependently inhibited the onset of EPC senescence in culture. Moreover, atorvastatin increased proliferation of EPCs as assessed by BrdU incorporation and colony-forming capacity. Whereas geranylgeranylpyrophosphate or farnesylpyrophosphate reduced the senescence inhibitory effect of atorvastatin, NO synthase inhibition, antioxidants, or Rho kinase inhibitors had no effect. To get further insights into the underlying downstream effects of statins, we measured telomerase activity and determined the expression of various cell cycle regulatory genes by using a microarray assay. Whereas telomerase activity did not change, atorvastatin modulated expression of cell cycle genes including upregulation of cyclins and downregulation of the cell cycle inhibitor p27 Kip1 . Taken together, statins inhibited senescence of EPCs independent of NO, reactive oxygen species, and Rho kinase, but dependent on geranylgeranylpyrophosphate. Atorvastatin-mediated prevention of EPC senescence appears to be mediated by the regulation of various cell cycle proteins. The inhibition of EPC senescence and induction of EPC proliferation by statins in vitro may importantly improve the functional activity of EPCs for potential cell therapy.
Just a song at twilight
Authors: J. O. Drife
Journal: BMJ (2010)

Like me, the Edinburgh International Festival was born in 1947 as a result of the second world war. My parents met during the Allied invasion of Italy. The festival was part of the effort to replace pan-European carnage with something better. Its organiser, Rudolf Bing, had fled Germany in 1934 and helped to found Glyndebourne Festival Opera—now, ironically, perceived as quintessentially English.

Edinburgh still has an international feel during its annual cultural jamboree, though nowadays aesthetes are outnumbered …
Creatine Phosphokinase as Indicator of Adenosine Triphosphate Activity
Authors: Jeffrey S. Wigand
Journal: JAMA (1973)

<h3>To the Editor.—</h3> Apropos of the findings of Nevins et al (224:1382, 1973), who demonstrated increased serum creatine phosphokinase (CPK) in a wide range of disease activities, we would like to present our findings of serum CPK elevation as an indicator of adenosine triphosphate (ATP) activity in an 18-month-old child with a progressive, since birth, neurogenic disease, Werding-Hoffman-Kugelberg-Welander complex, with adenosine-5-monophosphate (A5MP) therapy. <h3>Report of a Case.—</h3> The child had a serum CPK level of 0.3 international units (IU). After 12 days of alternate-day therapy with intragluteally injected AMP, his CPK level rose to 284 IU, and after nine months of biweekly administered AMP, the CPK level was 994 IU. In view of the high level, therapy was discontinued. Unlike the results in Nevin's studies, the CPK level in this child decreased slowly in three months to 217 IU, and after four more months returned to a value of 63
Nuchal test detects 80% of Down's syndrome pregnancies
Authors: J. Wise
Journal: BMJ (1998)

The nuchal translucency test for determining the risk of Down's syndrome has a detection rate of 80% and a rate of false positive results of 8%, according to a multicentre study in the United Kingdom.

This compares with a detection rate of 30% and a false positive rate of 5%xwhen age alone is used as a screening …
TEMPERAMENT AND DIGESTIVE DISORDERS
Authors: M. Culpin
Journal: BMJ (1935)

A cavity in a tuberculous lung is a source of danger, and adds to the gravity of the prognosis.At the same time a large number of cavities heal without any form of collapse treatment.The modern view that a cavity must be collapsed at all costs is open to the criticism that the danger of the treatment sometimes exceeds that of the disease.It is usually good treatment to try and collapse a cavity by artificial pneumothorax, but if this fails it does not follow that surgical methods, such as thoracoplasty or plombage, should be tried.McMahon and Kerper (Amer.Journ.Med., 1933, lxxx, 170) found that 27.7 per cent.cavities treated with simple medical means healed.They also state that prognosis varies with the size of the cavity.Spontaneous closure occurred in 40 per cent. of those not larger than 2 x 2 cm., but in only 6 per cent. of those over 4 x 4 cm.In a right-sided cavity spontaneous healing was twice as likely as in a left-sided, and three times as likely as in a bilateral, case.Healing is less likely in a peripheral cavity or a thick-walled one.It is usually the type of disease rather than the presence of a cavity which renders collapse treatment necessary.
Thick melanoma: the challenge persists
Authors: C.S. Murray, D.L. Stockton, V.R. Doherty
Journal: British Journal of Dermatology (2005)

Background Considerable resources have been channelled into primary and secondary prevention of cutaneous melanoma over the past 20 years. These efforts have been associated with a significant increase in the proportion of thin, good prognosis lesions and this is felt to be the principal reason for the current overall improvement in melanoma survival. Objectives Analysis of Scottish Melanoma Group (SMG) data was carried out to identify the proportion of thick melanomas presenting over time. SMG data were used to characterize the patients presenting with thick melanoma. Methods Using data from the SMG database 915 patients (392 male and 523 female) first diagnosed with invasive melanoma ≥ 3·5 mm thick in the two decades between 1979 and 1998, inclusive, were identified. The patients were from regions designated South-east Scotland, Tayside, Grampian and Highland, which together form half of all Scottish cases. Results The analysis shows that, although the proportion of thick, poor prognosis melanomas has decreased over time, the number presenting per year has not significantly altered. In the first decade, 50·5% of registrations were thick lesions and these fell to 31·0% in the second decade. In the first decade there were 419 cases (173 male), median age 66 years (range 5–99). Fifty-five patients were under the age of 40 years. Two hundred and twelve melanomas were nodular, 116 superficial spreading (SSM), 34 acral and 26 lentigo maligna melanoma. Sixty-nine patients had either lymph node involvement or distant spread at presentation. Despite a 93·3% increase in the total number of melanoma registrations by the end of the second decade, there was relatively little change in the absolute numbers of thick lesions. The total number of thick lesions was 496 (220 male), an increase of 18·4%. Median age was greater, at 70 years (range 1–98), and 31 patients were under the age of 40 years. Nodular was still the commonest type but its proportion had dropped significantly compared with the first decade, with a corresponding increase in SSM and acral types. Conclusions Over a 20-year period there was little change in the absolute number of patients presenting with thick melanoma each year, though these form a diminishing proportion of the rising number of total melanomas. This thick melanoma group is characterized by an increasingly older age group and a changing type profile, nodular and SSM being the most common types. This work suggests that the resources currently directed at public and professional education on melanoma are having no effect on this group of patients and that alternative strategies may need to be considered.
Restoration of Bone Morphogenetic Protein Receptor Type II Expression Leads to a Decreased Rate of Tumor Growth in Bladder Transitional Cell Carcinoma Cell Line TSU-Pr1
Authors: Isaac Yi Kim, Dong-Hyeon Lee, Dug Keun Lee, Wun Jae Kim, Moses M. Kim, Ronald A. Morton, Seth P. Lerner, Seong Jin Kim
Journal: Cancer Research (2004)

Abstract Bone morphogenetic proteins (BMPs), potential regulators of cellular growth and metastasis that signal through an interaction with plasma membrane receptors, have been suggested to be important regulators of malignant cells. The present study was carried out to evaluate the potential role of BMP receptor (BMP-R) types IA, IB, and II in bladder transitional cell carcinoma (TCC) cells. Initially, we investigated the expression of these BMP-Rs in 30 archival tissues of human bladder TCC using immunohistochemistry; 10 benign bladder specimens were used for comparison. The results demonstrated that the expression of BMP-Rs is localized preferentially to the transitional epithelium and that there was a significant association between loss of BMP-RII expression and tumor grade. To find a cell line that can serve as a model system for clinical observation, we subsequently examined sensitivity to BMP-4 and expression of BMP-RII, BMP-RIA, and BMP-RIB in three human bladder cancer cell lines, TCC-Sup, RT4, and TSU-Pr1. Of the three cell lines, TSU-Pr1 exhibited a decreased level of BMP-RII expression and was resistant to the growth-inhibitory effect of BMP-4. Overexpression of BMP-RII in TSU-Pr1 cells not only restored BMP-4 responsiveness but also significantly decreased tumorigenicity in vivo. Taken together, these results demonstrate that human bladder TCC tissues have a frequent loss of BMP-RII expression and that overexpression of BMP-RII leads to restoration of BMP signaling and decreased tumor growth in the human bladder TCC cell line TSU-Pr1.
Isoprenaline-evinced disturbances in action potentials from hearts of young cardiomyopathic hamsters
Authors: K. L ROSSNER
Journal: Cardiovascular Research (1985)

The electrophysiology of ventricular cells from prenecrotic stage 10 to 14 day old hamsters with hereditary cardiomyopathy (BIO 14.6 strain) was studied with the intent of learning more about the previously documented relationship of stimulation with β-adrenergic agonist and the sarcolemmal defect contributing to the excessive uptake of calcium by diseased cells. Before catecholamine treatment only slight differences were observed in the configuration of action potentials of myopathics and control random bred hamsters (BIO RB strain). However, isoprenaline in varying concentrations, increased the action potential duration (APD) at 50% and 95% repolarisation levels to a significantly greater extent in myopathics than in controls. Repetition of the dose-response to isoprenaline in the presence of the β-adrenergic antagonist propranolol (0.1 μmol·litre-1) permitted the calculation of the dissociation equilibrium constant for the antagonist. The similarity of dissociation constants between strains, 0.008 μmol·litre-1 for controls and 0.011 μmol·litre1 for myopathics, suggests that a difference in interstrain receptor affinities is an unlikely cause of the isoprenaline effect. Rather, the data are more consistent with the hyper-sensitivity resulting from larger numbers of β-adrenoceptors on sarcolemma of myopathic cells. Also, the increase in APD of myopathics indicates that isoproterenol elicits an imbalance of slow inward calcium and late outward potassium currents. The possible significance of the isoprenaline hyper-sensitivity, which is the earliest pathophysiology seen in this disease, to the etiology of cellular calcium overload and degeneration of diseased myocardium remains to be determined.
Hereditary Angioneurotic Edema, 1887 to 1987
Authors: Harvey R. Colten
Journal: New England Journal of Medicine (1987)

Nearly 100 years ago, on September 20, 1887, a 24-year-old woman was admitted to William Osier's service at the Philadelphia Infirmary for Nervous Diseases with chronic intermittent "attacks of transient swelling in various parts — hands or fingers, knee caps, elbows, buttocks, arm or thigh in fleshy parts, face, or more often the lips alone."1 Osier declined to speculate about mechanisms, but he did identify a genetic basis for the edema. From the patient's 92-year-old grandfather, Osier obtained a remarkable history of similar episodes in five generations of the family, beginning with the patient's great-grandmother, Margaret A, born in 1762. . . .
Who Is Maintaining Certification in Internal Medicine—and Why? A National Survey 10 Years after Initial Certification
Authors: Rebecca S. Lipner, Wayne H. Bylsma, Gerald K. Arnold, Gregory S. Fortna, John Tooker, Christine K. Cassel
Journal: Annals of Internal Medicine (2006)

Background: The American Board of Medical Specialties (ABMS) adopted a framework, called Maintenance of Certification (MOC), for all certifying boards to evaluate physicians' competence throughout their careers, with the goal of improving the quality of health care. The MOC participation rates of the American Board of Internal Medicine (ABIM) show that 23% of general internists and 14% of subspecialists choose not to renew their respective certificates. Objective: To study U.S. internists' perceptions about the forces driving them to maintain certification. Design: Mail survey. Setting: A nationally representative sample of certified internists in the United States. Participants: Physicians originally certified in internal medicine, a subspecialty, or an area of added qualifications in 1990, 1991, or 1992. Results: The overall rate of response to the survey was 51%. Although 91% of all participants are still working in internal medicine or its subspecialties, this percentage is notably lower among general internists (79%). Of those still working in the field of internal medicine or its subspecialties, approximately half report being required to maintain their specialty certificate by at least 1 employer, but only approximately one third of those who completed or enrolled in MOC report this requirement as a reason for participating. Those who completed or enrolled in MOC do so more for positive professional reasons than for monetary benefits or professional advancement. The most common reasons for not participating are the perceptions that it takes too much time, is too expensive, and is not required for employment. Limitations: Respondents were volunteers from an early cohort of diplomates entering the program, and those with less positive attitudes may have responded at higher rates. Results are based on self-reported data, and misconceptions about program requirements may have led to some inaccurate responses. Conclusions: The relatively large percentage of general internists who left internal medicine mostly to work in another medical field explains why rates of MOC participation for general internists seem lower than those for subspecialists (77% vs. 86%). Although positive professional reasons clearly have a compelling internal influence on program participation, it is less clear whether employers' requirements are an equally compelling external influence. Although half of all respondents report that MOC is required by 1 of their employers, only one third of those who participate in the program describe it as a reason for participating.
An E1B-19 kDa gene deletion mutant adenovirus demonstrates tumor necrosis factor-enhanced cancer selectivity and enhanced oncolytic potency
Authors: Ta-Chiang Liu, Gunnel Hallden, Yaohe Wang, Gabriel Brooks, Jennelle Francis, Nick Lemoine, David Kirn
Journal: Molecular Therapy (2004)

Oncolytic adenoviruses hold promise as a new treatment platform for cancer, but limitations have been identified, including limited spread and potency. The adenoviral protein E1B-19 kDa is a Bcl-2 homologue that blocks apoptosis induction via the intrinsic and extrinsic pathways, specifically including tumor necrosis factor-mediated cell death. We demonstrate that an E1B-19 kDa gene deletion mutant had tumor necrosis factor-enhanced cancer selectivity, in vitro and in vivo, due to genetic blocks in apoptosis pathways in cancer cells. In addition, this mutant demonstrated significantly enhanced viral spread and antitumoral potency relative to dl1520 (aka Onyx-015) and wild-type adenovirus in vitro. Significant antitumoral efficacy was demonstrated in vivo by intratumoral and intravenous routes of administration. E1B-19 kDa deletion should be considered as a feature of oncolytic adenoviruses to enhance their safety, spread, and efficacy.
VGLUT2-Dependent Glutamate Release from Nociceptors Is Required to Sense Pain and Suppress Itch
Authors: Yang Liu, Omar Abdel Samad, Ling Zhang, Bo Duan, Qingchun Tong, Claudia Lopes, Ru-Rong Ji, Bradford B. Lowell, Qiufu Ma
Journal: Neuron (2010)
Defective Esterase and Kinin-Forming Activity in Human Fletcher Trait Plasma
Authors: VIRGINIA H. DONALDSON, HIDEHIKO SAITO, OSCAR D. RATNOFF
Journal: Circulation Research (1974)

Fletcher trait plasma failed to generate kinin and developed only a small amount of arginine esterase activity at an abnormally slow rate following surface activation. Neither defect was due to a deficiency of Hageman factor (HF, factor XII) or kininogen or to an excessively rapid inactivation of evolving kinin. Pyrex pretreated with Fletcher trait plasma did not generate kinin normally in fresh normal plasma. Fractions rich in prekallikrein prepared from normal, HF-deficient, or plasma thromboplastin antecedent (PTA)-deficient plasma developed kallikrein activity by direct activation during incubation with trypsin or HF fragments formed by digesting partially purified HF with trypsin. In contrast, identical fractions of Fletcher trait plasma did not develop this activity. Although this finding suggested that Fletcher trait plasma was deficient in prekallikrein, materials eluted from Celite that had been incubated in Fletcher trait plasma contained both esterase and kinin-generating activities. Celite eluates prepared from normal and Fletcher trait plasma released kinin from partially purified kininogen equally well. This release was blocked by soybean trypsin inhibitor but not by lima-bean trypsin inhibitor. Therefore, although unfractionated Fletcher trait plasma appears to be functionally and antigenically deficient in normal prekallikrein, it may actually contain a different prekallikrein which is activated by exposure to Celite but not by exposure to activated HF or trypsin.