tbuckley/cabot-search huggingface dataset:
Phase I Trial of Irinotecan, Infusional 5-Fluorouracil, and Leucovorin (FOLFIRI) with Erlotinib (OSI-774)
Authors: Wells A. Messersmith, Daniel A. Laheru, Neil N. Senzer, Ross C. Donehower, Paula Grouleff, Theresa Rogers, Sean K. Kelley, David A. Ramies, Bert L. Lum, Manuel Hidalgo
Journal: Clinical Cancer Research (2004)

Abstract Purpose: This phase I study was conducted to establish the dose-limiting toxicities and maximum-tolerated dose of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in combination with FOLFIRI, a standard regimen of irinotecan, leucovorin, and infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer. Experimental Design: The trial used a dose-escalation design beginning with 100 mg/day erlotinib continuously and dose-reduced FOLFIRI (150 mg/m2 i.v. day 1 irinotecan, 200 mg/m2 i.v. leucovorin, 320 mg/m2 i.v. bolus days 1 to 2 5-FU, and 480 mg/m2 i.v. 5-FU infusion over 22 hours, days 1 to 2) administered in 6-week cycles (three FOLFIRI treatments). Plasma sampling was performed for irinotecan, erlotinib, and 5-FU for pharmacokinetic analysis during cycle 1. Results: The study was halted after six patients at the lowest dose level due to unexpectedly severe toxicities, including disfiguring grade 2 rash (three patients), grade 3 diarrhea (three patients), and grade ≥ 3 neutropenia (three patients). All patients required some dose interruption or reduction of either erlotinib or FOLFIRI, and only one patient completed two 6-week cycles of therapy. Five patients had stable disease after one cycle, and one patient had a partial response. No plasma pharmacokinetic interaction was observed that could explain the observed increased toxicity. Conclusions: FOLFIRI combined with erlotinib causes excessive toxicity at reduced doses. These findings contrast with available data regarding the optimal safety profile of trials combining small molecule epidermal growth factor receptor inhibitors with other conventional chemotherapy and highlight the need to perform safety-oriented studies of such combinations.
The epidemiology and clinical outcome of hepatitis D virus (delta) infection in Jordan
Authors: Ala U. Toukan, Omayma A. Abu-El-Rub, Salwa A. Abu-Laban, Musleh S. Tarawneh, Feisal M. Kamal, Stephen C. Hadler, Krzysztof Krawczynski, Harold S. Margolis, James E. Maynard
Journal: Hepatology (1987)

The epidemiology and clinical outcome of hepatitis D viral infection in HBsAg-positive acute hepatitis, chronic liver disease, primary hepatocellular carcinoma and the symptomless carrier state was studied in Jordan. The prevalence of hepatitis D viral infection was significantly higher in patients with chronic liver disease (18/79, 23%) and acute hepatitis (17/108, 16%) than in symptomless HBsAg carriers (2/136, 2%). The highest prevalence of hepatitis D viral infection was found in patients with primary hepatocellular carcinoma (10/15, 67%) who were also significantly older than such patients without hepatitis D viral infection. Antihepatitis D virus IgM was detected persistently in 83% of patients with antihepatitis D virus-positive chronic liver disease and transiently in 41% of patients with acute hepatitis. A trend to increased mortality was observed in acute hepatitis D viral superinfection (25%) compared to hepatitis D viral coinfection (0%) and to antihepatitis D virus-negative HBsAg-positive acute hepatitis (4%). In patients with established chronic liver disease, however, neither survival nor histological parameters of disease activity were significantly different in the antihepatitis D virus-positive and antihepatitis D virus-negative groups. While the early stage of hepatitis D viral super-infection is associated with increased mortality, it appears that in patients with late-stage chronic liver disease, severe histological activity subsides, and survival is no longer influenced by the factor of hepatitis D viral infection. However, primary hepatocellular carcinoma appears to complicate the course of those antihepatitis D virus-positive patients surviving beyond this stage.
Nitric Oxide Deficiency and Endothelial Dysfunction in Pulmonary Arterial Hypertension
Authors: James R. Klinger, Steven H. Abman, Mark T. Gladwin
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Nitric oxide (NO) signaling plays a major role in modulating vascular tone and remodeling in the pulmonary circulation, but its role in the pathogenesis of pulmonary vascular diseases is still not completely understood. Numerous abnormalities of NO synthesis and signaling have been identified in animal models of pulmonary vascular disease and in humans with pulmonary hypertension. Many of these abnormalities have become targets of new therapies for the treatment of pulmonary hypertension. However, it is unclear to what extent alterations in NO signaling contribute to pulmonary hypertensive responses or merely reflect abnormalities induced by the underlying disease. This perspective examines the current understanding of altered NO signaling in pulmonary hypertensive diseases and discusses how these alterations may contribute to the pathogenesis of pulmonary hypertension. The efficacy and limitations of presently available therapies for pulmonary hypertension that target NO signaling are reviewed along with an update on investigational therapies that use this pathway to reverse pulmonary hypertensive changes.
Mary Helen “Molly” Hargan (née McLaren)
Authors: Mary Cleary
Journal: BMJ (2005)

​FormerFormer general practitioner Rotherham (b 1909; q Glasgow 1933), d 24 February 2005.




Figure 1




Molly began her medical career at the Sick Children's Hospital, Glasgow. Six months later she moved to Rotherham to a resident house appointment at Moorgate Hospital. On her first night in Rotherham she met James Hargan, already an established doctor in the town, and they were married the following year. In 1947 she joined her husband in general practice. She was a magistrate and the first woman president of the Rotherham branch of the BMA. In 1999 she was noted as one of the Yorkshire women of the century. She was a staunch Catholic. She leaves eight children and 23 grandchildren.
Visionary GPs are extending scope of general practice
Authors: D. Macauley
Journal: BMJ (2010)

Sending 1500 Valentine cards to the vice chancellor of Nottingham University was one of the publicity ploys adopted by the university’s health practice, students’ union, and students’ welfare body when they began to lobby for a sexual health promotion officer. If 95% of your 34 000 patients are in the age range 18-30, sexual health is clearly a major issue.

The university health service also ran nurse led screening clinics for sexually transmitted diseases. It raised the profile of the clinics through evening “road shows” where asymptomatic screening was offered in halls of residence and where students could register for free condoms. It had “pee in the pot” days as part of chlamydia screening, and it ran a “sexual health awareness and guidance week,” with the memorable acronym of SHAG week. 

The team from the university health service, which is based at the Cripps Health Centre, Nottingham, is one of four groups that have been shortlisted for the BMJ Group’s Primary Care Team of the Year award, which is being offered this year for the first time. When the BMJ Group Awards were first launched last year, there was neither a primary care nor a secondary …
In Vivo AAV1 Transduction With hRheb(S16H) Protects Hippocampal Neurons by BDNF Production
Authors: Min-Tae Jeon, Jin Han Nam, Won-Ho Shin, Eunju Leem, Kyoung Hoon Jeong, Un Ju Jung, Young-Seuk Bae, Young-Ho Jin, Nikolai Kholodilov, Robert E Burke, Seok-Geun Lee, Byung Kwan Jin, Sang Ryong Kim
Journal: Molecular Therapy (2014)

Recent evidence has shown that Ras homolog enriched in brain (Rheb) is dysregulated in Alzheimer's disease (AD) brains. However, it is still unclear whether Rheb activation contributes to the survival and protection of hippocampal neurons in the adult brain. To assess the effects of active Rheb in hippocampal neurons in vivo, we transfected neurons in the cornu ammonis 1 (CA1) region in normal adult rats with an adeno-associated virus containing the constitutively active human Rheb (hRheb(S16H)) and evaluated the effects on thrombin-induced neurotoxicity. Transduction with hRheb(S16H) significantly induced neurotrophic effects in hippocampal neurons through activation of mammalian target of rapamycin complex 1 (mTORC1) without side effects such as long-term potentiation impairment and seizures from the alteration of cytoarchitecture, and the expression of hRheb(S16H) prevented thrombin-induced neurodegeneration in vivo, an effect that was diminished by treatment with specific neutralizing antibodies against brain-derived neurotrophic factor (BDNF). In addition, our results showed that the basal mTORC1 activity might be insufficient to mediate the level of BDNF expression, but hRheb(S16H)-activated mTORC1 stimulated BDNF production in hippocampal neurons. These results suggest that viral vector transduction with hRheb(S16H) may have therapeutic value in the treatment of neurodegenerative diseases such as AD. Recent evidence has shown that Ras homolog enriched in brain (Rheb) is dysregulated in Alzheimer's disease (AD) brains. However, it is still unclear whether Rheb activation contributes to the survival and protection of hippocampal neurons in the adult brain. To assess the effects of active Rheb in hippocampal neurons in vivo, we transfected neurons in the cornu ammonis 1 (CA1) region in normal adult rats with an adeno-associated virus containing the constitutively active human Rheb (hRheb(S16H)) and evaluated the effects on thrombin-induced neurotoxicity. Transduction with hRheb(S16H) significantly induced neurotrophic effects in hippocampal neurons through activation of mammalian target of rapamycin complex 1 (mTORC1) without side effects such as long-term potentiation impairment and seizures from the alteration of cytoarchitecture, and the expression of hRheb(S16H) prevented thrombin-induced neurodegeneration in vivo, an effect that was diminished by treatment with specific neutralizing antibodies against brain-derived neurotrophic factor (BDNF). In addition, our results showed that the basal mTORC1 activity might be insufficient to mediate the level of BDNF expression, but hRheb(S16H)-activated mTORC1 stimulated BDNF production in hippocampal neurons. These results suggest that viral vector transduction with hRheb(S16H) may have therapeutic value in the treatment of neurodegenerative diseases such as AD.
Abstract 5623: Eliminating pancreatic cancer metastases through inhibition of hedgehog and RAS signaling
Authors: Dongsheng Gu, Xiaoli Zhang, Jingwu Xie
Journal: Cancer Research (2012)

Abstract Pancreatic cancer is arguably one of the most challenging human malignancies, with the five year survival rate below 5%. Pancreatic cancer is often found in advanced stages, and is unresponsive to conventional cancer therapy. Thus, the need to develop novel treatment strategies targeting metastasis of pancreatic cancer has never been greater. The molecular hallmark of pancreatic cancer is an activating mutation in the small GTPase KRAS. Unfortunately, efforts to target RAS signaling are not very successful for pancreatic cancer treatment. Recently, inhibition of hedgehog (Hh) signaling emerges as a new cancer therapeutic option, but the available data from several current clinical trials in pancreatic cancer show only modest activity. At present, gemcitabine is the standard chemotherapy for metastatic pancreatic cancer but the response rate is less than 10%, with the median survival of only 6-7 months. A new chemotherapy combination of 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) was recently studied in Europe with a response rate of 30% and median survival of 11 months, but at a cost of significant toxicity. In order to design treatment strategies based on the molecular changes critical for cancer metastasis, we took the advantage of the knowledge recently generated in our laboratory and the newly developed molecularly targeted drugs currently in clinical trials. We compared primary pancreatic tumors with metastatic liver tumors for molecular alterations in an orthotopic mouse model, and discovered elevated expression of Indian hedgehog (Ihh) and ERK1/2 phosphorylation in liver metastases. Inhibition of Hh signaling or MEK activity alone reduced primary tumor size but did not significantly affect distal tumor metastases. In contrast, targeting Hh signaling and MEK activity in the orthotopic mouse model dramatically decreased the primary tumor size and nearly eliminated lung and liver metastases. Mice treated with two inhibitors lived two weeks longer than those in other groups. While MEK inhibition mainly interefered with cell proliferation, suppression of ligand-dependent Hh signaling affected the tumor microenvironment. These data indicate that simultaneous suppression of RAS and Hh signaling will be more effective in future pancreatic cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5623. doi:1538-7445.AM2012-5623
Association of QRS duration with left ventricular structure and function and risk of heart failure in middle‐aged and older adults: the Multi‐Ethnic Study of Atherosclerosis (MESA)
Authors: Leonard Ilkhanoff, Kiang Liu, Hongyan Ning, Saman Nazarian, David A. Bluemke, Elsayed Z. Soliman, Donald M. Lloyd‐Jones
Journal: European Journal of Heart Failure (2012)
Autoimmune diseases; pathogenesis, chemistry and therapy.
Authors: Lester S. King
Journal: JAMA (1963)

Medical scientists, meeting the challenge of socalled "autoimmune" diseases, have created new techniques and achieved new concepts which are altering markedly our outlook in immunology, immunochemistry, and pathology. Burnet, winner of the Nobel prize for medicine, collaborates with Mackay to present an exposition of this field. They discuss a group of diseases "for which an autoimmune etiology has been established either as a primary or an associated factor, or in which there is some likelihood that autoimmune processes are concerned." Analyzed at length are thyroiditis, systemic lupus erythematosis, certain hemolytic conditions, rheumatoid arthritis, glomerulonephritis, and certain liver and nervous system diseases, while numerous other conditions are treated more cursorily. To diagnose an autoimmune state the authors invoke the following criteria: an increase in gamma globulin, demonstrable autoantibodies against some body component, deposition of denatured gamma globulin at certain sites of elections, accumulation of lymphocytes and plasma cells, some degree of
Agnew's or Quimby's Operation?
Authors: Wm. P. Munn
Journal: JAMA (1893)

Denver Col., August 25, 1893. <h3>To the Editor:</h3> —In the last issue of theJournalI notice that in reporting the discussion upon Dr. Manley's paper on "Tarsal Amputations," Dr. Quimby is quoted as describing a modification of Pirogoff's amputation, and that other participants in the discussion are then quoted as calling this modified Pirogoff's procedure, "Quimby's operation." While it may be that the operation was original with Dr. Quimby, it was not necessarily originated by him, as it is described with brevity and clearness by Agnew in the second volume of his "Surgery." page 361, in the following words: "Instead of sawing off the malleoli and the articular surface of the tibia, I allowed them to remain, and placed the calcaneum in the mortise between the two; the union was complete and was followed by a remarkably useful stump. In other instances I have done this and with satisfactory
1405 ALISPORIVIR PLUS RIBAVIRIN IS HIGHLY EFFECTIVE AS INTERFERON-FREE OR INTERFERON-ADD-ON REGIMEN IN PREVIOUSLY UNTREATED HCV-GT2 OR GT3 PATIENTS: SVR12 RESULTS FROM VITAL-1 PHASE 2B STUDY
Authors: J.-M. Pawlotsky, S.K. Sarin, G. Foster, C.-Y. Peng, J. Rasenack, R. Flisiak, T. Piratvisuth, H. Wedemeyer, W.-L. Chuang, W.M. Zhang, N.V. Naoumov
Journal: Journal of Hepatology (2012)
Function of an ophthalmic "accident and emergency" department: results of a six month survey.
Authors: N P Jones, J M Hayward, P T Khaw, C M Claoue, A R Elkington
Journal: BMJ (1986)

A retrospective analysis was carried out of all patients attending the casualty department of Southampton Eye Hospital during 1 February to 31 July 1983. During the six month period 8092 patients made a total of 13 544 visits. Of these patients, 6178 were attending the hospital for the first time and 1914 had previously been seen in the outpatient clinic; many did not fall into the category of "accident and emergency." Some 37% of patients were managed by the ophthalmic nurse alone. The findings show that the department was providing a service far in excess of its defined function, which suggests that the structure of the acute ophthalmic services may require change. Certainly the value of the ophthalmic nurse was beyond question, her active participation in management allowing the doctor more time with the more complex clinical problems and thus enhancing efficiency.
Acute pulmonary toxicity of particulate matter filter extracts in rats: coherence with epidemiologic studies in Utah Valley residents.
Authors: J A Dye, J R Lehmann, J K McGee, D W Winsett, A D Ledbetter, J I Everitt, A J Ghio, D L Costa
Journal: Environmental Health Perspectives (2001)

Epidemiologic reports by C.A. Pope III et. al. demonstrated that in the Utah Valley, closure of an open-hearth steel mill over the winter of 1987 was associated with reductions in respiratory disease and related hospital admissions in valley residents. To better examine the relationship between plant-associated changes in ambient particulate matter (PM) and respiratory health effects, we obtained total suspended particulate filters originally collected near the steel mill during the winter of 1986 (before closure), 1987 (during closure), and 1988 (after plant reopening). PM subcomponents were water-extracted from these filters and Sprague-Dawley rats were intratracheally instilled with equivalent masses of extract. Data indicated that 24 hr later, rats exposed to 1986 or 1988 extracts developed significant pulmonary injury and neutrophilic inflammation. Additionally, 50% of rats exposed to 1986 or 1988 extracts had increased airway responsiveness to acetylcholine, compared to 17 and 25% of rats exposed to saline or the 1987 extract, respectively. By 96 hr, these effects were largely resolved except for increases in lung lavage fluid neutrophils and lymphocytes in 1986 extract-exposed rats. Analogous effects were observed with lung histologic assessment. Extract analysis using inductively coupled plasma-mass spectroscopy demonstrated in all three extracts nearly 70% of the mass appeared to be sodium-based salts derived from the glass filter matrix. Interestingly, relative to the 1987 extract, the 1986/1988 extracts contained more sulfate, cationic salts (i.e., calcium, potassium, magnesium), and certain metals (i.e., copper, zinc, iron, lead, strontium, arsenic, manganese, nickel). Although total metal content was (3/4) 1% of the extracts by mass, the greater quantity detected in the 1986 and 1988 extracts suggests metals may be important determinants of the pulmonary toxicity observed. In conclusion, the pulmonary effects induced by exposure of rats to water-based extracts of local ambient PM filters were in good accord with the cross-sectional epidemiologic reports of adverse respiratory health effects in Utah Valley residents.
Comparative effects of the opioids fentanyl and buprenorphine on ventricular vulnerability during acute coronary artery occlusion
Authors: V. SAINI, D. B CARR, R. L VERRIER
Journal: Cardiovascular Research (1989)

Fentanyl, a mu selective opioid agonist in wide clinical use, raises the ventricular fibrillation threshold in the normal canine myocardium. We have previously shown that this effect is amplified by haemorrhagic stress. In order to determine if mu receptor activation is antifibrillatory during acute myocardial ischaemia, we compared the effects of two mu selective agents, fentanyl and buprenorphine, in open chest chloralose anaesthetised dogs. Each drug was administered intravenously in two doses 1 h apart (fentanyl 30 micrograms.kg-1.dose; buprenorphine 0.3 mg.kg-1.dose). Ventricular fibrillation threshold was measured during right ventricular pacing using the single stimulus technique. The threshold was determined before and during a 10 min left anterior descending coronary artery occlusion. Prior to fentanyl administration, ventricular fibrillation threshold decreased from a control value of 19(SEM 2) mA to 12(1) mA during coronary artery occlusion. After the first dose of this drug an attenuation in the ischaemia induced fall in fibrillation threshold from 23(4) mA to 15(2) mA was observed. After the second dose of fentanyl the decline in fibrillation threshold was significantly blunted at 22(4) mA during control and 18(3) mA during occlusion, p less than 0.05 compared to no drug. In an additional series of experiments atropine sulphate abolished the antifibrillatory action of fentanyl, indicating that vagal efferent activation is responsible for the protective effect of the drug during acute myocardial ischaemia. This is in contrast with its mode of action during haemorrhage, when it enhances vagal afferent inhibition of sympathetic tone, and atropine pretreatment is without effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Human lymphoma mutations reveal CARD11 as the switch between self-antigen–induced B cell death or proliferation and autoantibody production
Authors: Yogesh S. Jeelall, James Q. Wang, Hsei-Di Law, Heather Domaschenz, Herman K.H. Fung, Axel Kallies, Stephen L. Nutt, Christopher C. Goodnow, Keisuke Horikawa
Journal: The Journal of Experimental Medicine (2012)

Self-tolerance and immunity are actively acquired in parallel through a poorly understood ability of antigen receptors to switch between signaling death or proliferation of antigen-binding lymphocytes in different contexts. It is not known whether this tolerance-immunity switch requires global rewiring of the signaling apparatus or if it can arise from a single molecular change. By introducing individual CARD11 mutations found in human lymphomas into antigen-activated mature B lymphocytes in mice, we find here that lymphoma-derived CARD11 mutations switch the effect of self-antigen from inducing B cell death into T cell–independent proliferation, Blimp1-mediated plasmablast differentiation, and autoantibody secretion. Our findings demonstrate that regulation of CARD11 signaling is a critical switch governing the decision between death and proliferation in antigen-stimulated mature B cells and that mutations in this switch represent a powerful initiator for aberrant B cell responses in vivo.
Sites of Focal Atrial Activity Characterized by Endocardial Mapping During Atrial Fibrillation
Authors: Yoshihide Takahashi, Mélèze Hocini, Mark D. O’Neill, Prashanthan Sanders, Martin Rotter, Thomas Rostock, Anders Jonsson, Frédéric Sacher, Jacques Clémenty, Pierre Jaïs, Michel Haïssaguerre
Journal: Journal of the American College of Cardiology (2006)