tbuckley/cabot-search huggingface dataset:
Metformin, B<sub>12</sub>, and Enhanced Breast Cancer Response to Chemotherapy
Authors: April Garcia, Glenn Tisman
Journal: Journal of Clinical Oncology (2009)

TO THE EDITOR: The report by Jiralerspong et al 1 revealed a three-fold greater complete pathologic response in diabetic patients with breast tumors ingesting metformin undergoing neoadjuvant chemotherapy compared with diabetic patients not ingesting metformin. Chemotherapy included fluorouracil, doxorubicin, and cyclophosphamide; doxorubicin and cyclophosphamide; or fluorouracil, epirubicin, and cyclophosphamide. Additional taxane chemotherapy (paclitaxel or docetaxel) was administered to 1,909 patients. Assuming the absence of a statistical quirk, their observationalfinding begs for a rational explanation. Jiralerspongetal 1 presentseveralpossibleexplanationsincluding
Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group
Authors: Jean-Pierre Pignon, Hélène Tribodet, Giorgio V. Scagliotti, Jean-Yves Douillard, Frances A. Shepherd, Richard J. Stephens, Ariane Dunant, Valter Torri, Rafael Rosell, Lesley Seymour, Stephen G. Spiro, Estelle Rolland, Roldano Fossati, Delphine Aubert, Keyue Ding, David Waller, Thierry Le Chevalier
Journal: Journal of Clinical Oncology (2008)

Several recent trials have shown a significant overall survival (OS) benefit from postoperative cisplatin-based chemotherapy in patients with non-small-cell lung cancer (NSCLC). The aim of the Lung Adjuvant Cisplatin Evaluation was to identify treatment options associated with a higher benefit or groups of patients who particularly benefit from postoperative chemotherapy.Individual patient data were collected and pooled from the five largest trials (4,584 patients) of cisplatin-based chemotherapy in completely resected patients that were conducted after the 1995 NSCLC meta-analysis. The interactions between patient subgroups or treatment types and chemotherapy effect on OS were analyzed using hazard ratios (HRs) and log-rank tests stratified by trial.With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82 to 0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. There was no heterogeneity of chemotherapy effect among trials. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95 to 2.06; HR for stage IB = 0.93; 95% CI, 0.78 to 1.10; HR for stage II = 0.83; 95% CI, 0.73 to 0.95; and HR for stage III = 0.83; 95% CI, 0.72 to 0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70 to 0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80 to 1.07), or other (HR = 0.97; 95% CI, 0.84 to 1.13). Chemotherapy effect was higher in patients with better performance status. There was no interaction between chemotherapy effect and sex, age, histology, type of surgery, planned radiotherapy, or planned total dose of cisplatin.Postoperative cisplatin-based chemotherapy significantly improves survival in patients with NSCLC.
The Effect of Inhibition of 5-Lipoxygenase by Zileuton in Mild-to-Moderate Asthma
Authors: Elliot Israel
Journal: Annals of Internal Medicine (1993)

Objective: To evaluate the effectiveness of inhibiting the formation of the 5-lipoxygenase products of arachidonic acid by the 5-lipoxygenase inhibitor zileuton in the treatment of mild-to-moderate asthma. Design: Randomized, double-blind, placebo-controlled study. Setting: University hospitals and private allergy and pulmonary practices. Patients: A total of 139 persons with asthma who had a forced expiratory volume in 1 second (FEV1) of 40% to 75% of the predicted value and who were not being treated with inhaled or oral steroids. Intervention: Zileuton, 2.4 g/d or 1.6 g/d, or placebo for 4 weeks. Measurements: Airway function, -agonist use, and symptoms; inhibition of 5-lipoxygenase assessed by measurement of urinary leukotriene E4 (LTE4). Results: Zileuton produced a 0.35-L (95% CI, 0.25 to 0.45 L) increase in the FEV1 within 1 hour of administration (P < 0.001 compared with placebo), equivalent to a 14.6% increase from baseline. After 4 weeks of zileuton therapy, airway function and symptoms improved, with the greatest improvements occurring in the 2.4 g/d group: This group's FEV1 increased by 0.32 L (CI, 0.16 to 0.48 L), a 13.4% increase, compared with a 0.05-L (CI, 0.10 to 0.20 L) increase in patients taking placebo (P = 0.02). Symptoms and frequency of -agonist use also decreased with zileuton, 2.4 g/d. The mean urinary LTE4 level decreased by 39.2 pg/mg creatinine (CI, 18.1 to 60.4 pg/mg creatinine) and 26.5 pg/mg creatinine (CI, 6.6 to 46.5 pg/mg creatinine) in the 2.4 g/d and 1.6 g/d groups, respectively, compared with a slight increase in the placebo group (P = 0.007 and P = 0.05). No difference was noted in the number of adverse events among treatment groups. Conclusions: Inhibition of 5-lipoxygenase can improve airway function and decrease symptoms and medication use in patients with asthma, suggesting that this inhibition can be useful therapy for asthma. Also, 5-lipoxygenase products may mediate part of the baseline airway obstruction in patients with mild-to-moderate asthma.
Beta cell expression of endogenous xenotropic retrovirus distinguishes diabetes-susceptible NOD/Lt from resistant NON/Lt mice.
Authors: H R Gaskins, M Prochazka, K Hamaguchi, D V Serreze, E H Leiter
Journal: Journal of Clinical Investigation (1992)

Endogeneous retroviral expression in beta cells is a feature of prediabetes in nonobese diabetic (NOD) mice. The purpose of this study was to characterize the class-specific pattern of retroviral gene expression in NOD/Lt beta cells versus a related, but diabetes-resistant strain, NON/Lt. Electron microscopic comparison of beta cells from both strains indicated low constitutive expression of the intracisternal type A (IAP) retroviral class. However, NOD beta cells, in contrast to NON beta cells, expressed an additional intracisternal retroviral form resembling a type C particle. Antibodies against both IAP and type C were detected in NOD, with the humoral response to type C, but not IAP, preceding decline in beta cell function. RNA was extracted from freshly isolated islets from NOD and NON males. Comparative Northern blot analysis of total type C retroviral gene expression using a gag-pol DNA probe corroborated expression of endogenous type C proviruses in both NOD and NON islet cells and thymus. Use of class-specific retroviral probes identified the class of expressed endogenous retrovirus distinguishing the two inbred strains. The single ecotropic provirus present in both the NOD and NON genome (Emv-30) was not expressed in islets or thymus of either strain. Comparison of endogenous xenotropic provirus content by Southern blot analysis revealed two unique xenotropic loci (Xmv-65, -66) in NOD; 8.4 and 3.0 kb xenotropic envelope (env) RNA transcripts were detected in NOD, but not NON islets and thymus. NON contained three xenotropic loci common to other inbred strains (Xmv-21, -25, and -28). Both strains were partially characterized for content of recombinant (polytropic and modified polytropic) proviruses. IAP RNA expression was common to both NOD and NON islets and hence could not be specifically associated with the unique intracisternal type C particle found in NOD, but not NON beta cells. In conclusion, this study shows that expression of xenotropic type C but not IAP distinguishes retroviral activity in NOD/Lt versus NON/Lt beta cells. The potential pathogenic role of retroviral gene expression in NOD beta cells is discussed.
Protocadherin-1: epithelial barrier dysfunction in asthma and eczema
Authors: G. Faura Tellez, M. C. Nawijn, G. H. Koppelman
Journal: European Respiratory Journal (2014)

A role for protocadherin-1 in loss of epithelial integrity in both asthma and eczema http://ow.ly/qM9mEAsthma and eczema result from the interaction between genetic susceptibility and environmental exposures.Over the last two decades, genetic studies have led to the identification of multiple susceptibility genes, increasing our understanding of the biological pathways leading to these diseases.Many asthma and eczema susceptibility genes are expressed in epithelial cells of airway mucosa and skin [1].The epithelium constitutes the first line of defence against allergens and invading microbes.Recently, loss of epithelial integrity has been implicated as an important mechanism leading to both asthma [2] and eczema [3].In this issue of the European Respiratory Journal, MORTENSEN et al. [4] report the association of genetic variants in the gene encoding protocadherin-1 (PCDH1) with asthma, wheeze and eczema in (early) childhood in the Danish birth cohort study COPSAC (Copenhagen Studies on Asthma in Childhood).Their studies also suggest a gene-environment interaction of PCDH1 with passive smoke exposure in early childhood in asthma development.These studies expand on previous data reporting a role for PCDH1 polymorphisms in the susceptibility to both asthma [4][5][6][7] and eczema [4,6,8].Given the replicated association of PCDH1 with both diseases, this gene might contribute to a biological pathway that constitutes a shared cause for both diseases.Here, we will summarise the cumulative data on PCDH1 polymorphisms in asthma and eczema, and make an attempt to interpret these genetic data in light of PCDH1 expression and function as a contributor to epithelial integrity.
First Model of Spontaneous Vagal Hyperreactivity and Its Mode of Genetic Transmission
Authors: Angelo Livolsi, Josiane Feldman, Josué Feingold, Laurence Weiss, Yves Alembik, Ismail M. Sharifah-Anion, Michel Fischbach, Jean Messer, Pascal Bousquet
Journal: Circulation (2002)

The main purpose of our study was to define an animal model of vagal hyperreactivity and its genetic transmission.We first investigated the vagal reactivity with phenylephrine in conscious rabbits. Barosensitivity and the maximal bradycardic response were measured at the upper mean blood pressure plateau. Hyperreactive (H) animals were selected and crossbred with normal (N) ones. Results showed no significant difference between calculated barosensitivity values after the different doses of phenylephrine. In contrast, an increase of the values and a great dispersion appeared 1 to 5 beats after the end of the ramp. Marked pauses (6000 to 20 000 ms) were obtained with some rabbits, which were blocked by atropine. A significant excess of hyperreactive offspring was observed in HxH crossings compared with NxN ones (39.4% male and 42.3% female offspring versus 14.4% and 4.4%, respectively). Few female offspring were hyperreactive compared with males in NxH and NxN crossings (4.1% versus 23.4% and 4.4% versus 14.4%, respectively).This study describes the first model of spontaneous vagal pauses. The inheritance could be polygenic with a partial sex-limited character.
IBS: prime problem in primary care
Authors: R JONES
Journal: Gut (2000)

See article on page 78 

The opening paragraph of the paper by Thompson et al (see page 78) goes to the heart of a major problem in clinical research which is that most thinking, research, teaching, and clinical guidance on medical conditions, in this case irritable bowel syndrome (IBS), are based on patients referred by general practitioners to specialists. For a number of reasons our knowledge of the natural history and optimum management of many conditions frequently encountered in general practice and primary care remain relatively scanty. Indeed, the stimulus to undertake this study came from a previous survey1 in which the same authors found that general practitioners, despite their unfamiliarity with diagnostic criteria for IBS, diagnosed the condition with reasonable confidence, found it less troublesome than many other painful conditions such as pelvic pain, headache and backache and only referred a minority of patients to specialists. In that questionnaire survey general practitioners estimated that they referred about one in seven patients with IBS to specialists and in the …
Economics of New Oncology Drug Development
Authors: Joseph A. DiMasi, Henry G. Grabowski
Journal: Journal of Clinical Oncology (2007)

Purpose Review existing studies and provide new results on the development, regulatory, and market aspects of new oncology drug development. Methods We utilized data from the US Food and Drug Administration (FDA), company surveys, and publicly available commercial business intelligence databases on new oncology drugs approved in the United States and on investigational oncology drugs to estimate average development and regulatory approval times, clinical approval success rates, first-in-class status, and global market diffusion. Results We found that approved new oncology drugs to have a disproportionately high share of FDA priority review ratings, of orphan drug designations at approval, and of drugs that were granted inclusion in at least one of the FDA's expedited access programs. US regulatory approval times were shorter, on average, for oncology drugs (0.5 years), but US clinical development times were longer on average (1.5 years). Clinical approval success rates were similar for oncology and other drugs, but proportionately more of the oncology failures reached expensive late-stage clinical testing before being abandoned. In relation to other drugs, new oncology drug approvals were more often first-in-class and diffused more widely across important international markets. Conclusion The market success of oncology drugs has induced a substantial amount of investment in oncology drug development in the last decade or so. However, given the great need for further progress, the extent to which efforts to develop new oncology drugs will grow depends on future public-sector investment in basic research, developments in translational medicine, and regulatory reforms that advance drug-development science.
Characterization of<i>BRCA1</i>and<i>BRCA2</i>Mutations in a Large United States Sample
Authors: Sining Chen, Edwin S. Iversen, Tara Friebel, Dianne Finkelstein, Barbara L. Weber, Andrea Eisen, Leif E. Peterson, Joellen M. Schildkraut, Claudine Isaacs, Beth N. Peshkin, Camille Corio, Leoni Leondaridis, Gail Tomlinson, Debra Dutson, Rich Kerber, Christopher I. Amos, Louise C. Strong, Donald A. Berry, David M. Euhus, Giovanni Parmigiani
Journal: Journal of Clinical Oncology (2006)

An accurate evaluation of the penetrance of BRCA1 and BRCA2 mutations is essential to the identification and clinical management of families at high risk of breast and ovarian cancer. Existing studies have focused on Ashkenazi Jews (AJ) or on families from outside the United States. In this article, we consider the US population using the largest US-based cohort to date of both AJ and non-AJ families.We collected 676 AJ families and 1,272 families of other ethnicities through the Cancer Genetics Network. Two hundred eighty-two AJ families were population based, whereas the remainder was collected through counseling clinics. We used a retrospective likelihood approach to correct for bias induced by oversampling of participants with a positive family history. Our approach takes full advantage of detailed family history information and the Mendelian transmission of mutated alleles in the family.In the US population, the estimated cumulative breast cancer risk at age 70 years was 0.46 (95% CI, 0.39 to 0.54) in BRCA1 carriers and 0.43 (95% CI, 0.36 to 0.51) in BRCA2 carriers, whereas ovarian cancer risk was 0.39 (95% CI, 0.30 to 0.50) in BRCA1 carriers and 0.22 (95% CI, 0.14 to 0.32) in BRCA2 carriers. We also reported the prospective risks of developing cancer for cancer-free carriers in 10-year age intervals. We noted a rapid decrease in the relative risk of breast cancer with age and derived its implication for genetic counseling.The penetrance of BRCA mutations in the United States is largely consistent with previous studies on Western populations given the large CIs on existing estimates. However, the absolute cumulative risks are on the lower end of the spectrum.
Effect of inhaled beclomethasone dipropionate on isocapnic hyperventilation with cold air in asthmatics, measured with forced oscillation technique
Authors: HJ Pennings, EF Wouters
Journal: European Respiratory Journal (1997)

Isocapnic hyperventilation with cold air (IHCA) is a reliable technique for assessing indirect bronchial hyperresponsiveness in patients with asthma. Impedance measurement of the respiratory system by the forced pseudorandom noise oscillation technique is a sensitive technique to assess changes in bronchial tone after IHCA. The aim of this study was to evaluate the effect of 6 weeks of treatment with beclomethasone dipropionate, 1,000 microg x day-1, on IHCA in asthmatic patients, measured with both forced oscillation technique and flow-volume recordings. Forty patients with mild asthma were included in this double-blind, placebo-controlled parallel-group study. Stratification on the basis of sex was performed to overcome differences in airway diameter. At entry and every 2 weeks during the treatment period, IHCA was performed and patient diaries were evaluated. Characteristic changes in forced oscillation parameters after IHCA were observed in all patients. After 6 weeks of treatment, BDP-treated patients showed statistically significant differences in impedance measurements after IHCA, manifested by significant attenuation of resistance at 8 Hz (p<0.01), slope of the frequency-resistance curve (p<0.01), reactance at 8 Hz (p=0.01), and resonant frequency (f0) (p<0.02). Flow-volume recordings showed only a statistically significant change in the decrease of inspiratory vital capacity (IVC) (p=0.01). Furthermore, a significant correlation was observed between serum immunoglobulin E (IgE) levels and the effect of BDP on IHCA, measured with forced oscillation technique. In this study, beclomethasone dipropionate, 1,000 microg x day(-1) for 6 weeks, decreased indirect bronchial hyperresponsiveness as assessed by cold air bronchoprovocation in asthmatic patients. The forced oscillation technique proved a more sensitive method of detecting changes in bronchial tone than flow-volume recordings.
Major improvements in health-related quality of life during the use of etanercept in patients with previously refractory juvenile idiopathic arthritis
Authors: F H M Prince, L M Geerdink, G J J M Borsboom, M Twilt, M A J van Rossum, E P A H Hoppenreijs, R ten Cate, Y Koopman-Keemink, M van Santen-Hoeufft, H Raat, L W A van Suijlekom-Smit
Journal: Annals of the Rheumatic Diseases (2009)

Objective: To evaluate changes in health-related quality of life (HRQoL) in patients with refractory juvenile idiopathic arthritis (JIA) who are being treated with etanercept. Methods: 53 patients with JIA from seven Dutch centres were included. HRQoL was measured by the Childhood Health Assessment Questionnaire (CHAQ), Child Health Questionnaire (CHQ) and Health Utilities Index mark 3 (HUI3) at the start and after 3, 15 and 27 months of treatment. At the same time points the following JIA disease activity variables were collected; physician’s global assessment through the visual analogue scale (VAS), number of active and limited joints and erythrocyte sedimentation rate. A statistical method linear mixed models was used to assess outcomes over time. Results: During etanercept treatment both disease-specific and generic HRQoL outcomes improved dramatically. Significant improvements were shown after 3 months and these improvements continued at least up to 27 months of treatment. The disease-specific CHAQ, including VAS pain and wellbeing, showed a significant improvement in all domains. The generic health-profile measure CHQ improved for all the health concepts except for “family cohesion”, which was normal. The generic preference-based HUI3 showed impairment and, subsequently, significant improvement in the more specific domains (“pain”, “ambulatory”, “dexterity”). In accordance disease activity variables also improved significantly over time. Conclusion: This study shows that the HRQoL of patients with refractory JIA can be substantially improved by the use of etanercept for all aspects impaired by JIA. Information on HRQoL is crucial to understand the complete impact of etanercept treatment on patients with JIA and their families.
Alveolar Instability Causes Early Ventilator-induced Lung Injury Independent of Neutrophils
Authors: Jay M. Steinberg, Henry J. Schiller, Jeffrey M. Halter, Louis A. Gatto, Hsi-Ming Lee, Lucio A. Pavone, Gary F. Nieman
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Intratracheal instillation of Tween causes a heterogeneous surfactant deactivation in the lung, with areas of unstable alveoli directly adjacent to normal stable alveoli. We employed in vivo video microscopy to directly assess alveolar stability in normal and surfactant-deactivated lung and tested our hypothesis that alveolar instability causes a mechanical injury, initiating an inflammatory response that results in a secondary neutrophil-mediated proteolytic injury. Pigs were mechanically ventilated (VT 10 cc/kg, positive end-expiratory pressure [PEEP] 3 cm H2O), randomized to into three groups, and followed for 4 hours: Control group (n = 3) surgery only; Tween group (n = 4) subjected to intratracheal Tween (surfactant deactivator causing alveolar instability); and Tween + PEEP group (n = 4) subjected to Tween with increased PEEP (15 cm H2O) to stabilize alveoli. The magnitude of alveolar instability was quantified by computer image analysis. Surfactant-deactivated lungs developed significant histopathology only in lung areas with unstable alveoli without an increase in neutrophil-derived proteases. PEEP stabilized alveoli and significantly reduced histologic evidence of lung injury. Thus, in this model, alveolar instability can independently cause ventilator-induced lung injury. To our knowledge, this is the first study to directly confirm that unstable alveoli are subjected to ventilator-induced lung injury whereas stable alveoli are not.
Shifting the Disease Management Paradigm From Glucose
Authors: Markolf Hanefeld, Stefan R. Bornstein, Frank Pistrosch
Journal: Diabetes Care (2009)

Vascular comorbidities and complications are the major causes of excessive mortality and costs in patients with diabetes (1,2). For more than half a century, overwhelming evidence has been accumulating that demonstrates significant harmful effects of hyperglycemia. As shown in the Multiple Risk Factor Intervention Trial (MRFIT) study, at any given level of major cardiovascular risk factors, diabetes is associated with an odds ratio of 2–4 for cardiovascular mortality, in comparison with subjects without diabetes (3).

In a recently published 18-year follow-up study on the impact of type 1 and type 2 diabetes on cardiovascular mortality in middle-aged subjects from Finland, the adjusted hazard ratio for patients with type 1 diabetes versus no diabetes was 3.6 in men and 13.3 in women (4). The corresponding hazard ratios for type 2 diabetes were 3.3 and 10.1, respectively. This study confirms harmful effects of hyperglycemia shown in high-level controlled trials, such as the Diabetes Control and Complications Trial (DCCT) for type 1 diabetes (5) and the U.K. Prospective Diabetes Study (UKPDS) for type 2 diabetes (6). For 25 years, the Joslin Clinic conducted the Diabetes Natural History Study that followed up diabetic patients diagnosed between 1939 and 1959. The lifetime was 5 years less for men and 12 years less for women than for those in the general population (7). A unique 29-year complete follow-up study was conducted on 166 patients (mean age 63 years) with newly diagnosed type 2 diabetes. These subjects were from a district outpatient department in East Germany. The study revealed a reduction in life expectancy by 5.3 and 6.4 years in men and women, respectively (8).

Thus, today, immense evidence exists on long-term follow-up, population-based studies in patients with types 1 and 2 diabetes. This evidence convincingly suggests that hyperglycemia or diabetes itself is …