tbuckley/cabot-search huggingface dataset:
Whole-genome sequencing reveals complex mechanisms of intrinsic resistance to BRAF inhibition
Authors: S. Turajlic, S.J. Furney, G. Stamp, S. Rana, G. Ricken, Y. Oduko, G. Saturno, C. Springer, A. Hayes, M. Gore, J. Larkin, R. Marais
Journal: Annals of Oncology (2014)

BRAF is mutated in ∼42% of human melanomas (COSMIC. http://www.sanger.ac.uk/genetics/CGP/cosmic/) and pharmacological BRAF inhibitors such as vemurafenib and dabrafenib achieve dramatic responses in patients whose tumours harbour BRAF(V600) mutations. Objective responses occur in ∼50% of patients and disease stabilisation in a further ∼30%, but ∼20% of patients present primary or innate resistance and do not respond. Here, we investigated the underlying cause of treatment failure in a patient with BRAF mutant melanoma who presented primary resistance.
Lactitol vs. lactulose in the treatment of acute hepatic encephalopathy in cirrhotic patients: A double-blind, randomized trial
Authors: Marsha Y. Morgan, Katherine E. Hawley
Journal: Hepatology (1987)

Lactitol (β-galactosido-sorbitol) is a nonabsorbable disaccharide available as a powder which, in open comparison, is as effective as lactulose in the treatment of chronic hepatic encephalopathy, but is better tolerated. Twenty-five cirrhotic patients experiencing 28 episodes of acute hepatic encephalopathy were randomized blindly to treatment with either lactitol (n = 15) or lactulose (n = 13). The sugars were dispensed in solutions identical in appearance, taste and pH and of similar osmolarity, which contained either 66.7 gm per 100 ml lactitol or 66.7 ml (44.5 gm) per 100 ml lactulose syrup. The initial dose of 0.75 ml per kg was adjusted to produce two semisoft stools per day. Patients were assessed every 12 hr for 5 days. There were no significant differences in sex ratio, age, body weight, clinical status, duration and extent of coma, etiology of liver disease or of heptic encephalopathy between the two groups of patients on entry to the trial. An adequate catharsis was obtained with an equivalent mean (± 1 S.D.) daily dose of 26 ± 5 gm lactitol or 31 ± 7 ml (21 ± 5 gm) lactulose syrup. During the trial, significant improvements occurred in clinical status and psychometric performance and in the electroencephalogram mean cycle frequencies in the majority of patients in both groups. At the end of the trial, 67% of the patients in the lactitol group and 69% of the lactulose group were clinically normal. However, patients treated with lactitol responded significantly more quickly than patients treated with lactulose. Thus, at 24, 36, 48 and 72 hr, significantly greater mean percentage improvements were seen in PSE Indices in patients receiving lactitol than in patients receiving lactulose. Both sugars are effective in the treatment of acute hepatic encephalopathy in cirrhotic patients, but patients treated with lactitol respond significantly more quickly. Lactitol may be the treatment of choice for this condition.
Calpastatin Controls Polymicrobial Sepsis by Limiting Procoagulant Microparticle Release
Authors: Lara Zafrani, Grigoris Gerotziafas, Colleen Byrnes, Xuzhen Hu, Joelle Perez, Charlène Lévi, Sandrine Placier, Emmanuel Letavernier, Asada Leelahavanichkul, Jean-philippe Haymann, Ismail Elalamy, Jeffrey L. Miller, Robert A. Star, Peter S. T. Yuen, Laurent Baud
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Sepsis, a leading cause of death worldwide, involves widespread activation of inflammation, massive activation of coagulation, and lymphocyte apoptosis. Calpains, calcium-activated cysteine proteases, have been shown to increase inflammatory reactions and lymphocyte apoptosis. Moreover, calpain plays an essential role in microparticle release.We investigated the contribution of calpain in eliciting tissue damage during sepsis.To test our hypothesis, we induced polymicrobial sepsis by cecal ligation and puncture in wild-type (WT) mice and transgenic mice expressing high levels of calpastatin, a calpain-specific inhibitor.In WT mice, calpain activity increased transiently peaking at 6 hours after cecal ligation and puncture surgery. Calpastatin overexpression improved survival, organ dysfunction (including lung, kidney, and liver damage), and lymphocyte apoptosis. It decreased the sepsis-induced systemic proinflammatory response and disseminated intravascular coagulation, by reducing the number of procoagulant circulating microparticles and therefore delaying thrombin generation. The deleterious effect of microparticles in this model was confirmed by transferring microparticles from septic WT to septic transgenic mice, worsening their survival and coagulopathy.These results demonstrate an important role of the calpain/calpastatin system in coagulation/inflammation pathways during sepsis, because calpain inhibition is associated with less severe disseminated intravascular coagulation and better overall outcomes in sepsis.
Daily energy expenditure and cardiovascular risk in Masai, rural and urban Bantu Tanzanians
Authors: J A Mbalilaki, Z Masesa, S B Strømme, A T Høstmark, J Sundquist, P Wändell, A Rosengren, M-L Hellenius
Journal: British Journal of Sports Medicine (2008)

Several studies have revealed that the Masai, pastoralists in Tanzania, have low rates of coronary heart disease despite a diet high in saturated fat. It has also been suggested that they may be genetically protected. Recent studies detailing other potential protective factors, however, are lacking.A cross-sectional investigation of 985 Tanzanian men and women (130 Masai, 371 rural Bantu and 484 urban Bantu) with mean age of 46 (9.3) years. Anthropometric measures, blood pressure, serum lipids, and the reported dietary pattern and physical activity level were assessed.82% of Masai subjects reported a high fat/low carbohydrate intake, whereas 77% of the rural Bantu subjects reported a low fat/high carbohydrate intake, while a high fat/high carbohydrate intake was the main dietary pattern of the urban Bantu group as, reported by 55%. The most conspicuous finding for the Masai was the extremely high energy expenditure, corresponding to 2565 kcal/day over basal requirements, compared with 1500 kcal/day in the rural and 891 kcal/day for the urban Bantu. Mean body mass index among the Masai was lower than the rural and urban Bantu. Mean systolic blood pressure of the Masai was also lower compared with their rural and urban Bantu counterparts. The Masai revealed a favourable lipid profile.The potentially atherogenic diet among the Masai was not reflected in serum lipids and was offset probably by very high energy expenditure levels and low body weight.
Endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of lymphoma
Authors: M P Kennedy, C A Jimenez, J F Bruzzi, A D Mhatre, X Lei, F J Giles, T Fanning, R C Morice, G A Eapen
Journal: Thorax (2007)

<h3>Background:</h3> The diagnostic accuracy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the diagnosis of lymphoma in patients with mediastinal lymphadenopathy is not well defined. <h3>Methods:</h3> A retrospective review was performed of all patients with mediastinal lymphadenopathy referred for EBUS-TBNA between August 2005 and December 2006 in whom lymphoma was suspected based on prior history or clinical presentation. Mediastinal biopsy specimens were taken using a linear array ultrasonic bronchoscope (Olympus XBF-UC 160F) and a 22-gauge cytology needle (NA-202C Olympus) with on-site cytopathological support. The EBUS-TBNA result was compared with a reference standard of pathological tissue diagnosis or a composite of ⩾6 months of clinical follow-up with radiographic imaging. <h3>Results:</h3> Of 236 patients who underwent EBUS-TBNA, 25 were eligible for inclusion. Indications for EBUS-TBNA were suspected mediastinal recurrence of lymphoma (n = 13) and mediastinal lymphadenopathy of unknown cause (n = 12). Adequate lymph node sampling was accomplished in 24/25 patients (96%); there were no complications. EBUS-TBNA identified lymphoma in 10 patients and benign disease in 14 patients. There was one false negative EBUS-TBNA for lymphoma (lymphoma prevalence 11/25 (44%)). Follow-up over a median of 10.5 months (range 1–19) confirmed stable or regressive lymphadenopathy in all 14 patients without a lymphoma diagnosis, consistent with a benign diagnosis. Overall, EBUS-TBNA had a sensitivity of 90.9%, specificity of 100%, positive predictive value of 100% and negative predictive value of 92.9% for the diagnosis of lymphoma. <h3>Conclusions:</h3> EBUS-TBNA is an accurate, safe and useful tool in the investigation of suspected lymphoma with isolated mediastinal adenopathy, and may diminish the need for more invasive procedures such as mediastinoscopy.
Androgen Receptor Defects: Historical, Clinical, and Molecular Perspectives*
Authors: CHARMIAN A. QUIGLEY, ALESSANDRA DE BELLIS, KEITH B. MARSCHKE, MOSTAFA K. EL-AWADY, ELIZABETH M. WILSON, FRANK S. FRENCH
Journal: Endocrine Reviews (1995)

IN 1953 lohn Morris, an obstetrician at Yale University, reported a series of 82 individuals (80 cases collated from the literature and two cases of his own) who had a female phenotype despite the presence of bilateral testes (1). Since his initial description, studies of the endocrinology, pathophysiology, biochemistry, and molecular biology of the androgen insensitivity syndrome (AIS) have provided insights into the role of androgens in male sex differentiation, the mechanisms of androgen action, and aspects of the structure/function relationships of the androgen receptor. AIS is an archetypal example of a hormone resistance disorder. Androgens are secreted by the testes of these 46,XY individuals in normal or increased amounts; however, due to defective androgen receptor (AR1) function, there is loss of target organ response to the hormone, and the effects of androgens are reduced or absent. Clinical disorders of the AR are reported far more commonly than resistance disorders of other members of the steroid receptor family and, in fact, more mutations have been reported in the AR gene than in that of any other transcription factor (2). This is, in part, due to the fact that the AR is encoded by a single copy X-chromosomal gene (it is the only X-chromosomal steroid receptor gene).
Essential Role for Ras Signaling in Glioblastoma Maintenance
Authors: Sheri L. Holmen, Bart O. Williams
Journal: Cancer Research (2005)

Malignant gliomas can be induced in mice through the combined expression of activated forms of both KRas and Akt in glial progenitor cells. To determine the reliance of these tumors on continued KRas signaling in vivo, we generated a viral vector that allows the expression of KRas to be controlled post-delivery. Tumor-free survival rates were compared between those animals with continued KRas expression and animals in which KRas expression was suppressed. KRas signaling was found to be required for the maintenance of these tumors in vivo; inhibition of KRas expression resulted in apoptotic tumor regression and increased survival. Subsequent reexpression of KRas reinitiated tumor growth, indicating that a percentage of the progenitor cells survived and retained tumorigenic properties.
Molecular Targeting and Treatment of an Epidermal Growth Factor Receptor–Positive Glioma Using Boronated Cetuximab
Authors: Gong Wu, Weilian Yang, Rolf F. Barth, Shinji Kawabata, Michele Swindall, Achintya K. Bandyopadhyaya, Werner Tjarks, Behrooz Khorsandi, Thomas E. Blue, Amy K. Ferketich, Ming Yang, Gregory A. Christoforidis, Thomas J. Sferra, Peter J. Binns, Kent J. Riley, Michael J. Ciesielski, Robert A. Fenstermaker
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The purpose of the present study was to evaluate the anti–epidermal growth factor monoclonal antibody (mAb) cetuximab (IMC-C225) as a delivery agent for boron neutron capture therapy (BNCT) of a human epidermal growth factor receptor (EGFR) gene-transfected rat glioma, designated as F98EGFR. Experimental Design: A heavily boronated polyamidoamine dendrimer was chemically linked to cetuximab by means of the heterobifunctional reagents N-succinimidyl 3-(2-pyridyldithio)-propionate and N-(k-maleimido undecanoic acid)-hydrazide. The bioconjugate, designated as BD-C225, was specifically taken up by F98EGFR glioma cells in vitro compared with receptor-negative F98 wild-type cells (41.8 versus 9.1 μg/g). For in vivo biodistribution studies, F98EGFR cells were implanted stereotactically into the brains of Fischer rats, and 14 days later, BD-C225 was given intracerebrally by either convection enhanced delivery (CED) or direct intratumoral (i.t.) injection. Results: The amount of boron retained by F98EGFR gliomas 24 h following CED or i.t. injection was 77.2 and 50.8 μg/g, respectively, with normal brain and blood boron values &amp;lt;0.05 μg/g. Boron neutron capture therapy was carried out at the Massachusetts Institute of Technology Research Reactor 24 h after CED of BD-C225, either alone or in combination with i.v. boronophenylalanine (BPA). The corresponding mean survival times (MST) were 54.5 and 70.9 days (P = 0.017), respectively, with one long-term survivor (more than 180 days). In contrast, the MSTs of irradiated and untreated controls, respectively, were 30.3 and 26.3 days. In a second study, the combination of BD-C225 and BPA plus sodium borocaptate, given by either i.v. or intracarotid injection, was evaluated and the MSTs were equivalent to that obtained with BD-C225 plus i.v. BPA. Conclusions: The survival data obtained with BD-C225 are comparable with those recently reported by us using boronated mAb L8A4 as the delivery agent. This mAb recognizes the mutant receptor, EGFRvIII. Taken together, these data convincingly show the therapeutic efficacy of molecular targeting of EGFR using a boronated mAb either alone or in combination with BPA and provide a platform for the future development of combinations of high and low molecular weight delivery agents for BNCT of brain tumors.
Y chromosome microchimerism in rheumatic autoimmune disease
Authors: Y. MIYASHITA
Journal: Annals of the Rheumatic Diseases (2000)

Incidence of RA in people with persistently raised RFA criticism of the study reported in the Annals 1 is that age was not taken into account in the evaluation of the probability of development of rheumatoid arthritis (RA) among symptom free subjects with persistently raised rheumatoid factor (RF).The prevalence of RF can be as high as 14.1% in apparently healthy people aged 67-95 (mean age 81). 2 RF is also 3.5 times more common in healthy elderly subjects (aged >65) than in their younger counterparts. 3All these factors may alter the natural history of arthritis in elderly patients who have RF either in good health or in a non-arthritic presentation of RA.The latter is exemplified by a patient admitted at the age of 76 with symptomatic, as well as echocardiographically validated rheumatoid pericarditis in the absence of arthritis.Rheumatoid arthritis latex fixation test (RA LFT) was positive with a titre of 1/160, antinuclear factor (ANF) titre was 1/250, and signs of active inflammatory disease included a platelet count of 750 × 10 9 /l, and an erythrocyte sedimentation rate (ESR) of 98 mm/1st h (Westergren).Arthralgia of the hands and wrists developed for the first time two years later (when she was no longer taking steroids), with a subsequent RA LFT titre of 1/80 and an ANF titre of 1/320 about four months after the onset of arthralgia.Radiography showed narrowing of the joint spaces of the hands 12 months later, but there were as yet no erosions at this stage.Erosions were seen in March 1992, approximately two and a half years after the onset of arthralgia, when the RA LFT titre was 1/160, ANF titre 1/160, platelet count 421 × 10 9 /l, ESR 18 mm/1st h.At her most recent attendance, on 2 February 2000, she was still very active, having continued to receive prednisolone (maximum dose 5 mg/d) continuously since 1989.Her only complaint was a little pain in the left thenar eminence and painful heels.RF was now 768 IU/ml, ANF titre 1/320, platelet count 340 × 10 9 /l, ESR 42 mm/1st h.Antibodies against double stranded DNA had not been reported at any stage. COMMENTThis case shows a remarkable dissociation between arthritic symptoms and levels of RF, perhaps signifying that when the immune status is altered in old age, 2 the relation between RF and the natural history of RA might be less clear than it is in younger people.
Measurement of low-frequency respiratory impedance in infants.
Authors: P D Sly, M J Hayden, F Peták, Z Hantos
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Low-frequency respiratory impedance (Zrs) data permit the separate estimation of the mechanical properties of the airways and the tissues, but they are difficult to collect in humans because of the need for apneic conditions. We exploited the apneic phase produced by invoking the Hering-Breuer reflex with end-inspiratory airway occlusion in five sedated infants aged 9 to 16 mo. A computer-controlled pump and solenoid valves were used to inflate the supine infants through a face mask to a transrespiratory pressure of 20 cm H2O and to affect the airway occlusion. A loudspeaker-in-box system was connected to the mask through a side-arm, and small-amplitude pseudorandom oscillations containing 23 frequency components between 0.5 and 20.75 Hz were applied for 6 s. Four consecutive measurements were made in each infant, and the averaged Zrs spectra were evaluated on the basis of a model containing the frequency-independent resistance (Raw) and inertance (law) of the airways, and the viscous damping (G) and elastance (H) parameters of the constant-phase compartment of the chest wall and parenchymal tissues. The measured Zrs values were consistent with the model up to 15 Hz, and the average fitting error was 0.89 +/- 0.11 (SD) cm H2O.s/L. The following parameter values were obtained: Raw = 10.0 +/- 2.1 cm H2O.s/L, law = 0.061 +/- 0.014 cm H2O.s2/L, G = 28.6 +/- 4.9 cm H2O/L, H = 141 +/- 55 cm H2O/L. The tissue hysteresivity (G/H) values were 0.218 +/- 0.061. Our results indicate that, in short apneic periods evoked by the Hering-Breuer reflex, reliable low-frequency Zrs data can be collected to partition the tissue and airway impedances in sedated infants.
Academic Medical Centers' Standards for Clinical-Trial Agreements with Industry
Authors: Michelle M. Mello, Brian R. Clarridge, David M. Studdert
Journal: New England Journal of Medicine (2005)

Although industry sponsors provide approximately 70 percent of the funding for clinical drug trials in the United States, little is known about the legal agreements that exist between industry sponsors and academic investigators. We studied institutional standards regarding contractual provisions that restrict investigators' control over trials.We used a structured, cross-sectional mail survey of medical-school research administrators responsible for negotiating clinical-trial agreements with industry sponsors.Of 122 institutions approached, 107 participated. There was a high degree of consensus among administrators about the acceptability of several contractual provisions relating to publications. For example, more than 85 percent reported that their office would not approve provisions giving industry sponsors the authority to revise manuscripts or decide whether results should be published. There was considerable disagreement about the acceptability of provisions allowing the sponsor to insert its own statistical analyses in manuscripts (24 percent allowed them, 47 percent disallowed them, and 29 percent were not sure whether they should allow them), draft the manuscript (50 percent allowed it, 40 percent disallowed it, and 11 percent were not sure whether they should allow it), and prohibit investigators from sharing data with third parties after the trial is over (41 percent allowed it, 34 percent disallowed it, and 24 percent were not sure whether they should allow it). Disputes were common after the agreements had been signed and most frequently centered on payment (75 percent of administrators reported at least one such dispute in the previous year), intellectual property (30 percent), and control of or access to data (17 percent).Standards for certain restrictive provisions in clinical-trial agreements with industry sponsors vary considerably among academic medical centers. Greater sharing of information about legal relationships with industry sponsors is desirable in order to build consensus about appropriate standards.
Acute Macrovascular Dysfunction in Patients With Type 2 Diabetes Induced by Ingestion of Advanced Glycated β-Lactoglobulins
Authors: Alin Stirban, Paraskevi Kotsi, Knut Franke, Ulf Strijowski, Weijing Cai, Christian Götting, Diethelm Tschoepe
Journal: Diabetes Care (2012)

Recent evidence indicates that heat-enhanced food advanced glycation end products (AGEs) adversely affect vascular function. The aim of this study was to examine the acute effects of an oral load of heat-treated, AGE-modified β-lactoglobulins (AGE-BLG) compared with heat-treated, nonglycated BLG (C-BLG) on vascular function in patients with type 2 diabetes mellitus (T2DM).In a double-blind, controlled, randomized, crossover study, 19 patients with T2DM received, on two different occasions, beverages containing either AGE-BLG or C-BLG. We measured macrovascular [brachial ultrasound of flow-mediated dilatation (FMD)] and microvascular (laser-Doppler measurements of reactive hyperemia in the hand) functions at baseline (T0), 90 (T90), and 180 (T180) min.Following the AGE-BLG, FMD decreased at T90 by 80% from baseline and remained decreased by 42% at T180 (P < 0.05 vs. baseline, P < 0.05 vs. C-BLG at T90). By comparison, following C-BLG, FMD decreased by 27% at T90 and 51% at T180 (P < 0.05 vs. baseline at T180). A significant decrease in nitrite (T180) and nitrate (T90 and T180), as well as a significant increase in N(ε)-carboxymethyllisine, accompanied intake of AGE-BLG. There was no change in microvascular function caused by either beverage.In patients with T2DM, acute oral administration of a single AGE-modified protein class significantly though transiently impaired macrovascular function in concert with decreased nitric oxide bioavailability. These AGE-related changes were independent of heat treatment.
Systematic review and meta-analysis of the relation between body mass index and short-term donor outcome of laparoscopic donor nephrectomy
Authors: Jeffrey A. Lafranca, Sander M. Hagen, Leonienke F.C. Dols, Lidia R. Arends, Willem Weimar, Jan N.M. IJzermans, Frank J.M.F Dor
Journal: Kidney International (2013)

In this era of organ donor shortage, live kidney donation has been proven to increase the donor pool; however, it is extremely important to make careful decisions in the selection of possible live donors. A body mass index (BMI) above 35 is generally considered as a relative contraindication for donation. To determine whether this is justified, a systematic review and meta-analysis were carried out to compare perioperative outcome of live donor nephrectomy between donors with high and low BMI. A comprehensive literature search was performed in MEDLINE, Embase, and CENTRAL (the Cochrane Library). All aspects of the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement were followed. Of 14 studies reviewed, eight perioperative donor outcome measures were meta-analyzed, and, of these, five were not different between BMI categories. Three found significant differences in favor of low BMI (29.9 and less) donors with significant mean differences in operation duration (16.9 min (confidence interval (CI) 9.1-24.8)), mean difference in rise in serum creatinine (0.05 mg/dl (CI 0.01-0.09)), and risk ratio for conversion (1.69 (CI 1.12-2.56)). Thus, a high body mass index (BMI) alone is no contraindication for live kidney donation regarding short-term outcome.