tbuckley/cabot-search huggingface dataset:
Severe sustained cholestatic hepatitis following temozolomide in a patient with glioblastoma multiforme: case study and review of data from the FDA adverse event reporting system
Authors: G. Sarganas, H. D. Orzechowski, A. Klimpel, M. Thomae, W. Kauffmann, H. Herbst, E. Bronder, E. Garbe
Journal: Neuro-Oncology (2012)

Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults. Its established first-line adjuvant treatment is radiotherapy in combination with temozolomide (TZM). Hematotoxicity is listed as a frequent adverse drug reaction in the US prescribing information and hepatotoxicity has been reported infrequently in the postmarketing period. We here present the case of a patient diagnosed with GBM who developed severe sustained cholestatic hepatitis following treatment with TZM. The cholestasis was not reversible after withdrawal of TZM during 6 months before the patient's death. Another 2 published case reports of sustained cholestasis following TZM treatment were identified; however, the sustained nature of cholestasis was not emphasized in these reports. Sixteen cases of cholestatic hepatitis/cholestasis associated with TZM were identified in the FDA spontaneous reporting system between 2007 and 2010. Information on the course of the cholestasis in these cases could not be retrieved. In the literature there are other published reports of hepatotoxicity associated with TZM that have reported reversibility upon withdrawal of the drug. Thus, TZM appears to cause different types of hepatotoxicity. Particular attention should be paid to sustained cholestasis as a very serious type of TZM-associated liver toxicity.
Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives
Authors: Stephan Urwyler
Journal: Pharmacological Reviews (2011)

Allosteric receptor modulation is an attractive concept in drug targeting because it offers important potential advantages over conventional orthosteric agonism or antagonism. Allosteric ligands modulate receptor function by binding to a site distinct from the recognition site for the endogenous agonist. They often have no effect on their own and therefore act only in conjunction with physiological receptor activation. This article reviews the current status of allosteric modulation at family C G-protein coupled receptors in the light of their specific structural features on the one hand and current concepts in receptor theory on the other hand. Family C G-protein-coupled receptors are characterized by a large extracellular domain containing the orthosteric agonist binding site known as the "venus flytrap module" because of its bilobal structure and the dynamics of its activation mechanism. Mutational analysis and chimeric constructs have revealed that allosteric modulators of the calcium-sensing, metabotropic glutamate and GABA(B) receptors bind to the seven transmembrane domain, through which they modify signal transduction after receptor activation. This is in contrast to taste-enhancing molecules, which bind to different parts of sweet and umami receptors. The complexity of interactions between orthosteric and allosteric ligands is revealed by a number of adequate biochemical and electrophysiological assay systems. Many allosteric family C GPCR modulators show in vivo efficacy in behavioral models for a variety of clinical indications. The positive allosteric calcium sensing receptor modulator cinacalcet is the first drug of this type to enter the market and therefore provides proof of principle in humans.
Nuclear Receptor LXR as a Novel Therapeutic Antitumoral Target in Glioblastoma
Authors: Antonio Moschetta
Journal: Cancer Discovery (2011)

Both primary and transformed cells need cholesterol for their growth. Guo and colleagues unraveled the connection between epidermal growth factor receptor mutations in glioblastoma and increased cholesterol influx via sterol regulatory element-binding protein 1 and low-density lipoprotein receptor (LDLR) increase. They propose the activation of the liver X receptor-inducible degrader of LDLR-LDLR axis as a therapeutic approach to reduce intracellular cholesterol, block tumor growth, and induce cell death.
Excessive Loss of Skeletal Muscle Mass in Older Adults With Type 2 Diabetes
Authors: Seok Won Park, Bret H. Goodpaster, Jung Sun Lee, Lewis H. Kuller, Robert Boudreau, Nathalie de Rekeneire, Tamara B. Harris, Stephen Kritchevsky, Frances A. Tylavsky, Michael Nevitt, Yong-wook Cho, Anne B. Newman
Journal: Diabetes Care (2009)

OBJECTIVE A loss of skeletal muscle mass is frequently observed in older adults. The aim of the study was to investigate the impact of type 2 diabetes on the changes in body composition, with particular interest in the skeletal muscle mass. RESEARCH DESIGN AND METHODS We examined total body composition with dual-energy X-ray absorptiometry annually for 6 years in 2,675 older adults. We also measured mid-thigh muscle cross-sectional area (CSA) with computed tomography in year 1 and year 6. At baseline, 75-g oral glucose challenge tests were performed. Diagnosed diabetes (n = 402, 15.0%) was identified by self-report or use of hypoglycemic agents. Undiagnosed diabetes (n = 226, 8.4%) was defined by fasting plasma glucose (≥7 mmol/l) or 2-h postchallenge plasma glucose (≥11.1 mmol/l). Longitudinal regression models were fit to examine the effect of diabetes on the changes in body composition variables. RESULTS Older adults with either diagnosed or undiagnosed type 2 diabetes showed excessive loss of appendicular lean mass and trunk fat mass compared with nondiabetic subjects. Thigh muscle CSA declined two times faster in older women with diabetes than their nondiabetic counterparts. These findings remained significant after adjusting for age, sex, race, clinic site, baseline BMI, weight change intention, and actual weight changes over time. CONCLUSIONS Type 2 diabetes is associated with excessive loss of skeletal muscle and trunk fat mass in community-dwelling older adults. Older women with type 2 diabetes are at especially high risk for loss of skeletal muscle mass.
Ultrasound Findings After Surgical Decompression of the Tarsal Tunnel in Patients With Painful Diabetic Polyneuropathy: A Prospective Randomized Study
Authors: Joanne F.M. Macaré van Maurik, Marita E.L. Schouten, Iris ten Katen, Mireille van Hal, Edgar J.G. Peters, Moshe Kon
Journal: Diabetes Care (2014)

It has been hypothesized that the development of diabetic polyneuropathy (DPN) is due to swelling of the nerve, as well as thickening and stiffening of the surrounding ligaments, causing chronic compression of nerves. We aimed to examine the effect of surgical decompression of the tibial nerve on the mean cross-sectional area (CSA).We performed a randomized controlled trial of 42 subjects with painful DPN diagnosed using the Diabetic Neuropathy Score. A computer randomized for the surgery arm of the study. A control group consisting of 38 healthy subjects was included. An experienced sonographer measured the CSA and thickness-to-width (T/W) ratio of the tibial nerve, as well as the thickness of the flexor retinaculum.CSA is significantly larger in patients with painful DPN (8.4 ± 3.9 mm(2)) than in control subjects (6.4 ± 1.3 mm(2)), P = 0.007. The T/W ratio in patients with painful DPN is 0.64 and in control subjects 0.59, P = 0.03. Patients with DPN have a significantly thicker retinaculum (1.07 mm) than control subjects (0.84 mm), P < 0.001. Mean follow-up was 28.2 weeks (range 23-45). Difference between baseline and follow-up in the operated leg was 1.49 mm(2) and in the control leg 1.81 mm(2), P = 0.674.Decompression of the tibial nerve does not result in a significant difference between baseline and follow-up in CSA using ultrasound between the operated and control leg. Ultrasound measurements show a significantly increased CSA, a significantly thicker retinaculum, and a significantly increased T/W ratio in patients with painful DPN compared with healthy control subjects. Clinical trial reg. no. NTR2344, www.trialregister.nl.
Chronic Lymphocytic Leukemia
Authors: Chadi Nabhan, Steven T. Rosen
Journal: JAMA (2014)

<h3>Importance</h3> The most common leukemia is chronic lymphocytic leukemia (CLL). Every year, there are 15 000 new diagnoses and 5000 CLL deaths in the United States. Although therapeutic choices were once limited, treatment of this disease has vastly improved in the last decade. <h3>Objective</h3> Evidence-based review of the diagnosis, staging, and treatment of CLL. <h3>Evidence Review</h3> PubMed, Cochrane Library, Scopus, and Google Scholar databases were searched through August 28, 2014. English-language peer-reviewed articles published between 2000-2014 were found using the keywords<i>chronic lymphocytic leukemia</i>,<i>upfront therapy</i>,<i>upfront therapies</i>,<i>upfront therapeutic</i>,<i>upfront therapeutics</i>,<i>upfront treatment</i>,<i>front-line treatment</i>,<i>first-line treatment</i>,<i>front-line treatments</i>,<i>first-line treatments</i>,<i>front-line therapy</i>,<i>front-line therapies</i>,<i>randomized</i>,<i>randomized studies</i>,<i>randomized study</i>,<i>clinical trial</i>,<i>clinical trials</i>,<i>phase 3</i>, and<i>phase 3 clinical trial</i>. Abstracts and presentations at scientific meetings were excluded. A total of 277 articles were retrieved, of which 24 met our predefined selection criteria; treatment recommendations were based on subsequent analysis of these 24 articles. <h3>Findings</h3> The Rai and Binet systems for staging CLL were established in 1975 and 1977, respectively. However, they do not account for new disease categories such as monoclonal B-cell lymphocytosis (peripheral blood clonal lymphocytosis that does not meet other criteria for CLL). Two subsets of CLL are now recognized based on risk stratification involving molecular and cytogenetic analyses. Outcomes are improved by the addition of immunotherapy to combination chemotherapy for initial treatment in all subsets of treated patients. Overall response rates between 75% and 90% and complete responses between 22% and 45% are expected in the current era, with more than 80% of treated patients alive at 3 years. Overall, 5-year survival has increased to 66% from 60% (<i>P</i> &lt; .001) in the past 10 years. <h3>Conclusions and Relevance</h3> Chemoimmunotherapy is the standard first-line option approach for CLL, the most common leukemia observed in adults. Treatment is initiated when the disease becomes symptomatic, and survival is high following treatment.
Evaluation of a 5-Marker Blood Test for Colorectal Cancer Early Detection in a Colorectal Cancer Screening Setting
Authors: Simone Werner, Friedemann Krause, Vinzent Rolny, Matthias Strobl, David Morgenstern, Christian Datz, Hongda Chen, Hermann Brenner
Journal: Clinical Cancer Research (2015)

In initial studies that included colorectal cancer patients undergoing diagnostic colonoscopy, we had identified a serum marker combination able to detect colorectal cancer with similar diagnostic performance as fecal immunochemical test (FIT). In this study, we aimed to validate the results in participants of a large colorectal cancer screening study conducted in the average-risk, asymptomatic screening population.We tested serum samples from 1,200 controls, 420 advanced adenoma patients, 4 carcinoma in situ patients, and 36 colorectal cancer patients with a 5-marker blood test [carcinoembryonic antigen (CEA)+anti-p53+osteopontin+seprase+ferritin]. The diagnostic performance of individual markers and marker combinations was assessed and compared with stool test results.AUCs for the detection of colorectal cancer and advanced adenomas with the 5-marker blood test were 0.78 [95% confidence interval (CI), 0.68-0.87] and 0.56 (95% CI, 0.53-0.59), respectively, which now is comparable with guaiac-based fecal occult blood test (gFOBT) but inferior to FIT. With cutoffs yielding specificities of 80%, 90%, and 95%, the sensitivities for the detection of colorectal cancer were 64%, 50%, and 42%, and early-stage cancers were detected as well as late-stage cancers. For osteopontin, seprase, and ferritin, the diagnostic performance in the screening setting was reduced compared with previous studies in diagnostic settings while CEA and anti-p53 showed similar diagnostic performance in both settings.Performance of the 5-marker blood test under screening conditions is inferior to FIT even though it is still comparable with the performance of gFOBT. CEA and anti-p53 could contribute to the development of a multiple marker blood-based test for early detection of colorectal cancer.
Screening for candidate hepatic growth factors by selective portal infusion after canine Eck’s fistula
Authors: Antonio Francavilla, Thomas E. Starzl, Ken Porter, Carlo Scotti Foglieni, George K. Michalopoulos, Giuseppe Carrieri, Jose Trejo, Alessandro Azzarone, Michele Barone, Qi Hua Zeng
Journal: Hepatology (1991)

Completely diverting portacaval shunt (Eck’s fistula) in dogs causes hepatocyte atrophy, disruption of hepatocyte organelles, fatty infiltration and lowgrade hyperplasia. The effect of hepatic growth regulatory substances on these changes was assessed by constantly infusing test substances for four postoperative days after Eck’s fistula into the detached left portal vein above the shunt. The directly infused left lobes were compared histopathologically with the untreated right lobes. In what has been called an hepatotrophic effect, stimulatory substances prevented the atrophy and increased hepatocyte mitoses. Of the hormones tested, only insulin was strongly hepatotrophic; T 3 had a minor effect, and glucagon, prolactin, angiotensin II, vasopressin, norepinephrine and estradiol were inert. Insulin-like growth factor, hepatic stimulatory substance, transforming growth factor-α and hepatocyte growth factor (also known as hematopoietin A) were powerfully hepatotrophic, but epidermal growth factor had a barely discernible effect. Transforming growth factor-β was inhibitory, but tamoxifen, interleukin-1 and interleukin-2 had no effect. The hepatotrophic action of insulin was not altered when the insulin infusate was mixed with transforming growth factor-β or tamoxifen. These experiments show the importance of in vivo in addition to in vitro testing of putative growth control factors. They illustrate how Eck’s fistula model can be used to screen for such substances and possibly to help delineate their mechanisms of action. (Hepatology 1991;14:665-670.)
Noninvasive Measurement of Airway Responsiveness in Allergic Mice Using Barometric Plethysmography
Authors: E. HAMELMANN, J. SCHWARZE, K. TAKEDA, A. OSHIBA, G. L. LARSEN, C. G. IRVIN, E. W. GELFAND
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

To study the mechanisms and kinetics underlying the development of increased airway responsiveness (AR) after allergic sensitization, animal models have been invaluable. Using barometric whole-body plethysmography and increases in enhanced pause (Penh) as an index of airway obstruction, we measured responses to inhaled methacholine in conscious, unrestrained mice after sensitization and airway challenge with ovalbumin (OVA). Sensitized and challenged animals had significantly increased AR to aerosolized methacholine compared with control animals. AR measured as Penh was associated with increased IgE production and eosinophil lung infiltration. In a separate approach we confirmed the involvement of the lower airways in the response to aerosolized methacholine using tracheotomized mice. Increases in Penh values after methacholine challenge were also correlated with increased intrapleural pressure, measured via an esophageal tube. Lastly, mice demonstrating AR using a noninvasive technique also demonstrated increased pulmonary resistance responses to aerosolized methacholine when measured using an invasive technique the following day in the same animals. The increases in Penh values were inhibited by pretreatment of the mice with a β2-agonist. These data indicate that measurement of AR to inhaled methacholine by barometric whole-body plethysmography is a valid indicator of airway hyperresponsiveness after allergic sensitization in mice. The measurement of AR in unrestrained, conscious animals provides new opportunities to evaluate the mechanisms and kinetics underlying the development and maintenance of airway hyperresponsiveness and to assess various therapeutic interventions.
Population-based survival for malignant mesothelioma after introduction of novel chemotherapy
Authors: Ronald A.M. Damhuis, Caroline Schroten, Jacobus A. Burgers
Journal: European Respiratory Journal (2011)

Malignant mesothelioma is known for its dismal prognosis and poor response to conventional treatment. Chemotherapy with cisplatin–antifolate combinations recently showed promising response rates and prolonged survival in randomised trials. To assess the impact of this development on clinical practice and survival at a population-based level, treatment patterns and survival trends were studied for patients diagnosed with mesothelioma in the period 1995–2006. 4,731 records were retrieved from the Netherlands Cancer Registry and chemotherapy use and median survival were analysed. For the periods 1995–1998 to 2005–2006, chemotherapy use increased from 8% to 36%. Median survival increased over time from 7.1 months to 9.2 months. For pleural mesothelioma, multivariable analysis demonstrated that survival was poorer for elderly patients and sarcomatoid tumours. The prognostic impact of chemotherapy increased with time. Median survival for chemotherapy treated patients improved from 10.1 months (1995–1998) to 13.1 months (2005–2006). For peritoneal mesothelioma, median survival was poor (3.9 months) but better for females and younger patients. This study demonstrates that chemotherapy use increased at a national level and coincided with an improvement in survival. The novel chemotherapy regimen appears to be more effective but, due to the observational nature of this study, alternative explanations cannot be excluded.
Government gives underperforming trusts a year to improve stroke services
Authors: A. O'Dowd
Journal: BMJ (2010)

Trusts and areas with poor stroke services are expected to make substantial improvements within the next 12 months, the government has underlined in a parliamentary session.

Experts from the Department of Health told MPs on the public accounts committee on 24 February that it could take five years from the launch of the National Stroke Strategy of 2007 before all hospitals in England were providing the best service for stroke patients. And time is almost up. 

The public accounts committee was holding an inquiry into the department’s progress in improving stroke care and a report about this subject published earlier in February by the National Audit …
ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R–mediated apoptosis
Authors: Thomas Condamine, Vinit Kumar, Indu R. Ramachandran, Je-In Youn, Esteban Celis, Niklas Finnberg, Wafik S. El-Deiry, Rafael Winograd, Robert H. Vonderheide, Nickolas R. English, Stella C. Knight, Hideo Yagita, Judith C. McCaffrey, Scott Antonia, Neil Hockstein, Robert Witt, Gregory Masters, Thomas Bauer, Dmitry I. Gabrilovich
Journal: Journal of Clinical Investigation (2014)

Myeloid-derived suppressor cells (MDSCs) dampen the immune response thorough inhibition of T cell activation and proliferation and often are expanded in pathological conditions. Here, we studied the fate of MDSCs in cancer. Unexpectedly, MDSCs had lower viability and a shorter half-life in tumor-bearing mice compared with neutrophils and monocytes. The reduction of MDSC viability was due to increased apoptosis, which was mediated by increased expression of TNF-related apoptosis–induced ligand receptors (TRAIL-Rs) in these cells. Targeting TRAIL-Rs in naive mice did not affect myeloid cell populations, but it dramatically reduced the presence of MDSCs and improved immune responses in tumor-bearing mice. Treatment of myeloid cells with proinflammatory cytokines did not affect TRAIL-R expression; however, induction of ER stress in myeloid cells recapitulated changes in TRAIL-R expression observed in tumor-bearing hosts. The ER stress response was detected in MDSCs isolated from cancer patients and tumor-bearing mice, but not in control neutrophils or monocytes, and blockade of ER stress abrogated tumor-associated changes in TRAIL-Rs. Together, these data indicate that MDSC pathophysiology is linked to ER stress, which shortens the lifespan of these cells in the periphery and promotes expansion in BM. Furthermore, TRAIL-Rs can be considered as potential targets for selectively inhibiting MDSCs.
A randomized, placebo-controlled phase 2 study of ganitumab or conatumumab in combination with FOLFIRI for second-line treatment of mutant KRAS metastatic colorectal cancer
Authors: A.L. Cohn, J. Tabernero, J. Maurel, E. Nowara, J. Sastre, B.Y.S. Chuah, M.V. Kopp, D.D. Sakaeva, E.P. Mitchell, S. Dubey, S. Suzuki, Y.-J. Hei, F. Galimi, I. McCaffery, Y. Pan, R. Loberg, S. Cottrell, S.-P. Choo
Journal: Annals of Oncology (2013)
Rapid and efficient clearance of airway tissue granulocytes through transepithelial migration
Authors: J S Erjefalt
Journal: Thorax (2004)

Clearance of tissue granulocytes is central to the resolution of airway inflammation. To date the focus has been on apoptotic mechanisms of cell removal and little attention has been given to alternative processes. The present study explores transepithelial migration as a mechanism of cell clearance.Guinea pig tracheobronchial airways where eosinophils are constitutively present in the mucosal tissue were studied. A complex topical stimulus (allergen challenge) was applied and the fate of the eosinophils was determined by selective tracheobronchial lavage and histological examination of the tissue.Within 10 minutes of the allergen challenge, massive migration of eosinophils into the airway lumen occurred together with a reduction in tissue eosinophil numbers. Cell clearance into the lumen continued at high speed and by 30 and 60 minutes the tissue eosinophilia had been reduced by 63% and 73%, respectively. The marked transepithelial migration (estimated maximal speed 35,000 cells/min x cm2 mucosal surface) took place ubiquitously between epithelial cells without affecting epithelial integrity as assessed by transmission and scanning electron microscopy. Eosinophil apoptosis was not detected but occasional cytolytic eosinophils occurred.This study shows that luminal entry has a remarkably high capacity as a granulocyte elimination process. The data also suggest that an appropriate stimulus of transepithelial migration may be used therapeutically to increase the resolution of inflammatory conditions of airway tissues.
Chondrogenic potential of stem cells derived from amniotic fluid, adipose tissue, or bone marrow encapsulated in fibrin gels containing TGF-β3
Authors: Ji Sun Park, Myung-Sun Shim, Sung Han Shim, Han Na Yang, Su Yeon Jeon, Dae Gyun Woo, Dong Ryul Lee, Tae Ki Yoon, Keun-Hong Park
Journal: Biomaterials (2011)