tbuckley/cabot-search huggingface dataset:
Clinical, Pathologic, and Biologic Features Associated with <i>BRAF</i> Mutations in Non–Small Cell Lung Cancer
Authors: Stephanie Cardarella, Atsuko Ogino, Mizuki Nishino, Mohit Butaney, Jeanne Shen, Christine Lydon, Beow Y. Yeap, Lynette M. Sholl, Bruce E. Johnson, Pasi A. Jänne
Journal: Clinical Cancer Research (2013)

Abstract Purpose: BRAF mutations are found in a subset of non–small cell lung cancers (NSCLC). We examined the clinical characteristics and treatment outcomes of patients with NSCLC harboring BRAF mutations. Experimental Design: Using DNA sequencing, we successfully screened 883 patients with NSCLC for BRAF mutations between July 1, 2009 and July 16, 2012. Baseline characteristics and treatment outcomes were compared between patients with and without BRAF mutations. Wild-type controls consisted of patients with NSCLC without a somatic alteration in BRAF, KRAS, EGFR, and ALK. In vitro studies assessed the biologic properties of selected non-V600E BRAF mutations identified from patients with NSCLC. Results: Of 883 tumors screened, 36 (4%) harbored BRAF mutations (V600E, 18; non-V600E, 18) and 257 were wild-type for BRAF, EGFR, KRAS, and ALK negative. Twenty-nine of 36 patients with BRAF mutations were smokers. There were no distinguishing clinical features between BRAF-mutant and wild-type patients. Patients with advanced NSCLC with BRAF mutations and wild-type tumors showed similar response rates and progression-free survival (PFS) to platinum-based combination chemotherapy and no difference in overall survival. Within the BRAF cohort, patients with V600E-mutated tumors had a shorter PFS to platinum-based chemotherapy compared with those with non-V600E mutations, although this did not reach statistical significance (4.1 vs. 8.9 months; P = 0.297). We identified five BRAF mutations not previously reported in NSCLC; two of five were associated with increased BRAF kinase activity. Conclusions: BRAF mutations occur in 4% of NSCLCs and half are non-V600E. Prospective trials are ongoing to validate BRAF as a therapeutic target in NSCLC. Clin Cancer Res; 19(16); 4532–40. ©2013 AACR.
What does the clinician need to improve patient care in systemic sclerosis?
Authors: M. C Vonk, F. H J van den Hoogen, P. L C M van Riel, G. Valentini
Journal: Annals of the Rheumatic Diseases (2007)

Validated clinimetric criteria, useful in the early phase of systemic sclerosis, are lacking S ystemic sclerosis (SSc) is a multisystemic disorder of unknown cause characterised by fibrotic and degenerative changes in skin, blood vessels and internal organs. 1 The clinical spectrum of SSc, and hence its prognosis, is quite variable. 2Validated subset classification, activity and severity criteria are available. 2-7However, despite their usefulness, these criteria have several limitations.Furthermore, diagnostic criteria of SSc are lacking.To improve the care of patients with scleroderma, the clinician needs to initiate optimal, early treatment.Diagnostic criteria that aid early diagnosis as well as classification, severity criteria that aid estimation of prognosis, and disease activity criteria that indicate active disease could help the clinician in daily practice.Present international collaborations such as the EULAR Scleroderma Trial and Research Group (EUSTAR) and the North American Scleroderma Clinical Trials Consortium (SCTC) are thriving, providing the ideal circumstances for clinimetric studies of SSc.
Genomic and Mutational Profiling to Assess Clonal Relationships Between Multiple Non–Small Cell Lung Cancers
Authors: Nicolas Girard, Irina Ostrovnaya, Christopher Lau, Bernard Park, Marc Ladanyi, David Finley, Charuhas Deshpande, Valerie Rusch, Irene Orlow, William D. Travis, William Pao, Colin B. Begg
Journal: Clinical Cancer Research (2009)

Abstract Purpose: In cases of multiple non–small cell lung cancer, clinicians must decide whether patients have independent tumors or metastases and tailor treatment accordingly. Decisions are currently made using the Martini and Melamed criteria, which are mostly based on tumor location and histologic type. New genomic tools could improve the ability to assess tumor clonality. Experimental Design: We obtained fresh-frozen tumors specimens from patients who underwent surgery on at least two occasions for presumptively independent NSCLC. We did array comparative genomic hybridization (aCGH), mutational profiling of select genes, and detailed clinicopathologic review. Results: We analyzed a total of 42 tumors from 20 patients (6 patients with synchronous tumors, 14 patients with metachronous tumors, 24 potential tumor pair comparisons); 22 tumor pairs were evaluable by aCGH. Surprisingly, classification based on genomic profiling contradicted the clinicopathologic diagnosis in four (18%) of the comparisons, identifying independent primaries in one case diagnosed as metastasis and metastases in three cases diagnosed as independent primaries. Matching somatic point mutations were observed in these latter three cases. Another four tumor pairings were assigned an “equivocal” result based on aCGH; however, matching somatic point mutations were also found in these tumor pairs. None of the tumor pairs deemed independent primaries by aCGH harbored matching mutations. Conclusion: Genomic analysis can help distinguish clonal tumors from independent primaries. The development of rapid, inexpensive, and reliable molecular tools may allow for refinement of clinicopathologic criteria currently used in this setting. (Clin Cancer Res 2009;15(16):5184–90)
Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy
Authors: Emanuela Zappia, Simona Casazza, Enrico Pedemonte, Federica Benvenuto, Ivan Bonanni, Ezio Gerdoni, Debora Giunti, Antonella Ceravolo, Francesco Cazzanti, Francesco Frassoni, Gianluigi Mancardi, Antonio Uccelli
Journal: Blood (2005)
Chronic labile hypertension produced by lesions of the nucleus tractus solitarii in the cat.
Authors: M A Nathan, D J Reis
Journal: Circulation Research (1977)

Bilateral electrolytic lesions of the nucleus tractus solitarii (NTS) were made at the level of the obex in seven cats. Within 1 hour the mean arterial pressure (MAP) rose to a maximum of 144 mm Hg (141% of control), and by 7 hours heart rate reached a peak of 236 beats/min (148% of control). The baroreceptor reflexes were abolished. After 24 hours the arterial pressure became extremely labile, with variations of 80-100 mm Hg observed. The lability occurred spontaneously and during behaviors that were self-initiated or elicited by environmental stimuli. The MAP in the lesion group was 144 mm Hg (180% of control) during the day, and 96 mm Hg (120% of control) at night. The lability, measured by the standard deviation, during the day in the lesion group was 4 times greater than in the control group and at night there were no differences. The heart rate of the lesion group was always higher than that of the control group but the lability of both groups was the same. We conclude that lesions of the NTS produced labile hypertension, probably by disinhibition of sympathetic activity through central interruption of the baroreceptor reflexes. The higher, more labile arterial pressures during the day may be caused by uninhibited increases in sympathetic activity elicited by environmental stimuli that are present during the day and absent at night. The daily variation of pressure may also be caused by somatomotor activity or by a daily rhythm of sympathetic activity which is unmasked by the lesions.
Diagnosis of Hymenoptera venom allergy
Authors: B. M. Biló, F. Rueff, H. Mosbech, F. Bonifazi, J. N. G. Oude‐Elberink
Journal: Allergy (2005)

The purpose of diagnostic procedure is to classify a sting reaction by history, identify the underlying pathogenetic mechanism, and identify the offending insect. Diagnosis of Hymenoptera venom allergy thus forms the basis for the treatment. In the central and northern Europe vespid (mainly Vespula spp.) and honeybee stings are the most prevalent, whereas in the Mediterranean area stings from Polistes and Vespula are more frequent than honeybee stings; bumblebee stings are rare throughout Europe and more of an occupational hazard. Several major allergens, usually glycoproteins with a molecular weight of 10–50 kDa, have been identified in venoms of bees, vespids. and ants. The sequences and structures of the majority of venom allergens have been determined and several have been expressed in recombinant form. A particular problem in the field of cross‐reactivity are specific immunoglobulin E (IgE) antibodies directed against carbohydrate epitopes, which may induce multiple positive test results (skin test, in vitro tests) of still unknown clinical significance. Venom hypersensitivity may be mediated by immunologic mechanisms (IgE‐mediated or non‐IgE‐mediated venom allergy) but also by nonimmunologic mechanisms. Reactions to Hymenoptera stings are classified into normal local reactions, large local reactions, systemic toxic reactions, systemic anaphylactic reactions, and unusual reactions. For most venom‐allergic patients an anaphylactic reaction after a sting is very traumatic event, resulting in an altered health‐related quality of life. Risk factors influencing the outcome of an anaphylactic reaction include the time interval between stings, the number of stings, the severity of the preceding reaction, age, cardiovascular diseases and drug intake, insect type, elevated serum tryptase, and mastocytosis. Diagnostic tests should be carried out in all patients with a history of a systemic sting reaction to detect sensitization. They are not recommended in subjects with a history of large local reaction or no history of a systemic reaction. Testing comprises skin tests with Hymenoptera venoms and analysis of the serum for Hymenoptera venom‐specific IgE. Stepwise skin testing with incremental venom concentrations is recommended. If diagnostic tests are negative they should be repeated several weeks later. Serum tryptase should be analyzed in patients with a history of a severe sting reaction.
G<scp>UGULIPID</scp>: A Natural Cholesterol-Lowering Agent
Authors: Nancy L. Urizar, David D. Moore
Journal: Annual Review of Nutrition (2003)

▪ Abstract The resin of the Commiphora mukul tree has been used in Ayurvedic medicine for more than 2000 years to treat a variety of ailments. Studies in both animal models and humans have shown that this resin, termed gum guggul, can decrease elevated lipid levels. The stereoisomers E- and Z-guggulsterone have been identified as the active agents in this resin. Recent studies have shown that these compounds are antagonist ligands for the bile acid receptor farnesoid X receptor (FXR), which is an important regulator of cholesterol homeostasis. It is likely that this effect accounts for the hypolipidemic activity of these phytosteroids.
Analysis of Diepoxide-Specific Cyclic <b> <i>N</i> </b>-Terminal Globin Adducts in Mice and Rats after Inhalation Exposure to 1,3-Butadiene
Authors: Gunnar Boysen, Nadia I. Georgieva, Patricia B. Upton, Karupiah Jayaraj, Yutai Li, Vernon E. Walker, James A. Swenberg
Journal: Cancer Research (2004)

1,3-Butadiene is an important industrial chemical used in the production of synthetic rubber and is also found in gasoline and combustion products. It is a multispecies, multisite carcinogen in rodents, with mice being the most sensitive species. 1,3-Butadiene is metabolized to several epoxides that form DNA and protein adducts. Previous analysis of 1,2,3-trihydroxybutyl-valine globin adducts suggested that most adducts resulted from 3-butene-1,2-diol metabolism to 3,4-epoxy-1,2-butanediol, rather than from 1,2;3,4-diepoxybutane. To specifically examine metabolism of 1,3-butadiene to 1,2;3,4-diepoxybutane, the formation of the 1,2;3,4-diepoxybutane-specific adduct N,N-(2,3-dihydroxy-1,4-butadiyl)-valine was evaluated in mice treated with 3, 62.5, or 1250 ppm 1,3-butadiene for 10 days and rats exposed to 3 or 62.5 ppm 1,3-butadiene for 10 days, or to 1000 ppm 1,3-butadiene for 90 days, using a newly developed immunoaffinity liquid chromatography tandem mass spectrometry assay. In addition, 2-hydroxy-3-butenyl-valine and 1,2,3-trihydroxybutyl-valine adducts were determined. The analyses of several adducts derived from 1,3-butadiene metabolites provided new insight into species and exposure differences in 1,3-butadiene metabolism. Mice formed much higher amounts of N,N-(2,3-dihydroxy-1,4-butadiyl)-valine than rats. The formation of 2-hydroxy-3-butenyl-valine and N,N-(2,3-dihydroxy-1,4-butadiyl)-valine was similar in mice exposed to 3 or 62.5 ppm 1,3-butadiene, whereas 2-hydroxy-3-butenyl-valine was 3-fold higher at 1250 ppm. In both species, 1,2,3-trihydroxybutyl-valine adducts were much higher than 2-hydroxy-3-butenyl-valine and N,N-(2,3-dihydroxy-1,4-butadiyl)-valine. Together, these data show that 1,3-butadiene is primarily metabolized via the 3-butene-1,2-diol pathway, but that mice are much more efficient at forming 1,2;3,4-diepoxybutane than rats, particularly at low exposures. This assay should also be readily adaptable to molecular epidemiology studies on 1,3-butadiene-exposed workers.
Links between triglyceride levels, hepatitis C virus infection and diabetes.
Authors: Chia-Yen Dai, Jee-Fu Huang, Ming-Yen Hsieh, Li-Po Lee, Nai-Jen Hou, Ming-Lung Yu, Wan-Long Chuang
Journal: Gut (2007)

We read the interesting article by Marzouk et al ( Gut 2007; 56 :1105–10). The authors enrolled 765 residents in Egypt and reported prevalences of hepatitis C virus (HCV) antibody (anti-HCV), chronic and past HCV infection of 23.5%, 14% and 8.8%, respectively. Patients with chronic HCV infection had lower triglyceride levels and those with past HCV infection had higher triglyceride levels than those never infected. With a diabetes prevalence of 5.4%, HCV infection status—but not triglyceride levels—was one of the independent factors associated with diabetes.

We have conducted a large-scale community-based study of 9932 residents aged 40–65 years in Kaohsiung City, Taiwan, a country endemic for hepatitis B virus (HBV) infection. The prevalences of anti-HCV, …
Long-Term Survival of Patients Undergoing Mitral Valve Repair and Replacement
Authors: Christina M. Vassileva, Gregory Mishkel, Christian McNeely, Theresa Boley, Stephen Markwell, Steven Scaife, Stephen Hazelrigg
Journal: Circulation (2013)

Background— Despite the established superiority of mitral repair over replacement, its adoption in the treatment of elderly patients has not been uniform, partly because of a lack of robust long-term survival data. We present the long-term survival of Medicare fee-for-service beneficiaries undergoing mitral valve repair and replacement over a 10-year period. Methods and Results— We used the Medicare database to identify 47 279 fee-for-service beneficiaries ≥65 years of age undergoing primary isolated mitral valve repair or replacement from 2000 to 2009. Operative mortality and long-term survival are presented for repair and replacement. Operative mortality was 3.9% for patients undergoing repair and 8.9% for patients undergoing replacement. The 1-, 5-, and 10-year Kaplan-Meier survival estimates for patients undergoing repair were 90.9%, 77.1%, and 53.6%. The 1-, 5-, and 10-year Kaplan-Meier survival estimates for patients undergoing replacement were 82.6%, 64.7%, and 37.2%. Important predictors of mitral repair included younger age (odds ratio, 1.10; 95% confidence interval, 1.05–1.14), elective admission status (odds ratio, 1.34; 95% confidence interval, 1.27–1.41), and annual mitral procedure volume &gt;40 cases per year (odds ratio, 1.57; 95% confidence interval, 1.36–1.81). Female sex and the presence of comorbidities were associated with a lower likelihood of repair. Conclusions— Mitral valve surgery in the Medicare population carries less risk than previously reported. Given the favorable outcomes of elderly patients undergoing mitral valve surgery, especially mitral valve repair, an approach of earlier identification and surgical referral appears justified regardless of age.
Representation of Number in the Brain
Authors: Andreas Nieder, Stanislas Dehaene
Journal: Annual Review of Neuroscience (2009)

Number symbols have allowed humans to develop superior mathematical skills that are a hallmark of technologically advanced cultures. Findings in animal cognition, developmental psychology, and anthropology indicate that these numerical skills are rooted in nonlinguistic biological primitives. Recent studies in human and nonhuman primates using a broad range of methodologies provide evidence that numerical information is represented and processed by regions of the prefrontal and posterior parietal lobes, with the intraparietal sulcus as a key node for the representation of the semantic aspect of numerical quantity.
Thiocyanate and Basal Blood Pressure
Authors: K. S. Alstad
Journal: BMJ (1948)

Many conflicting views have been published since thio- cyanates were first administered therapeutically at the beginning of this century; and although Hines (1946) and Watkinson and Evans (1947) stated that these are the only drugs capable of satisfactory use in the treatment of hypertensive disease, many are not con- vinced of their action.For example, Ayman (1930, 1931) endeavoured to show that their effect was nm,i not greater than that of placebos, basing his criteria of action mainly on sympto- matic improvement and not so much on pressure changes.
Parenchymal liver disease in the elderly
Authors: O F W JAMES
Journal: Gut (1997)

Until recently, the subject of parenchymal liver disease presenting in elderly patients had received little specific attention. Many studies have examined changes in morphology and function in the aging liver, initially in rodents and subsequently in humans. In summary, there are no age specific alterations in conventional liver biochemistry (serum bilirubin, serum aminotransferases, hepatic alkaline phosphatase, and other liver blood tests) but a number of dynamic measurements of liver function do decline from early adulthood to senescence.1 Liver size, liver blood flow and liver perfusion decline between the third and tenth decades by 30–40%.2 Most reflections of dynamic liver function—galactose elimination, aminopyrine demethylation, or caffeine clearance—fall pari passu with the reduction in liver volume and blood flow.3 4 Conceivably, some specific liver functions—for example, hepatic nitrogen clearance, are independently impaired, in this case by up to 50% with advancing age.5 It is probably in the area of liver regeneration, however, that reduction in functional capacity of the liver is most apparent and important. A number of studies have suggested increased susceptibility to stress insult in aged experimental animals6 but there are no comparable human studies. A clue to the possible mechanism of impaired liver cell proliferation with advanced age has been provided by the demonstration of an age related decline in mitogen activated protein kinase activity in epidermal growth factor stimulated rat hepatocytes.7 The above factors, combined with the influence of lifetime variation in diet, alcohol consumption and smoking, nutritional status, co-existent disease, and genetic influences, form the background for the age related features of parenchymal liver disease described in this article.

Although there are no specific age related diseases of the liver, it is increasingly recognised that consideration of special features and differences between old and young are important in respect of clinical …
Obesity, Autoimmunity, and Double Diabetes in Youth
Authors: Paolo Pozzilli, Chiara Guglielmi, Sonia Caprio, Raffaella Buzzetti
Journal: Diabetes Care (2011)

A few obese youth with type 2 diabetes have evidence of islet cell autoimmunity with autoantibodies toward β-cells typical of type 1 diabetes defining what is called “double diabetes” (DD). The increasingly “obesogenic” environment that favors insulin resistance could account for the development of islet cell autoimmunity through different mechanisms. Therefore, a rising obesity trend seems to have a role (in association with other environmental factors) in the increasing incidence and the changing phenotype of type 1 diabetes in youth.

Over the past decade, it has become apparent that more cases of type 1 diabetes are diagnosed in children and adolescents who were overweight or even obese before hyperglycemia developed. Accordingly, diagnosis of type 1 diabetes is not easy to place because of the phenotypic features typically associated with type 2 diabetes. In addition, the increase of obesity observed in children may contribute to the escalation of β-cell destruction, as suggested by the accelerator hypothesis in subjects genetically susceptible to type 1 diabetes. Lifestyle modifications, including diet and exercise, which are relevant for the prevention of type 2 diabetes, may be important modifiable environmental factors also for type 1 diabetes prevention in subjects with DD.

A few years ago, the terms “type 1 diabetes” and “type 2 diabetes” replaced “insulin-dependent diabetes” and “non-insulin-dependent diabetes,” respectively. This new nomenclature reflected two distinct forms of the disease in terms of pathogenesis (1). The classification is still maintained, although other subtypes have been included in the latest classification (2). An increase in blood glucose results either from failure of the β-cells to secrete insulin (type 1 diabetes) or reduction in insulin secretion combined with insulin resistance of peripheral tissues (type 2 diabetes), or a combination of both (3). The prevalence of both types of diabetes is rapidly increasing in industrialized countries, and although …
Target of Rapamycin Signaling in Leukemia and Lymphoma
Authors: Collin Vu, David A. Fruman
Journal: Clinical Cancer Research (2010)

Growth factors and many oncogenes activate the lipid kinase phosphoinositide 3-kinase (PI3K), initiating a signaling cascade that includes the protein kinases AKT and target of rapamycin (TOR). The PI3K/AKT/TOR signaling pathway is a significant contributor to disease in various human cancers, including hematologic malignancies. Here we discuss different strategies to inhibit TOR for the treatment of leukemia, lymphoma, and myeloma. The TOR enzyme exists in two complexes in cells, TORC1 and TORC2. The majority of preclinical and clinical efforts to target TOR have involved using rapamycin and its analogs (rapalogs), which suppress TORC1 only partially and do not acutely inhibit TORC2. A new class of small molecules targeting the ATP-binding site of the TOR kinase, termed active-site TOR inhibitors (asTORi), achieves greater inhibition of both TOR complexes, resulting in broader suppression of the PI3K/AKT/TOR signaling network. Preclinical evidence suggests that asTORi have greater efficacy than rapalogs in Philadelphia chromosome-positive acute lymphoblastic leukemia and in T-cell lymphoma. These agents also show greater tolerability in animal models relative to rapalogs or inhibitors of PI3K. These findings encourage broader evaluation of asTORi efficacy in acute myeloid leukemia, B-cell lymphoma, myeloma, and other blood cancers.
The clinical efficacy of fluoroquinolone and macrolide combination therapy compared with single-agent therapy against community-acquired pneumonia caused by Legionella Pneumophila
Authors: Shigeki Nakamura, Katsunori Yanagihara, Koichi Izumikawa, Masafumi Seki, Hiroshi Kakeya, Yoshihiro Yamamoto, Hideaki Senjyu, Atsushi Saito, Shigeru Kohno
Journal: Journal of Infection (2009)