tbuckley/cabot-search huggingface dataset:
Immunotherapeutic approaches to ovarian cancer treatment
Authors: Cariad Chester, Oliver Dorigo, Jonathan S Berek, Holbrook Kohrt
Journal: Journal for ImmunoTherapy of Cancer (2015)

Despite advances in combinatorial chemotherapy regimens and the advent of intraperitoneal chemotherapy administration, current therapeutic options for ovarian cancer patients are inadequate. Immunotherapy offers a novel and promising therapeutic strategy for treating ovarian tumors. Following the demonstration of the immunogenicity of ovarian tumors, multiple immunotherapeutic modalities have been developed. Antibody-based therapies, immune checkpoint blockade, cancer vaccines, and chimeric antigen receptor-modified T cells have demonstrated preclinical success and entered clinical testing. In this review, we discuss these promising immunotherapeutic approaches and emphasize the importance of combinatorial treatment strategies and biomarker discovery.
Vitamin D–Related Genetic Variation, Plasma Vitamin D, and Risk of Lethal Prostate Cancer: A Prospective Nested Case–Control Study
Authors: Irene M. Shui, Lorelei A. Mucci, Peter Kraft, Rulla M. Tamimi, Sara Lindstrom, Kathryn L. Penney, Katharina Nimptsch, Bruce W. Hollis, Natalie DuPre, Elizabeth A. Platz, Meir J. Stampfer, Edward Giovannucci
Journal: JNCI Journal of the National Cancer Institute (2012)

BackgroundThe association of vitamin D status with prostate cancer is controversial; no association has been observed for overall incidence, but there is a potential link with lethal disease.
Changes in ventilation and its components in normal subjects during sleep.
Authors: J R Stradling, G A Chadwick, A J Frew
Journal: Thorax (1985)

Non-invasive measurements were made of ventilation, its derivatives, the contributions of abdomen and rib cage and arterial oxygen saturation in six healthy normal men whilst awake and during sleep. Minute ventilation fell significantly during slow wave (SW) sleep and rapid eye movement (REM) sleep (awake = 6.3 1 min-1, SW sleep = 5.7 1 min-1, REM sleep = 5.4 1 min-1; p less than 0.04). Mean inspiratory flow also fell significantly but timing was unchanged. The abdominal (diaphragmatic) contribution to ventilation fell very significantly during SW sleep but returned to awake levels during REM sleep (awake 54%, SW sleep 38%, REM sleep 56%; p less than 0.007). There were also significant falls in arterial oxygen saturation during SW and REM sleep (awake 97.3%, SW sleep 96.5%, REM sleep 96.2%; p less than 0.002). These falls represent reductions in arterial oxygen tension similar to those seen in patients with chronic airways obstruction and can be accounted for entirely by the associated reduction in ventilation.
COPD among non-smokers
Authors: Dubravka Pelicaric, Bojana Butorac Petanjek, Sanja Grle Popovic, Tajana JaluÅ¡ic Gluncic, Mile Bogdan
Journal: European Respiratory Journal (2012)

AIM: This study aims at determining the number and percentage of non-smokers suffering from chronic obstructive pulmonary disease [COPD] and at investigating into its etiology.  SUBJECTS & METHODS: The study comprised a total of 250 subjects, diagnosed with COPD in line with 2010 Global Initiative for chronic Obstructive Lung Disease[GOLD]criteria.The subjects were first divided into 3 GOLD criteria-based subgroups[GOLD I, GOLD II & GOLD III/IV]and later on into the smoking and non-smoking arm.The non-smoking arm was also subdivided based on possible COPD risk factors.All study subjects underwent lung function and bronchodilator reversibility testing.  RESULTS:Age differences between the two study arms were proven statistically insignificant. Age differences between GOLD I and GOLD II subgroups proved statistically significant[p=0.0405].The disease severity registered across younger smokers equalled to that of far older non-smokers.  As for COPD risk factors,occupational exposure and earlier pulmonary TB were far more common in men, while passive smoking and the exposure to bio-fuel combustion releases were more common in women. Frequent respiratory infections experienced during childhood and adolescence were also more common in women.Out of 66 non-smokers,40 had only one,17 two and the remaining 9 none of the COPD risk factors,but this failed to affect the disease severity.  CONCLUSION:The results of this study prove that tobacco smoke and its constituents are not the only culprits for COPD onset.The disease can also be developed by non-smokers due to a number of risk factors elaborated herein.
Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice
Authors: Casper C. Hoogenraad, Bas Koekkoek, Anna Akhmanova, Harm Krugers, Bjorn Dortland, Marja Miedema, Arjan van Alphen, Werner M. Kistler, Martine Jaegle, Manoussos Koutsourakis, Nadja Van Camp, Marleen Verhoye, Annemie van der Linden, Irina Kaverina, Frank Grosveld, Chris I. De Zeeuw, Niels Galjart
Journal: Nature Genetics (2002)
Biliary phospholipases in the prairie dog model for cholesterol cholelithiasis
Authors: Michael L. Booker, Wayne W. Lamorte
Journal: Hepatology (1994)

Lysolecithin has been implicated as a contributing factor in the pathogenesis of cholecystitis and cholesterol cholelithiasis. The phospholipases are key enzymes in the generation of a number of metabolites including lysolecithin, but conflicting reports exist concerning the presence of these enzymes in the biliary tract. In this study, measurement of phosphatidylcholine-specific phospholipase activity by means of the hydrolysis of radiolabeled phosphatidylcholine (100 nmol) by 90 micrograms of homogenate protein during a 60-min incubation demonstrated substantial enzyme activities in gastric fundus and distal ileum (90% and 70% hydrolysis, respectively), whereas activity was virtually undetectable in gallbladder mucosa (0.7% hydrolysis). Additional studies were conducted in prairie dogs fed diets high in cholesterol or with trace amounts of cholesterol using homogenates of gallbladder mucosa, seromuscularis and full-thickness tissue, as well as samples of hepatic and gallbladder bile. The only hydrolytic activity in excess of blank values that was detected was a highly variable phospholipase A2 activity in several gallbladder biles from animals given diets with both low levels and high levels of cholesterol, with the enzyme activities of the two dietary groups being similar. These results demonstrate that prairie dog gallbladder contains extremely low levels of phospholipase activity, in marked contrast to other gastrointestinal tissues. However, there was evidence of a phospholipase A2 activity in gallbladder bile. In light of the low activity in gallbladder tissue, the source of this enzyme appears to be the liver and not the gallbladder.(ABSTRACT TRUNCATED AT 250 WORDS)
Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma
Authors: Ama-Tawiah Essilfie, Jay C Horvat, Richard Y Kim, Jemma R Mayall, James W Pinkerton, Emma L Beckett, Malcolm R Starkey, Jodie L Simpson, Paul S Foster, Peter G Gibson, Philip M Hansbro
Journal: Thorax (2015)

<h3>Background</h3> Steroid-insensitive endotypes of asthma are an important clinical problem and effective therapies are required. They are associated with bacterial infection and non-eosinophilic inflammatory responses in the asthmatic lung. Macrolide therapy is effective in steroid-insensitive endotypes, such as non-eosinophilic asthma. However, whether the effects of macrolides are due to antimicrobial or anti-inflammatory mechanisms is not known. <h3>Objective</h3> To determine and assess the efficacy of macrolide (ie, clarithromycin) and non-macrolide (ie, amoxicillin) antibiotic treatments in experimental models of infection-induced, severe, steroid-insensitive neutrophilic allergic airways disease (SSIAAD), compared with steroid-sensitive AAD and to delineate the antimicrobial and anti-inflammatory effects of macrolide therapy. <h3>Methods</h3> We developed and used novel mouse models of <i>Chlamydia</i> and <i>Haemophilus</i> lung infection-induced SSIAAD. We used these models to investigate the effects of clarithromycin and amoxicillin treatment on immune responses and airways hyper-responsiveness (AHR) in Ova-induced, T helper lymphocyte (Th) 2 -associated steroid-sensitive AAD and infection-induced Th1/Th17-associated SSIAAD compared with dexamethasone treatment. <h3>Results</h3> Clarithromycin and amoxicillin had similar antimicrobial effects on infection. Amoxicillin did attenuate some features, but did not broadly suppress either form of AAD. It did restore steroid sensitivity in SSIAAD by reducing infection. In contrast, clarithromycin alone widely suppressed inflammation and AHR in both steroid-sensitive AAD and SSIAAD. This occurred through reductions in Th2 responses that drive steroid-sensitive eosinophilic AAD and tumour necrosis factor α and interleukin 17 responses that induce SSIAAD. <h3>Conclusions</h3> Macrolides have broad anti-inflammatory effects in AAD that are likely independent of their antimicrobial effects. The specific responses that are suppressed are dependent upon the responses that dominate during AAD.
Combination Epigenetic Therapy Has Efficacy in Patients with Refractory Advanced Non–Small Cell Lung Cancer
Authors: Rosalyn A. Juergens, John Wrangle, Frank P. Vendetti, Sara C. Murphy, Ming Zhao, Barbara Coleman, Rosa Sebree, Kristen Rodgers, Craig M. Hooker, Noreli Franco, Beverly Lee, Salina Tsai, Igor Espinoza Delgado, Michelle A. Rudek, Steven A. Belinsky, James G. Herman, Stephen B. Baylin, Malcolm V. Brock, Charles M. Rudin
Journal: Cancer Discovery (2011)

Epigenetic alterations are strongly associated with the development of cancer. We conducted a phase I/II trial of combined epigenetic therapy with azacitidine and entinostat, inhibitors of DNA methylation and histone deacetylation, respectively, in extensively pretreated patients with recurrent metastatic non-small cell lung cancer. This therapy is well tolerated, and objective responses were observed, including a complete response and a partial response in a patient who remains alive and without disease progression approximately 2 years after completing protocol therapy. Median survival in the entire cohort was 6.4 months (95% CI 3.8-9.2), comparing favorably with existing therapeutic options. Demethylation of a set of 4 epigenetically silenced genes known to be associated with lung cancer was detectable in serial blood samples in these patients and was associated with improved progression-free (P = 0.034) and overall survival (P = 0.035). Four of 19 patients had major objective responses to subsequent anticancer therapies given immediately after epigenetic therapy.This study demonstrates that combined epigenetic therapy with low-dose azacitidine and entinostat results in objective, durable responses in patients with solid tumors and defines a blood-based biomarker that correlates with clinical benefit.
Fibrogenic Reactions in Lung Disease
Authors: Jun Araya, Stephen L. Nishimura
Journal: Annual Review of Pathology Mechanisms of Disease (2010)

Fibrogenic lung reactions occur as a common phenotype shared among disorders of heterogeneous etiologies. Even with a common etiology, the extent and pattern of fibrosis vary greatly among individuals, even within families, suggesting complex gene-environment interactions. The search for mechanisms shared among all fibrotic lung diseases would represent a major advance in the identification of therapeutic targets that could have a broad impact on lung health. Although it is difficult to grasp all of the complexities of the varied cell types and cytokine networks involved in lung fibrogenic responses, and to predict the biologic responses to the overexpression or deficiency of individual cytokines, a large body of evidence converges on a single common theme: the central importance of the transforming growth factor beta (TGF-beta) pathway. Therapies that act upstream or downstream of TGF-beta activation have the therapeutic potential to treat all fibrogenic responses in the lung.
The effects of fasting on metabolism and performance
Authors: R J Maughan, J Fallah, E F Coyle
Journal: British Journal of Sports Medicine (2010)

An overnight fast of 8–10 h is normal for most people. Fasting is characterised by a coordinated set of metabolic changes designed to spare carbohydrate and increase reliance on fat as a substrate for energy supply. As well as sparing the limited endogenous carbohydrate, and increased rate of gluconeogenesis from amino acids, glycerol and ketone bodies help maintain the supply of carbohydrate. Many individuals undergo periodic fasts for health, religious or cultural reasons. Ramadan fasting, involving 1 month of abstention from food and fluid intake during daylight hours, is practised by a large part of the world population. This period involves a shift in the pattern of intake from daytime to the hours of darkness. There seems to be little effect on overall daily dietary intake and only small metabolic effects, but there may be implications for both physical and cognitive function. The limited evidence suggests that effects of Ramadan-style fasting on exercise performance are generally small. This needs to be balanced, however, against the observation that small differences in performance are critical in determining the outcomes of sporting events. Studies involving challenging sporting events (prolonged sustained or intermittent high-intensity events, hot and humid environments) are needed. Increases in subjective sensations of fatigue may be the result of loss of sleep or disruption of normal sleep patterns. Modifications to the competition timetable may minimise or even eliminate any effect on performance in sport, but there may be negative effects on performance in some events.
Chromosomal Rearrangements as Barriers to Genetic Homogenization between Archaic and Modern Humans
Authors: Rebekah L. Rogers
Journal: Molecular Biology and Evolution (2015)

Chromosomal rearrangements, which shuffle DNA throughout the genome, are an important source of divergence across taxa. Using a paired-end read approach with Illumina sequence data for archaic humans, I identify changes in genome structure that occurred recently in human evolution. Hundreds of rearrangements indicate genomic trafficking between the sex chromosomes and autosomes, raising the possibility of sex-specific changes. Additionally, genes adjacent to genome structure changes in Neanderthals are associated with testis-specific expression, consistent with evolutionary theory that new genes commonly form with expression in the testes. I identify one case of new-gene creation through transposition from the Y chromosome to chromosome 10 that combines the 5' end of the testis-specific gene Fank1 with previously untranscribed sequence. This new transcript experienced copy number expansion in archaic genomes, indicating rapid genomic change. Among rearrangements identified in Neanderthals, 13% are transposition of selfish genetic elements, while 32% appear to be ectopic exchange between repeats. In Denisovan, the pattern is similar but numbers are significantly higher with 18% of rearrangements reflecting transposition and 40% ectopic exchange between distantly related repeats. There is an excess of divergent rearrangements relative to polymorphism in Denisovan, which might result from non-uniform rates of mutation, possibly reflecting a burst of TE activity in the lineage that led to Denisovan. Finally, loci containing genome structure changes show diminished rates of introgression from Neanderthals into modern humans, consistent with the hypothesis that rearrangements serve as barriers to gene flow during hybridization. Together, these results suggest that this previously unidentified source of genomic variation has important biological consequences in human evolution.
Promoter hypermethylation of MDR1 in tumor and serum DNA of invasive ductal breast carcinoma patients
Authors: gayatri sharma, Sameer Mirza, Rajindra Parshad, Siddhartha Gupta, Pranav Pandya, Ranju Ralhan
Journal: Clinical Cancer Research (2008)

B19    Purpose:  The appearance of tumor cells resistant to multiple anti cancer agents is a serious obstacle in cancer treatment. Such a multidrug resistance phenotype is often associated with increased expression of two representative ATP binding superfamily proteins,  MDR1  and  MRP . The expression of  MDR1  is one of the most critical molecular targets for drug sensitivity when many human cancer cells from tumor types are screened. Methylation at CpG sites on the  MDR1  promoter plays an important role in  MDR1  expression. The current study was designed to analyze the methylation status of this gene in sera of breast cancer patients and determine the correlation of promoter hypermethylation of this gene with chemotherapeutic resistance and disease recurrence.   Experimental design:  To test the hypothesis that promoter methylation of  MDR1  is associated with chemotherapeutic resistance and disease recurrence prognosis, the methylation status of this genes was analyzed in invasive ductal carcinoma tissues and corresponding sera of breast cancer patients and correlated with disease free survival of these patients.   Results:  The frequency of tumor hypermethylation is 58% in invasive breast cancer patients. There was concordance between DNA methylation in tumor and serum of each gene. Significant correlation was observed between promoter methylation of  MDR1  and hormonal receptor status (P MDR1  and disease recurrence.   Conclusion:  This study underscores the potential utility of DNA methylation based screening of serum as a surrogate for tumor DNA methylation as a tool for detection of chemotherapeutic response of breast cancer patients. Further studies in this direction involving larger patient base and gene panel may improve the significance of circulating tumor DNA in breast cancer management.
Adhesion molecule expression on epithelial cells infected with respiratory syncytial virus
Authors: S-Z. Wang, P.G. Hallsworth, K.D. Dowling, J.H Alpers, J.J. Bowden, K.D Forsyth
Journal: European Respiratory Journal (2000)

Respiratory epithelium is both a target and an effector of airway inflammation. Adhesion molecules on epithelium play an important role in a variety of airway diseases. Respiratory syncytial virus (RSV) is the most important pathogen for airway diseases in infants. The expression of adhesion molecules on epithelium in RSV infection, however, is unclear. The expression of selected adhesion molecules and major histocompatibility complex (MHC) class I and II antigens on a human alveolar type II epithelial cell line (A549) infected with RSV was investigated by means of flow cytometry and immunocytochemistry. The results showed that intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were expressed on A549 cells at a low level. E-cadherin and MHC class I antigen were constitutively expressed on the cells. RSV infection of A549 cells significantly upregulated the expression of ICAM-1, VCAM-1 and MHC class I and II antigens on these cells. RSV infection also altered the expression of E-cadherin on A549 cells. Immunostaining showed that E-cadherin was mainly upregulated around or in RSV-induced giant cells. These data suggest that respiratory syncytial virus infection of respiratory epithelial cells enhances the expression of adhesion molecules and major histocompatibility complex antigens. These changes may play an important role in the pathophysiology of respiratory syncytial virus disease.
Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans
Authors: Pervinder Sagoo, Esperanza Perucha, Birgit Sawitzki, Stefan Tomiuk, David A. Stephens, Patrick Miqueu, Stephanie Chapman, Ligia Craciun, Ruhena Sergeant, Sophie Brouard, Flavia Rovis, Elvira Jimenez, Amany Ballow, Magali Giral, Irene Rebollo-Mesa, Alain Le Moine, Cecile Braudeau, Rachel Hilton, Bernhard Gerstmayer, Katarzyna Bourcier, Adnan Sharif, Magdalena Krajewska, Graham M. Lord, Ian Roberts, Michel Goldman, Kathryn J. Wood, Kenneth Newell, Vicki Seyfert-Margolis, Anthony N. Warrens, Uwe Janssen, Hans-Dieter Volk, Jean-Paul Soulillou, Maria P. Hernandez-Fuentes, Robert I. Lechler
Journal: Journal of Clinical Investigation (2010)

Identifying transplant recipients in whom immunological tolerance is established or is developing would allow an individually tailored approach to their posttransplantation management. In this study, we aimed to develop reliable and reproducible in vitro assays capable of detecting tolerance in renal transplant recipients. Several biomarkers and bioassays were screened on a training set that included 11 operationally tolerant renal transplant recipients, recipient groups following different immunosuppressive regimes, recipients undergoing chronic rejection, and healthy controls. Highly predictive assays were repeated on an independent test set that included 24 tolerant renal transplant recipients. Tolerant patients displayed an expansion of peripheral blood B and NK lymphocytes, fewer activated CD4+ T cells, a lack of donor-specific antibodies, donor-specific hyporesponsiveness of CD4+ T cells, and a high ratio of forkhead box P3 to alpha-1,2-mannosidase gene expression. Microarray analysis further revealed in tolerant recipients a bias toward differential expression of B cell-related genes and their associated molecular pathways. By combining these indices of tolerance as a cross-platform biomarker signature, we were able to identify tolerant recipients in both the training set and the test set. This study provides an immunological profile of the tolerant state that, with further validation, should inform and shape drug-weaning protocols in renal transplant recipients.
Does This Adult Patient With Suspected Bacteremia Require Blood Cultures?
Authors: Bryan Coburn, Andrew M. Morris, George Tomlinson, Allan S. Detsky
Journal: JAMA (2012)

<h3>Context</h3>Clinicians order blood cultures liberally among patients in whom bacteremia is suspected, though a small proportion of blood cultures yield true-positive results. Ordering blood cultures inappropriately may be both wasteful and harmful.<h3>Objective</h3>To review the accuracy of easily obtained clinical and laboratory findings to inform the decision to obtain blood cultures in suspected bacteremia.<h3>Data Sources and Study Selection</h3>A MEDLINE and EMBASE search (inception to April 2012) yielded 35 studies that met inclusion criteria for evaluating the accuracy of clinical variables for bacteremia in adult immunocompetent patients, representing 4566 bacteremia and 25 946 negative blood culture episodes.<h3>Data Extraction</h3>Data were extracted to determine the prevalence and likelihood ratios (LRs) of findings for bacteremia.<h3>Data Synthesis</h3>The pretest probability of bacteremia varies depending on the clinical context, from low (eg, cellulitis: 2%) to high (eg, septic shock: 69%). Elevated temperatures alone do not accurately predict bacteremia (for ≥38°C [&gt;100.3°F], LR, 1.9 [95% CI, 1.4-2.4]; for ≥38.5°C [&gt;101.2°F], LR, 1.4 [95% CI, 1.1-2.0]), nor does isolated leukocytosis (LR, &lt;1.7). The severity of chills graded on an ordinal scale (shaking chills, LR, 4.7; 95% CI, 3.0-7.2) may be more useful. Both the systemic inflammatory response syndrome (SIRS) and a multivariable decision rule with major and minor criteria are sensitive (but not specific) predictors of bacteremia (SIRS, negative LR, 0.09 [95% CI, 0.03-0.26]; decision rule, negative LR, 0.08 [95% CI, 0.04-0.17]).<h3>Conclusions</h3>Blood cultures should not be ordered for adult patients with isolated fever or leukocytosis without considering the pretest probability. SIRS and the decision rule may be helpful in identifying patients who do not need blood cultures. These conclusions do not apply to immunocompromised patients or when endocarditis is suspected.