tbuckley/cabot-search huggingface dataset:
Designing Case-Control Studies: Decisions About the Controls
Authors: Susan E. Hodge, Ryan L. Subaran, Myrna M. Weissman, Abby J. Fyer
Journal: American Journal of Psychiatry (2012)

The authors quantified, first, the effect of misclassified controls (i.e., individuals who are affected with the disease under study but who are classified as controls) on the ability of a case-control study to detect an association between a disease and a genetic marker, and second, the effect of leaving misclassified controls in the study, as opposed to removing them (thus decreasing sample size). The authors developed an informativeness measure of a study's ability to identify real differences between cases and controls. They then examined this measure's behavior when there are no misclassified controls, when there are misclassified controls, and when there were misclassified controls but they have been removed from the study. The results show that if, for example, 10% of controls are misclassified, the study's informativeness is reduced to approximately 81% of what it would have been in a sample with no misclassified controls, whereas if these misclassified controls are removed from the study, the informativeness is only reduced to about 90%, despite the reduced sample size. If 25% are misclassified, those figures become approximately 56% and 75%, respectively. Thus, leaving the misclassified controls in the control sample is worse than removing them altogether. Finally, the authors illustrate how insufficient power is not necessarily circumvented by having an unlimited number of controls. The formulas provided by the authors enable investigators to make rational decisions about removing misclassified controls or leaving them in.
Why are long-acting beta-adrenoceptor agonists long-acting?
Authors: GP Anderson, A Linden, KF Rabe
Journal: European Respiratory Journal (1994)

The extended duration of bronchodilation due to formoterol and salmeterol greatly exceeds that of short acting beta 2-adrenoceptor agonists, such as salbutamol or terbutaline. This extended duration and their capacity to "reassert" airway smooth muscle relaxation in vitro despite repeated washing has prompted considerable debate on the underlying mechanism(s). The comparative pharmacology, and molecular modelling of these drugs and of the beta 2-adrenoceptor and its ligand binding core have cast doubt on the exosite/exoceptor model previously proposed to explain the behaviour of salmeterol. We present evidence supporting a unifying hypothesis that the duration of action both of formoterol and salmeterol is determined principally by their physicochemical interactions with membrane lipid bilayers (plasmalemma diffusion microkinetic model), rather than putative distinct exosite/exoceptor binding sites in or near the beta 2-adrenoceptor. This model provides a clearer understanding of the pharmacological profile of these drugs (rate of onset, duration, "reassertion", interaction with hydrophilic and hydrophobic beta 2-adrenoceptor antagonists), and explains why in human airway smooth muscle in vitro a true relaxation-concentration response may not exist for salmeterol.
Dendritic Cell Internalization of α-Galactosylceramide from CD8 T Cells Induces Potent Antitumor CD8 T-cell Responses
Authors: Dong Hoon Choi, Kwang Soon Kim, Se Hwan Yang, Doo Hyun Chung, Boyeong Song, Jonathan Sprent, Jae Ho Cho, Young Chul Sung
Journal: Cancer Research (2011)

Abstract Dendritic cells (DC) present α-galactosylceramide (αGalCer) to invariant T-cell receptor–expressing natural killer T cells (iNKT) activating these cells to secrete a variety of cytokines, which in turn results in DC maturation and activation of other cell types, including NK cells, B cells, and conventional T cells. In this study, we showed that αGalCer-pulsing of antigen-activated CD8 T cells before adoptive transfer to tumor-bearing mice caused a marked increase in donor T-cell proliferation, precursor frequency, and cytotoxic lymphocyte activity. This effect was interleukin (IL)-2 dependent and involved both natural killer T cells (NKT) and DCs, as mice lacking IL-2, NKTs, and DCs lacked any enhanced response to adoptively transferred αGalCer-loaded CD8 T cells. iNKT activation was mediated by transfer of αGalCer from the cell membrane of the donor CD8 T cells onto the αGalCer receptor CD1d which is present on host DCs. αGalCer transfer was increased by prior activation of the donor CD8 T cells and required AP-2–mediated endocytosis by host DCs. In addition, host iNKT cell activation led to strong IL-2 synthesis, thereby increasing expansion and differentiation of donor CD8 T cells. Transfer of these cells led to improved therapeutic efficacy against established solid tumors in mice. Thus, our findings illustrate how αGalCer loading of CD8 T cells after antigen activation in vitro may leverage the therapeutic potential of adoptive T-cell therapies. Cancer Res; 71(24); 7442–51. ©2011 AACR.
Myocardial Infarct Expansion and Matrix Metalloproteinase Inhibition
Authors: Rupak Mukherjee, Theresa A. Brinsa, Kathryn B. Dowdy, Amelia A. Scott, Julia M. Baskin, Anne M. Deschamps, Abigail S. Lowry, G. Patricia Escobar, David G. Lucas, William M. Yarbrough, Michael R. Zile, Francis G. Spinale
Journal: Circulation (2003)

A potential mechanism for left ventricular (LV) remodeling after myocardial infarction (MI) is activation of the matrix metalloproteinases (MMPs). This study examined the effects of MMP inhibition (MMPi) on regional LV geometry and MMP levels after MI.In pigs instrumented with radiopaque markers to measure regional myocardial geometry, MI was created by ligating the obtuse marginals of the circumflex artery. In the first study, pigs were randomized to MMPi (n=7; PD166793, 20 mg x kg(-1) x d(-1)) or MI only (n=7) at 5 days after MI, and measurements were performed at 2 weeks. Regional MI areas were equivalent at randomization and were increased in the MI-only group at 2 weeks after MI compared with the MMPi group. In the second study, pigs randomized to MMPi (n=9) or MI only (n=8) were serially followed up for 8 weeks. At 8 weeks after MI, LV end-diastolic dimension was lower with MMPi than in the MI-only group (4.7+/-0.1 versus 5.1+/-0.1 cm, P<0.05). Regional MI area was reduced with MMPi at 8 weeks after MI (1.3+/-0.1 versus 1.7+/-0.1 cm2, P<0.05). MMPi reduced ex vivo MMP proteolytic activity. In the MI region, membrane-type MMP levels were normalized and levels of the endogenous tissue inhibitor of MMPs (TIMP-1) were increased compared with normal levels with MMPi. These effects were not observed in the MI-only group.MMPi attenuated the degree of post-MI LV dilation and expansion of the infarct during the late phase of MI healing. In addition, exogenous MMPi caused region-specific modulation of certain MMP and TIMP species.
Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogenesis of classical Hodgkin lymphoma
Authors: Enrico Tiacci, Claudia Döring, Verena Brune, Carel J. M. van Noesel, Wolfram Klapper, Gunhild Mechtersheimer, Brunangelo Falini, Ralf Küppers, Martin-Leo Hansmann
Journal: Blood (2012)
Natural Killer T Cells Infiltrate Neuroblastomas Expressing the Chemokine CCL2
Authors: Leonid S. Metelitsa, Hong-Wei Wu, Hong Wang, Yujun Yang, Zamir Warsi, Shahab Asgharzadeh, Susan Groshen, S. Brian Wilson, Robert C. Seeger
Journal: The Journal of Experimental Medicine (2004)

CD1d-restricted Vα24-Jα18–invariant natural killer T cells (iNKTs) are potentially important in tumor immunity. However, little is known about their localization to tumors. We analyzed 98 untreated primary neuroblastomas from patients with metastatic disease (stage 4) for tumor-infiltrating iNKTs using TaqMan® reverse transcription polymerase chain reaction and immunofluorescent microscopy. 52 tumors (53%) contained iNKTs, and oligonucleotide microarray analysis of the iNKT+ and iNKT− tumors revealed that the former expressed higher levels of CCL2/MCP-1, CXCL12/SDF-1, CCL5/RANTES, and CCL21/SLC. Eight tested neuroblastoma cell lines secreted a range of CCL2 (0–21.6 ng/ml), little CXCL12 (≤0.1 ng/ml), and no detectable CCL5 or CCL21. CCR2, the receptor for CCL2, was more frequently expressed by iNKT compared with natural killer and T cells from blood (P &amp;lt; 0.001). Supernatants of neuroblastoma cell lines that produced CCL2 induced in vitro migration of iNKTs from blood of patients and normal adults; this was abrogated by an anti-CCL2 monoclonal antibody. CCL2 expression by tumors was found to inversely correlate with MYCN proto-oncogene amplification and expression (r = 0.5, P &amp;lt; 0.001), and MYCN-high/CCL2-low expression accurately predicted the absence of iNKTs (P &amp;lt; 0.001). In summary, iNKTs migrate toward neuroblastoma cells in a CCL2-dependent manner, preferentially infiltrating MYCN nonamplified tumors that express CCL2.
Symptom burden of sleep-disordered breathing in mild-to-moderate congestive heart failure patients
Authors: P. C. Hastings, A. Vazir, D. M. O'Driscoll, M. J. Morrell, A. K. Simonds
Journal: European Respiratory Journal (2006)

The symptom burden resulting from sleep-disordered breathing (SDB) in patients with mild-to-moderate congestive heart failure (CHF) is unclear. The current authors monitored 24-h activity levels and compared subjective and objective measures of daytime sleepiness in 39 CHF patients, New York Heart Association class 2-3, on optimal medication. A total of 22 patients were classified as SDB (apnoea/hypopnoea index (AHI) median (range) 22.3 (16.6-100) events.h-1), and 17 as no SDB (NoSDB; AHI 3.7 (0-12.3) events.h-1). SDB was defined as AHI>or=15 events.h-1. Patients were assessed by 24-h activity monitoring (actigraphy) for a period of up to 14 days, a single objective sleepiness test (Oxford Sleep Resistance test) and Epworth Sleepiness Scale. The duration of daytime activity was significantly shorter in the SDB group compared with the NoSDB group. The SDB group also had increased time in bed and poorer sleep quality, as shown by the fragmentation index. Objectively the SDB group when compared with the NoSDB group were significantly sleepier, subjectively the groups did not differ. The amount of napping was similar for both groups. Despite the lack of subjective symptoms of daytime sleepiness, congestive heart failure patients with sleep-disordered breathing were objectively sleepier during the day and had reduced daytime activity with longer periods in bed and poorer sleep quality when compared with those without sleep-disordered breathing.
Phase Ib dose-finding study of axitinib plus pembrolizumab in treatment-naïve patients with advanced renal cell carcinoma
Authors: Michael B Atkins, Shilpa Gupta, Toni K Choueiri, David F McDermott, Igor Puzanov, Jamal Tarazi, Stephen Keefe, Brad Rosbrook, Debasis Chakrabarti, Elizabeth R Plimack
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Axitinib, an inhibitor of vascular endothelial growth factor receptors (VEGFRs), is approved for second-line treatment of advanced renal cell carcinoma (aRCC). Pembrolizumab is a humanized monoclonal antibody that blocks binding of the immune-checkpoint receptor programmed death-1
Cough suppression during flexible bronchoscopy using combined sedation with midazolam and hydrocodone: a randomised, double blind, placebo controlled trial
Authors: D Stolz
Journal: Thorax (2004)

<b>Background:</b> Current British Thoracic Society guidelines do not recommend routinely the combined use of a benzodiazepine and opiate during flexible bronchoscopy (FB). A randomised, placebo controlled, double blind study was undertaken to determine whether hydrocodone in combination with midazolan improves cough suppression during FB without increasing the risk of desaturation. <b>Methods:</b> 120 patients were randomised to receive midazolam and 5 mg IV hydrocodone or midazolam and placebo with topical anaesthesia. Pulse oximetry was recorded continuously during FB. Bronchoscopists and nurses charted their perception of cough and the patients rated their discomfort during the procedure on a 10 cm visual analogue scale (VAS). <b>Results:</b> There was no significant difference between the two groups with regard to the indication for FB, duration of procedure (21 (11) min <i>v</i> 22 (10) min, p = 0.570), doses of supplemental lignocaine (171 (60) mg <i>v</i> 173 (66) mg, p = 0.766) and midazolam (4.5 (2.3) mg <i>v</i> 4.9 (2.7) mg, p = 0.309), lowest oxygen saturation (94.8 (2.7) <i>v</i> 94.9 (2.7), p = 0.433), and desaturations ⩽90%. Perception of cough by both the bronchoscopist and the nurse was significantly lower in the hydrocodone group (3 (0–10) and 3 (0–10)) than in the placebo group (6 (0–10) and 6 (0–10)), respectively (p = 0.001). According to the VAS scale, patients' tolerance was also significantly better with hydrocodone than with placebo (2 (0–8) <i>v</i> 3 (0–9), p = 0.043). <b>Conclusion:</b> The combination of midazolam and hydrocodone markedly reduces cough during FB without causing significant desaturation, especially when invasive diagnostic procedures are performed.
Null Mutation of Connexin43 Causes Slow Propagation of Ventricular Activation in the Late Stages of Mouse Embryonic Development
Authors: Dhananjay Vaidya, Houman S. Tamaddon, Cecilia W. Lo, Steven M. Taffet, Mario Delmar, Gregory E. Morley, José Jalife
Journal: Circulation Research (2001)

Connexin43 (Cx43) is the principal connexin isoform in the mouse ventricle, where it is thought to provide electrical coupling between cells. Knocking out this gene results in anatomic malformations that nevertheless allow for survival through early neonatal life. We examined electrical wave propagation in the left (LV) and right (RV) ventricles of isolated Cx43 null mutated (Cx43(-/-)), heterozygous (Cx43(+/)(-)), and wild-type (WT) embryos using high-resolution mapping of voltage-sensitive dye fluorescence. Consistent with the compensating presence of the other connexins, no reduction in propagation velocity was seen in Cx43(-/-) ventricles at postcoital day (dpc) 12.5 compared with WT or Cx43(+/)(-) ventricles. A gross reduction in conduction velocity was seen in the RV at 15.5 dpc (in cm/second, mean [1 SE confidence interval], WT 9.9 [8.7 to 11.2], Cx43(+/)(-) 9.9 [9.0 to 10.9], and Cx43(-/-) 2.2 [1.8 to 2.7; P<0.005]) and in both ventricles at 17.5 dpc (in RV, WT 8.4 [7.6 to 9.3], Cx43(+/)(-) 8.7 [8.1 to 9.3], and Cx43(-/-) 1.1 [0.1 to 1.3; P<0.005]; in LV, WT 10.1 [9.4 to 10.7], Cx43(+/)(-) 8.3 [7.8 to 8.9], and Cx43(-/-) 1.7 [1.3 to 2.1; P<0.005]) corresponding with the downregulation of Cx40. Cx40 and Cx45 mRNAs were detectable in ventricular homogenates even at 17.5 dpc, probably accounting for the residual conduction function. Neonatal knockout hearts were arrhythmic in vivo as well as ex vivo. This study demonstrates the contribution of Cx43 to the electrical function of the developing mouse heart and the essential role of this gene in maintaining heart rhythm in postnatal life.
Family history and molecular features of children, adolescents, and young adults with colorectal carcinoma
Authors: C Durno
Journal: Gut (2005)

Colorectal cancer is extremely rare in childhood. Published case series reporting children and adolescents with colorectal cancer have not focused on the underlying genetic aspects of the tumour or genetic susceptibility of the families.We examined a cohort of patients with early onset colorectal cancer to determine whether a specific genetic predisposition could be elucidated. In particular, we focused on whether DNA mismatch repair gene deficiency which causes hereditary non-polyposis colorectal cancer (HNPCC) could be elucidated.Patients with colorectal cancer </=24 years of age were identified from a database at the Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital, Toronto. Detailed pedigrees were ascertained from the proband or parents. Tumours were tested for microsatellite instability, a hallmark of HNPCC. Germline mismatch repair gene mutations (MSH2 and MLH1) were sought in some cases. Clinical data were obtained by chart audit.Among 1382 probands in our registry, 16 (1%) colorectal cancer patients were 24 years or younger at the time of diagnosis. Microsatellite instability was identified in tumours from eight (73%) of 11 evaluated patients. Germline mutations in mismatch repair genes were identified in six of 12 patients, including MSH2 (n = 3), MLH1 (n = 2), and PMS2 (n = 1). Ten (63%) of 16 families met the Amsterdam criteria for HNPCC. Among these, six were screened for mismatch repair gene mutations and three were found to carry MSH2 or MLH1 germline mutations. Location of the colorectal cancers included rectum/sigmoid (n = 9), splenic flexure (n = 2), hepatic flexure (n = 3), and caecum (n = 2). Forty four per cent (7/16) of these young cases developed additional malignancies (gastrointestinal (n = 8) and extraintestinal (n = 4)) during follow up (mean 12.8 (SD 12.4) years (range 0.08-30)).Patients with early onset colorectal carcinoma often have an inherited predisposition to the disease. Tumours with high frequency microsatellite instability and germline mutations of mismatch repair genes are sufficiently common in this patient population that they should be considered, even though family histories may not satisfy the stringent Amsterdam criteria for HNPCC. Young colorectal cancer patients are at increased risk of developing second gastrointestinal and extraintestinal malignancies.
Antiinflammatory Effects of Angiotensin II Subtype 1 Receptor Blockade in Hypertensive Patients With Microinflammation
Authors: Danilo Fliser, Konrad Buchholz, Hermann Haller
Journal: Circulation (2004)

Experimental studies revealed proinflammatory properties of angiotensin II. We evaluated antiinflammatory effects of the angiotensin II subtype 1 receptor antagonist olmesartan medoxomil alone and in cotherapy with the HMG-CoA reductase inhibitor pravastatin in patients with essential hypertension and microinflammation.We measured a panel of vascular inflammation markers, including high-sensitivity C-reactive protein, and lipid levels during 12 weeks of therapy with olmesartan (n=100) or placebo (n=99) in a prospective double-blind multicenter study. Pravastatin was added to the double-blind therapy at week 6 in both treatment arms. Blood pressure control was achieved with addition of hydrochlorothiazide. Olmesartan treatment had already significantly reduced serum levels of high-sensitivity C-reactive protein (-15.1%; P<0.05), high-sensitivity tumor necrosis factor-alpha (-8.9%; P<0.02), interleukin-6 (-14.0%; P<0.05), and monocyte chemotactic protein-1 (-6.5%; P<0.01) after 6 weeks of therapy, whereas placebo treatment (ie, blood pressure reduction) had no major effect on inflammation markers. After 12 weeks of therapy, high-sensitivity C-reactive protein (-21.1%; P<0.02), high-sensitivity tumor necrosis factor-alpha (-13.6%; P<0.01), and interleukin-6 (-18.0%; P<0.01) decreased further with olmesartan and pravastatin cotherapy, but treatment with pravastatin alone (ie, cotherapy with placebo) did not significantly alter inflammation markers. In contrast, addition of pravastatin led to a significant (P<0.001) reduction in LDL cholesterol serum concentrations in the olmesartan and placebo treatment groups (-15.1% and -12.1%, respectively).Angiotensin II receptor blockade significantly reduces vascular microinflammation in patients with essential hypertension by as early as week 6 of therapy. This antiinflammatory action of angiotensin II receptor antagonists may contribute to their beneficial cardiovascular effects.
LOH in the HLA Class I Region at 6p21 Is Associated with Shorter Survival in Newly Diagnosed Adult Glioblastoma
Authors: Jacky T. Yeung, Ronald L. Hamilton, Koji Ohnishi, Maki Ikeura, Douglas M. Potter, Marina N. Nikiforova, Soldano Ferrone, Regina I. Jakacki, Ian F. Pollack, Hideho Okada
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Glioblastoma (GBM) shows downregulated expression of human leukocyte antigen (HLA) class I, thereby escaping from cytotoxic T cells and limiting the efficacy of immunotherapy. Loss of heterozygosity (LOH) of HLA class I (6p21) and/or β-2 microglobulin (B2m) (15q21) regions represents irreversible downregulation. In this study, we examined the prevalence of these LOH events and their relations with overall survival in GBM. Experimental Design: In a cross-sectional analysis on 60 adult patients with GBM, DNA from formalin-fixed, paraffin-embedded specimens were evaluated for 10 microsatellite regions of HLA class I, B2m, HLA class II, HLA class III, and 6q by PCR as well as immunohistochemical evaluation of HLA class I expression and CD8+ T-cell infiltration. Results: LOH in HLA class I, B2m, HLA class II, HLA class III, and 6q regions was present in 41.4%, 18.2%, 9.4%, 77.8%, and 36.0% of informative cases, respectively. LOH of HLA class I was associated with shorter overall survival (HR = 4.89, P = 0.0078). HLA class I was downregulated in 22% to 43% of cases based on immunohistochemistry. Cases that displayed negative staining were significantly younger. HLA class I expression correlated with intratumoral CD8+ T-cell infiltration. Conclusion: LOH in the HLA class I region is frequent in adult GBMs. The association of shorter survival with LOH in this region suggests a crucial role for these genes in immunosurveillance. Clin Cancer Res; 19(7); 1816–26. ©2013 AACR.
Mechanism of the Attenuation of Proteolysis-Inducing Factor Stimulated Protein Degradation in Muscle by β-Hydroxy-β-Methylbutyrate
Authors: Helen J. Smith, Stacey M. Wyke, Michael J. Tisdale
Journal: Cancer Research (2004)

The leucine metabolite beta-hydroxy-beta-methylbutyrate (HMB) prevents muscle protein degradation in cancer-induced weight loss through attenuation of the ubiquitin-proteasome proteolytic pathway. To investigate the mechanism of this effect, the action of HMB on protein breakdown and intracellular signaling leading to increased proteasome expression by the tumor factor proteolysis-inducing factor (PIF) has been studied in vitro using murine myotubes as a surrogate model of skeletal muscle. A comparison has been made of the effects of HMB and those of eicosapentaenoic acid (EPA), a known inhibitor of PIF signaling. At a concentration of 50 mumol/L, EPA and HMB completely attenuated PIF-induced protein degradation and induction of the ubiquitin-proteasome proteolytic pathway, as determined by the "chymotrypsin-like" enzyme activity, as well as protein expression of 20S proteasome alpha- and beta-subunits and subunit p42 of the 19S regulator. The primary event in PIF-induced protein degradation is thought to be release of arachidonic acid from membrane phospholipids, and this process was attenuated by EPA, but not HMB, suggesting that HMB might act at another step in the PIF signaling pathway. EPA and HMB at a concentration of 50 mumol/L attenuated PIF-induced activation of protein kinase C and the subsequent degradation of inhibitor kappaBalpha and nuclear accumulation of nuclear factor kappaB. EPA and HMB also attenuated phosphorylation of p42/44 mitogen-activated protein kinase by PIF, thought to be important in PIF-induced proteasome expression. These results suggest that HMB attenuates PIF-induced activation and increased gene expression of the ubiquitin-proteasome proteolytic pathway, reducing protein degradation.
Preclinical and clinical evaluation of four gemcitabine plus carboplatin schedules as front-line treatment for stage IVnon-small-cell lung cancer
Authors: E. Bajetta, S.C. Stani, D. De Candis, N. Zaffaroni, N. Zilembo, D. Cortinovis, S. Aglione, L. Mariani, B. Formisano, P. Bidoli
Journal: Annals of Oncology (2003)