tbuckley/cabot-search huggingface dataset:
Inhibition of telomerase activity preferentially targets aldehyde dehydrogenase-positive cancer stem-like cells in lung cancer
Authors: Diego Serrano, Anne-Marie Bleau, Ignacio Fernandez-Garcia, Tamara Fernandez-Marcelo, Pilar Iniesta, Carlos Ortiz-de-Solorzano, Alfonso Calvo
Journal: Molecular Cancer (2011)

Mortality rates for advanced lung cancer have not declined for decades, even with the implementation of novel chemotherapeutic regimens or the use of tyrosine kinase inhibitors. Cancer Stem Cells (CSCs) are thought to be responsible for resistance to chemo/radiotherapy. Therefore, targeting CSCs with novel compounds may be an effective approach to reduce lung tumor growth and metastasis. We have isolated and characterized CSCs from non-small cell lung cancer (NSCLC) cell lines and measured their telomerase activity, telomere length, and sensitivity to the novel telomerase inhibitor MST312.The aldehyde dehydrogenase (ALDH) positive lung cancer cell fraction is enriched in markers of stemness and endowed with stem cell properties. ALDH+ CSCs display longer telomeres than the non-CSC population. Interestingly, MST312 has a strong antiproliferative effect on lung CSCs and induces p21, p27 and apoptosis in the whole tumor population. MST312 acts through activation of the ATM/pH2AX DNA damage pathway (short-term effect) and through decrease in telomere length (long-term effect). Administration of this telomerase inhibitor (40 mg/kg) in the H460 xenograft model results in significant tumor shrinkage (70% reduction, compared to controls). Combination therapy consisting of irradiation (10Gy) plus administration of MST312 did not improve the therapeutic efficacy of the telomerase inhibitor alone. Treatment with MST312 reduces significantly the number of ALDH+ CSCs and their telomeric length in vivo.We conclude that antitelomeric therapy using MST312 mainly targets lung CSCs and may represent a novel approach for effective treatment of lung cancer.
Effect of Varenicline on Smoking Cessation Through Smoking Reduction
Authors: Jon O. Ebbert, John R. Hughes, Robert J. West, Stephen I. Rennard, Cristina Russ, Thomas D. McRae, Joan Treadow, Ching-Ray Yu, Michael P. Dutro, Peter W. Park
Journal: JAMA (2015)

Some cigarette smokers may not be ready to quit immediately but may be willing to reduce cigarette consumption with the goal of quitting.To determine the efficacy and safety of varenicline for increasing smoking abstinence rates through smoking reduction.Randomized, double-blind, placebo-controlled, multinational clinical trial with a 24-week treatment period and 28-week follow-up conducted between July 2011 and July 2013 at 61 centers in 10 countries. The 1510 participants were cigarette smokers who were not willing or able to quit smoking within the next month but willing to reduce smoking and make a quit attempt within the next 3 months. Participants were recruited through advertising.Twenty-four weeks of varenicline titrated to 1 mg twice daily or placebo with a reduction target of 50% or more in number of cigarettes smoked by 4 weeks, 75% or more by 8 weeks, and a quit attempt by 12 weeks.Primary efficacy end point was carbon monoxide-confirmed self-reported abstinence during weeks 15 through 24. Secondary outcomes were carbon monoxide-confirmed self-reported abstinence for weeks 21 through 24 and weeks 21 through 52.The varenicline group (n = 760) had significantly higher continuous abstinence rates during weeks 15 through 24 vs the placebo group (n = 750) (32.1% for the varenicline group vs 6.9% for the placebo group; risk difference (RD), 25.2% [95% CI, 21.4%-29.0%]; relative risk (RR), 4.6 [95% CI, 3.5-6.1]). The varenicline group had significantly higher continuous abstinence rates vs the placebo group during weeks 21 through 24 (37.8% for the varenicline group vs 12.5% for the placebo group; RD, 25.2% [95% CI, 21.1%-29.4%]; RR, 3.0 [95% CI, 2.4-3.7]) and weeks 21 through 52 (27.0% for the varenicline group vs 9.9% for the placebo group; RD, 17.1% [95% CI, 13.3%-20.9%]; RR, 2.7 [95% CI, 2.1-3.5]). Serious adverse events occurred in 3.7% of the varenicline group and 2.2% of the placebo group (P = .07).Among cigarette smokers not willing or able to quit within the next month but willing to reduce cigarette consumption and make a quit attempt at 3 months, use of varenicline for 24 weeks compared with placebo significantly increased smoking cessation rates at the end of treatment, and also at 1 year. Varenicline offers a treatment option for smokers whose needs are not addressed by clinical guidelines recommending abrupt smoking cessation.clinicaltrials.gov Identifier: NCT01370356.
MARKERS FOR PREDICTING THE DEVELOPMENT OF ACUTE RESPIRATORY DISTRESS SYNDROME
Authors: Kevin G. Connelly, MD, John E. Repine, MD
Journal: Annual Review of Medicine (1997)

▪ Abstract The acute respiratory distress syndrome (ARDS) is a relatively common, inflammatory lung disorder that is associated with major morbidity and high mortality. The pathogenesis of ARDS is complex, and unfortunately, the development of ARDS in an individual patient is difficult to anticipate. In this chapter, we outline the rationale for why accurately predicting the development of ARDS would be valuable. We also review the accumulated data on approaches for predicting ARDS and discuss the potential difficulties in establishing predictive markers.
Quantitative Morphology of the Cerebellum and Fourth Ventricle in Childhood-Onset Schizophrenia
Authors: Leslie K. Jacobsen, Jay N. Giedd, Patrick C. Berquin, Amy L. Krain, Susan D. Hamburger, Sanjiv Kumra, Judith L. Rapoport
Journal: American Journal of Psychiatry (1997)

OBJECTIVE: Studies have suggested that the maldeveloped neural circuitry producing schizophrenic symptoms may include the cerebellum. The authors found further support for this hypothesis by examining cerebellar morphology in severely ill children and adolescents with childhood-onset schizophrenia. METHOD: Anatomic brain scans were acquired with a 1.5-T magnetic resonance imaging scanner for 24 patients (mean age=14.1 years, SD=2.2) with onset of schizophrenia by age 12 (mean age at onset=10.0 years, SD=1.9) and 52 healthy children. Volumes of the vermis, inferior posterior lobe, fourth ventricle, and total cerebellum and the midsagittal area of the vermis were measured manually. RESULTS: After adjustment for total cerebral volume, the volume of the vermis and the midsagittal area and volume of the inferior posterior lobe remained significantly smaller in the schizophrenic patients. There was no group difference in total cerebellar or fourth ventricle volume. CONCLUSIONS: These findings are consistent with observations of small vermal size in adult schizophrenia and provide further support for abnormal cerebellar function in childhood- and adult-onset schizophrenia. (Am J Psychiatry 1997; 154:1663–1669)
Functional diffusion maps (fDMs) evaluated before and after radiochemotherapy predict progression-free and overall survival in newly diagnosed glioblastoma
Authors: B. M. Ellingson, T. F. Cloughesy, T. Zaw, A. Lai, P. L. Nghiemphu, R. Harris, S. Lalezari, N. Wagle, K. M. Naeini, J. Carrillo, L. M. Liau, W. B. Pope
Journal: Neuro-Oncology (2012)

Functional diffusion mapping (fDM) has shown promise as a sensitive imaging biomarker for predicting survival in initial studies consisting of a small number of patients, mixed tumor grades, and before routine use of anti-angiogenic therapy. The current study tested whether fDM performed before and after radiochemotherapy could predict progression-free and overall survival in 143 patients with newly diagnosed glioblastoma from 2007 through 2010, many treated with anti-angiogenic therapy after recurrence. Diffusion and conventional MRI scans were obtained before and 4 weeks after completion of radiotherapy and concurrent temozolomide treatment. FDM was created by coregistering pre- and posttreatment apparent diffusion coefficient (ADC) maps and then performing voxel-wise subtraction. FDMs were categorized according to the degree of change in ADC in pre- and posttreatment fluid-attenuated inversion recovery (FLAIR) and contrast-enhancing regions. The volume fraction of fDM-classified increasing ADC(+), decreasing ADC(-), and change in ADC(+/-) were tested to determine whether they were predictive of survival. Both Bonferroni-corrected univariate log-rank analysis and Cox proportional hazards modeling demonstrated that patients with decreasing ADC in a large volume fraction of pretreatment FLAIR or contrast-enhancing regions were statistically more likely to progress earlier and expire sooner than in patients with a lower volume fraction. The current study supports the hypothesis that fDM is a sensitive imaging biomarker for predicting survival in glioblastoma.
Relative risk of dysplasia for patients with intestinal metaplasia in the distal oesophagus and in the gastric cardia
Authors: P Sharma
Journal: Gut (2000)

<h3>BACKGROUND</h3> Biopsy specimens obtained from the gastro-oesophageal junction can reveal intestinal metaplasia in patients presenting for routine upper endoscopy. The site of biopsy may play a critical role in determining the dysplasia risk of a patient. <h3>AIMS</h3> To evaluate prospectively the dysplasia risk in patients with intestinal metaplasia of the distal oesophagus or within the gastric cardia. <h3>METHODS</h3> Patients with short segment Barrett9s oesophagus (SSBO) and cardia intestinal metaplasia (CIM) were followed prospectively. <h3>RESULTS</h3> 177 patients with SSBO were identified (mean age 62 years, range 38–82; 91% whites). Twenty prevalence cases of dysplasia in SSBO were detected: 17 low grade dysplasia (LGD), three high grade dysplasia (HGD). Seventy six patients with CIM were identified (mean age 67 years, range 37–81; 81% whites). A single prevalence case of LGD in CIM was detected. During follow up of 78 SSBO and 34 CIM patients, dysplasia developed in nine (seven LGD, two HGD) with SSBO and in one (LGD) with CIM. There were significant differences between the two groups with respect to age, ethnicity, dysplasia prevalence, and incidence. Time to dysplasia progression was significantly longer in CIM compared with SSBO patients. Of the five patients with SSBO and HGD, one developed adenocarcinoma of the oesophagus on follow up. No HGD or cancers have been detected over this time period in CIM patients. <h3>CONCLUSIONS</h3> The dysplasia risk is significantly greater in SSBO than in CIM patients, indicating two potentially different clinical processes. Future studies should separate SSBO from CIM in order to enhance the understanding of the pathophysiology and malignant potential of each entity.
Glomerular filtration rate measurements in clinical trials. Modification of Diet in Renal Disease Study Group and the Diabetes Control and Complications Trial Research Group.
Authors: A S Levey, T Greene, M D Schluchter, P A Cleary, P E Teschan, R A Lorenz, M E Molitch, W E Mitch, C Siebert, P M Hall
Journal: Journal of the American Society of Nephrology (1993)

To assess the utility and precision of GFR measurements in multicenter trials, the test performance and variability of GFR were analyzed in 2,250 patients enrolled in 44 clinical centers participating in either the Modification of Diet in Renal Disease (MDRD) Study or the Diabetes Control and Complications Trial (DCCT). GRF was measured as the renal clearance of [125I]iothalamate after an sc injection without epinephrine. The studies used similar protocols for obtaining blood and urine, training clinical center staff, and processing specimens in central laboratories. The performance of GFR measurements, assessed from adherence to protocol and quality control analyses, was excellent. The variability among the four clearance periods (intratest coefficient of variation [CV]) was acceptable; the median intratest CV for GFR was 9.4% in the MDRD Study and 11.7% in the DCCT. The pattern of decline in serum counts was better approximated by an exponential rather than a linear relationship. The cause of the intratest variability in GFR measurements was explored by univariate and multivariate analysis. The intratest CV was highest at the extremes of GFR. Among patients with a high GFR (> 90 mL/min per 1.73 m2), most of whom were participants in the DCCT, the higher intratest GFR was due, in part, to a systematic decline in GFR during the test. Among patients with a very low GFR (< 13 mL/min per 1.73 m2), technical difficulties in urine collections contributed substantially to the higher intratest CV. Other patient characteristics, including age, gender, weight, serum glucose, renal diagnosis, and use of diuretics, were not strongly correlated with the intratest CV. The precision of GFR measurements was assessed from the variability from measurement to measurement (interest CV). Among MDRD Study subjects, in whom two measurements of GFR were performed over a 3-month interval, the median interest CV was relatively low (6.3%) and was only weakly related to the intratest CV. Thus, GFR measurements are reasonably precise, even if the intratest CV is high. Given the relatively high intratest CV that is characteristic of GFR measurements, the estimate of GFR in an individual is more precise if multiple clearance periods, rather than a single period, are included. Similarly, the estimate of mean GFR for a population is also more precise if multiple clearance periods are included. In conclusion, by the use of standardized methods, an acceptable precision of GFR results can be obtained in multicenter trials. The same methods can be applied in clinical practice.(ABSTRACT TRUNCATED AT 400 WORDS)
Serum Levels of the Adipokine Chemerin in Relation to Renal Function
Authors: Dörte Pfau, Anette Bachmann, Ulrike Lössner, Jürgen Kratzsch, Matthias Blüher, Michael Stumvoll, Mathias Fasshauer
Journal: Diabetes Care (2009)

OBJECTIVE To investigate serum levels of the adipokine chemerin in patients on chronic hemodialysis (CD) as compared with control patients with a glomerular filtration rate (GFR) &amp;gt;50 ml/min. RESEARCH DESIGN AND METHODS Chemerin was quantified by ELISA in control patients (n = 60) and CD patients (n = 60) and correlated with clinical and biochemical measures of renal function, glucose, and lipid metabolism, as well as inflammation, in both groups. RESULTS Median serum chemerin levels were more than twofold higher in CD patients (542.2 μg/l) compared with subjects with a GFR &amp;gt;50 ml/min (254.3 μg/l) (P &amp;lt; 0.001). Furthermore, GFR, as assessed by the original Modification of Diet in Renal Disease formula, independently predicted circulating chemerin concentrations in multiple regression analyses in both control patients (P &amp;lt; 0.05) and CD patients (P &amp;lt; 0.01). CONCLUSIONS We demonstrate that markers of renal function are independently related to circulating chemerin levels.
Thymopoietin and levamisole in chronic granulomatous inflammation
Authors: P. A. Thrower, A. D. Sedgwick, E. R. Smith, D. A. Willoughby, E. C. Huskisson
Journal: Annals of the Rheumatic Diseases (1983)

Two animal models were used to investigate the mode of action of levamisole and thymopoietin. Neither compound influenced the subcutaneous carrageenan air pouch. While thymopoietin inhibited the formation of cotton pellet granulomas, levamisole enhanced it. This supports the conclusions of clinical studies reported elsewhere that levamisole and thymopoietin do not act in the same way in rheumatoid arthritis.
Murine thymic CD4+ T cell subsets: a subset (Thy0) that secretes diverse cytokines and overexpresses the V beta 8 T cell receptor gene family.
Authors: K Hayakawa, B T Lin, R R Hardy
Journal: The Journal of Experimental Medicine (1992)

We demonstrate here the presence of a distinct mature CD4+8- T cell subset in mouse thymus. This subset, termed "Thy0," is delineated by the absence of 3G11 expression from about half of the 6C10-/HSAlow/- fraction of CD4+8- thymic cells. Thy0 is detectable from the neonatal period and largely contributes the Th0-type diverse cytokine production previously reported for the HSAlow/-CD4+ thymic population. Further, cells expressing the T cell receptor V beta 8 gene family are found at increasing frequency in Thy0 with age, comprising 40-60% of Thy0 in adult BALB/c mice. This alteration of V beta 8+ cell frequency is unique to Thy0, since no other CD4+ subset in thymus or spleen shows such V beta 8 overusage. All functional CD4+ T cell subsets, including Thy0, show appropriate V beta clonal deletion associated with endogenous superantigens. Thus, it appears that Thy0 is an intrathymically generated secondary cell subset produced after CD4+ T cell selection.
Adverse Events with 4 Months of Rifampin Therapy or 9 Months of Isoniazid Therapy for Latent Tuberculosis Infection
Authors: Dick Menzies, Richard Long, Anete Trajman, Marie-Jose Dion, Jae Yang, Hamdan Al Jahdali, Ziad Memish, Kamran Khan, Michael Gardam, Vernon Hoeppner, Andrea Benedetti, Kevin Schwartzman
Journal: Annals of Internal Medicine (2008)

Background: Treatment of latent tuberculosis infection with isoniazid for 9 months is complicated by poor patient adherence and the need for close follow-up of side effects, especially hepatotoxicity. Shorter and safer regimens are needed. Objective: To compare the frequency of adverse events and treatment completion in 2 treatment regimens for latent tuberculosis infection. Design: Multicenter, randomized, open-label trial. Setting: Tuberculosis clinics located in university hospitals in Canada, Brazil, and Saudi Arabia. Patients: 847 patients without a contraindication for rifampin and requiring treatment for latent tuberculosis infection. Intervention: Four months of daily rifampin therapy or 9 months of daily isoniazid therapy. Measurements: Grade 3 to 4 drug-related adverse events resulting in drug discontinuation (primary outcome), and on-time treatment completion, grade 1 to 2 drug-related adverse events, and changes in liver enzymes and hematologic variables (secondary outcomes). Results: Seventeen of 422 participants who started isoniazid therapy developed grade 3 to 4 adverse events compared with 7 of 418 who started rifampin therapy (risk difference [rifampin minus isoniazid], 2.3% [95% CI, 5% to 0.1%]; P= 0.040). Grade 3 or 4 hepatitis occurred in 16 of 422 isoniazid recipients compared with 3 of 418 rifampin recipients (risk difference, 3.1% [CI, 5% to 1%]; P= 0.003). Grade 1 or 2 adverse events attributed to study drugs occurred with similar frequency. Asymptomatic reduction in platelet and leukocyte counts were more frequent in rifampin recipients. More patients completed rifampin treatment (78%) than isoniazid treatment (60%) (difference, 18% [CI, 12% to 24%]; P< 0.001]). Limitation: The study did not measure efficacy, and the open-label design may increase the chance of bias in ascertainment of adverse events. Conclusion: Treatment of latent tuberculosis with 4 months of rifampin leads to fewer serious adverse events and better adherence than 9 months of isoniazid. These findings justify a large-scale trial to compare the efficacy of rifampin with that of isoniazid.
An Organ Culture Method for Adult Colon From Germfree and Conventional Mice: Effects of Donor Age and Carcinogen Treatment on Epithelial Mitotic Activity
Authors: Elizabeth A. Defries, L. M. Franks
Journal: JNCI Journal of the National Cancer Institute (1977)

An organ culture system by which adult mouse colon epithelium could be maintained in a modified form for several weeks was described. The effects of donor age and carcinogen pretreatment were studied as a preliminary to proposed experiments on the effect of carcinogen treatment in vitro on colon epithelium from mice of different ages. Mitotic activity was compared in explants of colon from germfree C57BL mice 5 weeks, 5 months, and 9 months old; no differences were detected. The effect of old age on mitotic activity was not studied, since colon epithelium from old (30 mo) conventional mice could not be maintained in culture. Colon explants from conventional mice that had been pretreated for 32 weeks with weekly doses of a carcinogen, 1,2-dimethylhydrazine, appeared to have a higher potential for mitotic activity in vitro than did those from age-matched, untreated controls, but the difference was only significant at the 10% level. The epithelial cells were normal in ultrastructure, and the method may be valuable for studies of the direct effects of substances on adult colon epithelium.
Escaping High Viral Load Exhaustion
Authors: Stephanie Reignat, George J.M. Webster, David Brown, Graham S. Ogg, Abigail King, Suranjith L. Seneviratne, Geoff Dusheiko, Roger Williams, Mala K. Maini, Antonio Bertoletti
Journal: The Journal of Experimental Medicine (2002)

Deletion, anergy, and a spectrum of functional impairments can affect virus-specific CD8 cells in chronic viral infections. Here we characterize a low frequency population of CD8 cells present in chronic hepatitis B virus (HBV) infection which survive in the face of a high quantity of viral antigen. Although they do not appear to exert immunological pressure in vivo, these CD8 cells are not classically “tolerant” since they proliferate, lyse, and produce antiviral cytokines in vitro. They are characterized by altered HLA/peptide tetramer reactivity, which is not explained by TCR down-regulation or reduced functional avidity and which can be reversed with repetitive stimulation. CD8 cells with altered tetramer binding appear to have a specificity restricted to envelope antigen and not to other HBV antigens, suggesting that mechanisms of CD8 cell dysfunction are differentially regulated according to the antigenic form and presentation of individual viral antigens.
A Genotype-Phenotype Examination of Cyclin D1 on Risk and Outcome of Squamous Cell Carcinoma of the Head and Neck
Authors: Carmen J. Marsit, Candice C. Black, Marshall R. Posner, Karl T. Kelsey
Journal: Clinical Cancer Research (2008)

The variant allele of CCND1 G870A encodes a splice variant of the cyclin D1 protein, which possesses an increased half-life. To confirm the phenotypic effect of the variant allele, we examined the immunohistochemical staining pattern of the protein in tumors from a case population of head and neck squamous cell carcinoma (HNSCC) and compared it with the genotype of these individuals. We also examined how this genotype was associated with the risk of HNSCC and if this genotype-phenotype association was related to patient outcome. In a population-based case-control study of 698 cases and 777 controls, we both genotyped all participants for the CCND1 gene and did immunohistochemical staining of the cyclin D1 protein in the HNSCC tumors. The variant AA genotype was significantly associated with positive immunohistochemical staining (P < 0.02), and this variant genotype was associated with a significantly elevated odds ratio of 1.5 (95% confidence interval, 1.1-2.0) for HNSCC overall, with risk greatest in oral and laryngeal sites. Positive immunohistochemical staining was inversely related to human papillomavirus 16 DNA present in the tumor (P < 0.03). The AA genotype and superpositive immunohistochemical staining for cyclin D1 also had independent and significant effects on patient survival. These results strongly suggest that this splice variant, when present in two copies, is a significant predictor of both the occurrence of HNSCC as well as patient survival after treatment. These data further indicate that this variant protein is an important determinant of individual response to therapy for this disease.