tbuckley/cabot-search huggingface dataset:
First-in-Human Dose Study of the Novel Transforming Growth Factor-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Patients with Advanced Cancer and Glioma
Authors: Jordi Rodon, Michael A. Carducci, Juan M Sepulveda-Sánchez, Analia Azaro, Emiliano Calvo, Joan Seoane, Irene Braña, Elisabet Sicart, Ivelina Gueorguieva, Ann L. Cleverly, N. Sokalingum Pillay, Durisala Desaiah, Shawn T. Estrem, Luis Paz-Ares, Matthias Holdhoff, Jaishri Blakeley, Michael M. Lahn, Jose Baselga
Journal: Clinical Cancer Research (2014)

TGFβ signaling plays a key role in tumor progression, including malignant glioma. Small-molecule inhibitors such as LY2157299 monohydrate (LY2157299) block TGFβ signaling and reduce tumor progression in preclinical models. To use LY2157299 in the treatment of malignancies, we investigated its properties in a first-in-human dose (FHD) study in patients with cancer.Sixty-five patients (58 with glioma) with measurable and progressive malignancies were enrolled. Oral LY2157299 was given as a split dose morning and evening on an intermittent schedule of 14 days on and 14 days off (28-day cycle). LY2157299 monotherapy was studied in dose escalation (part A) first and then evaluated in combination with standard doses of lomustine (part B). Safety was assessed using Common Terminology Criteria for Adverse Events version 3.0, echocardiography/Doppler imaging, serum troponin I, and brain natriuretic peptide (BNP) levels. Antitumor activity was assessed by RECIST and Macdonald criteria.In part A, 16.6% (5/30) and in part B, 7.7% (2/26) of evaluable patients with glioma had either a complete (CR) or a partial response (PR). In both parts, 15 patients with glioma had stable disease (SD), 5 of whom had SD ≥ 6 cycles of treatment. Therefore, clinical benefit (CR+PR+SD ≥ 6 cycles) was observed in 12 of 56 patients with glioma (21.4%). LY2157299 was safe, with no cardiac adverse events.On the basis of the safety, pharmacokinetics, and antitumor activity in patients with glioma, the intermittent administration of LY2157299 at 300 mg/day is safe for future clinical investigation.
Peritumoral Lymphatic Vessel Density and Vascular Endothelial Growth Factor C Expression in Early-Stage Squamous Cell Carcinoma of the Uterine Cervix
Authors: Zoltan Gombos, Xiaowei Xu, Christina S. Chu, Paul J. Zhang, Geza Acs
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Lymphatic invasion and nodal metastasis plays a major role in the spread of cervical cancer; however, little is known about the mechanisms whereby tumor cells enter the lymphatic system. Experimental Design: We examined the intra- and peritumoral lymphatic vessel density (LVD) using D2-40 immunohistochemistry in 111 cervical squamous cell carcinomas and correlated them with vascular endothelial growth factor (VEGF)-C expression, clinicopathologic tumor features, and outcome. Results: Compared with benign cervix, intratumoral and peritumoral LVD was significantly increased (P &amp;lt; 0.0001). Peritumoral LVD was significantly higher than intratumoral LVD (P = 0.009). High peritumoral, but not intratumoral, LVD showed significant correlation with high tumor stage, lymphatic invasion, and nodal metastasis. VEGF-C showed increased expression at the invasive edge compared with the center of tumors (P &amp;lt; 0.0001) and correlated with high peritumoral LVD, lymphatic invasion, and nodal metastasis. High peritumoral LVD and VEGF-C expression at the invasive edge of tumors were associated with poor overall and recurrence-free survival in univariate analysis. In multivariate analysis, peritumoral LVD was the only independent term predictive of overall survival. Conclusions: Our findings suggest a potential role for VEGF-C in tumor-induced lymphangiogenesis represented by high peritumoral LVD, which may be one of the mechanisms leading to lymphatic invasion and metastatic spread. High peritumoral LVD may be an independent prognostic factor in early-stage cervical cancer.
Neck injuries presenting to emergency departments in the United States from 1990 to 1999 for ice hockey, soccer, and American football
Authors: J S Delaney, A Al-Kashmiri
Journal: British Journal of Sports Medicine (2005)

To examine the number and rate of neck injuries in the community as a whole for ice hockey, soccer, and American football by analysing data from patients presenting to emergency departments in the United States from 1990 to 1999.Data compiled for the US Consumer Product Safety Commission were used to generate estimates for the total number of neck injuries and the more specific diagnoses of neck fractures, dislocations, contusions, sprains, strains, and lacerations occurring nationally from 1990 to 1999. These data were combined with yearly participation figures to generate rates of injury presenting to emergency departments for each sport.There were an estimated 5038 neck injuries from ice hockey, 19,341 from soccer, and 114 706 from American football. These could be broken down as follows: 4964 contusions, sprains, or strains from ice hockey, 17,927 from soccer, and 104 483 from football; 105 neck fractures or dislocations from ice hockey, 214 from soccer, and 1588 from football; 199 neck lacerations for ice hockey, 0 for soccer, and 621 for football. The rates for total neck injuries and combined neck contusions, sprains, or strains were higher for football than for ice hockey or soccer in all years for which data were available.The rate of neck injury in the United States was higher in football than in ice hockey or soccer in the time period studied.
Lack of Weight Gain and Relapse Risk in a Large Tuberculosis Treatment Trial
Authors: Awal Khan, Timothy R. Sterling, Randall Reves, Andrew Vernon, C. Robert Horsburgh
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Readily identified markers of tuberculosis relapse risk are needed, particularly in resource-limited settings. The association between weight gain or loss during antituberculosis therapy and relapse has not been well studied.Subjects in the Tuberculosis Trials Consortium Study 22 were studied. Underweight was defined as 10% or more below ideal body weight at diagnosis. Weight change was assessed between (1) diagnosis and completion of induction phase therapy, (2) diagnosis and end of continuation phase therapy, and (3) completion of induction to completion of continuation phase therapy.A total of 857 subjects were monitored for 2 yr, and 61 of 857 (7.1%) relapsed. Relapse risk was high among persons who were underweight at diagnosis (19.1 vs. 4.8%; p < 0.001) or who had a body mass index of less than 18.5 kg/m(2) (19.5 vs. 5.8%; p < 0.001). Among persons who were underweight at diagnosis, weight gain of 5% or less between diagnosis and completion of 2-mo intensive phase therapy was moderately associated with an increased relapse risk (18.4 vs. 10.3%; relative risk, 1.79, 95% confidence interval, 0.96-3.32; p = 0.06). In a multivariate logistic regression model that was adjusted for other risk factors, a weight gain of 5% or less between diagnosis and completion of 2-mo intensive phase therapy among persons underweight at diagnosis was significantly associated with relapse risk (odds ratio, 2.4; p = 0.03).Among persons underweight at diagnosis, weight gain of 5% or less during the first 2 mo of treatment is associated with an increased relapse risk. Such high-risk patients can be easily identified, even in resource-poor settings. Additional studies are warranted to identify interventions to decrease risk of relapse in such patients.
Evidence for hypomotility in non-ulcer dyspepsia: a prospective multifactorial study.
Authors: B Waldron, P T Cullen, R Kumar, D Smith, J Jankowski, D Hopwood, D Sutton, N Kennedy, F C Campbell
Journal: Gut (1991)

<h3>Abstract</h3> Bacteria can be harnessed to synthesise high-value chemicals. A promising strategy for increasing productivity uses inducible control systems to switch metabolism from growth to chemical synthesis once a large population of cell factories are generated. However, use of expensive chemical inducers limits scalability of this approach for biotechnological applications. Switching using cheap nutrients is an appealing alternative, but their tightly regulated uptake and consumption again limits scalability. Here, using mathematical models of fatty acid uptake in <i>E. coli</i> as an exemplary case study, we unravel how the cell's native regulation and program of induction can be engineered to minimise inducer usage. We show that integrating positive feedback loops into the circuitry creates an irreversible metabolic switch, which, requiring only temporary induction, drastically reduces inducer usage. Our proposed switch should be widely applicable, irrespective of the product of interest, and brings closer the realization of scalable and sustainable microbial chemical production.
Short-term safety of thoracoscopic talc pleurodesis for recurrent primary spontaneous pneumothorax: a prospective European multicentre study
Authors: P-O. Bridevaux, J-M. Tschopp, G. Cardillo, C-H. Marquette, M. Noppen, P. Astoul, P. Driesen, C.T. Bolliger, M.E. Froudarakis, J.P. Janssen
Journal: European Respiratory Journal (2011)

The safety of talc pleurodesis is under dispute following reports of talc-induced acute respiratory distress syndrome (ARDS) and death. We investigated the safety of large-particle talc for thoracoscopic pleurodesis to prevent recurrence of primary spontaneous pneumothorax (PSP). 418 patients with recurrent PSP were enrolled between 2002 and 2008 in nine centres in Europe and South Africa. The main exclusion criteria were infection, heart disease and coagulation disorders. Serious adverse events (ARDS, death or other) were recorded up to 30 days after the procedure. Oxygen saturation, supplemental oxygen use and temperature were recorded daily at baseline and after thoracoscopic pleurodesis (2 g graded talc). During the 30-day observation period following talc poudrage, no ARDS (95% CI 0.0-0.9%), intensive care unit admission or death were recorded. Seven patients presented with minor complications (1.7%, 95% CI 0.7-3.4%). After pleurodesis, mean body temperature increased by 0.41°C (95% CI 0.33-0.48°C; p<0.001) at day 1 and returned to baseline value at day 5. Pleural drains were removed after day 4 in 80% of patients. Serious adverse events, including ARDS or death, did not occur in this large, multicentre cohort. Thoracoscopic talc poudrage using larger particle talc to prevent recurrence of PSPS can be considered safe.
Comparing the American and European diagnostic guidelines for cystic fibrosis: same disease, different language?
Authors: Chee Y Ooi, Annie Dupuis, Lynda Ellis, Keith Jarvi, Sheelagh Martin, Tanja Gonska, Ruslan Dorfman, Paul Kortan, Melinda Solomon, Elizabeth Tullis, Peter R Durie
Journal: Thorax (2012)

<h3>Background</h3> The American and European cystic fibrosis (CF) guidelines recommend different diagnostic criteria. This study assessed diagnostic concordance between these recommendations. <h3>Methods</h3> Subjects with single organ manifestations suggestive of CF (chronic sinopulmonary disease (RESP), chronic/recurrent pancreatitis (PANC) or obstructive azoospermia (AZOOSP)) were prospectively evaluated by sweat test, nasal potential difference and genotyping. Concordance in diagnostic outcomes between the two algorithms was measured using observed agreement and κ statistics. <h3>Results</h3> A total of 208 subjects were evaluated. Observed agreement was 84.8% and level of agreement was excellent (κ=0.87) between the American and European recommendations. The RESP phenotype was associated with the highest degree of concordance (observed agreement ≥90%, κ=0.92) compared with the PANC (observed agreement 86%, κ=0.65) and AZOOSP (observed agreement 80%, κ=0.87) phenotypes. Incorporation of nasal potential difference into the American algorithm failed to improve the overall degree of concordance (good agreement level; κ=0.75); the level of agreement was unchanged in RESP and PANC subjects, but reduced in AZOOSP subjects (from excellent to good). Extensive genotyping had limited clinical utility in the diagnosis of CF in both algorithms. <h3>Conclusions</h3> Despite inconsistencies between the American and European diagnostic recommendations, concordance in diagnostic outcomes among subjects presenting with single organ manifestations of CF was good to excellent. These diagnostic guidelines provide guidance and promote rigorous evaluation for the diagnosis of CF but neither guideline should be regarded as dogma.
Metabolic syndrome on top of chronic hepatitis B: the more, the worse?
Authors: Li-Chun Chang, Chen-Shuan Chung, Chun-Jen Liu, Jia-Horng Kao
Journal: Gut (2010)

We read with interest the article entitled ‘Metabolic syndrome increases the risk of liver cirrhosis in chronic hepatitis B’ by Wong et al in the January 2009 of Gut .1 Chronic hepatitis B virus (HBV) infection remains a global health problem, affecting more than 350 million people worldwide. It is estimated that approximately one million chronic hepatitis B (CHB) patients die of liver-related diseases per annum. Through the launch of an effective hepatitis B vaccination programme for more than two decades, a dramatic decline of HBV infection rate as well as hepatocellular carcinoma (HCC) incidence rate has been observed in children of many HBV endemic countries.2 Nevertheless, CHB is still a health threat to adult HBV carriers. Therefore, it is important for …
Patients with chronic hepatitis B should be screened for hepatocellular carcinoma regardless of liver stiffness measurement
Authors: Philippe Sultanik, Philippe Sogni, Jean‐François Meritet, Stanislas Pol, Vincent Mallet
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. To the Editor: Kim and colleagues report that a high liver stiffness value (≥13 kPa) is an independent risk factor for hepatocellular carcinoma in patients with treated and untreated chronic hepatitis B viral infection.1 The problem is that the liver stiffness value is a function of fibrosis and necroinflammation2 and that liver stiffness may decrease when the latter is controlled.3 In our center, 627 patients with chronic hepatitis B viral infection underwent liver stiffness measurement between 2006 and 2014 and 16 (2.5%) developed hepatocellular carcinoma after a median follow‐up of 35 (interquartile range 17‐65) months. Considering the entire cohort, the liver stiffness value was correlated to hepatocellular carcinoma development with an area under the receiver operating characteristic curve of 0.87 (P < 0.0001). Nevertheless, a 13‐kPa threshold for prediction of hepatocellular carcinoma had a sensitivity and specificity at 31% and 95%, respectively. Among patients under treatment, the sensitivity and specificity for the same threshold were 36% and 91%, respectively, corresponding to seven patients with a median liver stiffness value of 7.4 (interquartile range 5.4‐9) kPa before the development of hepatocellular carcinoma. Moreover, three (43%) of them had overt cirrhosis or biopsy‐proven "occult" cirrhosis at the time of hepatocellular carcinoma. It is likely that a growing number of clinicians will perform serial liver stiffness measurements in their patients with chronic hepatitis B viral infection, including those under treatment, and that evidence‐based proven management of these patients will be inferred from such measurements. At the individual level, the liver stiffness value does not accurately predict the risk of hepatocellular carcinoma and liver stiffness measurement should not be used as a follow‐up tool. Patients at risk of hepatocellular carcinoma should comply with recommended follow‐up.4
THE CHEMOTACTIC EFFECT OF MIXTURES OF ANTIBODY AND ANTIGEN ON POLYMORPHONUCLEAR LEUCOCYTES
Authors: Stephen Boyden
Journal: The Journal of Experimental Medicine (1962)

An in vitro technique is described for assessing the chemotactic activity of soluble substances on motile cells. Antibody-antigen mixtures when incubated (37 degrees C) in medium containing fresh (i.e. non-inactivated) normal rabbit serum exert a strong chemotactic effect on rabbit polymorphonuclear leucocytes. Results are described which indicate that, when antibody-antigen complexes are incubated (37 degrees C) in fresh serum, a heat-stable (56 degrees C) substance (or substances) is produced which acts directly as a chemotactic stimulus on the polymorphs. This heat-stable chemotactic substance is not produced when antibody-antigen complexes are incubated in serum which has been heated at 56 degrees C for 30 minutes.
Gambling and Related Mental Disorders: A Public Health Analysis
Authors: Howard J. Shaffer, David A. Korn
Journal: Annual Review of Public Health (2002)

▪ Abstract This article reviews the prevalence of gambling and related mental disorders from a public health perspective. It traces the expansion of gambling in North America and the psychological, economic, and social consequences for the public's health, and then considers both the costs and benefits of gambling and the history of gambling prevalence research. A public health approach is applied to understanding the epidemiology of gambling-related problems. International prevalence rates are provided and the prevalence of mental disorders that often are comorbid with gambling problems is reviewed. Analysis includes an examination of groups vulnerable to gambling-related disorders and the methodological and conceptual matters that might influence epidemiological research and prevalence rates related to gambling. The major public health problems associated with gambling are considered and recommendations made for public health policy, practice, and research. The enduring value of a public health perspective is that it applies different ‘lenses’ for understanding gambling behaviour, analysing its benefits and costs, as well as identifying strategies for action. Harvey A. Skinner ( 160 , p. 286)
Smoking Cessation: It Is Never Too Late
Authors: Peter M. Nilsson, Karl-Olov Fagerström
Journal: Diabetes Care (2009)

Public health and smoking are old enemies because smoking is among the 10 leading causes of ill health on a global scale and is also possible to prevent, as repeatedly reported (1). In both developed and developing countries, smoking takes its heavy toll of lives every year, both directly and indirectly, through exposure to passively inhaled tobacco smoke (2) or via feto-placental effects. Much research efforts have been devoted to finding news ways to help the individual smoker quit the harmful habit, not only based on individual (3) or group-based support activities (4), as supported by the whole health care team, but also on ways of prescribing both older and newer drugs to support smoking cessation. Even if nicotine replacement therapy (5) in its various forms has been around for almost 3 decades and the atypical antidepressant bupropion (6) for ∼10 years, new target drugs are constantly being developed to support the addicted smoker in quitting permanently. Such drugs may be useful for very large groups of addicted smokers who have tried the other ways to quit in vain. One example is varenicline, a partial nicotine receptor agonist that has been proven successful in randomized controlled trials, both for smoking cessation and for relapse prevention (7–10). The effect is more pronounced than recorded by use of nicotine replacement therapy or bupropion.

Other ways might also exist to achieve smoking cessation, such as the use of acupuncture, hypnosis, or psychopharmacological approaches, but these remedies are less well proven and therefore not truly evidence based.

However, older drug preparations are developing. New faster delivery nicotine replacement drug delivery systems (11) bear the promise of addressing a broader list of indications, including treatment of nicotine withdrawal during …
Calcium Blocking Drugs for Angina Pectoris
Authors: R Zelis, S F Flaim
Journal: Annual Review of Medicine (1982)

The introduction of the calcium channel blockers for the treatment of angina pectoris has been heralded as the most significant medical event in cardiology since the introduction of the beta adrenergic receptor blocking drugs (1-5). Calcium blockers, sometimes called calcium antagonists or slow channel blockers, have as their primary mechanism of action the ability to reduce intracellular calcium ion (Ca2+) concentration in cardiac and vascular smooth muscle (6-10). In studies of isolated tissue, the drugs exert negative chronotropic, dromotropic, and inotropic effects on the heart and relax vascular smooth muscle. This latter property has generated the present intense interest in these drugs since it is now recognized that coro­ nary vasospasm may play a major role in a significant minority of patients with ischemic heart disease (11-18). In this paper we review the clinical picture of coronary vasospasm, the pharmacology of the major calcium blockers, and the use of these drugs in the treatment of Prinzmetal's or variant angina and chronic stable angina pectoris.
Identification of modifications in microbial, native tRNA that suppress immunostimulatory activity
Authors: Stefanie Gehrig, Mariel-Esther Eberle, Flavia Botschen, Katharina Rimbach, Florian Eberle, Tatjana Eigenbrod, Steffen Kaiser, Walter M. Holmes, Volker A. Erdmann, Mathias Sprinzl, Guillaume Bec, Gérard Keith, Alexander H. Dalpke, Mark Helm
Journal: The Journal of Experimental Medicine (2012)

Naturally occurring nucleotide modifications within RNA have been proposed to be structural determinants for innate immune recognition. We tested this hypothesis in the context of native nonself-RNAs. Isolated, fully modified native bacterial transfer RNAs (tRNAs) induced significant secretion of IFN-α from human peripheral blood mononuclear cells in a manner dependent on TLR7 and plasmacytoid dendritic cells. As a notable exception, tRNATyr from Escherichia coli was not immunostimulatory, as were all tested eukaryotic tRNAs. However, the unmodified, 5′-unphosphorylated in vitro transcript of tRNATyr induced IFN-α, thus revealing posttranscriptional modifications as a factor suppressing immunostimulation. Using a molecular surgery approach based on catalytic DNA, a panel of tRNATyr variants featuring differential modification patterns was examined. Out of seven modifications present in this tRNA, 2′-O-methylated Gm18 was identified as necessary and sufficient to suppress immunostimulation. Transplantation of this modification into the scaffold of yeast tRNAPhe also resulted in blocked immunostimulation. Moreover, an RNA preparation of an E. coli trmH mutant that lacks Gm18 2′-O-methyltransferase activity was significantly more stimulatory than the wild-type sample. The experiments identify the single methyl group on the 2′-oxygen of Gm18 as a natural modification in native tRNA that, beyond its primary structural role, has acquired a secondary function as an antagonist of TLR7.
Foxp3-Transduced Polyclonal Regulatory T Cells Protect against Chronic Renal Injury from Adriamycin
Authors: Yuan Min Wang, Geoff Yu Zhang, Yiping Wang, Min Hu, Huiling Wu, Debbie Watson, Shohei Hori, Ian E. Alexander, David C.H. Harris, Stephen I. Alexander
Journal: Journal of the American Society of Nephrology (2006)

Chronic proteinuric renal injury is a major cause of ESRD. Adriamycin nephropathy is a murine model of chronic proteinuric renal disease whereby chemical injury is followed by immune and structural changes that mimic human disease. Foxp3 is a gene that induces a regulatory T cell (Treg) phenotype. It was hypothesized that Foxp3-transduced Treg could protect against renal injury in Adriamycin nephropathy. CD4+ T cells were transduced with either a Foxp3-containing retrovirus or a control retrovirus. Foxp3-transduced T cells had a regulatory phenotype by functional and phenotypic assays. Adoptive transfer of Foxp3-transduced T cells protected against renal injury. Urinary protein excretion and serum creatinine were reduced (P<0.05), and there was significantly less glomerulosclerosis, tubular damage, and interstitial infiltrates (P<0.01). It is concluded that Foxp3-transduced Treg cells may have a therapeutic role in protecting against immune injury and disease progression in chronic proteinuric renal disease.