tbuckley/cabot-search huggingface dataset:
New method to monitor drugs at dance venues
Authors: J. Cole
Journal: BMJ (2002)

Editor—Ramsey et al report the analyses of illegally purchased controlled drugs that had been surrendered in a nightclub.1 They argue that monitoring such samples would provide important information to healthcare professionals, which they could use to “formulate better advice on avoiding injury through drug use and to design the most appropriate campaigns against drug use.”

Yet no indication is given of how this would be done, other than by increased use of the TICTAC database, which is edited by Ramsey.2 As this database is presumably already used by people reading this paper, its ability to fulfil this purpose is questionable. No evidence is presented that any evidence based harm reduction strategy uses these data or that an outcome evaluation has been conducted on them.

Two major problems arise with ecstasy tablets: the unknown amount of 3,4-methylenedioxymethamphetamine (MDMA) present, if at all, and other drugs being sold as 3,4-methylenedioxymethamphetamine, such as 4-methylthioamphetamine (4-MTA). Adverse reactions to 3,4-methylenedioxymethamphetamine seem to be both idiosyncratic and rare. Perhaps the information about tablet contents should be made available to people who are deciding whether or not to use the tablets, so that they can avoid ingesting tablets of unknown content.

On-site facilities for tablet testing in the Netherlands reduce the drug use of people attending organised dance parties.3 Information on tablets in circulation at the venue is immediately available to both the users and medical support staff. The TICTAC database, on the other hand, would not be able to provide this information without confirmatory analysis.

No controlled study has ever been conducted to evaluate whether the availability of information about the contents of ecstasy tablets either increases or decreases the harm associated with their use. What is evident is that restricted access to this information is not preventing adverse reactions and is having no effect on the drug use of young people.
Abstract 5390: The TRK inhibitor RXDX-101 enhances the efficacy of temozolomide and irinotecan in a xenograft model of neuroblastoma
Authors: Radhika Iyer, Rebecca L. Golden, Koumudi Naraparaju, Jamie L. Croucher, Peng Guan, Gang Li, Zachary Hornby, Garrett M. Brodeur
Journal: Cancer Research (2015)

Abstract Purpose: Neuroblastoma (NB) is one of the most common and deadly solid tumors of childhood. The Trk family of neurotrophin receptors plays an important role in clinical behavior of NBs. Overexpression of TrkB and its ligand, BDNF, is associated with poor prognosis. We wanted to determine if RXDX-101, an oral pan-TRK, ROS1 and ALK inhibitor, would be effective in our NB xenograft model, either alone or in combination with conventional chemotherapy. Experimental Design: We tested the in vitro effects of RXDX-101 as a single agent, or in combination with the chemotherapeutic agents irinotecan and temozolomide (Irino-TMZ), using a subclone of the SH-SY5Y NB cell line transfected with TrkB. We also examined in vivo growth inhibition of TrkB-expressing NB xenografts with RXDX-101 alone or in combination with Irino-TMZ. Results: RXDX-101 significantly inhibited growth of TrkB-expressing NB cells in vitro. Enhanced in vitro inhibition was observed when RXDX-101 was used in combination with Irino-TMZ. Single agent therapy with RXDX-101 resulted in significant tumor growth inhibition compared to control animals [p&amp;lt;0.0001 for event-free survival (EFS)]. The addition of RXDX-101 to Irino-TMZ also significantly improved the EFS of animals compared to vehicle or Irino-TMZ treated animals (p&amp;lt;0.0001 for combination vs. control, p = 0.0012 for combination vs. Irino-TMZ). Conclusions: We show that RXDX-101 inhibits growth of TrkB expressing NB cells in vitro and in vivo. Furthermore, RXDX-101 cotreatment enhanced the efficacy of conventional chemotherapy in our NB xenograft model. Our data suggest that RXDX-101 has potential for incorporation in clinical trials for NB and other Trk expressing tumors. Citation Format: Radhika Iyer, Rebecca L. Golden, Koumudi Naraparaju, Jamie L. Croucher, Peng Guan, Gang Li, Zachary Hornby, Garrett M. Brodeur. The TRK inhibitor RXDX-101 enhances the efficacy of temozolomide and irinotecan in a xenograft model of neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5390. doi:10.1158/1538-7445.AM2015-5390
Randomized clinical trials inHepatology: Predictors of quality
Authors: Lise Lotte Kjaergard, Dimitrinka Nikolova, Christian Gluud
Journal: Hepatology (1999)

Evidence shows that the quality of randomized clinical trials (RCTs) affects estimates of intervention efficacy, which is significantly exaggerated in low-quality trials. The present study examines the quality of all 235 RCTs published in Hepatology from the initiation in 1981 through August 1998. Quality was assessed by means of a validated 5-point scale and separate quality components associated with empirical evidence of bias. Only 26% of all RCTs reported sample size calculations, 52% adequate generation of the allocation sequence, 34% adequate allocation concealment and 34% double-blinding. The median quality score of all trials was 3 points (range, 1-5 points). Multiple logistic regression analysis explored the association between quality and therapeutic areas, number of centers, external funding, year of publication, and country of origin. High-quality trials were most likely to investigate portal hypertension (odds ratio [OR]: 2.4; 95% CI: 1.1-5.5; P = .03), be multicentered (OR: 3.4; 95% CI: 1.3-8.9; P = .01), sponsored by public organizations (OR: 4.2; 95% CI: 2.1-8.6; P = .0001), or the drug and device industry (OR: 4.7; 95% CI: 2.2-10.2; P = .0001) compared with other therapeutic areas, single-center trials, and trials with no external funding. Quality did not improve with time and was not associated with country of origin. The main conclusions are that the quality of RCTs in Hepatology needs improvement and that the probability of high quality increased with the number of centers involved and external funding.
Health care costs associated with depressive and anxiety disorders in primary care
Authors: G Simon, J Ormel, M VonKorff, W Barlow
Journal: American Journal of Psychiatry (1995)

The authors examined the overall health care costs associated with depression and anxiety among primary care patients.Of 2,110 consecutive primary care patients in a health maintenance organization, 1,962 were screened with the 12-item General Health Questionnaire. A stratified random sample of 615 patients were selected for further diagnostic assessment; 373 of these patients completed the Composite International Diagnostic Interview at baseline and 328 were reassessed 12 months later. Computerized cost records were used to calculate total health care costs for the 6-month period surrounding the baseline assessment and a similar period surrounding the follow-up assessment. Cost accounting data were available for 327 patients at baseline and for 206 patients at both assessments.Primary care patients with DSM-III-R anxiety or depressive disorders at baseline had markedly higher baseline costs ($2,390) than patients with subthreshold disorders ($1,098) and those with no anxiety or depressive disorder ($1,397). Large cost differences persisted after adjustment for medical morbidity. Cost differences reflected higher utilization of general medical services rather than higher mental health treatment costs. Although most patients with baseline anxiety or depressive disorders showed significant improvement, longitudinal analyses did not show any clear relationship between change in psychiatric diagnosis and change in health care cost.Among primary care patients, anxiety and depressive disorders are associated with markedly higher health care costs even after adjustment for medical comorbidity. In this small sample, improvement in depression over 1 year was not clearly associated with decreases in cost.
Abstract #LB-218: Examination of mutant EGF receptors linked to Non-Small Cell Lung Cancer and their responses to Gefitinib
Authors: Jia Luo, Chimera Peet, Paul Bertics
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Lung cancer is the leading cause of cancer mortalities and the altered activity of the EGF receptor, either via overexpression or mutation, is found in over half of lung tumors. Accordingly, the EGF receptor represents a promising target in lung cancer therapy. In 2004, somatic mutations (e.g., L834R) in the EGF receptor tyrosine kinase domain were reported in non-small cell lung cancer (NSCLC) patients that were sensitive to the EGF receptor-selective tyrosine kinase inhibitors Gefitinib and Erlotinib. The identification of these somatic mutations suggests that they are involved in tumorigenesis. It has been proposed that these mutants exhibit enhanced EGF-dependent activation of cell survival pathways (Akt, STAT3, and STAT5) and/or that these mutations promote EGF-independent activation of the receptor. Unfortunately, treatment with this drug over extended periods has revealed that Gefitinib becomes ineffective, and these patients appear to acquire a second EGFR mutation (T766M). These studies support the concept that the addition of the T766M EGFR mutation promotes resistance to Gefitinib-inhibition. In the present report, we have heterologously expressed lung cancer-associated L834R and L834R/T766M EGF receptor mutants in adult mouse B82L fibroblast cells, and these mutants display enhanced basal activity (independent of secondary mutations often associated with NSCLC). Moreover, whereas the L834M receptor mutant exhibits a more favorable IC50 for Gefitinib/Erlotinib than wild-type receptor with respect to EGF-induced autophosphorylation at Tyr-1068, the L834R/T766M EGF receptor mutant exhibits complete Gefitinib resistance as well as exaggerated Akt phosphorylation. These results further illustrate the EGF receptor dynamics associated with drug-resistant NSCLC patients (independent of secondary cell signaling defects often associated with NSCLC) and may help in further therapeutic development.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-218.
Abstract 15841: Genome-Wide Association Identifies Genetic Variants Associated With Vein Graft Stenosis After Coronary Artery Bypass Grafting
Authors: Asad A Shah, Damian M Craig, Carol Haynes, Jacqueline K Sebek, Elizabeth Grass, Karen Abramson, Peter K Smith, Elizabeth R Hauser, Simon G Gregory, William E Kraus, Svati H Shah
Journal: Circulation (2011)

Background: Vein graft stenosis after coronary artery bypass grafting (CABG) is common, with 50% of grafts occluded by 10 years. Identifying genes associated with vein graft stenosis after CABG cou...
Imaging Techniques for the Diagnosis of Hepatocellular Carcinoma
Authors: Roger Chou, Carlos Cuevas, Rongwei Fu, Beth Devine, Ngoc Wasson, Alexander Ginsburg, Bernadette Zakher, Miranda Pappas, Elaine Graham, Sean D. Sullivan
Journal: Annals of Internal Medicine (2015)

Several imaging modalities are available for diagnosis of hepatocellular carcinoma (HCC).To evaluate the test performance of imaging modalities for HCC.MEDLINE (1998 to December 2014), the Cochrane Library Database, Scopus, and reference lists.Studies on test performance of ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI).One investigator abstracted data, and a second investigator confirmed them; 2 investigators independently assessed study quality and strength of evidence.Few studies have evaluated imaging for HCC in surveillance settings. In nonsurveillance settings, sensitivity for detection of HCC lesions was lower for ultrasonography without contrast than for CT or MRI (pooled difference based on direct comparisons, 0.11 to 0.22), and MRI was associated with higher sensitivity than CT (pooled difference, 0.09 [95% CI, 0.07 to 12]). For evaluation of focal liver lesions, there were no clear differences in sensitivity among ultrasonography with contrast, CT, and MRI. Specificity was generally 0.85 or higher across imaging modalities, but this item was not reported in many studies. Factors associated with lower sensitivity included use of an explanted liver reference standard, and smaller or more well-differentiated HCC lesions. For MRI, sensitivity was slightly higher for hepatic-specific than nonspecific contrast agents.Only English-language articles were included, there was statistical heterogeneity in pooled analyses, and costs were not assessed. Most studies were conducted in Asia and had methodological limitations.CT and MRI are associated with higher sensitivity than ultrasonography without contrast for detection of HCC; sensitivity was higher for MRI than CT. For evaluation of focal liver lesions, the sensitivities of ultrasonography with contrast, CT, and MRI for HCC are similar.Agency for Healthcare Research and Quality. (CRD42014007016).
Inhibition of mammalian polyadenylation by ATP analogs
Authors: Lisa Chen, Vasupradha Vethantham, James Manley, Varsha Gandhi
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

3203 

Cancers such as chronic lymphocytic leukemia (CLL) are replicationally quiescent, and thus are not amenable to traditional DNA-targeting agents. However, these cells still actively synthesize mRNA transcripts for physiological processes and cell survival. Pre-mRNA transcripts must be polyadenylated to become mature transcripts, and poly(A) tails are required for the functional maintenance of these transcripts. Polyadenylation is catalyzed by poly(A) polymerase (PAP), which is a template-independent RNA polymerase that adds poly(A)-tails using ATP to the 3′-end of pre-mRNA. Hence, PAP is a viable therapeutic target in replicationally quiescent cancer cells. Two agents, 8-chloroadenosine (8-Cl-Ado) and 8-aminoadenosine (8-amino-Ado) induce cell death in quiescent CLL lymphocytes. We have previously shown that the corresponding triphosphates of these analogs, 8-Cl-ATP and 8-amino-ATP, inhibit polyadenylation by yeast PAP ( J Biol Chem 279: 40405, 2004). Both these analogs resulted in the reduction of poly(A)-tail length, and the site-specific incorporation of a 8-Cl-AMP residue into the 3′-terminus of RNA primers blocked primer extension with ATP by yeast PAP.

To further elucidate the potential RNA-directed mechanisms of 8-Cl-Ado and 8-amino-Ado, we have extended our polyadenylation studies to include mammalian systems. Recent studies have solved the three-dimensional structure of yeast PAP and bovine PAP ( EMBO J 19: 4193, 2000, Science 289:1346, 2000). Based on the structural similarities between these polymerases, we hypothesized that mammalian PAP will behave similarly as yeast PAP with these ATP analogs. To test this hypothesis, we have extended our previous findings in the yeast polyadenylation model by conducting similar experiments with bovine PAPII (obtained from the laboratory of Professor James Manley, Columbia University) and 32P-labeled RNA primers to examine the effects of adenosine analogs on mammalian polyadenylation. Our results with bovine PAPII are summarized as follows. First, both 8-Cl-ATP and 8-amino-ATP in the absence of ATP served as substrates for this enzyme. Second, incorporation of these ATP analogs resulted in chain termination in RNA primer extension assays. Third, in complete reaction conditions with ATP, both 8-Cl-ATP and 8-amino-ATP resulted in RNA primers with shorter poly(A)-tails compared with full length primer extensions with ATP alone, suggesting that these analog triphosphates were able to compete with the natural substrate, ATP. Finally, reactions were performed using synthetic RNA primers containing either 8-Cl-AMP or AMP at the 3′-termini. The halogenated modification of adenine blocked the ability of bovine PAPII to extend the RNA primer with ATP, while the AMP-terminated primer resulted in full-extension. Taken together, our results suggest that the substrate specificity and inhibitory potential of these C8-modified ATP analogs are similar between yeast and bovine PAP.
Aggressive periodontitis: case definition and diagnostic criteria
Authors: Jasim M. Albandar
Journal: Periodontology 2000 (2014)

Abstract Aggressive periodontitis is a destructive disease characterized by the following: the involvement of multiple teeth with a distinctive pattern of periodontal tissue loss; a high rate of disease progression; an early age of onset; and the absence of systemic diseases. In some patients periodontal tissue loss may commence before puberty, whereas in most patients the age of onset is during or somewhat after the circumpubertal period. Besides infection with specific microorganisms, a host predisposition seems to play a key role in the pathogenesis of aggressive periodontitis, as evidenced by the familial aggregation of the disease. In this article we review the historical background of the diagnostic criteria of aggressive periodontitis, present a contemporary case definition and describe the clinical parameters of the disease. At present, the diagnosis of aggressive periodontitis is achieved using case history, clinical examination and radiographic evaluation. The data gathered using these methods are prone to relatively high measurement errors. Besides, this diagnostic approach measures past disease history and may not reliably measure existing disease activity or accurately predict future tissue loss. A diagnosis is often made years after the onset of the disease, partly because current assessment methods detect established disease more readily and reliably than they detect incipient or initial lesions where the tissue loss is minimal and usually below the detection threshold of present examination methods. Future advancements in understanding the pathogenesis of this disease may contribute to an earlier diagnosis. Insofar, future case definitions may involve the identification of key etiologic and risk factors, combined with high‐precision methodologies that enable the early detection of initial lesions. This may significantly enhance the predictive value of these tests and detect cases of aggressive periodontitis before significant tissue loss develops.
Efficacy of a novel cytotoxic polybisphosphonate for treatment of bone metastasis in castration-resistant prostate cancer (CRPC).
Authors: Sten Nilsson, Henriette Lindberg, Camilla Thellenberg-Karlsson, Claes Nyman, Marcela Marquez, Lena Lennartsson, René Blom, Enrique Castellanos, Anders R Holmberg
Journal: Journal of Clinical Oncology (2015)

236 Background: A cytostatic polybisphosphonate was developed for Tx of mCRPC. It has a) anti-resorptive effects, osteoclast inhib., b) tum. cell spec./tox, confirmed in in-vivo models. Tox. study shows high tolerability. Animal PK study has shown T½ &lt; 3 hrs; principal accumulation in liver, spleen, kidneys. Methods: Clin phase I/IIa (clinicaltrials.gov NCT01595087): Prim obj: to define MTD of ODX given every 3 rd week. Sec. obj: OS, bone metab. and resp. markers, PSA, QoL and PK. Explorative in vitrostudies (basis for rand. phase IIb trial in pts. with docetax-res. mCRPC). A docetax-resist. cell-line was developed from DU145 in escalating conc. of docetax, then continuous growth in docetax 500 µg/ml. Cells subj. to cytotox. exp. with ODX (iCELLigence system and fluorom microculture cytotox assay). Results: Clin Phase I/IIa first-in-man trial (clinicaltrials.gov NCT01595087): 17/28 patients rec. 4-7 doses every 3rd week. No DLTs; max dose adm.: 3.0 mg/kg: no drug-related SAEs. Tx was well tolerated. Efficacy and QoL data w. considerable variability as to be expected in this population of pts. w. mCRPC. Max blood conc. ODX: 110-160 fmol/mL; 85-90 % cleared within first 1 hr. Efficacy of ODX in docetax-res DU145TR: A dose-dependent cytotox effect seen when adding ODX in “sub-clin.” doses. All cells were apparently killed in the clin. relevant dose 6 uM. Conclusions: ODX is a novel drug cand. w. high cytotox. efficacy in vivo and in vitro, even in highly docetax-res. cells. Animal studies and Phase I trial show excellent tolerability. Studies now ongoing to elucidate whether short-term treatment is as efficacious as continuous treatment and whether some cells de facto may develop resistance also to this new treatment concept. A multicenter rand. double-blind pbo. controlled trial (EudraCT 2014-002054-39) starts Q4 2014 in mCRPC pts failing docetax and/or cabazitaxel AND abiraterone and/or enzalutamide. Clinical trial information: NCT01595087.
Abstract 11002: Care and Outcomes of Acute Myocardial Infarction in Taiwan, 2004-2008: Get With the Guidelines in Taiwan
Authors: Yi-Heng Li, Cheng-Han Lee, Ching-Lan Cheng, Yea-Huei Kao Yang, Jyh-Hong Chen
Journal: Circulation (2012)

Background: Despite recent advances, acute myocardial infarction (AMI) still carries significant morbidity and mortality. The American Heart Association Get With the Guidelines program (GWTG) has i...
Single-cell transcriptomic reconstruction reveals cell cycle and multi-lineage differentiation defects in Bcl11a-deficient hematopoietic stem cells
Authors: Jason C. H. Tsang, Yong Yu, Shannon Burke, Florian Buettner, Cui Wang, Aleksandra A. Kolodziejczyk, Sarah A. Teichmann, Liming Lu, Pentao Liu
Journal: Genome biology (2015)

Hematopoietic stem cells (HSCs) are a rare cell type with the ability of long-term self-renewal and multipotency to reconstitute all blood lineages. HSCs are typically purified from the bone marrow using cell surface markers. Recent studies have identified significant cellular heterogeneities in the HSC compartment with subsets of HSCs displaying lineage bias. We previously discovered that the transcription factor Bcl11a has critical functions in the lymphoid development of the HSC compartment.In this report, we employ single-cell transcriptomic analysis to dissect the molecular heterogeneities in HSCs. We profile the transcriptomes of 180 highly purified HSCs (Bcl11a (+/+) and Bcl11a (-/-)). Detailed analysis of the RNA-seq data identifies cell cycle activity as the major source of transcriptomic variation in the HSC compartment, which allows reconstruction of HSC cell cycle progression in silico. Single-cell RNA-seq profiling of Bcl11a (-/-) HSCs reveals abnormal proliferative phenotypes. Analysis of lineage gene expression suggests that the Bcl11a (-/-) HSCs are constituted of two distinct myeloerythroid-restricted subpopulations. Remarkably, similar myeloid-restricted cells could also be detected in the wild-type HSC compartment, suggesting selective elimination of lymphoid-competent HSCs after Bcl11a deletion. These defects are experimentally validated in serial transplantation experiments where Bcl11a (-/-) HSCs are myeloerythroid-restricted and defective in self-renewal.Our study demonstrates the power of single-cell transcriptomics in dissecting cellular process and lineage heterogeneities in stem cell compartments, and further reveals the molecular and cellular defects in the Bcl11a-deficient HSC compartment.