tbuckley/cabot-search huggingface dataset:
State Differences in the Reporting of Diabetes-Related Incorrect Cause-of-Death Causal Sequences on Death Certificates
Authors: Tain-Junn Cheng, Tsung-Hsueh Lu, Ichiro Kawachi
Journal: Diabetes Care (2012)

To examine state differences in the reporting of diabetes-related incorrect cause-of-death (COD) causal sequences on death certificates in the U.S.We conducted a cross-sectional descriptive study to determine the prevalence of two types of incorrect COD causal sequences with data from the Multiple Cause Mortality File of the year 2004.Among deaths in which diabetes was reported as the first diagnosis on line a, b, c, or d in Part I of the death certificate in the U.S., 21% had below diabetes placement error (ranged from 30% in Maryland to 7% in Hawaii) and 11% had above diabetes placement error (ranged from 18% in Kentucky to 5% in California). The net effects of the two types of error ranged from -0.7% in Nevada to 19.6% in the District of Columbia.Because the rates of incorrect reporting of diabetes-related COD causal sequence varied across states, the comparability of the diabetes death rate between states may have been compromised.
AMP-Activated Protein Kinase as a Drug Target
Authors: D. Grahame Hardie
Journal: The Annual Review of Pharmacology and Toxicology (2006)

The AMP-activated protein kinase (AMPK) system is a regulator of energy balance at both the cellular and whole-body levels that, once activated by low energy status, effects a switch from ATP-consuming anabolic pathways to ATP-producing catabolic pathways. It now appears to be the major target for two existing classes of drug used to treat type 2 diabetes, i.e., the biguanides and thiazolidinediones. However, in both cases these activate AMPK indirectly, and an interesting question concerns whether a drug that directly activated AMPK would retain the therapeutic benefits of the existing drugs while eliminating unwanted side effects. AMPK activators also now have potential as anticancer drugs.
A Proinflammatory Cytokine Inhibits P53 Tumor Suppressor Activity
Authors: James D. Hudson, Mahmood A. Shoaibi, Roberta Maestro, Amancio Carnero, Gregory J. Hannon, David H. Beach
Journal: The Journal of Experimental Medicine (1999)

p53 has a key role in the negative regulation of cell proliferation, in the maintenance of genomic stability, and in the suppression of transformation and tumorigenesis. To identify novel regulators of p53, we undertook two functional screens to isolate genes which bypassed either p53-mediated growth arrest or apoptosis. In both screens, we isolated cDNAs encoding macrophage migration inhibitory factor (MIF), a cytokine that was shown previously to exert both local and systemic proinflammatory activities. Treatment with MIF overcame p53 activity in three different biological assays, and suppressed its activity as a transcriptional activator. The observation that a proinflammatory cytokine, MIF, is capable of functionally inactivating a tumor suppressor, p53, may provide a link between inflammation and tumorigenesis.
Riociguat, a novel therapy for pulmonary hypertension?
Authors: Sarah-Jane Bailey
Journal: Thorax (2013)

Riociguat, a novel therapy for pulmonary hypertension?This phase three, double-blind, randomised, placebo-controlled, multicentre study was carried out in 30 countries.It compared riociguat (maximum dose 2.5 mg three times a day) with placebo in the treatment of symptomatic pulmonary hypertension.The primary end point was change in baseline walking distance over 6 min assessed after 12 weeks of treatment.Patients in the riociguat group improved by a mean 30 m increase compared with a mean 6 m decrease in the placebo group (least-squares mean difference 36 m; 95% CI 20 to 52; p<0.001).Secondary end points included: change in pulmonary vascular resistance; N-terminal probrain natiuretic peptide levels; WHO functional class; time to clinical worsening; Borg dyspnoea scale score; quality of life; safety.Patients on riociguat showed significant improvements throughout.Gastrointestinal symptoms occurred more often with riociguat.Although not powered for subgroup analyses, improvements occurred in patients on background therapy plus riociguat and riociguat alone.Greatest benefits were seen in WHO functional classes III and IV.Patients on phosphodiesterase type 5 inhibitors, intravenous prostanoids and those with pulmonary hypertension secondary to HIV, schistosomiasis and chronic haemolytic anaemia were excluded.Care must be taken when extrapolating data to the wider population with pulmonary hypertension.The magnitude of the trial's primary end point was at the lower end of that expected by the authors, perhaps because some patients were already on standard therapies and had better than expected WHO functional class.However, baseline patient characteristics were balanced across the study arms and the percentage dropout was similar.This study supports the use of riociguat as a novel therapy in symptomatic pulmonary hypertension.Longer-term safety and efficacy data collection is ongoing.
Protein kinase C isoform levels in normal and sodium dodecyl sulphate-irritated mouse skin
Authors: None LI, None Fiedler, None Kumar
Journal: British Journal of Dermatology (1998)

Protein kinase C (PKC) comprises a family of related phospholipid-dependent serine/threonine protein kinases. PKC is important in signal transduction, regulating cell proliferation and differentiation. Recently, it has also been suggested that PKC may play a part in the pathogenesis of contact dermatitis. However, the expression of PKC isoforms in the skin of mice with irritant contact dermatitis (ICD) has not been examined. In this study, ICD was induced in mouse skin by applying 5%, 10% and 20% sodium dodecyl sulphate (SDS) in Finn chambers on the backs of mice and fixing with surgical dressings for 24 h. Depending upon the SDS concentration, mild to strong skin irritant reactions were observed 24 h after removal of the irritant patches. The intensity of the reactions increased with the increasing concentration of SDS. PKC isoforms alpha, beta, gamma and delta were all detected in normal mouse skin by Western immunoblotting. The specificity of the PKC isoforms detected was identified further by competitive Western immunoblotting. Compared with normal mouse skin treated with double-distilled water, the levels of PKC isoforms alpha, beta, gamma and delta in the SDS-irritated mouse skin was decreased by 24.8-75.8%. These results suggest that, in SDS-ICD, mouse skin PKC isoforms alpha, beta, gamma and delta are down-regulated. The significance of this decrease is under further investigation.
A Randomized, Multicenter, Placebo-Controlled Clinical Trial of Racotumomab-Alum Vaccine as Switch Maintenance Therapy in Advanced Non–Small Cell Lung Cancer Patients
Authors: Sailyn Alfonso, Anet Valdés-Zayas, Eduardo R. Santiesteban, Yoanna I. Flores, Fernando Areces, Maurenis Hernández, Carmen E. Viada, Ivis C. Mendoza, Pedro P. Guerra, Elena García, Ramón A. Ortiz, Ana V. de la Torre, Meylán Cepeda, Kirenia Pérez, Eric Chong, Ana María Hernández, Darien Toledo, Zuyén González, Zaima Mazorra, Tania Crombet, Rolando Pérez, Ana María Vázquez, Amparo E. Macías
Journal: Clinical Cancer Research (2014)

Racotumomab-alum is an anti-idiotype vaccine targeting the NeuGcGM3 tumor-associated ganglioside. This clinical trial was conducted to provide a preliminary estimate of efficacy and safety of racotumomab as switch maintenance for patients with advanced non-small cell lung cancer (NSCLC).Patients with stage IIIb/IV NSCLC who have at least stable disease after first-line chemotherapy were randomized 1:1 to racotumomab-alum (5 immunizations every 2 weeks and re-immunizations every 4 weeks) or placebo. Treatment was administered beyond progressive disease, until severe performance status worsening or toxicity. At progression, only five patients per group received further anticancer therapy. The primary endpoint was overall survival (OS).One-hundred and seventy-six patients were randomized to racotumomab-alum (n = 87) and placebo (n = 89). Median OS was 8.23 and 6.80 months, respectively [HR, 0.63; 95% confidence interval (CI), 0.46-0.87; P = 0.004]. Median progression-free survival (PFS) in vaccinated patients was 5.33 versus 3.90 months for placebo (HR, 0.73; 95% CI 0.53-0.99; P = 0.039). The most common adverse events in the racotumomab-alum arm were burning and pain at the injection site, bone pain, and asthenia. A high antibody response of IgM and IgG isotype against the NeuGcGM3 ganglioside was obtained. Hyperimmune sera were able to specifically recognize and kill the NeuGcGM3-expressing L1210 cell line. Patients who developed anti-NeuGcGM3 antibodies capable to bind and kill ≥30% L1210 cells showed longer median survival times.Switch maintenance with racotumomab-alum is an effective and a well-tolerated treatment option for patients with advanced NSCLC.
Fast relapse upon discontinuation of tumour necrosis factor blocking therapy in patients with peripheral spondyloarthritis
Authors: Jacqueline E Paramarta, Tanja F Heijda, Dominique L Baeten
Journal: Annals of the Rheumatic Diseases (2013)

Tumour necrosis factor (TNF) blockade is effective in axial spondyloarthritis (SpA), including both ankylosing spondylitis and non-radiographic axial SpA,1 as well as peripheral SpA, which comprises psoriatic arthritis (PsA) but also other SpA subtypes.2 It is well established that anti-TNF therapy discontinuation leads to fast relapse in almost all axial SpA patients.3–8 This study aimed to investigate if similar relapses are seen after anti-TNF therapy discontinuation in peripheral SpA.

Twenty-six patients from our randomised clinical trial with adalimumab in peripheral arthritis in non-AS, non-PsA SpA2 were included. Patients had received either 12 (n=12) or 24 weeks (n=14) of adalimumab2 before discontinuation of the anti-TNF therapy. After discontinuation, patients were followed for 16 weeks and seen for a relapse visit upon worsening of symptoms. Relapse was defined as increase of ≥1 swollen joint, or ≥2 points in patient's or physician's global assessment of disease activity or Bath Ankylosing Spondylitis Disease Activity Index. At the relapse visit, …
Countertransference Phenomena and Personality Pathology in Clinical Practice: An Empirical Investigation
Authors: Ephi Betan, Amy Kegley Heim, Carolyn Zittel Conklin, Drew Westen
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: This study provides initial data on the reliability and factor structure of a measure of countertransference processes in clinical practice and examines the relation between these processes and patients' personality pathology. METHOD: A national random sample of 181 psychiatrists and clinical psychologists in North America each completed a battery of instruments on a randomly selected patient in their care, including measures of axis II symptoms and the Countertransference Questionnaire, an instrument designed to assess clinicians' cognitive, affective, and behavioral responses in interacting with a particular patient. RESULTS: Factor analysis of the Countertransference Questionnaire yielded eight clinically and conceptually coherent factors that were independent of clinicians' theoretical orientation: 1) overwhelmed/disorganized, 2) helpless/inadequate, 3) positive, 4) special/overinvolved, 5) sexualized, 6) disengaged, 7) parental/protective, and 8) criticized/mistreated. The eight factors were associated in predictable ways with axis II pathology. An aggregated portrait of countertransference responses with narcissistic personality disorder patients provided a clinically rich, empirically based description that strongly resembled theoretical and clinical accounts. CONCLUSIONS: Countertransference phenomena can be measured in clinically sophisticated and psychometrically sound ways that tap the complexity of clinicians' reactions toward their patients. Countertransference patterns are systematically related to patients' personality pathology across therapeutic approaches, suggesting that clinicians, regardless of therapeutic orientation, can make diagnostic and therapeutic use of their own responses to the patient.
Nuclear Factor-κB Represses Hypoxia-Induced Mitochondrial Defects and Cell Death of Ventricular Myocytes
Authors: Kelly M. Regula, Delphine Baetz, Lorrie A. Kirshenbaum
Journal: Circulation (2004)

Background— Oxygen deprivation for prolonged periods of time provokes cardiac cell death and ventricular dysfunction. Preventing inappropriate cardiac cell death in patients with ischemic heart disease would be of significant therapeutic value as a means to improve ventricular performance. In the present study, we wished to ascertain whether activation of the cellular factor nuclear factor (NF)-κB suppresses mitochondrial defects and cell death of ventricular myocytes during hypoxic injury. Methods and Results— In contrast to normoxic control cells, ventricular myocytes subjected to hypoxia displayed a 9.1-fold increase ( P &lt;0.05) in cell death, as determined by Hoechst 33258 nuclear staining and vital dyes. Mitochondrial defects consistent with permeability transition pore opening, loss of mitochondrial membrane potential (ΔΨm), and Smac release were observed in cells subjected to hypoxia. An increase in postmitochondrial caspase 9 and caspase 3 activity was observed in hypoxic myocytes. Adenovirus-mediated delivery of wild-type IKKβ (IKKβwt) resulted in a significant increase in NF-κB-dependent DNA binding and gene transcription in ventricular myocytes. Interestingly, subcellular fractionation of myocytes revealed that the p65 subunit of NF-κB was localized to mitochondria. Hypoxia-induced mitochondrial defects and cell death were suppressed in cells expressing IKKβwt but not in cells expressing the kinase-defective IKKβ mutant. Conclusions— To the best of our knowledge, the data provide the first direct evidence that activation of the NF-κB signaling pathways is sufficient to suppress cell death of ventricular myocytes during hypoxia. Moreover, our data further suggest that NF-κB averts cell death through a mechanism that prevents perturbations to the mitochondrion during hypoxic injury.
Resolution of a chronic viral infection after interleukin-10 receptor blockade
Authors: Mette Ejrnaes, Christophe M. Filippi, Marianne M. Martinic, Eleanor M. Ling, Lisa M. Togher, Shane Crotty, Matthias G. von Herrath
Journal: The Journal of Experimental Medicine (2006)

A defining characteristic of persistent viral infections is the loss and functional inactivation of antiviral effector T cells, which prevents viral clearance. Interleukin-10 (IL-10) suppresses cellular immune responses by modulating the function of T cells and antigen-presenting cells. In this paper, we report that IL-10 production is drastically increased in mice persistently infected with lymphocytic choriomeningitis virus. In vivo blockade of the IL-10 receptor (IL-10R) with a neutralizing antibody resulted in rapid resolution of the persistent infection. IL-10 secretion was diminished and interferon γ production by antiviral CD8+ T cells was enhanced. In persistently infected mice, CD8α+ dendritic cell (DC) numbers declined early after infection, whereas CD8α− DC numbers were not affected. CD8α− DCs supported IL-10 production and subsequent dampening of antiviral T cell responses. Therapeutic IL-10R blockade broke the cycle of IL-10–mediated immune suppression, preventing IL-10 priming by CD8α− DCs and enhancing antiviral responses and thereby resolving infection without causing immunopathology.
Evidence for left ventricular dysfunction in patients with obstructive sleep apnoea syndrome
Authors: M. Alchanatis, G. Tourkohoriti, E.N. Kosmas, G. Panoutsopoulos, S. Kakouros, K. Papadima, M. Gaga, J.B. Jordanoglou
Journal: European Respiratory Journal (2002)

There is limited information on the development of left ventricular (LV) dysfunction in patients with obstructive sleep apnoea (OSA) in the absence of lung and cardiac comorbidity. This study aimed to investigate whether OSA patients without heart morbidity develop LV dysfunction, and to assess the effect of continuous positive airway pressure (CPAP) on LV function. Twenty-nine OSA patients and 12 control subjects were studied using technetium-99m ventriculography to estimate LV ejection fraction (LVEF), LV peak emptying rate (LVPER), time to peak emptying rate (TPER), peak filling rate (LVPFR) and time to peak filling rate (TPFR) before and after 6 months of treatment with CPAP. A significantly lower LVEF was found in OSA patients, compared to control subjects, (53±7 versus 61±6%) along with a reduced LVPER (2.82±0.58 versus 3.82±0.77 end-diastolic volumes·s −1 ). Furthermore, OSA patients had significantly lower LVPFR (2.67±0.71 versus 3.93±0.58 end-diastolic volumes·s −1 ) and delayed TPFR (0.19±0.04 versus 0.15±0.03 s) in comparison with the control group. Six-months of CPAP treatment was effective in significantly improving LVEF, LVPER, LVPFR and TPFR. In conclusion, obstructive sleep apnoea patients without any cardiovascular disease seem to develop left ventricular systolic and diastolic dysfunction, which may be reversed, either partially or completely, after 6 months of continuous positive airway pressure treatment.
CD8+ T Cell Tolerance to a Tumor-associated Antigen Is Maintained at the Level of Expansion Rather than Effector Function
Authors: Claes Öhlén, Michael Kalos, Laurence E. Cheng, Aaron C. Shur, Doley J. Hong, Bryan D. Carson, Niels C.T. Kokot, Cara G. Lerner, Blythe D. Sather, Eric S. Huseby, Philip D. Greenberg
Journal: The Journal of Experimental Medicine (2002)

CD8+ T cell tolerance to self-proteins prevents autoimmunity but represents an obstacle to generating T cell responses to tumor-associated antigens. We have made a T cell receptor (TCR) transgenic mouse specific for a tumor antigen and crossed TCR-TG mice to transgenic mice expressing the tumor antigen in hepatocytes (gag-TG). TCRxgag mice showed no signs of autoimmunity despite persistence of high avidity transgenic CD8+ T cells in the periphery. Peripheral CD8+ T cells expressed phenotypic markers consistent with antigen encounter in vivo and had upregulated the antiapoptotic molecule Bcl-2. TCRxgag cells failed to proliferate in response to antigen but demonstrated cytolytic activity and the ability to produce interferon γ. This split tolerance was accompanied by inhibition of Ca2+ flux, ERK1/2, and Jun kinasephosphorylation, and a block in both interleukin 2 production and response to exogenous interleukin 2. The data suggest that proliferation and expression of specific effector functions characteristic of reactive cells are not necessarily linked in CD8+ T cell tolerance.
Biomedical Information, Peer Review, and Conflict of Interest as They Influence Public Health
Authors: Erdem I. Cantekin
Journal: JAMA (1990)

The peer review process serves a vital role in the publication of biomedical information. When properly functioning, review should focus exclusively on questions of scientific validity and should avoid becoming enmeshed in questions such as "authorization" and "data ownership." We present a case in which the dissenting views of a coinvestigator were suppressed because the principal investigator and grantee institution informed a medical journal that the coinvestigator was not "authorized" to use the data generated by a publicly funded grant and because the editor of a scholarly journal refused to review the dissenting manuscript and to submit that dissent to external reviewers for peer review. The current peer review system, as shown by this case, is unable to embrace dissent within the peer review process and to use dissent to serve scientific truth and the public interest. (<i>JAMA</i>. 1990;263:1427-1430)
Molecular Pathways: HER3 Targeted Therapy
Authors: Kinisha Gala, Sarat Chandarlapaty
Journal: Clinical Cancer Research (2014)

Abstract The HER family of receptor tyrosine kinases, including EGF receptor (EGFR), HER2, HER3, and HER4, transduce growth-promoting signals in response to ligand binding to their extracellular domains (ECD). This family is deregulated in numerous cancers, with mutations in EGFR and HER2 often serving as “driver” events to activate key growth factor signaling pathways such as the RAS-ERK and PI3K-AKT pathways. Less attention has been paid to the oncogenic functions of HER3 due to its lack of intrinsic kinase activity. Recent work, however, has placed HER3 in the spotlight as a key signaling hub in several clinical contexts. First, HER3 has been shown to play a major role in mediating resistance to HER2 and phosphoinositide 3-kinase (PI3K) pathway-directed therapies due to its feedback regulation via AKT signaling. Second, activating mutations in HER3 have been identified in multiple cancer types, including gastric, colon, bladder, and non–small cell lung cancers. As a result, HER3 is now being examined as a direct therapeutic target. In the absence of a strong enzymatic activity to target, the focus has been on strategies to prevent HER3 activation including blocking its most relevant dimerization partner's kinase activity (erlotinib, gefitinib, and lapatinib), blocking its most relevant dimerization partner's ability to dimerize with HER3 (trastuzumab and pertuzumab), and directly targeting the HER3 ECD (MM-121, U3-1287, and LJM716). Although drugs targeting EGFR and HER2 have proven effective even as single agents, the preclinical and clinical data on the antibodies directly targeting HER3 suggest more limited potential for single-agent activity. Possible reasons for this include the lack of a suitable biomarker for activated HER3, the lack of potency of the antibodies, and the lack of relevance of HER3 for growth of some of the cancer types analyzed. Nevertheless, clear improvements in activity are being observed for many of these compounds when they are given in combination. In this snapshot, we will highlight the basis for HER3 activation in cancer, the different pharmacologic strategies being used, and opportunities for further development. Clin Cancer Res; 20(6); 1410–6. ©2014 AACR.
Effectiveness of speed cameras in preventing road traffic collisions and related casualties: systematic review
Authors: Paul Pilkington, Sanjay Kinra
Journal: BMJ (2005)

To assess whether speed cameras reduce road traffic collisions and related casualties.Systematic review.Cochrane Injuries Group Specialised Register, Cochrane Central Register of Controlled Trials, Medline, Embase, Social Science Citation Index, TRANSPORT database, ZETOC, the internet (including websites of road safety and motoring organisations), and contact with key individuals and organisations.Road traffic collisions, injuries, and deaths.Controlled trials and observational studies assessing the impact of fixed or mobile speed cameras on any of the selected outcomes.14 observational studies met the inclusion criteria; no randomised controlled trials were found. Most studies were before-after studies without controls (n = 8). All but one of the studies showed effectiveness of cameras up to three years or less after their introduction; one study showed sustained longer term effects (4.6 years after introduction). Reductions in outcomes across studies ranged from 5% to 69% for collisions, 12% to 65% for injuries, and 17% to 71% for deaths in the immediate vicinity of camera sites. The reductions over wider geographical areas were of a similar order of magnitude.Existing research consistently shows that speed cameras are an effective intervention in reducing road traffic collisions and related casualties. The level of evidence is relatively poor, however, as most studies did not have satisfactory comparison groups or adequate control for potential confounders. Controlled introduction of speed cameras with careful data collection may offer improved evidence of their effectiveness in the future.