tbuckley/cabot-search huggingface dataset:
Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1)
Authors: Norbert Schmitz, Maike Nickelsen, Marita Ziepert, Mathias Haenel, Peter Borchmann, Christian Schmidt, Andreas Viardot, Martin Bentz, Norma Peter, Gerhard Ehninger, Gottfried Doelken, Christian Ruebe, Lorenz Truemper, Andreas Rosenwald, Michael Pfreundschuh, Markus Loeffler, Bertram Glass
Journal: The Lancet Oncology (2012)
Psychiatric Genetics: Applications in Clinical Practiceedited by Jordan W. Smoller, M.D., Sc.D., Beth Rosen Sheidley, M.S., C.G.C., and Ming T. Tsuang, M.D., Ph.D., D.Sc. Arlington, Va., American Psychiatric Publishing, 2008, 337 pp., $60.00.
Authors: JOHN I. NURNBERGER
Journal: American Journal of Psychiatry (2009)
Pharmacological and Clinical Aspects of Heme Oxygenase
Authors: Nader G. Abraham, Attallah Kappas
Journal: Pharmacological Reviews (2008)

This review is intended to stimulate interest in the effect of increased expression of heme oxygenase-1 (HO-1) protein and increased levels of HO activity on normal and pathological states. The HO system includes the heme catabolic pathway, comprising HO and biliverdin reductase, and the products of heme degradation, carbon monoxide (CO), iron, and biliverdin/bilirubin. The role of the HO system in diabetes, inflammation, heart disease, hypertension, neurological disorders, transplantation, endotoxemia and other pathologies is a burgeoning area of research. This review focuses on the clinical potential of increased levels of HO-1 protein and HO activity to ameliorate tissue injury. The use of pharmacological and genetic probes to manipulate HO, leading to new insights into the complex relationship of the HO system with biological and pathological phenomena under investigation, is reviewed. This information is critical in both drug development and the implementation of clinical approaches to moderate and to alleviate the numerous chronic disorders in humans affected by perturbations in the HO system.
A Mouse Model for the Carney Complex Tumor Syndrome Develops Neoplasia in Cyclic AMP–Responsive Tissues
Authors: Lawrence S. Kirschner, Donna F. Kusewitt, Ludmila Matyakhina, William H. Towns, J. Aidan Carney, Heiner Westphal, Constantine A. Stratakis
Journal: Cancer Research (2005)

Abstract Carney complex is an autosomal dominant neoplasia syndrome characterized by spotty skin pigmentation, myxomatosis, endocrine tumors, and schwannomas. This condition may be caused by inactivating mutations in PRKAR1A, the gene encoding the type 1A regulatory subunit of protein kinase A. To better understand the mechanism by which PRKAR1A mutations cause disease, we have developed conventional and conditional null alleles for Prkar1a in the mouse. Prkar1a+/− mice developed nonpigmented schwannomas and fibro-osseous bone lesions beginning at ∼6 months of age. Although genotype-specific cardiac and adrenal lesions were not seen, benign and malignant thyroid neoplasias were observed in older mice. This spectrum of tumors overlaps that seen in Carney complex patients, confirming the validity of this mouse model. Genetic analysis indicated that allelic loss occurred in a subset of tumor cells, suggesting that complete loss of Prkar1a plays a key role in tumorigenesis. Similarly, tissue-specific ablation of Prkar1a from a subset of facial neural crest cells caused the formation of schwannomas with divergent differentiation. These observations confirm the identity of PRKAR1A as a tumor suppressor gene with specific importance to cyclic AMP–responsive tissues and suggest that these mice may be valuable tools not only for understanding endocrine tumorigenesis but also for understanding inherited predispositions for schwannoma formation.
Relapse after treatment with peginterferon -2b alone or in combination with lamivudine in HBeAg positive chronic hepatitis B
Authors: H J Flink, E H C J Buster, I Merican, F Nevens, G Kitis, J Cianciara, R A de Vries, B E Hansen, S W Schalm, H L A Janssen
Journal: Gut (2007)

Interferon induced HBeAg loss is persistent in up to 90% of patients with chronic hepatitis B (HBV).1–3 Older age and vertical transmission have been shown previously to be independent predictors of relapse after conventional IFN.4 Shorter duration of HBV DNA below 0.7 log10 IU/ml was found to predict relapse after lamivudine.5 Predictors of relapse after PEG-IFN treatment are, however, still unknown. Our aim in this study was to investigate the frequency and predictors of relapse after treatment with PEG-IFN α-2b alone or in combination with lamivudine.

Data for this study were extracted from a multicentre randomised controlled trial comparing 52 weeks of PEG-IFN α-2b monotherapy (100 μg/week) with combined PEG-IFN and lamivudine (100 mg/day) in 266 patients with HBeAg positive chronic hepatitis B. The inclusion and exclusion criteria for the study were reported previously.6 Relapse was defined as HBeAg negativity at the end of treatment (week 52) and recurrence of HBeAg at the end of follow up (week 78).

Treatment groups were comparable regarding baseline characteristics. At the end of treatment, 57 of 130 patients (44%) in the combination therapy group and 40 of 136 (29%) in the monotherapy group lost HBeAg (p = 0.01). HBeAg relapse occurred more often in patients treated with PEG-IFN α-2b and lamivudine combination therapy compared with PEG-IFN α-2b alone (22 of 57 patients (39%) vs five of 40 (13%), p = 0.005). Patients with HBeAg relapse were more likely to have relapse of HBV DNA >200 000 copies/ml than …
Chlordecone Exposure and Risk of Prostate Cancer
Authors: Luc Multigner, Jean Rodrigue Ndong, Arnaud Giusti, Marc Romana, Helene Delacroix-Maillard, Sylvaine Cordier, Bernard Jégou, Jean Pierre Thome, Pascal Blanchet
Journal: Journal of Clinical Oncology (2010)

Determining whether environmental estrogens are associated with the risk of prostate cancer may have important implications for our general understanding of this disease. The estrogenic insecticide chlordecone was used extensively in the French West Indies, contaminating the population for more than 30 years. We analyzed the relationship between exposure to chlordecone and the risk of prostate cancer.We investigated 623 men with prostate cancer and 671 controls. Exposure was analyzed according to case-control status, using either current plasma concentration or a cumulative exposure index based on years of exposure. We genotyped two single-nucleotide polymorphisms (rs3829125 and rs17134592) in the gene encoding chlordecone reductase.We found a significant increase in the risk of prostate cancer with increasing plasma chlordecone concentration (odds ratio [OR], 1.77; 95% CI, 1.21 to 2.58 for the highest tertile of values above the limit of detection [LD]; P trend = .002) and for cumulative exposure index (OR, 1.73; 95% CI, 1.04 to 2.88 for the highest quartile; P trend = .004). Stronger associations were observed among those with a positive family history of prostate cancer and among those who had lived in a Western country. The rs3829125 and rs17134592 allele variants were in complete linkage disequilibrium and were found at low frequency (0.04). Among subjects with plasma chlordecone concentrations above the LD, carriers of the allele variants had a higher risk of prostate cancer (OR, 5.23; 95% CI, 0.82 to 33.32).These findings support the hypothesis that exposure to environmental estrogens increases the risk of prostate cancer.
Pulmonary hypertension and COPD: Clinical assessment and biomarkers
Authors: Donato Lacedonia, Giuseppe Valerio, Gazia P. Palladino, Michele Correale, Giovanna E. Carpagnano, Matteo di Biase, Maria P. Foschino Barbaro
Journal: European Respiratory Journal (2013)

Background: The aim of this study was to define clinical characteristics of patients with COPD and PH with particular attention on subgroup which have PH “out of proportion”, investigating the differences in term of inflammatory and oxidative stress status.  Materials and Methods: Patients with COPD and low level of oxygen (PaO2  2), who showed, at echocardiographic study, PAPs > 30 mmHg without left heart systolic and diastolic dysfunction underwent to Right Heart Catheterization (RHC) to evaluate pulmonary pressures. The assay for human IL-6, LTB4, VIP and ET-1 were performed on blood sample taken during RHC in pulmonary artery.  Results: 83 patients were enrolled and divided in three groups: simple COPD when mPAP was less then 25 mmHg (37 pz); COPD with PH if mPAP > 25 mmHg (46 pz) and among these last ones who had mPAP >35mmHg and FEV1  Patients with PH were older and had a BMI higher than others groups, moreover they had lower FEV1 and DLCO. Despite these differences, lower level of PaO2 was observed in the group of patients OP. The levels of ET-1, IL-6 and LTB4 were similar in each groups; VIP was higher in the patients OP than in simple COPD, no difference were with PH-COPD. There was a strongly negative correlation between PaO2 and mPAP and weak positive correlation between mPAP and VIP.  Conclusions: In COPD with PH, the embalance beetween vasocostrictor and vasodilatator mediators seems to be lightly different then in idioptatic PH but the mechanism which leads to PH in this case is complex and not fully understood.
Sensitivity and specificity of a rapid point-of-care test for active yaws: a comparative study
Authors: Telek Ayove, Wendy Houniei, Regina Wangnapi, Sibauk V Bieb, Walter Kazadi, Lisol-Nirau Luke, Clement Manineng, Penias Moses, Raymond Paru, Javan Esfandiari, Pedro L Alonso, Elisa de Lazzari, Quique Bassat, David Mabey, Oriol Mitjà
Journal: The Lancet Global Health (2014)

To eradicate yaws, national control programmes use the Morges strategy (initial mass treatment and biannual resurveys). The resurvey component is designed to actively detect and treat remaining yaws cases and is initiated on the basis of laboratory-supported reactive non-treponemal serology (using the rapid plasma reagin [RPR] test). Unfortunately, the RPR test is available rarely in yaws-endemic areas. We sought to assess a new point-of-care assay-the Dual Path Platform (DPP) syphilis assay, which is based on simultaneous detection of antibodies to treponemal and non-treponemal antigens-for guiding use of antibiotics for yaws eradication. A secondary goal was to ascertain at what timepoint the DPP assay line reverted to negative after treatment.703 children (aged 1-18 years) with suspected clinical yaws living in two remote, yaws-endemic villages in Papua New Guinea were enrolled. Clinical suspicion of yaws was established according to a WHO pictorial guide. We obtained blood samples from all patients. We calculated the sensitivity and specificity of the DPP assay for detection of antibodies to treponemal (T1) and non-treponemal (T2) antigens and compared values against those obtained with standard laboratory tests (the Treponema pallidum haemagglutination assay [TPHA] and the RPR test). We followed up a subsample of children with dually positive serology (T1 and T2) to monitor changes in DPP optical density (using an automatic reader) at 3 and 6 months. This trial is registered with ClinicalTrials.gov, number NCT01841203.Of 703 participants, 389 (55%) were reactive for TPHA, 305 (43%) for the RPR test, and 287 (41%) for both TPHA and the RPR test. The DPP T1 (treponemal) assay had a sensitivity of 88·4% (95% CI 84·8-91·4) and specificity of 95·2% (92·2-97·3). The DPP T2 (non-treponemal) assay had a sensitivity of 87·9% (83·7-91·3) and specificity of 92·5% (89·4-94·9). In subgroup analyses, sensitivities and specificities did not differ according to type of specimen (plasma vs whole blood). For specimens with an RPR titre of 1:8 or greater, the sensitivity of the DPP T2 assay was 94·1% (95% CI 89·9-96·9). Serological cure (including seroreversion or a fourfold reduction in optical density value) was attained at 6 months in 173 (95%) of 182 children with dual-positive serology.The DPP assay is accurate for identification of antibodies to treponemal and non-treponemal antigens in patients with yaws and avoids the need for laboratory support. A change of diagnostic procedure from the currently implemented RPR test to the simpler DPP assay could ease the implementation of yaws eradication activities.Chembio Diagnostic Systems, Newcrest Mining, and the Papua New Guinea National Department of Health.
Renovascular Hypertension in Rats Immunized with Angiotensin II
Authors: IVAR EIDE
Journal: Circulation Research (1972)

The experimental design which most closely reproduces clinical renovascular hypertension is constriction of one renal artery, with the other renal artery and kidney left intact. To test the role of renin and angiotensin in the pathogenesis of renovascular hypertension, attempts were made to induce such hypertension in rats previously immunized with angiotensin. In 29 highly immunized and 33 control rats, one renal artery was partially constricted and the other kidney and renal artery left intact. Preoperative blood pressures were equal in all rats (means: immunized, 118 ± SE 0.95; controls, 117 ± 0.70 mm Hg). Both groups developed hypertension during the 13 days following operation (means: immunized, 173 ± 3.42; controls, 169 ± 4.65 mm Hg). The high blood pressures persisted throughout the observation period (56 days). Immune sera completely inactivated large amounts of angiotensin (mean, 1130 ± SD 887 ng/ml antiserum; range 200-4000), and high intravenous doses of renin and angiotensin had no effect on the blood pressure of immunized rats. These data provide strong evidence that the direct pressor effect of circulating angiotensin is not essential for the development of hypertension evoked by constricting one renal artery in the rat.
Treating Patients With EGFR-Sensitizing Mutations: First Line or Second Line—Is There a Difference?
Authors: Tony Mok, Jin-Ji Yang, Kwok-Chi Lam
Journal: Journal of Clinical Oncology (2013)

First-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is a standard treatment for patients with activating EGFR mutations. Six randomized studies have demonstrated consistent improvement in tumor response rate and progression-free survival over platinum-based combination chemotherapy. The only reason to consider EGFR TKI as second-line therapy is that none of the six comparative studies has shown improvement in overall survival, which can be explained by the high proportion of patients from the chemotherapy arm crossing over to the EGFR TKI arm on progression. It is true that patients with EGFR mutations may benefit from second-line EGFR TKI therapy, but we cannot conclude that the benefit is either equal to or inferior to first-line EGFR TKI therapy. To date, there are no direct comparative data between first- and second-line EGFR TKI in patients with activating EGFR mutations. Tumor response rates to second-line EGFR TKI have been inconsistent, which could potentially be explained by the impact of first-line chemotherapy on the abundance of tumor cells with activating EGFR mutations. However, numerous arguments, including assurance on drug exposure, improvement in quality of life, better tolerance by patients with poor performance status, and deferral of whole-brain radiation therapy for patients with brain metastasis, support the general application of first-line EGFR TKI.
Interleukin 6 Receptor Blockade in Patients With Neuromyelitis Optica Nonresponsive to Anti-CD20 Therapy
Authors: Ilya Ayzenberg, Ingo Kleiter, Alexandra Schröder, Kerstin Hellwig, Andrew Chan, Takashi Yamamura, Ralf Gold
Journal: JAMA Neurology (2013)

To report first experiences with interleukin 6 receptor inhibition in therapy-resistant neuromyelitis optica (NMO).Retrospective case series.Neurology department at a tertiary referral center.Patients with an aggressive course of NMO switched to tocilizumab after failure of anti-CD20 therapy.Annualized relapse rate and disability progression measured by the Expanded Disability Status Scale.We report 3 female patients with a median age of 39 years (range, 26-40 years) and aquaporin 4-positive NMO. All patients had been treated with different immunosuppressive and immunomodulating agents, followed by 1 to 3 cycles of rituximab. Despite complete CD20-cell depletion during rituximab therapy, the median annualized relapse rate was 3.0 (range, 2.3-3.0) and the median Expanded Disability Status Scale score increased from 5.0 (range, 4.5-7.0) to 6.5 (range, 5.0-7.0). After the switch to tocilizumab (median duration of therapy, 18 months), the median annualized relapse rate decreased to 0.6 (range, 0-1.3). A total of 2 relapses occurred; however, they were mild and there were no changes in clinical disability.Interleukin 6 receptor-blocking therapy can be effective in therapy-resistant cases of NMO. Larger controlled studies are needed to confirm the efficacy of tocilizumab.
Endotoxin-stimulated macrophages decrease bile acid uptake in WIF-B cells, a rat hepatoma hybrid cell line
Authors: Ekkehard Sturm, Tracy L. Zimmerman, Aleta R. Crawford, Stanislav I. Svetlov, Pazhani Sundaram, J. L. Ferrara, Saul J. Karpen, James M. Crawford
Journal: Hepatology (2000)

Endotoxemia leads to cytokine-mediated alterations of the hepatocellular sodium-taurocholate-cotransporting polypeptide (ntcp). We hypothesized that stimulated macrophages are essential transducers for down-regulating hepatocellular bile salt uptake in response to endotoxin (lipopolysaccharide [LPS]) exposure. Using an in vitro model, we exposed mouse macrophages (IC-21 cell line) to LPS for 24 hours. Concentrations of cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 increased 10.6-fold, 12.5-fold, and 444-fold, respectively, in LPS-conditioned IC-21 medium (CM) versus unconditioned IC-21 medium (UM). WIF-B rat hepatoma hybrid cells were incubated with either CM or UM or treated directly with medium containing recombinant TNF-alpha, IL-1beta, and IL-6. [(3)H]Taurocholate ([(3)H]TC) uptake decreased in WIF-B cells exposed to either TNF-alpha (54% of control), IL-1beta (78%), IL-6 (55%) as single additives, or in triple combination (TCC) (43%). A virtually identical decrease was observed after exposing WIF-B cells to CM (52%, P <.001). LPS had no direct effect on [(3)H]TC uptake. CM treatment did not decrease L-alanine transport in WIF-B cells. Blocking antibodies against TNF-alpha, IL-1beta, and IL-6 restored the diminished [(3)H]TC uptake in cells exposed to TCC and CM to 87% and 107% of controls, respectively. Northern blotting revealed that ntcp messenger RNA (mRNA) expression was significantly reduced in WIF-B cells after exposure to CM, and in primary rat hepatocytes exposed to CM or TNF-alpha (68%, 14%, and 29% of control, respectively). We conclude that macrophages and their ability to secrete the cytokines TNF-alpha, IL-1beta, and IL-6 may be essential in mediating the endotoxin-induced cholestatic effect of decreased hepatocellular bile salt uptake.
Correction of the Enzymatic and Functional Deficits in a Model of Pompe Disease Using Adeno-associated Virus Vectors
Authors: Thomas J. Fraites, Mary R. Schleissing, R.Andrew Shanely, Glenn A. Walter, Denise A. Cloutier, Irene Zolotukhin, Daniel F. Pauly, Nina Raben, Paul H. Plotz, Scott K. Powers, Paul D. Kessler, Barry J. Byrne
Journal: Molecular Therapy (2002)

Pompe disease is a lysosomal storage disease caused by the absence of acid α-1,4 glucosidase (GAA). The pathophysiology of Pompe disease includes generalized myopathy of both cardiac and skeletal muscle. We sought to use recombinant adeno-associated virus (rAAV) vectors to deliver functional GAA genes in vitro and in vivo. Myotubes and fibroblasts from Pompe patients were transduced in vitro with rAAV2-GAA. At 14 days postinfection, GAA activities were at least fourfold higher than in their respective untransduced controls, with a 10-fold increase observed in GAA-deficient myotubes. BALB/c and Gaa−/− mice were also treated with rAAV vectors. Persistent expression of vector-derived human GAA was observed in BALB/c mice up to 6 months after treatment. In Gaa−/− mice, intramuscular and intramyocardial delivery of rAAV2-Gaa (carrying the mouse Gaa cDNA) resulted in near-normal enzyme activities. Skeletal muscle contractility was partially restored in the soleus muscles of treated Gaa−/− mice, indicating the potential for vector-mediated restoration of both enzymatic activity and muscle function. Furthermore, intramuscular treatment with a recombinant AAV serotype 1 vector (rAAV1-Gaa) led to nearly eight times normal enzymatic activity in Gaa−/− mice, with concomitant glycogen clearance as assessed in vitro and by proton magnetic resonance spectroscopy. Pompe disease is a lysosomal storage disease caused by the absence of acid α-1,4 glucosidase (GAA). The pathophysiology of Pompe disease includes generalized myopathy of both cardiac and skeletal muscle. We sought to use recombinant adeno-associated virus (rAAV) vectors to deliver functional GAA genes in vitro and in vivo. Myotubes and fibroblasts from Pompe patients were transduced in vitro with rAAV2-GAA. At 14 days postinfection, GAA activities were at least fourfold higher than in their respective untransduced controls, with a 10-fold increase observed in GAA-deficient myotubes. BALB/c and Gaa−/− mice were also treated with rAAV vectors. Persistent expression of vector-derived human GAA was observed in BALB/c mice up to 6 months after treatment. In Gaa−/− mice, intramuscular and intramyocardial delivery of rAAV2-Gaa (carrying the mouse Gaa cDNA) resulted in near-normal enzyme activities. Skeletal muscle contractility was partially restored in the soleus muscles of treated Gaa−/− mice, indicating the potential for vector-mediated restoration of both enzymatic activity and muscle function. Furthermore, intramuscular treatment with a recombinant AAV serotype 1 vector (rAAV1-Gaa) led to nearly eight times normal enzymatic activity in Gaa−/− mice, with concomitant glycogen clearance as assessed in vitro and by proton magnetic resonance spectroscopy.
Influence of Coronary Flow upon Oxygen Consumption and Cardiac Performance
Authors: Howard Weisberg, Louis N. Katz, Eugene Boyd
Journal: Circulation Research (1963)

The influence of induced changes in coronary flow upon oxygen consumption and cardiac performance were observed in the in situ isovolumic left ventricle. This preparation was established with auxiliary pumps which bypass the dog's right and left heart and by inserting a balloon into the left ventricle so that the latter ejected no blood. Coronary flow was set or varied by a retrograde aortic perfusion pump. Oxygen consumption of the heart was found to be coronary flow dependent or independent, according to the conditions of the experiment. When it is coronary flow dependent there is usually a similar relationship between coronary flow and cardiac performance. In a single preparation, it was sometimes found that cardiac oxygen consumption was coronary flow dependent at lower rates of coronary flow and independent at higher flow rates. Possible explanations and clinical applications are given.