tbuckley/cabot-search huggingface dataset:
Prevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist
Authors: Hisashi Makino, Issei Tanaka, Masashi Mukoyama, Akira Sugawara, Kiyoshi Mori, Seiji Muro, Takayoshi Suganami, Kensei Yahata, Rieko Ishibashi, Shuichi Ohuchida, Takayuki Maruyama, Shuh Narumiya, Kazuwa Nakao
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Local production of prostaglandins (PGs) in the kidney is increased in clinical and experimental diabetic nephropathy, but the role of PGs in the pathogenesis and progression of diabetic nephropathy has remained unclear. It is here shown that an orally active antagonist selective for the PGE receptor EP1 subtype potently prevents the progression of nephropathy in streptozotocin-induced diabetic rats. The effects are shown by ameliorated renal and glomerular hypertrophy, decreased mesangial expansion, inhibited transcriptional activation of transforming growth factor-β (TGF-β) and fibronectin, and complete suppression of proteinuria. In vitro, this agent completely inhibits TGF-β and fibronectin upregulation in mesangial cells cultured under high-glucose conditions. These data indicate that the PGE2-EP1 system plays a crucial role in the development of diabetic renal injury in rats. It is further shown that both the EP1 antagonist and aspirin, a nonselective PG synthase inhibitor, markedly attenuate mesangial expansion, whereas only the EP1 antagonist inhibits glomerular hypertrophy and proteinuria, which suggests that these changes are caused by different mechanisms. This study reveals a potential usefulness of selective EP1 blockade as a novel therapeutic strategy for diabetic nephropathy and also brings a new insight into our understanding of this disease.
Sunscreen Use, Wearing Clothes, and Number of Nevi in 6- to 7-Year-Old European Children
Authors: P. Autier, M. Mezzetti, J.-F. Dore, I. Monjaud, M. S. Cattaruzza, H. Luther, F. Renard, M. Andry, A. R. Grivegnee, F. Gentiloni-Silverj, E. Zantedeschi, J. F. Osborn
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: Previous epidemiologic studies have suggested that sunscreen use is associated with an increased risk of melanoma skin cancer. Because high nevi (mole) count in adults is a strong predictor of melanoma, we conducted a study examining the number of nevi in 6- to 7-year-old European children, according to their sunscreen use. Methods: Whole-body and site-specific counts of nevi 2 mm or larger were performed in 631 children in their first year of primary school in four European cities. Independently, parents were interviewed regarding sun exposure, sunscreen use, and physical sun protection of their child. Results: After adjustment for sun exposure and host characteristics (e.g., skin phototype, eye color), the relative risk for high nevus count on the trunk was 1.68 (95% confidence interval [CI] = 1.09–2.59) for the highest level of sunscreen use and 0.59 (95% CI = 0.36–0.97) for the highest level of wearing of clothes while in the sun. The sun protection factor had no effect on nevus counts despite a high median value of 17.4. Sunburn number was not associated with nevus count. The highest risk associated with sunscreen use was found among children who had never experienced sunburn. Conclusions: In white, European children, sunscreen use appears to be associated with development of nevi, probably because it allows longer sun exposures. Wearing clothes may be an effective way to prevent proliferation of nevi. Since a high nevus count is a strong predictor of melanoma, sunscreen use may be involved in melanoma occurrence because it may encourage recreational sun exposure.
Commentary: cause and effect in occupational lung disease
Authors: P S Burge
Journal: Thorax (1995)

Sera were obtained in 415 known cases of malaria (88 residents, 327 immigrants) at different times after diagnosis. Three antigens were used in the indirect fluorscence antibody test to detect antibodies to either Plasmodium falciparum or P vivax. Results in residents and immigrants were analysed separately. Most residents had detectable antibodies within one week after an attack, which began to wane after a month. The strongest reactions were obtained in cases of falciparum malaria with the homologous antigen and in cases of vivax malaria with P fieldi. The overall pattern of results was the same in the immigrants but the proportions positive for malaria antibodies, mean titres, persistence of antibodies, and the cross-reaction were usually greater. Testing for malaria antibodies is probably of value in the retrospective differential diagnosis of malaria in patients who have not been exposed to malaria before but must be interpreted with caution in others.
Measuring tuberculosis burden, trends, and the impact of control programmes
Authors: C Dye, A Bassili, AL Bierrenbach, JF Broekmans, VK Chadha, P Glaziou, PG Gopi, M Hosseini, SJ Kim, D Manissero, I Onozaki, HL Rieder, S Scheele, F van Leth, M van der Werf, BG Williams
Journal: The Lancet Infectious Diseases (2008)
Monovalent type-1 oral poliovirus vaccine given at short intervals in Pakistan: a randomised controlled, four-arm, open-label, non-inferiority trial
Authors: Fatima Mir, Farheen Quadri, Ondrej Mach, Imran Ahmed, Zaid Bhatti, Asia Khan, Najeeb Ur Rehman, Elias Durry, Maha Salama, Steven M Oberste, William C Weldon, Roland W Sutter, Anita K M Zaidi
Journal: The Lancet Infectious Diseases (2015)
EP4 receptor as a new target for bronchodilator therapy
Authors: J. Buckley, M. A. Birrell, S. A. Maher, A. T. Nials, D. L. Clarke, M. G. Belvisi
Journal: Thorax (2011)

<h3>Background</h3> Asthma and chronic obstructive pulmonary disease are airway inflammatory diseases characterised by airflow obstruction. Currently approved bronchodilators such as long-acting β<sub>2</sub> adrenoceptor agonists are the mainstay treatments but often fail to relieve symptoms of chronic obstructive pulmonary disease and severe asthma and safety concerns have been raised over long-term use. The aim of the study was to identify the receptor involved in prostaglandin E<sub>2</sub> (PGE<sub>2</sub>)-induced relaxation in guinea pig, murine, monkey, rat and human airways <i>in vitro</i>. <h3>Methods</h3> Using an extensive range of pharmacological tools, the relaxant potential of PGE<sub>2</sub> and selective agonists for the EP<sub>1–4</sub> receptors in the presence and absence of selective antagonists in guinea pig, murine, monkey, rat and human isolated airways was investigated. <h3>Results</h3> In agreement with previous studies, it was found that the EP<sub>2</sub> receptor mediates PGE<sub>2</sub>-induced relaxation of guinea pig, murine and monkey trachea and that the EP<sub>4</sub> receptor mediates PGE<sub>2</sub>-induced relaxation of the rat trachea. These data have been confirmed in murine airways from EP<sub>2</sub> receptor-deficient mice (<i>Ptger2</i>). In contrast to previous publications, a role for the EP<sub>4</sub> receptor in relaxant responses in human airways <i>in vitro</i> was found. Relaxant activity of AH13205 (EP<sub>2</sub> agonist) was also demonstrated in guinea pig but not human airway tissue, which may explain its failure in clinical studies. <h3>Conclusion</h3> Identification of the receptor mediating PGE<sub>2</sub>-induced relaxation represents a key step in developing a novel bronchodilator therapy. These data explain the lack of bronchodilator activity observed with selective EP<sub>2</sub> receptor agonists in clinical studies.
A HGF/cMET Autocrine Loop Is Operative in Multiple Myeloma Bone Marrow Endothelial Cells and May Represent a Novel Therapeutic Target
Authors: Arianna Ferrucci, Michele Moschetta, Maria Antonia Frassanito, Simona Berardi, Ivana Catacchio, Roberto Ria, Vito Racanelli, Antonella Caivano, Antonio Giovanni Solimando, Daniele Vergara, Michele Maffia, Dominga Latorre, Antonia Rizzello, Alfredo Zito, Paolo Ditonno, Eugenio Maiorano, Domenico Ribatti, Angelo Vacca
Journal: Clinical Cancer Research (2014)

The aim of this study was to investigate the angiogenic role of the hepatocyte growth factor (HGF)/cMET pathway and its inhibition in bone marrow endothelial cells (EC) from patients with multiple myeloma versus from patients with monoclonal gammopathy of undetermined significance (MGUS) or benign anemia (control group).The HGF/cMET pathway was evaluated in ECs from patients with multiple myeloma (multiple myeloma ECs) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies, or on refractory phase to these drugs; in ECs from patients with MGUS (MGECs); and in those patients from the control group. The effects of a selective cMET tyrosine kinase inhibitor (SU11274) on multiple myeloma ECs' angiogenic activities were studied in vitro and in vivo.Multiple myeloma ECs express more HGF, cMET, and activated cMET (phospho (p)-cMET) at both RNA and protein levels versus MGECs and control ECs. Multiple myeloma ECs are able to maintain the HGF/cMET pathway activation in absence of external stimulation, whereas treatment with anti-HGF and anti-cMET neutralizing antibodies (Ab) is able to inhibit cMET activation. The cMET pathway regulates several multiple myeloma EC activities, including chemotaxis, motility, adhesion, spreading, and whole angiogenesis. Its inhibition by SU11274 impairs these activities in a statistically significant fashion when combined with bortezomib or lenalidomide, both in vitro and in vivo.An autocrine HGF/cMET loop sustains multiple myeloma angiogenesis and represents an appealing new target to potentiate the antiangiogenic management of patients with multiple myeloma.
Watchdog criticises drug company for misleading promotional material
Authors: A. O'Dowd
Journal: BMJ (2009)

A watchdog has criticised the drug company Ferring for five breaches of the United Kingdom’s drug advertising code, accusing it of misleading promotion of one of its products that omitted information about possible side effects.

Patients were also wrongly led to believe that they should ask their health professional to prescribe the gonadotrophin releasing hormone antagonist degarelix (sold as Firmagon), used to treat advanced prostate cancer, said the Prescription Medicines Code of Practice Authority in its newly issued ruling. The authority regulates the advertising code of the UK’s drug company representative body, the Association of the British Pharmaceutical Industry.

Ferring Pharmaceuticals employed a press relations agency to promote degarelix. It supplied an approved press release about the launch of degarelix to give to …
The relationship between human semen parameters and environmental exposure to polychlorinated biphenyls and p,p'-DDE.
Authors: Russ Hauser, Zuying Chen, Lucille Pothier, Louise Ryan, Larisa Altshul
Journal: Environmental Health Perspectives (2003)

Scientific and public concern exists about potential reproductive health effects of persistent chlorinated organic chemicals, such as polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane (DDT), and dichlorodiphenyldichloroethylene (DDE, the most stable daughter compound of DDT). To explore the hypothesis that environmental exposures to PCBs and DDE are associated with altered semen parameters, we conducted a cross-sectional study of 212 male partners of subfertile couples who presented to the Massachusetts General Hospital Andrology Laboratory. Semen parameters were analyzed as both a continuous measure and dichotomized based on World Health Organization reference values for sperm concentration (< 20 million/mL), motility (< 50% motile), and Kruger strict criteria for morphology (< 4% normal). The comparison group for the dichotomized analysis was men with all three semen parameters above the reference values. In serum, 57 PCB congeners and p,p -DDE were measured by congener-specific analysis using gas chromatography with electron capture detection. There were dose-response relationships among PCB-138 and sperm motility (odds ratio per tertile, adjusted for age, abstinence, and smoking, and p-value for trend were, respectively, 1.00, 1.68, 2.35, and p-value = 0.03) and morphology (1.00, 1.36, 2.53, p-value = 0.04). There was limited evidence of an inverse relationship between sum of PCBs, as well as those PCBs classified as cytochrome P450 enzyme inducers, with sperm motility and sperm morphology, as well as limited evidence of an inverse association between p,p -DDE and sperm motility. The lack of a consistent relationship among semen parameters and other individual PCB congeners and groupings of congeners may indicate a difference in spermatotoxicity between congeners.
Fluid compartments of the embryonic environment
Authors: E. Jauniaux
Journal: Human Reproduction Update (2000)

The exocoelomic cavity was probably the last remaining physiological body fluid cavity to be explored in the human embryo. Its unique anatomical position has enabled us to study the protein metabolism of the early placenta and secondary yolk sac and to explore materno-embryonic transfer pathways. The exocoelomic cavity forms inside the extraembryonic mesoderm alongside the placental chorionic plate and is now believed to be an important transfer interface and a reservoir of nutrients for the embryo. Maternal or placental proteins filtered in the extraembryonic coelomic cavity are probably absorbed by the secondary yolk sac which is directly connected with the primitive digestive system throughout embryonic development. Protein electrophoresis has shown that the coelomic fluid results from an ultrafiltrate of maternal serum with the addition of specific placental and secondary yolk sac bioproducts demonstrating that the exocoelomic cavity is a physiological liquid extension of the early placenta. The selective sampling of fluid from the exocoelomic cavity has also offered a novel approach to the study of drug and toxin transfer across the early human placenta and as a unique tool to explore embryonic physiology in vivo. Further investigation should include a comparison between the coelomic fluid values of a molecule and its quantifiable presence in decidual, placental and fetal tissues.
Interleukin 17–producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice
Authors: Hui-Chen Hsu, PingAr Yang, John Wang, Qi Wu, Riley Myers, Jian Chen, John Yi, Tanja Guentert, Albert Tousson, Andrea L Stanus, Thuc-vy L Le, Robin G Lorenz, Hui Xu, Jay K Kolls, Robert H Carter, David D Chaplin, Robert W Williams, John D Mountz
Journal: Nature Immunology (2007)
A Bayesian Phylogenetic Method to Estimate Unknown Sequence Ages
Authors: B. Shapiro, S. Y. W. Ho, A. J. Drummond, M. A. Suchard, O. G. Pybus, A. Rambaut
Journal: Molecular Biology and Evolution (2010)

Heterochronous data sets comprise molecular sequences sampled at different points in time. If the temporal range of the sampled sequences is large relative to the rate of mutation, the sampling times can directly calibrate evolutionary rates to calendar time. Here, we extend this calibration process to provide a full probabilistic method that utilizes temporal information in heterochronous data sets to estimate sampling times (leaf-ages) for sequenced for which this information unavailable. Our method is similar to relaxing the constraints of the molecular clock on specific lineages within a phylogenetic tree. Using a combination of synthetic and empirical data sets, we demonstrate that the method estimates leaf-ages reliably and accurately. Potential applications of our approach include incorporating samples of uncertain or radiocarbon-infinite age into ancient DNA analyses, evaluating the temporal signal in a particular sequence or data set, and exploring the reliability of sequence ages that are somehow contentious.
The effect of ambient air pollution on exhaled nitric oxide in the Children's Health Study
Authors: K. Berhane, Y. Zhang, W.S. Linn, E.B. Rappaport, T.M. Bastain, M.T. Salam, T. Islam, F. Lurmann, F.D. Gilliland
Journal: European Respiratory Journal (2010)

We assessed the effect of daily variations in ambient air pollutants on exhaled nitric oxide fraction ( F eNO ) using data from a cohort of school children with large differences in air pollutant exposures from the Children's Health Study. Based on a cohort of 2,240 school children from 13 Southern Californian communities, cumulative lagged average regression models were fitted to determine the association between F eNO and ambient air pollution levels from central site monitors with lags of up to 30 days prior to F eNO testing. Daily 24-h cumulative lagged averages of particles with a 50% cut-off aerodynamic diameter of 2.5 µm (PM 2.5 ; over 1–8 days) and particles with a 50% cut-off aerodynamic diameter of 10 µm (PM 10 ; over 1–7 days), as well as 10:00–18:00 h cumulative lagged average of O 3 (over 1–23 days) were significantly associated with 17.42% (p&lt;0.01), 9.25% (p&lt;0.05) and 14.25% (p&lt;0.01) higher F eNO levels over the interquartile range of 7.5 μg·m −3 , 12.97 μg·m −3 and 15.42 ppb, respectively. The effects of PM 2.5 , PM 10 and O 3 were higher in the warm season. The particulate matter effects were robust to adjustments for effects of O 3 and temperature and did not vary by asthma or allergy status. In summary, short-term increases in PM 2.5 , PM 10 and O 3 were associated with airway inflammation independent of asthma and allergy status, with PM 10 effects significantly higher in the warm season.
Voltage-gated potassium channels regulate calcium-dependent pathways involved in human T lymphocyte activation.
Authors: C S Lin, R C Boltz, J T Blake, M Nguyen, A Talento, P A Fischer, M S Springer, N H Sigal, R S Slaughter, M L Garcia
Journal: The Journal of Experimental Medicine (1993)

The role that potassium channels play in human T lymphocyte activation has been investigated by using specific potassium channel probes. Charybdotoxin (ChTX), a blocker of small conductance Ca(2+)-activated potassium channels (PK,Ca) and voltage-gated potassium channels (PK,V) that are present in human T cells, inhibits the activation of these cells. ChTX blocks T cell activation induced by signals (e.g., anti-CD2, anti-CD3, ionomycin) that elicit a rise in intracellular calcium ([Ca2+]i) by preventing the elevation of [Ca2+]i in a dose-dependent manner. However, ChTX has no effect on the activation pathways (e.g., anti-CD28, interleukin 2 [IL-2]) that are independent of a rise in [Ca2+]i. In the former case, both proliferative response and lymphokine production (IL-2 and interferon gamma) are inhibited by ChTX. The inhibitory effect of ChTX can be demonstrated when added simultaneously, or up to 4 h after the addition of the stimulants. Since ChTX inhibits both PK,Ca and PK,V, we investigated which channel is responsible for these immunosuppressive effects with the use of two other peptides, noxiustoxin (NxTX) and margatoxin (MgTX), which are specific for PK,V. These studies demonstrate that, similar to ChTX, both NxTX and MgTX inhibit lymphokine production and the rise in [Ca2+]i. Taken together, these data provide evidence that blockade of PK,V affects the Ca(2+)-dependent pathways involved in T lymphocyte proliferation and lymphokine production by diminishing the rise in [Ca2+]i that occurs upon T cell activation.
A non-inferiority trial of an attenuated combination strategy (‘COBRA-light’) compared to the original COBRA strategy: clinical results after 26 weeks
Authors: Debby den Uyl, Marieke ter Wee, Maarten Boers, Pit Kerstens, Alexandre Voskuyl, Mike Nurmohamed, Hennie Raterman, Dirkjan van Schaardenburg, Nancy van Dillen, Ben Dijkmans, Willem Lems
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Early, intensive treatment of rheumatoid arthritis (RA) with the combination of (initially high dose) prednisolone, methotrexate and sulfasalazine (COBRA therapy) considerably lowers disease activity and suppresses radiological progression, but is infrequently prescribed in daily practice. Attenuating the COBRA regimen might lessen concerns about side effects, but the efficacy of such strategies is unknown. <h3>Objective</h3> To compare the 'COBRA-light' strategy with only two drugs, comprising a lower dose of prednisolone (starting at 30 mg/day, tapered to 7.5 mg/day in 9 weeks) and methotrexate (escalated to 25 mg/week in 9 weeks) to COBRA therapy (prednisolone 60 mg/day, tapered to 7.5 mg/day in 6 weeks, methotrexate 7.5 mg/week and sulfasalazine 2 g/day). <h3>Method</h3> An open, randomised controlled, non-inferiority trial in 164 patients with early active RA, all treated according to a treat to target strategy. <h3>Results</h3> At baseline patients had moderately active disease: mean (SD) 44-joint disease activity score (DAS44) 4.13 (0.81) for COBRA and 3.95 (0.9) for COBRA-light. After 6 months, DAS44 significantly decreased in both groups (–2.50 (1.21) for COBRA and –2.18 (1.10) for COBRA-light). The adjusted difference in DAS44 improvement between the groups, 0.21 (95% CI –0.11 to 0.53), was smaller than the predefined clinically relevant difference of 0.5. Minimal disease activity (DAS44 &lt;1.6) was reached in almost half of patients in both groups (49% and 41% in COBRA and COBRA-light, respectively). <h3>Conclusions</h3> At 6 months COBRA-light therapy is most likely non-inferior to COBRA therapy. <h3>Clinical Trial Registration Number</h3> 55552928.
Randomized Phase III Study Comparing Preoperative Radiotherapy With Chemoradiotherapy in Nonresectable Rectal Cancer
Authors: Morten Brændengen, Kjell M. Tveit, Åke Berglund, Elke Birkemeyer, Gunilla Frykholm, Lars Påhlman, Johan N. Wiig, Per Byström, Krzysztof Bujko, Bengt Glimelius
Journal: Journal of Clinical Oncology (2008)

Purpose Preoperative chemoradiotherapy is considered standard treatment for locally advanced rectal cancer, although the scientific evidence for the chemotherapy addition is limited. This trial investigated whether chemotherapy as part of a multidisciplinary treatment approach would improve downstaging, survival, and relapse rate. Patients and Methods The randomized study included 207 patients with locally nonresectable T4 primary rectal carcinoma or local recurrence from rectal carcinoma in the period 1996 to 2003. The patients received either chemotherapy (fluorouracil/leucovorin) administered concurrently with radiotherapy (50 Gy) and adjuvant for 16 weeks after surgery (CRT group, n = 98) or radiotherapy alone (50 Gy; RT group, n = 109). Results The two groups were well balanced according to pretreatment characteristics. An R0 resection was performed in 82 patients (84%) in the CRT group and in 74 patients (68%) in the RT group (P = .009). Pathologic complete response was seen in 16% and 7%, respectively. After an R0 + R1 resection, local recurrence was found in 5% and 7%, and distant metastases in 26% and 39%, respectively. Local control (82% v 67% at 5 years; log-rank P = .03), time to treatment failure (63% v 44%; P = .003), cancer-specific survival (72% v 55%; P = .02), and overall survival (66% v 53%; P = .09) all favored the CRT group. Grade 3 or 4 toxicity, mainly GI, was seen in 28 (29%) of 98 and six (6%) of 109, respectively (P = .001). There was no difference in late toxicity. Conclusion CRT improved local control, time to treatment failure, and cancer-specific survival compared with RT alone in patients with nonresectable rectal cancer. The treatments were well tolerated.