tbuckley/cabot-search huggingface dataset:
Safety of long-acting β-agonists in asthma
Authors: Gustavo J Rodrigo, Jose A Castro-Rodriguez
Journal: Thorax (2012)

Safety of long-acting β-agonists in asthmaThe study by Wolfe et al 1 certainly does not support our claim that serious asthma exacerbations are more frequent in patients receiving formoterol 24 μg twice daily than in those receiving 12 μg twice daily, or placebo. 2 Actually, this statement should have been based on the review by Mann et al, 3 that assessed data from three prospective, randomised, placebo-controlled and double-blind studies of formoterol at different dosages submitted to the US Food and Drug Administration.The authors concluded that more patients treated regularly with formoterol 24 μg twice daily had serious asthma exacerbations than did patients who had been treated with formoterol 12 μg twice daily, or placebo (4.5% vs 2.0%, vs 0.4%, respectively).In any case, evidence from controlled studies suggests that the use of long-acting β-agonists added to inhaled corticosteroids is safe and effective for the treatment of asthma.
Mesenchymal stem cells overexpressing GCP-2 improve heart function through enhanced angiogenic properties in a myocardial infarction model
Authors: Sung-Whan Kim, Dong-Won Lee, Long-Hao Yu, Hong-Zhe Zhang, Chae Eun Kim, Jong-Min Kim, Tae-Ho Park, Kwang-Soo Cha, Su-Yeong Seo, Mee-Sook Roh, Keun-Cheol Lee, Jin-Sup Jung, Moo Hyun Kim
Journal: Cardiovascular Research (2012)

In this study, our aim was to evaluate the angio-vasculogenic properties of human adipose tissue-derived mesenchymal stem cells overexpressing the granulocyte chemotactic protein (GCP)-2 (hASCs/GCP-2) and to determine possible therapeutic effects in an experimental ischaemic heart model. Quantitative real-time (qRT)–PCR results revealed that hASCs/GCP-2 expressed significantly higher levels of pro-angiogenic genes, including vascular endothelial growth factor (VEGF)-A, hepatocyte growth factor (HGF), and interleukin (IL)-8, when compared with control-vector transduced hASCs or human umbilical vascular endothelial cells (HUVECs). In addition, the anti-apoptotic insulin-like growth factor (IGF)-1 and Akt-1 were also highly up-regulated in the hASCs/GCP-2 cells. In vitro cell migration and proliferation assays showed that hASCs/GCP-2-derived conditioned media (CM) significantly accelerated the migration and proliferation of fibroblast cells. Examination of in vitro endothelial differentiation showed that hASCs/GCP-2 cells spontaneously formed vascular-like structures and highly expressed endothelial-specific genes and proteins. In vivo study results of our mouse myocardial infarction (MI) model revealed that hASCs/GCP-2 implantation improved the cardiac function and reduced the infarct size. Finally, transplanted hASCs/GCP-2 cells unexpectedly differentiated into endothelial cells and the engraftment rate was significantly higher than control groups. We suggest that overexpression of GCP-2 in stem cells has the potential to enhance their angiogenic and survival properties.
Ice-water immersion and delayed-onset muscle soreness: a randomised controlled trial
Authors: Kylie Louise Sellwood, Peter Brukner, David Williams, Alastair Nicol, Rana Hinman
Journal: British Journal of Sports Medicine (2007)

Objective: To determine if ice-water immersion after eccentric quadriceps exercise minimises the symptoms of delayed-onset muscle soreness (DOMS). Design: A prospective randomised double-blind controlled trial was undertaken. 40 untrained volunteers performed an eccentric loading protocol with their non-dominant leg. Interventions: Participants were randomised to three 1-min immersions in either ice water (5±1°C) or tepid water (24°C). Main outcome measures: Pain and tenderness (visual analogue scale), swelling (thigh circumference), function (one-legged hop for distance), maximal isometric strength and serum creatine kinase (CK) recorded at baseline, 24, 48 and 72 h after exercise. Changes in outcome measures over time were compared to determine the effect of group allocation using independent t tests or Mann–Whitney U tests. Results: No significant differences were observed between groups with regard to changes in most pain parameters, tenderness, isometric strength, swelling, hop-for-distance or serum CK over time. There was a significant difference in pain on sit-to-stand at 24 h, with the intervention group demonstrating a greater increase in pain than the control group (median change 8.0 vs 2.0 mm, respectively, p = 0.009). Conclusions: The protocol of ice-water immersion used in this study was ineffectual in minimising markers of DOMS in untrained individuals. This study challenges the wide use of this intervention as a recovery strategy by athletes.
Schizophrenia: Putting context in context
Authors: Sohee Park, Junghee Lee, Bradley Folley, Jejoong Kim
Journal: Behavioral and Brain Sciences (2003)

Abstract Although context-processing deficits may be core features of schizophrenia, context remains a poorly defined concept. To test Phillips &amp; Silverstein's model, we need to operationalize context more precisely. We offer several useful ways of framing context and discuss enhancing or facilitating schizophrenic patients' performance under different contextual situations. Furthermore, creativity may be a byproduct of cognitive uncoordination.
Enhancement of 1,25-Dihydroxyvitamin D3-Mediated Antitumor Activity With Dexamethasone
Authors: Wei-bong Yu, Mariann C. McElwain, Ruth A. Modzelewski, Derick M. Russell, David C. Smith, Donald L. Trump, Candace S. Johnson
Journal: JNCI Journal of the National Cancer Institute (1998)

The active metabolite of vitamin D, i.e., 1,25-dihydroxycholecalciferol (1,25-D3), inhibits the growth of murine SCCVII/SF squamous cell carcinoma cells, both in vitro and in vivo. However, in vivo use of 1,25-D3 is hampered as a result of hypercalcemia (i.e., elevated levels of calcium in the blood). Glucocorticoids, such as dexamethasone, affect calcium absorption and modulate vitamin D receptor binding and have been used to treat hypercalcemia. In this study, we examined the effect of dexamethasone on tumor growth inhibition by 1,25-D3.The effects of 1,25-D3 and dexamethasone, alone and in combination, on the growth of SCCVII/SF cells in in vitro culture or in vivo in female C3H/HeJ mice were determined by clonogenic tumor cell assay and/or by actual changes in tumor volume. Vitamin D receptor-ligand-binding activities in whole-cell extracts from cells (in culture), tumors, and normal tissues were assayed by single-point saturation analysis and equilibrium binding.Treatment of cultured SCCVII/SF cells with 500 nM dexamethasone for 24 hours before addition of 1,25-D3 reduced their survival. The growth of SCCVII/SF tumors was inhibited in mice treated simultaneously with dexamethasone and 1,25-D3 (as compared with no treatment or single-agent treatment); hypercalcemia was also reduced. Total vitamin D receptor content in SCCVII/SF cells was increased after treatment with dexamethasone. Treatment of tumor-bearing animals with dexamethasone (9 microg/day) for 7 days led to increased vitamin D receptor-ligand-binding activities in whole-cell extracts from tumor or kidneys and decreased activity in intestinal mucosa.Dexamethasone may enhance the antitumor effect of 1,25-D3 by increasing vitamin D receptor-ligand-binding activity.
Farnesyltransferase inhibitors reduce ras activation and ameliorate acetaminophen-induced liver injury in mice
Authors: Banishree Saha, Dipankar Nandi
Journal: Hepatology (2009)

Hepatotoxicity due to overdose of the analgesic and antipyretic acetaminophen (APAP) is a major cause of liver failure in adults. To better understand the contributions of different signaling pathways, the expression and role of Ras activation was evaluated after oral dosing of mice with APAP (400-500 mg/kg). Ras-guanosine triphosphate (GTP) is induced early and in an oxidative stress-dependent manner. The functional role of Ras activation was studied by a single intraperitoneal injection of the neutral sphingomyelinase and farnesyltransferase inhibitor (FTI) manumycin A (1 mg/kg), which lowers induction of Ras-GTP and serum amounts of alanine aminotransferase (ALT). APAP dosing decreases hepatic glutathione amounts, which are not affected by manumycin A treatment. However, APAP-induced activation of c-Jun N-terminal kinase, which plays an important role, is reduced by manumycin A. Also, APAP-induced mitochondrial reactive oxygen species are reduced by manumycin A at a later time point during liver injury. Importantly, the induction of genes involved in the inflammatory response (including iNos, gp91phox, and Fasl) and serum amounts of proinflammatory cytokines interferon-gamma (IFNgamma) and tumor necrosis factor alpha, which increase greatly with APAP challenge, are suppressed with manumycin A. The FTI activity of manumycin A is most likely involved in reducing APAP-induced liver injury, because a specific neutral sphingomyelinase inhibitor, GW4869 (1 mg/kg), did not show any hepatoprotective effect. Notably, a structurally distinct FTI, gliotoxin (1 mg/kg), also inhibits Ras activation and reduces serum amounts of ALT and IFN-gamma after APAP dosing. Finally, histological analysis confirmed the hepatoprotective effect of manumycin A and gliotoxin during APAP-induced liver damage.This study identifies a key role for Ras activation and demonstrates the therapeutic efficacy of FTIs during APAP-induced liver injury.
Early Malignant Progression of Hereditary Medullary Thyroid Cancer
Authors: Andreas Machens, Patricia Niccoli-Sire, Josef Hoegel, Karin Frank-Raue, Theo J. van Vroonhoven, Hans-Dietrich Roeher, Robert A. Wahl, Peter Lamesch, Friedhelm Raue, Bernard Conte-Devolx, Henning Dralle
Journal: New England Journal of Medicine (2003)

An age-related progression from C-cell hyperplasia to medullary thyroid carcinoma is associated with various germ-line mutations in the rearranged during transfection (RET) proto-oncogene that could be used to identify the optimal time for prophylactic surgery.
Ubiquitin Proteasome System Stress Underlies Synergistic Killing of Ovarian Cancer Cells by Bortezomib and a Novel HDAC6 Inhibitor
Authors: Martina Bazzaro, Zhenhua Lin, Antonio Santillan, Michael K. Lee, Mei-Cheng Wang, Kwun C. Chan, Robert E. Bristow, Ralph Mazitschek, James Bradner, Richard B.S. Roden
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Elevated metabolic activity of ovarian cancer cells causes increased ubiquitin-proteasome-system (UPS) stress, resulting in their greater sensitivity to the toxic effects of proteasomal inhibition. The proteasomes and a potentially compensatory histone deacetylase 6 (HDAC6)-dependent lysosomal pathway mediate eukaryotic protein turnover. We hypothesized that up-regulation of the HDAC6-dependent lysosomal pathway occurs in response to UPS stress and proteasomal inhibition, and thus, ovarian cancer cell death can be triggered most effectively by coinhibition of both the proteasome- and HDAC6-dependent protein degradation pathways. Experimental Design: To address this hypothesis, we examined HDAC6 expression patterns in normal and cancerous ovarian tissues and used a novel HDAC6-specific inhibitor, NK84, to address HDAC6 function in ovarian cancer. Results: Abnormally high levels of HDAC6 are expressed by ovarian cancer cells in situ and in culture relative to benign epithelium and immortalized ovarian surface epithelium, respectively. Specific HDAC6 inhibition acts in synergy with the proteasome inhibitor Bortezomib (PS-341) to cause selective apoptotic cell death of ovarian cancer cells at doses that do not cause significant toxicity when used individually. Levels of UPS stress regulate the sensitivity of ovarian cancer cells to proteasome/HDAC6 inhibition. Pharmacologic inhibition of HDAC6 also reduces ovarian cancer cell spreading and migration consistent with its known function in regulating microtubule polymerization via deacetylation of α-tubulin. Conclusion: Our results suggest the elevation of both the proteasomal and alternate HDAC6-dependent proteolytic pathways in ovarian cancer and the potential of combined inhibition of proteasome and HDAC6 as a therapy for ovarian cancer.
Hemoglobin Hiroshima (β143 histidine → aspartic acid): a newly identified fast moving beta chain variant associated with increased oxygen affinity and compensatory erythremia
Authors: Howard B. Hamilton, Iwao Iuchi, Takaoki Miyaji, Susumu Shibata
Journal: Journal of Clinical Investigation (1969)

During a survey for hemoglobinopathies in over 9000 residents of Hiroshima Prefecture, Japan, a fast moving hemoglobin was identified in eight members of three generations in a Japanese family. The abnormal hemoglobin, named Hb Hiroshima, constitutes about 50% of the total hemoglobin in hemolysates from the carriers who have a mild erythremia but are otherwise apparently clinically unaffected. All preparations of Hb Hiroshima have increased affinity for oxygen, by either tonometric or oxygen electrode determinations. At pH 7.0, the oxygen pressure, P(50) required to half saturate an unfractionated hemolysate from a carrier was one-half that of Hb A, and the P(50) of a purified sample containing no Hb A was one-fourth that of Hb A. The pH dependence of the oxygen equilibrium (Bohr effect) is below normal, as shown by the absolute value of the Bohr effect factor which is about half that of Hb A, in the pH range between 7.0 and 7.4. The Hill constant, n, for Hb Hiroshima between pH 7.0 and 7.4 is 2-2.4, compared to 2.8-3 for Hb A under the same conditions, indicating reduction of, but not complete abolition of heme-heme interaction. Urea dissociation and canine hybridization tests located the biochemical lesion in the beta chain. Fingerprints (Ingram), carboxypeptidase digestion, and amino acid analysis demonstrated that the substitution was at residue 143 in the beta chain, where histidine was replaced by aspartic acid.In contrast to other recently described high oxygen affinity mutants that show intact Bohr effects, all three of the major characteristics of the reversible combination of hemoglobin with oxygen (oxygen equilibrium, heme-heme interaction, and pH dependence) are affected in Hb Hiroshima. A tentative interpretation of these effects, relating structure to function, is offered in terms of recently developed models of normal hemoglobin.
Virulent Strains of <i>Helicobacter pylori</i> Demonstrate Delayed Phagocytosis and Stimulate Homotypic Phagosome Fusion in Macrophages
Authors: Lee-Ann H. Allen, Larry S. Schlesinger, Byoung Kang
Journal: The Journal of Experimental Medicine (2000)

Helicobacter pylori colonizes the gastric epithelium of ∼50% of the world's population and plays a causative role in the development of gastric and duodenal ulcers. H. pylori is phagocytosed by mononuclear phagocytes, but the internalized bacteria are not killed and the reasons for this host defense defect are unclear. We now show using immunofluorescence and electron microscopy that H. pylori employs an unusual mechanism to avoid phagocytic killing: delayed entry followed by homotypic phagosome fusion. Unopsonized type I H. pylori bound readily to macrophages and were internalized into actin-rich phagosomes after a lag of ∼4 min. Although early (10 min) phagosomes contained single bacilli, H. pylori phagosomes coalesced over the next ∼2 h. The resulting “megasomes” contained multiple viable organisms and were stable for 24 h. Phagosome–phagosome fusion required bacterial protein synthesis and intact host microtubules, and both chloramphenicol and nocodazole increased killing of intracellular H. pylori. Type II strains of H. pylori are less virulent and lack the cag pathogenicity island. In contrast to type I strains, type II H. pylori were rapidly ingested and killed by macrophages and did not stimulate megasome formation. Collectively, our data suggest that megasome formation is an important feature of H. pylori pathogenesis.
Autotaxin–Lysophosphatidic Acid Signaling Axis Mediates Tumorigenesis and Development of Acquired Resistance to Sunitinib in Renal Cell Carcinoma
Authors: Shih-Chi Su, Xiaoxiao Hu, Patrick A. Kenney, Megan M. Merrill, Kara N. Babaian, Xiu-Ying Zhang, Tapati Maity, Shun-Fa Yang, Xin Lin, Christopher G. Wood
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Sunitinib is currently considered as the standard treatment for advanced renal cell carcinoma (RCC). We aimed to better understand the mechanisms of sunitinib action in kidney cancer treatment and in the development of acquired resistance. Experimental Design: Gene expression profiles of RCC tumor endothelium in sunitinib-treated and -untreated patients were analyzed and verified by quantitative PCR and immunohistochemistry. The functional role of the target gene identified was investigated in RCC cell lines and primary cultures in vitro and in preclinical animal models in vivo. Results: Altered expression of autotaxin, an extracellular lysophospholipase D, was detected in sunitinib-treated tumor vasculature of human RCC and in the tumor endothelial cells of RCC xenograft models when adapting to sunitinib. ATX and its catalytic product, lysophosphatidic acid (LPA), regulated the signaling pathways and cell motility of RCC in vitro. However, no marked in vitro effect of ATX-LPA signaling on endothelial cells was observed. Functional blockage of LPA receptor 1 (LPA1) using an LPA1 antagonist, Ki16425, or gene silencing of LPA1 in RCC cells attenuated LPA-mediated intracellular signaling and invasion responses in vitro. Ki16425 treatment also dampened RCC tumorigenesis in vivo. In addition, coadministration of Ki16425 with sunitinib prolonged the sensitivity of RCC to sunitinib in xenograft models, suggesting that ATX-LPA signaling in part mediates the acquired resistance against sunitinib in RCC. Conclusions: Our results reveal that endothelial ATX acts through LPA signaling to promote renal tumorigenesis and is functionally involved in the acquired resistance of RCC to sunitinib. Clin Cancer Res; 19(23); 6461–72. ©2013 AACR.
Optical coherence tomography evaluation of the corneal cap and stromal bed features after laser in situ keratomileusis for high myopia and astigmatism
Authors: Miguel J Maldonado, Lilian Ruiz-Oblitas, Juan M Munuera, Daniel Aliseda, Alfredo Garcı́a-Layana, Javier Moreno-Montañés
Journal: Ophthalmology (2000)
Zoledronic Acid Prevents Bone Loss in Premenopausal Women Undergoing Adjuvant Chemotherapy for Early-Stage Breast Cancer
Authors: Dawn L. Hershman, Donald J. McMahon, Katherine D. Crew, Serge Cremers, Dinaz Irani, Gina Cucchiara, Lois Brafman, Elizabeth Shane
Journal: Journal of Clinical Oncology (2008)

Purpose Adjuvant chemotherapy for breast cancer (BC) may be associated with increased rates of bone loss and decreased bone mineral density (BMD) and may lead to premature osteoporosis and increased fracture risk. We examined whether zoledronic acid (ZA) prevents bone loss in premenopausal women receiving chemotherapy for early-stage BC. Patients and Methods This study is a randomized, double-blind, multicenter, phase III trial comparing ZA (4 mg intravenously every 3 months) versus placebo for 1 year. Premenopausal women underwent serial BMD measurements before initiating chemotherapy and at 6 and 12 months. The primary outcome was percent change in lumbar spine (LS) BMD at 6 months. Secondary outcomes were percent change at any BMD site and markers of bone turnover at 12 months. Linear mixed model analysis for repeated measures was performed. Results Of 101 women who were randomly assigned and completed baseline evaluation, 96 completed the 6-month evaluation, and 85 completed the 12-month evaluation. Baseline characteristics were comparable between the groups. Mean age was 42 years. Placebo was associated with significant decline in LS BMD at both 6 (2.4%) and 12 (4.1%) months. Similarly, total hip BMD declined by 0.8% at 6 months and 2.6% at 12 months. In contrast, BMD remained stable in ZA patients (P &lt; .0001 compared with placebo). Conclusion Premenopausal women receiving chemotherapy for BC sustained significant bone loss at the LS and hip, whereas BMD remained stable in women who received ZA. Administration of ZA during the first year of chemotherapy is an effective and well-tolerated strategy for preventing bone loss.
Heterogeneity's ruses: the neglected role of between-individual variability in longitudinal studies of COPD exacerbations
Authors: M. Sadatsafavi, J. M. FitzGerald
Journal: Thorax (2014)

Studying the causal and temporal association between past and future exacerbations in COPD is an active area of research. Standard survival analysis techniques often used in such studies typically produce results that pertain to the overall population, whereas the greatest interest is in the study of associations within individuals. A factor that can lead to profound discrepancies between population-level and individual-level survival patterns is the between-individual heterogeneity in the rate of exacerbations. We briefly review two studies that, while reporting valid results for the overall population, drew conclusions at the individual level that could not be supported by the observations. We caution on the distinction between population and individual-level associations in survival analysis, and recommend accounting for heterogeneity in future studies.
γH2AX Expression in Tumors Exposed to Cisplatin and Fractionated Irradiation
Authors: C. Adriana Bañuelos, Judit P. Banáth, Joo-Young Kim, Christina Aquino-Parsons, Peggy L. Olive
Journal: Clinical Cancer Research (2009)

Is retention of gammaH2AX foci useful as a biomarker for predicting the response of xenograft tumors to cisplatin with X-ray? Is a similar approach feasible using biopsies from patients with cervical cancer?Mice bearing SiHa, WiDr, or HCT116 xenograft tumors were exposed to cisplatin and/or three daily doses of 2 Gy. Tumors were excised 24 h after treatment and single cells were analyzed for clonogenic fraction and retention of gammaH2AX foci. Tumor biopsies were examined using 47 paraffin-embedded sections from untreated tumors and 24 sections from 8 patients undergoing radiochemotherapy for advanced cancer of the cervix.Residual gammaH2AX measured 24 h after cisplatin injection accurately predicted surviving fraction in SiHa and WiDr xenografts. When a clinically equivalent protocol using cisplatin and fractionated irradiation was employed, the fraction of xenograft cells lacking gammaH2AX ranked survival accurately but underestimated tumor cell kill. Residual gammaH2AX foci were detected in clinical samples; on average, only 25% of tumor nuclei exhibited one or more gammaH2AX foci before treatment and 74% after the start of treatment.gammaH2AX can provide useful information on the response of human tumors to the combination of cisplatin and radiation, but prediction becomes less accurate as more time elapses between treatment and tumor biopsy. Use of residual gammaH2AX as a biomarker for response is feasible when cell survival exceeds approximately 20%, but heterogeneity in endogenous and treatment-induced gammaH2AX must be considered.