tbuckley/cabot-search huggingface dataset:
Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors
Authors: D.S. Boss, P.O. Witteveen, J. van der Sar, M.P. Lolkema, E.E. Voest, P.K. Stockman, O. Ataman, D. Wilson, S. Das, J.H. Schellens
Journal: Annals of Oncology (2010)

To determine, for each of two dosing schedules, the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of AZD1152, an Aurora B kinase inhibitor, and to evaluate its safety, biologic activity and pharmacokinetics (PK).Patients with advanced solid malignancies were treated with escalating doses (100-650 mg) of AZD1152, administered as a 2-h infusion every 7 days (A) or 14 days (B). Adverse events (AEs), PK variables and tumor response were assessed.Fifty-nine patients were treated; 19 in schedule A and 40 in schedule B. The MTDs were 200 and 450 mg, respectively. Neutropenia (with/without fever) was the most frequent AE and DLT in each schedule. Common Terminology Criteria of Adverse Events version 3.0 grade ≥3 neutropenia and leukopenia occurred in 58% and 11% of patients, respectively, in schedule A and 43% and 20%, respectively, in schedule B. No objective tumor responses were observed at any dose or schedule, although stable disease, as defined by RECIST, was achieved in 15 patients (25%) overall. Systemic exposure to AZD1152-hQPA (active drug) was observed by 1 h into the infusion and exhibited linear PK.AZD1152 was generally well tolerated with neutropenia being the most frequently reported AE and DLT. Exposure to AZD1152-hQPA, the active drug of AZD1152, was linear.
MiR-124-5p inhibits the growth of high-grade gliomas through posttranscriptional regulation of LAMB1
Authors: Q. Chen, G. Lu, Y. Cai, Y. Li, R. Xu, Y. Ke, S. Zhang
Journal: Neuro-Oncology (2014)

Glioblastoma multiforme (GBM) is the most aggressive form of human brain tumor. It was previously shown that high levels of laminin-8 expression were a predictor of tumor recurrence and patient survival. It is thus important to elucidate the mechanism by which laminin-8 expression is regulated and determine how this contributes to glioma progression. This study investigated the mechanism of regulation of LAMB1, which encodes the β1 chain of laminin-8, in glioma cells lines and in a mouse model of GBM. The expression levels of LAMB1 and miR-124-5p were examined in glioma cell lines (U87 and U251) and GBM tissue samples by quantitative PCR and Western blotting. The potential regulation of LAMB1 by miR-124-5p was investigated by assessing the effects of restored miR-124-5p expression on cell proliferation, colony formation, and tumor growth and angiogenesis. The effects of inhibiting LAMB1 on tumor growth and angiogenesis were also assessed. The upregulation of LAMB1 expression was highly correlated with the downregulation of miR-124-5p. LAMB1 protein expression was suppressed by miR-124-5p. The restoration of miR-124-5p expression suppressed glioma growth by inhibiting angiogenesis, effects that were also observed upon LAMB1 knockdown. The findings indicate that miR-124-5p functions as a tumor suppressor and could serve as a molecular marker for glioma diagnosis and as a potential therapeutic target in GBM treatment.
A Non-Nephrotoxic Gentamicin Congener That Retains Antimicrobial Efficacy
Authors: Ruben M Sandoval, James P Reilly, William Running, Silvia B Campos, Joseph R Santos, Carrie L Phillips, Bruce A Molitoris
Journal: Journal of the American Society of Nephrology (2006)

Aminoglycoside antibiotics, although of major clinical importance in the treatment of serious Gram- negative infections and a potential therapeutic agent in the amelioration of diseases that are characterized by premature stop mutations, are associated with a high incidence of acute renal failure. With the use of HPLC techniques, the four components (congeners) of gentamicin, the most commonly used aminoglycoside, were isolated and characterized. Described here is a congener with minimal cytotoxicity in cell culture and animal studies that retained normal bactericidal properties in both Bacillus subtilis and a multidrug-resistant form of Klebsiella pneumoniae. Furthermore, in animal studies, this congener failed to induce the functional and pathologic changes that are characteristic of gentamicin nephrotoxicity that is seen with the native compound. Finally, internalization of this non-nephrotoxic component was unaltered, but the subcellular distribution was different from native gentamicin or the other three cytotoxic congeners. These studies have identified a component of the native gentamicin congener mixture that retains its bactericidal properties with minimal or no apparent nephrotoxicity.
Engagement of major histocompatibility complex class II molecules by superantigen induces inflammatory cytokine gene expression in human rheumatoid fibroblast-like synoviocytes.
Authors: W Mourad, K Mehindate, T J Schall, S R McColl
Journal: The Journal of Experimental Medicine (1992)

Cells in the rheumatoid synovium express high levels of major histocompatibility complex (MHC) class II molecules in vivo. We have therefore examined the ability of engagement of MHC class II molecules by the superantigen Staphylococcal enterotoxin A (SEA) to activate interleukin 6 (IL-6) and IL-8 gene expression in type B synoviocytes isolated from patients with rheumatoid arthritis. SEA had a minimal or undetectable effect on the expression of either gene in resting synoviocytes, as determined by Northern blot and specific enzyme-linked immunosorbent assay. However, induction of MHC class II molecule expression after treatment of synoviocytes with interferon gamma (IFN-gamma) enabled the cells to respond to SEA in a dose-dependent manner, resulting in an increase in both the level of steady-state mRNA for IL-6 and IL-8, and the release of these cytokines into the supernatant. IFN-gamma by itself had no effect on the expression of either cytokine. Pretreatment of the cells with the transcription inhibitor actinomycin D prevented the increase in cytokine mRNA induced by SEA, whereas cycloheximide superinduced mRNA for both cytokines after stimulation by SEA. Taken together, these results indicate that signaling through MHC class II molecules may represent a novel mechanism by which inflammatory cytokine production is regulated in type B rheumatoid synoviocytes, and potentially provides insight into the manner by which superantigens may initiate and/or propagate autoimmune diseases.
Relationship Between Male Pattern Baldness and the Risk of Aggressive Prostate Cancer: An Analysis of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
Authors: Cindy Ke Zhou, Ruth M. Pfeiffer, Sean D. Cleary, Heather J. Hoffman, Paul H. Levine, Lisa W. Chu, Ann W. Hsing, Michael B. Cook
Journal: Journal of Clinical Oncology (2014)

Purpose Male pattern baldness and prostate cancer appear to share common pathophysiologic mechanisms. However, results from previous studies that assess their relationship have been inconsistent. Therefore, we investigated the association of male pattern baldness at age 45 years with risks of overall and subtypes of prostate cancer in a large, prospective cohort—the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Methods We included 39,070 men from the usual care and screening arms of the trial cohort who had no cancer diagnosis (excluding nonmelanoma skin cancer) at the start of follow-up and recalled their hair-loss patterns at age 45 years. Hazard ratios (HRs) and 95% CIs were estimated by using Cox proportional hazards regression models with age as the time metric. Results During follow-up (median, 2.78 years), 1,138 incident prostate cancer cases were diagnosed, 571 of which were aggressive (biopsy Gleason score ≥ 7, and/or clinical stage III or greater, and/or fatal). Compared with no baldness, frontal plus moderate vertex baldness at age 45 years was not significantly associated with overall (HR, 1.19; 95% CI, 0.98 to 1.45) or nonaggressive (HR, 0.97; 95% CI, 0.72 to 1.30) prostate cancer risk but was significantly associated with increased risk of aggressive prostate cancer (HR, 1.39; 95% CI, 1.07 to 1.80). Adjustment for covariates did not substantially alter these estimates. Other classes of baldness were not significantly associated with overall or subtypes of prostate cancer. Conclusion Our analysis indicates that frontal plus moderate vertex baldness at age 45 years is associated with an increased risk of aggressive prostate cancer and supports the possibility of common pathophysiologic mechanisms.
Galectin-1 Promotes Lung Cancer Progression and Chemoresistance by Upregulating p38 MAPK, ERK, and Cyclooxygenase-2
Authors: Ling-Yen Chung, Shye-Jye Tang, Guang-Huan Sun, Teh-Ying Chou, Tien-Shun Yeh, Sung-Liang Yu, Kuang-Hui Sun
Journal: Clinical Cancer Research (2012)

This study is aimed at investigating the role and novel molecular mechanisms of galectin-1 in lung cancer progression.The role of galectin-1 in lung cancer progression was evaluated both in vitro and in vivo by short hairpin RNA (shRNA)-mediated knockdown of galectin-1 in lung adenocarcinoma cell lines. To explore novel molecular mechanisms underlying galectin-1-mediated tumor progression, we analyzed gene expression profiles and signaling pathways using reverse transcription PCR and Western blotting. A tissue microarray containing samples from patients with lung cancer was used to examine the expression of galectin-1 in lung cancer.We found overexpression of galectin-1 in non-small cell lung cancer (NSCLC) cell lines. Suppression of endogenous galectin-1 in lung adenocarcinoma resulted in reduction of the cell migration, invasion, and anchorage-independent growth in vitro and tumor growth in mice. In particular, COX-2 was downregulated in galectin-1-knockdown cells. The decreased tumor invasion and anchorage-independent growth abilities were rescued after reexpression of COX-2 in galectin-1-knockdown cells. Furthermore, we found that TGF-β1 promoted COX-2 expression through galectin-1 interaction with Ras and subsequent activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and NF-κB pathway. Galectin-1 knockdown sensitized lung cancer cells to platinum-based chemotherapy (cisplatin). In addition, galectin-1 and COX-2 expression was correlated with the progression of lung adenocarcinoma, and high clinical relevance of both proteins was evidenced (n = 47).p38 MAPK, ERK, and COX-2 activation are novel mediators for the galectin-1-promoted tumor progression and chemoresistance in lung cancer. Galectin-1 may be an innovative target for combined modality therapy for lung cancer.
TRIM genes are part of the interferon signature observed in patients with primary Sjögren's syndrome
Authors: Maria Sjöstrand, Susanna Brauner, Marika Kvarnström, Marie Wahren-Herlenius, Alexander Espinosa
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background and objectives</h3> Autoimmune disease can arise when the immune system is overactive in response to a trigger. This results in an overproduction of proinflammatory cytokines and type I interferons (IFNs). The latter is associated with the pathology of several systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and primary Sjögren9s syndrome (pSS). In this study the authors wanted to identify interferon signature genes that contribute to the pathogenesis of pSS. To do so, the authors did gene expression profiling on patients with pSS. The authors identified several tripartite-motif (TRIM) genes that were overexpressed in patients and that are candidates for IFN signature effector genes. The human TRIM family consists of approximately 70 genes, many of which are important infection-restricting factors or immune regulators. Interestingly, altered expression of TRIMs has previously been reported in several autoimmune diseases. <h3>Materials and methods</h3> PBMCs from 14 female SSA positive and untreated patients with pSS and 18 age and gender matched healthy controls without any immunological disease were collected. mRNA was prepared using the QIAGEN RNeasy Plus Mini Kit and a gene expression array was performed using the Human Exon 1.0 ST chip from Affymetrix. CEL files were preprocessed using the RMA algorithm as implemented in Affymetrix Power Tools-1.12.0. <h3>Results</h3> A strong upregulation of IFN induced genes in PBMCs from patients with pSS compared with PBMCs from healthy controls was observed. Data also revealed differential expression of a set of TRIM genes between pSS patients and healthy controls. TRIM5, TRIM6, TRIM14, TRIM19, TRIM22 and TRIM25 were upregulated in the patients while TRIM18 and TRIM68 were downregulated. Of certain interest is TRIM5, a well-characterised retroviral restriction factor that acts on the viral capsid to destabilise it. Single nucleotide polymorphisms (SNPs) in the TRIM5 gene have been correlated to multiple sclerosis, indicating its possible importance in autoimmune disease. TRIM22 has also been identified as a retroviral restriction factor acting on HIV-1. TRIM68, also known as SS56, is an autoantigen in SLE and pSS. TRIM25 acts on the pattern recognition receptor RIG-1 after viral infection leading to an increased production of IFNα. TRIM25 is overexpressed in breast and ovarian cancers. <h3>Conclusions</h3> Our findings show that several TRIM genes are differentially expressed in patients with pSS compared to controls. TRIM genes are important for the proper regulation of immune responses suggesting that the identified TRIMs might contribute to the pathology of pSS.
Addition of sodium metabisulphite to left atrial catheter infusates as a means of preventing bacterial colonisation of the catheter tip.
Authors: R Freeman, M P Holden, R Lyon, N Hjersing
Journal: Thorax (1982)

Sodium metabisulphite (SMBS) was added at a concentration of 0.05% to the dextrose-heparin solution used to flush left atrial catheters in one group of open-heart surgery patients. Two other groups of patients had left atrial catheters flushed with dextrose-heparin alone. Comparison of the isolation rate of organisms from the tips of the catheters in the three groups showed that the addition of SMBS significantly reduced bacterial contamination in the lines (two isolations from 36 catheters with SMBS added, compared with 13 from 56 and 15 from 65 in the other groups--that is, 5.55% compared with 23.2% and 23.1%). The protective effect of the SMBS was particularly evident in the first 48 hours after catheter insertion. No haematological or biochemical insult was found.
Primary Gastric Plasmacytoma and <i>Helicobacter pylori</i> Infection
Authors: Roberto Stasi, Maria Laura Evangelista, Maurizio Brunetti, Stefano Bussa, Raffaele Maritati, Annalisa Gallo, Luca Turrini, Silvia Taccogna, Anna Crescenzi, Francesco Angelini
Journal: Journal of Clinical Oncology (2008)
A Stochastic Evolutionary Model for Protein Structure Alignment and Phylogeny
Authors: C. J. Challis, S. C. Schmidler
Journal: Molecular Biology and Evolution (2012)

We present a stochastic process model for the joint evolution of protein primary and tertiary structure, suitable for use in alignment and estimation of phylogeny. Indels arise from a classic Links model, and mutations follow a standard substitution matrix, whereas backbone atoms diffuse in three-dimensional space according to an Ornstein–Uhlenbeck process. The model allows for simultaneous estimation of evolutionary distances, indel rates, structural drift rates, and alignments, while fully accounting for uncertainty. The inclusion of structural information enables phylogenetic inference on time scales not previously attainable with sequence evolution models. The model also provides a tool for testing evolutionary hypotheses and improving our understanding of protein structural evolution.
Adeno-associated Virus Vector Serotypes Mediate Sustained Correction of Bilirubin UDP Glucuronosyltransferase Deficiency in Rats
Authors: Jurgen Seppen, Conny Bakker, Berry de Jong, Cindy Kunne, Karin van den Oever, Kristin Vandenberghe, Rudi de Waart, Jaap Twisk, Piter Bosma
Journal: Molecular Therapy (2006)

Crigler-Najjar (CN) patients have no bilirubin UDP glucuronosyltransferase (UGT1A1) activity and suffer brain damage because of bilirubin toxicity. Vectors based on adeno-associated virus (AAV) serotype 2 transduce liver cells with relatively low efficiency. Recently, AAV serotypes 1, 6, and 8 have been shown to be more efficient for liver cell transduction. We compared AAV serotypes 1, 2, 6, and 8 for correction of UGT1A1 deficiency in the Gunn rat model of CN disease. Adult Gunn rats were injected with CMV-UGT1A1 AAV vectors. Serum bilirubin was decreased over the first year by 64% for AAV1, 16% for AAV2, 25% for AAV6, and 35% for AAV8. Antibodies to UGT1A1 were detected after injection of all AAV serotypes. An AAV1 UGT1A1 vector with the liver-specific albumin promoter corrected serum bilirubin levels but did not induce UGT1A1 antibodies. Two years after injection of AAV vectors all animals had large lipid deposits in the liver. These lipid deposits were not seen in age-matched control animals. AAV1 vectors are promising candidates for CN gene therapy because they can mediate a reduction in serum bilirubin levels in Gunn rats that would be therapeutic in humans.
Diagnosis and follow up of aortitis in the elderly
Authors: A K Scheel
Journal: Annals of the Rheumatic Diseases (2004)

To evaluate the correlation of MRI and [(18)F]FDG-PET scans with the clinical course and inflammatory markers in patients with aortitis.Eight patients with aortitis presenting with unspecific GCA-like symptoms were examined. Aortitis was diagnosed and followed up by [(18)F]FDG-PET and MRI. The aorta was divided into three vascular regions (ascending aorta, aortic arch, and descending aorta) to localise the aortic inflammation and compare both imaging techniques.were correlated with clinical and laboratory examinations.At diagnosis, 20/24 vascular regions from eight patients were positive by [(18)F]FDG-PET scan and 15/21 aortic regions by MRI. Patients were treated with corticosteroids and followed up for a mean (SD) of 13.3 (4.7) months. In [(18)F]FDG-PET, 11/20 (55%) initially pathological aortic regions returned to normal in the follow up examination, which correlated closely with the clinical and laboratory follow up examination. Conversely, in MRI, 14/15 initially affected vascular regions were unchanged.[(18)F]FDG-PET and MRI are both effective techniques for detecting early aortitis and have a high correlation with laboratory inflammatory measures. However, during the follow up examination, [(18)F]FDG-PET uptake decreased in line with the clinical symptoms and inflammatory serum markers, whereas MRI scans gave more static results.
Traditional community resources for mental health: a report of temple healing from India
Authors: R Raguram, A Venkateswaran, Jayashree Ramakrishna, Mitchell G Weiss
Journal: BMJ (2002)

The use of complementary medicine and the traditional medicine of other cultures has been increasing in Europe and North America.3 Although less well documented, the use of complementary medicines and consultations with traditional healers is widely acknowledged in low income countries, such as India. Here too the limited availability of health services motivates the use of a wide range of alternative systems of care for various ailments, including mental illnesses4

In addition to herbal and other traditional medicines, healers and healing temples are seen as providing curative and restorative benefits. In India many people troubled by emotional distress or more serious mental illnesses go to Hindu, Muslim, Christian, and other religious centres. The healing power identified with these institutions may reside in the site itself, rather than in the religious leader or any medicines provided at the site. Studies of these healing sites have focused primarily on ethnographic accounts.5 Research has not systematically examined the psychiatric status of the people coming for help at these religious centres or the clinical impact of healing. It has focused primarily on possession and non-psychotic disorders, rather than serious psychotic illnesses.

Yet people with serious psychotic illnesses do visit such healing temples in India,6 and understanding the role of these institutions may help with planning for community mental health services in underserved rural areas. We describe here the work of a Hindu healing temple in South India known as a source of help for people with serious mental disorders. We also tried to measure the clinical effectiveness of religious healing at this site.

### Summary points

Traditional community resources, including temple healing practices, are widely used in managing mental illnesses in India

This research shows that a brief stay at one healing temple in South India improved objective measures of clinical psychopathology

In …
Role of 1-adrenoceptor activity in progression of cardiac hypertrophy in guinea pig hearts with pressure overload
Authors: J Tamai, M Hori, T Kagiya, K Iwakura, K Iwai, A Kitabatake, Y Watanabe, H Yoshida, M Inoue, T Kamada
Journal: Cardiovascular Research (1989)

To elucidate the role of alpha 1- and beta-adrenergic activities in pressure overload hypertrophy, changes of alpha 1- and beta-adrenoceptors were measured by radioligand binding assay, and the preventive effects of alpha 1- and beta-adrenoceptor blockade on cardiac hypertrophy were assessed in guinea pigs after aortic banding. Five days after banding, dry weight of left ventricle had not increased, though wet weight increased due to marked intercellular oedema. In this period, the maximum binding capacity of [3H] prazosin increased to 31.1 (SEM 2.2) fmol.mg-1 from (sham operation) 17.0(2.1) fmol.mg protein-1, p less than 0.01, whereas the maximum binding capacity of [3H]dihydroalprenolol did not increase: 143(16) fmol.mg-1 (banded) v 153(13) fmol.mg-1 (sham). Three weeks after aortic banding, the maximum binding capacity of both ligands increased to 45.6(5.5) fmol.mg-1 and 232(21) fmol.mg-1, respectively, accompanied by a significant increase in left ventricular dry weight, from 0.46(0.02) mg.g-1 (sham) to 0.62(0.08) mg.g-1 (banded), p less than 0.01. Continuous subcutaneous administration of the alpha 1-blocker bunazosin (0.1 mg.kg-1.d-1) significantly attenuated the increase in left ventricular dry weight whereas the beta-blocker propranolol (5 mg.kg-1.d-1) did not: 0.55(0.03) v 0.66(0.04) mg.g-1 respectively, after 3 weeks. These results show that pressure overload elicited an increase in myocardial alpha 1-adrenoceptors before the onset of cardiac hypertrophy, and that an alpha 1-blocker could prevent the development of hypertrophy in the pressure overloaded heart.