tbuckley/cabot-search huggingface dataset:
FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension
Authors: Edda Spiekerkoetter, Xuefei Tian, Jie Cai, Rachel K. Hopper, Deepti Sudheendra, Caiyun G. Li, Nesrine El-Bizri, Hirofumi Sawada, Roxanna Haghighat, Roshelle Chan, Leila Haghighat, Vinicio de Jesus Perez, Lingli Wang, Sushma Reddy, Mingming Zhao, Daniel Bernstein, David E. Solow-Cordero, Philip A. Beachy, Thomas J. Wandless, Peter ten Dijke, Marlene Rabinovitch
Journal: Journal of Clinical Investigation (2013)

Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH.
Incidence and Prognostic Significance of Complete Axillary Downstaging After Primary Chemotherapy in Breast Cancer Patients With T1 to T3 Tumors and Cytologically Proven Axillary Metastatic Lymph Nodes
Authors: Roman Rouzier, Jean-Marc Extra, Jerzy Klijanienko, Marie-Christine Falcou, Bernard Asselain, Anne Vincent-Salomon, Philippe Vielh, Edwige Bourstyn
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To determine the incidence and prognostic significance of eradication of cytologically proven axillary lymph node metastases in breast cancer patients treated with primary chemotherapy. PATIENTS AND METHODS: Between January 1985 and December 1994, 152 breast cancer patients with invasive T1 to T3 tumors and axillary metastases cytologically proven by fine-needle sampling underwent primary chemotherapy followed by lumpectomy or mastectomy, level I and II axillary lymph node dissection, and irradiation. We studied pathologic complete responses (pCRs) of axillary nodes and breast tumors, as well as predictors of distant metastases. RESULTS: Thirty-five patients (23%) had axillary pCRs, and 20 patients (13.2%) had pCRs of primary breast tumors. Scarff-Bloom-Richardson grade 3 tumors (P = .04) and a clinical response to chemotherapy ≥ 50% (P = .003) were associated with negative axillary status at dissection. An initial tumor size ≤ 3 cm (63 patients) was associated with pCR of the primary tumor (P = .02) but not with complete histologic clearance of axillary lymph nodes. The median length of follow-up was 75 months. In the univariate analysis, age greater than 40 years (P = .003), absence of residual nodal disease (P = .01), and pCR of the tumor (P = .05) were associated with better distant disease-free survival. Five-year distant disease-free survival rates were 73.5% ± 14.9% among patients with no involved nodes at the time of surgery and 48.7% ± 9.2% among patients with residual nodal disease. In the multivariate Cox regression analysis, parameters associated with poor distant disease-free survival were age ≤ 40 years (P = .002), persistence of nodal involvement (P = .03), and S-phase fraction greater than 4% (P = .02). CONCLUSION: Our results suggest that axillary status is a better prognostic factor than response of the primary tumor to primary chemotherapy.
Effectiveness of Chemotherapy for Advanced Lung Cancer in the Elderly: Instrumental Variable and Propensity Analysis
Authors: Craig C. Earle, Jerry S. Tsai, Richard D. Gelber, Milton C. Weinstein, Peter J. Neumann, Jane C. Weeks
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To compare the effectiveness of chemotherapy given to elderly patients in routine practice for stage IV non–small-cell lung cancer (NSCLC) with the efficacy observed in randomized trials. PATIENTS AND METHODS: We used instrumental variable analysis (IVA) and propensity scores (PS) to simulate the conditions of a randomized trial in a retrospective cohort of patients over age 65 from the Survival, Epidemiology, and End Results (SEER) tumor registry. Geographic variation in chemotherapy use served as the instrument for the IVA analysis, and propensity scores were calculated with a logistic model based on patient disease and sociodemographic characteristics. RESULTS: Among 6,232 elderly patients, the instrumental variable estimate indicated an increase in median survival of 33 days and an improvement in 1-year survival of 9% attributable to chemotherapy. In a Cox regression model, chemotherapy administration was associated with a hazard ratio of 0.81 (95% confidence interval, 0.76 to 0.85). When survival was analyzed separately within propensity score quintiles, the hazard ratios were all similar, ranging from 0.78 to 0.85. These results are comparable with those of a large meta-analysis, which found a hazard ratio of 0.87 in the subgroup of patients over age 65. CONCLUSION: Chemotherapy for stage IV NSCLC seems to have effectiveness for elderly patients and those with comorbid conditions that is similar to the efficacy seen in randomized trials containing mostly younger, highly selected patients. All suitable patients should be given the opportunity to consider palliative chemotherapy for metastatic NSCLC.
Understanding subfertility at a molecular level in the female through the application of nuclear magnetic resonance (NMR) spectroscopy
Authors: N. E. Baskind, C. McRae, V. Sharma, J. Fisher
Journal: Human Reproduction Update (2010)

BACKGROUNDUnderstanding the aetiology of subfertility and female reproductive tract disorders at a molecular level may improve success rates in fertility treatment. Such understanding may be gained by the application of metabonomics technologies to tissues or biofluids. Metabonomics is concerned with the quantification of molecules in the metabolome and uses nuclear magnetic resonance (NMR) spectroscopy as one of the main technological platforms. This review concentrates on NMR studies of the female reproductive tract and discusses further possible applications. While full metabolic profiling is relatively recent, targeted NMR studies of biofluid and tissue has a longer history.
Intratumoral PEG-interleukin-2 therapy in patients with locoregionally recurrent head and neck squamous-cell carcinoma
Authors: V. Mattijssen, P.H. De Mulder, A. De Graeff, P.S. Hupperets, F. Joosten, D.J. Ruiter, H. Bier, P.A. Palmer, P. Van den Broek
Journal: Annals of Oncology (1994)
Cohort Study of Fatty Acid Synthase Expression and Patient Survival in Colon Cancer
Authors: Shuji Ogino, Katsuhiko Nosho, Jeffrey A. Meyerhardt, Gregory J. Kirkner, Andrew T. Chan, Takako Kawasaki, Edward L. Giovannucci, Massimo Loda, Charles S. Fuchs
Journal: Journal of Clinical Oncology (2008)

Purpose Energy balance seems to be important in the pathogenesis of colon cancer. Fatty acid synthase (FASN) is physiologically regulated by energy balance and is often upregulated in colorectal cancer. Nonetheless, the influence of FASN expression on patient outcome is uncertain. Patients and Methods Using the database of 647 patients with colon cancer in two independent cohort studies, FASN overexpression was detected in 84 tumors (13%) by immunohistochemistry. Cox proportional hazards models calculated hazard ratios (HRs) of colon cancer–specific and overall mortalities, adjusted for patient characteristics and related tumoral features, including KRAS, BRAF, p53, microsatellite instability and the CpG island methylation phenotype. Results There were 279 deaths, including 160 colon cancer–specific deaths. FASN overexpression was associated with a significant reduction in colon cancer–specific mortality by both univariate and multivariate analyses (adjusted HR, 0.41; 95% CI, 0.19 to 0.89) and an insignificant trend toward improved overall mortality (adjusted HR, 0.75; 95% CI, 0.50 to 1.13). Notably, the effect of FASN expression on mortality might be different according to body mass index (BMI; P interaction = .019); the adjusted HR of overall mortality for FASN overexpression was 0.63 (95% CI, 0.39 to 1.02) among patients with BMI less than 27.5 kg/m 2 and 2.91 (95% CI, 1.19 to 7.12) among those with BMI ≥ 27.5 kg/m 2 . Moreover, the adverse effect of moderate overweight/obesity on overall survival was limited to FASN-positive tumors (adjusted HR, 4.10; 95% CI, 1.14 to 14.8; BMI ≥ 27.5 kg/m 2 v &lt; 27.5 kg/m 2 ). Conclusion Among nonobese patients with colon cancer, tumoral FASN overexpression is associated with improved survival, whereas among moderately overweight or obese patients (BMI ≥ 27.5 kg/m 2 ), FASN overexpression may predict a worse outcome.
Downregulation of the inhibitor of apoptosis protein survivin in keratinocytes and endothelial cells in psoriasis skin following infliximab therapy
Authors: T. Markham, C. Mathews, S. Rogers, R. Mullan, B. Bresnihan, O. FitzGerald, D.J. Veale, U. Fearon
Journal: British Journal of Dermatology (2006)

Journal Article Downregulation of the inhibitor of apoptosis protein survivin in keratinocytes and endothelial cells in psoriasis skin following infliximab therapy Get access T. Markham, T. Markham Department of Dermatology, Merlin Park Hospital, University of Galway, Galway, Ireland Departments of *Rheumatology and †Dermatology, St Vincent's University Hospital, Dublin 4, Ireland Search for other works by this author on: Oxford Academic Google Scholar C. Mathews, C. Mathews Department of Dermatology, Merlin Park Hospital, University of Galway, Galway, Ireland Departments of *Rheumatology and †Dermatology, St Vincent's University Hospital, Dublin 4, Ireland Search for other works by this author on: Oxford Academic Google Scholar S. Rogers, S. Rogers Department of Dermatology, Merlin Park Hospital, University of Galway, Galway, Ireland Departments of *Rheumatology and †Dermatology, St Vincent's University Hospital, Dublin 4, Ireland Search for other works by this author on: Oxford Academic Google Scholar R. Mullan, R. Mullan Department of Dermatology, Merlin Park Hospital, University of Galway, Galway, Ireland Departments of *Rheumatology and †Dermatology, St Vincent's University Hospital, Dublin 4, Ireland Search for other works by this author on: Oxford Academic Google Scholar B. Bresnihan, B. Bresnihan Department of Dermatology, Merlin Park Hospital, University of Galway, Galway, Ireland Departments of *Rheumatology and †Dermatology, St Vincent's University Hospital, Dublin 4, Ireland Search for other works by this author on: Oxford Academic Google Scholar O. FitzGerald, O. FitzGerald Department of Dermatology, Merlin Park Hospital, University of Galway, Galway, Ireland Departments of *Rheumatology and †Dermatology, St Vincent's University Hospital, Dublin 4, Ireland Search for other works by this author on: Oxford Academic Google Scholar D.J. Veale, D.J. Veale Department of Dermatology, Merlin Park Hospital, University of Galway, Galway, Ireland Departments of *Rheumatology and †Dermatology, St Vincent's University Hospital, Dublin 4, Ireland Search for other works by this author on: Oxford Academic Google Scholar U. Fearon U. Fearon Department of Dermatology, Merlin Park Hospital, University of Galway, Galway, Ireland Departments of *Rheumatology and †Dermatology, St Vincent's University Hospital, Dublin 4, Ireland Ursula Fearon. E‐mail: ursula.fearon@ucd.ie Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 155, Issue 6, 1 December 2006, Pages 1191–1196, https://doi.org/10.1111/j.1365-2133.2006.07522.x Published: 01 December 2006 Article history Accepted: 18 June 2006 Published: 01 December 2006
Histamine levels in plasma, blood, and urine in severe asthma, and the effect of corticosteroid treatment.
Authors: C Bruce, R Weatherstone, A Seaton, W H Taylor
Journal: Thorax (1976)

Plasma, whole blood, and urinary histamine levels have been determined in 64 normal subjects, in 10 patients with severe asthma, and in 10 control patients with other illnesses. The mean whole blood levels did not differ between the three groups. The mean plasma level in the asthmatics was significantly greater than that of the normal subjects but not of the control patients. The urinary histamine output was lower in the control patients than in the normal subjects but in the asthmatics did not differ from that of the normals. Corticosteroid therapy caused a marked fall, often to barely detectable levels, of the whole blood histamine concentration of the asthmatic patients and restored the plasma levels to normal but did not affect urinary histamine levels.
Technetium-99m labelled liposomes to image experimental arthritis
Authors: O. C Boerman, W. J G Oyen, G. Storm, M L. Corvo, L. van Bloois, J. W M van der Meer, F. H M Corstens
Journal: Annals of the Rheumatic Diseases (1997)

Liposomes sterically stabilised with polyethylene glycol (PEG) labelled with technetium-99m were tested for their ability to image adjuvant arthritis in a rat model.Adjuvant arthritis was induced in the ankle joint of the left hind foot by injection of Mycobacterium butyricum in Freund's incomplete adjuvant in the foot pad. Seven days later animals received the following radiopharmaceuticals labelled with 99mTc (a) non-PEG-liposomes, (b) PEG-liposomes or (c) non-specific human polyclonal IgG. For each of the radiopharmaceuticals the in vivo distribution of the radiolabel was monitored both scintigraphically as well as by counting the dissected tissues at two, eight, and 24 hours after injection.The pharmacokinetics of the radiopharmaceuticals differed considerably (halflife in the blood: PEG-liposomes (18 hours) > 99mTc-IgG (3 hours) > non-PEG liposomes (1 hour)). The inflamed focus was visualised with each of the agents. The uptake of each of the radiopharmaceuticals in the inflamed ankle region correlated with their residence time in the blood (inflamed joint uptake: PEG liposomes (1.15% injected dose (ID)/ g) > 99mTc-IgG (0.35% ID/g) > non-PEG-liposomes (0.05% ID/g)). Quantitative analysis of the images showed that the inflamed ankle to background ratio was highest with the PEG-liposomes (7.5 at 24 hours after injection), while with the other two agents this ratio did not exceed 4.This study shows that 99mTc-labelled PEG-liposomes may be an excellent agent to visualise arthritis. Increased label uptake in the inflamed joint and increased target to background ratios can be obtained with PEG-liposomes because of their long circulating properties. In addition to their use as vehicles for scintigraphic imaging of arthritis PEG-liposomes might also be used for the site specific delivery of antirheumatic drugs.
Genetic variants in inflammation pathway genes and asthma in glioma susceptibility
Authors: E. Amirian, Yanhong Liu, Michael E. Scheurer, Randa El-Zein, Mark R. Gilbert, Melissa L. Bondy
Journal: Neuro-Oncology (2010)

Single nucleotide polymorphisms (SNPs) in inflammation-related genes have previously been shown to alter risks of developing various cancers. However, the effects of such SNPs on glioma risk remain unclear. We used a multistrategic approach to elucidate the relationship between glioma risk, asthma/allergies, and 23 literature-based functional SNPs in 11 inflammation genes. Genotyping was conducted on 373 histologically confirmed adult glioma patients and 365 cancer-free controls from the Harris County Brain Tumor Study. Deviations from the Hardy–Weinberg equilibrium were assessed using the χ2-test, and Akaike's information criterion was used to determine the best genetic model for each SNP. Odds ratios (ORs) were calculated both for each SNP individually and for grouped analyses, examining the effects of the numbers of adverse alleles on glioma risk in participants with and without asthma. In the single-locus analysis of the 23 examined SNPs, 1 pro-inflammatory and 2 anti-inflammatory gene SNPs were significantly associated with glioma risk (COX2/PTGS2, rs20417 [OR = 1.41]; IL10, rs1800896 [OR = 1.57]; and IL13, rs20541 [OR = 0.39], respectively). When we examined the joint effects of the risk-conferring alleles of these 3 SNPs, we found a significant trend indicating that the risk increases as the number of adverse alleles increase (P = .005). Stratifying by asthma status, we found that this dose–response-like trend of increasing risk is only present among those without asthma/allergies (P < .0001). Our study indicates that polymorphisms in inflammation genes are associated with glioma susceptibility, especially when a history of asthma/allergies is absent.
Primary Hyperoxaluria Type I
Authors: CHONI RINAT, RONALD J. A. WANDERS, ALFRED DRUKKER, DAVID HALLE, YAACOV FRISHBERG
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Primary hyperoxaluria type 1 is an autosomal recessive inherited metabolic disease in which excessive oxalates are formed by the liver and excreted by the kidneys, causing a wide spectrum of phenotypes ranging from renal failure in infancy to mere renal stones in late adulthood. Mutations in the AGXT gene, encoding the liver-specific enzyme alanine:glyoxylate aminotransferase, are responsible for the disease. Seven mutations were detected in eight families in Israel. Four of these mutations are novel and three occur in children living in single-clan villages. The mutations are scattered along various exons (1, 4, 5, 7, 9, 10), and on different alleles comprissing at least five different haplotypes. All but one of the mutations are in a homozygous pattern, reflecting the high rate of consanguinity in our patient population. Two affected brothers are homozygous for two different mutations expressed on the same allele. The patients comprise a distinct ethnic group (Israeli Arabs) residing in a confined geographic area. These results, which are supported by previous data, suggest for the first time that the phenomenon of multiple mutations in a relatively closed isolate is common and almost exclusive to the Israeli-Arab population. Potential mechanisms including selective advantage to heterozygotes, digenic inheritance, and the recent emergence of multiple mutations are discussed.
Design of Next-Generation G Protein–Coupled Receptor Drugs: Linking Novel Pharmacology and In Vivo Animal Models
Authors: Sophie J. Bradley, Andrew B. Tobin
Journal: The Annual Review of Pharmacology and Toxicology (2016)

Despite the fact that G protein–coupled receptors (GPCRs) are the most successful drug targets in history, this supergene family of cell surface receptors has yet to be fully exploited as targets in the treatment of human disease. Here, we present optimism that this may change in the future by reviewing the substantial progress made in the understanding of GPCR molecular pharmacology that has generated an extensive toolbox of ligand types that include orthosteric, allosteric, and bitopic ligands, many of which show signaling bias. We discuss how combining these advances with recently described transgenic, chemical genetic, and optogenetic animal models will provide the framework to allow for the rational design of next-generation GPCR drugs that possess increased therapeutic efficacy and decreased adverse/toxic responses.
Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma
Authors: G. Folprecht, M.P. Lutz, P. Schöffski, T. Seufferlein, A. Nolting, P. Pollert, C.-H. Köhne
Journal: Annals of Oncology (2005)
Silencing of int6 gene restores function of the ischaemic hindlimb in a rat model of peripheral arterial disease
Authors: Noriko Okamoto, Akane Tanaka, Kyungsook Jung, Kaoru Karasawa, Kensuke Orito, Akira Matsuda, Yosuke Amagai, Kumiko Oida, Keitaro Ohmori, Hiroshi Matsuda
Journal: Cardiovascular Research (2011)

Intermittent claudication (IC) is one of the serious symptoms of peripheral arterial disease (PAD) and is characterized by pain in the legs or buttocks that worsens with exercise and subsides with rest. The concept of 'therapeutic angiogenesis' for PAD has been widely proposed; however, the methodology, including cell transplantation, is still unclear. In this study, we examined the clinical efficacy of silencing the int6 gene, which encodes a protein that stabilizes hypoxia-inducible factor (HIF)-2α, on angiogenesis in PAD. An animal model for IC was established in Sprague–Dawley rats by external iliac artery ligation and evaluated by quantitative analysis of gait disturbance. Next, we explored the therapeutic effects of int6 siRNA injected into the adductor magnus muscle on IC. Recovery of hindlimb function occurred in the early stages after int6 siRNA injection. The number of blood vessels showed an obvious increase in the int6 siRNA-treated muscles. Angiography revealed the recovery of peripheral circulation at the affected sites. Early up-regulation of HIF-2α and other angiogenic factors, including basic fibroblast growth factor and hepatocyte growth factor, was also apparent in the int6 siRNA-treated sites. We also confirmed the up-regulation of HIF-2α and its translocation to the nucleus in the int6 siRNA-injected muscle. A single injection of int6 siRNA promoted angiogenesis via up-regulation of HIF-2α-related angiogenic factors in the muscles of the affected hindlimb and reduced gait disturbance. The int6 gene may be a novel therapeutic target for the treatment of IC in patients with PAD.
Angiotensin converting enzyme inhibition and the upper limit of cerebral blood flow autoregulation: effect of sympathetic stimulation.
Authors: G Waldemar, O B Paulson, D I Barry, G M Knudsen
Journal: Circulation Research (1989)

The effect of stimulation of the cervical sympathetic ganglia on the upper limit of cerebral blood flow (CBF) autoregulation was studied in normotensive Wistar-Kyoto rats (WKY) and in spontaneously hypertensive rats (SHR) following intravenous administration of the angiotensin converting enzyme inhibitor captopril (10 mg/kg). CBF was measured using the intracarotid 133Xe injection method in halothane/nitrous oxide anaesthetized WKY and SHR. Arterial blood pressure was raised stepwise by the intravenous infusion of noradrenaline. Toward the end of the study, Evans blue was injected and the brains examined for gross blood-brain barrier breakdown. In SHR, sympathetic stimulation reextended the upper limit of CBF autoregulation, which was at a mean arterial blood pressure level of 120-139 mm Hg in the control group of eight SHR and above 170 mm Hg in the stimulated group of nine SHR. In the group of nine WKY subjected to sympathetic stimulation, the upper limit of CBF autoregulation was reached at a mean arterial blood pressure level of 110-129 mm Hg as opposed to 90-109 mm Hg in a previous unstimulated group of WKY. In the two groups subjected to sympathetic stimulation, there was no extravasation of Evans blue in any of the brains. In the control group of SHR, in which there had been marked increases in CBF, three out of eight brains had foci with extravasation of the dye. It is concluded that in normotensive and in hypertensive rats sympathetic stimulation attenuates the downward shift of the upper limit of CBF autoregulation, which is known to accompany intravenous administration of captopril.