tbuckley/cabot-search huggingface dataset:
Riociguat for the Treatment of Pulmonary Arterial Hypertension
Authors: Hossein-Ardeschir Ghofrani, Nazzareno Galiè, Friedrich Grimminger, Ekkehard Grünig, Marc Humbert, Zhi-Cheng Jing, Anne M. Keogh, David Langleben, Michael Ochan Kilama, Arno Fritsch, Dieter Neuser, Lewis J. Rubin
Journal: New England Journal of Medicine (2013)

Riociguat, a soluble guanylate cyclase stimulator, has been shown in a phase 2 trial to be beneficial in the treatment of pulmonary arterial hypertension.In this phase 3, double-blind study, we randomly assigned 443 patients with symptomatic pulmonary arterial hypertension to receive placebo, riociguat in individually adjusted doses of up to 2.5 mg three times daily (2.5 mg-maximum group), or riociguat in individually adjusted doses that were capped at 1.5 mg three times daily (1.5 mg-maximum group). The 1.5 mg-maximum group was included for exploratory purposes, and the data from that group were analyzed descriptively. Patients who were receiving no other treatment for pulmonary arterial hypertension and patients who were receiving endothelin-receptor antagonists or (nonintravenous) prostanoids were eligible. The primary end point was the change from baseline to the end of week 12 in the distance walked in 6 minutes. Secondary end points included the change in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, World Health Organization (WHO) functional class, time to clinical worsening, score on the Borg dyspnea scale, quality-of-life variables, and safety.By week 12, the 6-minute walk distance had increased by a mean of 30 m in the 2.5 mg-maximum group and had decreased by a mean of 6 m in the placebo group (least-squares mean difference, 36 m; 95% confidence interval, 20 to 52; P<0.001). Prespecified subgroup analyses showed that riociguat improved the 6-minute walk distance both in patients who were receiving no other treatment for the disease and in those who were receiving endothelin-receptor antagonists or prostanoids. There were significant improvements in pulmonary vascular resistance (P<0.001), NT-proBNP levels (P<0.001), WHO functional class (P=0.003), time to clinical worsening (P=0.005), and Borg dyspnea score (P=0.002). The most common serious adverse event in the placebo group and the 2.5 mg-maximum group was syncope (4% and 1%, respectively).Riociguat significantly improved exercise capacity and secondary efficacy end points in patients with pulmonary arterial hypertension. (Funded by Bayer HealthCare; PATENT-1 and PATENT-2 ClinicalTrials.gov numbers, NCT00810693 and NCT00863681, respectively.).
Neurological disturbances in ankylosing spondylitis.
Authors: P N Tyrrell, A M Davies, N Evans
Journal: Annals of the Rheumatic Diseases (1994)

Case historyA 56 year old man presented with a seven week history of tingling in both buttocks associated with numbness of the right buttock which radiated down the back of the leg to the level of the knee.He also gave a four year history of numbness along the heel and sole of the right foot.There was no motor symptoms.No specific urinary or bowel symptoms were evident.In the past he had experienced intermittent low back pain, but he had been asymptomatic in that regard for many years.On examination there was impaired sensation along the right S2 dermatome and also perianally in the S3 to S5 distribution on the right side.Movement of the spine was limited in all directions.No focal tenderness was elicited.Examination was otherwise normal.Plain radiographs of the lumbar spine were obtained.
Career switch for EC-CFU to modelling
Authors: N. M. S. van den Akker, M. J. Post
Journal: Cardiovascular Research (2013)

This editorial refers to ‘The constituents and mechanisms of generation of ‘endothelial cell—colony forming units’’ by G.J. Padfield et al. , pp. 288–296, this issue. 

Following the paper by Asahara et al. 1 in 1997, research into the role of circulating endothelial progenitor cells in vascular regeneration and neovascularization has led to many novel insights into monocyte-macrophage differentiation, the kinship between haematopoietic stem cells and angioblasts, and the role of innate immunity in vascular repair. It has gradually become acknowledged that the classically retrieved blood mononuclear fraction contains at least two flavours of circulating progenitor cells, the late outgrowth endothelial cells and the cells giving rise to endothelial cell colony-forming units (EC-CFUs). From the study by Padfield et al .,2 it is evident that the EC-CFU is a mixture of CD14+/CD68+ myeloid cells and T- and B-lymphocytes rather than CD34+ cells and therefore do not represent an endothelial precursor cell per se . The observations do confirm the gain of endothelial marker expression of the CD14+ fraction,3 but emphasize that this can reflect monocyte activation, rather than differentiation into endothelial cells. Besides the gain of endothelial markers, such as CD105, CD146, and Tie2, which are expressed by certain monocyte subtypes as well, a continuous expression of the leukocyte marker CD45 and an increase of the macrophage marker …
Role of alpha1 Acid Glycoprotein in the In Vivo Resistance of Human BCR-ABL+ Leukemic Cells to the Abl Inhibitor STI571
Authors: C. Gambacorti-Passerini
Journal: JNCI Journal of the National Cancer Institute (2000)

Chronic myeloid leukemia is caused by a chromosomal translocation that results in an oncogenic fusion protein, Bcr-Abl. Bcr-Abl is a tyrosine kinase whose activity is inhibited by the antineoplastic drug STI571. This drug can cure mice given an injection of human leukemic cells, but treatment ultimately fails in animals that have large tumors when treatment is initiated. We created a mouse model to explore the mechanism of resistance in vivo. METHODS Nude mice were injected with KU812 Bcr-Abl(+) human leukemic cells. After 1 day (no evident tumors), 8 days, or 15 days (tumors >1 g), mice were treated with STI571 (160 mg/kg every 8 hours). Cells recovered from relapsing animals were used for in vitro experiments. Statistical tests were two-sided.Tumors regressed initially in all STI571-treated mice, but all mice treated 15 days after injection of tumor cells eventually relapsed. Relapsed animals did not respond to further STI571 treatment, and their Bcr-Abl kinase activity in vivo was not inhibited by STI571, despite high plasma concentrations of the drug. However, tumor cells from resistant animals were sensitive to STI571 in vitro, suggesting that a molecule in the plasma of relapsed animals may inactivate the drug. The plasma protein alpha1 acid glycoprotein (AGP) bound STI571 at physiologic concentrations in vitro and blocked the ability of STI571 to inhibit Bcr-Abl kinase activity in a dose-dependent manner. Plasma AGP concentrations were strongly associated with tumor load. Erythromycin competed with STI571 for AGP binding. When animals bearing large tumors were treated with STI571 alone or with a combination of STI571 and erythromycin, greater tumor reductions and better long-term tumor-free survival (10 of 12 versus one of 13 at day 180; P:<.001) were observed after the combination treatment.AGP in the plasma of relapsed animals binds to STI571, preventing this compound from inhibiting the Bcr/Abl tyrosine kinase. Molecules such as erythromycin that compete with STI571 for binding to AGP may enhance the therapeutic potential of this drug.
Diabetic Microangiopathy in Ischemic Limb Is a Disease of Disturbance of the Platelet-Derived Growth Factor-BB/Protein Kinase C Axis but Not of Impaired Expression of Angiogenic Factors
Authors: Mitsugu Tanii, Yoshikazu Yonemitsu, Takaaki Fujii, Yasunori Shikada, Ri-ichiro Kohno, Mitsuho Onimaru, Shinji Okano, Makoto Inoue, Mamoru Hasegawa, Toshihiro Onohara, Yoshihiko Maehara, Katsuo Sueishi
Journal: Circulation Research (2005)

Diabetic foot is caused by microangiopathy and is suggested to be a result of impaired angiogenesis. Using a severe hindlimb ischemia model of streptozotocin-induced diabetic mice (STZ-DM), we show that diabetic foot is a disease solely of the disturbance of platelet-derived growth factor B-chain homodimer (PDGF-BB) expression but not responses of angiogenic factors. STZ-DM mice frequently lost their hindlimbs after induced ischemia, whereas non-DM mice did not. Screening of angiogenesis-related factors revealed that only the expression of PDGF-BB was impaired in the STZ-DM mice on baseline, as well as over a time course after limb ischemia. Supplementation of the PDGF-B gene resulted in the prevention of autoamputation, and, furthermore, a protein kinase C (PKC) inhibitor restored the PDGF-BB expression and also resulted in complete rescue of the limbs of the STZ-DM mice. Inhibition of overproduction of advanced-glycation end product resulted in dephosphorylation of PKC-α and restored expression of PDGF-BB irrespective of blood sugar and HbA1c, indicating that advanced-glycation end product is an essential regulator for PKC/PDGF-BB in diabetic state. These findings are clear evidence indicating that diabetic vascular complications are caused by impairment of the PKC/PDGF-B axis, but not by the impaired expression of angiogenic factors, and possibly imply the molecular target of diabetic foot.
Quantification of Myotrophin From Spontaneously Hypertensive and Normal Rat Hearts
Authors: Parames Sil, Debabrata Mukherjee, Subha Sen
Journal: Circulation Research (1995)

Abstract A novel peptide, myotrophin, has been isolated, purified, cloned, and sequenced from the hearts of spontaneously hypertensive rats (SHR) and from dilated cardiomyopathic human heart tissue. Myotrophin accelerates myocyte growth by stimulating protein synthesis (not by altering myocardial cell division). Our successive studies were conducted to evaluate the pathophysiological significance of myotrophin; a solid-phase radioimmunoassay technique was developed for quantifying the protein in hypertrophied and normal hearts. Specific antipeptide antibody was raised in rabbits against a peptide that represents a selected amino acid sequence of a 17–amino acid myotrophin segment by using the multiple antigenic peptide technique. The specificity of the antibody was evaluated by determining the affinity constant after constructing the Scatchard plot obtained from the ratio of bound to free myotrophin against bound myotrophin. The value obtained was 2.61×10 7 L/mol. The specificity was further demonstrated by Western blot analysis, in which a single protein band was obtained in the region of 12 kD. Pretreatment of the antibody with myotrophin completely blocked the binding sites, because no protein band was detected on the immunoblot. The antibody prevented the myocardial protein synthesis induced by myotrophin as revealed by the blockage of the stimulation of [ 3 H]leucine incorporation into myocyte protein. Quantification of myotrophin from different heart tissues was achieved by Western blot and dot blot analyses. Amounts of myotrophin present in different dots were determined by using a video image analyzer. The level of myotrophin in the embryonic tissue was found to be similar in male normal and SHR hearts. The level of myotrophin concentration then starts increasing by as early as 3 days of age in SHR. In 9-day-old SHR, the change is statistically significant. In 4-, 8-, 11-, and 17-week-old SHR, myotrophin concentration increased linearly and significantly compared with age- and sex-matched normal control rats. No detectable amount of myotrophin was found in kidney or lung. Our data suggest that myotrophin may play an important role in the pathogenesis of cardiac hypertrophy.
New-onset of adult asthma: Gender differences in the SAPALDIA cohort
Authors: Sofie Hansen, Nicole Probst-Hensch, Dirk Keidel, Robert Bettschart, Marco Pons, Luc Burdet, Pierre-Olivier Bridevaux, Tamara Schikowski, Christian Schindler, Thierry Rochat, Elisabeth Zemp-Stutz
Journal: European Respiratory Journal (2014)

In adulthood, a higher incidence of asthma is reported in women compared to men, but evidence on gender differences in later adulthood is limited.  We aimed to determine new onset of asthma in adult men and women over 20 years of follow-up in the Swiss Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA).  Methods: We calculated incidence of asthma (self-report of doctor diagnosed asthma) between SAPALDIA1 (S1, 1991/92) and SAPALDIA3 (S3, 2010/11) in 2,434 men and 2,681 women without asthma and aged 20-62 at baseline. The age-related probability of new onset of asthma was analysed by logistic regression adjusting for sex, smoking status, parental asthma, BMI, early life respiratory infections, education and area. Analyses were also stratified by sex and atopic status in S1.  Results: Over 20 years of follow-up, 135 men (5.01%) and 218 women (7.33%) newly reported doctor diagnosed asthma. In the adjusted analyses, the OR for female sex was 1.87 (95%CI 1.41-2.47) overall and 3.6 (95%CI 2.25-5.78) among non-atopic subjects and 1.2 (95%CI 0.83-1.74) in atopic subjects. The probability of new onset of asthma decreased with increasing baseline age in women but not in men. A higher probability of new asthma was present in atopic compared to non-atopic men, unrelated to age. In women, a higher probability was seen particularly in younger atopic than in older atopic women. These differences decreased with increasing age.  Conclusions: Gender differences in asthma incidence over 20 years of follow-up in subjects initially aged 20-60 years were limited to non-atopic subjects. A decline of incidence and of differences between atopic and non-atopic subjects with increasing age was seen only in women.
Is Long-Term Fatigue in Patients With Cancer an Infrequent Symptom?
Authors: Annalisa Giacalone, Massimiliano Berretta, Michele Spina, Umberto Tirelli
Journal: Journal of Clinical Oncology (2012)

TO THE EDITOR: The prospective study by Goldstein et al addresses an interesting ongoing and unresolved debate regarding the effects and prevalence of cancer-related fatigue (CRF) in patients with cancer. In a cohort of women who received adjuvant treatment for early-stage breast cancer, the authors showed that CRF was a common symptom but generally ran a self-limiting course. However, some concerns might affect the generalizability of their findings. First, the reasons for exclusion from the study of 118 patients (84 patients at the time of enrollment and 34 patients after 12 months) were not described. It is possible that, among these patients, some women were too fatigued to accept being enrolled or continuing on and completing the questionnaires. In theory, this effect could explain the surprisingly low numbers of patients who suffered from CRF 1 year after the end of treatment (18 of 218 patients) and 5 years after the end of treatment (26 of 218 patients). In addition, it would be interesting to know whether fatigue was also present before treatment started (ie, were enrolled patients fatigued weeks, months, or years before the diagnosis of cancer?). In other words, it could useful to differentiate patients with fatigue closely related to cancer and/or a cancer diagnosis from patients affected by chronic fatigue and breast cancer. Moreover, the article considered only women with breast cancer. It would be interesting to compare this cohort of patients with both male and female fatigued patients affected by other malignancies like lymphomas. On the basis of these considerations, we question the generalizability of the study by Goldstein et al. If the data were available, we hypothesize that the presence and course of fatigue in this population of patients with cancer could have been underestimated within the study. Additional research is needed on this topic to better define the fatigue experienced by patients with cancer.
Evidence for Common Clonal Origin of Multifocal Lung Cancers
Authors: Xiaoyan Wang, Mingsheng Wang, Gregory T. MacLennan, Fadi W. Abdul-Karim, John N. Eble, Timothy D. Jones, Felix Olobatuyi, Rosana Eisenberg, Oscar W. Cummings, Shaobo Zhang, Antonio Lopez-Beltran, Rodolfo Montironi, Suqin Zheng, Haiqun Lin, Darrell D. Davidson, Liang Cheng
Journal: JNCI Journal of the National Cancer Institute (2009)

Lung cancer is the most common cause of cancer death in the United States. Multiple anatomically separate but histologically similar lung tumors are often found in the same patient. The clonal origin of multiple lung tumors is uncertain.We analyzed 70 lung tumors from 30 patients (23 females and seven males) who underwent surgical resection for lung epithelial tumors, of whom 26 had non-small cell carcinomas and four had carcinoid/atypical carcinoid tumors. All patients had multiple tumors (two to five) involving one or both lungs. Genomic DNA was extracted from paraffin-embedded tissue sections using laser capture microdissection and analyzed for loss of heterozygosity, TP53 mutations, and X-chromosome inactivation status. The percentage (95% confidence interval [CI]) of patients in whom there were concordant patterns of genetic alteration was calculated.All 30 case subjects showed loss of heterozygosity (LOH) in at least one and at most four of the six polymorphic microsatellite markers. Completely concordant LOH patterns between synchronous and metachronous cancers in individual patients were seen in 26 (87%) of 30 informative patients (95% CI = 75% to 99%). Identical point mutations were present in eight of 10 patients who exhibited TP53 mutation by sequencing. Tumors in 18 (78%) of 23 female patients (95% CI = 67% to 98%) showed identical X-chromosome inactivation patterns. Combining the results of LOH studies, TP53 mutation screening analyses, and X-chromosome inactivation data, we demonstrated that the multiple separate tumors in 23 (77%) of 30 patients (95% CI = 62% to 92%) had identical genetic changes, consistent with monoclonal origin of the separate tumors.Our data indicate that the great majority of multifocal lung cancers have a common clonal origin and that multifocality in lung cancer represents local and regional intrapulmonary metastasis.
Radiolabeled fragments of monoclonal antibodies against carcinoembryonic antigen for localization of human colon carcinoma grafted into nude mice.
Authors: F Buchegger, C M Haskell, M Schreyer, B R Scazziga, S Randin, S Carrel, J P Mach
Journal: The Journal of Experimental Medicine (1983)

Four monoclonal antibodies against carcinoembryonic antigen (CEA) have been selected from 32 hybrids that produce antibodies against this antigen, by the criteria of high affinity for CEA and low cross-reactivity with granulocyte glycoprotein(s). The specificity of tumor localization in vivo of the four MAb, and their F(ab')2 and Fab fragments was compared in nude mice bearing grafts of a serially transplanted, CEA-producing, human colon carcinoma. The distribution of radiolabeled MAb and their fragments after intravenous injection was analyzed by direct measurement of radioactivity in tumor and normal organs, as well as by whole-body scanning and by autoradiography of tumor sections. Paired labeling experiments, in which 131I-labeled antibody or fragments and 125I-labeled control IgG are injected simultaneously, were undertaken to determine the relative tumor uptakes of each labeled protein. The tumor antibody uptake divided by that of control IgG defines the specificity index of localization. Tumor antibody uptakes (as compared with the whole mouse), ranging between 7 and 15, and specificity indices ranging between 3.4 and 6.8, were obtained with the four intact MAb at day 4-5 after injection. With F(ab')2 fragments of the four MAb, at day 3, the tumor antibody uptakes ranged between 12 and 24 and the specificity indices between 5.3 and 8.2. With the Fab fragments prepared from the two most promising MAb, the antibody uptakes reached values of 34 and 82 at day 2-3 and the specificity indices were as high as 12 and 19. The scanning results paralleled those obtained by direct measurement of radioactivity. With intact MAb, tumor grafts of 0.5-1 g gave very contrasted positive scans 3 d after injection. Using MAb fragments, tumors of smaller size were detectable earlier. The best results were obtained with Fab fragments of MAb 35, which gave clear detections of tumors weighing only 0.1 g as early as 48 h after injection. Autoradiographs of tumor sections from mice injected with 125I-labeled MAb demonstrated that the radioactivity was localized in the tumor tissues and not in the stromal connective tissue of mouse origin. The highest radioactivity concentration was localized in areas known to contain CEA such as the pseudolumen of glands and the apical side of carcinoma cells. The penetration of radioactivity in the central part of tumor nodules and the pseudolumen appeared to be increased with the use of MAb fragments.
A scaling normalization method for differential expression analysis of RNA-seq data
Authors: Mark D Robinson, Alicia Oshlack
Journal: Genome biology (2010)

Abstract The fine detail provided by sequencing-based transcriptome surveys suggests that RNA-seq is likely to become the platform of choice for interrogating steady state RNA. In order to discover biologically important changes in expression, we show that normalization continues to be an essential step in the analysis. We outline a simple and effective method for performing normalization and show dramatically improved results for inferring differential expression in simulated and publicly available data sets.
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Authors: Jeanette M. Smith
Journal: JAMA (2015)

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Microtubule Active Agents: Beyond the Taxane Frontier
Authors: Patrick G. Morris, Monica N. Fornier
Journal: Clinical Cancer Research (2008)

Abstract Microtubules are essential to cell transport, signaling, and mitosis. An increasing range of anticancer drugs interferes with the normal formation and function of microtubules. Vinca alkaloids act as microtubule destabilizers and the taxanes act as microtubule stabilizers. Taxanes are widely used cytotoxic agents that are active in a range of solid tumor malignancies and are routinely used in a variety of settings. Significant limitations with the taxanes exist, including acquired and intrinsic tumor resistance through the expression of multidrug resistance proteins such as P-glycoprotein, risk of hypersensitivity reactions, dose-limiting hematopoietic toxicity, and cumulative neurotoxicity. Hence, there is a need to develop novel agents that act on the microtubules. Epothilones are macrolide antibiotics that bind near the taxane-binding site on microtubules and have been extensively studied in recent and ongoing clinical trials. A variety of other agents that act on the microtubules at different sites with a variety of structures are at varying stages of development.