tbuckley/cabot-search huggingface dataset:
A phase I study of Iobenguane I 131 to evaluate MTD, efficacy and safety in patients with malignant pheochromocytoma/paraganglioma (Pheo)
Authors: M. A. Morse, J. W. Babich, N. LaFrance, K. A. Kacena, J. Gockerman, J. Moore, R. E. Coleman
Journal: Journal of Clinical Oncology (2008)

4605 Background: I-131-iobenguane, a substrate for the norepinephrine transporter, has been shown to be effective in the treatment of neuroendocrine cancers such as Pheo. Non-radioactive iobenguane has been shown to inhibit uptake of radioiodinated iobenguane by tumors and has potential to cause cardiovascular AEs. Ultratrace Iobenguane I 131 (Ultratrace) is prepared so that the final drug product is devoid of cold iobenguane thereby enhancing tumor accumulation and limiting dose dependent AEs. Methods: Patients with metastatic/recurrent Pheo with >1 CT-measurable lesion scintigraphically visualized with Ultratrace were enrolled. Ultratrace dose escalation used a 3+3 modified Fibonacci design; initiated at 6.0 mCi/kg and escalated in 1.0 mCi/kg increments. Safety and efficacy data were obtained including tumor measurements by CT/MRI volume, RECIST criteria and tumor markers. Results: 15 patients enrolled in the dose escalation study. Data were available for analysis on 9 patients (mean age: 51 yrs; 4 males) from 3 dose groups (6, 7 and 8 mCi/kg up to a max. of 75 kg body weight). The median weight was 84.2 kg (range: 42, 126). Total administered dose ranges for each dose cohort were 333 to 428 mCi, 325 to 536 mCi, and 473 to 601 mCi, respectively. No protocol defined DLTs were observed at the 6 or 7 mCi/kg dose levels. One patient at the 8 mCi/kg dose experienced grade 4 thrombocytopenia, and no intervention was required. No CV effects were observed. At 3- and 6-month follow up, CT/MRI scans were available for 5 and 2 patients, respectively. All patients showed decreases in the longest diameter per RECIST (-15%, -18%, -6%, -10%, -10%; -15%, -24%), and 4 and 2 patients with available data showed decreases or stabilization in tumor volume (-28%, -25%, 0%, -17%; -29% and -46%). Also, all 5 patients showed a decline in serum chromogranin A levels (range: -22% to -75%) and other tumor markers, and ∼50% showed improvements in HTN and tumor pain. Conclusions: Reductions in tumor volume, tumor dimension per RECIST, and tumor markers were observed in all 5 evaluable patients at 3 months after a single Ultratrace dose. Improvements in HTN and pain occurred in ∼50%. Dose escalation is proceeding. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Molecular Insight Pharmaceuticals, Inc. Molecular Insight Pharmaceuticals, Inc. Molecular Insight Pharmaceuticals, Inc. Molecular Insight Pharmaceuticals, Inc. Molecular Insight Pharmaceuticals, Inc.
Angiotensin II Activates Signal Transducer and Activators of Transcription 3 via Rac1 in Atrial Myocytes and Fibroblasts
Authors: Chia-Ti Tsai, Ling-Ping Lai, Kuan-Ting Kuo, Juey-Jen Hwang, Chia-Shan Hsieh, Kuan-Lih Hsu, Chuen-Den Tseng, Yung-Zu Tseng, Fu-Tien Chiang, Jiunn-Lee Lin
Journal: Circulation (2008)

Recently, activation of the local renin-angiotensin system and mitogen-activated protein kinase pathways in atrial myocardium has been found to play an important role in atrial structural remodeling related to atrial fibrillation. Another important mediator of the angiotensin II (Ang II) effect is the Janus kinase/signal transducers and activators of transcription (STAT) pathway, which has never been characterized in the atrium.In cultured atrial myocytes and fibroblasts, Ang II induced tyrosine phosphorylation of STAT3 through a Rac1-dependent mechanism, which was inhibited by dominant-negative Rac1, losartan, and simvastatin. In atrial myocytes, activation of STAT3 by Rac1 was mediated by direct association of Rac1 with STAT3; however, in atrial fibroblasts, it was mediated by an indirect paracrine effect. Constitutively active STAT3 increased protein synthesis, and dominant-negative STAT3 abrogated Ang II-induced protein synthesis in atrial myocytes and fibroblasts. Rats infused long term with Ang II exhibited higher levels of activated Rac1, phospho-STAT3, collagen synthesis, and atrial fibrosis in the atria, all of which were attenuated by oral losartan and simvastatin. In human atrial tissues from patients with atrial fibrillation, Ang II and phospho-STAT3 levels were also elevated.The Ang II/Rac1/STAT3 pathway is an important signaling pathway in the atrial myocardium to mediate atrial structural remodeling, and losartan and statin may be able to reverse Ang II-induced atrial structural remodeling in atrial fibrillation.
Multiple Sclerosis: Deeper Understanding of Its Pathogenesis Reveals New Targets for Therapy
Authors: Lawrence Steinman, Roland Martin, Claude Bernard, Paul Conlon, Jorge R. Oksenberg
Journal: Annual Review of Neuroscience (2002)

▪ Abstract Recent technological breakthroughs allowing for large-scale analysis of gene transcripts and large-scale monitoring of the immune response with protein chips are revealing new participants in the pathogenesis of multiple sclerosis. Some of these participants may be useful targets for therapy.
Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis
Authors: M M J Nielen, A R van der Horst, D van Schaardenburg, I E van der Horst-Bruinsma, R J van de Stadt, L Aarden, B A C Dijkmans, D Hamann
Journal: Annals of the Rheumatic Diseases (2005)

The anti-cyclic citrullinated peptide (CCP) test has a high sensitivity and specificity for rheumatoid arthritis, although CCP is not the physiological target of the autoantibodies. Citrullinated fibrin is abundant in inflamed synoviumTo assess the diagnostic and prognostic value of antibodies against citrullinated fibrinogen (ACF), a soluble precursor of fibrin, in comparison with IgM-rheumatoid factor (IgM-RF) and the second generation anti-CCP test.In 379 patients with early arthritis (258 rheumatoid and 121 undifferentiated), the sensitivity, specificity, and positive predictive value of ACF, anti-CCP, and IgM-RF for diagnosing rheumatoid arthritis were calculated. Multivariate logistic regression analysis was used to assess the diagnostic and prognostic value (radiographic progression after two years) of the tests.The sensitivities of the ACF, anti-CCP, and IgM-RF tests were 55.8%, 57.8%, and 44.6%, with specificities of 92.6%, 94.2%, and 96.7%, respectively. Approximately 30% of the IgM-RF negative patients were positive for ACF or anti-CCP or both. The ACF and anti-CCP test had a high agreement in early arthritis (kappa = 0.84). Of all baseline characteristics, the ACF test and the anti-CCP test were the best predictors for diagnosing rheumatoid arthritis at one year (odds ratio (OR) = 10.3 and 10.6, respectively) and for radiographic progression after two years (OR = 12.1 and 14.8).ACF is as sensitive as anti-CCP and more sensitive than IgM-RF in diagnosing rheumatoid arthritis in early arthritis. The ACF test is also a good predictor of radiographic progression, with a performance similar to the anti-CCP test. The ACF test and the anti-CCP test are especially valuable in IgM-RF negative arthritis.
Intrauterine device use, cervical infection with human papillomavirus, and risk of cervical cancer: a pooled analysis of 26 epidemiological studies
Authors: Xavier Castellsagué, Mireia Díaz, Salvatore Vaccarella, Silvia de Sanjosé, Nubia Muñoz, Rolando Herrero, Silvia Franceschi, Chris J L M Meijer, F Xavier Bosch
Journal: The Lancet Oncology (2011)
Smoking and Risk for Diabetes Incidence and Mortality in Korean Men and Women
Authors: Sun Ha Jee, Athena W. Foong, Nam Wook Hur, Jonathan M. Samet
Journal: Diabetes Care (2010)

Mounting evidence suggests that smoking is a cause of type 2 diabetes. We explored the association of cigarette smoking with diabetes incidence and mortality in a large cohort of Koreans.A 14-year prospective cohort study was performed on 1,236,443 Korean men and women, aged 30-95 years at baseline, who underwent standardized biennial medical examinations provided by the National Health Insurance Corporation (NHIC). Incident diabetes was identified on the basis of outpatient visits, hospitalization, or prescription medication treatment for diabetes, as captured in the NHIC database. Diabetes mortality was obtained through the national statistical office. Cox proportional hazards models were used to investigate associations of smoking with indicators of diabetes and diabetes mortality.Smoking was significantly associated with increased risk for diabetic outpatient treatment, hospitalization, and mortality among both men and women, and the risk among current smokers increased modestly with the number of cigarettes smoked daily (P(trend) < 0.0001 for all associations). Compared with never smokers, current male smokers who smoked ≥ 20 cigarettes/day had increased risk for incident diabetes defined by outpatient treatment (adjusted hazard ratio 1.55 [1.51-1.60]), incident diabetes defined by ≥ 3 prescription medications for diabetes (1.71 [1.63-1.80]), and death from diabetes (1.60 [1.25-2.06]). The risks for outpatient treatment among smokers were higher in men than in women with evidence for effect modification by sex and age (P(interaction) < 0.0001).Our study provides longitudinal evidence that smoking increases the risk of incident diabetes and mortality.
Medical treatment of myocardial ischemia in coronary artery disease: effect of drug regime and irregular dosing in the CAPE II trial
Authors: John E Deanfield, Jean-Marie Detry, Philippe Sellier, Paul R Lichtlen, Eric Thaulow, Jan Bultas, Claudia Brennan, Sarah T Young, Bruce Beckerman
Journal: Journal of the American College of Cardiology (2002)
Cancer Stem–like Cell Marker CD44 Promotes Bone Metastases by Enhancing Tumorigenicity, Cell Motility, and Hyaluronan Production
Authors: Toru Hiraga, Susumu Ito, Hiroaki Nakamura
Journal: Cancer Research (2013)

Abstract CD44, an adhesion molecule that binds to the extracellular matrix, primarily to hyaluronan (HA), has been implicated in cancer cell migration, invasion, and metastasis. CD44 has also recently been recognized as a marker for stem cells of several types of cancer. However, the roles of CD44 in the development of bone metastasis are unclear. Here, we addressed this issue by using bone metastatic cancer cell lines, in which CD44 was stably knocked down. Tumor sphere formation and cell migration and invasion were significantly inhibited by CD44 knockdown. Furthermore, the downregulation of CD44 markedly suppressed tumorigenicity and bone metastases in nude mice. Of note, the number of osteoclasts decreased in the bone metastases. Microarray analysis revealed that the expression of HA synthase 2 was downregulated in CD44-knockdown cells. The localization of HA in the bone metastatic tumors was also markedly reduced. We then examined the roles of CD44–HA interaction in bone metastasis using 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis. 4-MU decreased tumor sphere and osteoclast-like cell formation in vitro. Moreover, 4-MU inhibited bone metastases in vivo with reduced number of osteoclasts. These results collectively suggest that CD44 expression in cancer cells promotes bone metastases by enhancing tumorigenicity, cell migration and invasion, and HA production. Our results also suggest the possible involvement of CD44-expressing cancer stem cells in the development of bone metastases through interaction with HA. CD44–HA interaction could be a potential target for therapeutic intervention for bone metastases. Cancer Res; 73(13); 4112–22. ©2013 AACR.
Clinical Validity/Utility, Change in Practice Patterns, and Economic Implications of Risk Stratifiers to Predict Outcomes for Early-Stage Breast Cancer: A Systematic Review
Authors: J. Hornberger, M. D. Alvarado, C. Rebecca, H. R. Gutierrez, T. M. Yu, W. J. Gradishar
Journal: JNCI Journal of the National Cancer Institute (2012)

At least 14 stratifiers exist to assess recurrence risk, chemotherapy response, and overall survival (OS) in women with early-stage breast cancer (ESBC). These stratifiers have not been compared using a recently developed rigorous framework. We performed a systematic review of the literature on clinical validity/utility, change in clinical practice, and economic implications of ESBC stratifiers. A systematic literature search was performed using PubMed, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Database of Systematic Reviews, and bibliographies of relevant studies. Data were extracted by two investigators and graded using a previously published framework. The Level-of-Evidence determination for each study was summarized, and the studies that provide evidence on change in clinical practice and economic implications are reported. Fifty-six articles published original evidence addressing the 21-gene recurrence score (n = 31), 70-gene signature (n = 14), Adjuvant! Online (n = 12), 5-antibody immunohistochemistry panel (n = 3), 5-gene expression index (n = 1), and 14-gene signature (n = 1). The 21-gene recurrence score satisfied Level I evidence (the highest level of evidence among five levels) for estimating distant recurrence risk (DRR), OS, and response to adjuvant chemotherapy, and Level II for estimating local recurrence risk. The 5-antibody immunohistochemistry panel and 70-gene signature satisfied Level II evidence for estimating DRR and OS. Adjuvant! Online satisfied Level II evidence for estimating DRR, OS, and chemotherapy response. The 5-gene expression index satisfied Level III evidence for predicting DRR. The 14-gene signature satisfied Level III evidence for predicting DRR and OS. Ten studies reported changes in clinical practice patterns; seven studies reported economic implications. The available evidence on the ability of stratifiers to predict risks of recurrence and response to chemotherapy in ESBC is growing. Level-of-Evidence determinations using the newer framework provide a solid scientific foundation for clinical recommendations.
Pituitary Ablation and Disseminated Prostatic Carcinoma
Authors: Charles R. West
Journal: JAMA (1973)

Twenty-seven patients with disseminated carcinoma of the prostate underwent adenohypophysectomy by either open craniotomy (8 patients) or stereotaxic cryohypophysectomy (19 patients). All patients had growth hormone assay following insulin-induced hypoglycemia during the preoperative (control) period and twice during the postoperative (experimental) period. In the postoperative tests, a 73% or greater suppression of growth hormone levels following hypoglycemia correlated with significant clinical remission and prolongation of survival. The minimal degree of growth hormone suppression consistent with clinical remission and extended survival was shown to be between 22% and 73% (as compared with preoperative control values). Subtotal hypophysectomy is adequate to achieve significant clinical remission and extended survival. Growth hormone assay is a useful index of the adequacy of hypophysectomy.
Endosomal Actin Remodeling by Coronin-1A Controls Lipoprotein Uptake and Degradation in Macrophages
Authors: Maarit Hölttä-Vuori, Saara Vainio, Maria Kauppi, Miranda Van Eck, Eija Jokitalo, Elina Ikonen
Journal: Circulation Research (2012)

The actin cytoskeleton has been implicated in the processing of atherogenic lipoproteins in macrophages. However, the functional role of actin and the regulatory proteins involved are unknown.Coronin-1A (Coro1A) was identified as a differentially expressed transcript in wild-type versus Niemann-Pick type C1 deficient macrophages exposed to acetylated low-density lipoproteins (AcLDL). We investigated whether Coro1A plays a role in the uptake or processing of modified lipoproteins in macrophages and if this is related to its actin regulatory functions.In wild-type primary macrophages, filamentous actin transiently decorated AcLDL containing endosomes that also recruited Coro1A. This dynamic association of F-actin with endosomes was disturbed in Coro1A deficient macrophages. In Coro1A knockout macrophages the uptake of AcLDL was increased, rate of AcLDL delivery to lysosomes enhanced, and lipoprotein-derived cholesteryl ester hydrolysis accelerated. Overexpression of wild-type Coro1A normalized AcLDL uptake in Coro1A knockout macrophages while a Coro1A actin binding mutant did not. Furthermore, the effects of macrophage Coro1A silencing on endosomal actin association and AcLDL delivery to lysosomes resembled those of cofilin silencing.Coro1A controls actin association with endocytic organelles, thereby negatively regulating endo-lysosomal delivery, degradation of modified lipoproteins and cholesterol deposition in macrophages.
Levofloxacin versus clarithromycin in COPD exacerbation: focus on exacerbation-free interval
Authors: H. Lode, J. Eller, A. Linnhoff, M. Ioanas
Journal: European Respiratory Journal (2004)

Antibiotic treatment of bacterial exacerbation of chronic obstructive pulmonary disease (COPD) shows some immediate clinical benefits and may also minimise the frequency of further recurrences. Patients (n=511) were enrolled into a randomised double-blind multicentric study comparing the exacerbation-free interval (EFI), efficacy and safety of 7-day levofloxacin versus 10-day clarithromycin in patients with COPD exacerbation. Patients were monitored over a 1-yr period. A total of 434 patients (per protocol population) received the medication for ≥5 days. The median EFI in the per protocol population was 300 days for levofloxacin and 350 days for clarithromycin. For patients with a new documented exacerbation during follow-up (n=223), the median EFI was 100.5 days in the levofloxacin group and 95 days for clarithromycin. No significant differences in EFI between groups could be observed when stratifying the study population according to microbial aetiology and severity of bronchial obstruction. Levofloxacin and clarithromycin showed similar clinical success rates. The bacteriological success rate was significantly higher in the levofloxacin group. Both antibiotics were well tolerated. In summary, levofloxacin was associated with a significantly higher bacteriological eradication rate but similar exacerbation-free interval in patients with chronic obstructive pulmonary disease exacerbation compared to clarithromycin.
Family functioning and adolescents' emotional and behavioral problems: when a parent has cancer
Authors: S.M. Gazendam-Donofrio, H.J. Hoekstra, W.T.A. van der Graaf, H.B.M. van de Wiel, A. Visser, G.A. Huizinga, J.E.H.M. Hoekstra-Weebers
Journal: Annals of Oncology (2007)
Book: Prescription Games: Money, Ego and Power inside the Global Pharmaceutical Industry
Authors: G. Haines
Journal: BMJ (2001)

Jeffrey Robinson Simon and Schuster, £17.99, pp 343 ISBN 0 684 85837 1 Rating: ![Graphic][1]</img> Appraisals of the pharmaceutical world tend to group themselves into heroic chronicles of progress or exposés of an industry that Robinson, in this book, styles Big Pharma. Either way, stereotype replaces reality. Robinson's work, predictably with one reliant on media reports from 1995, brings out nothing new. The usual and expected threats and failures are there: how the third world and unprofitable diseases are ignored; how everything from markets to medical education and research is manipulated; how doctors are offered improper inducements to prescribe or support certain products regardless of cost, relative efficacy, … [1]: /embed/inline-graphic-1.gif
Carrier-directed anti-hapten responses by b-cell subsets
Authors: GK Lewis, JW Goodman
Journal: The Journal of Experimental Medicine (1977)

The capacity of the trinitrophenyl (TNP) haptenic group, coupled to a series of chemically dissimilar carriers, to cross-stimulate putative T- dependent and T-independent murine B-cell subpepulations was determined by using an in vitro limiting dilution technique to generate primary IgM responses. It was found that TNP-Ficoll and TNP-dextran, two T- independent antigens with little or no polyclonal mitogenicity, stimulate the same population of anti-TNP precursors, which is distinct from the precursor population activated by TNP-bacterial lipopolysaccharide (LPS), a T-independent polyclonal mitogen, or TNP-horse erythrocytes (HRBC), a T-dependent antigen. On the other hand, TNP-LPS and TNP-HRBC activate the same precursor population, indicating that LPS can substitute for the T- cell signal in T-dependent B-cell responses, whereas nonmitogenic T- independent antigens cannot. However, the cumulative evidence from this and other laboratories strongly indicates that LPS and T-dependent antigens activate B cells by different mechanisms. Of particular interest, LPS is incapable of activating B cells responsive to weakly- or nonmitogenic T-independent antigens. Based on clonal burst size, T-dependent antigens are capable of inducing greater antigen-specific B-cell proliferation than T-independent antigens. However, TNP conjugates of Ficoll and dextran, which are relatively poor inducers of polyclonal B-cell activation, induced larger anti-TNP clones than did TNP-LPS, a strong polyclonal mitogen. The findings reinforce the evidence favoring existence of multiple B- cell subpopulations with distinctive activation pathways. They also strengthen the proposition that a given B-cell subset can be activated by more than one mechanism.
Role of 5-hydroxytryptamine type 3 receptors in rat intestinal fluid and electrolyte secretion induced by cholera and Escherichia coli enterotoxins.
Authors: F H Mourad, L J O'Donnell, J A Dias, E Ogutu, E A Andre, J L Turvill, M J Farthing
Journal: Gut (1995)

Cholera toxin and Escherichia coli heat labile toxin (LT) induced intestinal secretion has in the past been attributed exclusively to an increase in intracellular cAMP whereas E coli heat stable toxin (ST) induced secretion is mediated through cGMP. Evidence is accumulating on the importance of 5-hydroxytryptamine (5-HT) in cholera toxin induced secretion, but its role in LT and ST is not well established. This study therefore investigated in vivo the effect of 5-HT3 receptor antagonist, granisetron, on intestinal fluid and electrolyte secretion induced by cholera toxin, LT, and ST. Granisetron (30, 75, 150, or 300 micrograms/kg) was given subcutaneously to adult male Wistar rats 90 minutes before instillation of 75 micrograms cholera toxin or 50 micrograms LT in isolated whole small intestine. In situ small intestinal perfusion was performed with an iso-osmotic plasma electrolyte solution (PES) to assess fluid movement. In a second group of animals, granisetron (300 micrograms/kg) was given subcutaneously and two hours later small intestinal perfusion with PES containing 200 micrograms/l ST was performed. Cholera toxin induced net fluid secretion (median -50.1 microliters/min/g (interquartile range -59.5 to -29.8)) was found to be dose dependently decreased or abolished by granisetron (plateau effect at 75 micrograms/kg: 18 (-7.8 to 28), p &lt; 0.01). Granisetron in high dose (300 micrograms/kg), however, failed to prevent LT or ST induced secretion (-52 (-121 to -71) v -31 (-44 to -18), and (-39 (-49 to 17) v (-22 (-39 to -3)), respectively). Sodium and chloride movement paralleled that of fluid. In conclusion, these data show that 5-HT and 5-HT3 receptors play an important part in cholera toxin induced secretion but are not involved in E coli heat stable or heat labile toxin induced secretion.