tbuckley/cabot-search huggingface dataset:
A multiple ascending dose, open-label, phase IIa study evaluating the safety and tolerability of PCK3145 administered intravenously in patients with metastatic hormone refractory prostate cancer (HRPC)
Authors: R. Hawkins, C. Panchal, H. Dulude, R. Cowan, A. Armstrong, J. Fenemore, L. Daigneault
Journal: Journal of Clinical Oncology (2004)

4636 Background: PCK3145 is a synthetic 15-mer peptide derived from the prostate secretory protein (PSP94) sequence. PCK3145 has demonstrated antiproliferative and antitumoral activity in the PC3 xenograft mouse model and the Dunning rat R-3327 MLL model. No drug related toxicities were found in the animal studies. The objectives of PCK3145-UK-2001 clinical trial were to evaluate the safety and tolerability, the pharmacokinetics, and efficacy of PCK3145 in metastatic HRPC patients. Methods: Dose-escalation study in which successive cohorts of 4 patients received 4 ascending doses (5, 20, 40 and 80 mg/m2) of PCK3145. One cycle consist of IV administration of PCK3145, three time per week for 4 weeks followed by a 7-day post-treatment observation period. Pharmacokinetics of PCK3145 was determined for all patients at day 1 and day 26. Tumours were assessed by CT-Scan prior to and after the PCK3145 treatment. Results: Median age is 67 y (53–75) and the median time from HRPC to enrolment is 16.2 months (3–33). Sites of disease were mainly bone and lymph node. No drug related Adverse Event was observed for patients treated at 5, 20 and 40 mg/m2 but two patients treated at 80 mg/m2 experienced Serious Adverse Event (tachycardia and vasovagal reaction) possibly related to study medication. Preliminary results indicate that the half-life of PCK3145 is 20 minutes and tumor assessments suggest that the patients are having stable disease at least after one cycle. Five patients showed a decline in PSA levels (one of them by almost 50%). All patients that had plasma MMP-9 levels over 100 ug/L before treatment had reductions ranging from 34% to 90% after the first cycle while those with levels below 100 ug/L remained low. Conclusions: This clinical trial indicated that PCK3145 has an excellent safety profile for patients treated at 5, 20 and 40 mg/m2. Some toxicities, possibly related were observed at 80 mg/ m2. The marked reduction in plasma MMP-9 levels of patients receiving PCK3145 treatment indicates a biological effect, possibly related to control of metastasis. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Procyon Biopharma, Inc. Procyon Biopharma, Inc. Procyon Biopharma, Inc. Procyon BioPharma, Inc.
Promoting Effect of Sodium Deoxycholate on Colon Adenocarcinomas in Germfree Rats2
Authors: Bandaru S. Reddy, T. Narasawa, J.H. Weisburger, E.L. Wynder
Journal: JNCI Journal of the National Cancer Institute (1976)

The promoting effect of sodium deoxycholate (DC) on colon carcinogenesis was studied in female F344 germfree rats. Animals received intrarectaI (ir) instillations of N-methyl-N′- nitro-N-nitrosoguanidine (MNNG) for 4 weeks (total dose, 16 mg/rat), then weekly ir doses of DC (total dose, 3 g/rat); the rats were autopsied 52 weeks after the first injection. DC increased the number ofMNNG-induced colon adenocarcinomas. No tumors were in the colons of germfree rats given DC alone. It was concluded that DC (present in high concentrations in human stools) had a promoting effect on colon carcinogenesis in rats.
Abstract 207: Mitochondrial Calcium Flux is Arrhythmogenic in Nonischemic Cardiomyopathy
Authors: an xie, Qiongyin Wang, Hong Liu, Lianzhi Gu, Man Liu, Cody Rutledge, Samuel C Dudley
Journal: Circulation Research (2013)

Introduction: Mitochondria participate in Ca2+ homeostasis and Ca2+ oscillations are thought to be involved in arrhythmogenesis. Nevertheless, the role of mitochondria in arrhythmogenesis is unclear. We have reported spontaneous and induced arrhythmias in a mouse model of nonischemic cardiomyopathy, so we investigated the role of mitochondrial Ca2+ handling in arrhythmias in this model. Methods: Nonischemic cardiomyopathy was induced in C57BL/6 mice by 6 weeks of hypertension evoked after unilateral nephrectomy, deoxycorticosterone acetate (DOCA) pellet implantation, and 1% salt water substitution. Sham operated mice were used as controls. ECG telemetry recording was used to monitor arrhythmias from DOCA mice and 7 sham mice at 18 weeks of age. Action potentials (APs) were recorded by perforated current-clamp in isolated mouse ventricular cells. Potassium and L-type Ca2+ currents were measured by voltage-clamp. Changes in cytoplasmic and mitochondrial Ca2+ were determined by fluorescent imaging using Fluo-4 and Rhod-2, respectively, in isolated ventricular cells. Results: Seven DOCA mice and two sham mice had isoproterenol (0.5 mg/kg)-induced premature ventricular contractions (PVCs, p&lt;0.05). Three DOCA mice and no sham mice had isoproterenol (2.5 mg/kg)-induced ventricular fibrillation. QTc was significantly prolonged from 41.9 ±1.4 in sham mice to 52.0 ± 2.1 ms in DOCA mice. At the cellular levels, myocytes had a prominent increase of APD90 from 66.6 ± 21.1 to 311.8 ± 44.9 ms, explained by augmented L-type Ca2+ current and decreased total K+ currents. Two of 12 sham mice ventricular cells and 8 from 12 DOCA mice ventricular cells had EADs (p&lt;0.05). Three of 12 DOCA mice but none of the sham myocytes had PVCs with stimulated APs. Trigger activity could be abolished by 10 µM Ru360, a mitochondrial calcium uniporter specific antagonist. Ru360 had no effect on L-type Ca2+ current, total K+ currents, or APD90. Ru360 inhibited mitochondrial Ca2+ uptake in DOCA mice ventricular cells, implicating mitochondrial Ca2+ release in modulating the arrhythmic risk. Conclusions: Mitochondrial Ca2+ handling appears to play an important role in triggered activity and may be important in the incidence of ventricular arrhythmias in nonischemic cardiomyopathy.
Diagnosis of Fasciola Hepatica by Endoscopic Ultrasound
Authors: R. Sotoudehmanesh, A. Yoonessi
Journal: Endoscopy (2003)

A 28-year-old woman was admitted for colicky abdominal pain. Mild eosinophilia (300/µl) and a slight increase in alkaline phosphatase were present. Transabdominal ultrasonography showed only mild dilation of the common bile duct. Figures [1 ] [2] show the endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) findings, respectively. Parasitology confirmed the diagnosis of Fasciola hepatica. Endoscopic ultrasound may be helpful in the diagnosis of parasites in the biliary tract.
Inflammation and Organ Failure Severely Affect Midazolam Clearance in Critically Ill Children
Authors: Nienke J. Vet, Janneke M. Brussee, Matthijs de Hoog, Miriam G. Mooij, Carin W. M. Verlaat, Isabel S. Jerchel, Ron H. N. van Schaik, Birgit C. P. Koch, Dick Tibboel, Catherijne A. J. Knibbe, Saskia N. de Wildt
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Various in vitro, animal, and limited human adult studies suggest a profound inhibitory effect of inflammation and disease on cytochrome P-450 3A (CYP3A)-mediated drug metabolism. Studies showing this relationship in critically ill patients are lacking, whereas clearance of many CYP3A drug substrates may be decreased, potentially leading to toxicity.To prospectively study the relationship between inflammation, organ failure, and midazolam clearance as a validated marker of CYP3A-mediated drug metabolism in critically ill children.From 83 critically ill children (median age, 5.1 mo [range, 0.02-202 mo]), midazolam plasma (n = 532), cytokine (e.g., IL-6, tumor necrosis factor-α), and C-reactive protein (CRP) levels; organ dysfunction scores (Pediatric Risk of Mortality II, Pediatric Index of Mortality 2, Pediatric Logistic Organ Dysfunction); and number of failing organs were prospectively collected. A population pharmacokinetic model to study the impact of inflammation and organ failure on midazolam pharmacokinetics was developed using NONMEM 7.3.In a two-compartmental pharmacokinetic model, body weight was the most significant covariate for clearance and volume of distribution. CRP and organ failure were significantly associated with clearance (P < 0.01), explaining both interindividual and interoccasional variability. In simulations, a CRP of 300 mg/L was associated with a 65% lower clearance compared with 10 mg/L, and three failing organs were associated with a 35% lower clearance compared with one failing organ.Inflammation and organ failure strongly reduce midazolam clearance, a surrogate marker of CYP3A-mediated drug metabolism, in critically ill children. Hence, critically ill patients receiving CYP3A substrate drugs may be at risk of increased drug levels and associated toxicity.
WHO calls for tax on sugary drinks to tackle child obesity
Authors: Anne Gulland
Journal: BMJ (2016)

Governments around the world are being urged to bring in a tax on sugar sweetened drinks in a bid to reduce the prevalence of childhood obesity.

A new report commissioned by the World Health Organization said that people in the lowest income groups have the greatest risk of obesity in many societies and that therefore taxation would have the greatest effect.1 The report, by the Commission on Ending Childhood Obesity, acknowledged that there was still not enough evidence on the benefits of a tax but said that as more governments implemented such a policy the evidence base would increase.

A study published in The BMJ this month found that a year after Mexico’s introduction of a tax on sugar sweetened drinks of one peso (£0.04; €0.05; $0.05) a litre the …
THE NATURE OF ADRENERGIC NERVE MEDIATORS
Authors: U.S. von EULER
Journal: Pharmacological Reviews (1951)

The chief points in the present concept of the adrenergic nerve mediators may be briefly summarized as follows: 1. Convincing evidence has been produced to show that l -noradrenaline is the chief adrenergic nerve mediator in mammals. In addition i-adrenaline occurs admixed in various small amounts with the noradrenaline. The hypothesis of purelyexcitatory or purely inhibitory sympathins is no longer tenable. The liberation of other related substances such as hydroxytyramine, tyramine and oxidation products of dihydroxyphenyl derivatives in adrenergic nerve activity has not been proven in mammals. 2. The adrenergic nerve mediators l-noradrenaline and i-adrenaline can account for most actions observed on stimulation of adrenergic nerves. 3. Noradrenaline and adrenaline are formed in the adrenergic neurons and appear in small quantities in the nerve trunks and in larger amounts in the innervated organs, presumably occurring in the terminal nerve structures. 4. The adrenergic nerve mediators disappear from an organ after degeneration of the nerves but reappear on nerve regeneration. 5. There is some evidence in favour of the formation of noradrenaline by decarboxylation of dihydroxyphenylalanine and subsequent introduction of a hydroxyl group in the side chain of the hydroxytyramine so formed. 6. The adrenergic nerve mediators are rapidly inactivated in the tissues by enzymes (amine oxydase and catechol oxidase). A smaller part is excreted in free or conjugated form in the urine. 7. The physiological actions of noradrenaline and adrenaline differ in many important respects. The main function of noradrenaline seems to be the normal control of the circulation, while adrenaline produces various effects in conditions of stress and emergency.
Recombinant human granulocyte colony-stimulating factor as an activator of human granulocytes: potentiation of responses triggered by receptor- mediated agonists and stimulation of C3bi receptor expression and adherence
Authors: A Yuo, S Kitagawa, A Ohsaka, M Ohta, K Miyazono, T Okabe, A Urabe, M Saito, F Takaku
Journal: Blood (1989)
Characterization of CKβ8 and CKβ8-1: Two Alternatively Spliced Forms of Human β-Chemokine, Chemoattractants for Neutrophils, Monocytes, and Lymphocytes, and Potent Agonists at CC Chemokine Receptor 1
Authors: Byung-S. Youn, Shang M. Zhang, Hal E. Broxmeyer, Scott Cooper, Kathleen Antol, Malcolm Fraser, Byoung S. Kwon
Journal: Blood (1998)
Superinfection With Adenovirus of Burkitt's Lymphoma Cell Lines2
Authors: N. Faucon, Y. Chardonnet, M. C. Perrinet, R. Sohier
Journal: JNCI Journal of the National Cancer Institute (1974)

Two Burkitt's lymphoma cell lines, Epstein Barr (EB) virus-positive (Jijoye cells), and EB virus-negative (Raji cells), were exposed to adenovirus type 5 to enhance replication of the EB virus. Average cell growth was not reduced compared with that of control populations. Adenovirus multiplied in Jijoye cells at a higher rate than in Raji cells. In the presence of fB virus antiserum, a few cells appeared fluorescent in the Raji cell line; in the JiJoye cell line, the number of EB viral antigen-producing cells increased.
Darbepoetin alfa improves quality of life in cancer patients undergoing radiation, final results of a multicenter, open study
Authors: D. Antonadou, P. Varveris, P. Karageorgis, V. Papadopoulos, G. Georgakopoulos, C. Kyprianou, A. Panousaki, H. Athanasiou, C. Beroukas, J. Skarlatos, D. Misailidou
Journal: Journal of Clinical Oncology (2006)

18531 Background: Anaemia is a poor prognostic factor for patients undergoing radiotherapy (XRT) and has been associated with decreased response to treatment. Darbepoetin alfa has been proven effective in treating anaemia and in improving QoL. The purpose of this study was to assess the efficacy, safety and the impact on QoL of darbepoetin alfa in these pts. Methods: Patients with Hb level 10–12 g/dl, PS ECOG &lt;2, and life expectancy &gt;6 mos were administered darbepoetin alfa SC 150 mcg once weekly during the 6 wk course of conventional XRT (2 Gy/5 days/week). All pts received iron supplem. Blood transfusion was given for Hb &lt;9 g/dl. Complete blood counts, serum iron, folate, B12, ferritin, serum LDH, bilirubin and reticulocyte count were measured weekly. The primary study endpoints were changes in Hb level during XRT, number of transfusions and evaluation of QoL. Results: Between Mar 2002 and Feb 2004, 140 pts were entered, 116 were evaluable. Mean Hb at baseline was 10.95 ± 1.76. There was a significant increase (17.1%) in mean Hb levels from 2nd wks onwards with the peak value at wk 10 from XRT initiation. Hb significantly increased to 12.03 ± 2.39 (p &lt; 0.001), 12.63 ± 2.10 (p &lt; 0.001) and 12.96 ± 2.33 (p &lt; 0.001) at 3,6 and 10 wks, respectively. Blood transfusion was necessary in 3 pts (2.6%). None of the pts experienced serious adverse events. There was a significant difference in physical well being score between Hb levels (p = .016) regardless the period of time (p = .17). Pts with high Hb levels had higher functional well being scores (p = .002) regardless time for the interaction (p = .24).There was a significant difference in mean fatigue score between Hb levels (p=.019) and a significant time by group interaction (p = .03).Pts with high Hb levels tend to have a higher social well being score than those with lower Hb (p = .08) while the differences were similar over time (p = .89).Those with Hb ≤ 12 g/dL had a tendency for increased emotional scores at 6 wks (p = .07) while the differences were similar over time (p = .138). Conclusion: Hb levels were significantly increased from baseline, irrespective of tumour localisation and stage. This increase reached the maximum value during wk 10 and remained significant 2 mos post XRT. QoL was significantly improved in these pts. No significant financial relationships to disclose.
Apact: a Phase III Trial of Nab-Paclitaxel (Nab-P) Plus Gemcitabine (Gem) Vs Gem Alone for Resected Pancreatic Cancer (Pc)
Authors: M.A. Tempero, D. Cardin, A. Biankin, D. Goldstein, M. Moore, E.M. O'Reilly, P.A. Philip, H. Riess, T. Macarulla, L. Yung, X. Wei, B. Lu
Journal: Annals of Oncology (2014)
Doxofylline: Efficacy and safety in complex treatment of COPD
Authors: Tetyana Pertseva, Kateryna Gashynova, Natalia Klimenko
Journal: European Respiratory Journal (2011)

Aim of study: To evaluate efficacy and safety of Aerofylline, ABC Farmaceutici (doxofylline) in patients with stable COPD.

Study population and methods: 30 out-patients (pts) with stable COPD, stage II were divided on two groups: 15 pts (11 men, mean age 47.5±8.6 yrs) treated with inhaled bronchodilators and doxofylline 400 mg bid (Group 1) and 15 pts (12 men, mean age 50.3±9.0 yrs), treated with inhaled bronchodilators only (Group 2).

Pulmonary function tests, respiratory muscles fatigue (by MasterLab, Jager), Holter ECG and dyspnoea (by MRC score) were evaluated in all pts before and 30 days after start of treatment.

Results: Both groups were similar regarding to age, sex, duration of disease, FEV1, PImax, and dyspnoea level at the beginning of treatment.

30 days after start of treatment the results were following: FEV1 did not change statistically significant in both groups. At the same time, dyspnoea score decrease significantly in Groupe 1 but not in Group II (down to 0.7±0.4 scores and 1.9±0.5 scores respectively). PImax in Groupe 1 increase on 21.3%, in Group 2 – on 11.9% only.

We did not find any difference in tachycardia and premature beat rate between the groups.

Conclusions: Doxofilline did not improve pulmonary function, but significantly decrease respiratory muscles fatigue and dyspnoea in patients with COPD, stage II.

Doxifilline did not influence significantly on a heart rhythm.
TCT-304 Intracoronary Doppler Flow Velocity And Pressure Derived Hyperemic Microvascular Resistance Is Independent Of Epicardial Obstruction In Stable Coronary Artery Disease
Authors: Guus A. de Waard, Koen Marques, Sukhjinder S. Nijjer, Paul F. Teunissen, Peter M. van de Ven, Justin E. Davies, Paul Knaapen, Niels van Royen
Journal: Journal of the American College of Cardiology (2015)
Sexual health services: divided and unprotected
Authors: Caroline White
Journal: BMJ (2016)

How are sexual health services weathering the storm in their new local authority home? Caroline White reports

Local authorities in England now oversee the lion’s share of commissioning sexual health services. The rest is left to the NHS: most contraceptive services, for example, are provided by general practitioners and commissioned by NHS England. So how are the country’s sexual health services faring under this new system, not yet even three years old, especially as a painful programme of government cuts begins to bite?

The BMJ sent freedom of information requests to all 152 local authorities in England to uncover what proportion of public health funds they spent on sexual health and to find out how protected services are from cuts. The results (99% response rate) show that the priority given to sexual health varies widely across councils, with spending varying from less than 10% of their public health budget (seven councils) up to 45% (24 councils).

All local authorities suffered an in-year cut of nearly 6% to the public health grant in November and are obliged to make 4% annual cuts to services from April for five years. The freedom of information data that The BMJ obtained (before the cuts were announced last autumn) show that so far only 10 local authorities have cut or restricted access to sexual health services over the past two years, but a further 37 (25% of respondents) indicated that reviews were planned.

Sexual health has been protected partly because many councils are tied into expensive hospital contracts in order to fulfil their statutory duty to provide comprehensive open access contraception and sexually transmitted infection (STI) services. STI testing and treatment services have …
Nucleotide polymorphism at the xanthine dehydrogenase locus in Drosophila pseudoobscura.
Authors: M A Riley, S R Kaplan, M Veuille
Journal: Molecular Biology and Evolution (1992)

Sequential polyacrylamide electrophoresis has revealed 20 allozymes of xanthine dehydrogenase (XDH) in Drosophila pseudoobscura. DNA sequence determination of seven isolates of the Xdh locus that represent six allozyme classes are presented here. Of the 5,456 sites examined, 180 are polymorphic, with 27 polymorphisms occurring at nonsynonymous, or replacement, sites. An average of nine amino acids differ between XDH allozyme classes, with 85% of the polymorphic amino acids singly represented. The level and pattern of variation observed at Xdh argue that the effective population size of the species is quite large--i.e., on the order of 2 x 10(6)--and that the populations sampled are quite ancient. In addition, as judged by two statistical tests, the levels of nucleotide polymorphism observed at Xdh are compatible with predictions from the neutral theory of molecular evolution.
Clarifying the clinical relevance of<i>SPINK1</i>intronic variants in chronic pancreatitis
Authors: Wen-Bin Zou, Arnaud Boulling, Emmanuelle Masson, David N Cooper, Zhuan Liao, Zhao-Shen Li, Claude Férec, Jian-Min Chen
Journal: Gut (2015)

Recently, we reported the identification of a functional PRSS1 promoter variant in perfect linkage disequilibrium (LD) with the chronic pancreatitis (CP)-‘protective’ rs10273639.1 This, together with several other recent papers published in Gut ,2–4 underscored the importance of functional analysis for improving our understanding of the underlying pathophysiological mechanisms and also more fundamentally for establishing the clinical relevance or otherwise of CP-associated variants from the outset. In many diseases, in vitro functional analysis often represents the only practical means to determine the pathogenicity of patient-derived sequence variants, particularly when they are rare. Herein, we present a new and successful example in the context of CP.

SPINK1 is one of the most extensively studied CP genes, with >100 variants being reported to date.5 Of 19 known intronic variants, the four in LD with the p.Asn34Ser variant have been functionally analysed in the context of both minigene6 and full-length genomic sequence7; none had any detectable effect on pre-mRNA splicing. In addition, the functional consequences of the c.194+2T>C splice donor site variant …