tbuckley/cabot-search huggingface dataset:
Australian junior doctors launch legal action against managers over working conditions
Authors: Paul Smith
Journal: BMJ (2019)

Registrars at an Australian hospital have launched legal action against its management amid claims that they are being worked beyond exhaustion while being denied their mandatory clinical training.

The alleged plight of the doctors at Melbourne’s Sunshine Hospital has become the latest instalment in a growing list of complaints among doctors in training over excessive workload pressures, exploitation, harassment, and bullying across the country’s public hospital system.1

The Australian Medical Association in Victoria says that, under the enterprise agreement setting minimum terms and conditions with the hospital, registrars are contracted to work 43 hours a week, but the total includes five hours that must be used for clinical training time.

AMA Victoria is now representing the registrars by taking Western Health, which runs Sunshine Hospital, to the Fair Work Commission. It claims that the hospital …
FRI0125 Cerebral single-photon emission computed tomography (spect) in patients with systemic lupus erythematosus
Authors: CM González, FJ López-Longo, A Ortega, M Suárez, N Caro, R Del Castillo, C González-Montagut, L Cebrián, MI Almoguera, I Monteagudo, L Carreño
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Hypoperfusion observed in cerebral SPECT studies of patients with SLE has been found to be related with clinical activity in 10 patients with SLE and no neuropsychiatric manifestations.<sup>1</sup> <h3>Objectives</h3> To study the clinical significance of cerebral SPECT in unselected patients with SLE. <h3>Methods</h3> We performed cerebral SPECT in 57 women with SLE seen consecutively in our clinic. In the same week that SPECT was performed, SLEDAI, ESR, the concentrations of anti-DNA antibody and the C3 and C4 complement fractions, and the SLICC/ACR tissue damage index were determined. <h3>Results</h3> The mean age of patients was 37 years (SD 13.1) and the mean duration of the disease was 9.7 years (SD 6.3). Cerebral SPECT revealed hypoperfusion in 49 patients (86%), which was diffuse in 33 (57.9%) and patchy in 16 (28.1%). The most frequent sites of hypoperfusion were the frontal, temporal, and parietal cortical areas. Normal perfusion or mild hypoperfusion (unappreciable) was observed in 22 patients (38.6%) and moderate or intense hypoperfusion (appreciable) was observed in 27 (47.4%). Appreciable hypoperfusion was unrelated to age, duration of SLE, or the concentrations of anti-DNA antibodies and the C3 and C4 fractions. Patients with appreciable cerebral hypoperfusion had a more active clinical disease (mean SLEDAI 13.92; SD 8.44 vs 4.56; SD 4.15) (Mann-Whitney p &lt; 0.005), more cumulative tissue damage (mean SLICC 2.66; SD 2.84 vs 1.03; SD 1.51) (p: 0.035), and higher ESR (mean 28.7; SD 22.5 vs 17.7; SD 13.3) (p: 0.023) than patients with a normal SPECT. Cerebral hypoperfusion was related with neuropsychiatric manifestations present at the time of study (17 of 27; 63% vs 3 of 30; 10%) (OR: 15.3) or cumulative (19 of 27; 70.4% vs 8 of 30; 26.7%) (OR: 6.5), whether mild (OR: 5.5) or severe (OR: 8.2). <h3>Conclusion</h3> Cerebral hypoperfusion detected by SPECT was related with concomitant and previous neuropsychiatric manifestations, the clinical activity of SLE, and cumulative tissue damage. <h3>Reference</h3> Rev Esp Reumatol. 2000;27:202
Effect of in-line drinking water chlorination at the point of collection on child diarrhoea in urban Bangladesh: a double-blind, cluster-randomised controlled trial
Authors: Amy J Pickering, Yoshika Crider, Sonia Sultana, Jenna Swarthout, Frederick GB Goddard, Syed Anjerul Islam, Shreyan Sen, Raga Ayyagari, Stephen P Luby
Journal: The Lancet Global Health (2019)

Previous blinded trials of household water treatment interventions in low-income settings have failed to detect a reduction in child diarrhoea. Technological advances have enabled the development of automated in-line chlorine dosers that can disinfect drinking water without electricity, while also allowing users to continue their typical water collection practices. We aimed to evaluate the effect of installing novel passive chlorination devices at shared water points on child diarrhoea prevalence in low-income, densely populated communities in urban Bangladesh.In this double-blind cluster-randomised controlled trial, 100 shared water points (clusters) in two low-income urban communities in Bangladesh were randomly assigned (1:1) to have their drinking water automatically chlorinated at the point of collection by a solid tablet chlorine doser (intervention group) or to be treated by a visually identical doser that supplied vitamin C (active control group). The trial followed an open cohort design; all children younger than 5 years residing in households accessing enrolled water points were measured every 2-3 months during a 14-month follow-up period (children could migrate into or out of the cluster). The primary outcome was caregiver-reported child diarrhoea (≥3 loose or watery stools in a 24-h period [WHO criteria]) with a 1-week recall, including all available childhood observations in the analyses. This trial is registered with ClinicalTrials.gov, number NCT02606981, and is completed.Between July 5, 2015, and Nov 11, 2015, 100 water points with 920 eligible households were enrolled into the study and randomly assigned to the treatment (50 water points; 517 children at baseline; 2073 child observations included in the primary analysis) or control groups (50; 519; 2154). Children in the treatment group had less WHO-defined diarrhoea than did children in the control group (control 216 [10·0%] of 2154; treatment 156 [7·5%] of 2073; prevalence ratio 0·77, 95% CI 0·65-0·91). Drinking water at the point of collection at treatment taps had detectable free chlorine residual 83% (mean 0·37 ppm) of the time compared with 0% at control taps (0·00 ppm).Passive chlorination at the point of collection could be an effective and scalable strategy in low-income urban settings for reducing child diarrhoea and for achieving global progress towards Sustainable Development Goal 6.1 to attain universal access to safe and affordable drinking water. Targeting a low chlorine residual (<0·5 ppm) in treated water can increase taste acceptability of chlorinated drinking water while still reducing the risk of diarrhoea.The World Bank.
Nonspherical Nanoparticle Shape Stability Is Affected by Complex Manufacturing Aspects: Its Implications for Drug Delivery and Targeting
Authors: Bernard Manuel Haryadi, Daniel Hafner, Ihsan Amin, Rene Schubel, Rainer Jordan, Gerhard Winter, Julia Engert
Journal: Advanced Healthcare Materials (2019)

The shape of nanoparticles is known recently as an important design parameter influencing considerably the fate of nanoparticles with and in biological systems. Several manufacturing techniques to generate nonspherical nanoparticles as well as studies on in vitro and in vivo effects thereof have been described. However, nonspherical nanoparticle shape stability in physiological-related conditions and the impact of formulation parameters on nonspherical nanoparticle resistance still need to be investigated. To address these issues, different nanoparticle fabrication methods using biodegradable polymers are explored to produce nonspherical nanoparticles via the prevailing film-stretching method. In addition, systematic comparisons to other nanoparticle systems prepared by different manufacturing techniques and less biodegradable materials (but still commonly utilized for drug delivery and targeting) are conducted. The study evinces that the strong interplay from multiple nanoparticle properties (i.e., internal structure, Young's modulus, surface roughness, liquefaction temperature [glass transition (Tg ) or melting (Tm )], porosity, and surface hydrophobicity) is present. It is not possible to predict the nonsphericity longevity by merely one or two factor(s). The most influential features in preserving the nonsphericity of nanoparticles are existence of internal structure and low surface hydrophobicity (i.e., surface-free energy (SFE) > ≈55 mN m-1 , material-water interfacial tension <6 mN m-1 ), especially if the nanoparticles are soft (<1 GPa), rough (Rrms > 10 nm), porous (>1 m2 g-1 ), and in possession of low bulk liquefaction temperature (<100 °C). Interestingly, low surface hydrophobicity of nanoparticles can be obtained indirectly by the significant presence of residual stabilizers. Therefore, it is strongly suggested that nonsphericity of particle systems is highly dependent on surface chemistry but cannot be appraised separately from other factors. These results and reviews allot valuable guidelines for the design and manufacturing of nonspherical nanoparticles having adequate shape stability, thereby appropriate with their usage purposes. Furthermore, they can assist in understanding and explaining the possible mechanisms of nonspherical nanoparticles effectivity loss and distinctive material behavior at the nanoscale.
Resveratrol trimer enhances gene delivery to hematopoietic stem cells by reducing antiviral restriction at endosomes
Authors: Stosh Ozog, Nina D. Timberlake, Kip Hermann, Olivia Garijo, Kevin G. Haworth, Guoli Shi, Christopher M. Glinkerman, Lauren E. Schefter, Saritha D’Souza, Elizabeth Simpson, Gabriella Sghia-Hughes, Raymond R. Carillo, Dale L. Boger, Hans-Peter Kiem, Igor Slukvin, Byoung Y. Ryu, Brian P. Sorrentino, Jennifer E. Adair, Scott A. Snyder, Alex A. Compton, Bruce E. Torbett
Journal: Blood (2019)
The influence of hypoxia on telomerase in human primary glioblastoma cell lines
Authors: Dietmar Payrhuber, Pamela Edelmayer, Sibylle Pramhas, Sabine Spiegl-Kreinecker, Walter Berger, Klaus Holzmann
Journal: Cancer Research (2007)

4590  Introduction: Previously, we investigated 49 primary human glioblastoma cell samples for expression of hTERT. 17 (35%) of them displayed hTERT gene expression and could be established as stable immortal cell lines in vitro. The aim of the present study was to investigate effects of modulating hTERT gene expression and telomerase activity in human primary glioblastoma cells. To influence hTERT activity we used hypoxic culture conditions and hTERT expression constructs.  Methods: To imitate hypoxic conditions in vitro, human primary glioblastoma cell lines were incubated in a modular incubator chamber (Billups-Rothenberg, USA) which was flushed by a gas mixture containing 5% CO2, 1% O2 and 94% N2. As hTERT expression constructs recombinant adenoviruses were used, producing a hTERT wild type (WT) or a dominant negative (DN) protein. Telomerase activity was detected by a modified PCR-based telomeric repeat amplification protocol according to the TRAPEZE Telomerase Detection Kit. Protein levels were analyzed by Western blot.  Results: Under hypoxic conditions, one third of our investigated cell lines showed a marked increase of hTERT gene expression. These hypoxia treated cell lines showed positive correlation of hypoxia inducible factor-1 α protein (HIF-1α) and hTERT protein levels. Telomerase activity was higher than previously observed in untreated glioblastoma cell lines.  We also observed positive proliferation effects. In contrast to these findings, overexpression of DN-hTERT protein caused negative effects on cell proliferation.  Conclusion: Our data demonstrate that under hypoxic conditions glioblastoma cells show a further increase of hTERT gene expression and telomerase activity.   1) These findings may indicate that HIF-1α plays a role in hTERT activity in human glioblastoma cells. This could be an important clinical aspect for further glioblastoma research.  2) Hypoxia could be a novel way to generate stable immortal glioblastoma cell lines more easily.  This project was supported in part by a grant from the Herzfelder Stiftung, Vienna, Austria.
Effects of Liraglutide Compared With Placebo on Events of Acute Gallbladder or Biliary Disease in Patients With Type 2 Diabetes at High Risk for Cardiovascular Events in the LEADER Randomized Trial
Authors: Michael A. Nauck, Marie Louise Muus Ghorbani, Eskil Kreiner, Hans A. Saevereid, John B. Buse
Journal: Diabetes Care (2019)

OBJECTIVE To explore gallbladder- and biliary tract–related events reported for the liraglutide and placebo groups in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial. RESEARCH DESIGN AND METHODS LEADER was an international, randomized, double-blind, controlled cardiovascular (CV) outcomes trial. Participants with type 2 diabetes at high risk for CV events (n = 9,340) were randomized 1:1 to receive either liraglutide (≤1.8 mg daily; n = 4,668) or placebo (n = 4,672), with both groups also receiving standard care (treatment period: 3.5–5 years). Acute gallstone disease was a medical event of special interest. This post hoc analysis categorized captured events of acute gallbladder or biliary disease into four groups: uncomplicated gallbladder stones, complicated gallbladder stones, cholecystitis, and biliary obstruction. Time to first event by treatment group was analyzed using Cox regression. RESULTS There was an increased risk of acute gallbladder or biliary disease with liraglutide versus placebo (n = 141 of 4,668 vs. n = 88 of 4,672 patients, respectively; hazard ratio [HR] 1.60; 95% CI 1.23, 2.09; P &amp;lt; 0.001). Similar trends were observed for each of the four categories of gallbladder- or biliary tract–related events. Cholecystectomy was performed more frequently in liraglutide-treated patients (HR 1.56; 95% CI 1.10, 2.20; P = 0.013) but for similar proportions of the patients who experienced gallbladder- or biliary tract–related events (57% with liraglutide vs. 59% with placebo). CONCLUSIONS Although LEADER was not specifically designed to assess acute gallbladder or biliary disease, the trial showed an increased risk of gallbladder- or biliary tract–related events with liraglutide versus placebo, which appeared to be consistent across four categories of these events. Further studies should investigate the relevant mechanisms.
The characteristics of pemetrexed transport mediated by the high-affinity proton-coupled folate transporter (PCFT); impact of the reduced folate carrier (RFC) and PCFT on the activities of pemetrexed and other antifolates
Authors: Rongbao Zhao, Andong Qiu, I. David Goldman
Journal: Cancer Research (2008)

681  Pemetrexed (PMX) is a novel antifolate that acts primarily by inhibition of thymidylate synthase. PMX has high affinity for both the recently cloned PCFT and RFC that are ubiquitously expressed in normal and malignant human epithelial tissues. The objectives of this study were to: (i) characterize the properties of PCFT-mediated PMX transport in the HepG2 cell line stably transfected with PCFT cDNA, and to (ii) evaluate the impact of PCFT alone, or in comparison with RFC alone, on the activity of this drug and other antifolates using a novel cell line which lacks both transporters. [3H]PMX influx mediated by PCFT was optimal at pH 5.5 and decreased as the pH increased due to an increase in Km with only a small decrease in Vmax. However, substantial PMX transport activity was retained over pH 7.0 to 7.4, unlike what was observed for 5-formytetrahydrofolate (5-formylTHF). Uptake of PMX was highly concentrative at low extracellular pH but this decreased as the pH gradient was decreased. The PMX influx Km was 0.2 µM at pH 5.5 and 12.7 µM at pH 7.4. These values were far lower than the Ki/Km’s observed for other folates and antifolates, except for ZD9331 which was comparable to PMX. High-level expression of PCFT in HepG2 cells markedly enhanced PMX and ZD9931 growth inhibition but not the activities of ZD1694, PT523, or methotrexate (MTX).  Further studies were undertaken to assess the relative contribution of PCFT or RFC, at levels comparable to their endogenous expression in Hela cells, to the growth inhibitory activities of antifolates. To achieve this, a highly stable RFC-null, PCFT-deficient HeLa cell variant was developed (R1-11) into which RFC or PCFT was stably transfected, driven by an SV40 promoter. Expression of PCFT, alone, restored PMX growth inhibitory activity in R1-11 cells to the same extent as the expression of RFC, alone, but without augmenting MTX, ZD1694 or PT523 activities in cells grown in medium with 25 nM 5-formylTHF. PCFT was far less efficient than RFC in reducing the growth requirement for 5-formylTHF, but was more efficient than RFC in reducing the growth requirement for folic acid. These results substantiate the key role that PCFT plays in the delivery of PMX to tumor cells and indicate that either PCFT or RFC, alone, is sufficient to sustain full PMX activity. Beyond its high affinity for PCFT, what distinguishes PMX transport from that of most other antifolates is the full preservation of activity even when RFC is absent due, in part, to the delivery of PMX to cells via PCFT. The data also indicate that PCFT represents a major route of folic acid transport into cells in the absence of RFC when folic acid is the growth substrate. (Supported by an NIH grant #CA82621)
NFAT2-HDAC1 signaling contributes to the malignant phenotype of glioblastoma
Authors: Yifu Song, Yang Jiang, Dongxia Tao, Zixun Wang, Run Wang, Minghao Wang, Sheng Han
Journal: Neuro-Oncology (2019)

Abstract Background Deregulation of the nuclear factor of activated T cell (NFAT) pathway has been reported in several human cancers. Particularly, NFAT2 is involved in the malignant transformation of tumor cells and is identified as an oncogene. However, the role of NFAT2 in glioblastoma (GBM) is largely unknown. Methods The expression and prognostic value of NFAT2 were examined in the databases of the Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas (TCGA) and clinical samples. The functional effects of silencing or overexpression of NFAT2 were evaluated in glioma stem cell (GSC) viability, invasion, and self-renewal in vitro and in tumorigenicity in vivo. The downstream target of NFAT2 was investigated. Results High NFAT2 expression was significantly associated with mesenchymal (MES) subtype and recurrent GBM and predicted poor survival. NFAT2 silencing inhibited the invasion and clonogenicity of MES GSC-enriched spheres in vitro and in vivo. NFAT2 overexpression promoted tumor growth and MES differentiation of GSCs. A TCGA database search showed that histone deacetylase 1 (HDAC1) expression was significantly correlated with that of NFAT2. NFAT2 regulates the transcriptional activity of HDAC1. Rescue of HDAC1 in NFAT2-knockdown GSCs partially restored tumor growth and MES phenotype. Loss of NFAT2 and HDAC1 expression resulted in hyperacetylation of nuclear factor-kappaB (NF-κB), which inhibits NF-κB–dependent transcriptional activity. Conclusion Our findings suggest that the NFAT2-HDAC1 pathway might play an important role in the maintenance of the malignant phenotype and promote MES transition in GSCs, which provide potential molecular targets for the treatment of GBMs.
A phase II-III clinical study with the immunomodulator MGN1703 in patients with advanced colorectal carcinoma: The IMPACT study.
Authors: Marina Tschaika, Hans-Joachim Schmoll, Jorge Riera-Knorrenschild, Hendrik Kröning, Frank Mayer, Ekaterina Weith, Matthias Schroff, Maxim Krikov, Manuel Schmidt, Burghardt Wittig
Journal: Journal of Clinical Oncology (2012)

e14152 Background: Based on promising data from a phase 1 study of MGN1703 in patients with metastatic solid tumors including those with CRC, a phase 2-3 study was initiated in patients with advanced CRC having disease control after first-line therapy. MGN1703 is a synthetic DNA-based immunomodulator which acts as an agonist of toll-like receptor 9. The objective of the study is to assess efficacy and safety of treatment with MGN1703 in comparison to placebo. Methods: The IMPACT study is designed as an international, multicentric, randomized double-blind placebo-controlled phase 2-3 study. It is conducted in patients with advanced CRC showing disease control after 1st-line therapy with standard chemotherapy regimen. The study treatment is administered s.c. twice weekly (60 mg MGN1703 or placebo; ratio 2:1). The efficacy and safety of the study treatment will be evaluated based on extensive immunological tests, radiological assessment, safety laboratory results and assessments of the quality of life. The study treatment is continued until tumor progression, intolerable toxicity, exclusion criteria or withdrawal of consent. Results: Up to now, the patients received a maximum of 132 (mean: 32.1) treatment administrations, which equals 66 weeks. Drug-related adverse events (as assessed by the investigator) include mild fever, injection site itching, muscle aching, arthralgia, fatigue, paresthesia, rash, and moderate subfebril temperature and increased ANA in single patients. These represent only 16% of all adverse events reported in the study so far. Nine serious adverse events have been reported and only one was assessed as probably drug-related (“atypical pneumonia”). Local reactions reported in single patients include such symptoms as mild redness and swelling at injection site. Currently no laboratory or clinical signs of dose-limiting toxicities have been reported. Conclusions: The preliminary results of the ongoing clinical study in patients with advanced CRC show a good safety profile of the treatment with MGN1703 at the dosage of 60 mg. Most adverse events which were assessed as possibly drug-related belong to expected study drug reactions known for immune modulating drugs.
Impact of race and age on surgery and outcomes of renal cell carcinoma (RCC): A population based analysis.
Authors: Mohan Preet, Amarpali Brar, Aparna Surapaneni, Ratesh Khillan, Gurinder Singh Sidhu
Journal: Journal of Clinical Oncology (2012)

e15097 Background: RCC is a surgically curable malignancy; the outcomes are typically based on tumor size/extent and histology. Partial nephrectomy (PN) is preferred as nephron sparing approach over radical nephrectomy (RN), especially in smaller tumors. Methods: We reviewed data from Surveillance, Epidemiology, and End Results (SEER) 17 Regs Research Data registry for adult patients (pts) with RCC who had data about age, race, pathology, surgery and survival outcome. Results: In all 84480 cases of pts: 31605 (37%) females (F) and 52875 (63%) males (M) were reviewed. There were 8663 (10%) African Americans (AA) and 70942 (84%) Caucasians (C). Of the AA pts, there were 3349(39%) AAF and 5314(61%) AAM. Of the C pts, there were 26412(37%) CF and 44530(63%) CM. Clear cell RCC (CRCC) was seen in 69336 (82%); AA pts with CRCC 6166 (71%) , AAF: 2588(77%) and AAM: 3578(67%). C pts with CRCC: 58936(83%) : CM 36443(82%), and CF-22493 (85%) were reviewed. In AA pts with CRCC PN was done 1282 (21%) and RN 4145 (67%)times. AA men had 818 (23%) PN and 2539 (71%) RN, where as AAF had 464 (16%) PN and 1606 (62%) RN. C pts with CRCC had PN 10402 (18%) and RN 37214 (63%) times. CM had PN 6692 (18%) and RN 23594 (65%) times; CF had PN 3710 (16%) and RN 13620 (61%) times. The median size of tumor in pts undergoing PN was 2-3 cm and independent of race or sex. In pts undergoing PN, the median survival for AAM, AAF, CM and CF was 22m, 18m, 23m and 23m respectively. In pts undergoing RN the median survival for AAM, AAF, CM and CF was 23m, 21m, 24m and 23m respectively. In pts over the age of 80, 8240 cases of CRCC were reviewed, and 3950 (48%) pts had no surgery, of pts having any surgery 376 (8%) and 2859 (68%) pts had PN and RN. Median survival of CRCC over 80 years old having no surgery, PN and RN was 5m, 27m and 29m. Race or sex made no impact on proportion of pts having no surgery. Conclusions: C pts esp. CF are more likely to have CRCC histology. The kind of surgery (PN vs. RN) and outcomes after that are similar across both ethnicities and sexes. Pts over 80 yr old are much less likely to have any surgery and have very poor outcomes, this is avoided if they have PN or RN.