tbuckley/cabot-search huggingface dataset:
A risk stratification tool for exacerbations of COPD: time to switch to DECAF
Authors: Richard W Costello, Breda Cushen
Journal: Thorax (2016)

To paraphrase Henry Kissinger's infamous quote ascribing the vicious nature of academic politics to their lack of importance, it seems that precisely because exacerbations of COPD are so important, they are so infrequently studied. COPD is one of the most common reasons that people are admitted acutely to hospital. An OECD (Organisation for Economic Co-operation and Development) report indicates that the rate of admissions is 164 for women and 251 for men per 100 000 population.1 The median length of stay is 5 days and 5%–7% of people die during the course of the admission. While many recover to be discharged, 30% are readmitted within the subsequent 90 days.2 Clinically, compared with all patients with COPD, those who experience exacerbations suffer increased morbidity, reduced quality of life and have shortened life expectancy. One important feature of COPD exacerbations about which we have relatively little information is which clinical features, on presentation, indicate that an individual person is at risk of a poor outcome. In this month's Thorax , work from Dr Bourke's group have addressed this important question and report a validation study of a previously described risk assessment score, termed DECAF.3

To put this study into context, it is worthwhile reviewing the nature of an exacerbation of COPD. Most exacerbations are precipitated by infections, both viral and bacterial. As there is a seasonal pattern to these exacerbations, temperature change, variations in environmental pollution levels and poor adherence to preventer inhalers are additional causative factors.4 Locally, the airway responds to these insults with increased production of protective mucus and a resulting increased cough frequency. Infection increases the individual's metabolic demand and the resulting increase in VO2, leads to an increase in respiratory rate. In obstructed airways, the increased rate of ventilation and the impairment of airflow, from …
One small SNP for receptor virus entry, one giant leap for hepatitis B?
Authors: Neil Rajoriya, Jordan J Feld
Journal: Gut (2016)

One small step for man, one giant leap for mankind: words that will be forever echoed in the annals of history from 1969 when Neil Armstrong set foot on the moon. Earlier that decade, another major landmark occurred in the field of hepatology with the discovery of hepatitis B (HBV) in 1967. The cure for HBV has since remained elusive; however, the recent discovery of sodium taurocholate contransporting polypeptide (NTCP), a key cell-surface transmembrane glycoprotein involved in HBV entry into hepatocytes1–3 marks a major opportunity for the development of novel therapeutic strategies.

In this issue of Gut , Hu and colleagues4 report on the role of NTCP in the natural history of HBV infection and its link to the risk of HBV-related complications in a large cohort of Taiwanese patients. Chronic HBV remains a major global public health problem with an estimated 350 million people infected worldwide5 ,6 leading to approximately 780 000 deaths every year due to HBV complications.7 New strategies are needed to identify patients at risk of progression of liver disease and those at risk of developing hepatocellular carcinoma (HCC), thus allowing for more targeted therapeutic interventions, more cost-effective and more focused screening approaches in high-prevalence populations.

NTCP is encoded by the SLC10A1 gene and specifically expressed on the basolateral membrane of differentiated hepatocytes,8 likely serving as a key factor in the hepatotropism and species specificity of the virus.9 NTCP cotransports sodium and bile acids across the cellular membrane as part of the enterohepatic circulation.8 ,10 The N-terminus of the pre-S1 domain of the large envelope protein binds to NTCP, facilitating HBV entry into hepatocytes in cell culture model.1 Transfection of NTCP allows HBV entry into non-susceptible HCC cell lines but not to non-human, non-hepatic cells,11 suggesting …
Effects of Frequency of Sensor-Augmented Pump Use on HbA1c and C-Peptide Levels in the First Year of Type 1 Diabetes
Authors: Taylor M. Triolo, David M. Maahs, Laura Pyle, Robert Slover, Bruce Buckingham, Peiyao Cheng, Linda A. DiMeglio, Andrew A. Bremer, Stuart A. Weinzimer, H. Peter Chase
Journal: Diabetes Care (2016)

Intensive glucose control after the onset of type 1 diabetes has been suggested to preserve C-peptide production (1–3). In people with type 1 diabetes, sensor-augmented pump (SAP) use improved glycemic control, particularly when used >6 days/week (4). As previously reported, subjects with type 1 diabetes were randomized to either 3 days of in-hospital hybrid closed-loop therapy followed by SAP therapy or usual care (5). In the primary intent-to-treat analysis, no significant differences existed in HbA1c or C-peptide between the two groups at 1 year. In our post hoc analysis, we hypothesized that more frequent sensor use in the SAP group would be associated with lower HbA1c levels and preservation of C-peptide production at 1 year.

Subjects in the SAP group ( n = 46) were stratified by median SAP use of 12.4 h/day. HbA1c and C-peptide levels were compared at baseline and 3, 6, 9, 12, and 24 months. At 12 months of follow-up, the median HbA1c values for those with SAP …
Presence of survivin-specific cytotoxic T-lymphocytes (CTLs) in pancreatic cancer patients, and specific killing of human pancreatic carcinoma cells <i>in vitro</i> by survivin-specific CTLs
Authors: D. Z. Chang, K. Zhu, S. Kopetz, K. Voo, Y. Li, P. Hwu, L. Radvanyi, J. L. Abbruzzese
Journal: Journal of Clinical Oncology (2007)

3070 Background: The apoptosis inhibitor protein Survivin is an attractive target for a cancer vaccine because of its differential overexpression by most human tumors, its importance for tumor survival, and its demonstrated immunogenicity. To examine Survivin’s potential as a vaccine target for pancreatic cancer (PC), we evaluated the presence of Survivin-specific cytotoxic T-lymphocytes (CTLs) in PC patients and assessed the specific killing of HLA-A*0201+ human pancreatic carcinoma cell lines in vitro by Survivin-specific CTL. Methods: Mononuclear cells from the peripheral blood (PBMC) of PC patients and normal donors and Survivin peptides were used to generate Survivin-specific CTLs in vitro. The presence of Survivin-specific CTLs was evaluated by IFN-γ ELISPOT analysis. Recognition of human PC cell lines (e.g., Panc-1 and CF-Pac-1) was analyzed by 51 Cr release assays. Results: Multiple CTL lines were generated from different donors against a number of Survivin 9-mer and 10-mer peptides, including Sur5–14, Sur95–104, and Sur96–104 and altered forms of these peptides with enhanced HLA-A*0201 binding. Sur5–14 (TLPPAWQPFL) and new modified mSur95–104 (ELMLGEFLKL) peptides could generate specific CTL from the PBMC of most donors, and the resulting CTL showed cytotoxicity against Survivin peptide-pulsed Panc-1 and CF-Pac-1 in an HLA-A2-dependent manner. We found for the first time that mSur95–104 could elicit CTL activity that cross-reacted with wild-type peptide and 9-mer Sur96–104 in IFN-γ ELISPOT assays. In our preliminary analysis, we detected Survivin peptide-specific CTLs in four of five PC patients for Sur5–14 and three of five for mSur95–104. All five PC patients had a positive response to a pool of A2 peptides as positive controls, indicating their immune competence. Conclusions: CTLs specific for human Survivin peptide Sur5–14 and the modified peptides mSur95–104 were detected in majority of the PC patients tested. Further, Survivin-specific CTLs killed pancreatic carcinoma cell lines in vitro. Our results suggest that these two peptides are potential vaccines for the treatment of PC. No significant financial relationships to disclose.
Anatomy of the Intrahepatic Portal Venous System in Children with Non-Cirrhotic Pre-Hepatic Portal Hypertension. Results of Wedged Retrograde Portography Imaging and Proposal for an Anatomo-Radiological Classification.
Authors: A Bertocchini, C Grimaldi, G Bolla, G D’Ambrosio, J de Ville de Goyet
Journal: Journal of Hepatology (2012)
Modelling local gene networks increases power to detect trans-acting genetic effects on gene expression
Authors: Barbara Rakitsch, Oliver Stegle
Journal: Genome biology (2016)

Expression quantitative trait loci (eQTL) mapping is a widely used tool to study the genetics of gene expression. Confounding factors and the burden of multiple testing limit the ability to map distal trans eQTLs, which is important to understand downstream genetic effects on genes and pathways. We propose a two-stage linear mixed model that first learns local directed gene-regulatory networks to then condition on the expression levels of selected genes. We show that this covariate selection approach controls for confounding factors and regulatory context, thereby increasing eQTL detection power and improving the consistency between studies. GNet-LMM is available at: https://github.com/PMBio/GNetLMM.
Effect of sunitinib and pazopanib on necrosis and autophagic cell death in cancer cells: Role of cathepsin B.
Authors: Matteo Santoni, Consuelo Amantini, Maria Beatrice Morelli, Valerio Farfariello, Massimo Nabissi, Sonia Liberati, Laura Bonfili, Anna Maria Eleuteri, Matteo Mozzicafreddo, Luciano Burattini, Rossana Berardi, Stefano Cascinu, Giorgio Santoni
Journal: Journal of Clinical Oncology (2013)

e15513 Background: Tyrosine kinase inhibitors (TKI), such as sunitinib, sorafenib and pazopanib, have replaced immunotherapy as the standard of care for metastatic renal cell carcinoma (mRCC). However, their use in sequential or combined strategies is limited by the lack of evidences on TKI-induced cell death in cancer cells. Aim of our study was to evaluate the different mechanisms responsible of the anti-proliferative and cytotoxic effects induced in vitro by µM doses of sunitinib, sorafenib and pazopanib in 5637 and J82 bladder cancer (BC) cell lines. Methods: The viability of BC cell lines were tested by MTT assay. Autophagy was evaluated by western blot analysis with anti-LC3 and anti-p62 antibodies, acridine orange staining and cytofluorimetric analysis. Necrotic cell death was evaluated by Annexin-V/PI staining and FACS analysis. The cathepsin B activation was evaluated by western blot using an anti-cathepsin B antibody; the cathepsin B proteolytic activity was determined using the fluorogenic Z-Arg-Arg-AMC peptide and the fluorescence of the hydrolyzed 7-amino-4-methyl-coumarin was detected by a SpectraMax Gemini XPS microplate reader. Results: We found that sunitinib and pazopanib markedly reduced at mM dose the viability of BC cells. Treatment for 24h with 20µM of sunitinib, by triggering “Incomplete autophagy”, induced necrosis of BC cells. In addition, sunitinib as a lysosomotropic agent, entered free within the lysosomes, where by increasing lysosomal pH and impairing cathepsin B activity, induced lysosomal-dependent necrosis. By contrast, treatment of BC cells for 72h with 20µM of pazopanib induced autophagic cell death, which was markedly reversed in a dose-dependent manner by the autophagic inhibitor 3-MA. The pazopanib-induced autophagic cell death was associated with increased procathepsin B cleavage and enhanced cathepsin B activity. Conclusions: Overall, our results show different cathepsin B-dependent cancer cell death mechanisms induced by sunitinib or pazopanib, providing the biological basis for novel molecularly targeted approaches.
Vascular expression of PDGFR-β isoform as a predictor of survival in non-metastatic clear renal cell carcinoma (CRCC)
Authors: A. Petit, X. Garcia-Albeniz, A. Gaspa, B. Mellado, P. Gascón, C. Mallofre
Journal: Journal of Clinical Oncology (2008)

22091 Background: Platelet-derived growth factor receptor (PDGFR) is a transmembrane tyrosine kinase with α and β isoforms involved in CRCC tumorigenesis. New drugs inhibiting this target have been proved effective in treating metastatic CRCC patients. Our objective was to characterize vascular expression of PDGFRβ in CRCC and to assess its prognostic role in non-metastatic CRCC Methods: Patients were recruited from January 1991 to June 2006. PDGFR-β vascular expression was assessed by immunohistochemistry on tissue microarrays andit was categorized semiquantitatively as diffuse (positive in >25% of tumor vessels) or focal/negative (positive in ≤25%). Cox regression was used to develop the multivariate analysis. Results: 97 patients were available for analysis. 72.2% were male, and the median age was 66 (range 26–88) years. 49 (50.5%), 13 (13.4%) and 35 (36.1%) pts were staged as pT1, pT2 and pT3 respectively. According to Fuhrman grade 16 cases (16.5%) were classified as 1, 42 (43.3%) as 2, 29 (29.9%) as 3 and 10 (10.3%) as 4. Sixty eight (70.1%) tumor samples showed focal or negative vascular expression of PDGFRβ with a median survival of 114.5 (95% CI 74.7–154.4) months. Twenty nine (29.9%) were categorized as diffuse and did not reach median survival (Log-Rank test p=0.164). Multivariate analysis identified the focal/negative vascular expression of PDGFRβ as an independent predictor of mortality (HR 2.44; 95% CI 1.03–5.78). Age (HR 1.06; 95% CI 1.02–1.1) and pT3 (HR 5.01; 95% CI 2.04–12.31) were also prognostic factors. Conclusions: In our sample focal/negative vascular expression of PDGFR-β is an independent prognostic factor associated with poorer survival in localized CRCC. Further studies are granted to assess its predictive role with the new targeted therapies. No significant financial relationships to disclose.
Multidrug-resistant tuberculosis (MDR-TB) and HIV co-infection in Romania
Authors: Laura Lihatchi, Cornelia Tudose, Irina Pele, Maria Dede, Elmira Ibraim
Journal: European Respiratory Journal (2011)

Background:  Although Romania is a country with high TB notification rate, the weight of HIV-positive patients among all TB cases is around 1%. Besides, the MDR-TB and HIV co-infected cases are only a few yearly, but they have very low chance to be successfully treated.   Aims:  To analyze treatment outcomes of MDR-TB and HIV co-infected patients reported in Romania, from 2006 to 2009.   Methods:  Descriptive retrospective analysis of MDR TB-HIV co infected patients reported between 2006- 2009 in the TB National Electronic Database.   Results:  A total of 23 such cases have been notified in those 4 years. All were under 50 years old (13 even under 21 years). Gender ratio was F/M = 10/13. Only 20 patients were on antiretroviral therapy. All had pulmonary TB. As case category 11 were new cases, 3 relapses, 3 chronics, 1 retreatment after default and 5 retreatments after failure. Smear microscopy was positive in 15 patients. Drug sensitivity tests showed 12 resistances only to isoniazid and rifampin (HR), 2 extensively drug resistant TB (XDR-TB) and 9 resistances to HR and at least one additional drug. Most of them received treatment with Pyrazinamide, Ethambutol, Kanamycine, Protionamide, Ciprofloxacin and Cycloserine. Duration of treatment varied between 2 and 24 months. The treatment outcomes were: 8 had successful treatment, 5 were still continuing at the time of analysis, 4 failed, 3 died and 3 defaulted.   Conclusions:  Treatment success rate in MDR-TB-HIV co-infected patients in Romania was 34.8% in the 4 analyzed years. Management of MDR-TB in sero-positive patients need to be improved.
Use of chromosome 9p status to identify a subset of high-risk localized renal cell carcinoma
Authors: J. C. LaRochelle, A. Dastane, N. Rao, T. Klatte, B. Shuch, F. Kabbinavar, J. Said, A. Belldegrun, A. Pantuck
Journal: Journal of Clinical Oncology (2009)

5090 Background: We investigated whether deletion of chromosome 9p in clear cell renal cell carcinoma (ccRCC) predicts worse disease-specific (DSS) and recurrence-free survival (RFS), and if it is associated with worse prognosis in tumors &lt; 4 cm. Methods: 316 patients undergoing nephrectomy prior to 2001 were included on a tissue microarray in whom FISH analysis using the LSI p16/CEP 9 Dual Color Probe was performed to assess chromosome 9p deletion status. An additional 389 patients undergoing nephrectomy after 2001 had 9p status determined by standard cytogenetics. Tumor grade, stage, size, 9p status, nodal involvement, and the presence of metastasis were recorded. Disease-specific and recurrence-free survival were determined, and independence was assessed using Cox proportional hazards models. Results: 9p deletions were detected in 14% of tumors. 54% of 9p-deleted tumors were high grade (G3–4) vs. 38% without 9p deletions, and 60% of 9p-deleted tumors were T3–4 vs 38% without 9p deletions (p &lt; 0.01). 55% of those with 9p deletions had positive nodes or metastases vs. 34% of those without 9p deletions (p &lt; 0.01). Median DSS for those with and without 9p deletions was 80 months and 37 months, respectively (p &lt; 0.01). In localized disease, median RFS for those with 9p deletions was 53 months and was not reached in those without 9p deletions (p&lt;0.01). In 188 patients presenting with localized RCC &lt; 4 cm, loss of 9p occurred in 3/7 (42.9%) of patients with post-nephrectomy recurrence vs. 13/168 (7.2%) of patients without disease recurrence (p = 0.001). DSS for patients with 9p deletion in tumors &lt; 4 cm was significantly worse than DSS in those without 9p deletions (HR 6.18; p = 0.02), and an independent effect on RFS was seen for 9p deletions in localized RCC (HR 2.3, p &lt; 0.01). 9p status was not a significant predictor in metastatic RCC. Conclusions: Deletion of chromosome 9p in ccRCC occurs in 14% of patients and is associated with higher grade and T stage, presence of nodal and distant disease, worse prognosis, and in patients with small NOMO tumors, 9p deletions but not tumor size was independently associated with RFS. Identifying high risk patients with 9p deletions will allow better risk stratification for surveillance protocols and for adjuvant trials. No significant financial relationships to disclose.
The ethics of clinical research in the Third World [editorial]
Authors: Angell M
Journal: New England Journal of Medicine (1997)

It is ethical to compare a potential new treatment with a placebo in a clinical trial only when there is no known effective treatment.  When effective treatment exists a placebo may not be used and subjects in the study control group must receive the best known treatment.  The World Health Organizations Declaration of Helsinki clearly states that research goals are always secondary to the well-being of study participants.  However when pursuing the answer to a particularly important research question researchers sometimes do not follow the tenets of the Helsinki Declaration.  The Tuskegee Study of Untreated Syphilis is an example of such highly unethical research.  The US Public Health Service-sponsored study forced 412 poor Black men to suffer untreated syphilis during 1932-72 so that they could be followed to determine the natural history of untreated syphilis.  The subjects did not provide their informed consent were denied the best known treatment and the study continued even after highly effective treatment became available.  The justifications offered for the Tuskegee Study are similar to those being raised for the ongoing trials in developing countries of therapy to prevent the vertical transmission of HIV infection.  All but one of the trials are using placebo-treated control groups even though zidovudine has already been shown to considerably reduce the rate of vertical HIV transmission.  Zidovudine is now being recommended in the US for all HIV-infected pregnant women.  Researchers need to strengthen their commitment to adhere to the highest ethical standards no matter where research is conducted.
Evaluation of tolerability, safety, and pharmacokinetics of INO-1001 plus temozolomide (TMZ) in patients with unresectable stage III/IV melanoma
Authors: C. Wang, A. Y. Bedikian, K. Kim, N. E. Papadopoulos, W. Hwu, P. Hwu
Journal: Journal of Clinical Oncology (2006)

12015 Background: TMZ, an orally bioavailable cytotoxic agent with the same active metabolite as DTIC, is a commonly used for treatment (Rx) of metastatic melanoma (MM). It causes methylation of the O6 position of guanine. Unrepaired O6-methylguanine pairs with thymine rather than guanine and activates DNA mismatch repair. Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear protein that functions as DNA damage sensor. PARP inhibitors increase TMZ cytotoxicity by causing interruption of the repair process of N-methylpurines generated by TMZ. INO-1001 (INO), an ultrapotent PARP inhibitor has been tested in combination of TMZ and found to be safe and well tolerated. Here we report the initial results of Phase Ib clinical trial. Methods: Patients (pts) with unresectable stage III/IV MM with no prior Rx with TMZ or DTIC were treated with INO given IV q 12 hours for 10 doses at the starting dose of 100mg/dose. The doses of INO are planned to escalate from 100 to 200mg/dose and then to the maximum dose of 400 mg/dose in successive groups of 3–6 pts. TMZ is taken po within 2 hours of the second dose of INO at the dose of 200mg/m 2 /day for 5 days. Blood samples are collected for pharmacokinetics study during cycle 1. The Rx cycles are repeated q 4 weeks and tumor responses are evaluated q 8 weeks. Results: 6 pts with median age 63 (range 55–67) years and median PS Zubrod 1 (range 0–2) have been treated. Initially 3 pts were treated with INO at the dose level of 100mg. One pt with a BSA of 2.76 had grade 4 neutropenia and thrombocytopenia with Rx cycle 1. TMZ dose was not adjusted to her ideal body weight. Subsequently, the dose of TMZ was reduced by 25% and the following 2 cycles were tolerated well. 3 more pts were entered at the dose level 1. To date, a total of 8 cycles of Rx have been completed. All except for the cycle mentioned earlier were tolerated well. 3 pts were evaluated for response, 1 pt had objective tumor regression, 1 had stable disease and 1 had tumor progression. The non-hematologic side effects were mild and are mostly related to TMZ. Conclusions: TMZ-INO combination is fairly well tolerated. A complete report will be presented. No significant financial relationships to disclose.