tbuckley/cabot-search huggingface dataset:
Abstract #8: A translational research paradigm by using pharmacological agents that will mimic or couple with dietary energy restriction for breast cancer prevention
Authors: Zongjian Zhu, Weiqin Jiang, John McGinley, Elizabeth Neil, Jennifer Sells, Denise Rush, Henry Thompson
Journal: Cancer Research (2009)

Emerging evidence from studies of human populations indicates that excessive energy intake is associated with an increased risk for cancer, but that dietary energy restriction (DER) is protective. Similarly, DER has been shown to be a potent inhibitor of carcinogenesis in most of the experimental models in which it has been investigated. However, current trends in the prevalence of overweight and obesity suggest that simply recommending limits to daily energy intake will be neither feasible nor attractive to most individuals as a cancer prevention strategy. It was for this reason that in our current work we decided to determine if it is possible to identify drugs that mimic the cancer preventive activity of DER in the absence of limiting energy intake. The objective of these experiments was to test two hypotheses: 1) that induction of the activity of AMP-activated protein kinase by metformin would inhibit mammary carcinogenesis and 2) that blocking the switch to aerobic glycolysis observed in cancers (the Warburg effect) by treatment with an dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, would block mammary tumor development. Female Sprague Dawley rats (n=30/group) were injected with 1-methyl-1-nitrosourea (50 mg/kg) at 21 days of age and 7 days thereafter randomized to control, metformin, or dichloroacetate (DCA) dietary groups and fed respective diets for 5 weeks. Both metformin and DCA significantly reduced the number of mammary adenocarcinoma per rat (p   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 8.
Lack of relationship between in vitro tumor cell growth and prognosis in extensive-stage small-cell lung cancer.
Authors: H C Stevenson, A F Gazdar, R I Linnoila, E K Russell, H K Oie, S M Steinberg, D C Ihde
Journal: Journal of Clinical Oncology (1989)

The ability to establish a continuously growing tumor cell line from fresh tumor specimens has been associated with shortened survival in some human malignancies. Therefore, we assessed the relationship between survival and in vitro tumor cell growth from specimens obtained during routine staging procedures in 68 consecutive patients with untreated, extensive-stage small-cell lung cancer (SCLC) who received etoposide/cisplatin chemotherapy. Three groups of SCLC patients could be distinguished: (1) 23 patients in whom a tumor cell line was established in vitro; (2) 28 patients in whom tumor-containing specimens were cultured but in vitro growth did not occur; and (3) 17 patients in whom no tumor-containing specimen could be procured. No significant difference in response rates to chemotherapy of the three groups was noted. Poor performance status (P2 = .001), male gender (P2 = .0008), liver metastases (P2 = .0033), brain metastases (P2 = .0152), and the ability to obtain a tumor-containing specimen from the patient for laboratory culture (P2 = .0005) were all significant independent predictors of decreased survival in this patient population. While the ability to obtain a tumor cell specimen for cell culture using routine staging and diagnostic procedures identified patients with shortened survival, we found no significant survival differences between patients whose tumor cell specimens grew in cell culture v those that did not (median survival of 7 months v 11 months, P2 = .72). Our study indicates that the clinical outcome of extensive-stage SCLC patients from whom tumor cell lines can be established is not significantly different than in those cases from whom tumor-containing specimens could not be grown in vitro.
Disclosing payments from drug companies should be mandatory for doctors, says academy:
Authors: Ingrid Torjesen
Journal: BMJ (2015)

Plans by the Association of the British Pharmaceutical Industry (ABPI) to bring in a system where healthcare professionals voluntarily declare payments and hospitality received from drug companies do not go far enough, the Academy of Medical Royal Colleges has said, calling for disclosure to be mandatory.

Thousands of healthcare professionals are expected to opt out of disclosing details of payments or hospitality from drug companies when the ABPI introduces a new database next year in an attempt to improve transparency.

The ABPI currently publishes aggregate details of the amounts drug companies spend on healthcare professionals for consultancy services or attending meetings. In 2014 this was about £41m (€58m; $64m), covering around 28 000 relationships1—although one healthcare professional may have a relationship with more than one drug company, so the overall number receiving payments is likely to …
Abstract MP37: Macroeconomic Growth is Associated with Increases in Cardiovascular Mortality in Countries with Lower Social Protection Spending
Authors: Usama Bilal, Manuel Franco, Thomas A Glass
Journal: Circulation (2015)

Background: Macroeconomic growth has been shown to be associated with increases in cardiovascular (CVD) mortality. However, it is unclear whether concurrent social protection policies may mitigate the observed associations. Objective: To study if social protection expenditure modifies the association between macroeconomic growth and cardiovascular mortality. Methods: We included 21 OECD countries from 1980 to 2010 with available data in the Comparative Welfare States Data Set and the WHO Mortality Database. Gross Domestic Product (GDP) was used as a proxy for economic growth. Age-adjusted cardiovascular mortality rates were calculated. Countries were divided into tertiles of average Social Protection expenditure. We used fixed-effect models to study the association of GDP growth with CVD mortality stratified by tertile of social protection expenditure. We included four lagged GDP terms to account for the cyclical nature of GDP. A second fixed-effects model was fitted with time-varying linear and quadratic social protection expenditure and its interaction with GDP. Results: Overall, a 1% increase in GDP was associated with an increase in CVD mortality of 0.5% (95% CI: 0.21-0.83%, p=0.001). In countries with high and medium social protection expenditure, GDP increases were not associated with changes in CVD mortality (p=0.80 and p=0.52 respectively). In countries with the lowest social protection expenditure, a 1% GDP increase was associated with a significant increase in CVD mortality of 0.7% (95% CI: 0.04-1.32% p=0.03). These results were consistent in analysis using time-varying social protection expenditure (Figure). Conclusion: Our results highlight the need for social protection policies to accompany economic growth to mitigate its potential deleterious effects on cardiovascular diseases. Further research should study specific policies that mitigate the harmful effects of macroeconomic growth.
Development and Characterization of a Rat Histiocyte-Macrophage Tumor Line
Authors: A Khar
Journal: JNCI Journal of the National Cancer Institute (1986)

A transplantable macrophage-like cell line has been obtained and established in W rats. This cell line is in its 85th passage and is perhaps the only established macrophage-like cell line that grows rapidly intraperitoneally in rats. The cells possess some of the typical characteristics of macrophages, such as adherence to glass, phagocytosis, presence of Fc receptors and C3d receptors, la determinants, leukocyte common antigen, lysozyme, non-specific esterase, and glycogen. The tumor also grows as solid when injected sc, intradermally, or intramuscularly. The cells have collagenase, tyrosine-specific protein kinase, and several other hydrolases. Histopathologic and ultrastructural observations suggest it to be a histiocytic tumor. The availability of a macrophage cell line of rat origin provides a useful experimental model to study different macrophage functions at the cellular and molecular level.
Repair of Indirect Inguinal Hernia
Authors: F. Forty
Journal: BMJ (1948)

BRITISNforward rotation of the right ilium on the sacrum, with an apparent lengthening of the right leg.In that case again a lift under the short leg would be contraindicated.The correct treatment would be manipulative backward rotation of the right ilium, which will result in equal length of legs and levelling of the sacral top.To decide if a shorter (or longer) leg is due to a backward (or forward) rotation of' the ilium the test described.by Downing is invaluable.If my memory serves me right it is also mentioned in Menell's book on backache.
Improvement in asthma severity and control by voriconazole and posaconazole in severe asthma with fungal sensitization (SAFS) and ABPA
Authors: Livingstone Chishimba, Robert Niven, David Denning
Journal: European Respiratory Journal (2012)

Rationale and Objectives: There is growing evidence linking asthma severity with fungal allergy. We assessed the effect of voriconazole or posaconazole therapy on asthma control and severity (GINA criteria) among patients with SAFS and ABPA.

Methods : We conducted a retrospective review of adult asthmatic patients with either ABPA or SAFS receiving voriconazole or posaconazole. Clinical, radiological and immunological evaluation was used to assess response. Voriconazole (300-600 mg/day) or posaconazole (800 mg/day) (adjusted by plasma level monitoring) was given for at least 6 months, if tolerated.

Results: There were 26 patients, ABPA (n =21, severe=17) or SAFS (n = 5), 11 males, median age = 59 yrs. Eighteen of 24 (75%) discontinued oral corticosteroids, 12 of them within 3 months of therapy. Asthma severity was downgraded from severe to moderate (n=8) and moderate to mild (n=1) in 9 of 24 (38%) patients. There was a marked reduction in OCS and SABA use, health care utilization due to asthma and improvement in overall health status. Furthermore, there was a statistically significant reduction in immunological markers appearing at 9 months (p=0.008) for total IgE and at 12 months for RAST IgE Aspergillus fumigatus (p=0.0056). Six of 23 (26%) patients on voriconazole had AEs requiring discontinuation before 6 months compared to none on posaconazole (p=0.15). Four relapsed (57%), one at 3 months and 3 at 12 months after discontinuation.

Conclusion : Both voriconazole and posaconazole are effective treatment options which can improve asthma control and severity, though larger prospective studies are required are required.
Bifidobacterium pseudocatenulatum CECT7765 induces an M2 anti-inflammatory transition in macrophages from patients with cirrhosis
Authors: Alba Moratalla, Esther Caparrós, Oriol Juanola, Kevin Portune, Amaya Puig-Kröger, Lizbeth Estrada-Capetillo, Pablo Bellot, Isabel Gómez-Hurtado, Paula Piñero, Pedro Zapater, José M. González-Navajas, José Such, Yolanda Sanz, Rubén Francés
Journal: Journal of Hepatology (2015)
Peginterferon lambda for the treatment of HBeAg-positive chronic hepatitis B: A randomized phase 2b study (LIRA-B)
Authors: Henry L.Y. Chan, Sang Hoon Ahn, Ting-Tsung Chang, Cheng-Yuan Peng, David Wong, Carla S. Coffin, Seng Gee Lim, Pei-Jer Chen, Harry L.A. Janssen, Patrick Marcellin, Lawrence Serfaty, Stefan Zeuzem, David Cohen, Linda Critelli, Dong Xu, Megan Wind-Rotolo, Elizabeth Cooney
Journal: Journal of Hepatology (2015)
Update: influenza activity - United States, April-August 2009.
Authors: L. Finelli, L. Brammer, L. Blanton, S. Epperson, R. Dhara, A. Fowlkes, D. Mustaquim, L. Kamimoto, K. Kniss, A. Klimov, L. Gubareva, A. Fry, A. Fiore, D. Jernigan, J. Bresee, D. Swerdlow
Journal: MMWR Morbidity and Mortality Weekly Report (2009)
Polychemotherapy for Early Breast Cancer: Results From the International Adjuvant Breast Cancer Chemotherapy Randomized Trial
Journal: JNCI Journal of the National Cancer Institute (2007)

Survival of patients with early-stage breast cancer is improved following treatment with single-modality tamoxifen, ovarian ablation or suppression, or chemotherapy. The Adjuvant Breast Cancer Trials were designed to ascertain any additional benefits of combined treatment.The Adjuvant Breast Cancer Chemotherapy Trial was a randomized phase III trial in which patients with early-stage breast cancer who were receiving prolonged (5 years) tamoxifen treatment, with or without ovarian ablation or suppression, were randomly assigned to standard chemotherapy versus none. Trial endpoints included relapse-free and overall survival. Hazard ratios (HRs) were derived from Cox models, and all statistical tests were two-sided.Between 1992 and 2000, 1991 patients between the ages of 26 and 81 years were randomly assigned (987 to chemotherapy, 1004 to no chemotherapy) from 106 UK and 16 non-UK centers. Nine hundred seven (92%) patients received chemotherapy as allocated (87% received cyclophosphamide, methotrexate, and 5-fluorouracil; 11% received anthracycline-containing regimens). A total of 244 of the 619 premenopausal patients received elective ovarian ablation or suppression. Chemotherapy improved relapse-free survival (relapse in the chemotherapy group versus no-chemotherapy group, 298 events versus 332 events, HR = 0.86, 95% confidence interval [CI] = 0.73 to 1.01; P = .06) and overall survival (death from any cause in the chemotherapy group versus no-chemotherapy group, 243 events versus 282 events, HR = 0.83, 95% CI = 0.70 to 0.99; P = .03) after adjustment for nodal status, estrogen receptor status, and age. Subgroup analyses showed that the benefit of chemotherapy was greatest in younger women (<50 years) and in particular for premenopausal women not receiving ovarian ablation or suppression.Modest yet sustainable benefits for chemoendocrine therapy occur in women with breast cancer. However, the full impact on overall survival may not emerge for several years.
Method of carrier-free delivery of therapeutic RNA importable into human mitochondria: Lipophilic conjugates with cleavable bonds
Authors: Ilya Dovydenko, Ivan Tarassov, Alya Venyaminova, Nina Entelis
Journal: Biomaterials (2015)

Defects in mitochondrial DNA often cause neuromuscular pathologies, for which no efficient therapy has yet been developed. MtDNA targeting nucleic acids might therefore be promising therapeutic candidates. Nevertheless, mitochondrial gene therapy has never been achieved because DNA molecules can not penetrate inside mitochondria in vivo. In contrast, some small non-coding RNAs are imported into mitochondrial matrix, and we recently designed mitochondrial RNA vectors that can be used to address therapeutic oligoribonucleotides into human mitochondria. Here we describe an approach of carrier-free targeting of the mitochondrially importable RNA into living human cells. For this purpose, we developed the protocol of chemical synthesis of oligoribonucleotides conjugated with cholesterol residue through cleavable covalent bonds. Conjugates containing pH-triggered hydrazone bond were stable during the cell transfection procedure and rapidly cleaved in acidic endosomal cellular compartments. RNAs conjugated to cholesterol through a hydrazone bond were characterized by efficient carrier-free cellular uptake and partial co-localization with mitochondrial network. Moreover, the imported oligoribonucleotide designed to target a pathogenic point mutation in mitochondrial DNA was able to induce a decrease in the proportion of mutant mitochondrial genomes. This newly developed approach can be useful for a carrier-free delivery of therapeutic RNA into mitochondria of living human cells.
Implantable synthetic cytokine converter cells with AND-gate logic treat experimental psoriasis
Authors: Lina Schukur, Barbara Geering, Ghislaine Charpin-El Hamri, Martin Fussenegger
Journal: Science Translational Medicine (2015)

Psoriasis is a chronic inflammatory skin disease characterized by a relapsing-remitting disease course and correlated with increased expression of proinflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin 22 (IL22). Psoriasis is hard to treat because of the unpredictable and asymptomatic flare-up, which limits handling of skin lesions to symptomatic treatment. Synthetic biology-based gene circuits are uniquely suited for the treatment of diseases with complex dynamics, such as psoriasis, because they can autonomously couple the detection of disease biomarkers with the production of therapeutic proteins. We designed a mammalian cell synthetic cytokine converter that quantifies psoriasis-associated TNF and IL22 levels using serially linked receptor-based synthetic signaling cascades, processes the levels of these proinflammatory cytokines with AND-gate logic, and triggers the corresponding expression of therapeutic levels of the anti-inflammatory/psoriatic cytokines IL4 and IL10, which have been shown to be immunomodulatory in patients. Implants of microencapsulated cytokine converter transgenic designer cells were insensitive to simulated bacterial and viral infections as well as psoriatic-unrelated inflammation. The designer cells specifically prevented the onset of psoriatic flares, stopped acute psoriasis, improved psoriatic skin lesions and restored normal skin-tissue morphology in mice. The antipsoriatic designer cells were equally responsive to blood samples from psoriasis patients, suggesting that the synthetic cytokine converter captures the clinically relevant cytokine range. Implanted designer cells that dynamically interface with the patient's metabolism by detecting specific disease metabolites or biomarkers, processing their blood levels with synthetic circuits in real time, and coordinating immediate production and systemic delivery of protein therapeutics may advance personalized gene- and cell-based therapies.
Use of a three-microRNA signature to discriminate prognostic groups in early-stage NSCLC patients in the IFCT-0002 trial.
Authors: C. Mascaux, G. Levallet, E. Bergot, L. Baudrin, M. Antoine, G. Anthoine, V. Westeel, A. Lavole, E. A. Quoix, D. Debieuvre, J. Mazieres, J. Pujol, D. Moro-Sibilot, F. Morin, B. Milleron, G. Zalcman
Journal: Journal of Clinical Oncology (2011)

7007 Background: No survival differences was observed between any arms in the 528 early stage NSCLC randomized patients of the IFCT-0002 phase III trial comparing two chemotherapy timing, all pre- vs. peri-operative, and two regimens, CDDP-Gem vs. CBDCA-Pac (V. Westeel, ASCO 2009). We hypothesized that microRNA (miRNA) expression profile could discriminate prognostic groups in these patients. Methods: Total RNA was extracted from 277 paraffin-embedded surgical macrodissected specimens. Expression of 17 miRNAs was successfully analyzed by Taqman qRT-PCR in 276 (99%) samples. Multivariate analysis with Cox model for overall survival (OS) was validated with a two-step bootstrap resampling analysis. Results: Low miR210 (under median) miR21, and miR15a, (under first quartile) expression significantly predicted a better survival when adjusted for stage and number of administered cycles, the two clinical variables influencing OS in multivariate analysis. A model including the three miRNAs discriminates three prognostic groups: Group 1: patients with the three miRNAs under the defined cut-off (n=129), Group 2: among the remaining patients, patients with miR21 under Q1, independently of the status of the two other miRNAs (n=82), and Group 3: all remaining patients (n=65). In univariate analysis, Group 1 showed the best OS (> 83 months), Group 2 intermediate OS (66 months), and Group 3 the worse OS (36 months, p=0.001, log-rank test). Adjusted HRs for OS with Group 3 as reference were 0.445, 95%CI [0.290-0.682], p=0.0002 and 0.632, 95%CI [0.406-0.986], p=0.043 for Group 1 and 2, respectively. Harrell’s concordance index of 0.83, 95%CI [0.67-0.95] showed a good predictive accuracy. A first bootstrap with 300 random resampling showed the stability of the miR model which significantly predicted OS in 260 samples (86.7%). The reproducibility of the model was confirmed by a second similar bootstrap procedure, the c-indexes of the created models ranging from 0.74 to 0.85. Conclusions: A miRNA model associating mIR15a, mIR21, and mIR210, accurately discriminates three prognostic groups in early-stage NSCLC patients treated by perioperative chemotherapy.
Phase II study of RAD001 (everolimus) and depot octreotide (sandostatin LAR) in advanced low grade neuroendocrine carcinoma (LGNET)
Authors: J. C. Yao, A. Phan, D. Z. Chang, R. A. Wolff, C. Jacobs, J. E. Mares, S. Gupta, F. Meric-Bernstam, A. Rashid
Journal: Journal of Clinical Oncology (2007)

4503 Background: Effective systemic therapy for advanced LGNET is lacking. Mutations involving the mTOR pathway including TSC2, NF-1, and vHL are associated with development of LGNET. mTOR also mediate signaling downstream of IGF1 and VEGF. RAD001 is a novel oral mTOR inhibitor. Octreotide has been described to inhibit VEGF and IGF1 production in solid tumors. Methods: Patients (pts) received depot octreotide 30 mg q28 days, and RAD001 5 (pts 1–30) or 10 mg (pts 31–60) po daily. Response was evaluated every 12 weeks (wks). Results: 30 carcinoid (C) and 30 islet cell (I) patients (pts) were enrolled between 2/05–7/06. 38 pts (23 C, 15 I) had prior octreotide. By RECIST criteria, there were 10 PR (17%), 45 SD (75%) (15 pts had &gt; 15% reduction), 5 PD (8%). The response rates within C, and I groups were 13% and 20%. The response rates within the 5 mg and 10 mg groups were 13% and 20% respectively. Of 39 pts with PD prior to study entry, there were 7 (18%) PR, 27 (69%) SD (9 pts had &gt; 15% reduction), 5 (13%) PD. PFS rate at 24 wks was 86%. The median PFS duration is 59 wks. The median PFS duration among the C and I groups were 69 and 39 wks. Among the 39 pts with progression at study entry, the median PFS duration was 38 wks. Of 24 pts with elevated chromogranin A at entry, 19 (56%) had &gt; 50% reduction. Treatment was well tolerated. The most common toxicity was mild aphthous ulceration. CTC G3/4 toxicities included: thrombocytopenia (3), neutropenia (3), hypophosphatemia (5), hyperglycemia (4), hypoglycemia (2), hypokalemia (2), fatigue (6), diarrhea (6), aphthous ulcer (5), rash (3), and 1 each of anemia, hypertriglyceridemia, bilirubin, AST/ALT, pain, nausea, nail, dysgeusia, pneumonitis. Conclusions: RAD001 at 5 or 10 mg daily was well tolerated in combination with octreotide. Promising anti-tumor activity has been observed. The RADIANT (RAD001 In Advanced Neuroendocrine Tumors) trials are underway to evaluate RAD001 in larger patient groups. No significant financial relationships to disclose.