tbuckley/cabot-search huggingface dataset:
Final results of a randomized phase III trial of docetaxel, carboplatin and 5FU versus epirubicin, cisplatin and 5FU for locally advanced gastric cancer
Authors: A. A. Elsaid, Y. Elkerm
Journal: Journal of Clinical Oncology (2005)

4014 Background: Docetaxel-based chemotherapy appears to have considerable promise in advanced gastric cancer. In phase II studies of single agent docetaxel, response rates (RRs) of 17% to 24% have been achieved in previously untreated patients. The aim of this study is to compare the efficacy and tolerability of Docetaxel, and fluorouracil Carboplatin (DF-Carbo regimen) with that of the reference protocol of epirubicin, cisplatin and fluorouracil (ECF regimen). Methods: Between 1999 and 2004, a total of 64 patients with metastatic adenocarcinoma of the stomach were randomized and analyzed for toxicity, tumor response, progression-free and overall survival. DF-Carbo (Docetaxel 75 mg/m2 D1, Carboplatin AUC6 D2 and continuous infusion 5FU 1200 mg/m2/day D1–3) every 3 weeks. 30 patients were taken DF-carbo regimen, while 34 patients were in ECF arm. G-CSF 5 microg/kg SC was also given on days 4 through 9 prophylactically to all patients. Results: The overall response rate was 47.1% with ECF, and 66.7% with DF-Carbo regimen. The median survival was 8.7 months with ECF and 12.4 months with DF-Carbo regimen (P = 0.0005). The 2-year survival rates were 14% for the ECF arm, and 20% for the DF-Carbo regimen arm (P = 0.03). Histologically complete surgical resection following chemotherapy was achieved in two patients in the ECF arm (pathological complete responses to chemotherapy) and five patients in the DF-Carbo regimen arm. Conclusions: The DF-Carbo regimen resulted in a response and survival advantage compared with ECF regimen chemotherapy. The probability of long-term survival following surgical resection of residual disease is increased by this treatment. The high response rates seen with DF-Carbo regimen support its use in the neoadjuvant setting. It is possible that data from this randomized study confirms the value of docetaxel-based chemotherapy in advanced gastric cancer and that docetaxel combinations will also be effective in the multidisciplinary efforts to cure earlier stage No significant financial relationships to disclose.
Glycemic Control in Older Adults With Diabetes Mellitus
Authors: Elbert S. Huang, Andrew M. Davis
Journal: JAMA (2015)

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Abstract 215: The Redox Activation of DUSP4 by N-Acetyl Cysteine Protects Endothelial Cells and the Myocardium against Oxidative Damage
Authors: Chun-An Chen, Alma Barajas-Espinosa, Ariel Basye, Haixu Yan, Erin Jesse, David Quan
Journal: Circulation Research (2014)

Background: Redox imbalance is the primary cause for endothelial dysfunction (ED), obstructed blood flow, and subsequent heart attack and failure. Under oxidant stress, many critical proteins regulating endothelial function undergo oxidative modifications that lead to ED. Cellular levels of glutathione (GSH), the primary reducing source, can significantly regulate cell function via reversible protein thiol modification. N-Acetyl cysteine (NAC), a precursor for GSH biosynthesis, is beneficial for many vascular diseases; however, the detailed mechanism of these benefits is still not clear. Methods: We employed EPR spin-trapping, HPLC, fluorescent microscopy, immunoblotting, and qPCR of both in vitro and ex vivo experiments using either cultured cells or the Langendorff heart preparation. Results: NAC treatment increases NO generation from endothelial cells, as well as the enzyme and cofactor responsible for its production, ie eNOS and BH4. Interestingly, NAC treatment also increased the expression of DUSP4, an inducible nuclear dual-specificity phosphatase implicated in cardiovascular function. We hereby establish that DUSP4 redox modulates two important kinases (p38 and ERK1/2) of MAPK signaling pathways and provides protection against Cd2+-induced ROS damage as well as hypoxia-reoxygenation insult to endothelial cells. Furthermore, a four week oral NAC pre-treatment promotes DUSP4 both protein and mRNA expression in the rat myocardium and renders the heart less susceptible to ex vivo ischemia-reperfusion injury. Protein expression profiles in the myocardium closely mimic those observed with cultured endothelial cells. The infarct size of NAC-treated hearts is significantly reduced. The myocardial rate pressure product is much improved above vehicle treated rats. Conclusion: NAC serves as a direct antioxidant and as a regulator of transcription and translation of DUSP4, modulating the activity of its downstream effectors: ERK1/2 and p38, and thus protects against ROS-induced damage both in vitro and ex vivo. As such, NAC-derived drugs can provide a novel therapy to oxidant-induced diseases via the specific up-regulation of protective proteins such as DUSP4 and eNOS.
The role of Frizzled8 in idiopathic pulmonary fibrosis
Authors: Lisette Oostenbrink, Hoeke Baarsma, Reinoud Gosens, Melanie Könighoff
Journal: European Respiratory Journal (2014)

Background:  Idiopathic pulmonary fibrosis (IPF) is a chronic and lethal interstitial lung disease. Repetitive micro-injuries to the epithelium change the homeostasis and initiate production of growth factors, such as TGFβ and WNT ligands, which subsequently leads to fibroblast activation and extracellular matrix (ECM) production. WNT signaling exerts its effect upon WNT ligand binding to Frizzled receptors (FZD), which therefore represent suitable therapeutic targets. FZD8 has been shown to modulated ECM production by smooth muscle cells. Here, we aim to elucidate the role of FZD8 in pulmonary fibrosis.  Methods:  MCR5 and primary human lung fibroblast (phF) were treated with TGFβ or TNFα for 24 or 48h. TGFβ treatment was also performed on alveolar epithelial cells (AEC). Expression of (myo)fibroblast markers and FZD8 receptor were measured by qPCR and immunoblotting.  Results:  TGFβ significantly induced FZD8 mRNA expression in MRC5 fibroblasts; ΔC t -values TGFβ versus control: 1.74±0.04  vs  -3.91±0.03. This was accompanied by increased expression of  PAI-1 ,  ACTA2 , and  fibronectin . Treatment of phF for 24h with TGFβ or TNFα led to upregulation of  FZD8  from -3.57± 0.97 (basal) to 0.96±1.73 and -1.93±0.06, respectively. Prolonged treatment (48h) further increased the expression of  FZD8  (basal -3.89±1.22, TGFβ 0.88±2.73, TNFα -1.29±0.51). Remarkably, FZD8 expression is unaltered in AEC upon TGFβ stimulation. Moreover, both mRNA and protein levels of WNT5A, a potential ligand for FZD8, were increased by TGFβ in MRC5 cells and phF.  Conclusion : FZD8 is expressed upon TGFβ treatment in lung fibroblasts, but not in AEC. Thus, FZD8 might be a suitable, cell-specific therapeutic target for pulmonary fibrosis.
Targets for glycated haemoglobin
Authors: P D Home
Journal: BMJ (1995)

additionally breast fed by a lactating relative or the child's natural mother.In my experience in Papua New Guinea this method worked well in all cases in which the adoptive mother was motivated and received the necessary support from her family.Side effects of the drugs used were rarely complained of, and only once was it necessary to add methyldopa in the sequence as described above.Clearly, in industrialised countries, where induction of lactation is not considered to be essential for the survival of the infant, the relative importance of side effects and concerns regarding excretion of the drugs into the milk are greater.Nevertheless, at least some of the aspects of the above method could well be adopted in in- dustrialised countries.
Bronchiolitis Obliterans and IgA Nephropathy
Authors: JOSÉ L. HERNÁNDEZ, JAVIER GÓMEZ-ROMÁN, EMILIO RODRIGO, JOSÉ M. OLMOS, CARMEN GONZÁLEZ-VELA, JUAN C. RUIZ, JOSÉ F. VAL, JOSÉ A. RIANCHO
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

IgA nephropathy is a common form of glomerulonephritis, classically manifested by asymptomatic hematuria. Although the exact pathophysiologic mechanism is still unknown, renal damage has been related to mesangial deposition of IgA-containing immune complexes. In recent years, some lung diseases have been associated with IgA nephropathy, including pulmonary hemorrhage and sarcoidosis. We report a patient with idiopathic bronchiolitis obliterans who developed a rapidly progressive glomerulonephritis due to IgA deposits. Extensive deposits of IgA were also found in the lungs, thus suggesting a pathogenetic role for IgA in tissue injury at both organ levels. To our knowledge this association has not been previously described in the literature.
Regulation of Vasopressin Action by Prostaglandins
Authors: Michael A. Kirschenbaum, Andrew G. Lowe, Walter Trizna, Leon G. Fine
Journal: Journal of Clinical Investigation (1982)

The present studies examined whether vasopressin increases prostaglandin biosynthesis in isolated rabbit cortical collecting tubules (CCT) and whether endogenous prostaglandin biosynthesis plays a role in modulating the response of this nephron segment to vasopressin. Three groups of studies were performed. In the first group, CCT and proximal straight tubules (PST) were incubated with [3H]arachidonic acid, and metabolites were separated and identified using silica gel thin-layer chromatography. CCT were capable of producing all of the major prostaglandins (PG) (PGE2 > thromboxane B2[TxB2] > PGF2α > PGI2). PST produced significantly lesser quantities of these lipids. In the second group, radiolabeled arachidonic acid was incorporated into the phospholipid pool of both CCT and PST, vasopressin was added to the incubation medium, and metabolities were separated and identified as above. Vasopressin stimulated the release of all of the major prostaglandins in CCT but had no effect on PST. PGE release into the incubation medium, as assessed by a radioreceptor assay, increased 108%, and a vasopressin analogue, 1-desamino-8-d-arginine vasopressin, had a quantitatively similar effect. In the third group, a submaximal dose of vasopressin was administered to isolated, perfused CCT studied in the presence and absence of indomethacin to assess whether endogenous prostaglandins play a role in modulating the antidiuretic response to vasopressin. Studies were performed in rabbits on a normal diet and in desoxycorticosterone acetate (DOCA)- or KCl-loaded animals. In the state of mineralocorticoid excess, basal prostaglandin synthesis was 63% lower, and vasopressin-stimulated prostaglandin synthesis 76% lower, than the synthesis observed in rabbits on a normal diet. Cyclooxygenase inhibition exposed a significant hydroosmotic response to a submaximal dose of vasopressin in CCT from DOCA- or KCl-loaded animals. With arachidonic acid in the bath, the same dose of vasopressin failed to elicit a hydroosmotic response in CCT from rabbits on a normal diet even in the presence of a cyclooxygenase inhibitor. However, removal of exogenous arachidonic acid, with a consequently lower rate of prostaglandin synthesis, allowed the cyclooxygenase inhibitor to enhance the hydroosmotic response to vasopressin in these tubules.
Removing more tissue around breast tumour reduces need for further surgery
Authors: S. Mayor
Journal: BMJ (2015)

Removing additional tissue around the cavity left after excising a tumour during partial mastectomy in women with early breast cancer halves the rate of positive margins that require further surgery, a randomised study reported in the New England Journal of Medicine has shown.1

Survival in women with early stage breast cancer who undergo partial mastectomy is equivalent to survival in those with total mastectomy. Margin status, which assesses whether cancer cells extend to the edge of the apparently healthy tissue removed …
Prevalence and outcome of donor transmitted Acinetobacter baumannii in lung transplant patients in Saudi Arabia
Authors: Eid Almutairy, Naseer Alshekaily, Basha Khan, Waleed Saleh, Imran Nizami
Journal: European Respiratory Journal (2012)

Background: Donor transmission of organism to the lung transplant recipient is a known entity. The shortage of ideal donors and the increasing pool of lung transplant candidates is increasing the pressure to utilize extended donors. Large number of our donors have been on ventilator for extended period of time, hence bringing the risk of nosocomial infections. We describe our experience with acinetobacter baumannii pneumonia in the lung transplant patients.  Methods: Retrospective chart review of all the patients transplanted between March 2010 and August 2011. The patients with acinetobacter baumannii pneumonia transmitted from donors were compared to those not affected by such infections. The primary graft dysfunction, duration of mechanical ventilation, ICU length of stay, acute kidney injury and mortality were measured.  Results: A total of 18 patients underwent lung transplant during this period. There were 8 male and 10 female recipients. A total of 6 patients developed acinetobacter baumannii multidrug resistant pneumonia. The primary graft dysfunction was seen in 100 % vs. 91 %; median duration of mechanical ventilation was 14 vs. 2; median ICU length of stay was 19.5 vs. 6.5; acute kidney injury was 33 % vs. 41 % and mortality was 33 % vs. 8 % in the acinetobacter vs. non acenetobacter group.  Conclusion: Isolation of acinetobacter baumannii in respiratory culture from donor lungs was associated with worse outcomes in transplanted patients as compared to donor lungs without acinetobacter. Antibiotic coverage should be tailored to include this organism when suspected as soon as possible. Also a method for rapid identification of acinetobacter baumannii is needed.
IL-2Rα mediates temporal regulation of IL-2 signaling and enhances immunotherapy
Authors: Ee W. Su, Caitlin J. Moore, Samantha Suriano, Christopher Bryce Johnson, Neizel Songalia, Alicia Patterson, Daniel J. Neitzke, Kristina Andrijauskaite, Elizabeth Garrett-Mayer, Shikhar Mehrotra, Chrystal M. Paulos, Andrew L. Doedens, Ananda W. Goldrath, Zihai Li, David J. Cole, Mark P. Rubinstein
Journal: Science Translational Medicine (2015)

Interleukin-2 (IL-2) is a lymphocyte growth factor that is an important component of many immune-based cancer therapies. The efficacy of IL-2 is thought to be limited by the expansion of T regulatory cells, which express the high-affinity IL-2 receptor subunit IL-2Rα. IL-15 is under investigation as an alternative to IL-2. Although both cytokines signal through IL-2Rβγ, IL-15 does not bind IL-2Rα and therefore induces less T regulatory cell expansion. However, we found that transferred effector CD8(+) T cells induced curative responses in lymphoreplete mice only with IL-2-based therapy. Although conventional in vitro assays showed similar effector T cell responsiveness to IL-2 and IL-15, upon removal of free cytokine, IL-2 mediated sustained signaling dependent on IL-2Rα. Mechanistically, IL-2Rα sustained signaling by promoting a cell surface IL-2 reservoir and recycling of IL-2 back to the cell surface. Our results demonstrate that IL-2Rα endows T cells with the ability to compete temporally for limited IL-2 via mechanisms beyond ligand affinity. These results suggest that strategies to enhance IL-2Rα expression on tumor-reactive lymphocytes may facilitate the development of more effective IL-2-based therapies.
More European smokers are deciding not to quit, survey shows
Authors: Susan Mayor
Journal: BMJ (2015)

The proportion of smokers who have no intention of quitting is increasing, figures from a European survey have shown.

The survey is part of the ongoing EUROASPIRE study, which collects information on preventive cardiology every few years.1 The new figures, reported at the European Society of Cardiology Congress, compared lifestyle, risk factors, and drug treatment in people at high risk of developing cardiovascular disease who were interviewed in 2006-08 and again in 2014-15.

Study participants were consecutive patients younger …
Impact of an electronic decision support tool on outcomes for emergency department patients with pneumonia
Authors: Barbara Jones, Jason Jones, Greg Stoddard, Caroline Vines, Al Jephson, Jeffrey Ferraro, Herman Post, Ben Briggs, Paula Griffith, Naresh Kumar, Todd Allen, Peter Haug, Nathan Dean
Journal: European Respiratory Journal (2013)

INTRODUCTION:  To improve pneumonia care, we developed a real-time electronic decision support tool that provides severity assessment and management recommendations in the Emergency Department (ED). We compared pre- and post-implementation outcomes of 4 hospital EDs where the tool was implemented versus 3 usual care hospitals with only paper guideline forms.  METHODS:  We included all ED patients in seven Intermountain-affiliated hospitals in urban Utah, USA, with ICD-9 codes plus radiographic evidence of pneumonia for two study periods: pre-implementation (Dec 1 2009 – Nov 30 2010, N=2394) and post-implementation (Dec 1 2011-Nov 30 2012, N=2583). We measured rates of over-diagnosis (patients with pneumonia diagnoses but negative chest radiography), hospital admission rates, guideline-concordant triage, length of hospital stay, inpatient mortality, and secondary hospitalization rates. We adjusted outcomes for severity using the previously validated “eCURB” mortality predictor.  RESULTS:  Median age was 59 years, with an admission rate of 61% and 30-day mortality rate of 5.9%. Implementation of the tool was associated with a significant increase in guideline-concordant hospitalizations (81% to 85%, p=0.02) and a reduction in severity-adjusted inpatient mortality (Odds Ratio 0.55, p=.02) that were not observed in the usual care group. There was no significant difference in rates of over-diagnosis, hospital admission, guideline-concordant outpatient triage, length of stay, or secondary hospitalization.  DISCUSSION:  Implementation of a real-time electronic decision support tool was associated with an increase in recommendation-concordant triage and a reduction in inpatient mortality.
Michael Patrick Ryan
Authors: Frank Stewart
Journal: BMJ (2015)

Michael Patrick Ryan (“Mike”) studied at the London School of Economics and graduated BSc in economics with first class honours in 1959. Many of us will consider it our good fortune that he did not long pursue what could have been a promising career in economics Instead he started all over again as a medical student, graduating at Oxford in 1968. After junior hospital appointments, he went into general medical practice in Oxfordshire and then in Lincolnshire.

In 1974 he boldly moved north with his family to take up a conjoint appointment in Livingston. At that time, the Scottish Home and Health Department was actively promoting the Livingston scheme to bring the various parts of the NHS closer together. We were all enthusiastic and mostly quite young.

Joining our …
Stable Mixed Hematopoietic Chimerism in Dogs Given Donor Antigen, CTLA4Ig, and 100 cGy Total Body Irradiation Before and Pharmacologic Immunosuppression After Marrow Transplant
Authors: Rainer Storb, Cong Yu, J. Maciej Zaucha, H. Joachim Deeg, George Georges, Hans-Peter Kiem, Richard A. Nash, Peter A. McSweeney, John L. Wagner
Journal: Blood (1999)
Analysis of <i>mTOR</i> Gene Aberrations in Melanoma Patients and Evaluation of Their Sensitivity to PI3K–AKT–mTOR Pathway Inhibitors
Authors: Yan Kong, Lu Si, Yiqian Li, Xiaowen Wu, Xiaowei Xu, Jie Dai, Huan Tang, Meng Ma, Zhihong Chi, Xinan Sheng, Chuanliang Cui, Jun Guo
Journal: Clinical Cancer Research (2015)

Abstract Purpose: mTOR is a validated target in cancer. It remains to be determined whether melanoma patients bearing mTOR mutation could be selected for treatment with PI3K–AKT–mTOR pathway inhibitors. Experimental Design: A total of 412 melanoma samples were included. Gene aberrations in all exons of mTOR were detected by Sanger sequencing and confirmed by using Agilent's SureSelect Target Enrichment System. HEK293T cells stably expressing mTOR mutants were constructed by using transcription activator-like effector nucleases technique. Function of mTOR mutants and in vitro sensitivity of gain-of-function mTOR mutations to PI3K–AKT–mTOR pathway inhibitors were analyzed. Results: The overall incidence of somatic nonsynonymous mutations of mTOR was 10.4% (43/412). mTOR nonsynonymous mutations were relatively more frequent in acral (11.0%) and mucosal (14.3%) melanomas than in chronic sun-induced damage (CSD; 6.7%) and non-CSD (3.4%) melanomas. Of the 43 cases with mTOR mutations, 41 different mutations were detected, affecting 25 different exons. The median survival time for melanoma patients with mTOR nonsynonymous mutation was significantly shorter than that for patients without mTOR nonsynonymous mutation (P = 0.028). Transient expression of mTOR mutants in HEK293T cells strongly activated the mTOR–p70S6K pathway. In HEK293T cells with stable expression of H1968Y or P2213S mTOR mutants, LY294002 and AZD5363 showed higher potency than temsirolimus or BYL719 in inhibiting the PI3K–AKT–mTOR pathway and cell proliferation. Conclusions: mTOR nonsynonymous mutations are frequent in melanoma patients. mTOR nonsynonymous mutation may predict a worse prognosis of melanoma. Clinical trials with PI3K–AKT–mTOR pathway inhibitors may be beneficial for melanoma patients with specific mTOR mutations. Clin Cancer Res; 22(4); 1018–27. ©2015 AACR.