Phase I study of everolimus and mitomycin C for patients with metastatic esophagogastric adenocarcinoma

This study aimed at determining the recommended dose of the mammalian target of rapamycin inhibitor everolimus in combination with mitomycin C (MMC) in patients with previously treated metastatic esophagogastric cancer. In this phase I trial, patients received escalated doses of oral everolimus (5, 7.5, and 10 mg/day) in combination with intravenous MMC 5 mg/m2 every 3 weeks. Endpoints were the dose-limiting toxicity (DLT), safety, and response rates. Tumor tissues were tested for HER2-status and mutations in the PTEN, PIK3CA, AKT1, CTNNB1, and E-cadherin type 1 genes. Sixteen patients (12 male, four female) with gastric/gastroesophageal junction cancer were included. All patients were previously treated with a platinum-based chemotherapy. Treatment cohorts were: 5 mg/day, three patients; 7.5 mg/day, three patients; and 10 mg/day, 10 patients. No DLTs occurred during dose escalation. Most frequent grade 3 toxicities were leukopenia (18.8%) and neutropenia (18.8%). All other grade 3 toxicities were below 10%. No grade 4 toxicities occurred. Three (18.8%) patients experienced partial responses and four patients had stable disease (SD). Antitumor activity according to Response Evaluation Criteria In Solid Tumors (RECIST)-criteria was highest in the 10 mg/day cohort. No associations between HER2-status or detected mutations and response were observed. The recommended dose of everolimus combined with MMC is 10 mg/day. Encouraging signs of antitumor activity were seen (http://www.ClinicalTrials.gov; Clinical trial registration number: NCT01042782)

Transcriptional response of pancreatic beta cells to metabolic stimulation: large scale identification of immediate-early and secondary response genes

<p>Abstract</p> <p>Background</p> <p>Physiological long term adaptation of pancreatic beta cells is driven by stimuli such as glucose and incretin hormones acting via cAMP (e.g. GLP-1) and involves regulated gene expression. Several rapidly inducible immediate-early genes (IEGs) have been identified in beta cells. Many of these IEGs code for transcription factors and have the potential to control the transcription of downstream <it>target </it>genes likely involved in long term cellular adaptation. The identity of these <it>target </it>genes has not been determined, and the sequence of events occurring during beta cell adaptation is still unclear.</p> <p>Results</p> <p>We have developed a microarray-based strategy for the systematic search of <it>targets</it>. In Min6 insulin-secreting cells, we identified 592 <it>targets </it>and 1278 IEGs responding to a co-stimulation with glucose and cAMP. Both IEGs and <it>targets </it>were involved in a large panel of functions, including those important to beta cell physiology (metabolism, secretion). Nearly 200 IEGs were involved in signaling and transcriptional regulation. To find specific examples of the regulatory link between IEGs and <it>targets</it>, <it>target </it>promoter sequences were analyzed <it>in silico</it>. Statistically significant over-representation of AP-1 response elements notably suggested an important role for this transcription factor, which was experimentally verified. Indeed, cell stimulation altered expression of IEG-encoded components of the AP-1 complex, activating AP-1-dependent transcription. Loss and gain-of-function experiments furthermore allowed to validate a new AP-1 regulated gene (<it>sulfiredoxin</it>) among the <it>targets</it>. AP-1 and <it>sulfiredoxin </it>are sequentially induced also in primary cells from rat islets of Langerhans.</p> <p>Conclusion</p> <p>By identifying IEGs and their downstream <it>targets</it>, this study brings a comprehensive description of the transcriptional response occurring after beta cell stimulation, as well as new mechanistic insights concerning the AP-1 transcription factor.</p

Evaluation of different POCT devices for glucose measurement in a clinical neonatal setting

Hypoglycaemia is a major cause of neonatal morbidity and may induce long-term developmental sequelae. Clinical signs of hypoglycaemia in neonatal infants are unspecific or even absent, and therefore, precise and accurate methods for the assessment of glycaemia are needed. Glycaemia measurement in newborns has some particularities like a very low limit of normal glucose concentration compared to adults and a large range of normal haematocrit values. Many bedside point-of-care testing (POCT) systems are available, but literature about their accuracy in newborn infants is scarce and not very convincing. In this retrospective study, we identified over a 1-year study period 1,324 paired glycaemia results, one obtained at bedside with one of three different POCT systems (Elite™ XL, Ascensia™ Contour™ and ABL 735) and the other in the central laboratory of the hospital with the hexokinase reference method. All three POCT systems tended to overestimate glycaemia values, and none of them fulfilled the ISO 15197 accuracy criteria. The Elite XL appeared to be more appropriate than Contour to detect hypoglycaemia, however with a low specificity. Contour additionally showed an important inaccuracy with increasing haematocrit. The bench analyzer ABL 735 was the most accurate of the three tested POCT systems. Both of the tested handheld glucometers have important drawbacks in their use as screening tools for hypoglycaemia in newborn infants. ABL 735 could be a valuable alternative, but the blood volume needed is more than 15 times higher than for handheld glucometers. Before daily use in the newborn population, careful clinical evaluation of each new POCT system for glucose measurement is of utmost importanc

How populist crisis rhetoric affects voters in Switzerland

Right-wing populism has a long tradition in Switzerland. Nevertheless, only little is known about how populist messages in the media contribute to the success of the Swiss People’s Party (SVP) and to the acceptance of the party’s anti-immigration policies. In this study, we combine data from a large media content analysis (including newspapers and TV news shows) with data from a panel-survey in order to address this research gap. Thereby we differentiate between effects driven by the content and the form of right-wing populist communication. While right-wing populist content depicts immigrants and the political elite as a threat to the Swiss people, populist style evokes the sense of a crisis by emotionalizing and dramatizing the message. Populist style is therefore assumed to increase the persuasiveness of populist claims. The results of this study suggest that this is the case only for some voters, while it backfires for others

Monographs on drugs which are frequently analyzed in therapeutic drug monitoring/Arzneimittel-Monographien für Medikamente, die regelmäßig im Rahmen des Therapeutic Drug Monitorings analysiert werden

In addition to the monographs which have been published in the last 6 years by the working group "Drug Monitoring” of the Swiss Society of Clinical Chemistry (SSCC) [Rentsch, Fathi, Grignaschi, Magnin, Printzen, Thormann, J Lab Med 29: 287-97, 2005 - Rentsch, Buhl, Eap, Fathi, Jöchle, Magnin, J Lab Med 34: 129-39, 2010], new monographs have been written. The data presented in these monographs provide an overview of the information which is important for the request and interpretation of the results. Therefore, laboratory health professionals and the receivers of the reports are the targeted readers. With the exception of digoxin, the drugs presented in this series are not administered frequently and are only analyzed in special situations. First, information about pharmacology and pharmacokinetics of these drugs (protein binding, metabolic pathways and enzymes involved, elimination half-life time and elimination route(s) of the parent drug and therapeutic as well as toxic concentrations) is given. Secondly, the indications for therapeutic drug monitoring are listed. Last but not least, important preanalytical information is provided, including time points of blood sampling and time interval after which steady-state concentrations are reached after changing the dose. Furthermore, the stability of the drug and its metabolite(s) after blood sampling are described. For readers with a specific interest, references to important publications are given. The number of the monographs will be further enlarged. The updated files are presented on the homepage of the SSCC (www.sscc.ch). We hope that these monographs are helpful for the better handling of therapeutic drug monitoring and we are looking forward to receiving comments from the readers.

Preliminary results on the postmortem measurement of 3-beta-hydroxybutyrate in liver homogenates

The concentrations of 3-beta-hydroxybutyrate (3HB) in blood and two liver samples were retrospectively examined in a series of medicolegal autopsies. These cases included diabetic ketoacidosis, nondiabetic individuals presenting moderate to severe decompositional changes and nondiabetic medicolegal cases privy of decompositional changes. 3HB concentrations in liver sample homogenates correlate well with blood values in all examined groups. Additionally, decompositional changes were not associated with increases in blood and liver 3HB levels. These results suggest that 3HB can be reliably measured in liver homogenates when blood is not available at autopsy. Furthermore, they suggest that metabolic disturbances potentially leading or contributing to death may be objectified through liver 3HB determination even in decomposed bodie

Privatization, Risk-Taking, and the Communist Firm

This paper studies alternative methods of privatizing a formerly communist firm in the presence of imperfect risk markets. The methods include cash sales, a give-away scheme, and a participation contract where the government retains a sleeping fractional ownership in the firm. It is shown that, with competitive bidding, the participation contract dominates cash sales because it generates both more private restructuring investment and a higher expected present value of revenue for the government. Under weak conditions, the participation contract will induce more investment than the giveaway scheme, and it may even share the cash sales' virtue of incentive compatibility.

Clinical relevance of Aspergillus isolation from respiratory tract samples in critically ill patients

INTRODUCTION: The diagnosis of invasive pulmonary aspergillosis, according to the criteria as defined by the European Organisation for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG), is difficult to establish in critically ill patients. The aim of this study is to address the clinical significance of isolation of Aspergillus spp. from lower respiratory tract samples in critically ill patients on the basis of medical and radiological files using an adapted diagnostic algorithm to discriminate proven and probable invasive pulmonary aspergillosis from Aspergillus colonisation. METHODS: Using a historical cohort (January 1997 to December 2003), all critically ill patients with respiratory tract samples positive for Aspergillus were studied. In comparison to the EORTC/MSG criteria, a different appreciation was given to radiological features and microbiological data, including semiquantitative cultures and direct microscopic examination of broncho-alveolar lavage samples. RESULTS: Over a 7 year period, 172 patients were identified with a positive culture. Of these, 83 patients were classified as invasive aspergillosis. In 50 of these patients (60%), no high risk predisposing conditions (neutropenia, hematologic cancer and stem cell or bone marrow transplantation) were found. Typical radiological imaging (halo and air-crescent sign) occurred in only 5% of patients. In 26 patients, histological examination either by ante-mortem lung biopsy (n = 10) or necropsy (n = 16) was performed, allowing a rough estimation of the predictive value of the diagnostic algorithm. In all patients with histology, all cases of clinical probable pulmonary aspergillosis were confirmed (n = 17). Conversely, all cases classified as colonisation had negative histology (n = 9). CONCLUSION: A respiratory tract sample positive for Aspergillus spp. in the critically ill should always prompt further diagnostic assessment, even in the absence of the typical hematological and immunological host risk factors. In a minority of patients, the value of the clinical diagnostic algorithm was confirmed by histological findings, supporting its predictive value. The proposed diagnostic algorithm needs prospective validation