Genetic association analyses reveal a role for vitamin D insufficiency in hepatitis C virus-associated hepatocellular carcinoma development

Background: V itamin D insufficiency has been associated with the occurrence of various types of cancer, but causal relationships remain elusive. Methods: Associations between t he r isk o f HCV-related HCC development and CYP2R1 , GC, and DHCR7 genotypes, which are genetic determinants of reduced 25-OH-vitamin D3 (25[OH]D3) serum levels, were determined. Results: A t otal of 5604 HCV-infected patients, 1279 with a nd 4325 without progression to HCC, w ere identified. The well-known association between 25(OH)D3 s erum levels and variations in CYP2R1 ( rs1993116, rs10741657), GC ( rs2282679), a nd DHCR7 ( rs7944926, rs12785878) g enotypes was also apparent in patients w ith chronic hepatitis C. The same genotypes of t hese single nucleotide polymorphisms (SNPs), w hich are associated with reduced 25(OH)D3 s erum levels, were significantly associated with HCV-associated HCC (P=0.07 [OR=1.13] for CYP2R1 , P=0.007 [OR=1.56] for GC, P=0.003 [OR=1.42] for DHCR7; ORs for risk genotypes). In contrast, no association between t hese genetic variations and the o utcome of antiviral therapy with pegylated interferon-α and ribavirin ( P>0.2 for e ach SNP) or liver fibrosis progression rate (P>0.2 for each SNP) was observed, s uggesting a specific influence o f the genetic d eterminants of 25(OH)D3 s erum levels o n hepatocarcinogenesis. Conclusions: Our data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related HCC development. Controlled clinical trials to assess the benefit of vitamin D supplementation in HCVinfected patients with advanced liver fibrosis or cirrhosis are warranted.

R&D Expenditures and Firm Performance: Empirical Evidence on Finnish Data

Tutkielman tavoitteena on tutkia yrityksen tutkimus- ja tuotekehitystoiminnan (T&K) vaikutuksia yrityksen suorituskykyyn. Tutkielmassa tarkastellaan myös lyhyesti T&K- toimintaa osana yrityksen toimintoja ja ympäristöä. Tutkielman empiirisessä osassa tutkitaan poikkileikkausmenetelmää käyttäen T&K- menojen vaikutusta yrityksen kasvuun, kannattavuuteen ja osakkeen hintaan (tuottoon). Tutkielman empiirinen osa toteutettiin keräämällä tilinpäätös- ja osaketiedot 65 yritykselle vuosilta 1999-2005. T&K- menojen vaikutusta yrityksen kasvuun, kannattavuuteen ja osakkeen tuottoon tutkittiin eri aikavälejä käyttäen, jotta mahdolliset syy-seuraussuhteet voitaisiin luotettavasti osoittaa. Tutkimustulokset osoittavat, että yrityksen T&K- menoilla on positiivinen vaikutus yrityksen kasvuun ja kannattavuuteen ja,siten tulokset tukevat kahta tutkimuksen päähypoteesia. Yrityksen T&K- menoilla ja osakkeen tuoton välillä ei kuitenkaan käytetyllä aineistolla empiiristä yhteyttä löytynyt, joten kolmas päähypoteesi hylättiin.

Quinupristin-dalfopristin combined with beta-lactams for treatment of experimental endocarditis due to Staphylococcus aureus constitutively resistant to macrolide-lincosamide-streptogramin B antibiotics.

Quinupristin-dalfopristin (Q-D) is an injectable streptogramin active against most gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). In experimental endocarditis, however, Q-D was less efficacious against MRSA isolates constitutively resistant to macrolide-lincosamide-streptogram B (C-MLS(B)) than against MLS(B)-susceptible isolates. To circumvent this problem, we used the checkerboard method to screen drug combinations that would increase the efficacy of Q-D against such bacteria. beta-Lactams consistently exhibited additive or synergistic activity with Q-D. Glycopeptides, quinolones, and aminoglycosides were indifferent. No drugs were antagonistic. The positive Q-D-beta-lactam interaction was independent of MLS(B) or beta-lactam resistance. Moreover, addition of Q-D at one-fourth the MIC to flucloxacillin-containing plates decreased the flucloxacillin MIC for MRSA from 500 to 1,000 mg/liter to 30 to 60 mg/liter. Yet, Q-D-beta-lactam combinations were not synergistic in bactericidal tests. Rats with aortic vegetations were infected with two C-MLS(B)-resistant MRSA isolates (isolates AW7 and P8) and were treated for 3 or 5 days with drug dosages simulating the following treatments in humans: (i) Q-D at 7 mg/kg two times a day (b.i.d.) (a relatively low dosage purposely used to help detect positive drug interactions), (ii) cefamandole at constant levels in serum of 30 mg/liter, (iii) cefepime at 2 g b.i.d., (iv) Q-D combined with either cefamandole or cefepime. Any of the drugs used alone resulted in treatment failure. In contrast, Q-D plus either cefamandole or cefepime significantly decreased valve infection compared to the levels of infection for both untreated controls and those that received monotherapy (P < 0.05). Importantly, Q-D prevented the growth of highly beta-lactam-resistant MRSA in vivo. The mechanism of this beneficial drug interaction is unknown. However, Q-D-beta-lactam combinations might be useful for the treatment of complicated infections caused by multiple organisms, including MRSA.

Global Diversity Lines-A Five-Continent Reference Panel of Sequenced Drosophila melanogaster Strains.

Reference collections of multiple Drosophila lines with accumulating collections of "omics" data have proven especially valuable for the study of population genetics and complex trait genetics. Here we present a description of a resource collection of 84 strains of Drosophila melanogaster whose genome sequences were obtained after 12 generations of full-sib inbreeding. The initial rationale for this resource was to foster development of a systems biology platform for modeling metabolic regulation by the use of natural polymorphisms as perturbations. As reference lines, they are amenable to repeated phenotypic measurements, and already a large collection of metabolic traits have been assayed. Another key feature of these strains is their widespread geographic origin, coming from Beijing, Ithaca, Netherlands, Tasmania, and Zimbabwe. After obtaining 12.5× coverage of paired-end Illumina sequence reads, SNP and indel calls were made with the GATK platform. Thorough quality control was enabled by deep sequencing one line to >100×, and single-nucleotide polymorphisms and indels were validated using ddRAD-sequencing as an orthogonal platform. In addition, a series of preliminary population genetic tests were performed with these single-nucleotide polymorphism data for assessment of data quality. We found 83 segregating inversions among the lines, and as expected these were especially abundant in the African sample. We anticipate that this will make a useful addition to the set of reference D. melanogaster strains, thanks to its geographic structuring and unusually high level of genetic diversity.

Fluence plays a critical role on the subsequent distribution of chemotherapy and tumor growth delay in murine mesothelioma xenografts pre-treated by photodynamic therapy.

BACKGROUND: The pre-conditioning of tumor vessels by low-dose photodynamic therapy (L-PDT) was shown to enhance the distribution of chemotherapy in different tumor types. However, how light dose affects drug distribution and tumor response is unknown. Here we determined the effect of L-PDT fluence on vascular transport in human mesothelioma xenografts. The best L-PDT conditions regarding drug transport were then combined with Lipoplatin(®) to determine tumor response. in vivo. Lasers Surg. Med. 47:323-330, 2015. © 2015 Wiley Periodicals, Inc. METHODS: Nude mice bearing dorsal skinfold chambers were implanted with H-Meso1 cells. Tumors were treated by Visudyne(®) -mediated photodynamic therapy with 100 mW/cm(2) fluence rate and a variable fluence (5, 10, 30, and 50 J/cm(2) ). FITC-Dextran (FITC-D) distribution was assessed in real time in tumor and normal tissues. Tumor response was then determined with best L-PDT conditions combined to Lipoplatin(®) and compared to controls in luciferase expressing H-Meso1 tumors by size and whole body bioluminescence assessment (n = 7/group). RESULTS: Tumor uptake of FITC-D following L-PDT was significantly enhanced by 10-fold in the 10 J/cm(2) but not in the 5, 30, and 50 J/cm(2) groups compared to controls. Normal surrounding tissue uptake of FITC-D following L-PDT was significantly enhanced in the 30 J/cm(2) and 50 J/cm(2) groups compared to controls. Altogether, the FITC-D tumor to normal tissue ratio was significantly higher in the 10 J/cm(2) group compared others. Tumor growth was significantly delayed in animals treated by 10 J/cm2-L-PDT combined to Lipoplatin(®) compared to controls. CONCLUSIONS: Fluence of L-PDT is critical for the optimal distribution and effect of subsequently administered chemotherapy. These findings have an importance for the clinical translation of the vascular L-PDT concept in the clinics. Lasers Surg. Med. 47:323-330, 2015.

Risks in R&D Collaboration between Small and Large Firms

The main aim of this thesis was to find out what kinds of risks arise from collabo-ration in R&D between small and large firms. The suitability and gain of some buyer/supplier risk frameworks in examining of R&D collaboration has been in-vestigated. A risk model has been based on the buyer/supplier risks models found in the literature. Its applicability has been tested empirically by means of theme interviews with firm representatives. The risk classification framework received some confirmation. But the study also showed that the theoretical framework was not completely adequate, as a new risk class arose from communication. Collaboration causes risks, and these risks should be taken into account when R&D collaboration is planned. The advantage of risk examination is the possibility to decrease failures and losses, and to in-crease possibilities for success and economical benefits. This study should be used as a managerial analysis tool in trying to understand the form and concept of risk in risk expectancy.

The international epidemiology of child sexual abuse: a continuation of Finkelhor

Objective: The purpose of this paper was to compare the prevalence rates of child sexual abuse reported by [Finkelhor, D. (1994). The international epidemiology of child sexual abuse. Child Abuse & Neglect, 18 (5), 409-417] with those found in recent publications in order to confirm the widespread prevalence of child sexual abuse. Methods: Relevant articles about prevalence of child sexual abuse were identified through searches of computerized databases and a handsearch of Child Abuse & Neglect and the Journal of Child Sexual Abuse. Results: Thirty-eight independent articles were identified, corresponding to 39 prevalence studies; these articles report the prevalence of childhood sexual abuse in 21 different countries, ranging from 0 to 53% for women and 0 to 60% for men. Conclusions: Comparison of the present study with that of [Finkelhor, D. (1994). The international epidemiology of child sexual abuse. Child Abuse & Neglect, 18 (5), 409-417] shows a similarity between prevalence distributions; there appears to be a general pattern that remains more or less constant over the years, especially in women. Practice implications: Twelve years after the first revision study about the international prevalence of child sexual abuse, there is still a need for new data about this topic. The present study shows child sexual abuse is still a widespread problem in the society. In this research, carried out on 38 independent studies, there is new data for 21 countries over the world, being especially relevant the results obtained from other countries different from those pertaining toNorth America or Europe. It is important to point out the high prevalence found in most of the countries, so this information could be a new warning to make society and governments aware of this problem and undertake actions to prevent sexual abuse in childhood.