Cancer susceptibility in nasopharyngeal carcinoma families--a population-based cohort study

Undifferentiated nasopharyngeal carcinoma is a result of environmental factors, in particular EBV infection, affecting genetically susceptible individuals. The familial risk of nasopharyngeal carcinoma is among the highest of any malignancy. Whether this susceptibility is restricted to nasopharyngeal carcinoma is unknown as information on the risk of other cancers in relatives is limited. We did a population-based study of the cancer incidence in nasopharyngeal carcinoma families in Greenland, a nasopharyngeal carcinoma-endemic area. Using population-based registers, a cohort of all persons born in Greenland was followed from 1973 to 2002. In this cohort, 134 individuals developed nasopharyngeal carcinoma and their relatives were identified through registers and interviews. Subsequently, the occurrence of cancer was determined by linkage to the population-based cancer register and the risk of cancer in nasopharyngeal carcinoma relatives and nonrelatives compared by relative risks. Among 766 first-degree relatives, the relative risk of nasopharyngeal carcinoma following the family index case was 8.0 [95% confidence interval (95% CI), 4.1-14.0]. Sex and age of the relative or the index case had no modifying effect on the familial risk of nasopharyngeal carcinoma. The relative risks of carcinoma of the salivary glands, 8.4 (95% CI, 2.7-19.5), and uterine cervix, 2.2 (95% CI, 1.1-3.9), were also significantly increased. In families with multiple cases of nasopharyngeal carcinoma, the risk of other cancers than nasopharyngeal carcinoma was further increased. These results indicate that the increased risk of cancer in nasopharyngeal carcinoma families is not restricted to nasopharyngeal carcinoma, but extends to the virally associated cancers of the salivary glands and cervical uteri.     

Preclinical Profile and Characterization of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir (BMS-650032)

Asunaprevir (ASV; BMS-650032) is a hepatitis C virus (HCV) NS3 protease inhibitor that has demonstrated efficacy in patients chronically infected with HCV genotype 1 when combined with alfa interferon and/or the NS5A replication complex inhibitor daclatasvir. ASV competitively binds to the NS3/4A protease complex, with K(i) values of 0.4 and 0.24 nM against recombinant enzymes representing genotypes 1a (H77) and 1b (J4L6S), respectively. Selectivity was demonstrated by the absence of any significant activity against the closely related GB virus-B NS3 protease and a panel of human serine or cysteine proteases. In cell culture, ASV inhibited replication of HCV replicons representing genotypes 1 and 4, with 50% effective concentrations (EC(50)s) ranging from 1 to 4 nM, and had weaker activity against genotypes 2 and 3 (EC(50), 67 to 1,162 nM). Selectivity was again demonstrated by the absence of activity (EC(50), >12 μM) against a panel of other RNA viruses. ASV exhibited additive or synergistic activity in combination studies with alfa interferon, ribavirin, and/or inhibitors specifically targeting NS5A or NS5B. Plasma and tissue exposures in vivo in several animal species indicated that ASV displayed a hepatotropic disposition (liver-to-plasma ratios ranging from 40- to 359-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥110-fold above the inhibitor EC(50)s observed with HCV genotype-1 replicons. Based on these virologic and exposure properties, ASV holds promise for future utility in a combination with other anti-HCV agents in the treatment of HCV-infected patients.     

Identification of I50L as the signature atazanavir (ATV)-resistance mutation in treatment-naive HIV-1-infected patients receiving ATV-containing regimens

Atazanavir (ATV) is a once-daily human immunodeficiency virus (HIV) protease inhibitor (PI) shown to be effective and well tolerated. ATV has a distinct resistance profile relative to other PIs, with susceptibility maintained against 86% of isolates resistant to 1-2 PIs. Clinical isolates obtained from PI-naive patients designated as experiencing virologic failure while receiving ATV-containing regimens contained a unique isoleucine-to-leucine substitution at amino acid residue 50 (I50L) of the HIV-1 protease. The I50L substitution, observed in all isolates exhibiting phenotypic resistance to ATV, emerged in a variety of different backgrounds and was most frequently accompanied by A71V, K45R, and/or G73S. Viruses containing an I50L substitution were growth impaired, displayed ATV-specific resistance, and had increased susceptibilities (相似文献   

Core pathology of eating disorders as measured by the Eating Disorder Examination Questionnaire (EDE‐Q): the predictive role of a nested general (g) and primary factors

The present study examined several factor models of the Eating Disorder Examination Questionnaire (EDE‐Q), and in particular, whether a nested general factor (‘g’) was present, hence supporting a common pathology factor. A total of 1094 women were randomly selected by Statistics Norway and mailed a questionnaire packet. The sample was randomly split, using the first half for exploratory analyses and the second for confirmatory validation purposes. A four‐factor solution received the best support, but the structure deviated from the original model of Fairburn. The internal consistency was high for the first three factors (.93, .82 and .86) and satisfactory for the fourth (.78). The additional specification of a general (g) factor improved model fit significantly, implying that the EDE‐Q scores are indicators of both a general core and four primary symptom patterns. Furthermore, the g was more strongly related to predictors like age and body mass index (BMI) than the four primary factors in a full structural equation model. The validity of interpreting the global EDE‐Q score as indicative of g was supported. A brief Shape and Weight Concern subscale of 11 items was strongly related to the g‐factor, and may provide an abbreviated measure of overall eating disorder pathology. Copyright © 2013 John Wiley & Sons, Ltd.     

Frequency of atopy in the Arctic in 1987 and 1998

Few studies have measured the frequency of atopy with objective measures, and most of these studies have been done in industrialised countries. We analysed serum samples from 859 15-80-year-old Greenlanders who had participated in population-based screening campaigns in 1987 and in 1998. We defined atopy as a positive result in an assay that tests for specific IgE against the eight most common inhalant allergens in one pool (grass, birch, mugwort, dog, cat, horse, Cladosporum herbarum, house dust mite). The frequency of atopy doubled between 1987 (39 [10%] of 392) and 1998 (87 [19%] of 467; risk ratio 1.88 [95% CI 1.31-2.68]). This increase was largest in 15-19-year olds, but also occurred in older people, suggesting that the risk factors responsible for the increase in atopy do not operate only in childhood.     

Combinations of Lambda Interferon with Direct-Acting Antiviral Agents Are Highly Efficient in Suppressing Hepatitis C Virus Replication

The clinical efficacy of a pegylated form of human lambda 1 interferon (IFN-λ1; also referred to herein as lambda) has been demonstrated in patients chronically infected with hepatitis C virus (HCV) representing genotypes 1 through 4. In these proof-of-concept studies, lambda showed an improved safety profile compared to the pegylated form of alfa interferon (referred to herein as alfa). In the study described in this report, an assessment of the in vitro antiviral activity of type III IFNs toward different HCV replicons revealed that the unpegylated recombinant form of IFN-λ1 (rIFN-λ1) exerted the most robust effect, while rIFN-λ3 exhibited greater activity than rIFN-λ2. More importantly, cross-resistance to rIFN-λ1 was not observed in replicon cell lines known to have reduced susceptibility to investigational direct-acting antiviral (DAA) agents targeting the essential HCV nonstructural protein NS3, NS5A, or NS5B. When combined with either rIFN-α, the NS3 protease inhibitor (NS3 PI) asunaprevir (ASV), the NS5A replication complex inhibitor (NS5A RCI) daclatasvir (DCV), or the NS5B polymerase site I inhibitor (NS5B I) BMS-791325, rIFN-λ1 displayed a mixture of additive and synergistic effects. In three-drug combination studies, inclusion of lambda with ASV and DCV also yielded additive to synergistic effects. In line with these observations, it was demonstrated that a regimen that used a combination of rIFN-λ1 with one or two DAAs was superior to an IFN-free regimen in clearing HCV RNA in genotype 1a cell lines representing wild-type and NS3 protease inhibitor-resistant sequences. Overall, these data support further clinical development of lambda as part of alternative combination treatments with DAAs for patients chronically infected with HCV.     

Mannose-Binding Lectin Genotypes and Susceptibility to Epstein-Barr Virus Infection in Infancy

In a cohort study of children <4 years of age in Greenland, mannose-binding lectin (MBL2) genotypes and Epstein-Barr virus (EBV) antibody levels were determined. EBV seropositivity was significantly lower and time to seroconversion increased in MBL-insufficient compared with MBL-sufficient children, indicating that MBL may be involved in primary EBV infection in infancy.Epstein-Barr virus (EBV) infection is ubiquitous, and the majority of individuals are infected early in life, but in developed countries 25 to 35% remain seronegative until adolescence (2, 12).The serum protein mannose-binding lectin (MBL) is a part of the innate immune system binding to a variety of infectious agents and promoting opsonophagocytosis and activating the complement system (27). Three variant alleles in exon 1 of the MBL2 gene on chromosome 10 coding for MBL independently reduce the amount of functional MBL subunits in heterozygous individuals 5- to 10-fold (18), while homozygous persons have only trace amounts of dysfunctional MBL in their blood (27). Furthermore, promoter polymorphisms in the MBL2 gene (X and Y) influence the level of functional MBL (18). MBL-deficient individuals are more susceptible to a range of infections, especially in early infancy before the maturation of the adaptive immune system (14), and MBL is known to modulate the response to viral infections, including herpesviruses (3, 4, 23). Thus, MBL increases neutralization of herpes simplex virus type 2 (HSV-2), MBL deficiency is more prevalent in symptomatic HSV-2 patients (4), and MBL-deficient individuals are at greater risk of recurrent HSV-2 infection (23). In contrast, a clear increase in HSV-2 infectivity was observed in mice following pretreatment with MBL, suggesting that MBL opsonization provides an alternative port of virion entry (3). Thus, MBL may facilitate or inhibit HSV-2 infection. The influence of MBL levels on other herpesviruses in humans is unknown, and the aim of this study was to determine whether MBL2 polymorphisms determining MBL levels are associated with EBV infection in unselected children aged 0 to 4 years.An open cohort study in the west Greenland community of Sisimiut was carried out from 1996 to 1998 (14, 15). Of all children <2 years of age, 294 (87%) participated and were followed regularly. At the end of the study period, or earlier if children left the study, a venous blood sample was drawn into EDTA containers and separated by centrifugation into plasma and blood cells, frozen, and stored at −80°C. Blood was drawn from 252 children, and for 247 children a plasma sample remained stored (mean age at bleeding, 2.3 years; age range, 3 months to 4 years and 2 months). Thus, some children had blood samples drawn later than the end of their monitoring period.As part of a population-based school survey for EBV infection in 2004, part of the cohort was reexamined. Blood samples were drawn and treated as described above. Prior to centrifugation, whole blood was allocated and stored at −80°C.MBL2 structural and promoter alleles were detected in the blood samples from 1997 to 1998, as previously described (7, 18). The three variant alleles (B, C, and D) in exon 1 of the MBL2 gene were grouped as allele O, and the normal allele was designated A. By combining these genotypes and the effects of the promoter variants X and Y, we were able to define six MBL genotypes divided into an MBL-sufficient group (YA/YA, YA/XA, YA/O, XA/XA) (n = 234) and an MBL-insufficient group (XA/O and O/O) (n = 13) with virtually undetectable amounts of functional MBL in the blood of the latter group (5, 6, 8).Levels of plasma IgG and IgM antibodies to the EBV viral capsid antigen (VCA) were determined in the 1997-1998 and 2004 blood samples using enzyme-linked immunosorbent assays (ELISAs) (Novitec, Freiburg, Germany) (9). Each assay included positive and negative controls and replicates of low, intermediate, and high calibrators. A standard curve based on the absorbance values of the calibrators was constructed and used to determine antibody concentrations in units per ml. EBV seropositivity was defined as either a VCA-IgG of >200 U/ml or a VCA-IgM of >500 U/ml.DNA was extracted from whole blood (500 μl) from the samples collected in 2004 using QIAamp DNA blood minikits (Qiagen, Crawley, United Kingdom). All samples were assayed using a real-time quantitative TaqMan PCR based on the pol gene of EBV (17). Where sufficient material was available, the sample was assayed in duplicate (83.5% of samples).Regression analyses were used to determine the associations between MBL2 genotypes and EBV seropositivity (logistic regression) and log VCA-IgG levels (linear regression), with adjustment for age and sex. The cumulative risk of EBV seroconversion by age according to MBL2 genotype was estimated by a nonparametric maximum likelihood estimator (25). A test of difference in the cumulative distribution according to MBL2 genotype and sex was performed in an additive hazard regression model for current status data including the two variables (16).The study was approved by the Commission for Scientific Research in Greenland, which acts as an ethics board for Greenland.At the time of blood sampling in 1997-1998, 84.6% of children (209 of 247) were EBV seropositive (Table ​(Table1).1). The rate of seropositivity increased with age. There was no gender difference in seropositivity or EBV VCA-IgG levels. Seropositivity was significantly lower for the MBL-insufficient group: 5 of 13 children (38.5%), compared with the 204 of 234 children (87.2%) for the MBL-sufficient group, and EBV VCA-IgG levels were also lower in the MBL-insufficient than in the MBL-sufficient group. None of the children were EBV VCA-IgM positive. EBV infection, measured by the presence of EBV antibodies, was on average acquired significantly later among MBL-insufficient children (P < 0.0001) (Fig. ​(Fig.11).Open in a separate windowFIG. 1.Cumulative risk of Epstein-Barr virus (EBV) infection (presence of EBV antibodies) by age in mannose-binding lectin (MBL)-sufficient (n = 234) and MBL-insufficient children (n = 13). Test for difference, adjusting for sex; P < 0.0001.

TABLE 1.

Epstein-Barr virus (EBV) seropositivity and median antibody levels in children in Greenland

Resilience as a moderator of pain and stress

OBJECTIVE: To study the predictive validity of the Resilience Scale for Adults (RSA) experimentally in relation to pain and stress. METHOD: The submaximum tourniquet method was used to induce ischemic pain and stress. Eighty-four subjects were randomized to a low- or a high stress group, and selected to a low- or a high resilience group according to their scores on the RSA. Measures of pain and stress were taken every 5 min. RESULTS: Perceived pain and stress increased significantly throughout the experimental session, but individuals scoring high on the RSA reported less pain and stress. This protection was more pronounced for the high stress group, thus supporting a protective effect of resilience as measured by the RSA. CONCLUSIONS: The predictive validity of the RSA was confirmed. Due to the positive role of these factors in pain and stress perception, it may also be a promising measure for studies on pain patients.