Val103Ile polymorphism of the melanocortin-4 receptor gene (MC4R) in cancer cachexia

<p>Abstract</p> <p>Background</p> <p>At present pathogenic mechanisms of cancer cachexia are poorly understood. Previous evidence in animal models implicates the melanocortin-4 receptor gene (<it>MC4R</it>) in the development of cancer cachexia. In humans, <it>MC4R </it>mutations that lead to an impaired receptor function are associated with obesity; in contrast, the most frequent polymorphism (Val103Ile, rs2229616; heterozygote frequency approximately 2%) was shown to be negatively associated with obesity. We tested if cancer patients that are homo-/heterozygous for the Val103Ile polymorphism are more likely to develop cachexia and/or a loss of appetite than non-carriers of the 103Ile-allele.</p> <p>Methods</p> <p>BMI (body mass index in kg/m²) of 509 patients (295 males) with malignant neoplasms was determined; additionally patients were asked about premorbid/pretherapeutical changes of appetite and weight loss. Cachexia was defined as a weight loss of at least 5% prior to initiation of therapy; to fulfil this criterion this weight loss had to occur independently of other plausible reasons; in single cases weight loss was the initial reason for seeing a physician. The average age in years (± SD) was 59.0 ± 14.5 (males: 58.8 ± 14.0, females 59.2 ± 14.0). Blood samples were taken for genotyping of the Val103Ile by PCR- RFLP.</p> <p>Results</p> <p>Most of the patients suffered from lymphoma, leukaemia and gastrointestinal tumours. 107 of the patients (21%) fulfilled our criteria for cancer cachexia. We did not detect association between the Val103Ile polymorphism and cancer cachexia. However, if we exploratively excluded the patients with early leucaemic stages, we detected a trend towards the opposite effect (p < 0.05); heterozygotes for the 103Ile-allele developed cancer cachexia less frequently in comparison to the rest of the study group. Changes of appetite were not associated with the 103Ile-allele carrier status (p > 0.39).</p> <p>Conclusion</p> <p>Heterozygotes for the 103Ile-allele are not more prone to develop cancer cachexia than patients without this allele; possibly, Ile103 carriers might be more resistant to cancer cachexia in patients with solid tumors. Further studies of the melanocortinergic system in cachexia of patients with solid tumors are warranted.</p

Women's job quality across family life stages: An analysis of female employees across 27 European countries

There is little empirical evidence on how working conditions affect women’s employment and fertility choices, despite a number of studies on the impact of individual-level and institutional factors. The article addresses this gap by examining how family life stages are related to particular aspects of job quality among employed women in 27 European countries. The central argument of the analysis is that high-quality jobs are conducive to both transitions to motherhood and employment after childbirth as women select into these roles. Accordingly, mothers of young children, if employed, are expected to have relatively better quality jobs. Four dimensions of job quality are considered: job security, career progression, working time and intrinsic job quality. The results indicate that mothers with young children are more likely to hold high-quality jobs than women at other life stages with respect to working time quality and job security, but with some variation across countries for job security. The findings highlight the importance of high-quality jobs for women’s fertility decisions and labour market attachment after childbirth, with implications for European employment policy

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Awakenings related to noises from various traffic modes

AIM: To test the hypothesis that aircraft noise causes more awakenings and alterations of sleep structure than rail and road traffic noise. METHODS: 12 women and 12 men (19-28 years) slept, following a habituation night, 4 nights each during 3 consecutive weeks in the laboratory. They were exposed with weekly changes to road-, rail-, or aircraft noise. Each week consisted of a random sequence of a quiet night and 3 nights with equivalent noise levels of 39, 44 and 50 dBA indoors. The polysomnogram was recorded throughout all nights, sleep quality was assessed and performance tests were completed in the morning. RESULTS: Noise-induced awakenings and structural parameters of sleep, subjective quality and performance indicated more disturbances with increasing noise levels. Where decreased subjective sleep quality was not related to the type of noise, noise-induced awakenings and other physiological parameters of sleep were most affected by rail and least by road traffic noise. CONCLUSIONS: As road-, rail- and aircraft noise caused the same after-effects but different physiological effects integrated noise metrics might be suitable for the prediction of subjective sleep quality but not for the physiological disturbances of sleep

Autonomic arousals related to traffic noise during sleep

AIM: To analyze the heart rate (HR) response to traffic noise during sleep and the influence of acoustic parameters, time of night, and momentary sleep stage on these responses. PARTICIPANTS: Twelve women and 12 men (19–28 years). MEASUREMENTS AND RESULTS: The participants slept in the laboratory for 4 consecutive nights in each of 3 consecutive weeks and were exposed to aircraft, road, or rail traffic noise with weekly permutations. The 4 nights of each week consisted of a random sequence of a quiet night (32 dBA) and 3 nights during which aircraft, rail traffic, or road traffic noises occurred with maximum levels of 45–77 dBA. The polysomnogram and the electrocardiogram were recorded during all nights. In case of awakenings, the HR alterations consisted of monophasic elevations for >1 min, with mean maximum HR elevations of 30 bpm. Though obviously triggered by the noise events, the awakenings per se rather than the acoustical parameters determined the extent and pattern of the response. Without awakenings, HR responses were biphasic and consisted of initial accelerations with maximum HR elevations of about 9 bpm followed by decelerations below the baseline. These alterations were clearly influenced by the acoustic parameters (traffic mode, maximum level, rate of rise) as well as by the momentary sleep stage. CONCLUSIONS: Cardiac responses did not habituate to traffic noise within the night and may therefore play a key role in promoting traffic noise induced cardiovascular disease. If so, these consequences are more likely for responses accompanied by awakenings than for situations without awakenings. CITATION: Griefahn B; Bröde P; Marks A; Basner M. Autonomic arousals related to traffic noise during sleep. SLEEP 2008;31(4):569-577

Comparison of Use and Appreciation of a Print-Delivered Versus CD-ROM-Delivered, Computer-Tailored Intervention Targeting Saturated Fat Intake: Randomized Controlled Trial

Background: Computer-tailored health education, a promising health education technique, is increasingly being delivered interactively, for example, over the Internet. It has been suggested that there may be differences in use and appreciation between print and interactive delivery of computer-tailored interventions, which may influence information processing. This may especially be the case for women, older people, and people of lower socioeconomic status. Knowledge about differences in use and appreciation could help in choosing the appropriate delivery mode for a particular target audience. Objective: The study investigates a content-identical, computer-tailored intervention addressing saturated fat intake delivered via print or CD-ROM. We analyzed consumer use and appreciation of the feedback information and explored whether possible differences exist among gender, age, and education subgroups. Methods: Healthy Dutch adults (18-65 years), none of whom were under treatment for hypercholesterolemia, were randomly allocated to receive a computer-tailored program on CD-ROM (n = 151) or in print (n = 141). At baseline, data were collected on gender, age, and education level. One month post-intervention, data were collected on the use (feedback information read, saved, discussed) and appreciation (trustworthiness, perceived individualization, perceived personal relevance, and user-friendliness) of the feedback. Statistical analyses on the use and appreciation items were performed using chi-square tests and independent-samples t tests. Results: After exclusion of individuals with missing values, a total of 257 and 240 respondents were included in the analyses of the use outcomes of feedback read and saved, respectively. The results indicate that among the total population, the print feedback was read more often than the CD-ROM feedback (95% vs 81%; P = .001) and saved more often than the CD-ROM feedback (97% vs 77%; P < .001). Similar results were found among the gender, age, and education subgroups. After exclusion of individuals who did not read the information and those with missing values, a total of 208-223 respondents were included in the analyses of the use outcome of feedback discussed and the appreciation items. The personal relevance of the print feedback was rated higher than for the CD-ROM-delivered feedback (0.97 vs 0.68; P = .04), but the effect size was small (0.28). These differences in personal relevance were also seen among women (1.06 vs 0.67; P = .04) and respondents aged 35-49 years (1.00 vs 0.58; P = .03), with moderate effect sizes (0.38 and 0.44, respectively). Conclusions: Despite the possible advantages of interactive feedback, the present study indicates that interactive-delivered feedback was used less and perceived as less personally relevant compared to the print-delivered feedback. These differences in use and appreciation of delivery modes should be taken into consideration when selecting a delivery mode for a specific subgroup in order to optimize exposure. Trial Registration: ISRCTN 01557410; http://www.webcitation.org/5XMylWleH