Homeostatic Imbalance between Apoptosis and Cell Renewal in the Liver of Premature Aging XpdTTD Mice

Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. XpdTTD mice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W), display severe symptoms of premature aging but have a reduced incidence of cancer. To gain further insight into the molecular basis of the mutant-specific manifestation of age-related phenotypes, we used comparative microarray analysis of young and old female livers to discover gene expression signatures distinguishing XpdTTD mice from their age-matched wild type controls. We found a transcription signature of increased apoptosis in the XpdTTD mice, which was confirmed by in situ immunohistochemical analysis and found to be accompanied by increased proliferation. However, apoptosis rate exceeded the rate of proliferation, resulting in homeostatic imbalance. Interestingly, a metabolic response signature was observed involving decreased energy metabolism and reduced IGF-1 signaling, a major modulator of life span. We conclude that while the increased apoptotic response to endogenous DNA damage contributes to the accelerated aging phenotypes and the reduced cancer incidence observed in the XpdTTD mice, the signature of reduced energy metabolism is likely to reflect a compensatory adjustment to limit the increased genotoxic stress in these mutants. These results support a general model for premature aging in DNA repair deficient mice based on cellular responses to DNA damage that impair normal tissue homeostasis

Checklists for Applicants submitting dossiers on Cosmetic Ingredients to be evaluated by the SCCS

Checklists for Applicants submitting dossiers on Cosmetic Ingredients to be evaluated by the SCCSThe SCCS adopted these Checklists on 07 March 2017Checklists for Applicants submitting dossiers on Cosmetic Ingredients to be evaluated by the SCCSThe SCCS adopted these Checklists on 07 March 201

Cross-sectional analysis of baseline differences of candidates for rotator cuff surgery: a sex and gender perspective

<p>Abstract</p> <p>Background</p> <p>The word "sex" refers to biological differences between men and women. Gender refers to roles, behaviors, activities, and attributes that a given society considers appropriate for men and women. Traditionally, treatment decisions have been based on patient's sex without including the gender. Assessment of disability secondary to musculoskeletal problems would not be complete or accurate unless potentially relevant biological and non-biological aspects of being a man or woman are taken into consideration. The purposes of this study were to: 1) investigate the difference in pre-operative characteristics between men and women who were candidates for rotator cuff surgery; and, 2) assess the relationship between level of disability and factors that represent sex and factors that signify gender.</p> <p>Method</p> <p>This was a cross-sectional study. The primary outcome measure of disability was a disease-specific outcome measure, the Western Ontario Rotator Cuff (WORC) index, and independent variables were sex, age, hand dominance, shoulder side involvement, BMI, co-morbidity, medication use, work status, smoking habits, strength, range of motion, level of pathology, concurrent osteoarthritis, expectations for recovery, and participation restriction. Parametric, non-parametric, univariable, subgroup, and multivariable analyses were conducted.</p> <p>Results</p> <p>One hundred and seventy patients were included in the study. The mean age was 57 ± 11, 85 were females. Women reported higher levels of disability despite similar or lower levels of pathology. Scores of the WORC were strongly influenced by factors that represented "gender" such as participation restriction (F = 28.91, p < 0.0001) and expectations for improved activities of daily living (F = 5.80, p = 0.004). Painfree combined range of motion, which represented an interaction between "sex" and "gender" was also associated with disability after being adjusted for all other relevant baseline factors (F = 25.82, p < 0.0001).</p> <p>Conclusion</p> <p>Gender-related factors such as expectations and participation limitations have an independent impact on disability in men and women undergoing rotator cuff related surgery.</p

Impaired Genome Maintenance Suppresses the Growth Hormone–Insulin-Like Growth Factor 1 Axis in Mice with Cockayne Syndrome

Cockayne syndrome (CS) is a photosensitive, DNA repair disorder associated with progeria that is caused by a defect in the transcription-coupled repair subpathway of nucleotide excision repair (NER). Here, complete inactivation of NER in Csb(m/m)/Xpa(−/−) mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csb(m/m)/Xpa(−/−) mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die before weaning. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the growth hormone/insulin-like growth factor 1 (GH/IGF1) somatotroph axis and oxidative metabolism, increased antioxidant responses, and hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csb(m/m)/Xpa(−/−) and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural ageing and the DNA repair–deficient mice. Importantly, wild-type mice exposed to a low dose of chronic genotoxic stress recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis

Tissue specific mutagenic and carcinogenic responses in NER defective mouse models.

Several mouse models with defects in genes encoding components of the nucleotide excision repair (NER) pathway have been developed. In NER two different sub-pathways are known, i.e. transcription-coupled repair (TC-NER) and global-genome repair (GG-NER). A defect in one particular NER protein can lead to a (partial) defect in GG-NER, TC-NER or both. GG-NER defects in mice predispose to cancer, both spontaneous as well as UV-induced. As such these models (Xpa, Xpc and Xpe) recapitulate the human xeroderma pigmentosum (XP) syndrome. Defects in TC-NER in humans are associated with Cockayne syndrome (CS), a disease not linked to tumor development. Mice with TC-NER defects (Csa and Csb) are - except for the skin - not susceptible to develop (carcinogen-induced) tumors. Some NER factors, i.e. XPB, XPD, XPF, XPG and ERCC1 have functions outside NER, like transcription initiation and inter-strand crosslink repair. Deficiencies in these processes in mice lead to very severe phenotypes, like trichothiodystrophy (TTD) or a combination of XP and CS. In most cases these animals have a (very) short life span, display segmental progeria, but do not develop tumors. Here we will overview the available NER-related mouse models and will discuss their phenotypes in terms of (chemical-induced) tissue-specific tumor development, mutagenesis and premature aging features

Integrated genomic characterization of oesophageal carcinoma

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies

Sex differences in consequences of musculoskeletal pain

STUDY DESIGN. Cross-sectional population-based study. OBJECTIVE. To study sex differences in consequences of musculoskeletal pain (MP): limited functioning, work leave or disability, and healthcare use. SUMMARY OF BACKGROUND DATA. MP is a major public health problem in developed countries due to high prevalence rates and considerable consequences. There are indications that consequences of MP differ for men and women. METHODS. Data of a Dutch population-based study were used, limited to persons 25 to 64 years of age (n = 2517). Data were collected by a postal questionnaire. RESULTS. Women with any MP report more healthcare use for MP, i.e., contact with a medical caregiver and use of medicines than men, while men report more work disability (ever in life) due to low back pain only, irrespective of work status. None of the sex differences can be explained by age, household composition, educational level, smoking status, overweight, physical activity, and pain catastrophizing. Older age was related to more limited functioning due to MP (women), work disability due to MP (men), and healthcare use due to MP (men and women). A one-person household was associated with work disability (women) and use of medicines (men). Low educational level was associated with limited functioning (men), work leave (men), contact with a medical caregiver (men), and work disability (men and women). Smoking was associated with limited functioning (men), work leave (women), and healthcare use (women). Physical inactivity was associated with limited functioning due to MP in women. Pain catastrophizing was associated with limited functioning, work leave, and healthcare use (men and women) and work disability (men). CONCLUSIONS. Consequences of MP show a slightly different pattern for men and women. Women with any MPreport more healthcare use for MP, while men report more work disability due to low back pain only. These sex differences can not be explained by general risk factors, but associations between these factors and consequences of MP show some sex differences

Prevalence of musculoskeletal disorders is systematically higher in women than in men

OBJECTIVES: Many studies report a higher prevalence of musculoskeletal pain in women than in men. This paper presents an overview of sex differences in musculoskeletal pain with specific attention for: different parameters for duration of musculoskeletal pain (ie, 1-y period prevalence, point prevalence, prevalence of chronic pain, and prevalence of persistent chronic pain); and (2) different anatomic pain sites. METHODS: For the analyses, data from 2 general population-based prospective surveys (Dutch population-based Musculoskeletal Complaints and Consequences Cohort study and Monitoring Project on Risk Factors for Chronic Diseases-study) were used. The study population consisted of persons aged 25 to 64 years living in the Netherlands. Data on self-reported pain complaints were assessed by written questionnaires. RESULTS: The results of this study showed that prevalence rates of musculoskeletal pain were higher for women than for men in the Dutch general population aged 25 to 64 years on the basis of 2 population-based surveys. For musculoskeletal pain in any location, 39% of men and 45% of women reported chronic complaints. Highest female predominance was found for the hip and wrist/hand, whereas lowest and not statistically significant sex differences were found for the lower back and knee. All duration parameters of musculoskeletal pain showed a female predominance of musculoskeletal pain (1-y period prevalence, point prevalence, prevalence of chronic pain, and prevalence of persistent chronic pain). In those with persistent chronic pain, women tended to report higher severity scores. DISCUSSION: The present study shows that women have higher prevalence rates of musculoskeletal pain in most anatomic pain sites, no matter the duration of musculoskeletal pain. Future research should focus on explaining these sex differences with the ultimate goal to develop better prevention and management strategies for musculoskeletal pain in both men and women