The use of urinary proteomics in the assessment of suitability of mouse models for ageing

Ageing is a complex process characterised by a systemic and progressive deterioration of biological functions. As ageing is associated with an increased prevalence of age-related chronic disorders, understanding its underlying molecular mechanisms can pave the way for therapeutic interventions and managing complications. Animal models such as mice are commonly used in ageing research as they have a shorter lifespan in comparison to humans and are also genetically close to humans. To assess the translatability of mouse ageing to human ageing, the urinary proteome in 89 wild-type (C57BL/6) mice aged between 8–96 weeks was investigated using capillary electrophoresis coupled to mass spectrometry (CE-MS). Using age as a continuous variable, 295 peptides significantly correlated with age in mice were identified. To investigate the relevance of using mouse models in human ageing studies, a comparison was performed with a previous correlation analysis using 1227 healthy subjects. In mice and humans, a decrease in urinary excretion of fibrillar collagens and an increase of uromodulin fragments was observed with advanced age. Of the 295 peptides correlating with age, 49 had a strong homology to the respective human age-related peptides. These ortholog peptides including several collagen (N = 44) and uromodulin (N = 5) fragments were used to generate an ageing classifier that was able to discriminate the age among both wild-type mice and healthy subjects. Additionally, the ageing classifier depicted that telomerase knock-out mice were older than their chronological age. Hence, with a focus on ortholog urinary peptides mouse ageing can be translated to human ageing

High prevalence and predominance of BRCA1 germline mutations in Pakistani triple-negative breast cancer patients

Background: Women harboring BRCA1/2 germline mutations have high lifetime risk of developing breast/ovarian cancer. The recommendation to pursue BRCA1/2 testing is based on patient’s family history of breast/ovarian cancer, age of disease-onset and/or pathologic parameters of breast tumors. Here, we investigated if diagnosis of triple-negative breast cancer (TNBC) independently increases risk of carrying a BRCA1/2 mutation in Pakistan. Methods: Five hundred and twenty-three breast cancer patients including 237 diagnosed ≤ 30 years of age and 286 with a family history of breast/ovarian cancer were screened for BRCA1/2 small-range mutations and large genomic rearrangements. Immunohistochemical analyses were performed at one center. Univariate and multiple logistic regression models were used to investigate possible differences in prevalence of BRCA1/2 mutations according to patient and tumor characteristics. Results: Thirty-seven percent of patients presented with TNBC. The prevalence of BRCA1 mutations was higher in patients with TNBC than non-TNBC (37% vs. 10%, P < 0.0001). 1% of TNBC patients were observed to have BRCA2 mutations. Subgroup analyses revealed a larger proportion of BRCA1 mutations in TNBC than non-TNBC among patients 1) diagnosed at early-age with no family history of breast/ovarian cancer (14% vs. 5%, P = 0.03), 2) diagnosed at early-age irrespective of family history (28% vs. 11%, P = 0.0003), 3) had a family history of breast cancer (49% vs. 12%, P < 0.0001), and 4) those with family history of breast and ovarian cancer (81% vs. 28%, P = 0.0005). TNBC patients harboring BRCA1 mutations were diagnosed at a later age than non-carriers (median age at diagnosis: 30 years (range 22–53) vs. 28 years (range 18–67), P = 0.002). The association between TNBC status and presence of BRCA1 mutations was independent of the simultaneous consideration of family phenotype, tumor histology and grade in a multiple logistic regression model (Ratio of the probability of carrying BRCA1/2 mutations for TNBC vs. non-TNBC 4.23; 95% CI 2.50–7.14; P < 0.0001). Conclusion: Genetic BRCA1 testing should be considered for Pakistani women diagnosed with TNBC

皮膚移植(第二回囘報告)

Deleterious BRCA1/2 germline mutations in Pakistani patients with TNBC. (DOCX 24 kb

IFNγ-Stat1 axis drives aging-associated loss of intestinal tissue homeostasis and regeneration

Abstract The influence of aging on intestinal stem cells and their niche can explain underlying causes for perturbation in their function observed during aging. Molecular mechanisms for such a decrease in the functionality of intestinal stem cells during aging remain largely undetermined. Using transcriptome-wide approaches, our study demonstrates that aging intestinal stem cells strongly upregulate antigen presenting pathway genes and over-express secretory lineage marker genes resulting in lineage skewed differentiation into the secretory lineage and strong upregulation of MHC class II antigens in the aged intestinal epithelium. Mechanistically, we identified an increase in proinflammatory cells in the lamina propria as the main source of elevated interferon gamma (IFNγ) in the aged intestine, that leads to the induction of Stat1 activity in intestinal stem cells thus priming the aberrant differentiation and elevated antigen presentation in epithelial cells. Of note, systemic inhibition of IFNγ-signaling completely reverses these aging phenotypes and reinstalls regenerative capacity of the aged intestinal epithelium

Ortholog peptides identified in mice and humans.

<p>Ortholog peptides identified in mice and humans.</p

Box-whisker plot depicting the age classification in wild-type and telomerase knock-out mice.

<p>* Statistically significant p-value, WT: wild-type, Terc^-/-: telomerase knock-out mice and w: weeks.</p

Abundance of ortholog peptides in wild-type mice.

<p>(A) Young mice (4 weeks old) and (B) wild-type old mice (84 weeks old). The green stars represent collagen alpha-1(I) chain peptides where as the red stars represent uromodulin peptides.</p

Box-whisker plot depicting the age classification in healthy subjects.

<p>Young subjects are between 20–39 years, mature subjects are between 40–59 years and old subjects are 60 years old and over. * Statistically significant p-value.</p