Diet quality in late midlife is associated with faster walking speed in later life in women, but not men: findings from a prospective British birth cohort

Healthy diet has been linked to better age-related physical functioning, but evidence on the relationship of overall diet quality in late midlife and clinically relevant measures of physical functioning in later life is limited. Research on potential sex differences in this relationship is scarce. The aim was to investigate the prospective association between overall diet quality, as assessed by the Healthy Eating Index-2015 at age 60-64y and measures of walking speed seven years later, among men and women from the Insight46, a neuroscience sub-study of the Medical Research Council National Survey of Health and Development. Diet was assessed at age 60-64y using five-day food diaries, from which total HEI-2015 was calculated. At age 69-71y, walking speed was estimated during four 10-meter walks at self-selected pace, using inertial measurement units. Multivariable linear regression models with sex as modifier, controlling for age, follow-up, lifestyle, health, social variables and physical performance were used. The final sample was 164 women and 167 men (n=331). Women had higher HEI-2015 scores and slower walking speed than men. A 10 point increase in HEI-2015 was associated with faster walking speed seven years later among women (B: 0.024, 95% CI: 0.006, 0.043), but not men. The association remained significant in the multivariable model (B: 0.021, 95% CI: 0.003, 0.040). In women in late midlife higher diet quality is associated with faster walking speed. A healthy diet in late midlife is likely to contribute towards better age-related physical capability and sex differences are likely to affect this relationship

Europeanization and the soft law process of EU corporate governance: how has the 2003 action plan impacted on national corporate governance codes?

This study explores Europeanization, the interrelationship between domestic and EU-level policy activity. Specifically, it asks how domestic policy is affected by EU-level (soft-law) policy processes. This contrasts with the hard-law focus of most Europeanization research. Our empirical analysis seeks to determine the extent to which the European Commission's 2003 plan to enhance corporate governance delivered on its aim of 'co-ordinating corporate governance efforts of member states'. This study thus differs from most others on convergence in corporate governance regimes, which look for evidence of convergence perse, rather than convergence towards a specified set of principles. Applying content analysis and econometric tests to 95 corporate governance codes issued between 1992 and mid-2010, we find that the Action Plan has influenced member states' corporate governance policies. However, the degree of national policy alignment to the Action Plan's priorities depends on when the corporate governance code was issued, here, and by whom

SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.

SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUT cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUT cancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population

Cryoglobulinemic vasculitis in primary Sj\uf6gren's Syndrome: Clinical presentation, association with lymphoma and comparison with Hepatitis C-related disease

Objective: To describe the clinical spectrum of cryoglobulinemic vasculitis (CV) in primary Sj\uf6gren's syndrome (pSS), investigate its relation to lymphoma and identify the differences with hepatitis C virus (HCV) related CV. Methods: From a multicentre study population of consecutive pSS patients, those who had been evaluated for cryoglobulins and fulfilled the 2011 classification criteria for CV were identified retrospectively. pSS-CV patients were matched with pSS patients without cryoglobulins (1:2) and HCV-CV patients (1:1). Clinical, laboratory and outcome features were analyzed. A data driven logistic regression model was applied for pSS-CV patients and their pSS cryoglobulin negative controls to identify independent features associated with lymphoma. Results: 1083 pSS patients were tested for cryoglobulins. 115 (10.6%) had cryoglobulinemia and 71 (6.5%) fulfilled the classification criteria for CV. pSS-CV patients had higher frequency of extraglandular manifestations and lymphoma (OR=9.87, 95% CI: 4.7\u201320.9) compared to pSS patients without cryoglobulins. Purpura was the commonest vasculitic manifestation (90%), presenting at disease onset in 39% of patients. One third of pSS-CV patients developed B-cell lymphoma within the first 5 years of CV course, with cryoglobulinemia being the strongest independent lymphoma associated feature. Compared to HCV-CV patients, pSS-CV individuals displayed more frequently lymphadenopathy, type II IgMk cryoglobulins and lymphoma (OR = 6.12, 95% CI: 2.7\u201314.4) and less frequently C4 hypocomplementemia and peripheral neuropathy. Conclusion: pSS-CV has a severe clinical course, overshadowing the typical clinical manifestations of pSS and higher risk for early lymphoma development compared to HCV related CV. Though infrequent, pSS-CV constitutes a distinct severe clinical phenotype of pSS

GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine

Pancreatic Cancer Research Fund and Avner Pancreatic Cancer Foundation (grants to MF)