Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses

The tyrosine kinase inhibitors sorafenib and sunitinib are approved for the treatment of patients with malignant diseases. To analyze the possible use of these compounds in combination with immunotherapeutic approaches, we analyzed the effects of both inhibitors on the immunostimulatory capacity of human dendritic cells (DCs) and the induction of primary immune responses in vivo. Sorafenib, but not sunitinib, inhibits function of DCs, characterized by reduced secretion of cytokines and expression of CD1a, major histocompatibility complex, and costimulatory molecules in response to TLR ligands as well as by their impaired ability to migrate and stimulate T-cell responses. These inhibitory effects are mediated by inhibition of PI3 and MAP kinases and NFB signaling. In contrast, sorafenib had no influence on the phenotype and proliferation of T cells. To analyze the effects of both TKIs on cytotoxic T-cell induction in vivo, C57BL/6 mice were pretreated with sorafenib or sunitinib and immunized with OVA_257-264 peptide. Sorafenib, but not sunitinib, application significantly reduced the induction of antigen-specific T cells. Numbers of regulatory T cells were reduced in peripheral blood mononuclear cells from mice treated with sunitinib. These results indicate that sunitinib, but not sorafenib, is suitable for combination with immunotherapeutic approaches for treatment of cancer patients.     

Long-term survival after post-hepatectomy liver failure for colorectal liver metastases

Background

While post-hepatectomy liver failure (PHLF) accurately predicts short-term mortality, its role in prognosticating long-term overall survival (OS) remains unclear.

A comparison of the performance characteristics of classification criteria for the diagnosis of psoriatic arthritis

OBJECTIVE: To compare the accuracy of published classification criteria for the diagnosis of psoriatic arthritis (PsA) and to see whether data-derived classification criteria would be more accurate. METHODS: Data were abstracted from case-note review and radiographic review of patients identified with PsA or rheumatoid arthritis (RA) from 2 clinical disease registers. Each patient was classified according to 7 criteria sets. The test performance characteristics were compared using conditional logistic regression analysis. In an attempt to overcome the problems of the diagnostic gold standard, latent class analysis also was used to calculate test-performance characteristics. Classification and regression-tree methodology was used to derive new criteria and to indicate the diagnostic importance of particular data items, especially rheumatoid factor (RF). RESULTS: Four hundred ninety-nine patients were identified with RA (n=156) or PsA (n=343). Excluding the criteria of Fournie, which could not be applied in 24% of subjects, 446 cases could be classified by all of the other 6 methods. The most sensitive criteria for the diagnosis of PsA were those of Vasey and Espinoza, McGonagle, and Gladman (99%), whereas the others were significantly less sensitive (between 56% and 94%). The specificity of the criteria was high and statistically similar (between 93% and 99%). The Fournie criteria were the most difficult to use, whereas the Vasey and Espinoza and Moll and Wright criteria were the easiest (98% of subjects were able to be classified). A 2-latent class model found very similar test-performance characteristics. Logistic regression and classification and regression-tree models suggested that negative RF was not necessary for diagnosis in the presence of other characteristic features of PsA. CONCLUSIONS: Apart from the Bennett and European Spondyloarthropathy Study Group criteria, which have inadequate sensitivity, the published classification criteria for PsA have similar test-performance characteristics. These data suggest that the criteria proposed by Vasey and Espinoza, Gladman, or McGonagle are the most accurate and feasible in distinguishing between PsA and RA. Relevance International agreement about classification criteria for PsA will assist the interpretation of clinical and epidemiologic research. However, further prospective studies on unselected patients with and without PsA, including controls with non-rheumatoid inflammatory arthritis, are required to confirm these findings.     

Regulation of cell growth and expression of 7B2, PC2, and PC1/3 by TGFbeta 1 and sodium butyrate in a human pituitary cell line (HP75)

Recent studies have shown that 7B2 and the neuroendocrine-specific proconvertase PC2 have important roles in pituitary cell proliferation and hormone secretion. Studies from our laboratory have also shown that TGFb1 regulates anterior pituitary cell proliferation and hormone secretion. To study the regulation of 7B2 in human pituitary tumors, we used a cell line derived from a human pituitary adenoma (HP75) that has been shown to express 7B2, PC1, PC2, and TGFβ receptors to analyze the effects of TGFβ1 and the histone deacetylase inhibitor (HDACI) sodium butyrate (NaB) treatment on 7B2 mRNA expression along with the neuroendocrine-specific proconvertases 1/3 (PC1) and PC2 mRNA and protein expression. RNA was quantified by real-time PCR and proteins were detected by immunohistochemistry and Western blotting. Treatment of cells with 1 mM NaB or 1 nM TGFβ1 for 4 d decreased cell proliferation with a concomitant increase in the cell cycle protein p21. Real-time PCR analysis showed a significant increase in 7B2 mRNA after NaB and TGFβ1 treatment. PC2 mRNA was down regulated by NaB while PC1 mRNA was unchanged. TGFβ1 stimulated PC1, but not PC2 mRNA levels. Changes in PC1 and PC2 protein were similar to changes in the mRNAs, but the differences were not significant. These results indicated that NaB and TGFβ1 inhibit pituitary cell proliferation and regulate the expression of 7B2, PC1, and PC2 in a cell culture model of pituitary tumors. Our results also indicate that inhibition of pituitary cell proliferation is associated with increased expression of 7B2 mRNA.     

The effectiveness of interventions to reduce the household economic burden of illness and injury: a systematic review

Objective

To determine the nature, scope and effectiveness of interventions to reduce the household economic burden of illness or injury.

Methods

We systematically reviewed reports published on or before 31 January 2014 that we found in the CENTRAL, CINAHL, Econlit, Embase, MEDLINE, PreMEDLINE and PsycINFO databases. We extracted data from prospective controlled trials and assessed the risk of bias. We narratively synthesized evidence.

Findings

Nine of the 4330 studies checked met our inclusion criteria – seven had evaluated changes to existing health-insurance programmes and two had evaluated different modes of delivering information. The only interventions found to reduce out-of-pocket expenditure significantly were those that eliminated or substantially reduced co-payments for a given patient population. However, the reductions only represented marginal changes in the total expenditures of patients. We found no studies that had been effective in addressing broader household economic impacts – such as catastrophic health expenditure – in the disease populations investigated.

Conclusion

In general, interventions designed to reduce the complex household economic burden of illness and injury appear to have had little impact on household economies. We only found a few relevant studies using rigorous study designs that were conducted in defined patient populations. The studies were limited in the range of interventions tested and they evaluated only a narrow range of household economic outcomes. There is a need for method development to advance the measurement of the household economic consequences of illness and injury and facilitate the development of innovative interventions to supplement the strategies based on health insurance.     

Obsessive–Compulsive Disorder is Characterized by a Lack of Adaptive Coping Rather than an Excess of Maladaptive Coping

The present study aimed to elucidate the profile of coping in patients with obsessive–compulsive disorder (OCD) in order to discern whether the disorder is characterized by an excess of maladaptive coping skills and/or a lack of adaptive coping skills. Sixty individuals with OCD were compared with 110 individuals with depression and 1050 nonclinical controls on the Maladaptive and Adaptive Coping Styles Questionnaire (MAX). Psychopathology was assessed with the Obsessive–Compulsive Inventory-Revised (OCI-R), the Yale-Brown Obsessive–Compulsive Scale (Y-BOCS), and the Patient Health Questionnaire-9 for depression (PHQ-9). Individuals with OCD and depression displayed more maladaptive coping and avoidance as well as less adaptive coping than nonclinical controls. Importantly, adaptive coping was significantly lower in individuals with OCD than in those with depression at a medium effect size, whereas the clinical groups were indistinguishable on maladaptive coping and avoidance. Lack of adaptive coping was strongly correlated with resistance to symptoms and poor insight in OCD (Y-BOCS), even after controlling for depression. Lack of adaptive coping skills may represent a specific pathogenetic factor in OCD. Longitudinal studies need to clarify whether strengthening adaptive skills during childhood and adolescence may help to prevent the progression from subclinical to manifest OCD.     

Predictors for Employment Status in People With Multiple Sclerosis: A 10-Year Longitudinal Observational Study

Objective

To identify predictors for employment status after 10 years in a cohort of people with multiple sclerosis (MS), with the aim to increase knowledge concerning factors present at an early stage that are important for working life and work-life balance.