Do statins,ACE inhibitors or sartans improve outcome in primary glioblastoma?

The prognosis of the association between Breast Cancer (BC) and Meningioma (M) is unknown. To evaluate the survival impact of tumor exposure sequence in patients with both tumors. Patients were divided in groups according to the tumors sequence: BC before M (group 1), synchronous BC?+?M (group 2) and BC after M (group 3). The SEER database was used. Demographics, meningioma and breast cancer variables were analyzed. The primary outcome was oncological survival. A total of 1715 patients were included (median follow-up:84 months). Group 2 had the shortest survival (median:32 months) and group 1 the longest (median:110 months). On the unadjusted analysis, group 2 had the shortest survival (HR:3.13, 95% CI 1.62–6.04) and adjusted analysis confirmed this finding (HR 3.11, 95% CI 1.58–6.19), with no statistical difference between the metachronous tumors groups. Increasing age (HR:1.13, 95% CI 1.11–1.15, p?<?0.005) and grade III meningioma (HR:4.51, 95% CI 1.90–10.69, p?<?0.005) were related with lower survival. Meningioma treatment had no influence on the survival (p?>?0.05). The association between surgery and radiotherapy in BC treatment improved the outcome (HR 0.37, 95% CI 0.23–0.93, p?<?0.05). Grade III meningioma and receptor hormonal status influenced synchronous tumors (p?<?0.05) but had no influence on metachronous tumors survival (p?>?0.05) on stratified analysis. Synchronous tumors were associated with lower survival. Increasing age had a negative influence on patient survival. Although surgery and radiotherapy for breast cancer had a positive influence in the outcome, meningioma treatment was not related with survival. Grade III meningioma and hormonal receptor status only influenced synchronous tumors patient survival.     

Moderate correlation between quality of life and disease activity in adult patients with atopic dermatitis

Background Studies assessing the relationship between disease activity and quality of life (QoL) in adults with atopic dermatitis (AD), before and after therapy are lacking. The relation between disease activity and QoL in AD patients was evaluated before (t = 0) and after 6 weeks (t = 6) of treatment with cyclosporin 5 mg/kg. Methods In 54 patients with severe AD, disease activity was assessed using objective Scoring Atopic Dermatitis index (SCORAD), Six Area Six Sign Atopic Dermatitis (SASSAD), ‘rule of nines’ extent score and serum levels of thymus and activation‐regulated chemokine (TARC). Patients filled out the Dermatology Life Quality Index (DLQI). To study the relation between disease activity and QoL, correlations were calculated and regression analysis was performed. Results At t = 0 there was a small, non‐significant correlation between the DLQI and the objective SCORAD, ‘rule of nines’ or serum TARC levels. At t = 6 the objective SCORAD, serum TARC and the ‘rule of nines’ score showed moderate and significant correlations with the DLQI (r = 0.34, P = 0.02; r = 0.31, P = 0.03; r = 0.49, P < 0.001). An individual’s improvement in disease activity (objective SCORAD, SASSAD and ‘rule of nines’) with 10 points was associated with an improvement of 1.3, 1.5 and 1.1 points respectively in DLQI. Conclusions Disease activity correlated better with QoL when disease activity was less severe and disease extent (‘rule of nines’) correlated better with QoL than disease severity. An individual’s improvement of 10 points in disease activity was accompanied by only a small improvement in QoL. Other factors than disease activity may influence QoL in patients with AD.     

Evidence for a dose-dependent effect of pulsed magnetic fields on pain processing

Functional magnetic resonance imaging (fMRI) was used to investigate the dose–response relationship (sham, 100, 200, 1000 μT) between a pulsed extremely low frequency magnetic field (ELFMF) and acute thermal pain on the dominant right hand. Forty-seven participants were recruited, and pulsed ELFMF was applied through the MRI gradient system using a novel technique. Regions of interest (ROIs) matching those of previous studies were examined for a potential dose response. Significant correlations between applied field strength and change in BOLD activity were found in the anterior cingulate and the ipsilateral insula, indicating that there might be either a dose response or a threshold effect of the ELFMF.     

Signal transduction by the platelet Fc receptor

We have evaluated the mechanism by which crosslinking human platelet Fc receptor (FcR) for IgG triggers platelet aggregation and the platelet release reaction. Platelet FcR was crosslinked by incubating purified human platelets with anti-FcRII monoclonal antibody and F(ab')2 anti- mouse Ig. The resultant [Ca2+]i increase, monitored by Fura-2 and measured in the absence of extracellular Ca2+, reached a peak of 750 +/- 50 nmol/L. The effects of cyclooxygenase inhibitors, aspirin and indomethacin, and a phospholipase A2 inhibitor, dibromoacetophenone, were examined. Regardless of the inhibitor, at least 25% of the [Ca2+]i increase remained. Thrombin (0.2 U/mL) stimulated an immediate [Ca2+]i increase that reached 1.95 +/- 0.8 mumol/L. The [Ca2+]i increase generated by thrombin was only slightly reduced by these inhibitors. Crosslinking the FcRII of platelets resulted in a fivefold increase in the production of [3H]inositol phosphates, (IP) which, in the absence of extracellular Ca2+ was insensitive to aspirin. The activation of a [Ca2+]i increase along with the measured increases in IP indicate that FcRII crosslinking leads to the activation of phospholipase C (PLC). In contrast to thrombin, platelet activation via FcRII depends to a large extent on arachidonic acid metabolites. However, neither cyclooxygenase nor phospholipase A2 inhibitors completely blocked FcRII-stimulated [Ca2+]i increase. These observations led us to propose that crosslinking of platelet FcRII initially activates PLC.     

Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu

Currently, no approved monoclonal antibody (mAb) therapies exist for human multiple myeloma (MM). Here we characterized cell surface CS1 as a novel MM antigen and further investigated the potential therapeutic utility of HuLuc63, a humanized anti-CS1 mAb, for treating human MM. CS1 mRNA and protein was highly expressed in CD138-purified primary tumor cells from the majority of MM patients (more than 97%) with low levels of circulating CS1 detectable in MM patient sera, but not in healthy donors. CS1 was expressed at adhesion-promoting uropod membranes of polarized MM cells, and short interfering RNA (siRNA) targeted to CS1 inhibited MM cell adhesion to bone marrow stromal cells (BMSCs). HuLuc63 inhibited MM cell binding to BMSCs and induced antibody-dependent cellular cytotoxicity (ADCC) against MM cells in dose-dependent and CS1-specific manners. HuLuc63 triggered autologous ADCC against primary MM cells resistant to conventional or novel therapies, including bortezomib and HSP90 inhibitor; and pretreatment with conventional or novel anti-MM drugs markedly enhanced HuLuc63-induced MM cell lysis. Administration of HuLuc63 significantly induces tumor regression in multiple xenograft models of human MM. These results thus define the functional significance of CS1 in MM and provide the preclinical rationale for testing HuLuc63 in clinical trials, either alone or in combination.     

Effectiveness of diabetes mellitus screening recommendations

Screening guidelines proposed by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus have been endorsed by several medical societies. However, one-third of cases are undiagnosed, and complications at the time of diagnosis indicate that disease may have been present for several years before diagnosis. This study evaluates the effectiveness of the guidelines for detecting new cases of diabetes mellitus. By using a cross-sectional, representative sample of the United States (National Health and Nutritional Examination Survey, NHANES III), the guidelines are tested on adults, 20 years and older without a prior diagnosis of diabetes. Individuals are classified as nondiabetics (n = 6,241) or as having undiagnosed diabetes (n = 274) based on their blood glucose. Screening when one risk factor is present, as stated in the guidelines, has a true-positive rate of 100% and would require that 83% of the population be tested. Screening when two risk factors are present is more efficient, with a comparable true-positive rate (98%), but requires that only 59% of the population be tested. A notable finding is the earlier age of onset among minorities, which may be associated with other health disparities. Because diabetes occurs at younger ages in minorities, screening whites who are > or =40 and minorities > or =30 years of age has a high true-positive rate (95%) and also reduces testing (60%). The screening guidelines would be effective, if followed, and would essentially eliminate undiagnosed cases of diabetes.     

The Role of Serotonin (5-HT) in Behavioral Control: Findings from Animal Research and Clinical Implications

The neurotransmitters serotonin and dopamine both have a critical role in the underlying neurobiology of different behaviors. With focus on the interplay between dopamine and serotonin, it has been proposed that dopamine biases behavior towards habitual responding, and with serotonin offsetting this phenomenon and directing the balance toward more flexible, goal-directed responding. The present focus paper stands in close relationship to the publication by Worbe et al. (2015), which deals with the effects of acute tryptophan depletion, a neurodietary physiological method to decrease central nervous serotonin synthesis in humans for a short period of time, on the balance between hypothetical goal-directed and habitual systems. In that research, acute tryptophan depletion challenge administration and a following short-term reduction in central nervous serotonin synthesis were associated with a shift of behavioral performance towards habitual responding, providing further evidence that central nervous serotonin function modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. In the present focus paper, we discuss the findings by Worbe and colleagues in light of animal experiments as well as clinical implications and discuss potential future avenues for related research.     

White Matter Changes in Dementia: Role of Impaired Drainage of Interstitial Fluid

White matter abnormalities on magnetic resonance imaging (MRI) are associated with dementia and include white matter hyperintensities (WMH; also termed leukoaraiosis) and visible perivascular spaces (PVS). We review the potential role of impaired drainage of interstitial fluid in the pathogenesis of WMH and PVS. Whereas the volume of extracellular space in the grey matter is tightly controlled, fluid accumulates and expands the extracellular spaces of the white matter in acute hydrocephalus, vasogenic edema and WMH. Although there are no conventional lymphatic vessels in the brain, there is very effective lymphatic drainage for fluid and solutes along restricted pathways in the basement membranes of cerebral capillaries and arteries in young individuals. Lymphatic drainage of the brain is impaired with age and in association with apolipoprotein E ε4, risk factors for Alzheimer's disease and cerebral amyloid angiopathy (CAA). Deposition of proteins in the lymphatic drainage pathways in the walls of cerebral arteries with age is recognized as protein elimination failure angiopathy (PEFA), as in CAA and cerebral autosomal dominant arteriopathy and leukoencephalopathy (CADASIL). Facilitating perivascular lymphatic drainage from the aging brain may play a significant role in the prevention of CAA, WMH and Alzheimer's disease and may enhance the efficacy of immunotherapy for Alzheimer's disease.     

2-Methoxyestradiol overcomes drug resistance in multiple myeloma cells

2-Methoxyestradiol (2ME2) an estrogen derivative, induces growth arrest and apoptosis in leukemic cells and is also antiangiogenic. In this study, we demonstrate that 2ME2 inhibits growth and induces apoptosis in multiple myeloma (MM) cell lines and patient cells. Significantly, 2ME2 also inhibits growth and induces apoptosis in MM cells resistant to conventional therapies including melphalan (LR-5), doxorubicin (Dox-40 and Dox-6), and dexamethasone (MM.1R). In contrast to its effects on MM cells, 2ME2 does not reduce the survival of normal peripheral blood lymphocytes. Moreover, 2ME2 enhances Dex-induced apoptosis, and its effect is not blocked by interleukin-6 (IL-6). We next examined the effect of 2ME2 on MM cells in the bone marrow (BM) milieu. 2ME2 decreases survival of BM stromal cells (BMSCs), as well as secretion of vascular endothelial growth factor (VEGF), and IL-6 triggered by the adhesion of MM cells to BMSCs. We show that apoptosis induced by 2ME2 is mediated by the release of mitochondrial cytochrome-c (cyto-c) and Smac, followed by the activation of caspases-8, -9, and -3. Finally, 2ME2 inhibits MM cell growth, prolongs survival, and decreases angiogenesis in a murine model. These studies, therefore, demonstrate that 2ME2 mediates anti-MM activity directly on MM cells and in the BM microenvironment. They provide a framework for the use of 2ME2, either alone or in combination with Dex, to overcome drug resistance and to improve outcome in MM.