Primary antitumor immune response mediated by CD4+ T cells

Gene-targeted mice have recently revealed a role for lymphocytes and interferon-gamma (IFNgamma) in conferring protection against cancer, but the mechanisms remain unclear. Here, we have characterized a successful primary antitumor immune response initiated by naive CD4+ T cells. Major histocompatibility complex class II (MHC-II)-negative myeloma cells injected subcutaneously into syngeneic mice were surrounded within 3 days by macrophages that captured tumor antigens. Within 6 days, naive myeloma-specific CD4+ T cells became activated in draining lymph nodes and subsequently migrated to the incipient tumor site. Upon recognition of tumor-derived antigenic peptides presented on MHC-II by macrophages, the myeloma-specific CD4+ T cells were reactivated and started to secrete cytokines. T cell-derived IFNgamma activated macrophages in close proximity to the tumor cells. Tumor cell growth was completely inhibited by such locally activated macrophages. These data indicate a mechanism for immunosurveillance of MHC-II-negative cancer cells by tumor-specific CD4+ T cells through collaboration with macrophages.     

Long-term care bioethics committees: A cooperative model

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Long-term care bioethics committees: A cooperative model     

TP53 gene mutations predict the response to neoadjuvant treatment with 5-fluorouracil and mitomycin in locally advanced breast cancer.

PURPOSE: Recent studies have found an association between certain TP53 mutations and resistance to anthracycline-based primary medical therapy in breast cancer. The purpose of this study was to investigate whether TP53 mutational status also might influence the response to a non-anthracycline-containing regimen in primary breast cancer. EXPERIMENTAL DESIGN: Thirty-five patients with locally advanced breast cancer were investigated for TP53 mutations before receiving combination chemotherapy with 5-fluorouracil (1000 mg/m(2) on days 1 and 2) and mitomycin (6 mg/m(2) on day 2), administered every 3 weeks for 2-10 cycles in the neoadjuvant setting. RESULTS: Mutations in the TP53 gene, in particular those affecting loop domains L2 or L3 of the p53 protein, were associated with lack of response to chemotherapy (i.e., increase in the diameter product of tumor lesion by >/=25%; P = 0.177 for all mutations and P = 0.006 for those affecting L2/L3 domains, respectively). No statistically significant correlation between TP53 LOH and response to therapy was seen. CONCLUSION: This study revealed a significant association between lack of response to 5-fluorouracil and mitomycin and mutations affecting the L2/L3 domains of the p53 protein. Together with our previous finding that such mutations predict resistance to weekly doxorubicin, our data suggest that mutations affecting this particular domain of the p53 protein may cause resistance to several different cytotoxic compounds applied in breast cancer treatment.     

Metabolite profiling of 14C-omacetaxine mepesuccinate in plasma and excreta of cancer patients

1. Omacetaxine mepesuccinate (hereafter referred to as omacetaxine) is a protein translation inhibitor approved by the US Food and Drug Administration for adult patients with chronic myeloid leukemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors.

2. The objective was to investigate the metabolite profile of omacetaxine in plasma, urine and faeces samples collected up to 72?h after a single 1.25-mg/m² subcutaneous dose of ¹⁴C-omacetaxine in cancer patients.

3. High-performance liquid chromatography mass spectrometry (MS) (high resolution) in combination with off-line radioactivity detection was used for metabolite identification.

4. In total, six metabolites of omacetaxine were detected. The reactions represented were mepesuccinate ester hydrolysis, methyl ester hydrolysis, pyrocatechol conversion from the 1,3-dioxole ring. Unchanged omacetaxine was the most prominent omacetaxine-related compound in plasma. In urine, unchanged omacetaxine was also dominant, together with 4′-DMHHT. In feces very little unchanged omacetaxine was found and the pyrocatechol metabolite of omacetaxine, M534 and 4′-desmethyl homoharringtonine (4′-DMHHT) was the most abundant metabolites.

5. Omacetaxine was extensively metabolized, with subsequent renal and hepatic elimination of the metabolites. The low levels of the metabolites found in plasma indicate that the metabolites are unlikely to contribute materially to the efficacy and/or toxicity of omacetaxine.

     

Effect of cold conditions on manual performance while wearing petroleum industry protective clothing

The purpose of this study was to investigate manual performance and thermal responses during low work intensity in persons wearing standard protective clothing in the petroleum industry when they were exposed to a range of temperatures (5, -5, -15 and -25℃) that are relevant to environmental conditions for petroleum industry personnel in northern regions. Twelve men participated in the study. Protective clothing was adjusted for the given cold exposure according to current practices. The subjects performed manual tests five times under each environmental condition. The manual performance test battery consisted of four different tests: tactile sensation (Semmes-Weinstein monofilaments), finger dexterity (Purdue Pegboard), hand dexterity (Complete Minnesota dexterity test) and grip strength (grip dynamometer). We found that exposure to -5℃ or colder lowered skin and body temperatures and reduced manual performance during low work intensity. In conclusion the current protective clothing at a given cold exposure is not adequate to maintain manual performance and thermal balance for petroleum workers in the high north.     

Motivation in pediatric motor rehabilitation: A systematic search of the literature using the self-determination theory as a conceptual framework

Objective: Motivation is suggested as an important factor in pediatric motor rehabilitation. Therefore, we reviewed the existing evidence of (motivational) motor rehabilitation paradigms, and how motivation influences rehabilitation outcome using self-determination theory as conceptual framework. Methods: PubMed and Web-of-Science databases were systematically searched until June 2015. Data were independently extracted and critiqued for quality by three authors. Studies reporting motivational aspects were included. Most studies examined new technology (e.g., virtual reality [VR]). Results: Out of 479 records, three RCT, six case-control, and six non-comparative studies were included with mixed quality. Motivation was rarely reported. Training individualization to the child’s capabilities with more variety seemed promising to increase motivation. Motivation increased when the exercises seemed helpful for daily activities. Conclusions: Motivation in pediatric rehabilitation should be comprehensively assessed within a theoretical framework as there are indications that motivated children have better rehabilitation outcomes, depending on the aspect of motivation.