Mentoring at Men's Sheds: an international survey about a community approach to health and well‐being

Men's Sheds are named within the Australian and Irish National Male Health Policies as an exemplar of male health and well‐being and offer a range of formal and informal mentoring to counter the known consequences of social exclusion. The study aimed to report on whether Men's Sheds undertake mentoring programmes, and if so, who is being mentored; are mentors being trained, and if so by whom; and the perceived effectiveness of the mentoring programme. Furthermore, the study aimed to explore associations between sheds with a mentoring programme and factors that reflect an inclusive and a health‐focused environment. All known Men's Sheds were invited to participate in the survey; of those, 324 (42.8%) Men's Sheds in Australia and 59 (48.0%) International sheds participated in the study between April and August 2012. Overall, 39.2% (n = 127) of Australian sheds and 23.7% (n = 14) of International sheds undertook formal mentoring. Youth was the most common group being mentored in both Australia (60.6%; n = 77) and Internationally (71.4%; n = 10). Over half of Australian shed co‐ordinators rated their mentoring programme as moderately effective (52.8%; n = 67) and over a third as highly effective (36.2%; n = 46), while half of International shed co‐ordinators rated theirs as highly effective (50.0%; n = 7). The findings from this paper support the notion that a large number of Men's Sheds offer formal mentoring programmes targeting a range of disadvantaged sub‐populations, thus supporting social inclusion. Inter‐generational mentoring is the most frequently occurring type of mentoring programme. While training mentors occurs at some sheds, the efficacy of this training and programme outcomes are unknown. A typology of shed types appears to be emerging based on a divergence of sheds with a more utilitarian focus and sheds that appear to embrace a health and well‐being focus.     

Short-term variability of systolic blood pressure and heart rate in normotensive subjects

Short-term fluctuations in systolic blood pressure (SBP) and heart rate (HR) and their inter-relationship were analysed in a group of normotensive middle-aged men (n = 16) using a multivariate autoregressive modelling technique. This study is the first to evaluate the beat-to-beat variability of SBP and HR in a group of real normotensive subjects. Direct intra-arterial blood pressure was registered together with ECG using an ambulatory tape recording technique (the Oxford method). Power spectrum density estimated (PSD) were used as a measure of the variability. PSDs were calculated over 3-min periods for four basic physiological conditions: during sleep and in the supine, sitting and standing positions. The inter-relationship between the blood pressure and heart rate variabilities was analysed using a closed-loop model. In agreement with results presented earlier in the literature, the beat-to-beat variation in SBP and HR was concentrated in three typical power spectrum regions: the high-frequency (HF = 0.15-0.35 Hz) region (respiration), the mid-frequency (MF = 0.075-0.15 Hz) region (vasomotor oscillation) and the low-frequency (LF = 0.02-0.075 Hz) region (thermoregulation). The variability changes considerably between different situations, especially that of the MF region. The variability was most prominent in the MF region and in the standing position. The variability was generally smallest in the HF region and in sleep. The results also demonstrate that the beat-to-beat variability in SBP and HR can considerably affect one another.     

Therapeutic control of B cell activation via recruitment of Fcγ receptor IIb (CD32B) inhibitory function with a novel bispecific antibody scaffold

Objective

To exploit the physiologic Fcγ receptor IIb (CD32B) inhibitory coupling mechanism to control B cell activation by constructing a novel bispecific diabody scaffold, termed a dual‐affinity retargeting (DART) molecule, for therapeutic applications.

Methods

DART molecules were constructed by pairing an Fv region from a monoclonal antibody (mAb) directed against CD32B with an Fv region from a mAb directed against CD79B, the β‐chain of the invariant signal‐transducing dimer of the B cell receptor complex. DART molecules were characterized physicochemically and for their ability to simultaneously bind the target receptors in vitro and in intact cells. The ability of the DART molecules to negatively control B cell activation was determined by calcium mobilization, by tyrosine phosphorylation of signaling molecules, and by proliferation and Ig secretion assays. A DART molecule specific for the mouse ortholog of CD32B and CD79B was also constructed and tested for its ability to inhibit B cell proliferation in vitro and to control disease severity in a collagen‐induced arthritis (CIA) model.

Results

DART molecules were able to specifically bind and coligate their target molecules on the surface of B cells and demonstrated a preferential simultaneous binding to both receptors on the same cell. DART molecules triggered the CD32B‐mediated inhibitory signaling pathway in activated B cells, which translated into inhibition of B cell proliferation and Ig secretion. A DART molecule directed against the mouse orthologs was effective in inhibiting the development of CIA in DBA/1 mice.

Conclusion

This innovative bispecific antibody scaffold that simultaneously engages activating and inhibitory receptors enables novel therapeutic approaches for the treatment of rheumatoid arthritis and potentially other autoimmune and inflammatory diseases in humans.

     

Somatic mutations of the protein kinase gene family in human lung cancer

Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (approximately 1.3 Mb of DNA per sample) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines. One hundred eighty-eight somatic mutations were detected in 141 genes. Of these, 35 were synonymous (silent) changes. This result indicates that most of the 188 mutations were "passenger" mutations that are not causally implicated in oncogenesis. However, an excess of approximately 40 nonsynonymous substitutions compared with that expected by chance (P = 0.07) suggests that some nonsynonymous mutations have been selected and are contributing to oncogenesis. There was considerable variation between individual lung cancers in the number of mutations observed and no mutations were found in lung carcinoids. The mutational spectra of most lung cancers were characterized by a high proportion of C:G > A:T transversions, compatible with the mutagenic effects of tobacco carcinogens. However, one neuroendocrine cancer cell line had a distinctive mutational spectrum reminiscent of UV-induced DNA damage. The results suggest that several mutated protein kinases may be contributing to lung cancer development, but that mutations in each one are infrequent.     

Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma

We describe the application of a novel, bispecific antibody platform termed dual affinity retargeting (DART) to eradicate B-cell lymphoma through coengagement of the B cell-specific antigen CD19 and the TCR/CD3 complex on effector T cells. Comparison with a single-chain, bispecific antibody bearing identical CD19 and CD3 antibody Fv sequences revealed DART molecules to be more potent in directing B-cell lysis. The enhanced activity with the CD19xCD3 DART molecules was observed on all CD19-expressing target B cells evaluated using resting and prestimulated human PBMCs or purified effector T-cell populations. Characterization of a CD19xTCR bispecific DART molecule revealed equivalent potency with the CD19xCD3 DART molecule, demonstrating flexibility of the DART structure to support T-cell/B-cell associations for redirected T cell-killing applications. The enhanced level of killing mediated by DART molecules was not accompanied by any increase in nonspecific T-cell activation or lysis of CD19(-) cells. Cell-association studies indicated that the DART architecture is well suited for maintaining cell-to-cell contact, apparently contributing to the high level of target cell killing. Finally, the ability of the CD19xTCR DART to inhibit B-cell lymphoma in NOD/SCID mice when coadministered with human PBMCs supports further evaluation of DART molecules for the treatment of B-cell malignancies.