Intratumoral administration of recombinant human interleukin 12 in head and neck squamous cell carcinoma patients elicits a T-helper 1 profile in the locoregional lymph nodes.

The objective of this Phase II study was to evaluate the pharmacodynamic and immune effects of intratumorally administered recombinant human interleukin-12 (IL-12) on regional lymph nodes, primary tumor, and peripheral blood. Ten previously untreated patients with head and neck squamous cell carcinoma were injected in the primary tumor two to three times, once/week, at two dose levels of 100 or 300 ng/kg, before surgery. We compared these patients with 20 control (non-IL-12-treated) patients. Toxicity was high, with unexpected dose-limiting toxicities at the 300 ng/kg dose level. Dose-dependent plasma IFN-gamma and IL-10 increments were detected. These cytokine levels were higher after the first injection than after the subsequent injections. A rapid, transient reduction in lymphocytes, monocytes, and all lymphocyte subsets, especially natural killer cells, was observed, due to a redistribution to the lymph nodes. In the enlarged lymph nodes of the IL-12-treated patients, a higher percentage of natural killer cells and a lower percentage of T-helper cells were found compared with control patients. The same pattern was detected in the infiltrate in the primary tumor. Real-time semiquantitative PCR analysis of peripheral blood mononuclear cells in the peripheral blood showed a transient decrease of T-bet mRNA. Interestingly, the peripheral blood mononuclear cells in the lymph nodes showed a 128-fold (mean) increase of IFN-gamma mRNA. A switch from the Th2 to a Th1 profile in the lymph nodes compared with the peripheral blood occurred in the IL-12-treated patients. In conclusion, in previously untreated head and neck squamous cell carcinoma patients, recombinant human IL-12 intratumorally showed dose-limiting toxicities at the dose level of 300 ng/kg and resulted in measurable immunological responses locoregionally at both dose levels.     

Thallium-201 single-photon emission computed tomography as an early predictor of outcome in recurrent glioma.

PURPOSE: With limited response rates and potential toxicity of chemotherapeutic treatment in patients with recurrent glioma, reliable response assessment is essential. Currently, the assessment of treatment response in glioma patients is based on the combination of radiologic and clinical findings. However, response monitoring with computed tomography (CT) or magnetic resonance imaging (MRI) is hampered by several pitfalls and is prone to interobserver variability. The aim of this study was to establish the value of thallium-201 single-photon emission computed tomography (201Tl-SPECT) as a predictor of overall survival and response to chemotherapy in recurrent glioma, and to compare the value of 201Tl-SPECT with that of CT and MRI. PATIENTS AND METHODS: We studied patients who underwent CT or MRI and 201Tl-SPECT before chemotherapy (n = 57), and patients who also had undergone CT or MRI and 201Tl-SPECT after two courses of chemotherapy (n = 44). The value of the radiologic variables (CT-MRI tumor size, 201Tl-SPECT tumor size, and maximal tumor intensity) at baseline and at follow-up in predicting overall survival, and the percentage of patients alive and progression-free at 6 months (APF6) were examined using Cox regression and logistic regression analysis. RESULTS: Both at baseline and at follow-up, 201Tl-SPECT maximal tumor intensity was the strongest predictive variable and was inversely related to overall survival and APF6. In particular, progression of maximal tumor intensity after two courses of chemotherapy was a powerful predictor of poor outcome. CONCLUSION: 201Tl-SPECT is superior to conventional CT-MRI in the early prediction of overall survival and response to chemotherapy in patients with recurrent glioma.     

The dopamine D2 receptor gene, perceived parental support, and adolescent loneliness: longitudinal evidence for gene-environment interactions

Background: Loneliness is a common problem in adolescence. Earlier research focused on genes within the serotonin and oxytocin systems, but no studies have examined the role of dopamine‐related genes in loneliness. In the present study, we focused on the dopamine D2 receptor gene (DRD2). Methods: Associations among the DRD2, sex, parental support, and loneliness were examined in a longitudinal study spanning five annual waves (N = 307). Results: Using Latent Growth Curve Modeling, DRD2 genotype was not directly related to loneliness. Interactions were found between parental support and DRD2 genotype, showing that adolescents with the A2A2 genotype who perceived little support from their parents had the highest baseline levels of loneliness. Adolescents with an A1 allele were not susceptible to the rewarding effect of parental support. Conclusions: The present study is the first to examine the role of the DRD2 genotype in loneliness. Our results contribute to a further understanding of the environmental and genetic basis of loneliness in adolescence.     

Physical activity at work may not be health enhancing. A systematic review with meta-analysis on the association between occupational physical activity and cardiovascular disease mortality covering 23 studies with 655 892 participants

ObjectivesEmerging evidence suggests contrasting health effects for leisure-time and occupational physical activity. In this systematic review, we synthesized and described the epidemiological evidence regarding the association between occupational physical activity and cardiovascular disease (CVD) mortality.MethodsA literature search was performed in PubMed, Embase, CINAHL, PsycINFO and Evidence-Based Medicine Reviews, from database inception to 17 April 2020. Articles were included if they described original observational prospective research, assessing the association between occupational physical activity and CVD mortality among adult workers. Reviews were included if they controlled for age and gender and at least one other relevant variable. We performed meta-analyses on the associations between occupational physical activity and CVD mortality.ResultsWe screened 3345 unique articles, and 31 articles (from 23 studies) were described in this review. In the meta-analysis, occupational physical activity showed no significant association with overall CVD mortality for both males [hazard ratio (HR) 1.00, 95% confidence interval (CI) 0.87–1.15] and females (HR 0.95, 95% CI 0.82–1.09). Additional analysis showed that higher levels of occupational physical activity were non-significantly associated with a 15% increase in studies reporting on the outcome ischemic heart disease mortality (HR 1.15, 95% CI 0.88–1.49).ConclusionsWhile the beneficial association between leisure-time physical activity and CVD mortality has been widely documented, occupational physical activity was not found to have a beneficial association with CVD mortality. This observation may have implications for our appreciation of the association between physical activity and health for workers in physically demanding jobs, as occupational physical activity may not be health enhancing.     

Distinguishing true from false positives in genomic studies: p values

Distinguishing true from false positive findings is a major challenge in human genetic epidemiology. Several strategies have been devised to facilitate this, including the positive predictive value (PPV) and a set of epidemiological criteria, known as the “Venice” criteria. The PPV measures the probability of a true association, given a statistically significant finding, while the Venice criteria grade the credibility based on the amount of evidence, consistency of replication and protection from bias. A vast majority of journals use significance thresholds to identify the true positive findings. We studied the effect of p value thresholds on the PPV and used the PPV and Venice criteria to define usable thresholds of statistical significance. Theoretical and empirical analyses of data published on AlzGene show that at a nominal p value threshold of 0.05 most “positive” findings will turn out to be false if the prior probability of association is below 0.10 even if the statistical power of the study is higher than 0.80. However, in underpowered studies (0.25) with a low prior probability of 1 × 10^?3, a p value of 1 × 10^?5 yields a high PPV (>96 %). Here we have shown that the p value threshold of 1 × 10^?5 gives a very strong evidence of association in almost all studies. However, in the case of a very high prior probability of association (0.50) a p value threshold of 0.05 may be sufficient, while for studies with very low prior probability of association (1 × 10^?4; genome-wide association studies for instance) 1 × 10^?7 may serve as a useful threshold to declare significance.     

Hiding Lipid Presentation: Viral Interference with CD1d-Restricted Invariant Natural Killer T (iNKT) Cell Activation

The immune system plays a major role in protecting the host against viral infection. Rapid initial protection is conveyed by innate immune cells, while adaptive immunity (including T lymphocytes) requires several days to develop, yet provides high specificity and long-lasting memory. Invariant natural killer T (iNKT) cells are an unusual subset of T lymphocytes, expressing a semi-invariant T cell receptor together with markers of the innate NK cell lineage. Activated iNKT cells can exert direct cytolysis and can rapidly release a variety of immune-polarizing cytokines, thereby regulating the ensuing adaptive immune response. iNKT cells recognize lipids in the context of the antigen-presenting molecule CD1d. Intriguingly, CD1d-restricted iNKT cells appear to play a critical role in anti-viral defense: increased susceptibility to disseminated viral infections is observed both in patients with iNKT cell deficiency as well as in CD1d- and iNKT cell-deficient mice. Moreover, viruses have recently been found to use sophisticated strategies to withstand iNKT cell-mediated elimination. This review focuses on CD1d-restricted lipid presentation and the strategies viruses deploy to subvert this pathway.