The role of cytokines in determining the Th1/Th2 phenotype of an immune response: Coherence of the T cell response and the Cytokine Implementation Hypothesis

The widely accepted Cytokine Milieu Hypothesis proposes that the cytokine milieu, in which antigen activates CD4 T cells, from a non-T cell source, primarily determines the Th subset to which the ensuing effector Th cells belong. We focus on the generation of Th1 and Th2 cells. We briefly restate the grounds for the Threshold Hypothesis we favour for how the Th1/Th2 phenotype of a response is primarily determined: tentative and robust thresholds of antigen-mediated CD4 T cell interactions lead to the generation of Th1 and Th2 cells. The component antigens of pathogens are present in different amounts. It is expected, within the context of the threshold mechanism that, although there is often an initial predominance of Th1 or Th2 cells, some Th cells of the opposing type are initially generated. An initially somewhat heterogeneous Th response is known to become with time more ‘coherent’ in its Th1/Th2 phenotype. I propose The Cytokine Implementation Hypothesis as a mechanism for how coherence is achieved. Most cytokines made by Th cells of one subset tend to facilitate the further generation of Th cells of this subset and/or inhibit the generation of Th cells of opposing subsets, accounting for how coherence may be achieved. Many observations on which The Cytokine Milieu Hypothesis is based are accounted for by this alternative hypothesis. We outline predictions of the new hypothesis and discuss the importance of coherence of immune responses for their efficacy in protecting against foreign invaders.     

A Mathematical Model of a Thermoelectric Device for the Treatment of Whitlow by Local Hypothermia

Biomedical Engineering - A mathematical model of a thermoelectric device for the treatment of whitlow by local hypothermia is discussed. The model is based on a solution of the heat conduction task...     

Day-level associations of physical activity and sedentary time in mother–child dyads across three years: a multi-wave longitudinal study using accelerometers

Journal of Behavioral Medicine - Understanding associations between mothers’ and children’s physical activity and sedentary behavior on more fine-grained timescales can provide insights...     

Functional estrogen receptor signal transduction pathway activity and antihormonal therapy response in low-grade ovarian carcinoma

Background

Advanced low-grade ovarian carcinoma (LGOC) is difficult to treat. In several studies, high estrogen receptor (ER) protein expression was observed in patients with LGOC, which suggests that antihormonal therapy (AHT) is a treatment option. However, only a subgroup of patients respond to AHT, and this response cannot be adequately predicted by currently used immunohistochemistry (IHC). A possible explanation is that IHC only takes the ligand, but not the activity, of the whole signal transduction pathway (STP) into account. Therefore, in this study, the authors assessed whether functional STP activity can be an alternative tool to predict response to AHT in LGOC.

Methods

Tumor tissue samples were obtained from patients with primary or recurrent LGOC who subsequently received AHT. Histoscores of ER and progesterone receptor (PR) were determined. In addition, STP activity of the ER STP and of six other STPs known to play a role in ovarian cancer was assessed and compared with the STP activity of healthy postmenopausal fallopian tube epithelium.

Results

Patients who had normal ER STP activity had a progression-free survival (PFS) of 16.1 months. This was significantly shorter in patients who had low and very high ER STP activity, with a median PFS of 6.0 and 2.1 months, respectively (p < .001). Unlike ER histoscores, PR histoscores were strongly correlated to the ER STP activity and thus to PFS.

Conclusions

Aberrant low and very high functional ER STP activity and low PR histoscores in patients with LGOC indicate decreased response to AHT. ER IHC is not representative of functional ER STP activity and is not related to PFS.     

Female reproductive and hormonal factors and lung cancer mortality among never-smokers: A prospective cohort study of 287 408 Chinese women

There is growing, but inconsistent evidence suggesting oestrogen may play a key role in lung cancer development, especially among never-smoking women for whom lung cancer risk factors remain largely elusive. Using the China Kadoorie Biobank, a large-scale prospective cohort with 302 510 women aged 30 to 79 years recruited from 10 regions in China during 2004 to 2008, we assessed the risk of lung cancer death among self-reported never-smoking women who were cancer-free at baseline, in relation to age at menarche, age at menopause, time since menopause, prior use of oral contraceptives (OCP), number of livebirths, breastfeeding and age at first livebirth. Women were followed up to December 31, 2016 with linkage to mortality data. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression, adjusting for key confounders including several socio-demographic, environmental and lifestyle factors. Among 287 408 never-smoking women, 814 died from lung cancer with a median follow-up of 10.3 years. Women who had used OCP within 15 years prior to baseline had a significantly higher hazard of lung cancer death compared with never-users: HR = 1.85 (95% CI: 1.14-3.00) and risk increased by 6% with each additional year of use: HR = 1.06 (1.01-1.10). Among parous women, the hazard of lung cancer death increased by 13% with each single livebirth: HR = 1.13 (1.05-1.23); and among post-menopausal women, the risk increased by 2% with each year since menopause: HR = 1.02 (1.01-1.04). These results suggest that reproductive factors which were proxies for lower endogenous oestrogen level, for example, longer duration of OCP use, could play a role in lung cancer development.