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Chronic inflammation as an important epigenetic and environmental factor for putative tumorigenesis and tumor progression may be associated with specific activation of Toll-like receptors (TLR). Recently, carcinogenesis has been suggested to be dependent on TLR7 signaling. In the present study, we determined the role of both TLR7 and TLR8 expression and signaling in tumor cell proliferation and chemoresistance in pancreatic cancer. Expression of TLR7/TLR8 in UICC stage I-IV pancreatic cancer, chronic pancreatitis, normal pancreatic tissue and human pancreatic (PANC1) cancer cell line was examined. For in vitro/in vivo studies TLR7/TLR8 overexpressing PANC1 cell lines were generated and analyzed for effects of (un-)stimulated TLR expression on tumor cell proliferation and chemoresistance. TLR expression was increased in pancreatic cancer, with stage-dependent upregulation in advanced tumors, compared to earlier stages and chronic pancreatitis. Stimulation of TLR7/TLR8 overexpressing PANC1 cells resulted in elevated NF-κB and COX-2 expression, increased cancer cell proliferation and reduced chemosensitivity. More importantly, TLR7/TLR8 expression increased tumor growth in vivo. Our data demonstrate a stage-dependent upregulation of both TLR7 and TLR8 expression in pancreatic cancer. Functional analysis in human pancreatic cancer cells point to a significant role of both TLRs in chronic inflammation-mediated TLR7/TLR8 signaling leading to tumor cell proliferation and chemoresistance.
Mask induced airway resistance and carbon dioxide rebreathing is discussed to impact gas exchange and to induce discomfort and impairments in cognitive performance. N = 23 healthy humans (13 females, 10 males; 23.5 ± 2.1 years) participated in this randomized crossover trial (3 arms, 48-h washout periods). During interventions participants wore either a surgical face mask (SM), a filtering face piece (FFP2) or no mask (NM). Interventions included a 20-min siting period and 20 min steady state cycling on an ergometer at 77% of the maximal heart rate (HR). Hemodynamic data (HR, blood pressure), metabolic outcomes (pulse derived oxygen saturation, capillary carbon dioxide (pCO2), and oxygen partial pressure (pO2), lactate, pH, base excess), subjective response (ability to concentrate, arousal, perceived exertion) and cognitive performance (Stroop Test) were assessed. Compared to NM, both masks increased pCO2 (NM 31.9 ± 3.3 mmHg, SM = 35.2 ± 4.0 mmHg, FFP2 = 34.5 ± 3.8 mmHg, F = 12.670, p < 0.001) and decreased pH (NM = 7.42 ± 0.03, SM = 7.39 ± 0.03, FFP2 = 7.39 ± 0.04, F = 11.4, p < 0.001) during exercise. The FFP2 increased blood pressure during exercise (NM = 158 ± 15 mmHg, SM = 159 ± 16 mmHg, FFP2 = 162 ± 17 mmHg, F = 3.21, p = 0.050), the SM increased HR during sitting (NM = 70 ± 8 bpm, SM = 74 ± 8 bpm, FFP2 = 73 ± 8 bpm, F = 4.70, p = 0.014). No mask showed any comparative effect on other hemodynamic, metabolic, subjective, or cognitive outcomes. Mask wearing leads to slightly increased cardiovascular stress and elevated carbon dioxide levels during exercise but did not affect cognitive performance or wellbeing.
In the recent decades, privacy scholarship has made significant progress. Most of it was achieved in monodisciplinary works. However, privacy has a deeply interdisciplinary nature. Most importantly, societies as well as individuals experience privacy as being influenced by legal, technical, and social norms and structures. In this article, we hence attempt to connect insights of different academic disciplines into a joint model, an Interdisciplinary Privacy and Communication Model. The model differentiates four different elements: communication context, protection needs, threat and risk analysis, as well as protection enforcement. On the one hand, with this model, we aim to describe how privacy unfolds. On the other hand, the model also prescribes how privacy can be furnished and regulated. As such, the model contributes to a general understanding of privacy as a theoretical guide and offers a practical basis to address new challenges of the digital age.
Background: The risk for major depression and obesity is increased in adolescents and adults with attention-deficit / hyperactivity disorder (ADHD) and adolescent ADHD predicts adult depression and obesity. Non-pharmacological interventions to treat and prevent these co-morbidities are urgently needed. Bright light therapy (BLT) improves day–night rhythm and is an emerging therapy for major depression. Exercise intervention (EI) reduces obesity and improves depressive symptoms. To date, no randomized controlled trial (RCT) has been performed to establish feasibility and efficacy of these interventions targeting the prevention of co-morbid depression and obesity in ADHD. We hypothesize that the two manualized interventions in combination with mobile health-based monitoring and reinforcement will result in less depressive symptoms and obesity compared to treatment as usual in adolescents and young adults with ADHD.
Methods: This trial is a prospective, pilot phase-IIa, parallel-group RCT with three arms (two add-on treatment groups [BLT, EI] and one treatment as usual [TAU] control group). The primary outcome variable is change in the Inventory of Depressive Symptomatology total score (observer-blinded assessment) between baseline and ten weeks of intervention. This variable is analyzed with a mixed model for repeated measures approach investigating the treatment effect with respect to all three groups. A total of 330 participants with ADHD, aged 14 – < 30 years, will be screened at the four study centers. To establish effect sizes, the sample size was planned at the liberal significance level of α = 0.10 (two-sided) and the power of 1-β = 80% in order to find medium effects. Secondary outcomes measures including change in obesity, ADHD symptoms, general psychopathology, health-related quality of life, neurocognitive function, chronotype, and physical fitness are explored after the end of the intervention and at the 12-week follow-up.
Discussion: This is the first pilot RCT on the use of BLT and EI in combination with mobile health-based monitoring and reinforcement targeting the prevention of co-morbid depression and obesity in adolescents and young adults with ADHD. If at least medium effects can be established with regard to the prevention of depressive symptoms and obesity, a larger scale confirmatory phase-III trial may be warranted.
Trial registration: German Clinical Trials Register, DRKS00011666. Registered on 9 February 2017. ClinicalTrials.gov, NCT03371810. Registered on 13 December 2017.