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Although immune checkpoint and targeted therapies offer remarkable benefits for lung cancer treatment, some patients do not qualify for these regimens or do not exhibit consistent benefit. Provided that lung cancer appears to be driven by transforming growth factor beta signaling, we investigated the single drug potency of Pirfenidone, an approved drug for the treatment of lung fibrosis. Five human lung cancer cell lines and one murine line were investigated for transforming growth factor beta inhibition via Pirfenidone by using flow cytometry, In-Cell western analysis, proliferation assays as well as comprehensive analyses of the transcriptome with subsequent bioinformatics analysis. Overall, Pirfenidone induced cell cycle arrest, down-regulated SMAD expression and reduced proliferation in lung cancer. Furthermore, cell stress pathways and pro-apoptotic signaling may be mediated by reduced expression of Survivin. A murine subcutaneous model was used to assess the in vivo drug efficacy of Pirfenidone and showed reduced tumor growth and increased infiltration of T cells and NK cells. This data warrant further clinical evaluation of Pirfenidone with advanced non-small cell lung cancer. The observed in vitro and in vivo effects point to a substantial benefit for using Pirfenidone to reactivate the local immune response and possible application in conjunction with current immunotherapies.
The dynamic and reversible post-translational modification of proteins and protein complexes with the ubiquitin-related SUMO modifier regulates a wide variety of nuclear functions, such as transcription, replication and DNA repair. SUMO can be attached as a monomer to its targets, but can also form polymeric SUMO chains. While monoSUMOylation is generally involved in the assembly of protein complexes, multi- or polySUMOylation may have very different consequences. The evolutionary conserved paradigmatic signaling process initiated by multi- or polySUMOylation is the SUMO-targeted Ubiquitin ligase (StUbL) pathway, where the presence of multiple SUMO moieties primes ubiquitylation by the mammalian E3 ubiquitin ligases RNF4 or RNF111, or the yeast Slx5/8 heterodimer. The mammalian SUMO chain-specific isopeptidases SENP6 or SENP7, or yeast Ulp2, counterbalance chain formation thereby limiting StUbL activity. Many facets of SUMO chain signaling are still incompletely understood, mainly because only a limited number of polySUMOylated substrates have been identified. Here we summarize recent work that revealed a highly interconnected network of candidate polySUMO modified proteins functioning in DNA damage response and chromatin organization. Based on these datasets and published work on distinct polySUMO-regulated processes we discuss overarching concepts in SUMO chain function. We propose an evolutionary conserved role of polySUMOylation in orchestrating chromatin dynamics and genome stability networks by balancing chromatin-residency of protein complexes. This concept will be exemplified in processes, such as centromere/kinetochore organization, sister chromatid cohesion, DNA repair and replication.
Suicide represents a major challenge to public mental health. In order to provide empirical evidence for prevention strategies, we hypothesized current levels of low socioeconomic status (SES) and high social isolation (SI) to be linked to increased suicide rates in N = 390 administrative districts since SES and SI are associated with mental illness. Effects of SES on suicide rates were further expected to be especially pronounced in districts with individuals showing high SI levels as SI reduces the reception of social support and moderates the impact of low SES on poor mental health. We linked German Microcensus data to register data on all 149,033 German suicides between 1997 and 2010 and estimated Prentice and Sheppard’s model for aggregate data to test the hypotheses, accounting for spatial effect correlations. The findings reveal increases in district suicide rates by 1.20% (p < 0.035) for 1% increases of district unemployment, suicide rate decreases of −0.39% (p < 0.028) for 1% increases in incomes, increases of 1.65% (p < 0.033) in suicides for 1% increases in one-person-households and increases in suicide rates of 0.54% (p < 0.036) for 1% decreases in single persons’ incomes as well as suicide rate increases of 3.52% (p < 0.000) for 1% increases in CASMIN scores of individuals who moved throughout the year preceding suicide. The results represent appropriate starting points for the development of suicide prevention strategies. For the definition of more precise measures, future work should focus on the causal mechanisms resulting in suicidality incorporating individual level data.
Study design: Systematic review with meta-analysis and meta-regression.
Background and objectives: We systematically reviewed and delineated the existing evidence on sustainability effects of motor control exercises on pain intensity and disability in chronic low back pain patients when compared with an inactive or passive control group or with other exercises. Secondary aims were to reveal whether moderating factors like the time after intervention completion, the study quality, and the training characteristics affect the potential sustainability effects.
Methods: Relevant scientific databases (Medline, Web of Knowledge, Cochrane) were screened. Eligibility criteria for selecting studies: All RCTs und CTs on chronic (≥ 12/13 weeks) nonspecific low back pain, written in English or German and adopting a longitudinal core-specific/stabilizing sensorimotor control exercise intervention with at least one pain intensity and disability outcome assessment at a follow-up (sustainability) timepoint of ≥ 4 weeks after exercise intervention completion.
Results and conclusions: From the 3,415 studies that were initially retrieved, 10 (2 CTs & 8 RCTs) on N = 1081 patients were included in the review and analyses. Low to moderate quality evidence shows a sustainable positive effect of motor control exercise on pain (SMD = -.46, Z = 2.9, p < .001) and disability (SMD = -.44, Z = 2.5, p < .001) in low back pain patients when compared to any control. The subgroups’ effects are less conclusive and no clear direction of the sustainability effect at short versus mid versus long-term, of the type of the comparator, or of the dose of the training is given. Low quality studies overestimated the effect of motor control exercises.
Endothelial dysfunction plays an important role in different pathological conditions, but whether endothelial cell death contributes to the development and progression of certain pathological conditions is rather unclear. Here we found that endothelial cells undergo cell death during pathologies such as LPS-induced sepsis and in models of hindlimb, renal and cardiac ischemia-reperfusion injury. Analyses of mice lacking endothelial key cell death regulators such as TAK1, RIPK3 and Caspase 8 gave us insight in the role of endothelial cell death in these pathological models. For example, increased endothelial necroptosis along with basal inflammation in lungs of TAK1ECKO mice affects susceptibility to LPS-induced sepsis and mortality, which correlated with elevated IFN-gamma and MIP-2 serum levels. Furthermore, we found that inhibition of RIPK3-mediated endothelial necroptosis could reduce the susceptibility of TAK1ECKO mice to LPS-induced sepsis and mortality. In ischemia or ischemia-reperfusion models, inhibition of RIPK3-mediated endothelial necroptosis did not reduce injury in the heart after ischemia, nor did it have any effect on organ function post-injury in the kidney or the heart. Inhibition of necroptosis also did not alter vascularization processes in hindlimb post-ischemia. Taken together, endothelial necroptosis contributes to increased sepsis severity and progression whereas inhibition of endothelial necroptosis can ameliorate susceptibility to sepsis in the absence of endothelial TAK1. Inhibition of endothelial necroptosis however does not play an important role during ischemia or ischemia-reperfusion induced organ injury.
To date, there is insufficient insight into inflammatory bowel disease (IBD)-associated stress, recognized disability, and contact with the social care system. We aimed to assess these parameters in IBD patients and a non-IBD control group, who were invited to participate in an online survey developed specifically for this study (www.soscisurvey.de) with the help of IBD patients. 505 IBD patients and 166 volunteers (i.e., control group) participated in the survey. IBD patients reported significantly increased levels of stress within the last six months and five years (p<0.0001) and were more likely to have a recognized disability (p<0.0001). A low academic status was the strongest indicator of a disability (p = 0.006). Only 153 IBD patients (30.3%) reported contact with the social care system, and a disability was the strongest indicator for this (p<0.0001). Our study provides data on stress and disability in a large unselected German IBD cohort. We showed that patients with IBD suffer more often from emotional stress and more often have a recognized disability. As only about 1/3 of the patients had come into contact with the social care system and the corresponding support, this patient group is undersupplied in this area.