Impact of different exercise modalities on tumor relevant Natural killer cell function and their regulation

The last decade has seen a significant rise in interest in using exercise as medicine. Epidemiologic evidence concludes that those who perform a higher level of physical activity have a reduced likelihood of developing a variety of cancers compared to those who engage in lower levels of physical activity (Brown et al. 2012; Campbell et al. 2019; Meyerhardt et al. 2006; Patel et al. 2019). Cormie et al. in their review had mentioned that regular physical exercise counteracts cancer development and progression and reduces treatment related side effects, such as depressions and fatigue (Cormie et al. 2017). An active lifestyle is associated with reduced breast cancer risk and improved survival in breast cancer patients (Bodai and Tuso 2015). Besides a reduction of chronic inflammation, physical exercise has been shown to regulate hormonal balance including catecholamine, prostaglandins, and cortisol (Keast et al. 1988) (Figure 1). Physical exercise has also been shown to mimic chemotherapy and has an additive effect (Ballard-Barbash et al. 2012; Betof et al. 2015). Although evidence for primary and tertiary prevention in randomized controlled trials is still lacking, preclinical research has shown that exercise has a direct effect on the immune function as shown for the first time in 1989 by Nieman and his team (Nieman et al. 1989). Despite these observational evidences, the underlying mechanisms associated between participation in physical activity, immune modulation and cancer risk reduction remains understudied

Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes

Pancreatic β-cell failure is the key pathogenic element of the complex metabolic deterioration in type 2 diabetes (T2D); its underlying pathomechanism is still elusive. Here, we identify pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1/2) as phosphatases whose upregulation leads to β-cell failure in diabetes. PHLPP levels are highly elevated in metabolically stressed human and rodent diabetic β-cells. Sustained hyper-activation of mechanistic target of rapamycin complex 1 (mTORC1) is the primary mechanism of the PHLPP upregulation linking chronic metabolic stress to ultimate β-cell death. PHLPPs directly dephosphorylate and regulate activities of β-cell survival-dependent kinases AKT and MST1, constituting a regulatory triangle loop to control β-cell apoptosis. Genetic inhibition of PHLPPs markedly improves β-cell survival and function in experimental models of diabetes in vitro, in vivo, and in primary human T2D islets. Our study presents PHLPPs as targets for functional regenerative therapy of pancreatic β cells in diabetes

Antithrombotic Management in Ischemic Stroke with Essential Thrombocythemia: Current Evidence and Dilemmas

The final, published version of this article is available at https://doi.org/10.1159/000516471Thrombotic diseases like ischemic stroke are common complications of essential thrombocythemia (ET) due to abnormal megakaryopoiesis and platelet dysfunction. Ischemic stroke in ET can occur as a result of both cerebral arterial and venous thrombosis. Management of ET is aimed at preventing vascular complications including thrombosis. Acute management of ischemic stroke in ET is the same as that in the general population without myeloproliferative disorders. However, an ET patient with ischemic stroke is at high risk for rethrombosis and is therefore additionally managed with cytoreductive therapy and antithrombotic agents. Given abnormal platelet production in ET, there is suboptimal suppression of platelets with the standard recommended dose of aspirin for cardiovascular (CV) prevention. Hence, for optimal CV protection in ET, low-dose aspirin is recommended twice daily in an arterial thrombotic disease like atherothrombotic ischemic stroke in presence of the following risk factors: age >60 years, Janus kinase2 V617F gene mutation, and presence of CV risk factors. In the presence of the same risk factors, concurrent antiplatelet and anticoagulant therapy is suggested for venous thrombosis. However, increased risk of bleeding with dual antithrombotic agents poses a significant challenge in their use in cerebral venous thromboembolism or atrial fibrillation in presence of the above-mentioned risk factors. We discuss these dilemmas regarding antithrombotic management in ischemic stroke in ET in this case-based review of literature in the light of current evidence

Different endurance exercises modulate NK cell cytotoxic and inhibiting receptors

Purpose!#!Induction of IDO depends on the activation of AhR forming the AhR/IDO axis. Activated AhR can transcribe various target genes including cytotoxic and inhibiting receptors of NK cells. We investigated whether AhR and IDO levels as well as activating (NKG2D) and inhibiting (KIR2DL1) NK cell receptors are influenced by acute exercise and different chronic endurance exercise programs.!##!Methods!#!21 adult breast and prostate cancer patients of the TOP study (NCT02883699) were randomized to intervention programs of 12 weeks of (1) endurance standard training or (2) endurance polarized training after a cardiopulmonary exercise test (CPET). Serum was collected pre-CPET, immediately post-CPET, 1 h post-CPET and after 12 weeks post-intervention. Flow cytometry analysis was performed on autologous serum incubated NK-92 cells for: AhR, IDO, KIR2DL1 and NKG2D. Differences were investigated using analysis-of-variance for acute and analysis-of-covariance for chronic effects.!##!Results!#!Acute exercise: IDO levels changed over time with a significant increase from post-CPET to 1 h post-CPET (p = 0.03). KIR2DL1 levels significantly decreased over time (p < 0.01). NKG2D levels remained constant (p = 0.31). Chronic exercise: for both IDO and NKG2D a significant group × time interaction, a significant time effect and a significant difference after 12 weeks of intervention were observed (IDO: all p < 0.01, NKG2D: all p > 0.05).!##!Conclusion!#!Both acute and chronic endurance training may regulate NK cell function via the AhR/IDO axis. This is clinically relevant, as exercise emerges to be a key player in immune regulation

Photosensitivity and charge injection dynamics of pentacene based thin-film transistors: influence of substrate temperature

In this work, we have performed an in-depth analysis to investigate the effect of substrate temperature on the molecular packing arrangement and energy levels of pentacene films. We have also explored their influence on the charge injection mechanism and photosensing behaviour of pentacene-based organic field-effect transistors (OFETs). In this study, we find the contact resistance and photosensitivity of the devices to be severely influenced by the active layer processing condition owing to the aforementioned structural and energy level modifications. Contact resistance of the devices at metal-semiconductor interfaces was observed to be reduced significantly upon increase in the substrate temperature; however, above a certain temperature, formation of pentacene thin-films was severely affected and no transistor characteristics were obtained afterwards. Detailed experimental analysis and theoretical investigations revealed that the processing temperature could strongly influence the grain structure and unit cell volume of the pentacene molecules, which consequently enhanced the carrier injection across the interface through a control over carrier mobility and the distribution of electronic states in the proximity of Fermi energy. Furthermore, our study demonstrates the role of substrate temperature in effectively enhancing the photosensitivity of the transistors. This report thus represents a step forward towards understanding a correlation between the processing temperature and the dynamics of charge injection in pentacene based organic transistors. The results also illustrate the viability of using proper substrate temperature to achieve an efficient photosensitivity from OFET devices

The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis

Diabetes results from a decline in functional pancreatic β-cells, but the molecular mechanisms underlying the pathological β-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces β-cell apoptosis and impaired function. LATS2 deficiency in β-cells and primary isolated human islets as well as β-cell specific LATS2 ablation in mice improves β-cell viability, insulin secretion and β-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in β-cells and genetic and pharmacological inhibition of mTORC1 counteracts the pro-apoptotic action of activated LATS2. We further show a direct interplay between Hippo and autophagy, in which LATS2 is an autophagy substrate. On the other hand, LATS2 regulates β-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating β-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic β-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic β-cell survival and function in diabetes