Machine Learning-Based Analysis Reveals Triterpene Saponins and Their Aglycones in Cimicifuga racemosa as Critical Mediators of AMPK Activation.

Cimicifuga racemosa (CR) extracts contain diverse constituents such as saponins. These saponins, which act as a defense against herbivores and pathogens also show promise in treating human conditions such as heart failure, pain, hypercholesterolemia, cancer, and inflammation. Some of these effects are mediated by activating AMP-dependent protein kinase (AMPK). Therefore, comprehensive screening for activating constituents in a CR extract is highly desirable. Employing machine learning (ML) techniques such as Deep Neural Networks (DNN), Logistic Regression Classification (LRC), and Random Forest Classification (RFC) with molecular fingerprint MACCS descriptors, 95 CR constituents were classified. Calibration involved 50 randomly chosen positive and negative controls. LRC achieved the highest overall test accuracy (90.2%), but DNN and RFC surpassed it in precision, sensitivity, specificity, and ROC AUC. All CR constituents were predicted as activators, except for three non-triterpene compounds. The validity of these classifications was supported by good calibration, with misclassifications ranging from 3% to 17% across the various models. High sensitivity (84.5-87.2%) and specificity (84.1-91.4%) suggest suitability for screening. The results demonstrate the potential of triterpene saponins and aglycones in activating AMP-dependent protein kinase (AMPK), providing the rationale for further clinical exploration of CR extracts in metabolic pathway-related conditions.

Intensity- and time-matched acute interval and continuous endurance exercise similarly induce an anti-inflammatory environment in recreationally active runners: focus on PD-1 expression in Tregs and the IL-6/IL-10 axis.

PURPOSE: Acute exercise elicits a transient anti-inflammatory state during the early recovery period. Since recent studies reported on regimen-specific effects on immune-related humoral factors and cellular subsets, this study compared the effects of intensity- and time-matched acute interval and continuous exercise on peripheral anti-inflammatory cellular and humoral immune parameters with a particular focus on the PD-1 expression in CD4+ regulatory T cells (Tregs). METHODS: Twenty-four recreationally active runners (age: 29.7 ± 4.3 years, BMI: 22.2 ± 2.4, VO2peak: 56.6 ± 6.4 ml × kg-1 × min-1) participated in this crossover RCT. Each subject conducted a moderate continuous (MCE) and a high-intensity interval exercise (HIIE) session in a counterbalanced design. Blood was drawn before, immediately after, and 1 h after exercise. Treg subsets and levels of PD-1 and Foxp3 were assessed by flow cytometry. Serum levels of IL-10 and IL-6 were quantified by ELISA. RESULTS: PD-1 levels on Tregs increased within the recovery period after HIIE (p < .001) and MCE (p <  0.001). Total counts of Tregs (HIIE: p = 0.044; MCE: p = .021), naïve Tregs (HIIE: p  < 0.001; MCE: p  < 0.001), and PD-1+ effector Tregs (eTregs) (HIIE: p = .002) decreased 1 h after exercise. IL-10 increased 1 h after HIIE (p < 0.001) and MCE (p = 0.018), while IL-6 increased immediately after both HIIE (p = 0.031) and MCE (p = 0.021). Correlations between changes in IL-6 and IL-10 (p = 0.017, r = 0.379) and baseline VO2peak and Treg frequency (p = 0.002, r = 0.660) were identified. CONCLUSION: This is the first study that investigates PD-1 expression in circulating Tregs after acute exercise, revealing an increase in PD-1 levels on eTregs during the early recovery period after intensity- and time-matched HIIE and MCE. Future studies are needed to investigate the PD-1 signalosome in eTregs, together with the expression of key effector molecules (i.e., IL-10, TGF-ß, IL-35, CTLA-4) to elucidate PD-1-dependent changes in cellular function. Based on changes in serum cytokines, this study further reveals a regimen-independent establishment of an anti-inflammatory milieu and underpins the role of the IL-6/IL-10 axis.

Distinct distribution patterns of exercise-induced natural killer cell mobilization into the circulation and tumor tissue of patients with prostate cancer.

The mobilization and activation of natural killer (NK) cells have been proposed as key mechanisms promoting anti-oncogenic effects of physical exercise. Although mouse models have proven that physical exercise recruits NK cells to tumor tissue and inhibits tumor growth, this preclinical finding has not been transferred to the clinical setting yet. In this first-in-human study, we found that physical exercise mobilizes and redistributes NK cells, especially those with a cytotoxic phenotype, in line with preclinical models. However, physical exercise did not increase NK cell tumor infiltrates. Future studies should carefully distinguish between acute and chronic exercise modalities and should be encouraged to investigate more immune-responsive tumor entities.

Sleep problems and their interaction with physical activity and fatigue in hematological cancer patients during onset of high dose chemotherapy.

PURPOSE: Sleep problems reported by hematological cancer patients are usually linked to higher levels of cancer-related fatigue. Although the awareness of sleep problems in solid cancer patients is rising, there has been less attention to the issue in hematological cancer patients. The present study assesses the differences in sleep by comparing physical activity and fatigue levels among hematological cancer patients during the onset of chemotherapy. Furthermore, it investigates the relationship between sleep, physical activity, and fatigue through mediation analysis. METHODS: The recruited sample consists of 58 newly diagnosed hematological cancer patients (47.1 ± 15.4 yrs; 51.7% males). Subjects completed questionnaires assessing sleep (PSQI), physical activity (visual analogue scale), fatigue (MFI-20), anxiety, depression (HADS), and quality of life (EORTC QLQ-C30) within two weeks from starting treatment. RESULTS: The sample reported more sleep problems in comparison to the German population norm. The classification as good (ca 25%) or bad sleepers (ca 75%) showed less frequent physical activity (p = .04), higher fatigue (p = .032), anxiety (p = .003), depression (p = .011) and pain (p = .011) in bad sleepers. The mediation analysis revealed significant indirect effects of sleep on fatigue through physical activity habits. CONCLUSIONS: This study highlights the combined action of sleep problems and physical activity on fatigue during the onset of induction chemotherapy. These two parameters could represent meaningful intervention targets to improve a patient's status during chemotherapy. TRIAL REGISTRATION: The study was registered on the WHO trial register (DRKS00007824).

Acute exercise impacts AhR and PD-1 levels of CD8+ T-cells-Exploratory results from a randomized cross-over trial comparing endurance versus resistance exercise.

PURPOSE: The programmed cell death protein 1 (PD-1) has become a promising target in cancer immunotherapy. PD-1 expression of CD8+ T-cells may be increased via the exploitation of aryl hydrocarbon receptor (AhR) signaling with kynurenine (KYN) as a ligand. Since exercise affects KYN metabolism, we exploratory investigated the influence of acute exercise bouts on AhR and PD-1 levels of CD8+ T-cells. METHOD: In this study, 24 healthy males (age: 24.6 ± 3.9 years; weight 83.9 ± 10.5 kg; height: 182.4 ± 6.2 cm) completed a single bout of endurance (EE) and resistance exercise (RE) in a randomly assigned order on separate days. Blood samples were drawn before (t0), after (t1), and 1 h after (t2) both conditions. T-cell populations, the level of cytoplasmic AhR, and surface PD-1 were assessed by flow cytometry. RESULTS: T-cell populations changed over time, indicated by an increase in the absolute numbers of CD3+ lymphocytes after EE (p < .001) and RE (p = .036) and in PD-1+ CD8+ T-cells after EE (p = .021). Proportions of T-cell populations changed only after EE (t0-t2: p = .029; t1-t2: p = .006). The level of cytoplasmic AhR decreased immediately after exercise in both exercise conditions (EE: p = .009; RE: p = .036). The level of surface PD-1 decreased 1 h after EE (p = .005). CONCLUSION: We analyzed the level of surface PD-1 and cytoplasmic AhR following acute physical exercise for the first time. Especially EE was observed to impact both AhR and PD-1 levels, undermining its role as the AhR-PD-1 axis modulator. These results provide new insights into the impact of exercise on AhR-signaling, which could potentially be relevant for various chronic diseases.

Effect of a Single Bout of Aerobic Exercise on Kynurenine Pathway Metabolites and Inflammatory Markers in Prostate Cancer Patients-A Pilot Randomized Controlled Trial.

The kynurenine (KYN) pathway gains growing research interest concerning the genesis, progression and therapy of solid tumors. Previous studies showed exercise-induced effects on metabolite levels along the KYN pathway. Modulations of the KYN pathway might be involved in the positive impact of exercise on prostate cancer progression and mortality. The objective of this trial was to investigate whether a single-physical exercise alters tryptophan (TRP) metabolism and related inflammatory markers in this population. We conducted a randomized controlled trial with 24 patients suffering from prostate cancer. While the control group remained inactive, the intervention group performed a 30-min aerobic exercise on a bicycle ergometer at 75% of individual VO2peak. Before (t0) and directly after the exercise intervention (t1) KYN, TRP, kynurenic acid, quinolinic acid as well as various inflammation markers (IL6, TNF-α, TGF-ß) were measured in blood serum. At baseline, the present sample showed robust correlations between TRP, KYN, quinolinic acid and inflammatory markers. Regarding the exercise intervention, interaction effects for TRP, the KYN/TRP ratio and TGF-ß were observed. The results show for the first time that acute physical exercise impacts TRP metabolism in prostate cancer patients. Moreover, baseline associations underline the relationship between inflammation and the KYN pathway in prostate cancer.

Exercise and the Kynurenine pathway: Current state of knowledge and results from a randomized cross-over study comparing acute effects of endurance and resistance training.

INTRODUCTION: The essential amino acid tryptophan (TRP) is primarily degraded through the kynurenine (KYN) pathway, which is dysregulated in several chronic diseases. KYN pathway metabolites have immune- and neuro-modulatory properties and are involved in th de novo synthesis of nicotinamide adenine dinucleotide (NAD+). Currently, little evidence exists demonstrating that physical exercise may influence this pathway. However, differences between acute and chronic stimuli as well as the influence of exercise modalities remain to be investigated. Here, we provide an overview of existing studies and present results of a randomized cross-over trial on acute effects of a single-bout of resistance and endurance exercise. METHODS: 24 healthy male adults conducted both an acute endurance exercise (EE) and resistance exercise (RE) session. Blood samples were collected before, immediately after and one hour after cessation of each exercise session. Outcomes comprised serum levels of TRP, KYN, kynurenic acid (KA), quinolinic acid (QA) and calculated ratios. Gene expression of the enzymes indoleamine 2,3 dioxygenase (IDO) 1 and kynurenine aminotransferase (KAT) 4 was measured in peripheral blood mononuclear cells (PBMCs). Moreover, serum concentrations of the potential KYN pathway mediators interleukin (IL)-6 and cortisol were determined. Finally, we investigated baseline correlations between immune cell subsets, potential mediators and initial KYN pathway activation outcomes. RESULTS: The KYN/TRP ratio correlated positively with IL-6 and CD56bright NK-cells and negatively with CD56dim NKcells. Expression of IDO1 in PBMCs correlated positively with IL-6, regulatory T-cells and CD56bright NK-cells, whereas negative correlations to cytotoxic T-cells and CD56dim NKcells were revealed. A significant time effect on KYN/TRP ratio was detected for RE. Regarding KA and KA/KYN ratio, an increase after exercise followed by a decrease at the follow- up measurement was revealed in EE. KAT4 expression also increased after exercise in EE. Moreover, elevated QA levels were observed after the EE session. CONCLUSIONS: In contrast to chronic exercise interventions, single-bouts of endurance exercise provoke acute alterations on KYN pathway outcomes in humans. Our results indicate that EE induces stronger alterations than RE. Enhanced conversion of KYN to both, KA and QA suggest a peripheral KYN clearance, thereby preventing pathological accumulation within the CNS. Future acute and chronic exercise studies are needed to examine the role of NAD+ synthesis starting with TRP and the interplay between KYN pathway activation and mid- to long-term immunological modulations.

Impact of Physical Exercise on Growth and Progression of Cancer in Rodents-A Systematic Review and Meta-Analysis.

Background: Physical exercise is suspected to reduce cancer risk and mortality. So far, little is known about the underlying mechanisms. Although limited, murine models represent a promising attempt in order to gain knowledge in this field. Objective: A systematic review and meta-analysis examining various treatment protocols was conducted in order to determine the impact of exercise on tumor growth in rodents. Methods: PubMed, Google scholar and System for information on Gray literature in Europe were screened from inception to October 2017. Risk of bias within individual studies was assessed using the Office of Health Assessment and Translation risk of bias rating tool for human and animal trials. The effect of exercise on tumor growth over and above non-exercise control was pooled using random-effects model. Subgroup analyses were conducted to identify potential moderators. Results: The quality of the included 17 articles ranged between "probably low" and "high risk of bias." A significant reduction in tumor growth in exercising animals compared to controls was detected (Hedges' g = -0.40; 95% CI -0.66 to -0.14, p < 0.01) with between-study heterogeneity (τ2 = 0.217, I 2 = 70.28%, p < 0.001). The heterogeneity was partially explained by three moderators representing the in-between group differences of "maximum daily exercise" R 2 = 33% (p < 0.01), "type of cancer administration" R 2 = 28% (p < 0.05), and "training initiation" R 2 = 27% (p < 0.05). Conclusion: This meta-analysis suggests that physical exercise leads to reduction of tumor size in rodents. Since "maximum daily exercise" was found to have at least modest impact on tumor growth, more clinical trials investigating dose-response relationships are needed.

Acute Exercise Increases the Expression of KIR2DS4 by Promoter Demethylation in NK Cells.

Positive effects of exercise on cancer prevention and progression have been proposed to be mediated by stimulating natural killer (NK) cells. Because NK cell receptors are regulated by epigenetic modifications, we investigated whether acute aerobic exercise and training change promoter DNA methylation and gene expression of the activating KIR2DS4 and the inhibiting KIR3DL1 gene. Sixteen healthy women (50-60 years) performed a graded exercise test (GXT) and were randomized into either a passive control group or an intervention group performing a four-week endurance exercise intervention. Blood samples (pre-, post-GXT and post-training) were used for isolation of DNA/RNA of NK cells to assess DNA promoter methylation by targeted deep-amplicon sequencing and gene expression by qRT-PCR. Potential changes in NK cell subsets were determined by flow cytometry. Acute and chronic exercise did not provoke significant alterations of NK cell proportions. Promoter methylation decreased and gene expression increased for KIR2DS4 after acute exercise. A high gene expression correlated with a low methylation of CpGs that were altered by acute exercise. Chronic exercise resulted in a minor decrease of DNA methylation and did not alter gene expression. Acute exercise provokes epigenetic modifications, affecting the balance between the activating KIR2DS4 and the inhibiting KIR3DL1, with potential benefits on NK cell function.

Eight-week, multimodal exercise counteracts a progress of chemotherapy-induced peripheral neuropathy and improves balance and strength in metastasized colorectal cancer patients: a randomized controlled trial.

PURPOSES: Physical activity is supposed to decrease mortality of colorectal cancer (CRC) and is suggested to reduce side-effects of the disease and its treatment. However, the knowledge about the influence of exercise interventions on patients suffering from CRC and metastasized CRC (mCRC) is still sparse. One frequently observed side effect in mCRC is chemotherapy-induced peripheral neuropathy (CIPN). This randomized controlled trial investigated the influence of a supervised exercise program on CIPN in mCRC. METHODS: Thirty patients (stage IV) undergoing outpatient palliative treatment including a median of 23.5 chemotherapy cycles of various regimens were randomly assigned to an intervention or control group (IG, n = 17; CG, n = 13). The IG participated in an eight-week supervised exercise program, including endurance, resistance and balance training (2×/week for 60 min) whereas the CG received written standard recommendations to obtain physical fitness. CIPN was assessed using the FACT/GOG-NTX questionnaire. Moreover, endurance capacity (6MWT), strength (h1RM) and balance (GGT-Reha) were evaluated before (t 0) and after (t 1) the intervention as well as after 4 weeks follow-up (t2). RESULTS: Neuropathic symptoms remained stable in the IG over time, while CIPN significantly worsened in the CG from t 0 to t 1 and t 0 to t 2. In contrast to the CG, the IG significantly improved in strength and balance function. Changes in CIPN correlated with changes in balance. CONCLUSIONS: This is the first investigation showing positive effects of a multimodal exercise program on CIPN, balance and strength on mCRC patients in a palliative setting, thereby consequently increasing patients` quality of life. The results support earlier findings stating a positive influence of balance exercise on CIPN.

Influence of Personalized Exercise Recommendations During Rehabilitation on the Sustainability of Objectively Measured Physical Activity Levels, Fatigue, and Fatigue-Related Biomarkers in Patients With Breast Cancer.

PURPOSE: Only one-third of patients with breast cancer reach the recommended activity level of 15 to 25 MET h/wk. The aim of this study was to determine the influence of personalized exercise recommendations during rehabilitation on patients' physical activity level, fatigue, and self-perceived cognitive function as well as on side effect-associated biomarkers. METHODS: Total metabolic rate, physical activity level, mean MET and steps, fatigue, self-perceived cognitive functioning , and biomarkers (C-reactive protein [CRP], interleukin 6, macrophage migration inhibiting factor [MIF], tumor necrosis factor [TNF]-α, brain-derived neurotrophic factor [BDNF], insulin-like growth factor 1 [IGF1]) were assessed in 60 patients with breast cancer in the aftercare phase before ( t0) and 8 months after ( t1) the intervention. The rehabilitation program consisted of an initial 3-week period and a 1-week stay after 4 months. RESULTS: Paired t-test indicated a statistically significant increase in all activity outcomes from t0 to t1. Patients' mean activity level significantly increased from 14.89 to 17.88 MET h/wk. Fatigue and self-perceived cognitive functioning significantly improved from t0 to t1. CRP levels significantly decreased, and BDNF as well as IGF1 levels significantly increased over time. Correlation analysis revealed statistically significant negative associations between fatigue, physical activity, and markers of inflammation (TNF-α and MIF). Furthermore, significant positive correlations between subjective cognitive functioning and all dimensions of fatigue were observed. CONCLUSIONS: The results support the importance of personalized exercise recommendations to increase physical activity levels in patients with breast cancer. Furthermore, the results highlighti an association between physical activity, fatigue, and inflammation.

Microbiota Normalization Reveals that Canonical Caspase-1 Activation Exacerbates Chemically Induced Intestinal Inflammation.

Inflammasomes play a central role in regulating intestinal barrier function and immunity during steady state and disease. Because the discoveries of a passenger mutation and a colitogenic microbiota in the widely used caspase-1-deficient mouse strain have cast doubt on previously identified direct functions of caspase-1, we reassessed the role of caspase-1 in the intestine. To this end, we generated Casp1-/- and Casp11-/- mice and rederived them into an enhanced barrier facility to standardize the microbiota. We found that caspase-11 does not influence caspase-1-dependent processing of IL-18 in homeostasis and during DSS colitis. Deficiency of caspase-1, but not caspase-11, ameliorated the severity of DSS colitis independent of microbiota composition. Ablation of caspase-1 in intestinal epithelial cells was sufficient to protect mice against DSS colitis. Moreover, Casp1-/- mice developed fewer inflammation-induced intestinal tumors than control mice. These data show that canonical inflammasome activation controls caspase-1 activity, contributing to exacerbation of chemical-induced colitis.

Exercise induced alterations in NK-cell cytotoxicity - methodological issues and future perspectives.

With their ability to recognize and eliminate virus-infected and neoplastic cells, natural killer cells (NK-cells) represent an important part of the innate immune system. NK-cells have attracted the attention of exercise scientists for more than thirty years ago. To date, it is widely accepted that NK-cell counts in the peripheral blood are strongly influenced by acute exercise. Additionally, many studies reported effects of both, acute and chronic exercise on NK-cell cytotoxicity. However, these findings are contradictory. The inconsistence in findings may be argued with different exercise paradigms (type, duration, intensity). Moreover, strongly varying methods were used to detect NK-cell cytotoxicity. This review gives an overview of studies, investigating the impact of acute and chronic exercise on NK-cell cytotoxicity in young and old healthy adults, as well as on specific populations, such as cancer patients. Furthermore, different methodological approaches to assess NK-cell cytotoxicity are critically discussed to state on inconsistent study results and to give perspectives for further research in this field.

Effects of Exercise Interventions and Physical Activity Behavior on Cancer Related Cognitive Impairments: A Systematic Review.

This systematic review analyzes current data on effects of exercise interventions and physical activity behavior on objective and subjective cancer related cognitive impairments (CRCI). Out of the 19 studies which met all inclusion criteria, five RCTs investigated rodents, whereas the other 14 trials explored humans and these included six RCTs, one controlled trial, two prospective noncontrolled trials, one case series, one observational study, and three cross-sectional studies. The results from animal models revealed positive effects of exercise during and after chemotherapy or radiation on structural alterations of the central nervous system, physiological as well as neuropsychological outcomes. The overall study quality in patient studies was poor. The current data on intervention studies showed preliminary positive effects of Asian-influenced movement programs (e.g., Yoga) with benefits on self-perceived cognitive functions as well as a reduction of chronic inflammation for breast cancer patients in the aftercare. Exercise potentially contributes to the prevention and rehabilitation of CRCI. Additional RCTs with standardized neuropsychological assessments and controlling for potential confounders are needed to confirm and expand preliminary findings.

Impact of a half marathon on cellular immune system, pro-inflammatory cytokine levels, and recovery behavior of breast cancer patients in the aftercare compared to healthy controls.

INTRODUCTION: Exercise has beneficial effects on cancer prevention as well as on prognosis of patients with cancer. To optimize the outcomes of exercise programs, more knowledge about the underlying mechanisms is needed. This study investigates the short-term effects of a half marathon on immune cell proportions, pro-inflammatory cytokine levels, and recovery behavior of patients with breast cancer in the aftercare compared to healthy controls. METHODS: Nine patients with breast cancer in the aftercare and 9 healthy age-matched controls participated in a half marathon. Blood samples were collected before, after, and 24 h after the run. Immune status was measured by flow cytometer analysis, while serum levels of the pro-inflammatory cytokines TNF-α, IL-6, and MIF were assessed using ELISA. Recovery behavior was determined using an ADL monitor. RESULTS: Both groups showed a similar recovery behavior and time courses in changes of granulocytes, monocytes, lymphocytes, and cytokine serum levels. Patients revealed increased proportions of cytotoxic and memory T cells, whereas helper and naïve T cells were decreased compared to healthy controls. Naïve and memory T-cell proportions were not affected by the intervention. CONCLUSIONS: Patients with breast cancer in the aftercare and healthy subjects show a similarly recovery behavior and immune response to the intervention. The detected differences in T-cell subsets need further investigation. Based on the results of the study, we hypothesize that immune cell subsets with known relevance in cancer were mobilized through the intervention. We confirm that the hypothesis of a midterm anti-inflammatory effect of exercise is also valid for patients with breast cancer in the aftercare.

UPLC TOF MS for sensitive quantification of naturally occurring pyrrolizidine alkaloids in Petasites hybridus extract (Ze 339).

Due to increasing regulatory awareness of their hepatotoxic, genotoxic and possibly carcinogenic potential, pyrrolizidine alkaloid (PA) content has to be thoroughly monitored in herbal medicinal preparations. Recently, new very low PA regulatory threshold concentrations have been requested by the authorities. Therefore, a highly sensitive and reproducible UPLC TOF MS method for the quantification of the PAs senkirkine, senecionine, seneciphylline, senecionine-N-oxide and seneciphylline-N-oxide in a CO2-extract of Petasites hybridus leaves (Ze 339) has been developed. The limit of quantification (LOQ) was 2ppb for all PAs. Recovery at the LOQ was between 88.9 and 141.9%, the repeatability precision between 3.5 and 13.6%. Linearity of the five PAs showed correlation coefficients between 0.9995 and 0.9998 and coefficients of variation between 7.44 and 8.56%. A working range between 2 ppb and 200 ppb could be fixed. In the tested batches of the P. hybridus extract Ze 339, the absence of PAs could be demonstrated. In conclusion, this assay allows to determine trace PA concentrations in P. hybridus extract Ze 339, making it suitable for analytical PA monitoring in accordance with regulatory requirements.

Post-chemotherapy cognitive impairment in patients with B-cell non-Hodgkin lymphoma: a first comprehensive approach to determine cognitive impairments after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone or rituximab and bendamustine.

To assess the effects of chemoimmunotherapy on post-chemotherapy cognitive impairments (PCCI) in patients with B-cell non-Hodgkin lymphoma (NHL), we used objective and subjective measures of cognitive functions in combination with serum parameters and neuroelectric recordings. Self-perceived status of cognition, fatigue and emotional functioning were reduced in patients (n=30) compared to healthy controls (n=10). Cognitive performance was impaired in patients with NHL compared to controls and a norm sample (n=1179). PCCI was more severe in patients treated with rituximab and bendamustine (BR) than in patients who received R in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) polychemotherapy (R-CHOP). Individual alpha peak frequency and serum brain-derived neurotrophic factor (BDNF) levels in patients with NHL correlated with accuracy in the objective cognition test. Higher serum interleukin-6 (IL-6) concentrations were associated with higher fatigue levels. Patients with NHL and especially those who were treated with BR were affected by PCCI. BDNF and IL-6 might be involved in the pathogenesis of PCCI and fatigue.

Impact of exercise on pro inflammatory cytokine levels and epigenetic modulations of tumor-competitive lymphocytes in Non-Hodgkin-Lymphoma patients-randomized controlled trial.

INTRODUCTION: Physical activity is associated with decreased cancer (recurrence) risk and a reduction in treatment-specific side effects. Exercise modulates cytokine expression and shows beneficial effects on cancer patients' immune system. We investigated the following: (i) whether Non-Hodgkin-Lymphoma patients have increased serum macrophage migration inhibiting factor (MIF) and Interleukin-6 (IL-6) levels after immunochemotherapy; (ii) whether physical activity influences cytokine serum levels; and (iii) whether serum cytokine levels are associated with histone modifications in tumor-competitive immune cells. METHODS: Thirty patients and 10 healthy controls were randomised into an intervention and a control group. Participants of the intervention group exercised once for 30 min at moderate intensity on a bicycle ergometer. Blood samples were collected twice, before and after the intervention. MIF and IL-6 serum concentrations were detected by ELISA. Natural killer cells and CD8(+) T-lymphocytes were isolated by magnetic labeled cell sorting. Isolated cells were stained and analyzed for global histone acetylation at histone 4, lysine 5 and histone three, lysine 9. RESULTS: Patients showed higher serum MIF and IL-6 baseline levels, and reduced NK-cell histone acetylation, indicating a reduced transcriptional activity of tumor-competitive lymphocytes. Changes in MIF correlated with altered NK-cell histone acetylation, leading to the hypothesis that MIF impacts NK-cells via epigenetic modifications. Further, the exercise intervention was associated with an increase in IL-6 and CD8(+) T-lymphocyte histone acetylation. CONCLUSIONS: We conclude that exercise induces changes in cytokine levels, thereby possibly affecting epigenetic patterns and activity of tumor-competitive lymphocytes.

Thermo-responsive expression and differential secretion of the extracellular enzyme levansucrase in the plant pathogenic bacterium Pseudomonas syringae pv. glycinea.

In the plant pathogen Pseudomonas syringae, production of the exopolysaccharide levan is mediated by extracellular levansucrase (Lsc), which is encoded by two functional genes, lscB and lscC. Comparison of extracellular protein profiles of P. syringae pv. glycinea PG4180 grown at 18 and 28 degrees C and Western blots revealed that Lsc was predominantly found in the supernatant at 18 degrees C, a temperature fostering virulence of this pathogen. Northern blot analysis indicated that transcription of lscB and lscC was temperature-dependent. Quantification of Lsc in supernatants and cellular protein samples of mutants defective in either lscB or lscC confirmed that LscB secretion at low temperature was due to a combination of thermo-regulated transcription and secretion. In contrast, LscC accumulated in the periplasmic space. LscB and LscC differ in only five amino acid residues, one of which is a cysteine residue. Temperature shift experiments suggested that de novo synthesized protein(s) at 18 degrees C might be responsible for differential LscB secretion and that the presumed secretory machinery was stable when cells were shifted to 28 degrees C. Our results imply that Lsc export and secretion may occur by yet-to-be identified novel mechanism(s).