Cancer-related fatigue: Quality, credibility, usability, and readability of information on websites of health care institutions in Germany.

OBJECTIVES: This study aimed to portray available information on cancer-related fatigue on German health care institution websites considering the idea of patient empowerment. METHODS: Based on website quality criteria, we developed a website-rating tool comprising 18 items. Descriptive analyses, a KruskalWallis test, and corresponding post hoc tests comparing rating sum scores between institution groups were performed. RESULTS: Websites of 283 systematically compiled health care institutions were included in the rating. Cancer-related fatigue was introduced on 21.9% and detailed information was provided on 27.9% of the websites. Information material was offered on 9.2% of the websites, while fatigue treatment offers were presented on 21.6% of the websites. The rating sum scores differed between institution groups (p < 0.001), with Comprehensive Cancer Centers scoring significantly higher than the others. CONCLUSION: The rating revealed an overall sparse provision of information, with fatigue being addressed on less than half of the websites. PRACTICE IMPLICATIONS: For patients who have access to at least one introduction about fatigue, institutions need to extend their websites. Patients could further be referred to external institutions or information booklets. The naming of contact persons may help linking patients to providers.

Design and Preclinical Characterization Program toward Asundexian (BAY 2433334), an Oral Factor XIa Inhibitor for the Prevention and Treatment of Thromboembolic Disorders.

Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based de novo design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.

Protective effects of caffeine against palmitate-induced lipid toxicity in primary rat hepatocytes is associated with modulation of adenosine receptor A1 signaling.

BACKGROUND: Epidemiological evidence has shown an association between coffee consumption and reduced risk for chronic liver diseases, including metabolic-dysfunction-associated liver disease (MALFD). Lipotoxicity is a key cause of hepatocyte injury during MAFLD. The coffee component caffeine is known to modulate adenosine receptor signaling via the antagonism of adenosine receptors. The involvement of these receptors in the prevention of hepatic lipotoxicity has not yet been explored. The aim of this study was to explore whether caffeine protects against palmitate-induced lipotoxicity by modulating adenosine receptor signaling. METHODS: Primary hepatocytes were isolated from male rats. Hepatocytes were treated with palmitate with or without caffeine or 1,7DMX. Lipotoxicity was verified using Sytox viability staining and mitochondrial JC-10 staining. PKA activation was verified by Western blotting. Selective (ant)agonists of A1AR (DPCPX and CPA, respectively) and A2AR (istradefyline and regadenoson, respectively), the AMPK inhibitor compound C, and the Protein Kinase A (PKA) inhibitor Rp8CTP were used. Lipid accumulation was verified by ORO and BODIPY 453/50 staining. RESULTS: Caffeine and its metabolite 1,7DMX prevented palmitate-induced toxicity in hepatocytes. The A1AR antagonist DPCPX also prevented lipotoxicity, whereas both the inhibition of PKA and the A1AR agonist CPA (partially) abolished the protective effect. Caffeine and DPCPX increased lipid droplet formation only in palmitate-treated hepatocytes and decreased mitochondrial ROS production. CONCLUSIONS: The protective effect of caffeine against palmitate lipotoxicity was shown to be dependent on A1AR receptor and PKA activation. Antagonism of A1AR also protects against lipotoxicity. Targeting A1AR receptor may be a potential therapeutic intervention with which to treat MAFLD.

Meta-Analysis of Randomized Controlled Trials on Yoga, Psychosocial, and Mindfulness-Based Interventions for Cancer-Related Fatigue: What Intervention Characteristics Are Related to Higher Efficacy?

Cancer-related fatigue (CRF) is a burdensome sequela of cancer treatments. Besides exercise, recommended therapies for CRF include yoga, psychosocial, and mindfulness-based interventions. However, interventions conducted vary widely, and not all show a significant effect. This meta-analysis aimed to explore intervention characteristics related to greater reductions in CRF. We included randomized controlled trials published before October 2021. Standardized mean differences were used to assess intervention efficacy for CRF and multimodel inference to explore intervention characteristics associated with higher efficacy. For the meta-analysis, we included 70 interventions (24 yoga interventions, 31 psychosocial interventions, and 15 mindfulness-based interventions) with 6387 participants. The results showed a significant effect of yoga, psychosocial, and mindfulness-based interventions on CRF but with high heterogeneity between studies. For yoga and mindfulness-based interventions, no particular intervention characteristic was identified to be advantageous for reducing CRF. Regarding psychosocial interventions, a group setting and work on cognition were related to higher intervention effects on CRF. The results of this meta-analysis suggest options to maximize the intervention effects of psychosocial interventions for CRF. The effects of yoga and mindfulness-based interventions for CRF appear to be independent of their design, although the limited number of studies points to the need for further research.

Glucosamine protects against neuronal but not vascular damage in experimental diabetic retinopathy.

OBJECTIVE: Glucosamine, an intermetabolite of the hexosamine biosynthesis pathway (HBP), is a widely used nutritional supplement in osteoarthritis patients, a subset of whom also suffer from diabetes. HBP is activated in diabetic retinopathy (DR). The aim of this study is to investigate the yet unclear effects of glucosamine on DR. METHODS: In this study, we tested the effect of glucosamine on vascular and neuronal pathology in a mouse model of streptozotocin-induced DR in vivo and on cultured endothelial and Müller cells to elucidate the underlying mechanisms of action in vitro. RESULTS: Glucosamine did not alter the blood glucose or HbA1c levels in the animals, but induced body weight gain in the non-diabetic animals. Interestingly, the impaired neuronal function in diabetic animals could be prevented by glucosamine treatment. Correspondingly, the activation of Müller cells was prevented in the retina as well as in cell culture. Conversely, glucosamine administration in the normal retina damaged the retinal vasculature by increasing pericyte loss and acellular capillary formation, likely by interfering with endothelial survival signals as seen in vitro in cultured endothelial cells. Nevertheless, under diabetic conditions, no further increase in the detrimental effects were observed. CONCLUSIONS: In conclusion, the effects of glucosamine supplementation in the retina appear to be a double-edged sword: neuronal protection in the diabetic retina and vascular damage in the normal retina. Thus, glucosamine supplementation in osteoarthritis patients with or without diabetes should be taken with care.

Effects of physical and mind-body exercise on sleep problems during and after breast cancer treatment: a systematic review and meta-analysis.

PURPOSE: We conducted a meta-analysis evaluating the effects of different exercise interventions on self-reported and objective sleep measurements during or after breast cancer treatment. METHODS: Three databases were systematically searched for randomized controlled trials with any type of exercise intervention in women with breast cancer. Outcomes were self-reported or objective sleep measurements. Standardized mean differences (SMDs) were calculated using random-effects models. RESULTS: The meta-analysis included 22 trials with 2107 participants. Of these, 17 studies used the Pittsburgh Sleep Quality Index (PSQI), six studies included objective sleep assessments (ActiGraph). Physical exercise interventions included walking, aerobic exercise, resistance exercise or a combination of both. Mind-body exercise interventions included yoga, Tai Chi and Qigong. Most interventions were supervised. Both, physical (SMD - 0.32; 95% CI - 0.54 to - 0.10) and mind-body exercise interventions (SMD - 0.27; 95% CI - 0.44 to - 0.09), resulted in improvements of total sleep scores. Subgroup analyses revealed no clear differences between interventions conducted during versus after breast cancer treatment. Considering the PSQI subscales, exercise resulted in improvements of sleep quality (SMD - 0.28; 95% CI - 0.44 to - 0.11) and sleep disturbances (SMD - 0.26; 95% CI - 0.45 to - 0.06). Regarding the objective measurements, no significant effects were found. CONCLUSIONS: Physical as well as mind-body exercise can improve subjective sleep problems in breast cancer patients. In contrast, there was no effect of exercise on objective sleep measures. Future studies should clarify which type of intervention might be most effective depending on individual patients' and treatments' characteristics.

Return to work after breast cancer: The role of treatment-related side effects and potential impact on quality of life.

For breast cancer survivors return to work (RTW) is important from an economic, societal and personal perspective. Thus, we investigated the impact of side effects and other factors on RTW. Five years post-diagnosis 135 disease-free breast cancer survivors below retirement age who were employed pre-diagnosis recorded their current and previous working status and reasons for impaired RTW. Patient-reported outcomes were prospectively reported over the cancer continuum. One year post-surgery 57% of survivors worked the same and 22% with reduced working time compared to pre-diagnosis. Logistic regression revealed significant associations of depressive symptoms, arm morbidity, lower education and younger age with impaired RTW after 1 year, and persisting physical fatigue and living with partner with impaired RTW after 5 years. Major self-reported reasons included fatigue and cognitive problems. Temporal patterns of general quality of life (QoL), physical, cognitive and role function, and financial problems were significantly worse among women with no RTW compared to those working again. In conclusion, cessation of work after breast cancer seems associated with worse QoL. Fatigue, psychological and cognitive problems as well as arm morbidity seemed to hinder RTW. Thus, a better management of these problems might help women to stay in working life.

Young age at school entry and attention-deficit hyperactivity disorder-related symptoms during primary school: results of a prospective cohort study conducted at German Rudolf Steiner Schools.

OBJECTIVES: Young age at school entry (ASE) for students has been related to their impaired mental health in higher grades. To avoid the negative health consequences of young ASE, preschool examinations and individual school entry deferral for young children are routinely performed by some school authorities. We aimed to investigate whether ASE was associated with attention-deficit hyperactivity disorder (ADHD)-related symptoms in pupils attending schools using a selective school enrolment procedure. DESIGN: Prospective open cohort study with baseline assessments at school entry and two follow-ups in the second and fourth grades. SETTING: Up to 128 Rudolf Steiner Schools (Waldorf Schools) located within Germany. PARTICIPANTS: Of the 3079 children from whom data were gathered in the second or fourth grade, 2671 children born between 1 July 2001 and 31 October 2002 (age at baseline: mean 6.7, min 5.91, max 7.24 years, 50% girls) were selected for analysis to avoid bias introduced by individuals at the edges of the ASE distribution. MAIN OUTCOME MEASURES: ADHD-related symptoms were assessed at school entry and second and fourth grades by parent-reported and teacher-reported versions of the Strengths and Difficulties Questionnaire (Hyperactivity-Inattention Subscale). RESULTS: The agreement between parent-reported and teacher-reported symptoms was poor (intra-class correlation: 0.41 and 0.44 in second and fourth grade assessments, respectively). Regarding teacher reports, ASE was negatively associated with ADHD-related symptoms in the second grade (regression coefficient ß=-0.66 per year, P=0.0006) and fourth grade (ß=-0.56, P=0.0014). Associations remained after adjusting for potential confounders and pre-existing symptoms at baseline. Regarding parent reports, associations were markedly weaker in both grades (second grade: ß=-0.22, P=0.12; fourth grade: ß=-0.09, P=0.48). CONCLUSIONS: Using a prospective study design and comprehensive adjustment for confounding and baseline symptoms, we confirmed prior evidence of the association between young ASE and teacher-reported ADHD symptoms in primary school.

Progressive resistance versus relaxation training for breast cancer patients during adjuvant chemotherapy: design and rationale of a randomized controlled trial (BEATE study).

BACKGROUND AND RATIONALE: Cancer-related fatigue is a common severe symptom in breast cancer patients, especially during chemotherapy. Exercise appears to be promising in prevention or treatment of fatigue. Resistance training as an accompanying treatment to chemotherapy has been minimally investigated, yet might counteract muscle degradation and inflammation caused by many chemotherapeutics, and thus forestall or reduce fatigue. Previous exercise trials mostly compared the intervention with 'usual care'. Therefore, it is unclear to what extent the observed effects on fatigue are based on physical adaptations by exercise itself, or rather on psycho-social factors linked to the group support or attention by the trainer. METHODS AND DESIGN: The BEATE study is a randomized, controlled intervention trial comparing a 12-week supervised progressive resistance training program with a supervised group-based progressive muscle relaxation training in 100 patients with breast cancer under adjuvant chemotherapy. The primary endpoint is cancer-related fatigue; secondary endpoints include quality of life, depression, and cognitive capacity. In addition, isokinetic and isometric muscle strength, cardiorespiratory fitness, and body composition are measured, and biomarkers, such as inflammatory parameters, cortisol, and oxidative stress are analyzed in blood, saliva and urine. Safety of the resistance training during chemotherapy is monitored. DISCUSSION: Strengths of the BEATE study include the investigation of progressive resistance training parallel with chemotherapy, the choice of a control group that enables an evaluation of the physiological effects of exercise beyond potential psycho-social effects, and the comprehensive and high-quality assessment of physiological factors and biomarkers potentially related to fatigue.

The use of herbal preparations to alleviate climacteric disorders and risk of postmenopausal breast cancer in a German case-control study.

BACKGROUND: The use of herbal preparations (HEP) to alleviate climacteric disorders is expected to increase as women seek alternatives to menopausal hormone therapy to avoid the associated breast cancer risk. Data are sparse on the long-term effects of HEP containing phytoestrogens and black cohosh on breast cancer risk. METHODS: Within a German case-control study, associations between patterns of HEP use and incident breast cancer were investigated in 10,121 postmenopausal women (3,464 cases, 6,657 controls). Information on HEP use was collected in face-to-face interviews supported by a list of brand names. Multivariate logistic and polytomous regression analyses were done. FINDINGS: Ever use of HEP (9.9%) was inversely associated with invasive breast cancer [odds ratio (OR), 0.74; 95% confidence interval (CI), 0.63-0.87] in a dose-dependent manner (OR, 0.96 per year of use; P = 0.03). Classes of HEP did not differ significantly (P(heterogeneity) = 0.81). Risks for invasive ductal (OR, 0.72; 95% CI, 0.60-0.87) and combined lobular/mixed/tubular tumors (OR, 0.76; 95% CI, 0.58-1.01) were similarly reduced by any HEP use but not for in situ carcinomas (1.34; 95% CI, 0.86-2.09). There were no substantial differences in associations of HEP use by estrogen receptor status (ER(+) OR, 0.74; 95% CI, 0.62-0.89; ER- OR, 0.68, 95% CI, 0.50-0.93) and progesterone receptor status of the tumor. INTERPRETATION: Our findings support the hypothesis that HEP use protects from invasive breast cancer in postmenopausal women. Among conceivable modes of action, those independent of estrogen receptor-mediated pathways seem to be involved (i.e., cytotoxicity, apoptosis).

Stimulation of phospholipase C-epsilon by the M3 muscarinic acetylcholine receptor mediated by cyclic AMP and the GTPase Rap2B.

Stimulation of phospholipase C (PLC) by G(q)-coupled receptors such as the M(3) muscarinic acetylcholine receptor (mAChR) is caused by direct activation of PLC-beta enzymes by Galpha(q) proteins. We have recently shown that G(s)-coupled receptors can stimulate PLC-epsilon, apparently via formation of cyclic AMP and activation of the Ras-related GTPase Rap2B. Here we report that PLC stimulation by the M(3) mAChR expressed in HEK-293 cells also involves, in part, similar mechanisms. M(3) mAChR-mediated PLC stimulation and [Ca(2+)](i) increase were reduced by 2',5'-dideoxyadenosine (dd-Ado), a direct adenylyl cyclase inhibitor. On the other hand, overexpression of Galpha(s) or Epac1, a cyclic AMP-regulated guanine nucleotide exchange factor for Rap GTPases, enhanced M(3) mAChR-mediated PLC stimulation. Inactivation of Ras-related GTPases with clostridial toxins suppressed the M(3) mAChR responses. The inhibitory toxin effects were mimicked by expression of inactive Rap2B, but not of other inactive GTPases (Rac1, Ras, RalA, Rap1A, and Rap2A). Activation of the M(3) mAChR induced GTP loading of Rap2B, an effect strongly enhanced by overexpression of Galpha(s) and inhibited by dd-Ado. Overexpression of PLC-epsilon and PLC-beta1, but not PLC-gamma1 or PLC-delta1, enhanced M(3) mAChR-mediated PLC stimulation and [Ca(2+)](i) increase. In contrast, expression of a catalytically inactive PLC-epsilon mutant reduced PLC stimulation by the M(3) mAChR and abrogated the potentiating effect of Galpha(s). In conclusion, our findings suggest that PLC stimulation by the M(3) mAChR is a composite action of PLC-beta1 stimulation by Galpha(q) and stimulation of PLC-epsilon apparently mediated by G(s)-dependent cyclic AMP formation and subsequent activation of Rap2B.