Combined inhibition of RAD51 and CHK1 causes synergistic toxicity in cisplatin resistant cancer cells by triggering replication fork collapse.

The therapeutic efficacy of the anticancer drug cisplatin is limited by acquired drug resistance. Cisplatin forms DNA crosslinks, that, if not removed, lead to replication stress. Due to this, the DNA damage response (DDR) gets activated regulating cell cycle arrest, DNA repair, cell death or survival. This makes DDR components promising targets for the development of new therapeutic approaches aiming to overcome acquired drug resistance. To this end, cisplatin-resistant bladder cancer cells were analyzed regarding their sensitivity to combination treatments with selected pharmacological DDR inhibitors. Synergistic cytolethal effects were achieved after combined treatment with low to moderate doses of the non-genotoxic RAD51-inhibitor (RAD51i) B02 and CHK1-inhibitor (CHK1i) PF477736. This effect was also found in cisplatin resistant tumor cells of other origin as well as with other RAD51i and CHK1i. Combined treatments promoted decelerated replication, S-phase blockage, accumulation of DNA strand breaks, DDR activation and stimulation of apoptotic cell death as compared to mono-treatment, which is independent of the expression of RAD51, CHK1, and PrimPol. Based on these data, we suggest combined inhibition of RAD51 and CHK1 to overcome acquired cisplatin resistance of malignant cells. We propose that the molecular mechanism of this synergistic toxicity relies on a simultaneous inactivation of two key DNA damage tolerance pathways regulating replication fork restart, thereby circumventing the activation of alternative compensatory mechanisms and, in consequence, eventually effectively triggering apoptotic cell death by replication fork collapse.

Efficacy and quality of life for FOLFOX/bevacizumab +/- irinotecan in first-line metastatic colorectal cancer-final results of the AIO CHARTA trial.

BACKGROUND: FOLFOXIRI plus bevacizumab has demonstrated benefits for metastatic colorectal cancer (mCRC) patients. However, challenges arise in its clinical implementation due to expected side effects and a lack of stratification criteria. METHODS: The AIO "CHARTA" trial randomised mCRC patients into clinical Group 1 (potentially resectable), 2 (unresectable/risk of rapid progression), or 3 (asymptomatic). They received FOLFOX/bevacizumab +/- irinotecan. The primary endpoint was the 9-month progression-free survival rate (PFSR@9). Secondary endpoints included efficacy in stratified groups, QoL, PFS, OS, ORR, secondary resection rate, and toxicity. RESULTS: The addition of irinotecan to FOLFOX/bevacizumab increased PFSR@9 from 56 to 67%, meeting the primary endpoint. The objective response rate was 61% vs. 69% (P = 0.21) and median PFS was 10.3 vs. 12 months (HR 0.83; P = 0.17). The PFS was (11.4 vs. 12.9 months; HR 0.83; P = 0.46) in potentially resectable patients, with a secondary resection rate of 37% vs. 51%. Moreover, Group 3 (asymptomatic) patients had a PFS of 11.1 vs. 16.1 months (HR 0.6; P = 0.14). The addition of irinotecan did not diminish QoL. CONCLUSION: The CHARTA trial, along with other studies, confirms the efficacy and tolerability of FOLFOXIRI/bevacizumab as a first-line treatment for mCRC. Importantly, clinical stratification may lead to its implementation. TRIAL REGISTRATION: The trial was registered as NCT01321957.

Effects of a structured counselling-based intervention to improve physical activity behaviour of adolescents and young adult cancer survivors - the randomized phase II Motivate AYA - MAYA trial.

OBJECTIVE: To explore whether a structured counselling-based intervention increases vigorous physical activity behaviour of adolescent and young adult cancer survivors. DESIGN: Randomized controlled phase II trial. SETTING: University Cancer Center Hamburg, Germany. SUBJECTS: Eighty-nine participants (mean age 24.1 ± 6.3) were randomized to control (n = 44) or intervention group (n = 45). INTERVENTIONS: The intervention group was consulted about physical activity behaviour via interview (week 0), and telephone counselling (weeks 1, 3 and 12). The control group only received general physical activity guidelines for cancer survivors (week 0). MAIN MEASURES: The primary outcome was the rate of participants with ⩾9 metabolic equivalent (MET)-hours per week of vigorous activity post-intervention, measured with the International Physical Activity Questionnaire. Secondary outcomes included assessing physical activity behaviour (e.g. amount and type of physical activity) and quality of life. Assessments were completed in weeks 0 (baseline), 12 (post-intervention) and 52 (follow-up). RESULTS: Sixty-nine participants completed the post-intervention- and 47 the follow-up-assessment. The rate of participants performing vigorous physical activity increased from baseline to post-intervention for both without differing significantly (P = 0.541). Both increased their total metabolic equivalent from baseline to post-intervention (intervention group from 55.2 ± 43.7 to 61.7 ± 29.4, control group from 75.3 ± 81.4 to 88.3 ± 80.2). At follow-up the intervention group (73.7 ± 80.2) was more active than baseline when compared to the control group (78.5 ± 50.0). CONCLUSIONS: A structured counselling-based physical activity intervention did not significantly impact the level of vigorous physical activity behaviour in adolescent and young adult cancer survivors.

Effect of heat treatment on.wheat dough rheology and wheat protein solubility.

In the present study, the influence of moisture content, temperature and time during heat treatment of wheat flour was investigated. Heat treatment was carried out on laboratory scale in a water bath at 50-90 degrees C for times up to 3 h. Flour functionality was evaluated by analysing protein solubility in acetic acid as well as by the formation of bread-like doughs, which were then analysed with dynamic oscillatory and rotational rheometry. Effects during heat treatment were explained on a molecular level using a simplified physical model describing wheat dough as a continuous gluten matrix with starch as filler particles. Heat treatment causes the formation of gluten aggregates resulting in decreased protein solubility and lower network strength of dough. Rheological data also indicate the formation of starch aggregates and modified interactions between gluten and starch. The effects were more pronounced in heat-treated flours with increased moisture content due to a higher mobility of the molecules.

A Multimodal Lifestyle Psychosocial Survivorship Program in Young Cancer Survivors: The CARE for CAYA Program-A Randomized Clinical Trial Embedded in a Longitudinal Cohort Study.

Importance: There is a lack of trials examining the effect of counseling interventions for child, adolescent, and younger adult (CAYA) cancer survivors. Objective: To assess lifestyle habits and the psychosocial situation of CAYAs to determine the efficacy of needs-based interventions in the CARE for CAYA program (CFC-P). Design, Setting, and Participants: The CFC-P was conducted as a multicenter program in 14 German outpatient clinics, mainly university cancer centers. Recruitment began January 1, 2018; a randomized clinical trial was conducted until July 15, 2019; and intervention was continued as a longitudinal cohort study until March 31, 2021. Data preparation was conducted from April 1, 2021, and analysis was conducted from August 14, 2021, to May 31, 2022. Herein, predefined confirmatory analyses pertain to the RCT and descriptive results relate to the overall longitudinal study. Data analysis was based on the full analysis set, which is as close as possible to the intention-to-treat principle. Intervention: A comprehensive assessment determined needs in physical activity, nutrition and psychooncology. Those with high needs participated in 1 to 3 modules. In the RCT, the IG received 5 counseling sessions plus newsletters, while the control group CG received 1 counseling session. Main Outcomes and Measures: The primary outcome was the change in the rate of CAYAs with high needs at 52 weeks. Secondary outcomes were feasibility, modular-specific end points, satisfaction, quality of life, and fatigue. Results: Of 1502 approached CAYAs aged 15 to 39 years, 692 declined participation. Another 22 CAYAs were excluded, resulting in 788 participants. In the randomized clinical trial, 359 CAYAs were randomized (intervention group [IG], n = 183; control group [CG], n = 176), and 274 were followed up. In the RCT, the median age was 25.0 (IQR, 19.9-32.2) years; 226 were female (63.0%) and 133 male (37.0%). After 52 weeks, 120 CAYAs (87.0%) in the IG and 115 (86.5%) in the CG still had a high need in at least 1 module (odds ratio, 1.04; 95% CI, 0.51-2.11; P = .91). Both groups reported reduced needs, improved quality of life, reduced fatigue, and high satisfaction with the CFC-P. Conclusions and Relevance: In this randomized clinical trial, the implementation of a lifestyle program in this cohort was deemed necessary, despite not meeting the primary outcome. The interventions did not alter the rate of high needs. The results may provide guidance for the development of multimodal interventions in the follow-up care of CAYAs. Trial Registration: German Clinical Trial Register: DRKS00012504.

Disordered eating in a digital age: eating behaviors, health, and quality of life in users of websites with pro-eating disorder content.

BACKGROUND: Much concern has been raised over pro-eating disorder (pro-ED) website communities, but little quantitative research has been conducted on these websites and their users. OBJECTIVE: To examine associations between levels of pro-ED website usage, disordered eating behaviors, and quality of life. METHODS: We conducted a cross-sectional, Internet-based survey of adult pro-ED website users. Main outcomes were Eating Disorder Examination Questionnaire (EDE-Q) and Eating Disorder Quality of Life (EDQOL) scores. RESULTS: We included responses from 1291 participants; 1254 (97.13%) participants were female. Participants had an average age of 22.0 years and a mean body mass index of 22.1 kg/m(2); 24.83% (296/1192) were underweight; 20.89% (249/1192) were overweight or obese. Over 70% of participants had purged, binged, or used laxatives to control their weight; only 12.91% (163/1263) were in treatment. Mean EDE-Q scores were above the 90th percentile and mean EDQOL scores were in the severely impaired range. When compared with moderate and light usage, heavy pro-ED website usage was associated with higher EDE-Q global (4.89 vs 4.56 for medium and 4.0 for light usage, P < .001) and EDQOL total scores (1.64 vs 1.45 for medium and 1.25 for light usage, P < .001), and more extreme weight loss behaviors and harmful post-website usage activities. In a multivariate model, the level of pro-ED website usage remained a significant predictor of EDE-Q scores. CONCLUSIONS: Pro-ED website visitors reported many disordered eating behaviors, although few had been treated. Heavy users reported poorer quality of life and more disordered eating behaviors.

Selinexor (KPT-330), an Oral Selective Inhibitor of Nuclear Export (SINE) Compound, in Combination with FOLFOX in Patients with Metastatic Colorectal Cancer (mCRC) - Final Results of the Phase I Trial SENTINEL.

BACKGROUND: Selinexor is an oral Selective Inhibitor of Nuclear Export compound that specifically blocks Chromosomal Region Maintenance protein 1. OBJECTIVE: To evaluate the safety and tolerability of escalating doses of selinexor plus 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) in metastatic colorectal cancer (mCRC) patients. METHODS: In this multicenter phase I trial, mCRC patients, eligible for oxaliplatin-based treatment, were enrolled to receive oral selinexor on days 1, 3, and 8 plus mFOLFOX6 every two weeks. Primary endpoint was the maximum tolerated dose. Secondary endpoints were toxicity, overall response rate, progression free survival, and overall survival. RESULTS: Overall, 10 patients were enrolled, who had prior treatment with oxaliplatin (6/10), irinotecan (8/10), bevacizumab (6/10) or anti-EGFR therapy (5/10). Four consecutive patients received 40 mg selinexor plus mFOLFOX6. All four experienced dose-limiting toxicities and withdrew from the study after a median of two cycles. Thus, this dose level was regarded as toxic and no further patients were evaluated at this dose. Six patients were enrolled with 20 mg selinexor plus mFOLFOX6. Despite better tolerability, four patients withdrew (patient wish) after the first cycle and only two patients continued until disease progression. Most commonly reported treatment emergent adverse events were nausea (80%), diarrhea (70%), vomiting (60%), fatigue (60%), anorexia (40%), and impaired vision (40%). Due to the short treatment exposure, no relevant clinical activity was observed. CONCLUSION: In patients with metastatic colorectal cancer, selinexor on this dose schedule plus mFOLFOX6 was not tolerable. Other dosing schedules or combinations may be evaluated. Clinical trial identifier NCT02384850.

Impact of taste and smell training on taste disorders during chemotherapy - TASTE trial.

PURPOSE: Two-thirds of cancer patients report taste disorders during and after chemotherapy. Taste disorders impact on nutritional status which is highly relevant for treatment efficacy and overall prognosis. Improvement of taste disorder is of particular importance for cancer patients' outcomes, thus the TASTE trial was conducted to improve taste disorders with a taste and smell training. METHODS: In this trial, patients undergoing chemotherapy were screened for taste disorders. Subsequently, patients were allocated based on the detection of taste disorders (≤8 taste strips points) to an intervention group with a taste and smell training at baseline and week 3-5 or were only followed up, if no taste disorder was detected (≥9 taste strips points) (non-intervention group). At baseline, all patients received a nutritional counseling. The primary endpoint was the minimal clinically relevant improvement of taste strips score by 2 taste strips points in at least 50% of the patients with taste disorders. RESULTS: The trial included 62 patients (48 women [77%], 14 male [23%], age 54.5±11.6 years) who had gastrointestinal (n=29), breast (n=31), or lung cancer (n=2). Taste disorders were more frequent in gastrointestinal than in breast cancer patients. Out of 62 patients screened, 30 patients showed taste disorders. The primary endpoint was met with 92% (n=23 of 25) of the patients completing the intervention. In the intervention group, the patients' taste significantly improved from baseline (median taste strips: 7.0 points) to week 12 (median taste strips: 10.0 points) (P≤0.001). Patients of the non-intervention group who completed the reassessment (n=27 of 32) experienced no change in taste perception in the 3-month follow-up (P=0.897). CONCLUSION: Intensified nutritional counseling with taste and smell training may improve taste perception of patients undergoing chemotherapy. A confirmatory randomized trial is planned.

Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes.

Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10-7), particularly in the female subsample (p = 9.8 × 10-9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10-4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.

Effects of oral ATP supplementation on anaerobic power and muscular strength.

PURPOSE: We examined 14 d of oral adenosine 5'-triphosphate (ATP) supplementation on indices of anaerobic capacity and muscular strength. METHODS: Twenty-seven healthy males successfully completed the trial, after randomly receiving in a double-blind manner an oral dose of low dose (150 mg) or high dose (225 mg) ATP, or matched placebo. To improve absorption characteristics, the ATP was enterically coated. Total blood ATP (whole blood and plasma ATP) concentrations, two Wingate anaerobic power tests (30 s), and muscular strength (1RM and three sets of repetitions to fatigue at 70% of 1RM) were measured under three conditions: (i) baseline; (ii) acutely (7d later, no prior supplementation and 75 min after ATP ingestion); and (iii) after 14 d of daily ingestion (post). RESULTS: Statistical analyses showed no significant between or within group treatment effects for whole blood ATP or plasma ATP concentrations for any treatment condition. We also did not observe any treatment effects for any Wingate testing parameter including peak PO, total work, average PO for 30 s, or post-Wingate lactate accumulation. Overall, we observed no significant between group treatment effects for any muscular strength parameter. We did observe several within group differences for the group ingesting the high ATP dosage including 1RM (6.6%; P < 0.04) and repetitions to fatigue during set 1 of posttesting (18.5%; P < 0.007) and total lifting volume at post (22%; P < 0.003). CONCLUSIONS: We conclude that enterically coated oral ATP supplementation may provide small ergogenic effects on muscular strength under some treatment conditions.