Changes in physical activity, sedentary behavior, and self-reported cognitive function in cancer survivors before and during the COVID-19 pandemic: A cross-sectional study.

BACKGROUND: Physical activity (PA) and reductions in sedentary behavior (SED) may mitigate cancer-related cognitive impairment. The purpose of this study was to examine (a) the associations between changes in PA, SED, and cognitive function in cancer survivors before and during the coronavirus disease 2019 (COVID-19) pandemic; and (b) clinical subgroups that moderate this association. METHODS: A cross-sectional survey was administered online to adult cancer survivors globally between July and November of 2020. This was a secondary analysis of a cross-sectional survey examining changes in self-reported PA and quality of life in cancer survivors before and during the COVID-19 pandemic. Self-reported Questionnaires assessed moderate-to-vigorous PA (MVPA) using the modified Godin Leisure Time Exercise Questionnaire, cognitive function using the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) scale, and SED using the Domain-specific Sitting Time questionnaire. Cancer survivors were classified into no change in behavior, desirable change (i.e., increase MVPA to meet PA guidelines or decrease SED by ≥60 min/day), and undesirable change (i.e., decrease MVPA to <150 min/week or increase SED by ≥60 min/day). Analysis of covariance examined differences in FACT-Cog scores across the activity change categories. Planned contrasts compared differences in FACT-Cog scores between cancer survivors with (a) no meaningful change vs. any change, and (b) a desirable change vs. an undesirable change. RESULTS: There were no significant differences in FACT-Cog scores across activity-change categories in the full sample of cancer survivors (n = 371; age = 48.6 ± 15.3 years (mean ± SD)). However, cancer survivors who were diagnosed ≥5 years ago (t(160) = -2.15, p = 0.03) or who received treatment ≥5 years ago (t(102) = -2.23, p = 0.03) and who had a desirable change in activity reported better perceived cognitive abilities than those who had an undesirable change. CONCLUSION: PA promotion efforts should consider reducing SED in addition to maintaining MVPA in long-term cancer survivors to mitigate cancer-related cognitive impairment during the COVID-19 pandemic.

The importance of collaboration between medical and exercise professionals in addressing patient physical inactivity.

Physical activity has declined further during the coronavirus disease 2019 (COVID-19) pandemic. Physicians are at the front lines of proactively educating and promoting physical activity to patients; however, physicians do not feel confident and face numerous barriers in prescribing exercise to patients. Exercise referral schemes, comprising collaborations with qualified exercise professionals, represent a fruitful option for supporting physicians hoping to promote physical activity to more patients. Herein, we provide practical suggestions for establishing and creating a successful referral scheme. Ultimately, exercise referral schemes offer an alternative to help physician burnout and mitigate patient physical inactivity during and beyond the COVID-19 pandemic.

Sleep Quality and the Importance Women Place on Healthy Eating Interact to Influence Psychological Resilience.

Objectives: The impact women's daily habits may have on psychological resilience is not well understood. This cross-sectional analysis examined: (1) the impact of sleep quality on resilience, and (2) whether this association was modified by the importance women place on healthy eating. Methods: We collected data from 64 women (aged 18-67 years). The Pittsburgh Sleep Quality Index and Connor-Davidson Resilience Scale-10 assessed sleep quality and resilience, respectively, with lower scores indicating reduced resilience. One item assessed attitudes towards healthy eating. Linear regression models and 95% confidence intervals examined associations adjusted for age and income. Results: Reduced sleep quality was associated with a decreased resilience score (B=0.55, 95% CI: -1.06, -0.04, p=.04) when adjusted for age and income. After stratification, sleep quality and resilience were not associated among women who indicated healthy eating was very important. Among women who indicated healthy eating was less than very important, reduced sleep quality was associated with decreased psychological resilience (B=0.85, 95% CI: -1.55, -0.15, p=.02). Conclusions: Poor sleep quality was associated with reduced resilience among women. Placing a strong emphasis on healthy eating helped buffer the impact of poor sleep quality on women's psychological resilience.

Deciphering radiological stable disease to immune checkpoint inhibitors.

BACKGROUND: 'Stable disease (SD)' as per RECIST is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. Understanding SD would facilitate drug development and improve precision in correlative research. PATIENTS AND METHODS: A systematic review was carried out to characterize SD in ICI trials. SD and objective response were compared to proliferation index using The Cancer Genome Atlas gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of non-small-cell lung cancer (NSCLC). Serial cutpoints of two variables, % best overall response and progression-free survival (PFS), were tested to define a subgroup of patients with SD with similar survival as responders. Results were then tested in external validation cohorts. RESULTS: Among trials of ICIs (59 studies, 14 280 patients), SD ranged from 16% to 42% in different tumor types and was associated with disease-specific proliferation index (ρ = -0.75, P = 0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of NSCLC [1220 patients, 313 (26%) with SD to ICIs], PFS ranged widely in SD (0.2-49 months, median 4.9 months). The subset with PFS >6 months and no tumor growth mirrored partial response (PR) minor (overall survival hazard ratio 1.0) and was proposed as the definition of SD responder. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab and found to apply in tumor types treated with immunotherapy in which depth and duration of benefit were correlated. CONCLUSIONS: RECIST-defined SD to immunotherapy is common, heterogeneous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS >6 months and no tumor growth may be considered 'SD responders'. This definition may improve the efficiency of and insight derivable from clinical and translational research.

Effectiveness of Live Health Professional-Led Group eHealth Interventions for Adult Mental Health: Systematic Review of Randomized Controlled Trials.

BACKGROUND: The COVID-19 pandemic has had adverse impacts on mental health and substance use worldwide. Systematic reviews suggest eHealth interventions can be effective at addressing these problems. However, strong positive eHealth outcomes are often tied to the intensity of web-based therapist guidance, which has time and cost implications that can make the population scale-up of more effective interventions difficult. A way to offset cost while maintaining the intensity of therapist guidance is to offer eHealth programs to groups rather than more standard one-on-one formats. OBJECTIVE: This systematic review aims to assess experimental evidence for the effectiveness of live health professional-led group eHealth interventions on mental health, substance use, or bereavement among community-dwelling adults. Within the articles selected for our primary aim, we also seek to examine the impact of interventions that encourage physical activity compared with those that do not. METHODS: Overall, 4 databases (MEDLINE, CINAHL, PsycINFO, and the Cochrane Library) were searched in July 2020. Eligible studies were randomized controlled trials (RCTs) of eHealth interventions led by health professionals and delivered entirely to adult groups by videoconference, teleconference, or webchat. Eligible studies reported mental health, substance use, or bereavement as primary outcomes. The results were examined by outcome, eHealth platform, and intervention length. Postintervention data were used to calculate effect size by study. The findings were summarized using the Synthesis Without Meta-Analysis guidelines. Risk of bias was assessed using the Cochrane Collaboration Tool. RESULTS: Of the 4099 identified studies, 21 (0.51%) RCTs representing 20 interventions met the inclusion criteria. These studies examined mental health outcomes among 2438 participants (sample size range: 47-361 participants per study) across 7 countries. When effect sizes were pooled, live health professional-led group eHealth interventions had a medium effect on reducing anxiety compared with inactive (Cohen d=0.57) or active control (Cohen d=0.48), a medium to small effect on reducing depression compared with inactive (Cohen d=0.61) or active control (Cohen d=0.21), and mixed effects on mental distress and coping. Interventions led by videoconference, and those that provided 8-12 hours of live health professional-led group contact had more robust effects on adult mental health. Risk of bias was high in 91% (19/21) of the studies. Heterogeneity across interventions was significant, resulting in low to very low quality of evidence. No eligible RCT was found that examined substance use, bereavement, or physical activity. CONCLUSIONS: Live eHealth group interventions led by health professionals can foster moderate improvements in anxiety and moderate to small improvements in depression among community-based adults, particularly those delivered by videoconference and those providing 8-12 hours of synchronous engagement. TRIAL REGISTRATION: PROSPERO CRD42020187551; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=187551. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13643-020-01479-3.

The role of treatment delays in surgical site infection after appendicectomy in a South African rural regional hospital.

BACKGROUND: Delays to surgery for acute appendicitis in low- and middle-income countries lead to significant morbidity. OBJECTIVES: To investigate the role of time to surgery in the development of complicated appendicitis and surgical site infection (SSI) in a rural referral hospital in South Africa (SA). METHODS: A prospective cohort study was conducted of all patients presenting to a regional hospital in SA with acute appendicitis during 2017. Inpatient interview and data collection were followed by 30-day post-surgical follow-up to assess time periods to surgery and operative outcomes. RESULTS: A total of 188 patients underwent surgery for acute appendicitis. The median (interquartile range (IQR)) age was 19 (3 - 73) years, and 62% were male. The median (IQR) time from symptoms to surgery was 60 (42 - 86) hours and from hospital admission to surgery 8 (4 - 16) hours. Forty-one percent were managed laparoscopically, 62% had complicated appendicitis, and 25% developed SSI. Time from symptoms to surgery >72 hours was associated with an increased risk of complicated appendicitis (odds ratio (OR) 4.32; 95% confidence interval (CI) 1.36 - 13.75; p=0.013). Patients with SSI had an increased median delay of 15 hours (p=0.05) compared with those without SSI. Multivariable analysis showed that the risk of SSI increased with complicated appendicitis (OR 8.96; 95% CI 2.73 - 29.41; p<0,001) and decreased with laparoscopic surgery (OR 0.21; 95% CI 0.07 - 0.59; p=0.003). Time to surgery had no effect on the risk of SSI in adjusted analyses. CONCLUSIONS: Delays to surgery beyond 72 hours significantly increased complicated appendicitis, an important risk factor for SSI. Access to facilities with surgical capability and the use of laparoscopic surgery are modifiable risk factors for SSI.

IgE blockade with omalizumab reduces pruritus related to immune checkpoint inhibitors and anti-HER2 therapies.

BACKGROUND: Immunoglobulin E (IgE) blockade with omalizumab has demonstrated clinical benefit in pruritus-associated dermatoses (e.g. atopic dermatitis, bullous pemphigoid, urticaria). In oncology, pruritus-associated cutaneous adverse events (paCAEs) are frequent with immune checkpoint inhibitors (CPIs) and targeted anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we sought to evaluate the efficacy and safety of IgE blockade with omalizumab in cancer patients with refractory paCAEs related to CPIs and anti-HER2 agents. PATIENTS AND METHODS: Patients included in this multicenter retrospective analysis received monthly subcutaneous injections of omalizumab for CPI or anti-HER2 therapy-related grade 2/3 pruritus that was refractory to topical corticosteroids plus at least one additional systemic intervention. To assess clinical response to omalizumab, we used the Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was defined as reduction in the severity of paCAEs to grade 1/0. RESULTS: A total of 34 patients (50% female, median age 67.5 years) received omalizumab for cancer therapy-related paCAEs (71% CPIs; 29% anti-HER2). All had solid tumors (29% breast, 29% genitourinary, 15% lung, 26% other), and most (n = 18, 64%) presented with an urticarial phenotype. In total 28 of 34 (82%) patients responded to omalizumab. The proportion of patients receiving oral corticosteroids as supportive treatment for management of paCAEs decreased with IgE blockade, from 50% to 9% (P < 0.001). Ten of 32 (31%) patients had interruption of oncologic therapy due to skin toxicity; four of six (67%) were successfully rechallenged following omalizumab. There were no reports of anaphylaxis or hypersensitivity reactions related to omalizumab. CONCLUSIONS: IgE blockade with omalizumab demonstrated clinical efficacy and was well tolerated in cancer patients with pruritus related to CPIs and anti-HER2 therapies.

The impact of eHealth group interventions on the mental, behavioral, and physical health of adults: a systematic review protocol.

BACKGROUND: COVID-19 has resulted in an increased demand for eHealth services globally. There is emerging evidence for the efficacy for group eHealth interventions that support population-based mental health and wellbeing, but a systematic review is lacking. The primary objective of this systematic review is to summarize the evidence for eHealth group counseling and coaching programs for adults. A second objective is to assess, within studies selected for our primary objective, the impact of programs that encourage PA on outcomes compared to those that do not. METHODS: Randomized controlled trials that assess the impact of eHealth group counseling or coaching programs on mental health, health behavior, or physical health activity among community-dwelling adults will be included. We will search the following electronic databases (from January 2005 onwards): MEDLINE, PsycINFO, CINHAL, and the Central Register of Controlled Trials. The primary outcomes will be changes in mental health conditions (e.g., depression, anxiety, stress, quality of life), behavioral health conditions (e.g., substance use, smoking, sexual behavior, eating behavior, medication adherence), and physical health conditions (e.g., coping with cancer, menopausal symptoms, arthritis pain). Secondary outcomes will be changes in physical activity. Two reviewers will independently screen all citations, full-text articles, and abstract data. Potential conflicts will be resolved through discussion with a third reviewer. A narrative synthesis without meta-analysis will be conducted. The strength of the body of evidence will be assessed using GRADE. The risk of bias in individual studies will be appraised using the Cochrane Risk of Bias 2.0 tool. Potential sources of gender bias in included studies will be considered at all stages of the planned review. DISCUSSION: This review will contribute to the literature by providing evidence on the effectiveness of eHealth counseling and coaching programs delivered to adults in a group format. SYSTEMATIC REVIEW REGISTRATION: The protocol has been registered at the International Prospective Register of Systematic Reviews (PROSPERO: CRD42020187551 ).

Stand When You Can: development and pilot testing of an intervention to reduce sedentary time in assisted living.

BACKGROUND: Prolonged daily sedentary time is associated with increased risk of cardiometabolic diseases, impaired physical function, and mortality. Older adults are more sedentary than any other age group and those in assisted living residences accumulate more sedentary time as they often have little need to engage in light-intensity or standing activities such as cleaning or meal preparation. This "low movement" environment can hasten functional decline. Thus, the purpose of this study was to develop a multi-level intervention to reduce and interrupt sedentary time within assisted living residences and conduct a pilot study to determine if the intervention is feasible and if further testing is warranted. METHODS: "Stand When You Can" (SWYC) was developed using a Social Ecological framework based on a review of literature and consultation with residents and staff at assisted living residences. After development, a six-week pilot study was conducted in two different residences with 10 older adults (82.2 ± 8.7 years). Before and after the 6 weeks, ActivPAL™ inclinometers were used to measure daily movement behaviours and self-report questionnaires assessed time spent in different sedentary behaviours and quality of life. Physical function was assessed using the Short Physical Performance Battery. Paired sample t-tests examined pre-post differences for pooled data and individual sites. At the end of the pilot study, feedback on the intervention was gathered from both residents and staff to examine feasibility. RESULTS: There was a trend towards a decrease in self-reported sitting time (142 min/day; p = 0.09), although device-measured sedentary time did not change significantly. Participants with lower physical function at baseline showed clinically meaningful improvements in physical function after the 6 weeks (p = 0.04, Cohen's d = 0.89). There was no change in quality of life. Residents and staff reported that the intervention strategies were acceptable and practical. CONCLUSION: This study suggests that a multi-level intervention for reducing prolonged sedentary time is feasible for implementation at assisted living residences. The intervention could potentially help delay functional decline among older adults when they transition to a supportive living environment. Longer and larger trials to test the efficacy of SWYC are necessary. TRIAL REGISTRATION: Name of Clinical Trial Registry: clinicaltrials.gov Trial Registration number: NCT04458896 . Date of registration: July 8, 2020. (Retrospectively registered).

Reducing Sedentary Time among Older Adults in Assisted Living: Perceptions, Barriers, and Motivators.

Older adults accumulate more sedentary time (ST) than any other age group, especially those in assisted living residences (ALRs). Reducing prolonged ST could help maintain function among older adults. However, to develop effective intervention strategies, it is important to understand the factors that influence sedentary behavior. The purpose of this study was to explore perceptions of ST as well as barriers and motivators to reducing ST among older adults in assisted living, in the context of the Social Ecological Model (SEM). Using a qualitative description approach, we sought to learn about participants' perceptions of sedentary time in their daily lives. Semi-structured focus groups were held at six ALRs with 31 participants (84% women, 83.5 ± 6.5 years). Data were transcribed and coded using an inductive thematic approach. Themes were categorized based on four levels of the SEM: individual, social, physical environment, and organization. Many reported barriers were at the individual level (e.g., lack of motivation, pain, fatigue) while others were associated with the organization or social environment (e.g., safety concerns, lack of activities outside of business hours, and social norms). These findings suggest that there are unique challenges and opportunities to consider when designing ST interventions for assisted living.

[Effect of humor training on stress, cheerfulness and depression in patients with coronary artery disease and refractory angina pectoris]. / Effekt von Humortraining auf Stress, Heiterkeit und Depression bei Patienten mit koronarer Herzkrankheit und therapierefraktärer Angina pectoris.

BACKGROUND: Angina pectoris refractory to conventional medical treatment is a common phenomenon in patients with stable coronary artery disease (CAD). Many of these patients suffer from depression and generate substantial costs in the healthcare system. Therefore, the development of new therapeutic concepts is of particular importance. This study investigated whether professional, structured humor training has a positive effect on the symptoms of patients with treatment refractory angina pectoris. METHODS: Between 2013 and 2014 a total of 35 patients with stable CAD were included. Enrolment was possible if patients suffered from treatment refractory angina pectoris (Canadian Cardiovascular Society, CCS grades II-IV) despite optimal antianginal medication and exhaustion of options for myocardial revascularization. Previously, 25.8% of the patients had had a myocardial infarction. In this study, a professional humor coaching was conducted with a duration of 7 weeks. In order to evaluate the effects of the coaching, the following examinations were performed before and after the intervention: exercise stress test (treadmill), hair segment cortisol analysis, Beck Depression Inventory (BDI), the Trier Inventory for the Assessment of Chronic Stress (TICS) and the State-Trait-Cheerfulness Inventory (STCI). RESULTS: Out of the 35 initially recruited patients 31 completed the study. The mean age was 65.5 years and 94.5% were female. There was a significant improvement in cheerfulness (STCI, pre 23.3 ± 5.4, post 27.5 ± 5, p = 0,03). This effect was even stronger in a subgroup analysis in which only female patients were included (pre 23.6 ± 5.5, post 27.7 ± 4.6, p = 0.003). The results of the BDI showed a remarkable improvement in the pre-post analysis (pre 14.6 ± 8.1, post 11.0 ± 6.5, p = 0.064). Analyzing only the female patients, this difference became significant (pre 13.1 ± 6.4, post 9.9 ± 4.6 p = 0,037). The hair segment investigations showed that patients who had a higher cortisol level in the beginning (>25. percentile, n = 22) showed a significant reduction of the cortisol concentration (pre 6.54 pg/mg, 3.78-12.12 pg/mg, post 3.65 pg/mg, 2.82-7.68 pg/mg, p = 0.029). CONCLUSION: Patients with refractory angina pectoris and stable CAD benefit from a professional humor coaching. This effect was shown in a) a significant decrease in cortisol concentrations in the hair segment analysis, b) an improvement in cheerfulness in the STCI and c) a significant difference in the BDI between pre-post values.

Trauma-informed interventions versus control for cancer-risk behaviours among adults: rationale and design for a randomized trial.

BACKGROUND: Tobacco use, alcohol use, and sugar-sweetened beverage consumption are each associated with increased cancer-risk. Psychological trauma is a common experience and a key driver of these behaviours among adults. The primary aim of this study is to evaluate the effect of trauma-informed yoga, drumming, and psychoeducation compared to control on tobacco use, alcohol use, and sugar-sweetened beverage consumption among community-based adults. Secondary aims are to evaluate the effect of these interventions compared to control on psychological and physiological stress symptomology, social connection, and coping behaviour. METHODS: Recruitment for this single-blinded randomized trial began in April 2019 in the Faculty of Health Sciences at the University of Lethbridge. Adults who consumed tobacco, alcohol, or sugar-sweetened beverages in the past month and live in Lethbridge, Alberta are being recruited using ads placed in public spaces. Participants are randomly allocated to a 12-session group yoga class, 12-session group drumming class, a 12-session psychoeducation class, or control. Participants attend an appointment in-person to fill out an online questionnaire package, provide a saliva sample, and complete physical measures pre-intervention, and 1-month and 6-months post-intervention. DISCUSSION: This study provides a unique opportunity to compare the impacts of two trauma-informed body-based interventions to psychoeducation and control for cancer-risk behaviour among community-based adults. The findings can be used to develop trauma-informed group interventions to reduce cancer-risk behaviour in general populations. Results are expected in 2022. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov ISRCTN15583681 on 22 August 2019 (retrospectively registered).

Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are being increasingly utilised in the front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) vascular endothelial growth factor-receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy after 1L ICI therapy. PATIENTS AND METHODS: This is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists' review using Response Evaluation Criteria in Solid Tumours v1.1. Descriptive statistics and Kaplan-Meier method were used. RESULTS: Seventy patients were included in the analysis. Median age at mccRCC diagnosis was 59 years; 8 patients (11%) had international metastatic database consortium favourable-risk disease, 48 (69%) had intermediate-risk disease and 14 (20%) had poor-risk disease. As 1L therapy, 12 patients (17%) received anti-programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti-PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete response, 27 patients (39.7%) a partial response and 36 patients (52.9%) stable disease. Median progression-free survival (mPFS) was 13.2 months (95% confidence interval: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity. CONCLUSIONS: In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy after 1L ICI, we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI.

Immune checkpoint inhibitors in MITF family translocation renal cell carcinomas and genetic correlates of exceptional responders.

BACKGROUND: Microphthalmia Transcription Factor (MITF)family translocation renal cell carcinoma (tRCC) is a rare RCC subtype harboring TFE3/TFEB translocations. The prognosis in the metastatic (m) setting is poor. Programmed death ligand-1 expression was reported in 90% of cases, prompting us to analyze the benefit of immune checkpoint inhibitors (ICI) in this population. PATIENTS AND METHODS: This multicenter retrospective study identified patients with MITF family mtRCC who had received an ICI in any of 12 referral centers in France or the USA. Response rate according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. Genomic alterations associated with response were determined for 8 patients. RESULTS: Overall, 24 patients with metastatic disease who received an ICI as second or later line of treatment were identified. Nineteen (82.6%) of these patients had received a VEGFR inhibitor as first-line treatment, with a median PFS of 3 months (range, 1-22 months). The median PFS for patients during first ICI treatment was 2.5 months (range, 1-40 months); 4 patients experienced partial response (16,7%) and 3 (12,5%) had stable disease. Of the patients whose genomic alterations were analyzed, two patients with mutations in bromodomain-containing genes (PBRM1 and BRD8) had a clinical benefit. Resistant clones in a patient with exceptional response to ipilimumab showed loss of BRD8 mutations and increased mutational load driven by parallel evolution affecting 17 genes (median mutations per gene, 3), which were enriched mainly for O-glycan processing (29.4%, FDR = 9.7 × 10- 6). CONCLUSIONS: MITF family tRCC is an aggressive disease with similar responses to ICIs as clear-cell RCC. Mutations in bromodomain-containing genes might be associated with clinical benefit. The unexpected observation about parallel evolution of genes involved in O-glycosylation as a mechanism of resistance to ICI warrants exploration.

Genetic approach to select against embryo mortality caused by Enterococcus faecalis infection in laying hens.

Selection to reduce susceptibility to Enterococcus faecalis infection in laying hens may contribute to the prevention of amyloid arthropathy since it is mainly induced by this bacterium. Therefore, the aim of the present study was to investigate the possibility to select more laying hens that are resistant against E. faecalis infection through the embryo lethality assay (ELA), which is proposed as an alternative model to replace the adult avian challenge assay. Ten-day-old embryos of 500 Lohmann Brown layers were inoculated into the allantoic cavity with an infectious dose of 2.5 colony-forming units (cfu)/mL of the avian E. faecalis strain K923/96 in 3 ELAs. The embryonic mortality rate (EMR) was determined by candling the eggs daily over a period of 4 d. The average EMR estimated during the 3 ELAs was 50% and the highest EMR occurred 3 to 4 d post inoculation. The estimated heritability for embryonic survivability to the infection was h2 = 0.12-0.14, calculated with the logistic and probit link function, respectively, indicating that the selection of more laying hens that are resistant to E. faecalis infection is feasible. A highly negative genetic correlation was estimated between embryonic survivability and laying performance at the peak of lay (rg = -0.22) and at the end of the production (rg = -0.65), as well as with breaking strength (rg = -0.30 to -0.37). A positive correlation was found between egg weight and the embryonic survivability (rg = +0.16), and no genetic correlation was found with body weight and dynamic stiffness. Therefore, although it was demonstrated that it is possible to breed for E. faecalis resistance, special care should be taken to monitor and to take all traits and their genetic correlations into account in order to achieve a balanced genetic progress. Besides, the ELA does not require that the hens are exposed to pathogens thereby saving labor and cost. Therefore, it could be feasible that ELA be implemented in selection programs.

Targeting mitochondrial translation by inhibiting DDX3: a novel radiosensitization strategy for cancer treatment.

DDX3 is a DEAD box RNA helicase with oncogenic properties. RK-33 is developed as a small-molecule inhibitor of DDX3 and showed potent radiosensitizing activity in preclinical tumor models. This study aimed to assess DDX3 as a target in breast cancer and to elucidate how RK-33 exerts its anti-neoplastic effects. High DDX3 expression was present in 35% of breast cancer patient samples and correlated with markers of aggressiveness and shorter survival. With a quantitative proteomics approach, we identified proteins involved in the mitochondrial translation and respiratory electron transport pathways to be significantly downregulated after RK-33 or DDX3 knockdown. DDX3 localized to the mitochondria and DDX3 inhibition with RK-33 reduced mitochondrial translation. As a consequence, oxygen consumption rates and intracellular ATP concentrations decreased and reactive oxygen species (ROS) increased. RK-33 antagonized the increase in oxygen consumption and ATP production observed after exposure to ionizing radiation and reduced DNA repair. Overall, we conclude that DDX3 inhibition with RK-33 causes radiosensitization in breast cancer through inhibition of mitochondrial translation, which results in reduced oxidative phosphorylation capacity and increased ROS levels, culminating in a bioenergetic catastrophe.

A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma.

BACKGROUND: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC. PATIENTS AND METHODS: Patients with mRCC and 2-3 prior lines of therapy were randomized 1 : 1 to CRLX101 + bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. RESULTS: In total, 111 patients were randomized and received ≥1 dose of drug (CRLX101 + bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101 + bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P = 0.831). The objective response rate by IRR was 5% with CRLX101 + bevacizumab versus 14% with SOC (Mantel-Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101 + bevacizumab combination was generally well tolerated, and no new safety signal was identified. CONCLUSIONS: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 + bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned. CLINICAL TRIAL IDENTIFICATION: NCT02187302 (NIH).

Isolation of entomopathogenic nematodes in an apple orchard in Southern Brazil and its virulence to Anastrepha fraterculus (Diptera: Tephritidae) larvae, under laboratory conditions / Isolamento de nematoides entomopatogênicos em pomar de macieira no sul do Brasil e virulência em larvas de Anastrepha fraterculus (Diptera: Tephritidae) em condições de laboratório

Abstract Entomopathogenic nematodes (EPNs) are a promising alternative to integrated control in many fruit pests. Few studies were made on the relationship of Anastrepha fraterculus natural population with native EPNs population and other biotic and abiotic factors. The aim of this work was to verify the occurrence of endemic nematodes in an apple orchard, concerning environmental conditions and technical procedure, and access isolates virulence to A. fraterculus larvae. The experiment was conducted during a year taking monthly soil samples from an apple orchard, with and without fallen fruits just above the soil. Samples were baited with Tenebrium molitor and A. fraterculus larvae in laboratory. Canopy and fallen fruits were sampled to access the pest infestation. Seventy three EPN isolates were captured, in 23.2% soil samples, more with T. molitor than with A. fraterculus baits. From the 20 isolates tested against A. fraterculus, only five were pathogenic, and they were identified as Oscheius sp. The nematodes were captured during all seasons in a similar frequency. Soil and weather conditions, presence of fruit over the orchard soil, and A. fraterculus pupae in the fruits had no significant influence on the capture. As a conclusion, nematodes of the genera Oscheius are found in an apple orchard of Porto Amazonas constantly along the year, independently of fluctuations in A. fraterculus population, climate conditions and presence of fruit over the soil. Some of the isolates are pathogenic to A. fraterculus.

Resumo Nematoides entomopatogênicos (NEPs) são alternativa promissora para o controle integrado de várias pragas de frutíferas. Foram feitos poucos estudos ecológicos sobre a relação de populações naturais de Anastrepha fraterculus com a de NEPs nativos e outros fatores bióticos e abióticos. O objetivo desse trabalho foi verificar a ocorrência de nematoides endêmicos de um pomar de macieira, considerando condições ambientais e procedimentos técnicos, e testar a virulência de isolados para larvas de A. fraterculus. O experimento foi conduzido durante um ano coletando mensalmente amostras de solo de um pomar de macieira com e sem frutos acima do solo. Foram feitas armadilhas com larvas de Tenebrium molitor e de A. fraterculus em laboratório. Frutos na copa e caídos no solo foram amostrados para quantificar a infestação da praga. Setenta e três isolados de NEPs foram capturados em 23,2% das amostras de solo, mais em armadilhas de T. molitor do que em A. fraterculus. Dos 20 isolados testados contra A. fraterculus, apenas cinco foram patogênicos, e eles foram identificados como Oscheius sp. Os nematoides foram capturados durante todas as estações e em frequência similar. Condições edáficas e climáticas, presença do fruto acima do solo amostrado e de pupas de A. fraterculus nos frutos não tiveram influência significativa na captura. Como conclusão, nematoides do gênero Oscheius ocorrem em pomar de macieira de Porto Amazonas de forma constante ao longo do ano, independentemente de flutuações na população de A. fraterculus, condições climáticas e presença de fruto sobre a superfície do solo. Alguns isolados são patogênicos para A. fraterculus.

Relationship between individual differences in functional connectivity and facial-emotion recognition abilities in adults with traumatic brain injury.

Although several studies have demonstrated that facial-affect recognition impairment is common following moderate-severe traumatic brain injury (TBI), and that there are diffuse alterations in large-scale functional brain networks in TBI populations, little is known about the relationship between the two. Here, in a sample of 26 participants with TBI and 20 healthy comparison participants (HC) we measured facial-affect recognition abilities and resting-state functional connectivity (rs-FC) using fMRI. We then used network-based statistics to examine (A) the presence of rs-FC differences between individuals with TBI and HC within the facial-affect processing network, and (B) the association between inter-individual differences in emotion recognition skills and rs-FC within the facial-affect processing network. We found that participants with TBI showed significantly lower rs-FC in a component comprising homotopic and within-hemisphere, anterior-posterior connections within the facial-affect processing network. In addition, within the TBI group, participants with higher emotion-labeling skills showed stronger rs-FC within a network comprised of intra- and inter-hemispheric bilateral connections. Findings indicate that the ability to successfully recognize facial-affect after TBI is related to rs-FC within components of facial-affective networks, and provide new evidence that further our understanding of the mechanisms underlying emotion recognition impairment in TBI.

Isolation of entomopathogenic nematodes in an apple orchard in Southern Brazil and its virulence to Anastrepha fraterculus (Diptera: Tephritidae) larvae, under laboratory conditions.

Entomopathogenic nematodes (EPNs) are a promising alternative to integrated control in many fruit pests. Few studies were made on the relationship of Anastrepha fraterculus natural population with native EPNs population and other biotic and abiotic factors. The aim of this work was to verify the occurrence of endemic nematodes in an apple orchard, concerning environmental conditions and technical procedure, and access isolates virulence to A. fraterculus larvae. The experiment was conducted during a year taking monthly soil samples from an apple orchard, with and without fallen fruits just above the soil. Samples were baited with Tenebrium molitor and A. fraterculus larvae in laboratory. Canopy and fallen fruits were sampled to access the pest infestation. Seventy three EPN isolates were captured, in 23.2% soil samples, more with T. molitor than with A. fraterculus baits. From the 20 isolates tested against A. fraterculus, only five were pathogenic, and they were identified as Oscheius sp. The nematodes were captured during all seasons in a similar frequency. Soil and weather conditions, presence of fruit over the orchard soil, and A. fraterculus pupae in the fruits had no significant influence on the capture. As a conclusion, nematodes of the genera Oscheius are found in an apple orchard of Porto Amazonas constantly along the year, independently of fluctuations in A. fraterculus population, climate conditions and presence of fruit over the soil. Some of the isolates are pathogenic to A. fraterculus.