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PurposeMen with metastatic castration-resistant prostate cancer (mCRPC) have limited treatment options after progressing on hormonal therapy and chemotherapy. Here, we evaluate the safety and efficacy of atezolizumab (anti-PD-L1) + radium-223 dichloride (radium-223) in men with mCRPC.Patients and methodsThis phase Ib study evaluated atezolizumab + radium-223 in men with mCRPC and bone and lymph node and/or visceral metastases that progressed after androgen pathway inhibitor treatment. Following safety assessment of concurrent dosing, 45 men were randomized 1:1:1 to concurrent or one of two staggered dosing schedules with either agent introduced one cycle before the other. This was followed by a safety-efficacy expansion cohort (randomized 1:1:1). The primary endpoints were safety and objective response rate (ORR) by RECIST 1.1. Secondary endpoints included radiographic progression-free survival (rPFS), PSA responses, and overall survival (OS).ResultsAs of October 4, 2019, 44 of 45 men were evaluable. All 44 had ≥1 all-cause adverse event (AE); 23 (52.3%) had a grade 3/4 AE. Fifteen (34.1%) grade 3/4 and 3 (6.8%) grade 5 AEs were related to atezolizumab; none were related to radium-223. Confirmed ORR was 6.8% [95% confidence interval (CI), 1.4-18.7], median rPFS was 3.0 months (95% CI, 2.8-4.6), median PSA progression was 3.0 months (95% CI, 2.8-3.3), and median OS was 16.3 months (95% CI, 10.9-22.3).ConclusionsThis phase Ib study demonstrated that atezolizumab + radium-223, regardless of administration schedule, had greater toxicity than either drug alone, with no clear evidence of additional clinical benefit for patients with mCRPC and bone and lymph node and/or visceral metastases.

Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease and relapse.sup.1. We evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer. This trial did not reach its efficacy end point in the intention-to-treat population. Here we show that ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm hazard ratio = 6.3 (95% confidence interval: 4.45-8.92); P < 0.0001). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43-0.79); P = 0.0024, overall survival hazard ratio = 0.59 (95% confidence interval: 0.41-0.86)). No difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA. The rate of ctDNA clearance at week 6 was higher in the atezolizumab arm (18%) than in the observation arm (4%) (P = 0.0204). Transcriptomic analysis of tumours from patients who were positive for ctDNA revealed higher expression levels of cell-cycle and keratin genes. For patients who were positive for ctDNA and who were treated with atezolizumab, non-relapse was associated with immune response signatures and basal-squamous gene features, whereas relapse was associated with angiogenesis and fibroblast TGF[beta] signatures. These data suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse. These findings, if validated in other settings, would shift approaches to postoperative cancer care. The authors report on prospective exploratory analyses of circulating tumour DNA in an urothelial carcinoma immunotherapy clinical trial., Author(s): Thomas Powles [sup.1] , Zoe June Assaf [sup.2] , Nicole Davarpanah [sup.2] , Romain Banchereau [sup.2] , Bernadett E. Szabados [sup.3] , Kobe C. Yuen [sup.2] , Petros Grivas [...]

Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade.sup.1, this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and IL8 gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8.sup.+ T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and that high IL8 expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors. In a retrospective analysis of data from three clinical trials, increased baseline peripheral and tumor IL-8 levels were associated with worse clinical outcomes in patients with metastatic urothelial carcinoma and metastatic renal cell carcinoma treated with anti-PD-L1 therapy., Author(s): Kobe C. Yuen [sup.1] , Li-Fen Liu [sup.1] , Vinita Gupta [sup.1] , Shravan Madireddi [sup.1] , Shilpa Keerthivasan [sup.1] , Congfen Li [sup.1] , Deepali Rishipathak [sup.1] , [...]

Neural crest cells (NCC) comprise a multipotent, migratory stem cell and progenitor population that gives rise to numerous cell and tissue types within a developing embryo, including craniofacial bone and cartilage, neurons and glia of the peripheral nervous system, and melanocytes within the skin. Here we describe two novel stable transgenic mouse lines suitable for lineage tracing and analysis of gene function in NCC. Firstly, using the F10N enhancer of the Mef2c gene (Mef2c-F10N) linked to LacZ, we generated transgenic mice (Mef2c-F10N-LacZ) that express LacZ in the majority, if not all migrating NCC that delaminate from the neural tube. Mef2c-F10N-LacZ then continues to be expressed primarily in neurogenic, gliogenic and melanocytic NCC and their derivatives, but not in ectomesenchymal derivatives. Secondly, we used the same Mef2c-F10N enhancer together with Cre recombinase to generate transgenic mice (Mef2c-F10N-Cre) that can be used to indelibly label, or alter gene function in, migrating NCC and their derivatives. At early stages of development, Mef2c-F10N-LacZ and Mef2c-F10N-Cre label NCC in a pattern similar to Wnt1-Cre mice, with the exception that Mef2c-F10N-LacZ and Mef2c-F10N-Cre specifically label NCC that have delaminated from the neural plate, while premigratory NCC are not labeled. Thus, our Mef2c-F10N-LacZ and Mef2c-F10N-Cre transgenic mice provide new resources for tracing migratory NCC and analyzing gene function in migrating and differentiating NCC independently of NCC formation.

Purpose: To examine the utility of a standardized small-sided game (SSG) for monitoring within-player changes in mean exercise heart rate (HRex) when compared with a submaximal interval shuttle-run test (ISRT). Methods:Thirty-six elite youth football players (17 [1] y) took part in 6 test sessions across an in-season period (every 4 wk). Sessions consisted of the ISRT (20-m shuttles, 30″:15″ work:rest ratio, 70% maximal ISRT) followed by an SSG (7v7, 80 × 56 m, 6 min). HRex was collected during both protocols, with SSG external load measured as high-speed running distance (>19.8 km·h–1) and acceleration distance (>2 m·s−2). Data were analyzed using linear mixed-effect models. Results:Controlling for SSG external load improved the model fit describing the SSG–ISRT HRex relationship (χ2 = 12.6, P =.002). When SSG high-speed running distance and SSG acceleration distance were held constant, a 1% point change in SSG HRex was associated with a 0.5% point change in ISRT HRex (90% CI: 0.4 to 0.6). Inversely, when SSG HRex was held constant, the effects of a 100-m change in SSG high-speed running distance and a 21-m change in SSG acceleration distance on ISRT HRex were −1.0% (−1.5 to −0.4) and −0.6% points (−1.1 to 0.0), respectively. Conclusions:An SSG can be used to track within-player changes in HRex for monitoring physiological state. Given the uncertainty in estimates, we advise to only give meaning to changes in SSG HRex >2% points. Additionally, we highlight the importance of considering external load when monitoring SSG HRex. [ABSTRACT FROM AUTHOR]

Purpose: To examine the utility of differential ratings of perceived exertion (dRPE) for monitoring internal intensity and load in association football. Methods: Data were collected from 2 elite senior male football teams during 1 season (N = 55). External intensity and load data (duration × intensity) were collected during each training and match session using electronic performance and tracking systems. After each session, players rated their perceived breathlessness and leg-muscle exertion. Descriptive statistics were calculated to quantify how often players rated the 2 types of rating of perceived exertion differently (dRPEDIFF). In addition, the association between dRPEDIFF and external intensity and load was examined. First, the associations between single external variables and dRPEDIFF were analyzed using a mixed-effects logistic regression model. Second, the link between dRPEDIFF and session types with distinctive external profiles was examined using the Pearson chi-square test of independence. Results: On average, players rated their session perceived breathlessness and leg-muscle exertion differently in 22% of the sessions (range: 0%–64%). Confidence limits for the effect of single external variables on dRPEDIFF spanned across largely positive and negative values for all variables, indicating no conclusive findings. The analysis based on session type indicated that players differentiated more often in matches and intense training sessions, but there was no pattern in the direction of differentiation. Conclusions: The findings of this study provide no evidence supporting the utility of dRPE for monitoring internal intensity and load in football. [ABSTRACT FROM AUTHOR]

The description of current load monitoring practices may serve to highlight developmental needs for both the training ground, academia and related industries. While previous studies described these practices in elite men's football, no study has provided an overview of load monitoring practices in elite women's football. Given the clear organizational differences (i.e., professionalization and infrastructure) between men's and women's clubs, making inferences based on men's data is not appropriate. Therefore, this study aims to provide a first overview of the current load monitoring practices in elite women's football. Twenty-two elite European women's football clubs participated in a closed online survey (40% response rate). The survey consisted of 33 questions using multiple choice or Likert scales. The questions covered three topics; type of data collected and collection purpose, analysis methods, and staff member involvement. All 22 clubs collected data related to different load monitoring purposes, with 18 (82%), 21 (95%), and 22 (100%) clubs collecting external load, internal load, and training outcome data, respectively. Most respondents indicated that their club use training models and take into account multiple indicators to analyse and interpret the data. While sports-science staff members were most involved in the monitoring process, coaching, and sports-medicine staff members also contributed to the discussion of the data. Overall, the results of this study show that most elite women's clubs apply load monitoring practices extensively. Despite the organizational challenges compared to men's football, these observations indicate that women's clubs have a vested interest in load monitoring. We hope these findings encourage future developments within women's football.

Load monitoring is considered important to manage the physical training process in team sports such as Association Football. Previous studies have described the load monitoring practices of elite English football clubs and clubs with an established sports-science department. An examination of a broader international sample is currently not available. In addition, previous research has suggested factors that may improve the implementation of load monitoring practices, such as a strong club belief on the benefit of evidence-based practice (EBP) and high club financial resources. However, no study has examined yet the actual impact of these factors on the monitoring practices. Therefore, this study aims (1) to provide an overview of load monitoring practices in European elite football and (2) to provide insight into the differences in implementation between clubs by examining the impact of the club beliefs on the benefit of EBP and the club financial resources. An online survey, consisting of multiple choice and Likert scale questions, was distributed among sports-science and sports-medicine staff (n = 99, 50% response rate). Information was asked about the types of data collected, collection purposes, analysis methods, and staff involvement. The results indicated that external load data (e.g., global navigation satellite system, accelerometer…) was collected the most whilst respondents also indicated to collect internal load (e.g., heart rate, rating of perceived exertion…) and training outcome data (e.g., aerobic fitness, neuromuscular fatigue…) for multiple purposes. Considerable diversity in data analysis was observed suggesting that analysis is often limited to reporting the gathered data. Sports-science staff were responsible for data collection and analysis. Other staff were involved in data discussion to share decision-making. These practices were positively impacted by a stronger club belief on the benefit of EBP and greater financial resources. Creating an organizational culture, characterized by a strong belief on the benefit of EBP, is important to increase the impact of load monitoring. However, the actual potential may still be largely determined by financial resources. High-level clubs could therefore play a leading role in generating and sharing knowledge to improve training practices and player health.

Elite sport practitioners increasingly use data to support training process decisions related to athletes' health and performance. A careful application of data analytics is essential to gain valuable insights and recommendations that can guide decision making. In business organizations, data analytics are developed based on conceptual data analytics frameworks. The translation of such a framework to elite sport may benefit the use of data to support training process decisions. Purpose: The authors aim to present and discuss a conceptual data analytics framework, based on a taxonomy used in business analytics literature to help develop data analytics within elite sport organizations. Conclusions: The presented framework consists of 4 analytical steps structured by value and difficulty/complexity. While descriptive (step 1) and diagnostic analytics (step 2) focus on understanding the past training process, predictive (step 3) and prescriptive analytics (step 4) provide more guidance in planning the future. Although descriptive, diagnostic, and predictive analytics generate insights to inform decisions, prescriptive analytics can be used to drive decisions. However, the application of this type of advanced analytics is still challenging in elite sport. Thus, the current use of data in elite sport is more focused on informing decisions rather than driving them. The presented conceptual framework may help practitioners develop their analytical reasoning by providing new insights and guidance and may stimulate future collaborations between practitioners, researchers, and analytics experts. [ABSTRACT FROM AUTHOR]

NIPBL, a cohesin loader, has been implicated in transcriptional control and genome organization. Mutations in NIPBL, cohesin, and its deacetylase HDAC8 result in Cornelia de Lange syndrome. We report activation of the RNA-sensing kinase PKR in human lymphoblastoid cell lines carrying NIPBL or HDAC8 mutations, but not SMC1A or SMC3 mutations. PKR activation can be triggered by unmodified RNAs. Gene expression profiles in NIPBL-deficient lymphoblastoid cells and mouse embryonic stem cells reveal lower expression of genes involved in RNA processing and modification. NIPBL mutant lymphoblastoid cells show reduced proliferation and protein synthesis with increased apoptosis, all of which are partially reversed by a PKR inhibitor. Non-coding RNAs from an NIPBL mutant line had less m6A modification and activated PKR activity in vitro. This study provides insight into the molecular pathology of Cornelia de Lange syndrome by establishing a relationship between NIPBL and HDAC8 mutations and PKR activation.

Structural maintenance of chromosome (SMC) protein complexes, including cohesin and condensin, are increasingly being recognized for their important role in cancer and development, making it critical that we understand how these evolutionarily conserved multi-subunit protein complexes associate with and organize the genome. We review adaptor proteins for SMC complexes and how these adaptors may capture SMC complexes following loop extrusion to provide a framework for chromosome organization.