Trustworthiness matters: Building equitable and ethical science.

Trustworthy science requires research practices that center issues of ethics, equity, and inclusion. We announce the Leadership in the Equitable and Ethical Design (LEED) of Science, Technology, Mathematics, and Medicine (STEM) initiative to create best practices for integrating ethical expertise and fostering equitable collaboration.

Challenges and potential solutions to health disparities in genomic medicine.

Significant disparities in the clinical usefulness of genomic information across diverse groups are due to underrepresentation in genetic databases and inequitable access to genetic services. Remedying disparities is immediately needed to ensure that genomic medicine is more equitable but will take a long-term commitment and active engagement of diverse communities.

Mitochondrial calcium regulation of cardiac metabolism in health and disease.

Oxidative phosphorylation is regulated by mitochondrial calcium (Ca2+) in health and disease. In physiological states, Ca2+ enters via the mitochondrial Ca2+ uniporter and rapidly enhances NADH and ATP production. However, maintaining Ca2+ homeostasis is critical: insufficient Ca2+ impairs stress adaptation, while Ca2+ overload can trigger cell death. In this review, we delve into recent insights further defining the relationship between mitochondrial Ca2+ dynamics and oxidative phosphorylation. Our focus is on how such regulation affects cardiac function in health and disease, including heart failure, ischemia-reperfusion, arrhythmias, catecholaminergic polymorphic ventricular tachycardia, mitochondrial cardiomyopathies, Barth syndrome, and Friedreich's ataxia. Several themes emerge from recent data. First, mitochondrial Ca2+ regulation is critical for fuel substrate selection, metabolite import, and matching of ATP supply to demand. Second, mitochondrial Ca2+ regulates both the production and response to reactive oxygen species (ROS), and the balance between its pro- and antioxidant effects is key to how it contributes to physiological and pathological states. Third, Ca2+ exerts localized effects on the electron transport chain (ETC), not through traditional allosteric mechanisms, but rather indirectly. These effects hinge on specific transporters, such as the uniporter or the Na+-Ca2+ exchanger and may not be noticeable acutely, contributing differently to phenotypes depending on whether Ca2+ transporters are acutely or chronically modified. Perturbations in these novel relationships during disease states may either serve as compensatory mechanisms or exacerbate impairments in oxidative phosphorylation. Consequently, targeting mitochondrial Ca2+ holds promise as a therapeutic strategy for a variety of cardiac diseases characterized by contractile failure or arrhythmias.

Family secrets: Experiences and outcomes of participating in direct-to-consumer genetic relative-finder services.

In recent decades, genetic genealogy has become popular as a result of direct-to-consumer (DTC) genetic testing. Some DTC genetic testing companies offer genetic relative-finder (GRF) services that compare the DNA of consenting participants to identify genetic relatives among them and provide each participant a list of their relative matches. We surveyed a convenience sample of GRF service participants to understand the prevalence of discoveries and associated experiences. Almost half (46%) of the 23,196 respondents had participated in GRF services only for non-specific reasons that included interest in building family trees and general curiosity. However, most (82%) also learned the identity of at least one genetic relative. Separately, most respondents (61%) reported learning something new about themselves or their relatives, including potentially disruptive information such as that a person they believed to be their biological parent is in fact not or that they have a sibling they had not known about. Respondents generally reported that discovering this new information had a neutral or positive impact on their lives, and most had low regret regarding their decision to participate in GRF services. Yet some reported making life changes as a result of their discoveries. Compared to respondents making other types of discoveries, those who learned that they were donor conceived reported the highest decisional regret and represented the largest proportion reporting net-negative consequences for themselves. Our findings indicate that discoveries from GRF services may be common and that the consequences for individuals, while generally positive, can be far-reaching and complex.

Infiltrative pattern of invasion is independently associated with shorter survival and desmoplastic stroma markers FAP and THBS2 in mucinous ovarian carcinoma.

AIMS: Mucinous ovarian carcinoma (MOC) is a rare ovarian cancer histotype with generally good prognosis when diagnosed at an early stage. However, MOC with the infiltrative pattern of invasion has a worse prognosis, although to date studies have not been large enough to control for covariables. Data on reproducibility of classifying the invasion pattern are limited, as are molecular correlates for infiltrative invasion. We hypothesized that the invasion pattern would be associated with an aberrant tumour microenvironment. METHODS AND RESULTS: Four subspecialty pathologists assessed interobserver reproducibility of the pattern of invasion in 134 MOC. Immunohistochemistry on fibroblast activation protein (FAP) and THBS2 was performed on 98 cases. Association with survival was tested using Cox regression. The average interobserver agreement for the infiltrative pattern was moderate (kappa 0.60, agreement 86.3%). After reproducibility review, 24/134 MOC (18%) were determined to have the infiltrative pattern and this was associated with a higher risk of death, independent of FIGO stage, grade, and patient age in a time-dependent manner (hazard ratio [HR] = 10.2, 95% confidence interval [CI] 3.0-34.5). High stromal expression of FAP and THBS2 was more common in infiltrative MOC (FAP: 60%, THBS2: 58%, both P < 0.001) and associated with survival (multivariate HR for FAP: 1.5 [95% CI 1.1-2.1] and THBS2: 1.91 [95% CI 1.1-3.2]). CONCLUSIONS: The pattern of invasion should be included in reporting for MOC due to the strong prognostic implications. We highlight the histological features that should be considered to improve reproducibility. FAP and THBS2 are associated with infiltrative invasion in MOC.

Intraoperative Hypotension in Patients Having Major Noncardiac Surgery Under General Anesthesia: A Systematic Review of Blood Pressure Optimization Strategies.

INTRODUCTION: Intraoperative hypotension is associated with increased risks of postoperative complications. Consequently, a variety of blood pressure optimization strategies have been tested to prevent or promptly treat intraoperative hypotension. We performed a systematic review to summarize randomized controlled trials that evaluated the efficacy of blood pressure optimization interventions in either mitigating exposure to intraoperative hypotension or reducing risks of postoperative complications. METHODS: Medline, Embase, PubMed, and Cochrane Controlled Register of Trials were searched from database inception to August 2, 2023, for randomized controlled trials (without language restriction) that evaluated the impact of any blood pressure optimization intervention on intraoperative hypotension and/or postoperative outcomes. RESULTS: The review included 48 studies (N = 46,377), which evaluated 10 classes of blood pressure optimization interventions. Commonly assessed interventions included hemodynamic protocols using arterial waveform analysis, preoperative withholding of antihypertensive medications, continuous blood pressure monitoring, and adjuvant agents (vasopressors, anticholinergics, anticonvulsants). These same interventions reduced intraoperative exposure to hypotension. Conversely, low blood pressure alarms had an inconsistent impact on exposure to hypotension. Aside from limited evidence that higher prespecified intraoperative blood pressure targets led to a reduced risk of complications, there were few data suggesting that these interventions prevented postoperative complications. Heterogeneity in interventions and outcomes precluded meta-analysis. CONCLUSIONS: Several different blood pressure optimization interventions show promise in reducing exposure to intraoperative hypotension. Nonetheless, the impact of these interventions on clinical outcomes remains unclear. Future trials should assess promising interventions in samples sufficiently large to identify clinically plausible treatment effects on important outcomes.

Understanding individualised genetic interventions as research-treatment hybrids.

Until recently, medicine has had little to offer most of the millions of patients suffering from rare and ultrarare genetic conditions. But the development in 2019 of Milasen, the first genetic intervention developed for and administered to a single patient suffering from an ultrarare genetic disorder, has offered hope to patients and families. In addition, Milasen raised a series of conceptual and ethical questions about how individualised genetic interventions should be developed, assessed for safety and efficacy and financially supported. The answers to these questions depend in large part on whether individualised therapies are understood as human subjects research or clinical innovation, different domains of biomedicine that are regulated by different modes of oversight, funding and professional norms. In this article, with development and administration of the drug Milasen as our case study, we argue that at least some individualised genetic therapies are not, as some have argued, either research or treatment. Instead, they are research-treatment hybrids, a category that has both epistemological and pragmatic repercussions for funding, ethics oversight and regulation.

Analysis of Breast Cancer Mortality in the US-1975 to 2019.

Importance: Breast cancer mortality in the US declined between 1975 and 2019. The association of changes in metastatic breast cancer treatment with improved breast cancer mortality is unclear. Objective: To simulate the relative associations of breast cancer screening, treatment of stage I to III breast cancer, and treatment of metastatic breast cancer with improved breast cancer mortality. Design, Setting, and Participants: Using aggregated observational and clinical trial data on the dissemination and effects of screening and treatment, 4 Cancer Intervention and Surveillance Modeling Network (CISNET) models simulated US breast cancer mortality rates. Death due to breast cancer, overall and by estrogen receptor and ERBB2 (formerly HER2) status, among women aged 30 to 79 years in the US from 1975 to 2019 was simulated. Exposures: Screening mammography, treatment of stage I to III breast cancer, and treatment of metastatic breast cancer. Main Outcomes and Measures: Model-estimated age-adjusted breast cancer mortality rate associated with screening, stage I to III treatment, and metastatic treatment relative to the absence of these exposures was assessed, as was model-estimated median survival after breast cancer metastatic recurrence. Results: The breast cancer mortality rate in the US (age adjusted) was 48/100 000 women in 1975 and 27/100 000 women in 2019. In 2019, the combination of screening, stage I to III treatment, and metastatic treatment was associated with a 58% reduction (model range, 55%-61%) in breast cancer mortality. Of this reduction, 29% (model range, 19%-33%) was associated with treatment of metastatic breast cancer, 47% (model range, 35%-60%) with treatment of stage I to III breast cancer, and 25% (model range, 21%-33%) with mammography screening. Based on simulations, the greatest change in survival after metastatic recurrence occurred between 2000 and 2019, from 1.9 years (model range, 1.0-2.7 years) to 3.2 years (model range, 2.0-4.9 years). Median survival for estrogen receptor (ER)-positive/ERBB2-positive breast cancer improved by 2.5 years (model range, 2.0-3.4 years), whereas median survival for ER-/ERBB2- breast cancer improved by 0.5 years (model range, 0.3-0.8 years). Conclusions and Relevance: According to 4 simulation models, breast cancer screening and treatment in 2019 were associated with a 58% reduction in US breast cancer mortality compared with interventions in 1975. Simulations suggested that treatment for stage I to III breast cancer was associated with approximately 47% of the mortality reduction, whereas treatment for metastatic breast cancer was associated with 29% of the reduction and screening with 25% of the reduction.

Collaborative Modeling to Compare Different Breast Cancer Screening Strategies: A Decision Analysis for the US Preventive Services Task Force.

Importance: The effects of breast cancer incidence changes and advances in screening and treatment on outcomes of different screening strategies are not well known. Objective: To estimate outcomes of various mammography screening strategies. Design, Setting, and Population: Comparison of outcomes using 6 Cancer Intervention and Surveillance Modeling Network (CISNET) models and national data on breast cancer incidence, mammography performance, treatment effects, and other-cause mortality in US women without previous cancer diagnoses. Exposures: Thirty-six screening strategies with varying start ages (40, 45, 50 years) and stop ages (74, 79 years) with digital mammography or digital breast tomosynthesis (DBT) annually, biennially, or a combination of intervals. Strategies were evaluated for all women and for Black women, assuming 100% screening adherence and "real-world" treatment. Main Outcomes and Measures: Estimated lifetime benefits (breast cancer deaths averted, percent reduction in breast cancer mortality, life-years gained), harms (false-positive recalls, benign biopsies, overdiagnosis), and number of mammograms per 1000 women. Results: Biennial screening with DBT starting at age 40, 45, or 50 years until age 74 years averted a median of 8.2, 7.5, or 6.7 breast cancer deaths per 1000 women screened, respectively, vs no screening. Biennial DBT screening at age 40 to 74 years (vs no screening) was associated with a 30.0% breast cancer mortality reduction, 1376 false-positive recalls, and 14 overdiagnosed cases per 1000 women screened. Digital mammography screening benefits were similar to those for DBT but had more false-positive recalls. Annual screening increased benefits but resulted in more false-positive recalls and overdiagnosed cases. Benefit-to-harm ratios of continuing screening until age 79 years were similar or superior to stopping at age 74. In all strategies, women with higher-than-average breast cancer risk, higher breast density, and lower comorbidity level experienced greater screening benefits than other groups. Annual screening of Black women from age 40 to 49 years with biennial screening thereafter reduced breast cancer mortality disparities while maintaining similar benefit-to-harm trade-offs as for all women. Conclusions: This modeling analysis suggests that biennial mammography screening starting at age 40 years reduces breast cancer mortality and increases life-years gained per mammogram. More intensive screening for women with greater risk of breast cancer diagnosis or death can maintain similar benefit-to-harm trade-offs and reduce mortality disparities.

Beyond the TCA cycle: new insights into mitochondrial calcium regulation of oxidative phosphorylation.

While mitochondria oxidative phosphorylation is broadly regulated, the impact of mitochondrial Ca2+ on substrate flux under both physiological and pathological conditions is increasingly being recognized. Under physiologic conditions, mitochondrial Ca2+ enters through the mitochondrial Ca2+ uniporter and boosts ATP production. However, maintaining Ca2+ homeostasis is crucial as too little Ca2+ inhibits adaptation to stress and Ca2+ overload can trigger cell death. In this review, we discuss new insights obtained over the past several years expanding the relationship between mitochondrial Ca2+ and oxidative phosphorylation, with most data obtained from heart, liver, or skeletal muscle. Two new themes are emerging. First, beyond boosting ATP synthesis, Ca2+ appears to be a critical determinant of fuel substrate choice between glucose and fatty acids. Second, Ca2+ exerts local effects on the electron transport chain indirectly, not via traditional allosteric mechanisms. These depend critically on the transporters involved, such as the uniporter or the Na+-Ca2+ exchanger. Alteration of these new relationships during disease can be either compensatory or harmful and suggest that targeting mitochondrial Ca2+ may be of therapeutic benefit during diseases featuring impairments in oxidative phosphorylation.

Individualized interventions for rare genetic conditions and the research-treatment spectrum: Stakeholder perspectives.

PURPOSE: Advances in the study of ultrarare genetic conditions are leading to the development of targeted interventions developed for single or very small numbers of patients. Owing to the experimental but also highly individualized nature of these interventions, they are difficult to classify cleanly as either research or clinical care. Our goal was to understand how parents, institutional review board members, and clinical geneticists familiar with individualized genetic interventions conceptualize these activities and their implications for the relationship between research and clinical care. METHODS: We conducted qualitative, semi-structured interviews with 28 parents, institutional review board members, and clinical geneticists and derived themes from those interviews through content analysis. RESULTS: Individuals described individualized interventions as blurring the lines between research and clinical care and focused on hopes for therapeutic benefit and expectations for generalizability of knowledge and benefit to future patients. CONCLUSION: Individualized interventions aimed at one or few patients reveal the limitations of a binary framing of research and clinical care. As a hybrid set of activities, individualized interventions suggest the need for flexibility and new frameworks that acknowledge these activities across the spectrum of research and clinical care.

Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8+ TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas.

ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis-associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumour-infiltrating lymphocytes (CD8+ TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p = 0.012) and was associated with MMRd (p < 0.001) and the presence of CD8+ TILs (p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss-of-function mutation as a result of small indels (p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8+ TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8+ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance. © 2021 The Pathological Society of Great Britain and Ireland.

Changes in physical activity and sedentary time among children with asthma during the COVID-19 pandemic and influencing factors.

OBJECTIVE: Regular physical activity is essential for asthma control in children, but it remains understudied within the context of COVID-19. Physical activity and sedentary time levels before and during the COVID-19 pandemic among children with asthma were documented and differences by characteristics were explored. METHODS: This was a cross-sectional self-administered online survey study of 5- to 17-year-old children with asthma from the United States between December 2020 and April 2021. RESULTS: This study included 68 children with asthma. Although only 4.6% of the children were fully inactive before the pandemic, this number increased to 24.6% during the survey period (p < 0.001). Children spent significantly less time outdoors and more time in front of screens during the pandemic versus before (p < 0.001). The variety of activities in which children with asthma engaged in during the pandemic was lower than what they used to do prior to the COVID-19 crisis. Boys, Hispanic children, those of low-income households, and those not attending school in-person were significantly associated with less participation in physical activity during the pandemic. Ethnicity remained significantly associated after adjusting for multiple comparisons. CONCLUSIONS: During the COVID-19 pandemic, children with asthma were less active and spent more time in front of screens and less time outdoors. Subgroup analyses revealed individual, parental, and organizational characteristics being associated with differential participation in physical activity, highlighting disparities in opportunities for children with asthma of different circumstances to remain active and healthy during the pandemic. Additional, more robust longitudinal studies are needed to confirm these results.

Patient-reported tolerability of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk stage III-IV melanoma in phase III trial E1609.

PURPOSE: Trial E1609 demonstrated superior overall survival with ipilimumab 3 mg/kg (ipi3) compared to high-dose interferon (HDI) for patients with resected high-risk melanoma. To inform treatment tolerability, we compared health-related quality of life (HRQoL), gastrointestinal (GI), and treatment-specific physical and cognitive/emotional symptoms. We also compared treatment-specific concerns between all arms. METHODS: We assessed HRQoL using the Functional Assessment of Cancer Therapy-General, physical and cognitive/emotional concerns using the FACT-Biologic Response Modifier subscale, and GI symptoms with the Functional Assessment of Chronic Illness Therapy-Diarrhea subscale pre-treatment and every 3 months. The primary outcome was the difference in HRQoL at 3 months between ipi3/ipi10 vs. HDI. RESULTS: 549 patients (n = 158 ipi3; n = 191 ipi10; n = 200 HDI) were analyzed. 3-month completion was 58.7%. Compared to HDI, ipilimumab patients reported better HRQoL (ipi3 = 87.5 ± 14.6 vs. HDI = 74.7 ± 15.4, p < .001; ipi10 = 84.9 ± 16.5 vs. HDI, p < .001) and fewer physical (ipi3 = 22.3 ± 4.6 vs. HDI = 17.1 ± 5.4, p < .001; ipi10 = 21.8 ± 5.0 vs. HDI p < .001) and cognitive/emotional (ipi3 = 18.6 ± 4.4 vs. HDI = 15.0 ± 5.3, p < .001; ipi10 = 17.7 ± 4.8 vs. HDI p < .001) concerns, but worse GI symptoms (ipi3 = 40.8 ± 5.0 vs. HDI = 42.2 ± 2.9, p = .011; ipi10 = 39.5 ± 7.0 vs. HDI, p < .001). Fewer ipilimumab patients reported worsening treatment-specific concerns (e.g., 52% of ipi3 and 58% of ipi10 reported worsening fatigue vs. 82% HDI, p's < .001). CONCLUSION: PROs demonstrated less toxicity of ipi3 compared to HDI and ipi10. Priorities for symptom management among patients receiving ipilimumab include GI toxicities, fatigue, weakness, appetite loss, arthralgia, and depression. TRIAL REGISTRATION: NCT01274338, January 11, 2011 (first posted date) https://clinicaltrials.gov/ct2/show/NCT01274338?term=NCT01274338&draw=2&rank=1 .

General versus loco-regional anesthesia for endovascular aortic aneurysm repair.

BACKGROUND: Aortic aneurysms occur when the aorta, the body's largest artery, grows in size, and can occur in the thoracic or abdominal aorta. The approaches to repair aortic aneurysms include directly exposing the aorta and replacing the diseased segment via open repair, or endovascular repair. Endovascular repair uses fluoroscopic-guidance to access the aorta and deliver a device to exclude the aneurysmal aortic segment without requiring a large surgical incision. Endovascular repair can be performed under a general anesthetic, during which the unconscious patient is paralyzed and reliant on an anesthetic machine to maintain the airway and provide oxygen to the lungs, or a loco-regional anesethetic, for which medications are administered to provide the person with sufficient sedation and pain control without requiring a general anesthetic. While people undergoing general anesthesia are more likely to remain still during surgery and have a well-controlled airway in the event of unanticipated complications, loco-regional anesthesia is associated with fewer postoperative complications in some studies. It remains unclear which anesthetic technique is associated with better outcomes following the endovascular repair of aortic aneurysms. OBJECTIVES: To evaluate the benefits and harms of general anesthesia compared to loco-regional anesthesia for endovascular aortic aneurysm repair. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search was 11 March 2022. SELECTION CRITERIA: We searched for all randomized controlled trials that assessed the effects of general anesthesia compared to loco-regional anesthesia for endovascular aortic aneurysm repairs. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were: all-cause mortality, length of hospital stay, length of intensive care unit stay. Our secondary outcomes were: incidence of endoleaks, requirement for re-intervention, incidence of myocardial infarction, quality of life, incidence of respiratory complications, incidence of pulmonary embolism, incidence of deep vein thrombosis, and length of procedure. We planned to use GRADE methodology to assess the certainty of evidence for each outcome. MAIN RESULTS: We found no studies, published or ongoing, that met our inclusion criteria. AUTHORS' CONCLUSIONS: We did not identify any randomized controlled trials that compared general versus loco-regional anesthesia for endovascular aortic aneurysm repair. There is currently insufficient high-quality evidence to determine the benefits or harms of either anesthetic approach during endovascular aortic aneurysm repair. Well-designed prospective randomized trials with relevant clinical outcomes are needed to adequately address this.

From the Individual to the Group: Using Idiographic Analyses and Two-Stage Random Effects Meta-Analysis to Obtain Population Level Inferences for within-Person Processes.

In psychology, the use of portable technology and wearable devices to ease participant burden in data collection is on the rise. This creates increased interest in collecting real-time or near real-time data from individuals within their natural environments. As a result, vast amounts of observational time series data are generated. Often, motivation for collecting this data hinges on understanding within-person processes that underlie psychological phenomena. Motivated by the body of Dr. Peter Molenaar's life work calling for analytical approaches that consider potential heterogeneity and non-ergodicity, the focus of this paper is on using idiographic analyses to generate population inferences for within-person processes. Meta-analysis techniques using one-stage and two-stage random effects meta-analysis as implemented in single-case experimental designs are presented. The case for preferring a two-stage approach for meta-analysis of single-subject observational time series data is made and demonstrated using an empirical example. This provides a novel implementation of the methodology as prior implementations focus on applications to short time series with experimental designs. Inspired by Dr. Molenaar's work, we describe how an approach, two-stage random effects meta-analysis (2SRE-MA), aligns with recent calls to consider idiographic approaches when making population-level inferences regarding within-person processes.

EFHD1 ablation inhibits cardiac mitoflash activation and protects cardiomyocytes from ischemia.

Altered levels of intracellular calcium (Ca2+) are a highly prevalent feature in different forms of cardiac injury, producing changes in contractility, arrhythmias, and mitochondrial dysfunction. In cardiac ischemia-reperfusion injury, mitochondrial Ca2+ overload leads to pathological production of reactive oxygen species (ROS), activates the permeability transition, and cardiomyocyte death. Here we investigated the cardiac phenotype caused by deletion of EF-hand domain-containing protein D1 (Efhd1-/-), a Ca2+-binding mitochondrial protein whose function is poorly understood. Efhd1-/- mice are viable and have no adverse cardiac phenotypes. They feature reductions in basal ROS levels and mitoflash events, both important precursors for mitochondrial injury, though cardiac mitochondria have normal susceptibility to Ca2+ overload. Notably, we also find that Efhd1-/- mice and their cardiomyocytes are resistant to hypoxic injury.

Enhanced immune activation within the tumor microenvironment and circulation of female high-risk melanoma patients and improved survival with adjuvant CTLA4 blockade compared to males.

BACKGROUND: We hypothesized that a gender difference in clinical response may exist to adjuvant CTLA4 blockade with ipilimumab versus high-dose IFNα (HDI). We investigated differences in candidate immune biomarkers in the circulation and tumor microenvironment (TME). PATIENTS AND METHODS: This gender-based analysis was nested within the E1609 trial that tested adjuvant therapy with ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus HDI in high risk resected melanoma. We investigated gender differences in treatment efficacy with ipi3 and ipi10 versus HDI while adjusting for age, stage, ECOG performance (PS), ulceration, primary tumor status and lymph node number. Forest plots were created to compare overall survival (OS) and relapse free survival (RFS) between ipi and HDI. Gene expression profiling (GEP) was performed on tumors of 718 (454 male, 264 female) patients. Similarly, serum and peripheral blood mononuclear cells (PBMC) samples were tested for soluble and cellular biomarkers (N = 321 patients; 109 female and 212 male). RESULTS: The subgroups of female, stage IIIC, PS = 1, ulcerated primary, in-transit metastasis demonstrated significant improvement in RFS and/or OS with ipi3 versus HDI. Female gender was significant for both OS and RFS and was further explored. In the RFS comparison, a multivariate Cox regression model including significant variables indicated a significant interaction between gender and treatment (P = 0.024). In peripheral blood, percentages of CD3+ T cells (P = 0.024) and CD3+ CD4+ helper T cells (P = 0.0001) were higher in females compared to males. Trends toward higher circulating levels of IL1ß (P = 0.07) and IL6 (P = 0.06) were also found in females. Males had higher percentages of monocytes (P = 0.03) with trends toward higher percentages of regulatory T cells (T-reg). Tumor GEP analysis supported enhanced infiltration with immune cells including gammadelta T cells (P = 0.005), NK cells (P = 0.01), dendritic cells (P = 0.01), CD4+ T cells (P = 0.03), CD8+ T cells (P = 0.03) and T-reg (P = 0.008) in the tumors of females compared to males and a higher T-effector and IFNγ gene signature score (P = 0.0244). CONCLUSION: Female gender was associated with adjuvant CTLA4 blockade clinical benefits and female patients were more likely to have evidence of type1 immune activation within the TME and the circulation. Trial registration ClinicalTrials.gov NCT01274338. Registered 11 January 2011, https://www. CLINICALTRIALS: gov/ct2/show/NCT01274338.

Reflecting on 20 years of breast cancer modeling in CISNET: Recommendations for future cancer systems modeling efforts.

Since 2000, the National Cancer Institute's Cancer Intervention and Surveillance Modeling Network (CISNET) modeling teams have developed and applied microsimulation and statistical models of breast cancer. Here, we illustrate the use of collaborative breast cancer multilevel systems modeling in CISNET to demonstrate the flexibility of systems modeling to address important clinical and policy-relevant questions. Challenges and opportunities of future systems modeling are also summarized. The 6 CISNET breast cancer models embody the key features of systems modeling by incorporating numerous data sources and reflecting tumor, person, and health system factors that change over time and interact to affect the burden of breast cancer. Multidisciplinary modeling teams have explored alternative representations of breast cancer to reveal insights into breast cancer natural history, including the role of overdiagnosis and race differences in tumor characteristics. The models have been used to compare strategies for improving the balance of benefits and harms of breast cancer screening based on personal risk factors, including age, breast density, polygenic risk, and history of Down syndrome or a history of childhood cancer. The models have also provided evidence to support the delivery of care by simulating outcomes following clinical decisions about breast cancer treatment and estimating the relative impact of screening and treatment on the United States population. The insights provided by the CISNET breast cancer multilevel modeling efforts have informed policy and clinical guidelines. The 20 years of CISNET modeling experience has highlighted opportunities and challenges to expanding the impact of systems modeling. Moving forward, CISNET research will continue to use systems modeling to address cancer control issues, including modeling structural inequities affecting racial disparities in the burden of breast cancer. Future work will also leverage the lessons from team science, expand resource sharing, and foster the careers of early stage modeling scientists to ensure the sustainability of these efforts.