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The value of low dose whole thoracic radiation therapy (LD-WTRT) for SARS-CoV-2 (COVID-19) pneumonia is unknown. Should ongoing clinical trials demonstrate that LD-WTRT proves effective for COVID-19 pneumonia recovery, widespread rapid implementation will be helpful globally. Our aim was to outline a pragmatic process for safe and efficient administration of LD-WTRT to patients with COVID-19 pneumonia that could be implemented successfully in a community hospital setting based upon participation in the PreVent clinical trial of LD-WTRT.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer with an imperative need for new treatments. Immunotherapy has had marked success in some cancer types; however, clinical trials studying the efficacy of immune checkpoint inhibitors for the treatment of EOC benefited less than 15% of patients. Given that EOC develops from multiple tissues in the reproductive system and metastasizes widely throughout the peritoneal cavity, responses to immunotherapy are likely hindered by heterogeneous tumor microenvironments (TME) containing a variety of immune profiles. To fully characterize and compare syngeneic model systems that may reflect this diversity, we determined the immunogenicity of six ovarian tumor models in vivo, the T and myeloid profile of orthotopic tumors and the immune composition and cytokine profile of ascites, by single-cell RNA sequencing, flow cytometry, and IHC. The selected models reflect the different cellular origins of EOC (ovarian and fallopian tube epithelium) and harbor mutations relevant to human disease, including Tp53 mutation, PTEN suppression, and constitutive KRAS activation. ID8-p53−/− and ID8-C3 tumors were most highly infiltrated by T cells, whereas STOSE and MOE-PTEN/KRAS tumors were primarily infiltrated by tumor-associated macrophages and were unique in MHC class I and II expression. MOE-PTEN/KRAS tumors were capable of forming T-cell clusters. This panel of well-defined murine EOC models reflects some of the heterogeneity found in human disease and can serve as a valuable resource for studies that aim to test immunotherapies, explore the mechanisms of immune response to therapy, and guide selection of treatments for patient populations. Significance: This study highlights the main differences in the immunogenicity and immune composition found in six different models of orthotopic ovarian cancer as an essential tool for future preclinical investigations of cancer immunotherapy.

Figure S1 shows differential gene expression between cancer cell populations of orthotopic ID8-WT and STOSE tumors.Figure S2 shows UMAP plots of M0/M1/M2 gene set enrichment in ID8-WT and STOSE tumors.Figure S3 shows expression of MHC-I and PD-L1 under IFNγ treatment in various ovarian cancer cell lines.Figure S4 shows tumor phenotypes of various murine ovarian cancer models.Figure S5 shows the gating strategy for analysis of flow cytometry data.Figure S6 shows abundance of T cell populations in the TME of syngeneic ovarian cancer models.Figure S7 shows abundance of myeloid-like cell populations in the TME of various syngeneic ovarian cancer models.Figure S8 shows MHC-II expression in immune and stromal compartments of orthotopic tumors from syngeneic ovarian cancer models.Figure S9 shows PD-L1 expression in immune and stromal compartments of orthotopic tumors from syngeneic ovarian cancer models.Figure S10 shows relative immune cell frequencies found in spleens of ovarian tumor-bearing mice.Figure S11 shows MHC-II and PD-L1 expression in the TME and ascites of ovarian tumor-bearing mice.Figure S12 shows the chemokine and cytokine network found in the ascites and plasma of ovarian tumor-bearing mice.Figure S13 shows chemokine and cytokine expression from single-cell RNA-sequencing analysis of ID8 and STOSE tumors.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer with an imperative need for new treatments. Immunotherapy has had marked success in some cancer types; however, clinical trials studying the efficacy of immune checkpoint inhibitors for the treatment of EOC benefited less than 15% of patients. Given that EOC develops from multiple tissues in the reproductive system and metastasizes widely throughout the peritoneal cavity, responses to immunotherapy are likely hindered by heterogeneous tumor microenvironments (TME) containing a variety of immune profiles. To fully characterize and compare syngeneic model systems that may reflect this diversity, we determined the immunogenicity of six ovarian tumor models in vivo, the T and myeloid profile of orthotopic tumors and the immune composition and cytokine profile of ascites, by single-cell RNA sequencing, flow cytometry, and IHC. The selected models reflect the different cellular origins of EOC (ovarian and fallopian tube epithelium) and harbor mutations relevant to human disease, including Tp53 mutation, PTEN suppression, and constitutive KRAS activation. ID8-p53−/− and ID8-C3 tumors were most highly infiltrated by T cells, whereas STOSE and MOE-PTEN/KRAS tumors were primarily infiltrated by tumor-associated macrophages and were unique in MHC class I and II expression. MOE-PTEN/KRAS tumors were capable of forming T-cell clusters. This panel of well-defined murine EOC models reflects some of the heterogeneity found in human disease and can serve as a valuable resource for studies that aim to test immunotherapies, explore the mechanisms of immune response to therapy, and guide selection of treatments for patient populations.Significance:This study highlights the main differences in the immunogenicity and immune composition found in six different models of orthotopic ovarian cancer as an essential tool for future preclinical investigations of cancer immunotherapy.

Table S1 contains antibodies used in flow cytometry staining of ascites/PW, spleen, and mouse ovarian tumors.Table S2 contains primary antibodies used for IHC and IF staining of mouse ovarian tumors.Table S3 contains primer Sequences used for qPCR of ovarian cancer cell lines.Table S4 contains hallmark gene list for ID8 and STOSE cancer cells.Table S5 contains M0/M1/M2 gene-sets.Table S6 contains tumor development characteristics of murine orthotopic ovarian cancer models.Table S7 contains average and standard deviation of concentrations of cytokines and chemokines in the ascites of syngeneic mouse models of ovarian cancer at endpoint.Table S8 contains average and standard deviation of concentrations of cytokines and chemokines in the plasma of syngeneic mouse models of ovarian cancer collected near endpoint.Table S9 summarizes key features of syngeneic models of ovarian cancer.

Figure S4 shows that radiotherapy and immunotherapy can synergistically induce tumoral ferroptosis

A challenge in oncology is to rationally and effectively integrate immunotherapy with traditional modalities, including radiotherapy. Here, we demonstrate that radiotherapy induces tumor-cell ferroptosis. Ferroptosis agonists augment and ferroptosis antagonists limit radiotherapy efficacy in tumor models. Immunotherapy sensitizes tumors to radiotherapy by promoting tumor-cell ferroptosis. Mechanistically, IFNγ derived from immunotherapy-activated CD8+ T cells and radiotherapy-activated ATM independently, yet synergistically, suppresses SLC7A11, a unit of the glutamate–cystine antiporter xc−, resulting in reduced cystine uptake, enhanced tumor lipid oxidation and ferroptosis, and improved tumor control. Thus, ferroptosis is an unappreciated mechanism and focus for the development of effective combinatorial cancer therapy.Significance:This article describes ferroptosis as a previously unappreciated mechanism of action for radiotherapy. Further, it shows that ferroptosis is a novel point of synergy between immunotherapy and radiotherapy. Finally, it nominates SLC7A11, a critical regulator of ferroptosis, as a mechanistic determinant of synergy between radiotherapy and immunotherapy.This article is highlighted in the In This Issue feature, p. 1631

Table S1 shows the information on the antagonists and agonists used in this study

Objective: he goal of this work was to perform a systematic review and meta-analysis evaluating and comparing exercise related improvements in various executive function (EF) domains among children and adolescents with attention-deficit hyperactivity disorder (ADHD), Autism Spectrum Disorders (ASD), and Fetal Alcohol Spectrum Disorders (FASD). Methods: A systematic literature research was conducted in PubMed, CENTRAL, and PsycInfo from October 1st, 2018 through January 30th, 2019 for original peer-reviewed articles investigating the relationship between exercise interventions and improvements in three domains of executive function (working memory, attention/set shifting, and response inhibition) among children and adolescents with ADHD, ASD, and FASD. Effect sizes (ES) were extracted and combined with random-effects meta-analytic methods. Covariates and moderators were then analyzed using meta-regression and subgroup analyses. Results: A total of 28 studies met inclusion criteria, containing information on 1,281 youth (N=1197 ADHD, N= 54 ASD, N=30 FASD). For ADHD, exercise interventions were associated with moderate improvements in attention/set-shifting (ES 0.38, 95% CI 0.01-0.75, k=14) and approached significance for working memory (ES 0.35, 95%CI −0.17-0.88, k=5) and response inhibition (ES 0.39, 95%CI −0.02-0.80, k=12). For ASD and FASD, exercise interventions were associated with large improvements in working memory (ES 1.36, 95%CI 1.08-1.64) and response inhibition (ES 0.78, 95%CI 0.21-1.35) and approached significance for attention/set-shifting (ES 0.69, 95% −0.28-1.66). There was evidence of substantial methodologic and substantive heterogeneity among studies. Sample size, mean age, study design, and the number or duration of intervention sessions did not significantly moderate the relationship between exercise and executive function. Conclusion: Exercise interventions among children and adolescents with neurodevelopmental disorders were associated with moderate improvements in executive function domains. Of note, studies of youth with ASD and FASD tended to report higher effect sizes compared to studies of youth with ADHD, albeit few existing studies. Exercise may be a potentially cost-effective and readily implementable intervention to improve executive function in these populations.

A challenge in oncology is to rationally and effectively integrate immunotherapy with traditional modalities, including radiotherapy. Here, we demonstrate that radiotherapy induces tumor-cell ferroptosis. Ferroptosis agonists augment and ferroptosis antagonists limit radiotherapy efficacy in tumor models. Immunotherapy sensitizes tumors to radiotherapy by promoting tumor-cell ferroptosis. Mechanistically, IFNγ derived from immunotherapy-activated CD8+ T cells and radiotherapy-activated ATM independently, yet synergistically, suppresses SLC7A11, a unit of the glutamate–cystine antiporter xc−, resulting in reduced cystine uptake, enhanced tumor lipid oxidation and ferroptosis, and improved tumor control. Thus, ferroptosis is an unappreciated mechanism and focus for the development of effective combinatorial cancer therapy. Significance: This article describes ferroptosis as a previously unappreciated mechanism of action for radiotherapy. Further, it shows that ferroptosis is a novel point of synergy between immunotherapy and radiotherapy. Finally, it nominates SLC7A11, a critical regulator of ferroptosis, as a mechanistic determinant of synergy between radiotherapy and immunotherapy. This article is highlighted in the In This Issue feature, p. 1631

BACKGROUND We sought to investigate the prognostic value of volumetric positron emission tomography (PET) parameters in patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) and a ≤10 pack-year smoking history treated with chemoradiation. METHODS A total of 142 patients were included. Maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis (TLG) of the primary tumor, involved regional lymph nodes, and total lesion were calculated. Cox proportional hazard modeling was used to evaluate associations of clinical and PET parameters with locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), and overall survival (OS). RESULTS On univariate analysis, volumetric PET parameters were significantly associated with all endpoints, and 8th edition American Joint Committee on Cancer/Union Internationale Contre le Cancer staging was significantly associated with DMFS and OS. On multivariate analysis, total lesion TLG was significantly associated with LRFFS, while staging was most significantly prognostic for DMFS and OS. CONCLUSION Volumetric PET parameters are uniquely prognostic of LRFFS in low-risk HPV-related OPSCC and may be useful for directing de-intensification strategies.

We sought to investigate the prognostic value of volumetric positron emission tomography (PET) parameters in patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) and a ≤10 pack-year smoking history treated with chemoradiation.A total of 142 patients were included. Maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis (TLG) of the primary tumor, involved regional lymph nodes, and total lesion were calculated. Cox proportional hazard modeling was used to evaluate associations of clinical and PET parameters with locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), and overall survival (OS).On univariate analysis, volumetric PET parameters were significantly associated with all endpoints, and 8th edition American Joint Committee on Cancer/Union Internationale Contre le Cancer staging was significantly associated with DMFS and OS. On multivariate analysis, total lesion TLG was significantly associated with LRFFS, while staging was most significantly prognostic for DMFS and OS.Volumetric PET parameters are uniquely prognostic of LRFFS in low-risk HPV-related OPSCC and may be useful for directing de-intensification strategies.

Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for pediatric major depressive disorder (MDD). We conducted a meta-analysis to examine the following: the time-course of response to SSRIs in pediatric depression; whether higher doses of SSRIs are associated with an improved response in pediatric depression; differences in efficacy between SSRI agents; and whether the time-course and magnitude of response to SSRIs is different in pediatric and adult patients with MDD.We searched PubMed and CENTRAL for randomized controlled trials comparing SSRIs to placebo for the treatment of pediatric MDD. We extracted weekly symptom data from trials to characterize the trajectory of pharmacological response to SSRIs. Pooled estimates of treatment effect were calculated based on standardized mean differences between treatment and placebo groups.The meta-analysis included 13 pediatric MDD trials with a total of 3,004 patients. A logarithmic model indicating that the greatest benefits of SSRIs occurred early in treatment best fit the longitudinal data (log[week] = 0.10, 95% CI = 0.06-0.15, p .0001). There were no significant differences based on maximum SSRI dose or between particular SSRI agents. SSRIs were demonstrated to have a smaller benefit in pediatric compared to adult MDD.Treatment gains in pediatric MDD are greatest early in treatment and are, on average, minimal after 4 weeks of SSRI pharmacotherapy in pediatric MDD. Further research is needed using individual patient data to examine the power of early SSRI response (e.g., 2-4 weeks) to predict outcomes in short-term pharmacological trials.

Skeletal muscle contraction results from molecular interactions of myosin “crossbridges” with adjacent actin filament binding sites. The binding of myosin to actin can be “weak” or “strong,” and only strong binding states contribute to force production. During active shortening, the number of strongly bound crossbridges declines with increasing shortening velocity. Forcibly stretching a muscle that is actively shortening at high velocity results in no apparent negative consequences, whereas stretch of an isometrically (fixed-length) contracting muscle causes ultrastructural damage and a decline in force-generating capability. Our working hypothesis is that stretch-induced damage is uniquely attributable to the population of crossbridges that are strongly bound. We tested the hypothesis that stretch-induced force deficits decline as the prevailing shortening velocity is increased. Experiments were performed on permeabilized segments of individual skeletal muscle fibers obtained from human subjects. Fibers were maximally activated and allowed either to generate maximum isometric force (Fo), or to shorten at velocities that resulted in force maintenance of ≈50% Fo or ≈2% Fo. For each test condition, a rapid stretch equivalent to 0.1 × optimal fiber length was applied. Relative to prestretch Fo, force deficits resulting from stretches applied during force maintenance of 100, ≈50, and ≈2% Fo were 23.2 ± 8.6, 7.8 ± 4.2, and 0.3 ± 3.3%, respectively (means ± SD, n = 20). We conclude that stretch-induced damage declines with increasing shortening velocity, consistent with the working hypothesis that the fraction of strongly bound crossbridges is a causative factor in the susceptibility of skeletal muscle to stretch-induced damage. NEW & NOTEWORTHY Force deficits caused by stretch of contracting muscle are most severe when the stretch is applied during an isometric contraction, but prevented if the muscle is shortening at high velocity when the stretch occurs. This study indicates that velocity-controlled modulation of the number of strongly bound crossbridges is the basis for the observed relationship between stretch-induced muscle damage and prevailing shortening velocity.