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To investigate the effect of radiation treatment at a high-volume center on overall survival in men with intermediate-risk prostate cancer.From 2004 to 2015, 430,347 patients with intermediate-risk prostate cancer were identified in the National Cancer Database. Radiation case volume (RCV) of each hospital was calculated based on number of patients treated. After excluding certain patients including those with metastatic disease, our final analysis population included 116,091 intermediate-risk prostate cancer patients receiving radiation therapy or radiation with androgen deprivation therapy. Characteristics analyzed include age, race, distance to treatment facility, Charlson-Deyo Score, and socioeconomic factors. Primary outcome was overall survival (OS). Five-year survival rates were estimated using the Kaplan-Meier method. Adjusted hazard ratios with 95% confidence intervals were computed using multivariate analysis. Cox regression and propensity score-matched analysis was performed.Median follow up was 63.5 months and estimated 5-year OS was 90.1% at high RCV centers and 88.2% at low RCV centers (P.0001). Treatment at high RCV facility was associated with significantly lower mortality compared to treatment at a low RCV facility on multivariate analysis and propensity score matching analysis. The survival benefit of treatment at a high RCV facility remained when high RCV facilities were defined as those above the 80th, 90th, and 95th percentile in patient volume (P.05).Treatment at a high radiation case volume facility is associated with improved OS in patients with radiation-treated intermediate-risk prostate cancer. This survival benefit is important to consider when choosing a treatment center for radiation therapy.

Background & aimsNonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide. The NLRP3 inflammasome, a platform for caspase-1 activation and release of interleukin 1β, is increasingly recognized in the induction of inflammation and liver fibrosis during NAFLD. However, the cell-specific contribution of NLRP3 inflammasome activation in NAFLD remains unknown.MethodsTo investigate the role of NLRP3 inflammasome activation in hepatocytes, hepatic stellate cells (HSCs) and myeloid cells, a conditional Nlrp3 knock-out mouse was generated and bred to cell-specific Cre mice. Both acute and chronic liver injury models were used: lipopolysaccharide/adenosine-triphosphate to induce invivo NLRP3 activation, choline-deficient, L-amino acid-defined high-fat diet, and Western-type diet to induce fibrotic nonalcoholic steatohepatitis (NASH). Invitro co-culture studies were performed to dissect the crosstalk between myeloid cells and HSCs.ResultsMyeloid-specific deletion of Nlrp3 blunted the systemic and hepatic increase in interleukin 1β induced by lipopolysaccharide/adenosine-triphosphate injection. In the choline-deficient, L-amino acid-defined high-fat diet model of fibrotic NASH, myeloid-specific Nlrp3 knock-out but not hepatocyte- or HSC-specific knock-out mice showed significant reduction in inflammation independent of steatosis development. Moreover, myeloid-specific Nlrp3 knock-out mice showed ameliorated liver fibrosis and decreased HSC activation. These results were validated in the Western-type diet model. Invitro co-cultured studies with human cell lines demonstrated that HSC can be activated by inflammasome stimulation in monocytes, and this effect was significantly reduced if NLRP3 was downregulated in monocytes.ConclusionsThe study provides new insights in the cell-specific role of NLRP3 in liver inflammation and fibrosis. NLRP3 inflammasome activation in myeloid cells was identified as crucial for the progression of NAFLD to fibrotic NASH. These results may have implications for the development of cell-specific strategies for modulation of NLRP3 activation for treatment of fibrotic NASH.

Introduction The identification of acute injury of the kidney relies on serum creatinine (SCr), a functional marker with poor temporal resolution as well as limited sensitivity and specificity for cellular injury. In contrast, urinary biomarkers of kidney injury have the potential to detect cellular stress and damage in real time. Methods To detect the response of the kidney to injury, we have tested a lateral flow dipstick that measures a urinary protein called neutrophil gelatinase-associated lipocalin (NGAL). Analysis of urine was performed in a prospective cohort of 479 patients (final cohort N = 426) entering an emergency department in New York City and subsequently admitted for inpatient care. Results Colorimetric development had high interrater reliability (88% concordance rate) and correlated with traditional enzyme-linked immunosorbent assay (ELISA) measurements (ρ = 0.732, P < .0001). Of the 14% of the cohort who met Acute Kidney Injury Network (AKIN) SCr criteria for acute kidney injury (AKI), 67% demonstrated transient (2 days) elevation of SCr. Comparing the outcomes of patients with sustained versus transient or undetectable changes in SCr revealed that the urinary NGAL (uNGAL) dipstick had high specificity and negative predictive value (NPV) (high- vs. low-intermediate readings, sensitivity = 0.55, specificity = 0.91, positive predictive value = 0.24, NPV = 0.97, χ2 = 20.39, P < 0.001). Conclusion We show that the introduction of a bedside uNGAL dipstick permits accurate triage by identifying individuals who do not have tubular injury. In an era of shortening length of stay and rapid decisions based on isolated SCr measurements, real-time exclusion of kidney injury by a dipstick will be particularly useful to overcome the retrospective, insensitive, and nonspecific attributes of SCr., Graphical abstract

During the past century, from the advent of preclinical modeling to the establishment of clinical trials, the hypothesis that host defenses regulate tumor growth (posited and refined by leaders in the field of cancer immunity) has become accepted as a scientific pillar in oncology. Since the turn of the millennium, a search has been under way for the best therapeutic approach to reprogram the immune system to recognize tumor cells that have undergone "immune escape." This quest has led some to question conventional scientific views of tumor cell kill, including the role of host immunity in patients treated with radiation therapy. In the last two decades, evidence has accumulated that radiation therapy can effectively convert a potentially lethal cancer into an in situ personalized vaccine. Herein, we review the underlying mechanisms and maneuvers responsible for in situ vaccine production.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating disorder with a wide spectrum of symptoms, including pain, depression, and neurocognitive deterioration. Over 17 million people around the world have ME/CFS, predominantly women with peak onset at 30–50 years. Given the wide spectrum of symptoms and unclear etiology, specific biomarkers for diagnosis and stratification of ME/CFS are lacking. Here we show that actin network proteins in circulating extracellular vesicles (EVs) offer specific non-invasive biomarkers for ME/CFS. We found that circulating EVs were significantly increased in ME/CFS patients correlating to C-reactive protein, as well as biological antioxidant potential. Area under the receiver operating characteristic curve for circulating EVs was 0.80, allowing correct diagnosis in 90–94% of ME/CFS cases. From two independent proteomic analyses using circulating EVs from ME/CFS, healthy controls, idiopathic chronic fatigue, and depression, proteins identified from ME/CFS patients are involved in focal adhesion, actin skeletal regulation, PI3K-Akt signaling pathway, and Epstein-Barr virus infection. In particular, talin-1, filamin-A, and 14-3-3 family proteins were the most abundant proteins, representing highly specific ME/CFS biomarkers. Our results identified circulating EV number and EV-specific proteins as novel biomarkers for diagnosing ME/CFS, providing important information on the pathogenic mechanisms of ME/CFS.

Histopathological grading of meningiomas is insufficient for optimal risk stratification. The purpose of the present study was to determine the prognostic value of atypical histopathological features across all nonmalignant meningiomas (World Health Organization [WHO] grade I-II).The data from 334 patients with WHO grade I (n = 275) and grade II (n = 59) meningiomas who had undergone surgical resection from 2001 to 2015 at 2 academic centers were pooled. Progression/recurrence (P/R) was determined radiographically and measured from the date of surgery.The median follow-up was 52 months. The patients were stratified by the number of atypical features: 0 (n = 151), 1 (n = 71), 2 (n = 66), 3 (n = 22), and 4 or 5 (n = 24). The risk of P/R increased with an increasing number of atypical features (log-rank test, P = 0.001). The 5-year actuarial rates of P/R stratified by the number of atypical features were as follows: 0, 16.3% (95% confidence interval [CI], 10.7-24.4); 1, 21.7% (95% CI, 12.8-35.2); 2, 28.2% (95% CI, 18.4-41.7); 3, 30.4% (95% CI, 13.8-58.7); and 4 or 5, 51.4% (95% CI, 31.7-74.5). On univariate analysis, the presence of high nuclear/cytoplasmic ratio (P = 0.007), prominent nucleoli (P = 0.007), and necrosis (P0.00005) were associated with an increased risk of P/R. On multivariate analysis, the number of atypical features (hazard ratio [HR], 1.30; 95% CI, 1.03-1.63; P = 0.03), ≥4 mitoses per high-power fields (HR, 2.45; 95% CI, 1.17-5.15; P = 0.02), subtotal resection (HR, 3.9; 95% CI, 2.5-6.3; P0.0005), and the lack of adjuvant radiotherapy (HR, 2.40; 95% CI, 1.19-4.80; P = 0.01) were associated with an increased risk of P/R.An increased number of atypical features, ≥4 mitoses per 10 high-power fields, subtotal resection, and the lack of adjuvant radiotherapy were independently associated with P/R of WHO grade I-II meningiomas. Patients with these features might benefit from intensified therapy.

Prosopis strombulifera (Lam.) Benth. is a halophytic shrub found in highly saline soils in Argentina, with high tolerance against NaCl but strong growth inhibition by Na2SO4. In the present study, the differences in the physiological responses caused by these salts and an iso-osmotic combination thereof on photosynthesis, mineral composition and metabolism were analyzed. Na2SO4 treated plants were the most affected by salinity, showing a significant decrease in several photosynthetic parameters. Proline and cysteine accumulated significantly in the plants in response to salt stress. These results show by the first time that the SO42− anion is triggering damage in the photosynthetic apparatus and consequently affecting the photosynthetic process, which may explain the strong growth inhibition in these plants at high salinity. Moreover, the SO42− anion provoke challenges in the incorporation of nutrients, decreasing the levels of K, Ca, P and Mg, and inducing a strong antioxidant activity in P. strombulifera. Fil: Reginato, Mariana Andrea. Universidad Nacional de Rio Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Investigaciones Agrobiotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Agrobiotecnológicas; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Departamento de Botánica. Laboratorio de Fisiología Vegetal; Argentina Fil: Turcios, Ariel E.. Leibniz Universitat Hannover; Alemania Fil: Luna, Maria Virginia. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Departamento de Botánica. Laboratorio de Fisiología Vegetal; Argentina. Universidad Nacional de Rio Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Investigaciones Agrobiotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Agrobiotecnológicas; Argentina Fil: Papenbrock, Jutta. Leibniz Universitat Hannover; Alemania

Although scientific breakthroughs can promote health equity, there is concern that adults with intellectual disability, a health disparities population, may be excluded from clinical trials.To determine the extent to which adults with intellectual disability are subject to exclusion from National Institutes of Health (NIH)-funded clinical trials.We studied recent NIH-funded Phase 2/3, 3, and 4 clinical trials of United States-based working-age adults (18 55 years of age) listed in ClinicalTrials.gov. We coded eligibility criteria for inclusion, direct exclusion, and indirect exclusion of adults with intellectual disability.We rarely identified studies that directly include adults with intellectual disability. Most studies (74.6%) had eligibility criteria that directly and/or indirectly exclude adults with intellectual disability. Approximately one-third of studies had direct exclusion criteria based on cognitive impairment or diagnosis of intellectual disability. Nearly 65% of studies indirectly excluded adults with intellectual disability based on factors likely associated with intellectual disability (e.g., functional capacity, inability to read/write, and/or research staff discretion).We found less exclusion based on diagnosis of intellectual disability than anticipated. Nonetheless, about three-fourths of studies had eligibility criteria which would likely lead to the direct and/or indirect exclusion of adults with intellectual disability. Our findings suggest substantial cause for concern that adults with intellectual disability experience widespread exclusion from NIH-funded clinical trials-exclusion that may lack appropriate justification and assessment. Consequently, this group is denied equal access to the potential benefits of scientific discovery. We provide recommendations for approaches to include adults with intellectual disability.

Purpose/Objective(s) Radiation courses generally involve multiple visits over the course of weeks, depending on the disease site and treatment technique. Therefore, radiation therapy (RT) may be discontinued prior to planned treatment completion. The purpose of this analysis is to identify any clinical or socioeconomic factors that could serve as predictors of RT discontinuation. Materials/Methods Using the National Cancer Database (NCDB) data from 2017, we identified 7,561 cases treated with RT, chemoradiation (CRT), surgery with RT (S+RT), or surgery with CRT (S+CRT) that had information on radiation discontinuation. The variables that we assessed include age (18- Results Of the 7,561 patients with information on RT discontinuation, 7,349 (97.2%) patients completed RT, whereas RT was discontinued in 212 (2.8%) patients. The reasons for discontinuation are shown in Table 1. Patients who are 70+ years old (3.7%, P = 0.008), male (3.4%, P = 0.014), Black (3.2%, P = 0.030), Medicaid/uninsured (3.9%, P Conclusion In this NCDB analysis, both clinical and socioeconomic characteristics, including age, gender, race, insurance status, income level, comorbidities, treatment type, and disease site, correlated with RT discontinuation rates. While toxicity of treatment was reported, patient decision was the most common reason for RT discontinuation. Table 1. Reasons for RT discontinuation (N = 212).

PURPOSE/OBJECTIVE(S) At our institution, students receive formal research mentorship by radiation oncology faculty mentors through structured research programs, such as the Medical Student Summer Research Program (MSSRP) and radiation oncology research elective, as well as in extracurricular research time. In this analysis, we report the research productivity of students who engaged in formal radiation oncology mentorship over the past 15 years. MATERIALS/METHODS We compiled a database of all publications, consisting of abstracts (including oral and poster presentations) and manuscripts, co-authored by 58 students from 2005 to 2020. We searched radiation oncology faculty curriculum vitae as well as PubMed to identify publications with student authors. The means, medians, ranges, and interquartile ranges (IQR) of co-authorships and first authorships were calculated for the overall cohort and compared for male versus female students as well as students who matched into radiation oncology and those who matched into other fields. RESULTS Among all 58 students, 106 unique abstracts and 70 unique manuscripts were identified. Of the 58 students, 54 (93.1%) published at least one abstract or manuscript. The mean number of abstract co-authorships per student was 3.07 (median 2, range 0-25, IQR 0-4), and the mean number of manuscript co-authorships per student was 2.22 (median 1, range 0-18, IQR 1-3). There were no significant differences in research output between male and female students. However, the students who matched into radiation oncology published more co-author manuscripts (mean 3.67, median 3, IQR 1-5) than those who matched into other fields (mean 1.63, median 1, IQR 1-2), P = 0.014. They also published more first-author manuscripts (mean 1.62, median 2, IQR 0-3) than those who matched into other fields (mean 0.53, median 0, IQR 0-1), P = 0.006. Among the 51 students who have graduated, the top three specialties that students matched into were radiation oncology with 21 (41.2%) students, internal medicine with 9 (17.6%) students, and radiology with 6 (11.8%) students. CONCLUSION In this 15-year analysis, students mentored by radiation oncology faculty are successful with high research productivity. The results of this analysis lay the groundwork for further implementation of formal medical student research mentorship programs, which will in turn allow for more research on the benefits of mentorship. Further research is warranted to assess whether skills gained from student-directed research translate into residency and beyond.

Purpose/Objective(s) Medical students underrepresented in medicine (UIM) are less likely to attend medical schools with associated radiation oncology (RO) programs. In response, the Radiation oncology Intensive Shadowing Experience (RISE) was created to proactively address inequities in exposure to RO for UIM. This analysis describes the experiences of participating mentors. We hypothesize that RISE will have an overall positive impact on participating physician mentors. Materials/Methods RISE was developed as a one-week virtual opportunity for UIM senior medical students, interested in RO, attending US or US-affiliated medical schools. Participating medical students were matched with 1-2 RO attendings, a senior resident, a physicist, and a dosimetrist. Mentors were provided with course objectives and a detailed schedule for the week. Mentors completed a post-program survey. Statistical analyses were performed using Fisher's exact test and Mann–Whitney U test. Free text responses provided additional descriptive data. Results Forty-three mentors participated in RISE across two academic medical centers from July-October 2020. Survey response rate was 93% (40/43); 14 attendings, 12 residents, 9 physicists and 5 dosimetrists. Mentors self-identified as White (55%), Asian (34%), Multiracial (5%), Black or African American (3%), and Hispanic/Latino (3%). The majority of attendings and residents found that the goals and objectives were clearly stated, interactions with students were meaningful, and they would recommend the experience to other colleagues (Table 1). Attendings reported a median of 6 hours [interquartile range (IQR) 5,8 hours] on RISE activities per week while residents reported 10 hours [IQR 9,13.5 hours] (P = 0.01). All attendings (100%) and 83% of residents agreed the time commitment was appropriate. Qualitative data revealed themes including positive mentor-mentee connections, improvement in student RO knowledge, positive perception of mentee enthusiasm and engagement, and a sense of personal fulfillment from participation. Conclusion RISE mentors reported a positive and fulfilling experience with the program, and manageable time commitments. Time commitment for resident mentors may need to be improved to ensure sustainability. Future work is merited to determine the long-term impact on both mentors and mentees.

Gene regulatory networks (GRNs), consisting of transcription factors and their target cis-regulatory sequences, control neurogenesis and cell fate specification in the developing central nervous system, but their organization is poorly characterized. In this study, we performed integrated single-cell RNA- and scATAC-seq analysis in both mouse and human retina to profile dynamic changes in gene expression, chromatin accessibility and transcription factor footprinting during retinal neurogenesis. We identified multiple interconnected, evolutionarily-conserved GRNs consisting of cell type-specific transcription factors that both activate expression of genes within their own network and often inhibit expression of genes in other networks. These GRNs control state transitions within primary retinal progenitors that underlie temporal patterning, regulate the transition from primary to neurogenic progenitors, and drive specification of each major retinal cell type. We confirmed the prediction of this analysis that the NFI transcription factors Nfia, Nfib, and Nfix selectively activate expression of genes that promote late-stage temporal identity in primary retinal progenitors. We also used GRNs to identify additional transcription factors that promote (Insm1/2) and inhibit (Tbx3 and Tcf7l1/2) rod photoreceptor specification in postnatal retina. This study provides an inventory of cis- and trans-acting factors that control retinal development, identifies transcription factors that control the temporal identity of retinal progenitors and cell fate specification, and will potentially guide cell-based therapies aimed at replacing retinal neurons lost due to disease.

Fibrosis or cirrhosis is the major risk factor associated with morbidity and mortality in patients with non-alcoholic steatohepatitis (NASH)-driven chronic liver disease. While numerous efforts have been made to identify mediators of the initiation of liver fibrosis, the molecular underpinnings of fibrosis progression remain poorly understood and anti-fibrotic therapies to arrest liver fibrosis progression and promote resolution are elusive. Here, we identify a pathway involving WNT1 inducible signaling pathway protein 1 (WISP1) and myocardin related transcription factor (MRTF), as a central mechanism driving liver fibrosis progression through transcriptional reprogramming of myofibroblast cytoskeleton and motility. WISP1 expression is highly correlated with MRTF activity in human cirrhotic livers and can activate MRTF signaling in vitro. In mice, WISP1 deficiency protects against fibrosis progression but not fibrosis onset and leads to reduced myofibroblast accumulation in tissue interstitial areas and diminished expression of MRTF target cytoskeleton genes. WISP1 activates MRTF signaling via multiple integrins including αVβ1/3/5/8 and α11β1. Moreover, therapeutic administration of a novel antibody blocking WISP1-MRTF signaling axis halted the progression of existing liver fibrosis. These findings implicate the WISP1-MRTF axis as a crucial determinant of liver fibrosis progression and support targeting this pathway by antibody-based therapy for the treatment of NASH fibrosis and its associated complications.