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To better understand veterans' decisions about germline testing, we conducted a single-site, qualitative study of 32 veterans with advanced prostate cancer. Seven days after oncologist-patient discussions about germline testing, we conducted semistructured interviews with patients to explore their decision-making process using an interview guide. Four of 14 veterans with service-connected disability benefits for prostate cancer declined germline testing for fear of losing benefits because their livelihood depended on these benefits. All 18 veterans without service-connected benefits agreed to testing. Veterans declining germline testing based on this concern can lead to suboptimal cancer care because targeted treatments that could improve their outcomes may go unrecognized. Our findings contributed to new language in the Veterans Benefits Administration Compensation and Pension Manual clarifying that genetic testing showing hereditary predisposition is insufficient to deny service-connected benefits for conditions presumed to be caused by military exposures. Clinicians should communicate this protection when counseling veterans about genetic testing., (Published by Oxford University Press 2024.)

Microsatellite instability-high (MSI-H) tumors are malignant tumors that, despite harboring a high mutational burden, often have intact TP53. One of the most frequent mutations in MSI-H tumors is a frameshift mutation in RPL22, a ribosomal protein. Here, we identified RPL22 as a modulator of MDM4 splicing through an alternative splicing switch in exon 6. RPL22 loss increases MDM4 exon 6 inclusion and cell proliferation and augments resistance to the MDM inhibitor Nutlin-3a. RPL22 represses the expression of its paralog, RPL22L1, by mediating the splicing of a cryptic exon corresponding to a truncated transcript. Therefore, damaging mutations in RPL22 drive oncogenic MDM4 induction and reveal a common splicing circuit in MSI-H tumors that may inform therapeutic targeting of the MDM4-p53 axis and oncogenic RPL22L1 induction., Competing Interests: Declaration of interests F.V. receives research support from the Dependency Map Consortium, Riva Therapeutics, Bristol Myers Squibb, Merck, Illumina, and Deerfield Management. F.V. is on the scientific advisory board of GSK, is a consultant and holds equity in Riva Therapeutics, and is a co-founder and holds equity in Jumble Therapeutics., (Published by Elsevier Inc.)

The checkpoint immunotherapeutic pembrolizumab induces responses in a small minority of patients with metastatic castration-resistant prostate cancer (mCRPC). Radium-223 (R223) may increase immunogenicity of bone metastases and increase pembrolizumab (P) activity. In a randomized phase II study, we assessed the effect of R223+P compared with R223 on tumor immune infiltration, safety, and clinical outcomes in patients with mCRPC. The primary endpoint was differences in CD4+ and CD8+ T-cell infiltrate in 8-week versus baseline bone metastasis biopsies; secondary endpoints were safety, radiographic progression-free survival (rPFS), and overall survival (OS). Of the 42 treated patients (29 R223+P, 13 R223), 18 R223+P and 8 R223 patients had evaluable paired tumor biopsies. Median fold-change of CD4+ T cells was -0.7 (range: -9.3 to 4.7) with R223+P and 0.1 (-11.1 to 3.7) with R223 (P = 0.66); for CD8+ T cells, median fold-change was -0.6 (-7.4 to 5.3) with R223+P and -1.3 (-3.1 to 4.8) with R223 (P = 0.66). Median rPFS and OS was 6.1 (95% confidence interval: 2.7-11.0) and 16.9 months [12.7-not reached (NR)], respectively, with R223+P and 5.7 (2.6-NR) and 16.0 (9.0-NR), respectively, with R223. Although R223+P was well tolerated with no unexpected toxicity, the combination did not improve efficacy. High-dimensional flow cytometry demonstrated minimal immune modulation with R223, whereas R223+P induced CTLA-4 expression on circulating CD4+ T cells. Clinical responders possessed lower circulating frequencies of Ki67+ T and myeloid cells at baseline and higher circulating frequencies of TIM-3+ T and myeloid cells by week 9. Although R223+P did not induce T-cell infiltration into the tumor microenvironment, exhaustion of induced peripheral T-cell immune responses may dampen the combination's clinical activity., (©2024 The Authors; Published by the American Association for Cancer Research.)

Three-dimensional (3D)-printed biodegradable polymer scaffolds are at the forefront of personalized constructs for bone tissue engineering. However, it remains challenging to create a biological microenvironment for bone growth. Herein, we developed a novel yet feasible approach to facilitate biomimetic mineralization via self-adaptive nanotopography, which overcomes difficulties in the surface biofunctionalization of 3D-printed polycaprolactone (PCL) scaffolds. The building blocks of self-adaptive nanotopography were PCL lamellae that formed on the 3D-printed PCL scaffold via surface-directed epitaxial crystallization and acted as a linker to nucleate and generate hydroxyapatite crystals. Accordingly, a uniform and robust mineralized layer was immobilized throughout the scaffolds, which strongly bound to the strands and had no effect on the mechanical properties of the scaffolds. In vitro cell culture experiments revealed that the resulting scaffold was biocompatible and enhanced the proliferation and osteogenic differentiation of mouse embryolous osteoblast cells. Furthermore, we demonstrated that the resulting scaffold showed a strong capability to accelerate in vivo bone regeneration using a rabbit bone defect model. This study provides valuable opportunities to enhance the application of 3D-printed scaffolds in bone repair, paving the way for translation to other orthopedic implants.

By recombining natural cell signaling systems and further reprogramming cell functions, use of genetically engineered cells and bacteria as therapies is an innovative emerging concept. However, the inherent properties and structures of the natural signal sensing and response pathways constrain further development. We present a universal DNA-based sensing toolbox on the cell surface to endow new signal sensing abilities for cells, control cell states, and reprogram multiple cell functions. The sensing toolbox contains a triangular-prismatic-shaped DNA origami framework and a sensing core anchored inside the internal confined space to enhance the specificity and efficacy of the toolbox. As a proof of principle, the sensing toolbox uses the customizable sensing core with signal sensing switches and converters to recognize unconventional signal inputs, deliver functional components to cells, and then control cell responses, including specific tumor cell death, immune cell disinhibition and adhesion, and bacterial expression. This work expands the diversity of cell sensing signals and reprograms biological functions by constructing nanomechanical-natural hybrid cells, providing new strategies for engineering cells and bacteria in diagnosis and treatment applications.

We present a novel framework enhancing the prediction of whether novel lineage poses the threat of eventually dominating the viral population. The framework is based purely on genomic sequence data, without requiring prior established biological analysis. Its building blocks are sets of coevolving sites in the alignment (motifs), identified via coevolutionary signals. The collection of such motifs forms a relational structure over the polymorphic sites. Motifs are constructed using distances quantifying the coevolutionary coupling of pairs and manifest as coevolving clusters of sites. We present an approach to genomic surveillance based on this notion of relational structure. Our system will issue an alert regarding a lineage, based on its contribution to drastic changes in the relational structure. We then conduct a comprehensive retrospective analysis of the COVID-19 pandemic based on SARS-CoV-2 genomic sequence data in GISAID from October 2020 to September 2022, across 21 lineages and 27 countries with weekly resolution. We investigate the performance of this surveillance system in terms of its accuracy, timeliness, and robustness. Lastly, we study how well each lineage is classified by such a system., (© 2024 Barrett et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Introduction: Sleep disturbance and insufficient sleep have been linked to metabolic syndrome, increasing cardiovascular disease and mortality risk. However, few studies investigate the joint effect of sleep and exercise on metabolic syndrome. We hypothesized that regular exercise can mitigate the exacerbation of metabolic syndrome by sleep insufficiency., Objective: The aim of this study was to investigate whether exercise can attenuate or eliminate the relationship between sleep insufficiency and metabolic syndrome., Method: A total of 6,289 adults (mean age = 33.96 years; women: 74.81%) were included in the study, a cross-sectional study conducted based on the results of employee health screening questionnaires and databases from a large healthcare system in central Taiwan. Participants reported sleep insufficiency or not. Self-reported exercise habits were classified into 3 levels: no exercise, exercise <150 min/week, and exercise ≧150 min/week. Multiple logistic regression and sensitivity analyses were conducted to understand the joint associations of sleep patterns and exercise with metabolic syndrome with exposure variables combining sleep duration/disturbances and PA., Results: Compared with the reference group (sufficient sleep), individuals with sleep insufficiency had a higher risk for metabolic syndrome [adjusted odds ratio (AOR) = 1.40, 95% confidence interval (95% CI): 1.01-1.94, p  < 0.05] in females aged 40-64 years, but not in other populations. Sleep insufficiency was not associated with the risk of metabolic syndrome among individuals achieving an exercise level of <150 min/week, and in particular among those achieving ≧150 min/week in all populations in our study., Conclusion: Sleep insufficiency was related to a higher risk of metabolic syndrome in female healthcare staff aged 40-64 years. Being physically active with exercise habits in these individuals, the risk of metabolic syndrome was no longer significant., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Chou, Chiu, Huang, Hsu, Liu, Lin, Huang, Lin and Wu.)

Club cells are a type of bronchiolar epithelial cell that serve a protective role in the lung and regenerate damaged lung epithelium. Single-cell RNA sequencing (scRNA-seq) of young adult human prostate and urethra identified cell populations in the prostatic urethra and collecting ducts similar in morphology and transcriptomic profile to lung club cells. We further identified club cell-like epithelial cells by scRNA-seq of prostate peripheral zone tissues. Here, we aimed to identify and spatially localize club cells in situ in the prostate, including in the peripheral zone. We performed chromogenic RNA in situ hybridization for five club cell markers (CP, LTF, MMP7, PIGR, SCGB1A1) in a series of (1) nondiseased organ donor prostate and (2) radical prostatectomy specimens from individuals with prostate cancer. We report that expression of club cell genes in the peripheral zone is associated with inflammation and limited to luminal epithelial cells classified as intermediate cells in proliferative inflammatory atrophy (PIA). Club-like cells were enriched in radical prostatectomy specimens compared to nondiseased prostates and associated with high-grade prostate cancer. We previously reported that luminal epithelial cells in PIA can rarely harbor oncogenic TMPRSS2:ERG (ERG+) gene fusions, and we now demonstrate that club cells are present in association with ERG+ PIA that is transitioning to early adenocarcinoma. Finally, prostate epithelial organoids derived from prostatectomy specimens demonstrate that club-like epithelial cells can be established in organoids and are sensitive to anti-androgen-directed treatment in vitro in terms of decreased androgen signaling gene expression signatures compared to basal or hillock cells. Overall, our study identifies a population of club-like cells in PIA and proposes that these cells play an analogous role to that of club cells in bronchiolar epithelium. Our results further suggest that inflammation drives lineage plasticity in the human prostate and that club cells in PIA may be prone to oncogenic transformation. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Background: Significant racial disparities in prostate cancer incidence and mortality have been reported between African American Men (AAM), who are at increased risk for prostate cancer, and European American Men (EAM). In most of the studies carried out on prostate cancer, this population is underrepresented. With the advancement of genome-wide association studies, several genetic predictor models of prostate cancer risk have been elaborated, as well as numerous studies that identify both germline and somatic mutations with clinical utility., Recent Findings: Despite significant advances, the AAM population continues to be underrepresented in genomic studies, which can limit generalizability and potentially widen disparities. Here we outline racial disparities in currently available genomic applications that are used to estimate the risk of individuals developing prostate cancer and to identify personalized oncology treatment strategies. While the incidence and mortality of prostate cancer are different between AAM and EAM, samples from AAM remain to be unrepresented in different studies., Conclusion: This disparity impacts the available genomic data on prostate cancer. As a result, the disparity can limit the predictive utility of the genomic applications and may lead to the widening of the existing disparities. More studies with substantially higher recruitment and engagement of African American patients are necessary to overcome this disparity., (© 2023 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: Dual antiplatelet therapy (DAPT) is a standard treatment option for acute myocardial infarction (AMI). The difference between the efficacy of ticagrelor and clopidogrel in the emergency department (ED) before percutaneous coronary intervention (PCI) remains unknown. The present study compared the in-hospital major adverse cardiovascular event (MACE) rates between patients with AMI treated with clopidogrel and those treated with ticagrelor in the ED before PCI., Methods: We retrospectively collected the data of patients diagnosed as having AMI in the ED. Patients were only included if they had successfully received complete DAPT with aspirin and ticagrelor/clopidogrel in the ED and had undergone PCI. The patients were divided into two groups according to their DAPT regimen. The primary outcome was the rate of in-hospital MACEs. The secondary outcomes included an unexpected return to the ED within 72 h, readmission within 14 d, and revascularization., Results: A total of 1836 patients were enrolled. Patients in the ticagrelor group had a lower in-hospital MACE rate (3.01% versus 7.51%, p < 0.001) and in-hospital mortality rate (2.15% versus 5.70%, p < 0.001) than those in the clopidogrel group. Multivariate logistic regression analysis revealed ticagrelor was independently associated with a lower risk of in-hospital MACEs (odds ratio [OR]: 0.53, 95% CI: 0.32-0.88, p = 0.013). After propensity score matching, the risk of in-hospital MACEs remained significantly lower in the ticagrelor group (OR 0.42, 95% CI: 0.21-0.85, p = 0.016)., Conclusion: DAPT with ticagrelor and aspirin in the ED before PCI is associated with a lower in-hospital MACE rate among patients with AMI.

Purpose: Obstructive sleep apnea (OSA) is a chronic disease that affects 1%-6% of children. Our study aims to explore the effectiveness and clinical characteristics of integrative Traditional Chinese Medicine (ITCM) for pediatric OSA., Materials and Methods: In this retrospective cohort study, we assessed differences of polysomnography (PSG) parameters and clinical characteristics between 2009 and 2020. Children <12 years old diagnosed with OSA (n = 508) were included and were categorized into ITCM cohort, western medicine (WM) cohort ,and surgery cohort. Outcomes were apnea-hypopnea index (AHI), respiratory disturbance index (RDI), and body mass index (BMI)., Results: There were 56 (11%), 324 (63.8%), and 128 (25.2%) patients in the ITCM, WM, and surgery cohorts. Among 17, 26, and 33 patients in the ITCM, WM, and surgery cohorts underwent follow-up PSG studies, respectively. In the ITCM follow-up cohort, AHI were significantly reduced (9.59 to 5.71, p < 0.05). BMI significantly increased in the WM follow-up cohort (19.46 to 20.50, p < 0.05) and the surgery follow-up cohort (18.04 to 18.85, p < 0.01). Comparing ITCM to WM cohort, a significant difference was found between the changes in RDI (ITCM: -6.78, WM: 0.51, p < 0.05) after treatment. Among ITCM follow-up cohort, the most prescribed TCM formula was Forsythia and Laminaria Combination. The most prescribed TCM herb was Ephedrae Herba., Conclusions: ITCM therapy can significantly reduce RDI and control BMI. We identified potential TCM treatments for pediatric OSA. Further study of the pharmacological mechanisms and clinical efficacy is warranted., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.)

Somatic mutational profiling is increasingly being used to identify potential targets for breast cancer. However, limited tumor-sequencing data from Hispanic/Latinas (H/L) are available to guide treatment. To address this gap, we performed whole-exome sequencing (WES) and RNA sequencing on 146 tumors and WES of matched germline DNA from 140 H/L women in California. Tumor intrinsic subtype, somatic mutations, copy-number alterations, and expression profiles of the tumors were characterized and compared with data from tumors of non-Hispanic White (White) women in The Cancer Genome Atlas (TCGA). Eight genes were significantly mutated in the H/L tumors including PIK3CA, TP53, GATA3, MAP3K1, CDH1, CBFB, PTEN, and RUNX1; the prevalence of mutations in these genes was similar to that observed in White women in TCGA. Four previously reported Catalogue of Somatic Mutations in Cancer (COSMIC) mutation signatures (1, 2, 3, 13) were found in the H/L dataset, along with signature 16 that has not been previously reported in other breast cancer datasets. Recurrent amplifications were observed in breast cancer drivers including MYC, FGFR1, CCND1, and ERBB2, as well as a recurrent amplification in 17q11.2 associated with high KIAA0100 gene expression that has been implicated in breast cancer aggressiveness. In conclusion, this study identified a higher prevalence of COSMIC signature 16 and a recurrent copy-number amplification affecting expression of KIAA0100 in breast tumors from H/L compared with White women. These results highlight the necessity of studying underrepresented populations., Significance: Comprehensive characterization of genomic and transcriptomic alterations in breast tumors from Hispanic/Latina patients reveals distinct genetic alterations and signatures, demonstrating the importance of inclusive studies to ensure equitable care for patients. See related commentary by Schmit et al., p. 2443., (©2023 The Authors; Published by the American Association for Cancer Research.)

Periodontitis is a worldwide bacterial infectious disease, resulting in the resorption of tooth-supporting structures. Biodegradable polymeric microspheres are emerging as an appealing local therapy candidate for periodontal defect regeneration but suffer from tedious procedures and low yields. Herein, we developed a facile yet scalable approach to prepare polylactide composite microspheres with outstanding drug-loading capability. It was realized by blending equimolar polylactide enantiomers at the temperature between the melting point of homocrystallites and stereocomplex (sc) crystallites, enabling the precipitation of sc crystallites in the form of microspheres. Meanwhile, epigallocatechin gallate (EGCG) and nano-hydroxyapatite were encapsulated in the microspheres in the designated amount. Such an assembly allowed the fast and sustained release of EGCG and Ca 2+ ions. The resultant hybrid composite microspheres not only exhibited strong antimicrobial activity against typical oral pathogens ( Porphyromonas gingivalis and Enterococcus faecalis ), but also directly promoted osteogenic differentiation of periodontal ligament stem cells with good cytocompatibility. These dual-functional composite microspheres offer a desired drug delivery platform to address the practical needs for periodontitis treatment.

Background: Belize is a middle-income Caribbean country with poorly described cancer epidemiology and no comprehensive cancer care capacity. In 2018, GO, Inc., a US-based NGO, partnered with the Ministry of Health and the national hospital in Belize City to create the first public oncology clinic in the country. Here, we report demographics from the clinic and describe time intervals to care milestones to allow for public health targeting of gaps., Patients and Methods: Using paper charts and a mobile health platform, we performed a retrospective chart review at the Karl Heusner Memorial Hospital (KHMH) clinic from 2018 to 2022., Results: During this time period, 465 patients with cancer presented to the clinic. Breast cancer (28%) and cervical cancer (12%) were most common. Most patients (68%) presented with stage 3 or 4 disease and were uninsured (78%) and unemployed (79%). Only 21% of patients ever started curative intent treatment. Median time from patient-reported symptoms to a biopsy or treatment was 130 and 189 days. For the most common cancer, breast, similar times were seen at 140 and 178 days. Time intervals at the clinic: <30 days from initial visit to biopsy (if not previously performed) and <30 days to starting chemotherapy., Conclusion: This study reports the first clinic-based cancer statistics for Belize. Many patients have months between symptom onset and treatment. In this setting, the clinic has built infrastructure allowing for minimal delays in care despite an underserved population. This further affirms the need for infrastructure investment and early detection programs to improve outcomes in Belize., (© The Author(s) 2023. Published by Oxford University Press.)

Advances in molecular diagnostics have enabled the identification of targetable driver pathogenic variants, forming the basis of precision oncology care. However, the adoption of new technologies, such as next-generation sequencing (NGS) panels, can exacerbate healthcare disparities. Here, we summarize data on use patterns of advanced biomarker testing, highlight the disparities in both accessing NGS testing and using this data to match patients to appropriate personalized therapies and propose multidisciplinary strategies to address inequities looking forward., (© 2023. Springer Nature America, Inc.)

Objectives: Acute cholecystitis is a gallbladder inflammation, and the Tokyo Guidelines 2018 (TG18) can be used to predict its presence and severity with high sensitivity and specificity. However, TG18 grading require the collection of excessive parameters. Monocyte distribution width (MDW) is a parameter used to detect sepsis early. Therefore, we investigated the correlation between MDW and cholecystitis severity., Methods: We conducted a retrospective study of patients with cholecystitis admitted to our hospital from November 1, 2020, to August 31, 2021. The primary outcome was severe cholecystitis analyzed as a composite of intensive care unit (ICU) admission and mortality. The secondary outcomes were length of hospital stay, ICU stay, and TG18 grade., Results: A total of 331 patients with cholecystitis were enrolled in this study. The average MDWs for TG18 grades 1, 2, and 3 were 20.21 ± 3.99, 20.34 ± 3.68, and 25.77 ± 6.61, respectively. For patients with severe cholecystitis, the average MDW was 25.42 ± 6.83. Using the Youden J statistic, we set a cutoff MDW of 21.6. Multivariate logistic regression revealed that patients with an MDW≥21.6 had a higher risk of severe cholecystitis (odds ratio=4.94; 95 % CI, 1.71-14.21; p=0.003). The Cox model revealed that patients with an MDW≥21.6 were more likely to have a prolonged hospital stay., Conclusions: MDW is a reliable indicator of severe cholecystitis and prolonged length of stay. Additional MDW testing and a complete blood count may provide simple information for predicting severe cholecystitis early., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Men of African ancestry have disproportionately high incidence rates of prostate cancer (PCa) and have high mortality rates. While there is evidence for a higher genetic predisposition for incidence of PCa in men of African ancestry compared to men of European ancestry, there have been few transcriptomic studies on PCa in men of African ancestry in the African continent., Objective: We performed transcriptomic profiling and fusion analysis on bulk RNA sequencing (RNA-seq) samples from 24 Nigerian PCa patients to investigate the transcriptomic and genomic rearrangement landscape of PCa in Nigerian men., Design: Bulk RNA-seq was performed on 24 formalin-fixed paraffin-embeded (FFPE) prostatectomy specimens of Nigerian men. Transcriptomic analysis was performed on 11 high-quality samples. Arriba Fusion and STAR Fusion were used for fusion detection., Results: 4/11 (36%) of the samples harbored an erythroblast transformation-specific (ETS) fusion event; 1/11 (9%) had a TMPRSS2-ERG fusion; 2/11 had a TMPRSS2-ETV5 fusion, and 1/11 had a SLC45A3-SKIL fusion. Hierarchical clustering of normalized and mean-centered gene expression showed clustering of fusion positive samples. Furthermore, we developed gene set signatures for Nigerian PCa based on fusion events. By projecting the cancer genome atlas prostate adenocarcinoma (TCGA-PRAD) bulk RNA-seq data set onto the transcriptional space defined by these signatures derived from Nigerian PCa patients, we identified a positive correlation between the Nigerian fusion signature and fusion positive samples in the TCGA-PRAD data set., Conclusions: Less frequent ETS fusion events other than TMPRSS2-ERG such as TMPRSS2-ETV5 and non-ETS fusion events such as SLC45A3-SKIL may be more common in PCa in Nigerian men. This study provides useful working transcriptomic signatures that characterize oncogenic states representative of specific gene fusion events in PCa from Nigerian men., (© 2023 Wiley Periodicals LLC.)

Background: Colonic diverticulitis is a leading cause of abdominal pain. The monocyte distribution width (MDW) is a novel inflammatory biomarker with prognostic significance for coronavirus disease and pancreatitis; however, no study has assessed its correlation with the severity of colonic diverticulitis., Methods: This single-center retrospective cohort study included patients older than 18 years who presented to the emergency department between November 1, 2020, and May 31, 2021, and received a diagnosis of acute colonic diverticulitis after abdominal computed tomography. The characteristics and laboratory parameters of patients with simple versus complicated diverticulitis were compared. The significance of categorical data was assessed using the chi-square or Fisher's exact test. The Mann-Whitney U test was used for continuous variables. Multivariable regression analysis was performed to identify predictors of complicated colonic diverticulitis. Receiver operator characteristic (ROC) curves were used to test the efficacy of inflammatory biomarkers in distinguishing simple from complicated cases., Results: Of the 160 patients enrolled, 21 (13.125%) had complicated diverticulitis. Although right-sided was more prevalent than left-sided colonic diverticulitis (70% versus 30%), complicated diverticulitis was more common in those with left-sided colonic diverticulitis (61.905%, p = 0.001). Age, white blood cell (WBC) count, neutrophil count, C-reactive protein (CRP) level, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and MDW were significantly higher in the complicated diverticulitis group (p < 0.05). Logistic regression analysis indicated that the left-sided location and the MDW were significant and independent predictors of complicated diverticulitis. The area under the ROC curve (AUC) was as follows: MDW, 0.870 (95% confidence interval [CI], 0.784-0.956); CRP, 0.800 (95% CI, 0.707-0.892); NLR, 0.724 (95% CI, 0.616-0.832); PLR, 0.662 (95% CI, 0.525-0.798); and WBC, 0.679 (95% CI, 0.563-0.795). When the MDW cutoff was 20.38, the sensitivity and specificity were maximized to 90.5% and 80.6%, respectively., Conclusions: A large MDW was a significant and independent predictor of complicated diverticulitis. The optimal cutoff value for MDW is 20.38 as it exhibits maximum sensitivity and specificity for distinguishing between simple and complicated diverticulitis The MDW may aid in planning antibiotic therapy for patients with colonic diverticulitis in the emergency department., (© 2023. The Author(s).)

The cap-and-trade mechanism affects firms' production and operation decisions and carbon emissions, making them move towards environmental sustainability. This article develops a contingent claims model to examine the impact of the regulatory cap-and-trade mechanism on the green finance strategy of an insurer during a war. Participating in the cap-and-trade scheme of the insurer that funds the borrowing firms also implicitly affects firm production and carbon emissions. The results show that increasing the green loans decreases the interest margin of the insurer but helps policyholder protection. The insurer is reluctant to provide green loans for the green borrowing firm and thus retards sustainable development. A stringent regulatory cap of the cap-and-trade mechanism raises the insurer's interest margin but hurts policyholder protection. From the perspective of the insurer's profit, regulatory cap efficiently derives insurer lending toward sustainability through borrowing-firm cleaner production. An increased war impacting the polluting borrowing firm increases the insurer's interest margin but harms policyholder protection, affecting insurance stability adversely. This research enriches related literature and knowledge concerning insurer green finance practices indirectly associated with cleaner production. The research also highlights the significance of the regulatory cap-and-trade mechanism that reflects cleaner production in affecting insurer performance during a war., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Huang, Lin. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Advanced prostate malignancies are a leading cause of cancer-related deaths in men, in large part due to our incomplete understanding of cellular drivers of disease progression. We investigate prostate cancer cell dynamics at single-cell resolution from disease onset to the development of androgen independence in an in vivo murine model. We observe an expansion of a castration-resistant intermediate luminal cell type that correlates with treatment resistance and poor prognosis in human patients. Moreover, transformed epithelial cells and associated fibroblasts create a microenvironment conducive to pro-tumorigenic immune infiltration, which is partially androgen responsive. Androgen-independent prostate cancer leads to significant diversification of intermediate luminal cell populations characterized by a range of androgen signaling activity, which is inversely correlated with proliferation and mRNA translation. Accordingly, distinct epithelial populations are exquisitely sensitive to translation inhibition, which leads to epithelial cell death, loss of pro-tumorigenic signaling, and decreased tumor heterogeneity. Our findings reveal a complex tumor environment largely dominated by castration-resistant luminal cells and immunosuppressive infiltrates., Competing Interests: AG, SA, YZ, EG, IC, AK, SW, HS, NB, RA, MZ, AL, YY, JB, RG, DR, FH, CG, PN, AS, MS, AH No competing interests declared

Human prostate cancer can result from chromosomal rearrangements that lead to aberrant ETS gene expression. The mechanisms that lead to fusion-independent ETS factor upregulation and prostate oncogenesis remain relatively unknown. Here, we show that two neighboring transcription factors, Capicua ( CIC ) and ETS2 repressor factor ( ERF ), which are co-deleted in human prostate tumors can drive prostate oncogenesis. Concurrent CIC and ERF loss commonly occur through focal genomic deletions at chromosome 19q13.2. Mechanistically, CIC and ERF co-bind the proximal regulatory element and mutually repress the ETS transcription factor, ETV1 . Targeting ETV1 in CIC and ERF -deficient prostate cancer limits tumor growth. Thus, we have uncovered a fusion-independent mode of ETS transcriptional activation defined by concurrent loss of CIC and ERF ., Competing Interests: NG, HS, WW, RP, YL, JK, ES, FF, FH, RO No competing interests declared, (© 2022, Gupta et al.)

Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease., Significance: In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: The prognostic significance of conversion into a shockable rhythm in patients who experienced out-of-hospital cardiac arrest (OHCA) with an initially nonshockable rhythm is controversial, perhaps due to the timing of rhythm conversion not being considered previously. We aimed to compare the different prognoses of patients with OHCA and early and late conversion of their rhythm into a shockable rhythm., Methods: This was a single-centre retrospective cohort study. We enrolled patients with OHCA who were sent to a medical centre in central Taiwan from 2016 to 2020. Patients <18 years old, those with cardiac arrest due to trauma or a circumstantial cause, and those for whom resuscitation was not attempted were excluded. Patients were divided into two groups in accordance with presentation with an initially shockable rhythm. Those with an initially nonshockable rhythm were divided into three subgroups: early-conversion, late-conversion, and nonconversion groups. The primary outcome was the neurological functional status upon discharge from hospital., Results: A total of 1645 patients with OHCA were included: initially shockable rhythm group, 339; early conversion group, 68; late-conversion group, 166; and nonconversion group, 1072. After adjustment, multivariate logistic regression revealed that a favourable neurological outcome was more common in the early conversion group than the nonconversion group (odds ratio [OR] 2.4; 95% confidence interval [CI], 1.1-5.3; p = 0.035), whereas the late-conversion group did not significantly differ from the nonconversion group (OR 0.5; 95% CI, 0.1-1.5; p = 0.211). The proportions of sustained return of spontaneous circulation and survival to discharge were also higher in the early conversion group than the late-conversion group (OR 2.9 95% CI 1.6-5.5, p = 0.001 and OR 4.5, 1.8-11.0, p = 0.001, respectively)., Conclusion: In patients who experience OHCA and have an initially nonshockable rhythm, early conversion into a shockable rhythm resulted in a better prognosis, whereas late conversion was not significantly different from nonconversion., Competing Interests: Declaration of Competing Interest The authors have stated explicitly that there are no conflicts of interest in connection with this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Sudden cardiac arrest (SCA) is a critical complication of acute myocardial infarction, especially ST-segment elevation myocardial infarction (STEMI). This study identified the risk factors for SCA in patients with STEMI before receiving catheterization., Methods: We retrospectively analyzed the data of patients with STEMI and cardiac arrest who presented to a tertiary care center in Taiwan between January 1, 2016, and December 31, 2019. Only patients with coronary artery disease (CAD) confirmed by coronary angiography were included in this study. We collected the patients' demographic and clinical data, such as age, sex, medical history, estimated glomerular filtration rate (eGFR), and coronary angiographic findings. The primary outcome of this study was SCA in patients with STEMI. Continuous and nominal variables were compared using the two-sample Student's t-test and chi-squared test, respectively. The results of logistic regression were subjected to multivariate analysis with adjustment for possible confounders., Results: A total of 920 patients with STEMI and coronary angiography-documented CAD and 108 patients with SCA who presented between January 1, 2016, and December 31, 2019, were included. The bivariate logistic regression analysis of patients' demographic data revealed that patients with STEMI and SCA were slightly younger, were more likely to have diabetes mellitus, and had a lower eGFR than did the patients without SCA. The coronary angiographic findings indicated a higher prevalence of left main CAD and three-vessel disease in patients with SCA than in patients without SCA. Multivariate logistic regression revealed that left main CAD (odds ratio [OR]: 3.77; 95% confidence interval [CI], 1.84 to 7.72), a lower eGFR (OR: 0.97; 95% CI, 0.96 to 0.98), and younger age (OR: 0.98; 95% CI, 0.96 to 0.99) were the risk factors for SCA in patients with STEMI., Conclusions: Left main CAD, lower eGFR, and younger age are the risk factors for cardiac arrest in patients with acute myocardial infarction., (© 2022. The Author(s).)

Pediatric hepatoblastoma is the most common primary liver cancer in infants and children. Studies of hepatoblastoma that focus exclusively on tumor cells demonstrate sparse somatic mutations and a common cell of origin, the hepatoblast, across patients. In contrast to the homogeneity these studies would suggest, hepatoblastoma tumors have a high degree of heterogeneity that can portend poor prognosis. In this study, we use single-cell transcriptomic techniques to analyze resected human pediatric hepatoblastoma specimens, and identify five hepatoblastoma tumor signatures that may account for the tumor heterogeneity observed in this disease. Notably, patient-derived hepatoblastoma spheroid cultures predict differential responses to treatment based on the transcriptomic signature of each tumor, suggesting a path forward for precision oncology for these tumors. In this work, we define hepatoblastoma tumor heterogeneity with single-cell resolution and demonstrate that patient-derived spheroids can be used to evaluate responses to chemotherapy., (© 2022. The Author(s).)

Background: Persistent sinonasal symptoms are common in children with chronic rhinosinusitis. The Sinus and Nasal Quality of Life (QoL) Survey (SN-5) was the first validated questionnaire measuring sinonasal-related QoL in populations aged 2-12 years. No norm has been established for Chinese-speaking countries. We translated the SN-5 into traditional Chinese and evaluated validity and reliability., Methods: From December 2016 to December 2017, healthy volunteers and children with persistent sinonasal symptoms were enrolled. Guardians of the participants completed the SN-5, a visual analog scale (VAS) of nasal symptoms, and the Obstructive Sleep Apnea-18 (OSA-18); the responses were used to assess internal consistency, discriminant validity, and treatment responsiveness. A nontreatment group was administered the SN-5 1 week later to assess test-retest reliability., Results: We recruited 31 healthy volunteers and 85 children with rhinosinusitis, 50 and 35 in the treatment and nontreatment groups, respectively. The SN-5 demonstrated good internal consistency (Cronbach's α = 0.86) and test-retest reliability (0.74, p < 0.01). It exhibited good discriminant validity between the healthy and rhinosinusitis groups (p < 0.001). The SN-5 scores were correlated with the VAS scores (0.63, p < 0.001). The effect size of the SN-5 scores was 0.51. The total SN-5 and OSA-18 scores changed significantly after 4-week treatment (p < 0.05) and demonstrated good responsiveness. The SN-5 and OSA-18 scores were significantly and positively correlated (r 2  = 0.53, p < 0.001)., Conclusion: Our traditional Chinese version of the SN-5 is reliable and valid for measuring sinonasal-related QoL in children in Chinese-speaking countries., Trial Registration Number: NCT04836403., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Background: The interaction between cancer diagnoses and COVID-19 infection and outcomes is unclear. We leveraged a state-wide, multi-institutional database to assess cancer-related risk factors for poor COVID-19 outcomes., Methods: We conducted a retrospective cohort study using the University of California Health COVID Research Dataset, which includes electronic health data of patients tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at 17 California medical centers. We identified adults tested for SARS-CoV-2 from 2/1/2020-12/31/2020 and selected a cohort of patients with cancer. We obtained demographic, clinical, cancer type, and antineoplastic therapy data. The primary outcome was hospitalization within 30d after the first positive SARS-CoV-2 test. Secondary outcomes were SARS-CoV-2 positivity and severe COVID-19 (intensive care, mechanical ventilation, or death within 30d after the first positive test). We used multivariable logistic regression to identify cancer-related factors associated with outcomes., Results: We identified 409,462 patients undergoing SARS-CoV-2 testing. Of 49,918 patients with cancer, 1781 (3.6%) tested positive. Patients with cancer were less likely to test positive (RR 0.70, 95% CI: 0.67-0.74, p < 0.001). Among the 1781 SARS-CoV-2-positive patients with cancer, BCR/ABL-negative myeloproliferative neoplasms (RR 2.15, 95% CI: 1.25-3.41, p = 0.007), venetoclax (RR 2.96, 95% CI: 1.14-5.66, p = 0.028), and methotrexate (RR 2.72, 95% CI: 1.10-5.19, p = 0.032) were associated with greater hospitalization risk. Cancer and therapy types were not associated with severe COVID-19., Conclusions: In this large, diverse cohort, cancer was associated with a decreased risk of SARS-CoV-2 positivity. Patients with BCR/ABL-negative myeloproliferative neoplasm or receiving methotrexate or venetoclax may be at increased risk of hospitalization following SARS-CoV-2 infection. Mechanistic and comparative studies are needed to validate findings., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Overcrowding in emergency departments (ED) is a critical problem worldwide, and streaming can alleviate crowding to improve patient flows. Among triage scales, patients labeled as "triage level 3" or "urgent" generally comprise the majority, but there is no uniform criterion for classifying low-severity patients in this diverse population. Our aim is to establish a machine learning model for prediction of low-severity patients with short discharge length of stay (DLOS) in ED., Methods: This was a retrospective study in the ED of China Medical University Hospital (CMUH) and Asia University Hospital (AUH) in Taiwan. Adult patients (aged over 20 years) with Taiwan Triage Acuity Scale level 3 were enrolled between 2018 and 2019. We used available information during triage to establish a machine learning model that can predict low-severity patients with short DLOS. To achieve this goal, we trained five models-CatBoost, XGBoost, decision tree, random forest, and logistic regression-by using large ED visit data and examined their performance in internal and external validation., Results: For internal validation in CMUH, 33,986 patients (75.9%) had a short DLOS (shorter than 4 h), and for external validation in AUH, there were 13,269 (82.7%) patients with short DLOS. The best prediction model was CatBoost in internal validation, and area under the receiver operating cha racteristic curve (AUC) was 0.755 (95% confidence interval (CI): 0.743-0.767). Under the same threshold, XGBoost yielded the best performance, with an AUC value of 0.761 (95% CI: 0.742- 0.765) in external validation., Conclusions: This is the first study to establish a machine learning model by applying triage information alone for prediction of short DLOS in ED with both internal and external validation. In future work, the models could be developed as an assisting tool in real-time triage to identify low-severity patients as fast track candidates., (© 2022. The Author(s).)

Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.

Background: Primary and metastatic prostate cancers have low mutation rates and recurrent alterations in a small set of genes, enabling targeted sequencing of prostate cancer-associated genes as an efficient approach to characterizing patient samples (compared to whole-exome and whole-genome sequencing). For example, targeted sequencing provides a flexible, rapid, and cost-effective method for genomic assessment of patient-derived cell lines to evaluate fidelity to initial patient tumor samples., Methods: We developed a prostate cancer-specific targeted next-generation sequencing (NGS) panel to detect alterations in 62 prostate cancer-associated genes as well as recurring gene fusions with ETS family members, representing the majority of common alterations in prostate cancer. We tested this panel on primary prostate cancer tissues and blood biopsies from patients with metastatic prostate cancer. We generated patient-derived cell lines from primary prostate cancers using conditional reprogramming methods and applied targeted sequencing to evaluate the fidelity of these cell lines to the original patient tumors., Results: The prostate cancer-specific panel identified biologically and clinically relevant alterations, including point mutations in driver oncogenes and ETS family fusion genes, in tumor tissues from 29 radical prostatectomy samples. The targeted panel also identified genomic alterations in cell-free DNA and circulating tumor cells (CTCs) from patients with metastatic prostate cancer, and in standard prostate cancer cell lines. We used the targeted panel to sequence our set of patient-derived cell lines; however, no prostate cancer-specific mutations were identified in the tumor-derived cell lines, suggesting preferential outgrowth of normal prostate epithelial cells., Conclusions: We evaluated a prostate cancer-specific targeted NGS panel to detect common and clinically relevant alterations (including ETS family gene fusions) in prostate cancer. The panel detected driver mutations in a diverse set of clinical samples of prostate cancer, including fresh-frozen tumors, cell-free DNA, CTCs, and cell lines. Targeted sequencing of patient-derived cell lines highlights the challenge of deriving cell lines from primary prostate cancers and the importance of genomic characterization to credential candidate cell lines. Our study supports that a prostate cancer-specific targeted sequencing panel provides an efficient, clinically feasible approach to identify genetic alterations across a spectrum of prostate cancer samples and cell lines., (© 2022 Wiley Periodicals LLC.)

A laccase catalyzed colorimetric biosensing approach is promising for the detection of pheochromocytoma biomarkers, yet suffers from the poor stability of enzymes and high cost for production. Here we report for the first time an easy to produce, cheap, stable and reliable laccase-mimicking CuCoFe-LDHzyme, which can catalyze the oxidation of pheochromocytoma biomarkers to form a chromogenic product for smartphone-based colorimetric detection.

Prostate cancer is the second most common malignancy in men worldwide and consists of a mixture of tumor and non-tumor cell types. To characterize the prostate cancer tumor microenvironment, we perform single-cell RNA-sequencing on prostate biopsies, prostatectomy specimens, and patient-derived organoids from localized prostate cancer patients. We uncover heterogeneous cellular states in prostate epithelial cells marked by high androgen signaling states that are enriched in prostate cancer and identify a population of tumor-associated club cells that may be associated with prostate carcinogenesis. ERG-negative tumor cells, compared to ERG-positive cells, demonstrate shared heterogeneity with surrounding luminal epithelial cells and appear to give rise to common tumor microenvironment responses. Finally, we show that prostate epithelial organoids harbor tumor-associated epithelial cell states and are enriched with distinct cell types and states from their parent tissues. Our results provide diagnostically relevant insights and advance our understanding of the cellular states associated with prostate carcinogenesis., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Competing Interests: Sophia C. KamranEmployment: Sanofi (I) Elina L. PalapattuStock and Other Ownership Interests: NantKwest (I)Research Funding: Minomic (I) Alexander GusevPatents, Royalties, Other Intellectual Property: Pending patent on an immunotherapy biomarker Eliezer M. Van AllenThis author is an Associate Editor for JCO Precision Oncology. Journal policy recused the author from having any role in the peer review of this manuscript.Stock and Other Ownership Interests: Syapse, Tango Therapeutics, Genome Medical, Microsoft, Ervaxx, Monte Rosa Therapeutics, Manifold BioConsulting or Advisory Role: Syapse, Roche, Third Rock Ventures, Takeda, Novartis, Genome Medical, InVitae, Illumina, Tango Therapeutics, Ervaxx, Janssen, Monte Rosa Therapeutics, Manifold BioSpeakers' Bureau: IlluminaResearch Funding: Bristol Myers Squibb, NovartisPatents, Royalties, Other Intellectual Property: Patent on discovery of retained intron as source of cancer neoantigens, Patent on discovery of chromatin regulators as biomarkers of response to cancer immunotherapy, Patent on clinical interpretation algorithms using cancer molecular dataTravel, Accommodations, Expenses: Roche/Genentech Franklin W. HuangStock and Other Ownership Interests: GlaxoSmithKlineNo potential conflicts of interest were reported.

In cancer, telomere maintenance is critical for the development of replicative immortality. Using genome sequences from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer Project, we calculated telomere content across 1299 cancer cell lines. We find that telomerase reverse transcriptase ( TERT ) expression correlates with telomere content in lung, central nervous system, and leukemia cell lines. Using CRISPR/Cas9 screening data, we show that lower telomeric content is associated with dependency of CST telomere maintenance genes. Increased dependencies of shelterin members are associated with wild-type TP53 status. Investigating the epigenetic regulation of TERT , we find widespread allele-specific expression in promoter-wildtype contexts. TERT promoter-mutant cell lines exhibit hypomethylation at PRC2-repressed regions, suggesting a cooperative global epigenetic state in the reactivation of telomerase. By incorporating telomere content with genomic features across comprehensively characterized cell lines, we provide further insights into the role of telomere regulation in cancer immortality., Competing Interests: KH, FH No competing interests declared, MG MG is an employee and holds equity in Monte Rosa Therapeutics and is a founding member at Cambridge Data Science LLC., (© 2021, Hu et al.)

Background: Emergency medical service (EMS) personnel have high COVID-19 risk during resuscitation. The resuscitation protocol for patients with out-of-hospital cardiac arrest (OHCA) was modified in response to the COVID-19 pandemic. However, how the adjustments in the EMS system affected patients with OHCA remains unclear., Methods: We analysed data from the Taichung OHCA registry system. We compared OHCA outcomes and rescue records for 622 cases during the COVID-19 outbreak period (1 February to 30 April 2020) with those recorded for 570 cases during the same period in 2019., Results: The two periods did not differ significantly with respect to patient age, patient sex, the presence of witnesses or OHCA location. Bystander cardiopulmonary resuscitation and defibrillation with automated external defibrillators were more common in 2020 (52.81% vs 65.76%, p<0.001%, and 23.51% vs 31.67%, p=0.001, respectively). The EMS response time was longer during the COVID-19 pandemic (445.8±210.2 s in 2020 vs 389.7±201.8 s in 2019, p<0.001). The rate of prehospital return of spontaneous circulation was lower in 2020 (6.49% vs 2.57%, p=0.001); 2019 and 2020 had similar rates of survival discharge (5.96% vs 4.98%). However, significantly fewer cases had favourable neurological function in 2020 (4.21% vs 2.09%, p=0.035)., Conclusion: EMS response time for patients with OHCA was prolonged during the COVID-19 pandemic. Early advanced life support by EMS personnel remains crucial for patients with OHCA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: As access to cancer care expands in low-income countries, developing tools to educate patients is paramount. We took a picture booklet, which was initially developed by the nonprofit Global Oncology for Malawi and Rwanda, and adapted it for use in Nigeria. The primary goal was to assess acceptability and provide education. The secondary goals were (1) to describe the collaboration, (2) to assess knowledge gained from the intervention, (3) to assess patient understanding of their therapy intent, and (4) to explore patient's experiences via qualitative analysis., Methods: We piloted the original English booklet at a single site and requested feedback from patients and providers. The booklet was updated; translated into Hausa, Yoruba, Igbo, and Pidgin English; and used at three additional sites. For the three-site cohort, we collected basic demographics, pretest and post-test assessing content in the booklet, and performed a qualitative analysis., Results: The original booklet was widely acceptable and recommended by patients at site one (n = 31) and by providers (N = 26) representing all four sites. In the three-site cohort (n = 103), 94% of patients recommended the booklet. An immediate post-test focusing on when patients should present to care showed a statistically significant improvement in one of the seven questions. Fifty-one percent of the patients (n = 103) knew their treatment intent (curative v palliative). Qualitative analysis highlighted that the patient's thoughts on cancer are dominated by negative associations, although curability and modern therapy are also frequently cited., Conclusion: We adapted an educational booklet to a novel context and had it delivered by local partners. The booklet was widely recommended to future patients. The booklet had an impact on patient's knowledge of cancer treatment, potentially allowing for decreased abandonment., Competing Interests: Abubakar BelloHonoraria: PfizerConsulting or Advisory Role: Pfizer, Roche¸ Merck SeronoSpeakers' Bureau: NCCN Vivienne MulemaEmployment: Mavie Life PharmacyConsulting or Advisory Role: Beyond Logistics Limited Danna RemenEmployment: Allurion (I)Stock and Other Ownership Interests: Allurion (I)Research Funding: Allurion (I) Ami S. BhattEmployment: January.ai (I), Varian Medical Systems (I)Consulting or Advisory Role: Janssen Research & Development, ArcBio, January.ai, Kaleido Biosciences¸ Caribou Biosciences, Guardant Health, BiomXPatents, Royalties, Other Intellectual Property: I have a single patent pending related to SARS-CoV-2 detection in fecal samples. My spouse has several patents pending related to the use of artificial intelligence for blood glucose prediction and radiation therapy planning. Mohana RoyResearch Funding: Varian Medical Systems (Inst)No other potential conflicts of interest were reported.

Disparities in cancer incidence, prevalence, burden, and outcome exist among specific population groups in the United States. Researchers have identified germline genetic risk single-nucleotide polymorphisms (SNP) that differ by ancestry and may contribute to some of these differences. In this issue of Cancer Research , Han and colleagues found the prostate cancer risk SNP rs4713266 is associated with increased risk of patients with African ancestry. The authors investigated the functional role of the risk SNP, finding that it alters activity of a NEDD9 enhancer and increases NEDD9 expression. The study provides epidemiologic and mechanistic insight into factors that may drive prostate cancer disparities. See related article by Han et al., p. 3766 ., (©2021 American Association for Cancer Research.)

The TGF-β type V receptor (TβR-V) mediates growth inhibition by IGFBP-3 and TGF-β in epithelial cells and loss of TβR-V expression in these cells leads to development of carcinoma. The mechanisms by which TβR-V mediates growth inhibition (tumor suppressor) signaling remain elusive. Previous studies revealed that IGFBP-3 and TGF-β inhibit growth in epithelial cells by stimulating TβR-V-mediated IRS-1/2-dependent activation and cytoplasm-to-nucleus translocation of IGFBP-3- or TGF-β-stimulated protein phosphatase (PPase), resulting in dephosphorylation of pRb-related proteins (p107, p130) or pRb, and growth arrest. To define the signaling, we characterized/identified the IGFBP-3- and TGF-β-stimulated PPases in cell lysates and nucleus fractions in Mv1Lu cells treated with IGFBP-3 and TGF-β, using a cell-free assay with 32 P-labeled casein as a substrate. Both IGFBP-3- and TGF-β-stimulated PPase activities in cell lysates are abolished when cells are co-treated with TGF-β/IGFBP-3 antagonist or RAP (LRP-1/TβR-V antagonist). However, the IGFBP-3-stimulated PPase activity, but not TGF-β-stimulated PPase activity, is sensitive to inhibition by okadaic acid (OA). In addition, OA or PP2A c siRNA reverses IGFBP-3 growth inhibition, but not TGF-β growth inhibition, in Mv1Lu and 32D cells. These suggest that IGFBP-3- and TGF-β-stimulated PPases are identical to PP2A and PP1, respectively. By Western blot/phosphorimager/immunofluorescence-microscopy analyses, IGFBP-3 and TGF-β stimulate TβR-V-mediated IRS-2-dependent activation and cytoplasm-to-nucleus translocation of PP2A c and PP1 c , resulting in dephosphorylation of p130/p107 and pRb, respectively, and growth arrest. Small molecule TGF-β enhancers, which potentiate TGF-β growth inhibition by enhancing TβR-I-TβR-II-mediated canonical signaling and thus activating TβR-V-mediated tumor suppressor signaling cascade (TβR-V/IRS-2/PP1/pRb), could be used to prevent and treat carcinoma., Competing Interests: The authors declare that there are no competing financial interest associated with this work., (© 2021 The Authors. FASEB BioAdvances published by the Federation of American Societies for Experimental Biology.)

The smallest genomic region causing Prader-Willi Syndrome (PWS) deletes the non-coding RNA SNORD116 cluster; however, the function of SNORD116 remains a mystery. Previous work in the field revealed the tantalizing possibility that expression of NHLH2, a gene previously implicated in both obesity and hypogonadism, was downregulated in PWS patients and differentiated stem cells. In silico RNA: RNA modeling identified several potential interaction domains between SNORD116 and NHLH2 mRNA. One of these interaction domains was highly conserved in most vertebrate NHLH2 mRNAs examined. A construct containing the Nhlh2 mRNA, including its 3'-UTR, linked to a c-myc tag was transfected into a hypothalamic neuron cell line in the presence and absence of exogenously-expressed Snord116. Nhlh2 mRNA expression was upregulated in the presence of Snord116 dependent on the length and type of 3'UTR used on the construct. Furthermore, use of actinomycin D to stop new transcription in N29/2 cells demonstrated that the upregulation occurred through increased stability of the Nhlh2 mRNA in the 45 minutes immediately following transcription. In silico modeling also revealed that a single nucleotide variant (SNV) in the NHLH2 mRNA could reduce the predicted interaction strength of the NHLH2:SNORD116 diad. Indeed, use of an Nhlh2 mRNA construct containing this SNV significantly reduces the ability of Snord116 to increase Nhlh2 mRNA levels. For the first time, these data identify a motif and mechanism for SNORD116-mediated regulation of NHLH2, clarifying the mechanism by which deletion of the SNORD116 snoRNAs locus leads to PWS phenotypes., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Genotype-phenotype maps provide a meaningful filtration of sequence space and RNA secondary structures are particular such phenotypes. Compatible sequences, which satisfy the base-pairing constraints of a given RNA structure, play an important role in the context of neutral evolution. Sequences that are simultaneously compatible with two given structures (bicompatible sequences), are beacons in phenotypic transitions, induced by erroneously replicating populations of RNA sequences. RNA riboswitches, which are capable of expressing two distinct secondary structures without changing the underlying sequence, are one example of bicompatible sequences in living organisms., Results: We present a full loop energy model Boltzmann sampler of bicompatible sequences for pairs of structures. The sequence sampler employs a dynamic programming routine whose time complexity is polynomial when assuming the maximum number of exposed vertices, [Formula: see text], is a constant. The parameter [Formula: see text] depends on the two structures and can be very large. We introduce a novel topological framework encapsulating the relations between loops that sheds light on the understanding of [Formula: see text]. Based on this framework, we give an algorithm to sample sequences with minimum [Formula: see text] on a particular topologically classified case as well as giving hints to the solution in the other cases. As a result, we utilize our sequence sampler to study some established riboswitches., Conclusion: Our analysis of riboswitch sequences shows that a pair of structures needs to satisfy key properties in order to facilitate phenotypic transitions and that pairs of random structures are unlikely to do so. Our analysis observes a distinct signature of riboswitch sequences, suggesting a new criterion for identifying native sequences and sequences subjected to evolutionary pressure. Our free software is available at: https://github.com/FenixHuang667/Bifold .

Pairs of related bladder cancer cases who belong to pedigrees with an excess of bladder cancer were sequenced to identify rare, shared variants as candidate predisposition variants. Candidate variants were tested for association with bladder cancer risk. A validated variant was assayed for segregation to other related cancer cases, and the predicted protein structure of this variant was analyzed. This study of affected bladder cancer relative pairs from high-risk pedigrees identified 152 bladder cancer predisposition candidate variants. One variant in ERF (ETS Repressing Factor) was significantly associated with bladder cancer risk in an independent population, was observed to segregate with bladder and prostate cancer in relatives, and showed evidence for altering the function of the associated protein. This finding of a rare variant in ERF that is strongly associated with bladder and prostate cancer risk in an extended pedigree both validates ERF as a cancer predisposition gene and shows the continuing value of analyzing affected members of high-risk pedigrees to identify and validate rare cancer predisposition variants.

Background: Immune checkpoint inhibitors (ICI) can achieve durable responses in a subset of patients with locally advanced or metastatic urothelial carcinoma (aUC). The use of tumor genomic profiling in clinical practice may help suggest biomarkers to identify patients most likely to benefit from ICI., Methods: We undertook a retrospective analysis of patients treated with an ICI for aUC at a large academic medical center. Patient clinical and histopathological variables were collected. Responses to treatment were assessed for all patients with at least one post-baseline scan or clear evidence of clinical progression following treatment start. Genomic profiling information was also collected for patients when available. Associations between patient clinical/genomic characteristics and objective response were assessed by logistic regression; associations between the characteristics and progression-free survival (PFS) and overall survival (OS) were examined by Cox regression. Multivariable analyses were performed to identify independent prognostic factors., Results: We identified 119 aUC patients treated with an ICI from December 2014 to January 2020. Genomic profiling was available for 78 patients. Overall response rate to ICI was 29%, and median OS (mOS) was 13.4 months. Favorable performance status at the start of therapy was associated with improved OS (HR 0.46, p=0.025) after accounting for other covariates. Similarly, the presence of a TERT promoter mutation was an independent predictor of improved PFS (HR 0.38, p=0.012) and OS (HR 0.32, p=0.037) among patients who had genomic profiling available. Patients with both a favorable performance status and a TERT promoter mutation had a particularly good prognosis with mOS of 21.1 months as compared with 7.5 months in all other patients (p=0.03)., Conclusions: The presence of a TERT promoter mutation was an independent predictor of improved OS in a cohort of aUC patients treated with an ICI who had genomic data available. Most of the clinical and laboratory variables previously shown to be prognostic in aUC patients treated with chemotherapy did not have prognostic value among patients treated with an ICI. Genomic profiling may provide important prognostic information and affect clinical decision making in this patient population. Validation of these findings in prospective patient cohorts is needed., Competing Interests: Competing interests: AD reports personal fees from Dendreon. JC reports funding from Bristol-Meyers Squibb. FWH reports funding from GlaxoSmithKline DYO reports research support from Roche/Genentech, Merck and PACT Pharma, as well as consulting fees from Maze Therapeutics. LF reports grants from Abbvie, Bavarian Nordic, BMS, Dendreon, Janssen, Merck ansd Roche-Genentech. EJS reports personal fees and funding from Fortis Therapeutics, personal fees and funding from Harpoon Therapeutics, as well as personal fees from Janssen, Johnson and Johnson, Teon Therapeutics, Ultragenyx, Beigene and Tolero. TWF reports personal fees from EMD Serono, Astra Zeneca, grants from Roche/Genentech, as well as grants and personal fees from Seattle Genetics. VK reports grants and personal fees from Clovis, personal fees from Pfizer, AstraZeneca, Dendreon and Seattle Genetics, as well as grants from Nektar and Endocyte. The other authors have declared no relevant competing interests related to this manuscript., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: Metabolic acidosis is observed in 98% of patients with out-of-hospital cardiac arrest (OHCA). The longer the no-flow or low-flow duration, the more severe is the acidosis in these patients. This study explored whether blood pH in early stages of advanced life support (ALS) was an independent predictor of neurological prognosis in patients with OHCA.We retrospectively enrolled patients with OHCA from January 2012 to June 2018 in a single-medical tertiary hospital in Taiwan. Patients with OHCA whose blood gas analyses within 5 minutes after receiving ALS at the emergency department (ED) were enrolled. Patients younger than 20 years old, with cardiac arrest resulting from traumatic or circumstantial causes, with return of spontaneous circulation (ROSC) before ED arrival, lacking record of initial blood gas analysis, and with do-not-resuscitate orders were excluded. The primary outcome of this study was neurological status at hospital discharge.In total, 2034 patients with OHCA were enrolled. The majority were male (61.89%), and the average age was 67.8 ± 17.0 years. Witnessed OHCA was noted in 571 cases, cardiopulmonary resuscitation was performed before paramedic arrival in 512 (25.2%) cases, and a shockable rhythm was observed in 269 (13.2%). Blood pH from initial blood gas analysis remained an independent predictor of neurological outcome after multivariate regression.Blood pH at early stages of ALS was an independent prognostic factor of post-OHCA neurological outcome. Blood gas analysis on arrival at the ED may provide additional information about the prognosis of patients with OHCA., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Cancer researchers use cell lines, patient-derived xenografts, engineered mice, and tumoroids as models to investigate tumor biology and to identify therapies. The generalizability and power of a model derive from the fidelity with which it represents the tumor type under investigation; however, the extent to which this is true is often unclear. The preponderance of models and the ability to readily generate new ones has created a demand for tools that can measure the extent and ways in which cancer models resemble or diverge from native tumors., Methods: We developed a machine learning-based computational tool, CancerCellNet, that measures the similarity of cancer models to 22 naturally occurring tumor types and 36 subtypes, in a platform and species agnostic manner. We applied this tool to 657 cancer cell lines, 415 patient-derived xenografts, 26 distinct genetically engineered mouse models, and 131 tumoroids. We validated CancerCellNet by application to independent data, and we tested several predictions with immunofluorescence., Results: We have documented the cancer models with the greatest transcriptional fidelity to natural tumors, we have identified cancers underserved by adequate models, and we have found models with annotations that do not match their classification. By comparing models across modalities, we report that, on average, genetically engineered mice and tumoroids have higher transcriptional fidelity than patient-derived xenografts and cell lines in four out of five tumor types. However, several patient-derived xenografts and tumoroids have classification scores that are on par with native tumors, highlighting both their potential as faithful model classes and their heterogeneity., Conclusions: CancerCellNet enables the rapid assessment of transcriptional fidelity of tumor models. We have made CancerCellNet available as a freely downloadable R package ( https://github.com/pcahan1/cancerCellNet ) and as a web application ( http://www.cahanlab.org/resources/cancerCellNet&#95;web ) that can be applied to new cancer models that allows for direct comparison to the cancer models evaluated here.

Prostate cancer disproportionately affects racial and ethnic minority populations. Reasons for disparate outcomes among minority patients are multifaceted and complex, involving factors at the patient, provider, and system levels. Although advancements in our understanding of disease biology have led to novel therapeutics for men with advanced prostate cancer, including the introduction of biomarker-driven therapeutics, pivotal translational studies and clinical trials are underrepresented by minority populations. Despite attempts to bridge the disparities gap, there remains an unmet need to expand minority engagement and participation in clinical trials to better define the impact of therapy on efficacy outcomes, quality of life, and role of biomarkers in diverse patient populations. The IRONMAN registry (ClinicalTrials.gov identifier: NCT03151629), a global, prospective, population-based study, was borne from this unmet medical need to address persistent gaps in our knowledge of advanced prostate cancer. Through integrated collection of clinical outcomes, patient-reported outcomes, epidemiologic data, and biospecimens, IRONMAN has the goal of expanding our understanding of how and why prostate cancer outcomes differ by race and ethnicity. To this end, the Diversity Working Group of the IRONMAN registry has developed informed strategies for site selection, recruitment, engagement and retention, and trial design and eligibility criteria to ensure broad inclusion and needs awareness of minority participants. In concert with systematic strategies to tackle the complex levels of disparate care, our ultimate goal is to expand minority engagement in clinical research and bridge the disparities gap in prostate cancer care., Competing Interests: Rana R. McKayConsulting or Advisory Role: Janssen, Novartis, Tempus, Exelixis, Pfizer, Bristol-Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion Therapeutics, AstraZeneca, CalitheraResearch Funding: Pfizer, Bayer, Tempus Jelani C. ZarifConsulting or Advisory Role: Riptide Bioscience Elisabeth HeathHonoraria: Bayer, Dendreon, Seattle Genetics, Sanofi, AstraZenecaConsulting or Advisory Role: Agensys, Bayer, Dendreon, Sanofi, AstraZenecaSpeakers' Bureau: SanofiResearch Funding: Tokai Pharmaceuticals, Seattle Genetics, Agensys, Dendreon, Genentech/Roche, Millennium, Celldex, Inovio Pharmaceuticals, Celgene, Zenith Epigenetics, Merck, AstraZeneca, Esanik, Zenith Epigenetics, Oncolys BioPharma, Curemeta, Bristol-Myers Squibb, eFFECTOR Therapeutics, Fortis, Astellas Pharma, Medivation, Ignyta, Synta, Caris Life Sciences, Boehringer Ingelheim, GlaxoSmithKline, Merck Sharp & Dohme, Plexxikon, Corcept Therapeutics, Infinity Pharmaceuticals, Bayer, Modra Pharmaceuticals, Pellficure, Champions Oncology, AIQ Solutions, Novartis, Janssen Research & Development, Mirati Therapeutics, Peloton Therapeutics, Daiichi Sankyo Inc, Calibr, Eisai, Pharmacyclics, Five Prime TherapeuticsTravel, Accommodations, Expenses: Agensys, Bayer, SanofiOther Relationship: Caris Centers of Excellence Franklin W. HuangStock and Other Ownership Interests: GlaxoSmithKline Brandon MahalStock and Other Ownership Interests: Novavax, Moderna TherapeuticsHonoraria: Prostate Health Education Network Kellie PaichConsulting or Advisory Role: Bayer Stacey SimmonsEmployment: NovartisStock and Other Ownership Interests: Pfizer, BayerTravel, Accommodations, Expenses: Novartis, Bayer Clayton YatesStock and Other Ownership Interests: Riptide BioscienceConsulting or Advisory Role: Riptide Bioscience, QED TherapeuticsResearch Funding: Riptide BiosciencePatents, Royalties, Other Intellectual Property: I am a co-inventor on several patents assigned to Riptide Biosciences Philip W. KantoffLeadership: Context TherapeuticsStock and Other Ownership Interests: Placon, Druggablity Technologies, Context Therapeutics, SeerConsulting or Advisory Role: Bavarian Nordic, Janssen, Merck, OncoCellMDX, Genentech/Roche, Tarveda Therapeutics, Druggablity Technologies, Progenity, Context Therapeutics, GE Healthcare, SeerPatents, Royalties, Other Intellectual Property: Method for Predicting the Risk of Prostate Cancer Morbidity and Mortality, Predicting and Treating Prostate Cancer, Methods for Predicting Likelihood of Responding to Treatment, Chromosome Copy Number Gain as a Biomarker of Urothelial Carcinoma Lethality, Drug Combinations to Treat Cancer, Somatic ERCC2 Mutations Correlate with Cisplatin sensitivity in muscle-invasive Urothelial Carcinoma (Patent), Up-to-Date Royalties, Wolters Kluwer Royalties, Methods and Kits for Determining Sensitivity to Cancer Treatment, Composition and Methods for Screening and Diagnosis of Prostate CancerOpen Payments Link: https://openpaymentsdata.cms.gov/physician/55315/summary Daniel J. GeorgeLeadership: Capio BioSciencesHonoraria: Sanofi, Bayer, Exelixis, EMD Serono, OncLive, Pfizer, UroToday, Acceleron Pharma, American Association for Cancer Research, Axess Oncology, Janssen Oncology, Millennium Medical PublishingConsulting or Advisory Role: Bayer, Exelixis, Pfizer, Sanofi, Astellas Pharma, Innocrin Pharma, Bristol-Myers Squibb, Genentech, Janssen, Merck Sharp & Dohme, Myovant Sciences, AstraZeneca, Michael J. Hennessy Associates, Vizuri, Constellation Pharmaceuticals, Physician Education Resource LLCSpeakers' Bureau: Sanofi, Bayer, ExelixisResearch Funding: Exelixis, Janssen Oncology, Novartis, Pfizer, Astellas Pharma, Bristol-Myers Squibb, Acerta Pharma, Bayer, Dendreon, Innocrin Pharma, Calithera Biosciences, Sanofi/AventisTravel, Accommodations, Expenses: Bayer, Exelixis, Merck, Pfizer, Sanofi, Janssen Oncology, UroToday Lorelei A. MucciResearch Funding: Sanofi, Astellas Pharma, Bayer, JanssenNo other potential conflicts of interest were reported.