Artificial intelligence enhances whole-slide interpretation of PD-L1 CPS in triple-negative breast cancer: A multi-institutional ring study.

BACKGROUND AND AIMS: Evaluation of the programmed cell death ligand-1 (PD-L1) combined positive score (CPS) is vital to predict the efficacy of the immunotherapy in triple-negative breast cancer (TNBC), but pathologists show substantial variability in the consistency and accuracy of the interpretation. It is of great importance to establish an objective and effective method which is highly repeatable. METHODS: We proposed a model in a deep learning-based framework, which at the patch level incorporated cell analysis and tissue region analysis, followed by the whole-slide level fusion of patch results. Three rounds of ring studies (RSs) were conducted. Twenty-one pathologists of different levels from four institutions evaluated the PD-L1 CPS in TNBC specimens as continuous scores by visual assessment and our artificial intelligence (AI)-assisted method. RESULTS: In the visual assessment, the interpretation results of PD-L1 (Dako 22C3) CPS by different levels of pathologists have significant differences and showed weak consistency. Using AI-assisted interpretation, there were no significant differences between all pathologists (P = 0.43), and the intraclass correlation coefficient (ICC) value was increased from 0.618 [95% confidence interval (CI) = 0.524-0.719] to 0.931 (95% CI = 0.902-0.955). The accuracy of interpretation result is further improved to 0.919 (95% CI = 0.886-0.947). Acceptance of AI results by junior pathologists was the highest among all levels, and 80% of the AI results were accepted overall. CONCLUSION: With the help of the AI-assisted diagnostic method, different levels of pathologists achieved excellent consistency and repeatability in the interpretation of PD-L1 (Dako 22C3) CPS. Our AI-assisted diagnostic approach was proved to strengthen the consistency and repeatability in clinical practice.

Activating innate immune responses repolarizes hPSC-derived CAR macrophages to improve anti-tumor activity.

Generation of chimeric antigen receptor macrophages (CAR-Ms) from human pluripotent stem cells (hPSCs) offers new prospects for cancer immunotherapy but is currently challenged by low differentiation efficiency and limited function. Here, we develop a highly efficient monolayer-based system that can produce around 6,000 macrophages from a single hPSC within 3 weeks. Based on CAR structure screening, we generate hPSC-CAR-Ms with stable CAR expression and potent tumoricidal activity in vitro. To overcome the loss of tumoricidal activity of hPSC-CAR-Ms in vivo, we use interferon-γ and monophosphoryl lipid A to activate an innate immune response that repolarizes the hPSC-CAR-Ms to tumoricidal macrophages. Moreover, through combined activation of T cells by hPSC-CAR-Ms, we demonstrate that activating a collaborative innate-adaptive immune response can further enhance the anti-tumor effect of hPSC-CAR-Ms in vivo. Collectively, our study provides feasible methodologies that significantly improve the production and function of hPSC-CAR-Ms to support their translation into clinical applications.

Disulfidptosis-related lncRNA signature reveals immune microenvironment and novel molecular subtyping of stomach adenocarcinoma.

The main challenge in treating stomach adenocarcinoma (STAD) is chemotherapy resistance, which is characterized by changes in the immune microenvironment. Disulfidptosis, a novel form of programmed cell death, is involved in STAD but its mechanism is not fully understood. Long non-coding RNAs (LncRNAs) may play a role in regulating disulfidptosis and influencing the immune microenvironment and chemotherapy resistance in STAD. This study aims to establish disulfidptosis-related lncRNA (DRL) features and explore their significance in the immune microenvironment and chemotherapy resistance in STAD patients. By analyzing RNA sequencing and clinical data from STAD patients and extracting disulfidptosis-related genes, we identified DRLs through co-expression, single-factor and multi-factor Cox regression, and Lasso regression analyses. We also investigated differences in the immune microenvironment, immune function, immune checkpoint gene expression, and chemotherapy resistance between different risk groups using various algorithms. A prognostic risk model consisting of 2 DRLs was constructed, with a strong predictive value for patient survival, outperforming other clinical-pathological factors in predicting 3-year and 5-year survival. Immune-related analysis revealed a strong positive correlation between T cell CD4+ cells and risk score across all algorithms, and higher expression of immune checkpoint genes in the high-risk group. In addition, high-risk patients showed better sensitivity to Erlotinib, Oxaliplatin, and Gefitinib. Furthermore, three novel molecular subtypes of STAD were identified based on the 2-DRLs features, with evaluation of the immune microenvironment and chemotherapy drug sensitivity for each subgroup, which holds significant implications for achieving precise treatment in STAD. Overall, our 2-DRLs prognostic model demonstrates high predictive value for patient survival in STAD, potentially providing new targets for individualized immune and chemical therapy.

Lipid metabolism-related long noncoding RNA RP11-817I4.1 promotes fatty acid synthesis and tumor progression in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of tumors. The influence of lipid metabolism disruption on the development of HCC has been demonstrated in published studies. AIM: To establish an HCC prognostic model for lipid metabolism-related long non-coding RNAs (LMR-lncRNAs) and conduct in-depth research on the specific role of novel LMR-lncRNAs in HCC. METHODS: Correlation and differential expression analyses of The Cancer Genome Atlas data were used to identify differentially expressed LMR-lncRNAs. Quantitative real-time polymerase chain reaction analysis was used to evaluate the expression of LMR-lncRNAs. Nile red staining was employed to observe intracellular lipid levels. The interaction between RP11-817I4.1, miR-3120-3p, and ATP citrate lyase (ACLY) was validated through the performance of dual-luciferase reporter gene and RIP assays. RESULTS: Three LMR-lncRNAs (negative regulator of antiviral response, RNA transmembrane and coiled-coil domain family 1 antisense RNA 1, and RP11-817I4.1) were identified as predictive markers for HCC patients and were utilized in the construction of risk models. Additionally, proliferation, migration, and invasion were reduced by RP11-817I4.1 knockdown. An increase in lipid levels in HCC cells was significantly induced by RP11-817I4.1 through the miR-3120-3p/ACLY axis. CONCLUSION: LMR-lncRNAs have the capacity to predict the clinical characteristics and prognoses of HCC patients, and the discovery of a novel LMR-lncRNAs, RP11-817I4.1, revealed its role in promoting lipid accumulation, thereby accelerating the onset and progression of HCC.

Potential molecular biomarkers for the diagnosis and prognosis of bladder cancer.

Bladder cancer (BC) is a common malignant tumor of urinary system, which can be divided into muscle-invasive BC (MIBC) and nonmuscle-invasive BC (NMIBC). The number of BC patients has been gradually increasing currently. At present, bladder tumours are diagnosed and followed-up using a combination of cystoscopic examination, cytology and histology. However, the detection of early grade tumors, which is much easier to treat effectively than advanced stage disease, is still insufficient. It frequently recurs and can progress when not expeditiously diagnosed and monitored following initial therapy for NMIBC. Treatment strategies are totally different for different stage diseases. Therefore, it is of great practical significance to study new biomarkers for diagnosis and prognosis. In this review, we summarize the current state of biomarker development in BC diagnosis and prognosis prediction. We retrospectively analyse eight diagnostic biomarkers and eight prognostic biomarkers, in which CK, P53, PPARγ, PTEN and ncRNA are emphasized for discussion. Eight molecular subtype systems are also identified. Clinical translation of biomarkers for diagnosis, prognosis, monitoring and treatment will hopefully improve outcomes for patients. These potential biomarkers provide an opportunity to diagnose tumors earlier and with greater accuracy, and help identify those patients most at risk of disease recurrence.

Trends of Prostate Cancer Morbidity in Low-Incidence Countries from 1990-2019.

BACKGROUND: Our study was designed to elucidate the morbidity trends of prostate cancer in low-incidence countries. METHODS: Data on prostate cancer were extracted from the 2019 Global Burden of Disease study. A cluster analysis of growth rates stratified by age was conducted, and correlation analyses were performed between age-standardized incidence rates (ASIR), estimated annual percent change (EAPC), and socio-demographic index (SDI). RESULTS: Among 35 low-incidence countries for prostate cancer, predominantly located in Asia and North Africa, the SDI ranged from low to high-middle levels. Higher SDI regions exhibited considerably higher ASIR. With the exception of Kyrgyzstan, Kiribati, and Samoa that experienced a decrease in ASIR, the remaining 32 countries displayed an upward morbidity trend since 1990, with all their EAPCs exceeding the global average. In addition, men ages 90 years and above consistently exhibited the highest ASIR for prostate cancer. The most notable growth rate of ASIR was observed in individuals ages 20 to 44 years. CONCLUSIONS: Overall, low-incidence countries generally witnessed an increase in prostate cancer morbidity, albeit at levels lower than those seen in Western countries. Individuals ages 90 years and above consistently maintained the highest ASIR since 1990. Notably, more substantial increase of ASIR in younger age was also observed in low-incidence countries. IMPACT: This study offers a comprehensive overview of prostate cancer morbidity in low-incidence countries worldwide from 1990 to 2019. Future research should delve into the associations between incidence, clinical stages, PSA screening, environmental factors, lifestyle, and genetic risk in these low-incidence countries.

The relationship between nonsteroidal anti-inflammatory drugs and cancer incidence: An umbrella review.

Several clinical and preclinical studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, reduce the incidence of various cancer types. However, there is still a lack of literature evaluating the overall association between multiple cancer morbidities and NSAIDs. Thus, we conducted an umbrella review to evaluate the quality of evidence, validity, and biases of the existing systematic reviews and meta-analyses on the relationships between NSAIDS and multiple tumor incidence outcomes. We found that NSAIDs might be associated with a decreased risk of several cancers, including the central nervous system, breast, esophageal, gastric, head and neck, hepatocellular, cholangiocarcinoma, colorectal, endometrial, lung, ovary, prostate, and pancreatic cancers, but regular intake of any dose of non-aspirin NSAIDs (NA-NSAIDs) could increase the incidence of kidney cancer. However, most of included studies are evaluated as low quality according to our evidence assessment. Furthermore, due to the potential side effects, such as hemorrhage, digestive symptoms and peptic ulcer, it is still not recommend to use NSAIDs regularly to prevent cancers.

Construction of a prognostic prediction model in liver cancer based on genes involved in integrin cell surface interactions pathway by multi-omics screening.

Background: Liver cancer is a common malignant tumor with an increasing incidence in recent years. We aimed to develop a model by integrating clinical information and multi-omics profiles of genes to predict survival of patients with liver cancer. Methods: The multi-omics data were integrated to identify liver cancer survival-associated signal pathways. Then, a prognostic risk score model was established based on key genes in a specific pathway, followed by the analysis of the relationship between the risk score and clinical features as well as molecular and immunologic characterization of the key genes included in the prediction model. The function experiments were performed to further elucidate the undergoing molecular mechanism. Results: Totally, 4 pathways associated with liver cancer patients' survival were identified. In the pathway of integrin cell surface interactions, low expression of COMP and SPP1, and low CNVs level of COL4A2 and ITGAV were significantly related to prognosis. Based on above 4 genes, the risk score model for prognosis was established. Risk score, ITGAV and SPP1 were the most significantly positively related to activated dendritic cell. COL4A2 and COMP were the most significantly positively associated with Type 1 T helper cell and regulatory T cell, respectively. The nomogram (involved T stage and risk score) may better predict short-term survival. The cell assay showed that overexpression of ITGAV promoted tumorigenesis. Conclusion: The risk score model constructed with four genes (COMP, SPP1, COL4A2, and ITGAV) may be used to predict survival in liver cancer patients.

Concordance of assessments of four PD-L1 immunohistochemical assays in esophageal squamous cell carcinoma (ESCC).

OBJECTIVE: Given real-world limitations in programmed death-ligand 1 (PD-L1) testing, concordance studies between PD-L1 assays are needed. We undertook comparisons of PD-L1 assays (DAKO22C3, Ventana SP263, Ventana SP142, E1L3N) among observers in esophageal squamous cell carcinoma (ESCC) to provide information on the analytical and clinical comparability of four PD-L1 IHC assays. METHODS: Paraffin embedded samples of 50 cases of esophageal squamous cell carcinoma were obtained, satined with all four PD-L1 assays. PD-L1 was evaluated by 68 pathologists from 19 different hospitals. PD-L1 expression was assessed for combined positive score (CPS). RESULTS: The expression sensitivity of SP263 was the highest in ESCC, followed by 22C3, E1L3N and SP142. Taking CPS 10 as the critical value, inter-observer concordance for CPS scores among 68 physicians was assessed for the 22C3, SP263, SP142, and E1L3N assays, yielding values of 0.777, 0.790, 0.758, and 0.782, respectively. In the comparison between assays, the overall CPS scores concordance rates between 22C3 and SP263, SP142, and E1L3N were 0.896, 0.833, and 0.853, respectively. 22C3 and SP263 have high concordance, with OPA of 0.896, while E1L3N and SP142 have the highest concordance, with OPA of 0.908. CONCLUSION: In ESCC, the concordance of PD-L1 evaluation among observers is good, and the immune cell score is still an important factor affecting the concordance of interpretation among observers. Cases near the specific threshold are still the difficult problem of interpretation. SP263 had the highest CPS score of the four assays. SP263 cannot identify all 22C3 positive cases, but had good concordance with 22C3.E1L3N and SP142 showed high concordance.

Robot-assisted radical cystectomy with intracorporeal urinary diversion: an updated systematic review and meta-analysis of its differential effect on effectiveness and safety.

BACKGROUND: Robot-assisted laparoscopic cystectomy with intracorporeal urinary diversion (iRARC) is increasingly being used in recent years. Whether iRARC offers advantages over open radical cystectomy (ORC) remains controversial. This study aimed to compare the difference of perioperative outcomes, oncological outcomes and complications between iRARC and ORC. METHODS: The PubMed, Embase, Cochrane Library, Web of Science and CNKI databases were searched in July 2023 according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement. Studies were identified to be eligible if they compared perioperative outcomes, oncological outcomes and complications in patients who underwent iRARC with ORC. RESULTS: Twenty-two studies involving 7020 patients were included. Compared to ORC, iRARC was superior for estimated blood loss [estimated blood loss (EBL) weighted mean difference (WMD): -555.52; 95% CI, -681.64 to -429.39; P <0.001], blood transfusion rate [odds ratio (OR): 0.16; 95% CI, 0.09-0.28; P <0.001], length of hospital stay [length of hospital stay (LOS) WMD: -2.05; 95% CI, -2.93 to -1.17; P <0.001], Clavien-Dindo grades ≥III complication rate [30 days: OR: 0.57; 95% CI 0.44-0.75; P <0.001; 90 days: OR: 0.71; 95% CI 0.60-0.84; P <0.001], and positive surgical margin [positive surgical margin (PSM) OR: 0.65; 95% CI 0.49-0.85; P =0.002]. However, iRARC had a longer operative time [operative time (OT) WMD: 68.54; 95% CI 47.41-89.67; P <0.001] and a higher rate of ureteroenteric stricture [ureteroenteric stricture (UES) OR: 1.56; 95% CI 1.16-2.11; P =0.003]. Time to flatus, time to bowel, time to regular diet, readmission rate, Clavien-Dindo grades less than III complication rate for iRARC were similar to that for ORC. Interestingly, the results of subgroup analysis revealed no difference in EBL between iRARC and ORC when the diversion type was neobladder. When the ileal conduit was selected as the diversion type, the LOS was similar in both procedures. CONCLUSION: Robot-assisted laparoscopic cystectomy with intracorporeal urinary diversion appears to be superior to open radical cystectomy in terms of effectiveness and safety. However, attention should be paid to the occurrence of ureteroenteric stricture during follow-up.

Disulfidptosis-related lncRNA signatures assess immune microenvironment and drug sensitivity in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is associated with a high mortality rate, where resistance to immunotherapy and chemotherapy plays a crucial role. A newly identified form of cell death called disulfidptosis shows promise, but its biological mechanism in HCC remains uncertain. In this study, a prognostic model was developed for Disulfidptosis-related long non-coding RNAs (DRLs) from 370 HCC patients sourced from TCGA-LIHC, utilizing five key features: AC026356.1, AC073254.1, PXN-AS1 expression, AC026412.3, and AC099066.2. High-risk HCC patients had lower survival, CD4+ T cell infiltration, and elevated immune checkpoint gene expression. Furthermore, based on the features of DRLs, HCC was classified into three subtypes. Notably, patients belonging to different subtypes demonstrated varying overall survival rates, immune cell infiltration patterns, and sensitivity to immune therapy. Moreover, the novel DRL AC026412.3 (HR = 40.207) emerged as the most significant prognostic factor, exhibiting high expression across all HCC cells. Elevated expression of AC026412.3 promoted HCC cell proliferation and induced resistance to gefitinib. In conclusion, we have discovered five DRLs and constructed a prognostic risk model. Our findings validate the correlation between DRL-related prognostic models, tumor subtypes, and the HCC immune microenvironment along with its implications for immunotherapy. Moreover, further investigation into the molecular mechanisms of key biomarkers like AC026412.3 in the future will contribute significantly to advancing our comprehension of HCC's pathogenesis and drug resistance mechanisms.

Diagnosis and Prognosis of Thyroid Cancer by Immune-related Genes.

BACKGROUND: Thyroid carcinoma (THCA) is the most common malignant endocrine tumor with low mortality and a relatively good prognosis. Immune genes have attracted much attention as molecular markers of THCA prognosis and potential targets of immunotherapy. METHODS: Our study analyzed the transcriptome and clinical data of immune-related genes (IRGs) of THCA in gene expression omnibus, the cancer genome atlas-THCA, and ImmPort databases. By univariate Cox regression analysis, 15 genes were significantly correlated with the survival of patients with THCA. Five IRGs ( NMU, UBE2C, CDKN2A, COL19A1, and GPM6A ) were selected by LASSO regression analysis as independent prognostic factors to construct a disease-free survival-related prognostic risk model. RESULTS: Kaplan-Meier survival analysis showed that there was a significant difference in disease-free survival between high and low-risk groups. The higher the risk score, the worse the survival of patients. Clinical correlation analysis showed that age and Stage stage of patients were correlated with risk score ( P < 0.05). Quantitative real-time polymerase chain reaction confirmed that there were differences in the expression of 5 IRGs between tumor tissues and normal thyroid tissues. Spearman correlation analysis indicated that the relative expression levels of NMU, CDKN2A, UBE2C, COL19A1 , and GPM6A were positively correlated with programmed death-ligand 1 and recombinant a disintegrin and metalloproteinase with thrombospondin 1. CONCLUSION: Based on the bioinformatics method, we constructed a prognosis evaluation model and risk score system of IRGs in THCA, which provided a reference for predicting the prognosis of patients with THCA.

A risk signature based on endoplasmic reticulum stress-associated genes predicts prognosis and immunity in pancreatic cancer.

Introduction: The involvement of endoplasmic reticulum (ER) stress in cancer biology is increasingly recognized, yet its role in pancreatic cancer (PC) remains unclear. This study aims to elucidate the impact of ER stress on prognosis and biological characteristics in PC patients. Methods: A bioinformatic analysis was conducted using RNA-seq data and clinicopathological information from PC patients in the TCGA and ICGC databases. The ER stress-associated gene sets were extracted from MSigDB. ER stress-associated genes closely linked with overall survival (OS) of PC patients were identified via log-rank test and univariate Cox analysis, and further narrowed by LASSO method. A risk signature associated with ER stress was formulated using multivariate Cox regression and assessed through Kaplan-Meier curves, receiver operating characteristic (ROC) analyses, and Harrell's concordance index. External validation was performed with the ICGC cohort. The single-sample gene-set enrichment analysis (ssGSEA) algorithm appraised the immune cell infiltration landscape. Results: Worse OS in PC patients with high-risk signature score was observed. Multivariate analysis underscored our ER stress-associated signature as a valuable and independent predictor of prognosis. Importantly, these results based on TCGA were further validated in ICGC dataset. In addition, our risk signature was closely associated with homeostasis, protein secretion, and immune regulation in PC patients. In particular, PC microenvironment in the high-risk cluster exhibited a more immunosuppressive status. At last, we established a nomogram model by incorporating the risk signature and clinicopathological parameters, which behaves better in predicting prognosis of PC patients. Discussion: This comprehensive molecular analysis presents a new predictive model for the prognosis of PC patients, highlighting ER stress as a potential therapeutic target. Besides, the findings indicate that ER stress can have effect modulating PC immune responses.

The Impact of Nutrient Supply on Prostate Cancer Risk Worldwide.

We aim to explore the association between nutrient supply and the incidence of prostate cancer globally. We utilized national nutrient supply data from the Food and Agriculture Organization of the United Nations for 150 countries, including the average supply of total protein (APS), animal protein (AAPS), fat (AFS), animal protein/total protein ratio (ATR), and share of dietary energy supply derived from cereals, roots, and tubers (CR). Prostate cancer incidence data were sourced from the Global Burden Disease 2019 (GBD2019). Correlation, regression analyses, and subgroup analysis were conducted. Our findings imply that incidence of prostate cancer is significantly correlated to APS (ρ = 0.394, p < 0.01), AAPS (ρ = 0.560, p < 0.01), AFS (ρ = 0.522, p < 0.01), ATR (ρ = 0.592, p < 0.01), and CR (ρ = -0.667, p < 0.01). After adjusting for confounders, regression analysis showed linear relationships between the AAPS (ß = 0.605, p = 0.006), ATR (ß = 70.76, p = 0.005), CR (ß = -1.4451, p < 0.01), and age-standardized incidence rates (ASIRs) of prostate cancer, while no association was observed with APS (ß = 0.030, p = 0.483) or AFS (ß = 0.237, p = 0.405). Subgroup analysis suggested that dietary supply indicators were associated with ASIR in middle, middle-high, and high SDI, but not in countries with low and middle-low SDI. In summary, prostate cancer rates globally correlate significantly with AAPS, ATR, and CR, but not with APS and AFS. When considering the SDI of countries, the relationship is generally more pronounced in economically advanced nations, but not evident in low and middle-low SDI countries.

A Case of ALK-Positive Anaplastic Large Cell Lymphoma of the Male Breast.

Background: Primary breast lymphoma (PBL) is a very rare form of non-Hodgkin's lymphoma (NHL). A primary T-cell lymphoma in the breast with no previously identified lymphomatous lesions is an even rarer form of this malignancy. Case Presentation: A biopsy of a breast mass in a 60-year-old Caucasian man showed a morphologic-immunophenotypic profile with features characteristic of an ALK-positive (AKT+), anaplastic large cell lymphoma. Fluorescence in situ hybridization (FISH) analysis of fixed, paraffin-embedded tissue of this lesion was performed at our institution for IRF4/DUSP22 gene rearrangement. No rearrangement was detected. The patient presented with mutations in the following genes; BCOR_p.Q600X, DNMT3A_p.F609fs, NOTCH1_p.P2320fs, and IDH2_p.R140Q. However, the patient's consultation was complicated by the fact that he had been diagnosed with breast cancer at a local hospital and had come to our institution for further consultation. The histology findings were confirmed by immunohistochemistry and FISH. Computed tomography and positron emission tomography did not reveal nodules elsewhere in the body, which allowed the staging of the patient to be completed. However, although the patient had previously received the chemotherapy CCOP regimen (ie, cyclophosphamide, vincristine, prednisolone acetate) he did not go into remission in a timely manner and relapsed after six months, followed by a drastic deterioration in his condition after four months, resulting in his death in less than one month. Conclusion: This report of a male patient describes a case of a rare T-cell lymphoma of the breast that occurs considerably more frequently in female patients. The differential diagnosis of the histology of this tumor showed mutations that occur more often in lymphoblastic lymphoma or leukemia. This rare malignancy and associated mutations led to the death of this patient during treatment.

The risk and outcome of malignant brain edema in post-mechanical thrombectomy: acute ischemic stroke by anterior circulation occlusion.

BACKGROUND AND PURPOSE: Malignant brain edema (MBE) occurring after mechanical thrombectomy (MT) in acute ischemic stroke (AIS) could lead to severe disability and mortality. We aimed to investigate the incidence, predictors, and clinical outcomes of MBE in patients with AIS after MT. METHODS: The clinical and imaging data of 155 patients with AIS of anterior circulation after MT were studied. Standard non-contrast CT was used to evaluate baseline imaging characteristics at admission. Clinical outcomes were measured using the 90-day modified Rankin Scale (mRS) score. Based on the follow-up CT scans performed within 72 h after MT, the patients were classified into MBE and non-MBE group. MBE was defined as a midline shift of ≥ 5 mm with signs of local brain swelling. Univariate and multivariate regression analyses were used to analyze the relationship between MBE and clinical outcomes and identify the predictors that correlate with MBE. RESULTS: MBE was observed in 19.4% of the patients who underwent MT and was associated with a lower rate of favorable 90-day clinical outcomes. Significant differences were observed in both MBE and non-MBE groups: baseline Alberta Stroke Program Early CT (ASPECT) score, hyperdense middle cerebral artery sign (HMCAS), baseline signs of early infarct, angiographic favorable collaterals, number of retrieval attempts, and revascularization rate. Multivariate analysis indicated that low baseline ASPECT score, absent HMCAS, angiographic poor collaterals, more retrieval attempt count, and poor revascularization independently influenced the occurrence of MBE in AIS patients with anterior circulation after MT. CONCLUSION: MBE was associated with a lower rate of favorable 90-day clinical outcomes. Low baseline ASPECT score, absent HMCAS, angiographic poor collaterals, more retrieval attempt count and poor revascularization were independently associated with MBE after MT.

Selenium intake and multiple health-related outcomes: an umbrella review of meta-analyses.

Selenium is an essential trace metalloid element that is associated with fundamental importance to human health. Our umbrella review aimed to evaluate the quality of evidence, validity, and biases in the relationship between selenium intake and health-related outcomes according to published systematic reviews with pooled data and meta-analyses. Selenium intake is associated with a decreased risk of digestive system cancers, all-cause mortality, depression, and Keshan disease, when in children reduce the risk of Kashin-Beck disease. Additionally, selenium supplementation can improve sperm quality, polycystic ovary syndrome, autoimmune thyroid disease, cardiovascular disease, and infective outcomes. Selenium supplementation also has relationship with a decreased concentration of serum lipids including total cholesterol and very low-density lipoprotein cholesterol. However, no evidence has shown that selenium is associated with better outcomes among patients in intensive care units. Furthermore, selenium intake may be related with a higher risk of type 2 diabetes and non-melanoma skin cancers. Moreover, most of included studies are evaluated as low quality according to our evidence assessment. Based on our study findings and the limited advantages of selenium intake, it is not recommended to receive extra supplementary selenium for general populations, and selenium supplementation should not be continued in patients whose selenium-deficient status has been corrected.

A strategy for Cas13 miniaturization based on the structure and AlphaFold.

The small size of the Cas nuclease fused with various effector domains enables a broad range of function. Although there are several ways of reducing the size of the Cas nuclease complex, no efficient or generalizable method has been demonstrated to achieve protein miniaturization. In this study, we establish an Interaction, Dynamics and Conservation (IDC) strategy for protein miniaturization and generate five compact variants of Cas13 with full RNA binding and cleavage activity comparable the wild-type enzymes based on a combination of IDC strategy and AlphaFold2. In addition, we construct an RNA base editor, mini-Vx, and a single AAV (adeno-associated virus) carrying a mini-RfxCas13d and crRNA expression cassette, which individually shows efficient conversion rate and RNA-knockdown activity. In summary, these findings highlight a feasible strategy for generating downsized CRISPR/Cas13 systems based on structure predicted by AlphaFold2, enabling targeted degradation of RNAs and RNA editing for basic research and therapeutic applications.

A torus source and its application for non-primary radiation evaluation.

Objective. Non-primary radiation doses to normal tissues from proton therapy may be associated with an increased risk of secondary malignancies, particularly in long-term survivors. Thus, a systematic method to evaluate if the dose level of non-primary radiation meets the IEC standard requirements is needed.Approach. Different from the traditional photon radiation therapy system, proton therapy systems are composed of several subsystems in a thick bunker. These subsystems are all possible sources of non-primary radiation threatening the patient. As a case study, 7 sources in the P-Cure synchrotron-based proton therapy system are modeled in Monte Carlo (MC) code: tandem injector, injection, synchrotron ring, extraction, beam transport line, scanning nozzle and concrete reflection/scattering. To accurately evaluate the synchrotron beam loss and non-primary dose, a new model called the torus source model is developed. Its parametric equations define the position and direction of the off-orbit particle bombardment on the torus pipe shell in the Cartesian coordinate system. Non-primary doses are finally calculated by several FLUKA simulations.Main results. The ratios of summarized non-primary doses from different sources to the planned dose of 2 Gy are all much smaller than the IEC requirements in both the 15-50 cm and 50-200 cm regions. Thus, the P-Cure synchrotron-based proton therapy system is clean and patient-friendly, and there is no need an inner shielding concrete between the accelerator and patient.Significance. Non-primary radiation dose level is a very important indicator to evaluate the quality of a PT system. This manuscript provides a feasible MC procedure for synchrotron-based proton therapy with new beam loss model. Which could help people figure out precisely whether this level complies with the IEC standard before the system put into clinical treatment. What' more, the torus source model could be widely used for bending magnets in gantries and synchrotrons to evaluate non-primary doses or other radiation doses.

A new compact adenine base editor generated through deletion of HNH and REC2 domain of SpCas9.

BACKGROUND: Adenine base editors (ABEs) are promising therapeutic gene editing tools that can efficiently convert targeted A•T to G•C base pairs in the genome. However, the large size of commonly used ABEs based on SpCas9 hinders its delivery in vivo using certain vectors such as adeno-associated virus (AAV) during preclinical applications. Despite a number of approaches having previously been attempted to overcome that challenge, including split Cas9-derived and numerous domain-deleted versions of editors, whether base editor (BE) and prime editor (PE) systems can also allow deletion of those domains remains to be proven. In this study, we present a new small ABE (sABE) with significantly reduced size. RESULTS: We discovered that ABE8e can tolerate large single deletions in the REC2 (Δ174-296) and HNH (Δ786-855) domains of SpCas9, and these deletions can be stacked together to create a new sABE. The sABE showed higher precision than the original ABE8e, with proximally shifted protospacer adjacent motif (PAM) editing windows (A3- A15), and comparable editing efficiencies to 8e-SaCas9-KKH. The sABE system efficiently generated A-G mutations at disease-relevant loci (T1214C in GAA and A494G in MFN2) in HEK293T cells and several canonical Pcsk9 splice sites in N2a cells. Moreover, the sABE enabled in vivo delivery in a single adeno-associated virus (AAV) vector with slight efficiency. Furthermore, we also successfully edited the genome of mouse embryos by microinjecting mRNA and sgRNA of sABE system into zygotes. CONCLUSIONS: We have developed a substantially smaller sABE system that expands the targeting scope and offers higher precision of genome editing. Our findings suggest that the sABE system holds great therapeutic potential in preclinical applications.