Immunological role of Gas6/TAM signaling in hemostasis and thrombosis.

The immune system is an emerging regulator of hemostasis and thrombosis. The concept of immunothrombosis redefines the relationship between coagulation and immunomodulation, and the Gas6/Tyro3-Axl-MerTK (TAM) signaling pathway builds the bridge across them. During coagulation, Gas6/TAM signaling pathway not only activates platelets, but also promotes thrombosis through endothelial cells and vascular smooth muscle cells involved in inflammatory responses. Thrombosis appears to be a common result of a Gas6/TAM signaling pathway-mediated immune dysregulation. TAM TK and its ligands have been found to be involved in coagulation through the PI3K/AKT or JAK/STAT pathway in various systemic diseases, providing new perspectives in the understanding of immunothrombosis. Gas6/TAM signaling pathway serves as a breakthrough target for novel therapeutic strategies to improve disease management. Many preclinical and clinical studies of TAM receptor inhibitors are in process, confirming the pivotal role of Gas6/TAM signaling pathway in immunothrombosis. Therapeutics targeting the TAM receptor show potential both in anticoagulation management and immunotherapy. Here, we review the immunological functions of the Gas6/TAM signaling pathway in coagulation and its multiple mechanisms in diseases identified to date, and discuss the new clinical strategies that may generated by these roles.

Engineering the cyanobacterial ATP-driven BCT1 bicarbonate transporter for functional targeting to C3 plant chloroplasts.

The ATP-driven bicarbonate transporter 1 (BCT1), a four-component complex in the cyanobacterial CO2-concentrating mechanism, could enhance photosynthetic CO2 assimilation in plant chloroplasts. However, directing its subunits (CmpA, CmpB, CmpC and CmpD) to three chloroplast sub-compartments is highly complex. Investigating BCT1 integration into Nicotiana benthamiana chloroplasts revealed promising targeting strategies using transit peptides from the intermembrane space protein Tic22 for correct CmpA targeting, while the transit peptide of the chloroplastic ABCD2 transporter effectively targeted CmpB to the inner envelope membrane. CmpC and CmpD were targeted to the stroma by RecA and recruited to the inner envelope membrane by CmpB. Despite successful targeting, expression of this complex in CO2-dependent Escherichia coli failed to demonstrate bicarbonate uptake. We then used rational design and directed evolution to generate new BCT1 forms that were constitutively active. Several mutants were recovered, including a CmpCD fusion. Selected mutants were further characterized and stably expressed in Arabidopsis thaliana, but the transformed plants did not have higher carbon assimilation rates or decreased CO2 compensation points in mature leaves. While further analysis is required, this directed evolution and heterologous testing approach presents potential for iterative modification and assessment of CO2-concentrating mechanism components to improve plant photosynthesis.

Efficacy and Safety of Ripretinib in Advanced Gastrointestinal Stromal Tumors within an Expanded Access Program: A Cohort Study.

Ripretinib, a novel tyrosine kinase inhibitor used in advanced gastrointestinal stromal tumors (GIST) resistant to standard therapies, was assessed in the United Kingdom (UK) within an Expanded Access Program (EAP). A retrospective review of patients treated between January 2020 and October 2021 within the ripretinib EAP in our Institution was conducted. Clinician-documented and mRECIST 1.1 assessments were collected. The primary endpoints were progression-free survival (PFS) and time to treatment discontinuation (TTD). Treatment beyond progression (TBP), overall survival (OS), objective response rates and safety data were also analyzed. Survival curves were constructed using the Kaplan-Meier method, and univariate and multivariate Cox regression analyses were performed. All analyses were performed with R software. Overall, forty-five patients were included. After a median follow-up of 24.2 (95% CI 19.7-29.7) months, the median PFS of the group receiving 150 mg ripretinib once daily (OD) was 7.9 (95% CI 5.6-19.3) months. In the cohort of 22 patients with dose escalation upon tumor progression to 150 mg ripretinib twice daily (BD), the median PFS from BD was 5.4 (95% CI 2.8-9.3) months. Overall, median PFS and OS values for patients on ripretinib were 9.7 (95% CI 8.3-18.1) and 14.0 (95% CI 9.9-NA) months, respectively. TTD was similar to PFS. TBP was observed in about one third of all patients. Objective responses to ripretinib OD and BD treatments were observed in 16.7% and 10.0% of the patients, respectively. No new safety signals were identified. In conclusion, patients with advanced GIST receiving ripretinib in the UK within the EAP reported prolonged benefits, in line with the recent phase III clinical trials.

Elevated expression of hsa_circ_0000479 in neutrophils correlates with features of systemic lupus erythematosus.

OBJECTIVE: Accumulating evidence suggests that differentially expressed circular RNAs (circRNAs) play critical roles in immune cells of systemic lupus erythematosus (SLE) patients. Hsa_circ_0000479 has been studied in the field of cancer and infection, whereas seldom studied in autoimmune diseases. The aim of this study was to investigate the role and clinical value of neutrophil hsa_circ_0000479 in SLE. METHODS: The expression levels of hsa_circ_0000479 in both healthy individuals and SLE patients' neutrophils were detected by qPCR and compared with those in peripheral blood mononuclear cells (PBMCs) . In addition, the correlation of hsa_circ_0000479 levels in neutrophils with the clinical and immunological features of SLE patients was also analysed. RESULTS: The expression levels of hsa_circ_0000479 in the patients with SLE were significantly higher in neutrophils than that of PBMCs, and also significantly higher than that in healthy controls (HCs). Moreover, the expression levels of hsa_circ_0000479 in neutrophils were negatively associated with absolute neutrophil count and complement 3 (C3), whereas positively correlated with anti-dsDNA and anti-nucleosome antibodies in SLE. In addition, SLE patients with higher levels of hsa_circ_0000479 demonstrated more several clinical manifestations, including Raynaud's phenomenon, alopecia and leucopenia. CONCLUSIONS: Hsa_circ_0000479 is up-regulated in neutrophils of SLE patients, and is also associated with several important laboratory indicators and clinical manifestations, suggesting that hsa_circ_0000479 in neutrophils was one of probable factors involved in the pathogenesis of SLE with potential clinical value.

Hsa_circ_0000479 was expressed in neutrophils and was considerably higher than that of PBMCs in SLE patients.The neutrophil hsa_circ_0000479 was correlated with laboratory parameters, including NEUT, C3, anti-dsDNA antibodies and AnuA, in addition to being associated with Raynaud's phenomenon, alopecia, and leucopenia in patients with SLE.Hsa_circ_0000479 in neutrophils may play an influential role in SLE patients and will be important to understand the pathogenesis, stratification and treatment in SLE.

PKC-independent PI3K signalling diminishes PKC inhibitor sensitivity in uveal melanoma.

Protein kinase C (PKC) is activated downstream of gain-of-function GNAQ or GNA11 (GNAQ/GNA11) mutations in over 90% of uveal melanoma (UM). Phase I clinical trials of PKC inhibitors have shown modest response rates with no survival benefit in metastatic UM. Although PKC inhibitors actively suppress mitogen-activated protein kinase (MAPK) signalling in UM, the effect on other UM signalling cascades is not well understood. We examined the transcriptome of UM biopsies collected pre- and post-PKC inhibitor therapy and confirmed that MAPK, but not PI3K/AKT signalling, was inhibited early during treatment with the second-generation PKC inhibitor IDE196. Similarly, in GNAQ/GNA11-mutant UM cell models, PKC inhibitor monotherapy effectively suppressed MAPK activity, but PI3K/AKT signalling remained active, and thus, concurrent inhibition of PKC and PI3K/AKT signalling was required to synergistically induce cell death in a panel of GNAQ/GNA11-mutant UM cell lines. We also show that re-activation of MAPK signalling has a dominant role in regulating PKC inhibitor responses in UM and that PI3K/AKT signalling diminishes UM cell sensitivity to PKC inhibitor monotherapy. Thus, combination therapies targeting PKC and PKC-independent signalling nodes, including PI3K/AKT activity, are required to improve responses in patients with metastatic UM.

Single-cell RNA sequencing in melanoma: what have we learned so far?

Over the past decade, there have been remarkable improvements in the treatment and survival rates of melanoma patients. Treatment resistance remains a persistent challenge, however, and is partly attributable to intratumoural heterogeneity. Melanoma cells can transition through a series of phenotypic and transcriptional cell states that vary in invasiveness and treatment responsiveness. The diverse stromal and immune contexture of the tumour microenvironment also contributes to intratumoural heterogeneity and disparities in treatment response in melanoma patients. Recent advances in single-cell sequencing technologies have enabled a more detailed understanding of melanoma heterogeneity and the underlying transcriptional programs that regulate melanoma cell diversity and behaviour. In this review, we examine the concept of intratumoural heterogeneity and the challenges it poses to achieving long-lasting treatment responses. We focus on the significance of next generation single-cell sequencing in advancing our understanding of melanoma diversity and the unique insights gained from single-cell studies.

Association Between Anesthesiologist Sex and Patients' Postoperative Outcomes: A Population-based Cohort Study.

OBJECTIVE: To examine the association of anesthesiologist sex on postoperative outcomes. BACKGROUND: Differences in patient postoperative outcomes exist, depending on whether the primary surgeon is male or female, with better outcomes seen among patients treated by female surgeons. Whether the intraoperative anesthesiologist's sex is associated with differential postoperative patient outcomes is unknown. METHODS: We performed a population-based, retrospective cohort study among adult patients undergoing one of 25 common elective or emergent surgical procedures from 2007 to 2019 in Ontario, Canada. We assessed the association between the sex of the intraoperative anesthesiologist and the primary end point of the adverse postoperative outcome, defined as death, readmission, or complication within 30 days after surgery, using generalized estimating equations. RESULTS: Among 1,165,711 patients treated by 3006 surgeons and 1477 anesthesiologists, 311,822 (26.7%) received care from a female anesthesiologist and 853,889 (73.3%) from a male anesthesiologist. Overall, 10.8% of patients experienced one or more adverse postoperative outcomes, of whom 1.1% died. Multivariable adjusted rates of the composite primary end point were higher among patients treated by male anesthesiologists (10.6%) compared with female anesthesiologists (10.4%; adjusted odds ratio 1.02, 95% CI: 1.00-1.05, P =0.048). CONCLUSIONS: We demonstrated a significant association between sex of the intraoperative anesthesiologist and patient short-term outcomes after surgery in a large cohort study. This study supports the growing literature of improved patient outcomes among female practitioners. The underlying mechanisms of why outcomes differ between male and female physicians remain elusive and require further in-depth study.

Prognostic factors in patients with secondary hemophagocytic lymphohistioc ytosis in a Chinese cohort.

Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome with high mortality mediated by an unbridled and persistent activation of cytotoxic T lymphocytes and natural killer cells. However, the influence factors of early death in adult sHLH patients are still not fully elucidated, which need further investigating. We have conducted an observational study of adult HLH patients between January 2016 and December 2022. All patients are enrolled according to HLH-2004 criteria. Clinical manifestations, laboratory data, treatments, and outcomes have been recorded. Influence factors associated with prognosis are calculated by using logistic regression models. Overall, 220 patients enrolled in this study. The etiologies of HLH were divided into five groups including autoimmune-associated hemophagocytic syndrome (AAHS) (n = 90, 40.9%), malignancies (n = 73, 33.2%), EBV-HLH (n = 18, 8.2%), infection excluded EBV (n = 24, 10.9%), and other triggers (n = 15, 6.8%). Among them, EBV-HLH had the highest mortality (77.8%), and AAHS had the lowest mortality (14.4%). Multivariate analysis indicated that age (≥ 38 years old), cytopenia ≥ 2 lines, platelets (≤ 50 × 109/L), aspartate aminotransferase (≥ 135U/L), prothrombin time (≥ 14.9 s) and activated partial thromboplastin time (≥ 38.5s), EBV, and fungal infection are independent risk factors for poor prognosis of HLH. Adult HLH patients with elder age, cytopenia ≥ 2 lines, levels of decreased platelets, increased AST, prolonged PT and APTT, EBV, and fungal infection tend to have a poor prognosis.

Detection of high-risk HPV 16 genotypes in cervical cancers using isothermal DNA amplification with electrochemical genosensor.

Cervical cancer emerges as the third most prevalent types of malignancy among women on a global scale. Cervical cancer is significantly associated with the persistent infection of human papillomavirus (HPV) type 16. The process of diagnosing is crucial in order to prevent the progression of a condition into a malignant state. The early detection of cervical cancer through initial stage screening is of the utmost significance in both the prevention and effective management of this disease. The present detection methodology is dependent on quantitative polymerase chain reaction (qPCR), which necessitates the use of a costly heat cycler instrument. In this study, we report the development of an electrochemical DNA biosensor integrated with an isothermal recombinase polymerase amplification (RPA) reaction for the detection and identification of the high-risk HPV-16 genotype. The electrochemical biosensor exhibited a high degree of specificity and sensitivity, as evidenced by its limit of detection (LOD) of 0.23 copies/µL of HPV-16 DNA. The validity of this electrochemical platform was confirmed through the analysis of 40 cervical tissues samples, and the findings were consistent with those obtained through polymerase chain reaction (PCR) testing. Our straightforward electrochemical detection technology and quick turnaround time at 75 min make the assay suitable for point-of-care testing in low-resource settings.

Serum sCD25 is an indicator for rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: CD25 (IL-2Rα) is one of IL-2 receptor's polypeptide subunits, and its soluble form is increased in patients with various inflammatory or autoimmune diseases. This study aimed to evaluate the clinical correlation of serum soluble CD25 (sCD25) with interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients. METHODS: 294 RA patients, including 72 in the discovery cohort (15 patients with ILD, 57 patients without ILD), 222 in the validation cohort (41 patients with ILD and 181 patients without ILD), and 58 healthy controls (HCs) were recruited. High-resolution computed tomography (HRCT) scan provided evidence and patterns of RA-ILD. Serum sCD25 concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Clinical and laboratory data were recorded and the association with sCD25 was also analysed. RESULTS: In the discovery cohort, 16 RA-related molecules including cytokines, chemokines and functional soluble cell surface proteins were investigated. The results showed that sCD25 was significantly higher in RA-ILD than in RA-no-ILD group (p=0.004). ROC analysis also showed RA-ILD was discriminated with RA-no-ILD by sCD25 (AUC=0.695, 95% CI=0.541-0.849). Logistics regression demonstrated that sCD25 was one of the risk factors of RA-ILD. This result was further confirmed in validation cohort (p<0.001). According to the cut-off value in the discovery cohort, the sensitivity and specificity of sCD25 in RA-ILD were 51.2%, 77.3%, respectively. Compared with RA-no-ILD, serum level of sCD25 was also higher in different HRCT patterns including UIP, NSIP and RA-ILA. The ROC curves revealed sCD25 as diagnostic marker in UIP, NSIP and RA-ILA (with AUCs of 0.730, 0.761, and 0. 694, respectively, p<0.05). The result indicated that sCD25 was a biomarker for RA-ILD subtypes. Although sCD25 was not correlated with HRCT scores, it was significantly higher in consolidation pattern by HRCT. CONCLUSIONS: sCD25 was significantly elevated in RA-ILD (including UIP, NSIP and RA-ILA) compared to RA-no-ILD and HCs, which supports their value as a potential biomarker in RA-ILD screening and assessment.

Factors Affecting Patient and Caregiver Preferences for Treatment of Myeloma and Indolent Lymphoma.

PURPOSE: Treatment options for myeloma and indolent lymphoma are increasing exponentially, with distinct efficacy, side effects, and cost. We aim to determine the factors influencing patient and caregiver treatment preferences. METHODS: Patients and caregivers of patients with myeloma and indolent lymphoma were recruited from two cancer centers in Singapore. Preferences were elicited using a discrete choice experiment. Attributes and levels were selected based on a previous qualitative study. The relative preference for levels within each attribute (part worth utility values) and the extent to which an attribute would influence decision making (relative importance) were calculated. Patient and caregiver participation in the treatment plan selection process were assessed using the Control Preference Scale. RESULTS: One hundred ninety-nine patients and 169 caregivers were recruited. Patients placed the highest importance on out-of-pocket costs (relative importance = 35%), followed by efficacy (25%), persistent side effects (19%), administration route (8%), treatment duration (7%), and short-term side effects (5%). Caregivers ranked efficacy (27%) as the most important attribute, over out-of-pocket costs (24%). Most patients preferred a collaborative role in the shared decision-making process, while similar proportions of caregivers favored active and collaborative roles. CONCLUSION: Our study demonstrates that both patients and caregivers consider cost seriously when making treatment decisions. Furthermore, as patient and caregiver preferences may differ, there are implications for treatment selection and counseling, especially in cultures where caregivers have more prominent roles in treatment planning.

Dose-response formation of N7-(3-benzo[1,3]dioxol-5-yl-2-hydroxypropyl)guanine in liver and urine correlates with micronucleated reticulocyte frequencies in mice administered safrole oxide.

Safrole oxide (SAFO), a metabolite of naturally occurring hepatocarcinogen safrole, is implicated in causing DNA adduct formation. Our previous study first detected the most abundant SAFO-induced DNA adduct, N7-(3-benzo[1,3] dioxol-5-yl-2-hydroxypropyl)guanine (N7γ-SAFO-G), in mouse urine using a well-developed isotope-dilution high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (ID-HPLC-ESI-MS/MS) method. This study further elucidated the genotoxic mode of action of SAFO in mice treated with SAFO 30, 60, 90, or 120 mg/kg for 28 days. The ID-HPLC-ESI-MS/MS method detected N7γ-SAFO-G with excellent sensitivity and specificity in mouse liver and urine of SAFO-treated mice. Our data provide the first direct evidence of SAFO-DNA adduct formation in rodent tissues. N7γ-SAFO-G levels in liver were significantly increased by SAFO 120 mg/kg compared with SAFO 30 mg/kg, suggesting rapid spontaneous or enzymatic depurination of N7γ-SAFO-G in tissue DNA. Urinary N7γ-SAFO-G exhibited a sublinear dose response. Moreover, the micronucleated peripheral reticulocyte frequencies increased dose-dependently and significantly correlated with N7γ-SAFO-G levels in liver (r = 0.8647; p < 0.0001) and urine (r = 0.846; p < 0.0001). Our study suggests that safrole-mediated genotoxicity may be caused partly by its metabolic activation to SAFO and that urinary N7γ-SAFO-G may serve as a chemically-specific cancer risk biomarker for safrole exposure.

Ensemble learning model for identifying the hallmark genes of NFκB/TNF signaling pathway in cancers.

BACKGROUND: The nuclear factor kappa B (NFκB) regulatory pathways downstream of tumor necrosis factor (TNF) play a critical role in carcinogenesis. However, the widespread influence of NFκB in cells can result in off-target effects, making it a challenging therapeutic target. Ensemble learning is a machine learning technique where multiple models are combined to improve the performance and robustness of the prediction. Accordingly, an ensemble learning model could uncover more precise targets within the NFκB/TNF signaling pathway for cancer therapy. METHODS: In this study, we trained an ensemble learning model on the transcriptome profiles from 16 cancer types in the TCGA database to identify a robust set of genes that are consistently associated with the NFκB/TNF pathway in cancer. Our model uses cancer patients as features to predict the genes involved in the NFκB/TNF signaling pathway and can be adapted to predict the genes for different cancer types by switching the cancer type of patients. We also performed functional analysis, survival analysis, and a case study of triple-negative breast cancer to demonstrate our model's potential in translational cancer medicine. RESULTS: Our model accurately identified genes regulated by NFκB in response to TNF in cancer patients. The downstream analysis showed that the identified genes are typically involved in the canonical NFκB-regulated pathways, particularly in adaptive immunity, anti-apoptosis, and cellular response to cytokine stimuli. These genes were found to have oncogenic properties and detrimental effects on patient survival. Our model also could distinguish patients with a specific cancer subtype, triple-negative breast cancer (TNBC), which is known to be influenced by NFκB-regulated pathways downstream of TNF. Furthermore, a functional module known as mononuclear cell differentiation was identified that accurately predicts TNBC patients and poor short-term survival in non-TNBC patients, providing a potential avenue for developing precision medicine for cancer subtypes. CONCLUSIONS: In conclusion, our approach enables the discovery of genes in NFκB-regulated pathways in response to TNF and their relevance to carcinogenesis. We successfully categorized these genes into functional groups, providing valuable insights for discovering more precise and targeted cancer therapeutics.

Simultaneous toxicokinetic studies of aristolochic acid I and II and aristolactam I and II using a newly-developed microdialysis liquid chromatography-tandem mass spectrometry.

Aristolochic acids (AAs) are naturally occurring genotoxic carcinogens linked to Balkan endemic nephropathy and aristolochic acid nephropathy. Aristolochic acid I and II (AA-I and AA-II) are the most abundant AAs, and AA-I has been reported to be more genotoxic and nephrotoxic than AA-II. This study aimed to explore metabolic differences underlying the differential toxicity. We developed a novel microdialysis sampling coupled with solid-phase extraction liquid chromatography-tandem mass spectrometry (MD-SPE-LC-MS/MS) to simultaneously study the toxicokinetics (TK) of AA-I and AA-II and their corresponding aristolactams (AL-I and AL-II) in the blood of Sprague Dawley rats co-treated with AA-1 and AA-II. Near real-time monitoring of these analytes in the blood of treated rats revealed that AA-I was absorbed, distributed, and eliminated more rapidly than AA-II. Moreover, the metabolism efficiency of AA-I to AL-I was higher compared to AA-II to AL-II. Only 0.58% of AA-I and 0.084% of AA-II was reduced to AL-I and AL-II, respectively. The findings are consistent with previous studies and support the contention that differences in the in vivo metabolism of AA-I and AA-II may be critical factors for their differential toxicities.

The molecular and functional landscape of resistance to immune checkpoint blockade in melanoma.

Resistance to immune checkpoint inhibitor therapies in melanoma is common and remains an intractable clinical challenge. In this study, we comprehensively profile immune checkpoint inhibitor resistance mechanisms in short-term tumor cell lines and matched tumor samples from melanoma patients progressing on immune checkpoint inhibitors. Combining genome, transcriptome, and high dimensional flow cytometric profiling with functional analysis, we identify three distinct programs of immunotherapy resistance. Here we show that resistance programs include (1) the loss of wild-type antigen expression, resulting from tumor-intrinsic IFNγ signaling and melanoma de-differentiation, (2) the disruption of antigen presentation via multiple independent mechanisms affecting MHC expression, and (3) immune cell exclusion associated with PTEN loss. The dominant role of compromised antigen production and presentation in melanoma resistance to immune checkpoint inhibition highlights the importance of treatment salvage strategies aimed at the restoration of MHC expression, stimulation of innate immunity, and re-expression of wild-type differentiation antigens.

IFN-γ Signaling Sensitizes Melanoma Cells to BH3 Mimetics.

Immunotherapy targeting PD-1 and/or CTLA4 leads to durable responses in a proportion of patients with melanoma. However, many patients will not respond to these immune checkpoint inhibitors, and up to 60% of responding patients will develop treatment resistance. We describe a vulnerability in melanoma driven by immune cell activity that provides a pathway towards additional treatment options. This study evaluated short-term melanoma cell lines (referred to as PD1 PROG cells) derived from melanoma metastases that progressed on PD-1 inhibitor-based therapy. We show that the cytokine IFN-γ primes melanoma cells for apoptosis by promoting changes in the accumulation and interactions of apoptotic regulators MCL-1, NOXA, and BAK. The addition of pro-apoptotic BH3 mimetic drugs sensitized PD1 PROG melanoma cells to apoptosis in response to IFN-γ or autologous immune cell activation. These findings provide translatable strategies for combination therapies in melanoma.

Current Recommendations for Perioperative Brain Health: A Scoping Review.

Perioperative complications such as stroke, delirium, and neurocognitive dysfunction are common and responsible for increased morbidity and mortality. Our objective was to characterize and synthesize the contemporary guidelines on perioperative brain health for noncardiac, non-neurologic surgery in a scoping review. We performed a structured search for articles providing recommendations on brain health published between 2016 and 2021 and included the following complications: perioperative stroke and perioperative neurocognitive disorders, the latter of which encompasses postoperative delirium and a spectrum of postoperative cognitive dysfunction. We categorized recommendations by subtopic (stroke, postoperative delirium, postoperative cognitive dysfunction), type (disclosure/ethics/policies, prevention, risk stratification, screening/diagnosis, and management), and pharmacological versus nonpharmacological strategies. We noted country of origin, specialty of the authors, evidence grade (if available), and concordance/discordance between recommendations. Eight publications provided 129 recommendations, originating from the United States (n=5), Europe (n=1), United Kingdom (n=1), and China (n=1). Three publications (37%) applied grading of evidence as follows: Grading of Recommendations, Assessment, Development, and Evaluations (GRADE): A, 30%; B, 36%; C, 30%; D, 4%. We identified 42 instances of concordant recommendations (≥2 publications) on 15 themes, including risk factor identification, risk disclosure, baseline neurocognitive testing, nonpharmacological perioperative neurocognitive disorder prevention, intraoperative monitoring to prevent perioperative neurocognitive disorders, avoidance of benzodiazepines, delaying elective surgery after stroke, and emergency imaging and rapid restoration of cerebral perfusion after perioperative stroke. We identified 19 instances of discordant recommendations on 7 themes, including the use of regional anesthesia and monitoring for perioperative stroke prevention, pharmacological perioperative neurocognitive disorder management, and postoperative stroke screening. We synthesized recommendations for clinical practice and highlighted areas where high-quality evidence is required to inform best practices in perioperative brain health.

Radiomics based on preoperative rectal cancer MRI to predict the metachronous liver metastasis.

PURPOSE: At present, there are few effective method to predict metachronous liver metastasis (MLM) from rectal cancer. We aim to investigate the efficacy of radiomics based on multiparametric MRI of first diagnosed rectal cancer in predicting MLM from rectal cancer. METHODS: From 301 consecutive histopathologically confirmed rectal cancer patients, 130 patients who have no distant metastasis detected at the time of diagnosis were enrolled and divided into MLM group (n = 49) and non-MLM group (n = 81) according to whether liver metastasis be detected later than 6 month after the first diagnosis of rectal cancer within 3 years' follow-up. The 130 patients were divided into a training set (n = 91) and a testing set (n = 39) at a ratio of 7:3 by stratified sampling using SPSS 24.0 software. The DWI model, HD T2WI model, and DWI + HD T2WI model were constructed respectively. The best performing model was selected and combined with the screened clinical features (including non-radiomics MRI features) to construct a fusion model. The testing set was used to evaluate the performance of the models, and the area under the curve (AUC) of receiver operating characteristics (ROC) was calculated for both the training set and the testing set. RESULTS: The AUC of the DWI + HD T2WI model in the testing set was higher than that of the DWI or the HD T2 model alone with statistically significance (P < 0.05). The screened clinical features were extramural vascular invasion (EMVI), T and N stages in MRI (mrT, mrN), and the distance from the lower edge of the tumor to the anal verge. The AUC of the fusion model in the testing set was 0.911. Decision curves and nomogram also showed that the fusion model had excellent clinical performance. CONCLUSION: The fusion model of primary rectal cancer MRI based radiomics combing clinical features can effectively predict MLM from rectal cancer, which may assist clinicians in formulating individualized monitoring and treatment plans.

Study of urinary mercapturic acids as biomarkers of human acrylonitrile exposure.

Exposure to the vinyl monomer acrylonitrile (AN) is primarily occupational. AN is also found in cigarette smoke. AN can be detoxified to form N-acetyl-S-(2-cyanoethyl)-cysteine (CEMA) or activated to 2-cyanoethylene oxide (CEO) and detoxified to form N-acetyl-S-(1-cyano-2-hydroxyethyl)-cysteine (CHEMA) and N-acetyl-S-(2-hydroxyethyl)-cysteine (HEMA). These urinary mercapturic acids (MAs) are considered to be potential biomarkers of AN exposure. This study assessed personal AN exposure, urinary MAs (CEMA, CHEMA, and HEMA), and cotinine (a biomarker of cigarette smoke) in 80 AN-exposed and 23 non-exposed factory workers from urine samples provided before and after work shifts. Unambiguous linear correlations were observed between levels of urinary CEMA and CHEMA with personal AN exposures, indicating their potential as chemically-specific biomarkers for AN exposures. AN exposure was the dominant factor in MA formation for AN-exposed workers, whereas urinary cotinine used as a biomarker showed that cigarette smoke exposure was the primary factor for non-exposed workers. The CHEMA/CEMA and (CHEMA+HEMA)/CEMA ratios in this human study differ from those in similar studies of AN-treated rats and mice in literature, suggesting a possible dose- and species-dependent effect in AN metabolic activation and detoxification.

Decreased perforin-producing B cells correlate with systemic lupus erythematosus.

OBJECTIVES: It has been proved that B cells play indispensable roles in immunity via producing cytokines and secreting antibodies. Aberrant B cells are considered as the major participants in the pathogenesis of systemic lupus erythematosus (SLE). Recently, perforin (PFP)-producing B cell has been identified, serving as a new type of potential anti-tumour effector cells. However, the roles and characteristics of the PFP-producing B cells in SLE remain unclear. METHODS: The frequencies of PFP-producing B cells in peripheral blood of heathy controls (HC) and SLE patients were detected by flow cytometry, and their correlation with the patient clinical and immunological features were analysed. The capacities of these cells in producing PFP were also compared between HC and SLE by RT-qPCR and ELISpot analyses. RESULTS: In this study, we demonstrated that B cells could produce PFP and was further enhanced upon anti-BCR and IL-21 stimulation. In patients with SLE, the frequencies of these PFP-producing B cells were decreased and negatively correlated with the clinical characteristics. Further analysis revealed that SLE patients with vasculitis and pleurisy showed even lower frequencies of PFP-producing B cells. CONCLUSIONS: These findings revealed that B cells could produce PFP, and a decrease in these cells was associated with SLE pathogenesis.