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Metastatic castration-resistant prostate cancer; Olaparib; Pembrolizumab Cáncer de próstata metastásico resistente a la castración; Olaparib; Pembrolizumab Càncer de pròstata metastàtic resistent a la castració; Olaparib; Pembrolizumab Background Pembrolizumab and olaparib have shown single-agent activity in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC). Objective To evaluate the efficacy and safety of pembrolizumab plus olaparib in mCRPC. Design, setting, and participants Cohort A of the phase 1b/2 KEYNOTE-365 study enrolled patients with molecularly unselected, docetaxel-pretreated mCRPC whose disease progressed within 6 mo of screening. Intervention Pembrolizumab 200 mg intravenously every 3 wk plus olaparib 400-mg capsule or 300-mg tablet orally twice daily. Outcome measurements and statistical analysis The primary endpoints were safety, confirmed prostate-specific antigen (PSA) response rate, and objective response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, by blinded independent central review. The secondary endpoints included radiographic progression-free survival (rPFS) and overall survival (OS). Results and limitations Of 104 enrolled patients, 102 were treated. The median age was 70 yr (interquartile range [IQR], 65–76), and 59 patients (58%) had measurable disease as per RECIST v1.1. The median time from the first dose to database cutoff was 24 mo (IQR, 22–47). The confirmed PSA response rate was 15%. The confirmed ORR was 8.5% (five partial responses) for patients with measurable disease. The median rPFS was 4.5 mo (95% confidence interval [CI], 4.0–6.5) and median OS was 14 mo (95% CI, 10.4–18.2). Clinical activity was consistent across the programmed death ligand 1 (PD-L1)-positive and homologous recombination repair mutation subgroups. Treatment-related adverse events (TRAEs) occurred in 93 patients (91%). Grade 3–5 TRAEs occurred in 49 patients (48%). Six deaths (5.9%) were due to adverse events; two (myocardial infarction and unknown cause) were attributed to treatment. Limitations of the study include the single-arm design. Conclusions Pembrolizumab plus olaparib had a safety profile consistent with the profiles of the individual agents and demonstrated antitumor activity in previously treated patients with molecularly unselected, docetaxel-pretreated mCRPC.

Excessive cardiac fibrosis is central to adverse cardiac remodeling and dysfunction leading to heart failure in many cardiac diseases. Histone methylation plays a crucial role in various pathophysiological events. However, the role of histone methylation modification enzymes in pathological cardiac fibrosis needs to be fully elucidated. Here, we identified lysine demethylase 5B (KDM5B), a histone H3K4me2/me3 demethylase, as a key epigenetic mediator of pathological cardiac fibrosis. KDM5B expression was upregulated in cardiac fibroblasts and myocardial tissues in response to pathological stress. KDM5B deficiency markedly ameliorated cardiac fibrosis, improved cardiac function, and prevented adverse cardiac remodeling following myocardial infarction (MI) or pressure overload. KDM5B knockout or inhibitor treatment constrained the transition of cardiac fibroblasts to profibrogenic myofibroblasts and suppressed fibrotic responses. KDM5B deficiency also facilitated the transformation of cardiac fibroblasts to endothelial-like cells and promoted angiogenesis in response to myocardial injury. Mechanistically, KDM5B bound to the promoter of activating transcription factor 3 (Atf3), an antifibrotic regulator of cardiac fibrosis, and inhibited ATF3 expression by demethylating the activated H3K4me2/3 modification, leading to the enhanced activation of TGF-β signaling and excessive expression of profibrotic genes. Our study indicates that KDM5B drives pathological cardiac fibrosis and represents a candidate target for intervention in cardiac dysfunction and heart failure.

Patients undergoing explantation of left ventricular assist devices (LVADs) after improvement of myocardial function remain a minority. Nevertheless, considering the growing population of LVAD patients, increasing demand for new explantation strategies is expected. Herein, we present a retrospective review of seven patients undergoing HeartMate3 explantation with the use of a custom-made apical ring plug in four medical centers. The primary outcome was status at intensive care unit discharge. Secondary outcomes included perioperative complications and transfusions. Six out of seven patients were males. The median age at explantation and time on LVAD support was 35 years (range:13-73) and 10 months (range:9-24), respectively. No technical difficulties were experienced during plug implantation via a conventional sternotomy or through a left lateral thoracotomy, either with or without cardiopulmonary bypass. Perioperative transfusions ranged from 0 to 3 units/patient. No re-operations for bleeding, hemorrhagic, embolic, or plug-related infective events were observed. Heparin was started 6 hours after surgery as a bridge to oral anticoagulation (international normalized ratio: 2-2.5). All patients were discharged alive from intensive care unit. This novel plug device for HeartMate3 explantation was successfully and safely implanted in this first patient series. Notwithstanding, its use should still be considered off-label and larger studies are required to investigate its long-term results.

Genome sequencing of cancers often reveals mosaics of different subclones present in the same tumour1–3. Although these are believed to arise according to the principles of somatic evolution, the exact spatial growth patterns and underlying mechanisms remain elusive4,5. Here, to address this need, we developed a workflow that generates detailed quantitative maps of genetic subclone composition across whole-tumour sections. These provide the basis for studying clonal growth patterns, and the histological characteristics, microanatomy and microenvironmental composition of each clone. The approach rests on whole-genome sequencing, followed by highly multiplexed base-specific in situ sequencing, single-cell resolved transcriptomics and dedicated algorithms to link these layers. Applying the base-specific in situ sequencing workflow to eight tissue sections from two multifocal primary breast cancers revealed intricate subclonal growth patterns that were validated by microdissection. In a case of ductal carcinoma in situ, polyclonal neoplastic expansions occurred at the macroscopic scale but segregated within microanatomical structures. Across the stages of ductal carcinoma in situ, invasive cancer and lymph node metastasis, subclone territories are shown to exhibit distinct transcriptional and histological features and cellular microenvironments. These results provide examples of the benefits afforded by spatial genomics for deciphering the mechanisms underlying cancer evolution and microenvironmental ecology.

Background: The optimum systolic blood pressure after endovascular thrombectomy for acute ischaemic stroke is uncertain. We aimed to compare the safety and efficacy of blood pressure lowering treatment according to more intensive versus less intensive treatment targets in patients with elevated blood pressure after reperfusion with endovascular treatment. Methods: We conducted an open-label, blinded-endpoint, randomised controlled trial at 44 tertiary-level hospitals in China. Eligible patients (aged ≥18 years) had persistently elevated systolic blood pressure (≥140 mm Hg for >10 min) following successful reperfusion with endovascular thrombectomy for acute ischaemic stroke from any intracranial large-vessel occlusion. Patients were randomly assigned (1:1, by a central, web-based program with a minimisation algorithm) to more intensive treatment (systolic blood pressure target

OBJECTIVES: Historically, females were described as suffering from worse outcomes after left ventricular assist device (LVAD) implantation. However, females' preoperative conditions are unique, making direct comparisons with males challenging. This study aimed to select through propensity score (PS) matching two preoperatively comparable populations of females and males and test if any real sex-related difference exists regarding survival and adverse events after LVAD implantation.METHODS: This retrospective single-center observational study investigated patients who received LVAD implantation between 2010 and 2018. PS matching was applied to balance preoperative heterogeneity between males and females. Primary endpoint was survival at follow-up. Secondary endpoints included perioperative outcomes and LVAD-related adverse events.RESULTS: 92 fully comparable females(n=46) and males(n=46) were selected after PS matching (median age:57 years, min-max:18-75). 26.1% of patients required preoperative mechanical circulatory support. Females needed more intraoperative fresh frozen plasma (pCONCLUSIONS: After reducing preoperative heterogeneity between females and males, survival after LVAD implantation does not differ based on sex. However, differences might exist in terms of higher transfusions and strokes in females. Reducing preoperative sex disparities and developing intraoperative and anticoagulation strategies which acknowledge sex-related variations might help abolishing differences in LVAD outcomes.

BACKGROUND: Among patients referred for cardiac surgeries, atrial fibrillation (AF) is a common comorbidity and a risk factor for post-operative arrhythmias (such as sinus node dysfunction or atrioventricular heart blocks), including those requiring permanent pacemaker (PPM) implantation.OBJECTIVE: The current study aimed to evaluate the prevalence and long-term survival of post-operative PPM implantation in patients with pre-operative AF who underwent valve surgery with or without concomitant procedures.METHODS: Presented analysis pertains to the HEIST (HEart surgery In atrial fibrillation and Supraventricular Tachycardia) registry. During study period 11,949 patients underwent valvular (aortic, mitral or tricuspid valve replacement or repair) surgery and/or surgical ablation (SA) and were stratified according to post-operative PPM status.RESULTS: Permanent pacemaker implantation after surgery was necessary in 2.5% of patients, with a significant variation depending on the type of surgery (from 1.1% in mitral valve repair to 3.3% in combined mitral and tricuspid valve surgery). In a multivariate logistic regression model, tricuspid intervention (PCONCLUSION: In patients with pre-operative AF, the need for PPM implantation after valve surgery or SA is not an infrequent outcome, with SA not affecting its prevalence but actually improving long-term survival.

Background: Atrial fibrillation (AF) is a relatively common comorbidity among patients referred for coronary artery bypass grafting (CABG) and is associated with poorer prognosis. However, little is known about how surgical technique influences survival in this population. Aim: The current analysis aimed to determine whether total arterial revascularization (TAR) is associated with improved long-term outcomes in patients with preoperative AF. Methods: We analyzed patients' data from the HEIST (HEart surgery In atrial fibrillation and Supraventricular Tachycardia) registry. The registry, to date, involves five tertiary high-volume centers in Poland. Between 2006 and 2019, 4746 patients presented with preoperative AF and multivessel coronary artery disease and underwent CABG. We identified cases of TAR and used propensity score matching to determine non-TAR controls. Median follow-up was 4.1 years (interquartile range [IQR], 1.9-6.8 years). Results: Propensity matching resulted in 295 pairs of TAR vs. non-TAR. The mean (standard deviation [SD]) number of distal anastomoses was 2.5 (0.6) vs. 2.5 (0.6) (P = 0.94), respectively. Operative and 30-day mortality was not different between TAR and non-TAR patients (hazard ratio [HR] and 95% confidence intervals [CIs], 0.17 (0.02-1.38); P = 0.12 and 0.74 [0.40-1.35]; P = 0.33, respectively). By contrast, TAR was associated with nearly 30% improved late survival: HR, 0.72 (0.55-0.93); P = 0.01. This benefit was sustained in subgroup analyses, yet most pronounced in low-risk patients (

This study demonstrated the prevalence of self-reported glaucoma and its strong association with preexisting systemic chronic diseases in China using the baseline data from China Health and Retirement Longitudinal Study (CHARLS), a nationwide population-based cohort.The purpose of this study is to estimate the prevalence of self-reported glaucoma and its risk factors using data from the CHARLS.Data on age, sex, area of residence, education, marital status, health-related behaviors, and preexisting comorbidities for this cross-sectional study were retrieved from the CHARLS for 17,713 subjects who completed a questionnaire between June 2011 and March 2012. The prevalence of glaucoma was estimated, and a multivariate weighted analysis was performed to estimate the odds ratios (ORs) of its risk factors.Of 16,599 respondents (93.7%) who answered questions regarding glaucoma and their history of systemic chronic diseases, 314 (1.89%) reported having glaucoma before the index date. Qinghai and Beijing had the highest prevalence of glaucoma in China. Glaucoma was significantly associated with hypertension [OR: 1.362; 95% confidence interval (CI), 1.801-2.470], diabetes (OR: 2.597; 95% CI, 1.661-10.207), dyslipidemia (OR: 1.757; 95% CI, 1.157-3.650), lung disease (OR: 2.098; 95% CI, 1.674-6.527), stroke (OR: 5.278; 95% CI, 1.094-25.462), heart disease (OR: 1.893; 95% CI, 1.237-3.363), and health-related behaviors such as smoking and alcohol consumption after adjusting for age, sex, area, education, marital status, and medical insurance.Geographic variation in the prevalence of self-reported glaucoma and its strong association with preexisting systemic chronic diseases were observed, suggesting that in addition to ophthalmological examinations, regular physical examinations are necessary for glaucoma patients, especially in areas of high incidence. Appropriate strategies to improve preventive measures for glaucoma are recommended for the Chinese population.

Objective. This study focused on mood regulations and their association with sociodemographic status, exercise pattern, and physical conditions of adults and older adults in China who did not undergo interventions. Method. Data were based on the 2016 to 2018 Guangdong National Physique Monitoring data, in which 5242 participants aged 20-69 years were recruited. Multiple statistical analysis methods, such as descriptive and logistic regression analyses, were used to study each exercise motivation and its association with influencing factors, including sociodemographic characteristics, exercise measurements, and physical conditions. An exercise index for mental health was also used to investigate the number and types of people who were more likely to meet the index. Results. We observed that 44.9% (2355/5242) of participants did not engage in physical exercise in this study. Only older participants (40 to 69 years old) and those with an average level of education (high school/technical secondary school) showed a significant association with exercising for mood regulation. Few people met the index that is good for mental health (16.64% [872/5242] met index 1, and 2.84% (149/5242) met index 2), and higher education showed a significant association with a reduction in the mental health burden and the prevention of depression. Conclusion. This study found that motivating people to be more active and educating them on the potential mental health benefits of exercise could help them to exercise more.

Patients with metastatic castration-resistant prostate cancer (mCRPC) frequently receive docetaxel after they develop resistance to abiraterone or enzalutamide and need more efficacious treatments.To evaluate the efficacy and safety of pembrolizumab plus docetaxel and prednisone in patients with mCRPC.The trial included patients with mCRPC in the phase 1b/2 KEYNOTE-365 cohort B study who were chemotherapy naïve and who experienced failure of or were intolerant to ≥4 wk of abiraterone or enzalutamide for mCRPC with progressive disease within 6 mo of screening.Pembrolizumab 200 mg intravenously (IV) every 3 wk (Q3W), docetaxel 75 mg/mThe primary endpoints were safety, the prostate-specific antigen (PSA) response rate, and the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary endpoints included time to PSA progression; the disease control rate (DCR) and duration of response (DOR) according to RECIST v1.1 by BICR; ORR, DCR, DOR, and radiographic progression-free survival (rPFS) according to Prostate Cancer Working Group 3-modified RECIST v1.1 by BICR; and overall survival (OS).Among 104 treated patients, 52 had measurable disease. The median time from allocation to data cutoff (July 9, 2020) was 32.4 mo, during which 101 patients discontinued treatment, 81 (78%) for disease progression. The confirmed PSA response rate was 34% and the confirmed ORR (RECIST v1.1) was 23%. Median rPFS and OS were 8.5 mo and 20.2 mo, respectively. Treatment-related adverse events (TRAEs) occurred in 100 patients (96%). Grade 3-5 TRAEs occurred in 46 patients (44%). Seven AE-related deaths (6.7%) occurred (2 due to treatment-related pneumonitis). Limitations of the study include the single-arm design and small sample size.Pembrolizumab plus docetaxel and prednisone demonstrated antitumor activity in chemotherapy-naïve patients with mCRPC treated with abiraterone or enzalutamide for mCRPC. Safety was consistent with profiles for the individual agents. Further investigation is warranted.We evaluated the efficacy and safety of the anti-PD-1 antibody pembrolizumab combined with the chemotherapy drug docetaxel and the steroid prednisone for patients with metastatic prostate cancer resistant to androgen deprivation therapy , and who never received chemotherapy. The combination showed antitumor activity and manageable safety in this patient population. This trial is registered on ClinicalTrials.gov as NCT02861573.

Triple-negative breast cancer (TNBC) is one of the most malignant subtypes of breast cancer with an unsatisfied prognosis. Effective biomarkers could predict the risk and improve patients' survival. Whether LINC00466 possesses the potential to serve as a biomarker of the progression and prognosis of TNBC was evaluated.A total of 122 TNBC patients were included in this study and provided paired clinical tissues. The expression of LINC00466 in TNBC was evaluated by RT-qPCR and evaluated the clinical significance with a series of statistical analyses. The biological effects and the mechanism were investigated in TNBC cells with CCK8, Transwell, and luciferase reporter assays.LINC00466 was significantly upregulated in TNBC and showed close association with the clinical features of patients, which indicates the development, and severity of patients. LINC00466 functioned as a prognostic biomarker predicting the survival of patients and a tumor promoter improving the proliferation, migration, and invasion of TNBC cells through sponging miR-539-5p.LINC00466 promotes the progression of TNBC via regulating miR-539-5p. The inhibition of LINC00466 might be a novel therapeutic strategy for TNBC.

Background Patients receiving left ventricle assist devices (LVADs) as bridge to recovery remain a minority with 1%-5% of LVADs explanted after improvement of myocardial function. Nevertheless, considering the growing population of patients supported with LVADs, an increasing demand of new explantation strategies is expected in the near future. A novel plug for LVAD explantation has been developed and its biocompatibility profile needs to be proved. This study tested the biocompatibility of this novel plug in an in vivo ovine model. Methods Six adult Blackhead Persian female sheep received plug implantation on the cardiac apex via minimally invasive approach and were clinically observed up to 90 days. Echocardiography was performed to detect thrombus formation or further plug-related complications. After the observation period, euthanasia was performed and samples including the plug and the surrounding tissues were obtained to be analyzed with correlative light and electron microscopy. Organ necrosis, ischemia and peripheral embolism were investigated. Results Three animals survived surgery and completed the follow-up time without experiencing clinical complications. Echocardiographic controls excluded the presence of an intracavitary thrombus in the left ventricle (LV). Autopsy confirmed no signs of local infection, LV thrombus or peripheral embolism. Light and electron microscopy revealed an intact epithelium covering a layer of connective tissue on the plug surface facing the heart lumen. Conclusions This novel apical plug for LVAD explantation allows for endothelial and connective tissue growth on its ventricular side within 90 days from surgery. Further studies are required to fully demonstrate the biocompatibility of this apical plug and investigate the optimal anticoagulation regimen to be applied after implantation.

OBJECTIVE: Myocardial damage occurs in up to 25% of coronavirus disease 2019 (COVID-19) cases. While veno-venous extracorporeal life support (V-V ECLS) is used as respiratory support, mechanical circulatory support (MCS) may be required for severe cardiac dysfunction. This systematic review summarizes the available literature regarding MCS use rates, disease drivers for MCS initiation, and MCS outcomes in COVID-19 patients. METHODS: PubMed/EMBASE were searched until October 14, 2021. Articles including adults receiving ECLS for COVID-19 were included. The primary outcome was the rate of MCS use. Secondary outcomes included mortality at follow-up, ECLS conversion rate, intubation-to-cannulation time, time on ECLS, cardiac diseases, use of inotropes, and vasopressors. RESULTS: Twenty-eight observational studies (comprising both ECLS-only populations and ECLS patients as part of larger populations) included 4218 COVID-19 patients (females: 28.8%; median age: 54.3 years, 95%CI: 50.7-57.8) of whom 2774 (65.8%) required ECLS with the majority (92.7%) on V-V ECLS, 4.7% on veno-arterial ECLS and/or Impella, and 2.6% on other ECLS. Acute heart failure, cardiogenic shock, and cardiac arrest were reported in 7.8%, 9.7%, and 6.6% of patients, respectively. Vasopressors were used in 37.2%. Overall, 3.1% of patients required an ECLS change from V-V ECLS to MCS for heart failure, myocarditis, or myocardial infarction. The median ECLS duration was 15.9 days (95%CI: 13.9-16.3), with an overall survival of 54.6% and 28.1% in V-V ECLS and MCS patients. One study reported 61.1% survival with oxy-right ventricular assist device. CONCLUSION: MCS use for cardiocirculatory compromise has been reported in 7.3% of COVID-19 patients requiring ECLS, which is a lower percentage compared to the incidence of any severe cardiocirculatory complication. Based on the poor survival rates, further investigations are warranted to establish the most appropriated indications and timing for MCS in COVID-19.

Background. The role of ketamine as an adjuvant for morphine in the treatment of cancer pain and immune functions has been confirmed. This study aimed to explore the role of morphine and ketamine on cancer pain and T cells of patients with cervical cancer (CC). Methods. T cells were isolated from peripheral blood mononuclear cells (PBMC) of CC patients by positive selection using anti-CD3 beads. The isolated T cells were assigned into three groups: the control group, the morphine group, and the morphine + ketamine (Mor + Ket) group. The percentages of CD4+ and CD8+ were analyzed by flow cytometry. The levels of interferon (IFN)-γ, interleukin (IL)-2, and IL-17 and the corresponding mRNA expression in vitro were determined using ELISA and qRT-PCR, respectively. Western blotting was used for detection of JAK3/STAT5 pathway-related proteins after naltrexone treatment in vitro. Afterwards, all the patients were further divided into the morphine group and the Mor + Ket group in accordance with the principles of the randomized and double-blind method to assess pain intensity. Results. Our in vivo results showed that drug combinations relieved cancer pain more effectively than morphine intervention. The in vitro results demonstrated that the combination of morphine and ketamine may decrease CD4+ percentage, CD4+/CD8+ ratio, and the levels of IFN-γ, IL-2, and IL-17 via the JAK3/STAT5 pathway. Conclusions. Our finding indicated that morphine-ketamine combination could improve cancer pain and repress immune function via the JAK3/STAT5 pathway in the progression of CC.

Flexible implantable medical devices (IMDs) are an emerging technology that may substantially improve the disease treatment efficacy and quality of life of patients. While many advancements have been achieved in IMDs, the constantly straining application conditions impose extra requirements for the packaging material, which needs to retain both high stretchability and high water resistivity under dynamic strains in a physiological environment. This work reports a polyisobutylene (PIB) blend-based elastomer that simultaneously offers a tissue-like elastic modulus and excellent water resistivity under dynamic strains. The PIB blend is a homogeneous mixture of two types of PIB molecules with distinct molecular weights. The blend achieved an optimal Young’s modulus of 62 kPa, matching those of soft biological tissues. The PIB blend film also exhibited an extremely low water permittivity of 1.6–2.9 g m(−2) day(−1), from unstrained to 50% strain states. The combination of high flexibility and dynamic water resistivity was tested using triboelectric nanogenerators (TENGs). The PIB blend-packaged TENG was able to stably operate in water for 2 weeks, substantially surpassing the protection offered by Ecoflex. This work offered a promising material solution for packaging flexible IMDs to achieve stable performance in a strained physiological environment.

Background We examined whether digital breast tomosynthesis (DBT) detects differentially in high- or low-density screens. Methods We searched six databases (2009–2020) for studies comparing DBT and digital mammography (DM), and reporting cancer detection rate (CDR) and/or recall rate by breast density. Meta-analysis was performed to pool incremental CDR and recall rate for DBT (versus DM) for high- and low-density (dichotomised based on BI-RADS) and within-study differences in incremental estimates between high- and low-density. Screening settings (European/US) were compared. Results Pooled within-study difference in incremental CDR for high- versus low-density was 1.0/1000 screens (95% CI: 0.3, 1.6; p = 0.003). Estimates were not significantly different in US (0.6/1000; 95% CI: 0.0, 1.3; p = 0.05) and European (1.9/1000; 95% CI: 0.3, 3.5; p = 0.02) settings (p for subgroup difference = 0.15). For incremental recall rate, within-study differences between density subgroups differed by setting (p p p = 0.001) in European screening. Conclusions DBT has differential incremental cancer detection and recall by breast density. Although incremental CDR is greater in high-density, a substantial proportion of additional cancers is likely to be detected in low-density screens. Our findings may assist screening programmes considering DBT for density-tailored screening.

This study aims at understanding mammographic density profile in China by comparing the density between women in China and Australia.Data of 3250 women aged 45-69 were obtained from the Cancer Screening Program in Urban China and data of 1384 Australian counterparts at same age range were gathered from the Lifepool project. Demographic and reproductive details and mammograms for each cohort were collected. Mammographic density was assessed using AutoDensity, and two metrics, percentage density (PD) and dense area (DA), were applied. T-tests were used to compare the means of mammographic density between two populations of all, premenopausal, and postmenopausal women. Two-way ANOVA was conducted to examine interactions of population (Chinese/Australian) and each variable of interest upon mammographic density.Chinese women had 9.61%, 8.20%, and 9.28% higher PD than their Australian counterparts in all, premenopausal, and postmenopausal women, respectively (all p 0.001). The mean differences in DA between two population were 1.81 cmBoth PD and DA were found to be higher in Chinese women compared to Australian women. The density difference by menopause status was shown and breastfeeding history affected breast density differently in both populations.

To investigate if positive changes in the clinical performance of radiologists are associated with reading mammographic test sets.This study investigated the clinical audit history for a cohort of 39 participants in the BreastScreen Reader Assessment Strategy who have read for BreastScreen New South Wales in the period between 2010 and 2018, inclusively. Based on the year in which each radiologist completed his or her first test set, data of multiple clinical audit metrics from two calendar years before test-set reading were compared against similar data from three different periods after test-set completion. The same process was repeated after dividing radiologists into two subgroups based on their median screen-reading volume (3,688), to test if experience is a determinant of post-test set performance.On average, radiologists showed significant improvements (p0.05) in the recall rate for subsequent screening rounds, in positive predictive value 1 (PPV1), and in specificity. When dividing radiologists based on their average annual reading volume, radiologists with higher reading numbers demonstrated similar significant improvements in the recall rate and in PPV1. In addition, they showed significant improvements in the detection rates of invasive breast cancer and ductal carcinoma in situ (DCIS). In contrast, the radiologists with lower reading volume indicated significant changes in the recall rate and in PPV1, both accruing in one of the three compared periods.Mammographic test-set participants improve over time in identifying normal breast screens and detecting breast cancer in association with reading higher volumes of breast screening cases.

Alzheimer's disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-β (Aβ) protein into amyloid plaques in patient brains. Mutations in presenilin (PS) lead to abnormal generation of Aβ, which is the major cause of familial AD (FAD), and apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) onset. However, whether dysfunction of PS is involved in the pathogenesis of SAD is largely unknown. We found that ApoE secretion was completely abolished in PS-deficient cells and markedly decreased by inhibition of γ-secretase activity. Blockade of γ-secretase activity by a γ-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of γ-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin-deficient cells with reduced γ-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin α4, a nuclear transport receptor. Moreover, the expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with the expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal control subjects. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion.SIGNIFICANCE STATEMENTFamilial AD (FAD) typically results from mutations in the genes encoding amyloid precursor protein, presenilin 1 (PS1), or PS2. Many PS mutants have been found to exert impaired γ-secretase activity and increased amyloid-β 42 (Aβ42)/Aβ40 ratio, which induce early amyloid deposition and FAD. On the other hand, apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) and contributes to AD pathogenesis because it has reduced Aβ clearance capability compared with ApoE3 and ApoE2. FAD and SAD have long been considered to be caused by these two independent mechanisms; however, for the first time, we demonstrated that PS is essential for ApoE secretion and PS mutants affected ApoE secretionin vitroand in human samples, suggesting a novel mechanism by which PS is also involved in SAD pathogenesis.

Developing carbon-based materials with high catalytic performance and sensitivity has significance in low-cost and highly efficient nanozymes. Herein, for the first time, Cu,N-codoped hollow carbon nanospheres (CuNHCNs) with highly active Cu-Nx sites were successfully assembled through a template-free strategy, in which Cu

Young patients with type 2 diabetes and myocardial infarction (MI) have higher long-term all-cause and cardiovascular mortality. In addition, the observed increased, mildly abnormal baseline lipid levels, but not lipid variability, are associated with an increased risk of atherosclerotic cardiovascular disease events, particularly MI. This study investigated differentially expressed genes (DEGs), which might be potential targets for young patients with MI and a high-fat diet (HFD). GSE114695 and GSE69187 were downloaded and processed using the limma package. A Venn diagram was applied to identify the same DEGs, and further pathway analysis was performed using Metascape. Protein-protein interaction (PPI) network analysis was then applied, and the hub genes were screened out. Pivotal miRNAs were predicted and validated using the miRNA dataset in GSE114695. To investigate the cardiac function of the screened genes, an MI mouse model, echocardiogram, and ELISA of hub genes were applied, and a correlation analysis was also performed. From aged mice fed HFD, 138 DEGs were extracted. From aged mice fed with chow, 227 DEGs were extracted. Pathway enrichment analysis revealed that DEGs in aging mice fed HFD were enriched in lipid transport and lipid biosynthetic process 1 d after MI and in the MAPK signaling pathway at 1 w after MI, suggesting that HFD has less effect on aging with MI. A total of 148 DEGs were extracted from the intersection between plaques fed with HFD and chow in young mice and MI_1d, respectively, which demonstrated increased inflammatory and adaptive immune responses, in addition to myeloid leukocyte activation. A total of 183 DEGs were screened out between plaques fed with HFD vs. chow in young mice and MI_1w, respectively, which were mainly enriched in inflammatory response, cytokine production, and myeloid leukocyte activation. After validation, PAK3, CD44, CD5, SOCS3, VAV1, and PIK3CD were demonstrated to be negatively correlated with LVEF; however, P2RY1 was demonstrated to be positively correlated. This study demonstrated that the screened hub genes may be therapeutic targets for treating STEMI patients and preventing MI recurrence, especially in young MI patients with HFD or diabetes.

Bing Xu, Mengmeng Yan, Fei Zhou, Desheng Cai, Wenbo Guo, Xiaohui Jia, Runping Liu, Tao Ma, Tong Li, Feng Gao, Penglong Wang, Haimin Lei School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of ChinaCorrespondence: Penglong Wang; Haimin Lei Email wpl581@126.com; hm_lei@126.comBackground: The clinical utility of camptothecin (CPT) is restricted by poor aqueous solubility, high lipophilicity, active lactone ring instability, and off-targeted toxicities. We report here a prostate-specific membrane antigen (PSMA) and esterase dual responsive self-assembled nanoparticles (CPT-WT-H NPs) for highly efficient CPT delivery and effective cancer therapy.Methods and Results: In this study, smart self-assembled nanoparticles CPT-WT-H NPs were elaborately designed and synthesized by combing hydrophobic CPT with hydrophilic PSMA-responsive penta-peptide via a cleavable ester bond. This dual responsive nanoparticle with negatively charged surface first respond to the extracellular PSMA and then to the intracellular esterase, achieving a programmable release of CPT at the tumor site and producing the byproducts of biocompatible glutamic acid and aspartic acid. Our data demonstrated that CPT-WT-H NPs exhibited greatly improved water solubility and stability. Results from MTT and flow cytometry showed CPT-WT-H NPs exhibited significantly higher cytotoxicity as well as apoptosis-inducing activity against PSMA-expressing LNCaP-FGC cells than the non-PSMA-expressing cancer cells, showing excellent cytotoxic selectivity. Moreover, the unique nanostructure provided the efficient transportation of CPT to tumor site, which resulted in the effective inhibition of tumor growth and low systemic toxicity in vivo.Conclusion: CPT-WT-H NPs exhibited excellent in vitro PSMA-response ability and in vivo antitumor activity and safety, holding the promise to become a new and potent anticancer drug. The current research presents a promising strategy for efficient drug delivery.Keywords: CPT prodrug, dual responsive, sequential drug release, prostate-specific membrane antigen, self-assembly

The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense single-cell and spatial reference maps of the human uterus and three-dimensional endometrial organoid cultures. We dissect the signaling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids reveals the pathways and cell states regulating differentiation of the secretory and ciliated lineages both in vivo and in vitro. In vitro downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. We utilize our cellular maps to deconvolute bulk data from endometrial cancers and endometriotic lesions, illuminating the cell types dominating in each of these disorders. These mechanistic insights provide a platform for future development of treatments for common conditions including endometriosis and endometrial carcinoma. Single-cell and spatial transcriptomic profiling of the human endometrium highlights pathways governing the proliferative and secretory phases of the menstrual cycle. Analyses of endometrial organoids show that WNT and NOTCH signaling modulate differentiation into the secretory and ciliated epithelial lineages, respectively. Correction in: Nature Genetics, 55, page 165 (2023)DOI: 10.1038/s41588-022-01287-6

INTRODUCTION In many western countries, there is good evidence documenting the performance of radiologists reading digital breast tomosynthesis (DBT) images. However, the diagnostic efficiency of Chinese radiologists using DBT, particularly type of errors being made and type of cancers being missed, is understudied. This study aims to investigate the pattern of diagnostic errors across different lesion types produced by Chinese radiologists diagnosing from DBT images. Australian radiologists will be used as a benchmark. METHODS Twelve Chinese radiologists read a DBT test set and located each perceived cancer lesion. True positives, false positives (FP), true negatives and false negatives (FN) were generated. The same test set was also read by 14 Australian radiologists. Z-scores and Pearson correlations were used to compare interpretation of lesions and identification of normal appearances between two groups of radiologists. RESULTS Architectural distortions (p

An aptamer is a short oligonucleotide chain that can specifically recognize targeting analytes. Due to its high specificity, low cost, and good biocompatibility, aptamers as the targeting elements of biosensors have been applied widely in non‐invasive tumor imaging and treatment in situ to replace traditional methods. In this review, we will summarize recent advances in using aptamer‐based biosensors in tumor diagnosis. After a brief introduction of the advantage of aptamers compared with enzyme sensors and immune sensors, the different sensing designs and mechanisms based on 3 signal transduction modes will be reviewed to cover different kinds of analytical methods, including: electrochemistry analysis, colorimetry analysis, and fluorescence analysis. Finally, the prospective advantages of aptamer‐based biosensors in tumor theranostics and post‐treatment monitoring are also evaluated in this review., This review introduces the advantages of aptamer sensors in disease diagnosis compared with traditional biosensors. It also shows the design strategies of the 3 most studied aptamer sensors: fluorescent aptasensors, electrochemical aptasensors, and colorimetric aptasensors, and their application in early tumor diagnosis. Moreover, taking the fluorescent aptasensor as an example, the design of aptasensors combined with nanomaterials can not only be used for tumor imaging, but also has important significance in tumor treatment and efficacy evaluation. The design provides a new idea for the integration of tumor theranostics.

To develop a deep learning algorithm based on automatic detection of landmarks that can be used to automatically calculate forefoot imaging parameters from radiographs and test its performance. A total of 1023 weight-bearing dorsoplantar (DP) radiographs were included. A total of 776 radiographs were used for training and verification of the model, and 247 radiographs were used for testing the performance of the model. The radiologists manually marked 18 landmarks on each image. By training our model to automatically label these landmarks, 4 imaging parameters commonly used for the diagnosis of hallux valgus could be measured, including the first–second intermetatarsal angle (IMA), hallux valgus angle (HVA), hallux interphalangeal angle (HIA), and distal metatarsal articular angle (DMAA). The reference standard was determined by the radiologists’ measurements. The percentage of correct key points (PCK), intragroup correlation coefficient (ICC), Pearson correlation coefficient (r), root mean square error (RMSE), and mean absolute error (MAE) between the predicted value of the model and the reference standard were calculated. The Bland–Altman plot shows the mean difference and 95% LoA. The PCK was 84–99% at the 3-mm threshold. The correlation between the observed and predicted values of the four angles was high (ICC: 0.89–0.96, r: 0.81–0.97, RMSE: 3.76–6.77, MAE: 3.22–5.52). However, there was a systematic error between the model predicted value and the reference standard (the mean difference ranged from − 3.00 to − 5.08°, and the standard deviation ranged from 2.25 to 4.47°). Our model can accurately identify landmarks, but there is a certain amount of error in the angle measurement, which needs further improvement.

Background Fine-needle aspiration cytology (FNAC) is a basic diagnostic tool for thyroid nodules. However, 15–30% of nodules are cytologically indeterminate. Midkine (MK), a pleiotropic growth factor, is often upregulated in patients with cancers. This study aimed to evaluate the role of MK and its ratios in fine-needle aspirates (FNA) for predicting thyroid malignancy. Methods This retrospective study included patients with thyroid nodules who underwent preoperative FNA and/or thyroidectomy between April 2017 and September 2017. MK levels in FNA washout were measured by enzyme-linked immunosorbent assay, and thyroglobulin (TG) and free thyroxine (FT4) levels in FNA washout were measured by chemiluminescent immunometric assays. Results A total of 217 patients with 242 nodules were included in this study. The concentrations of TG, FT4, MK/TG, MK/FT4, and FT4/MK were significantly different between papillary thyroid carcinomas and benign thyroid nodules. Both MK/TG and MK/FT4 ratios were positively correlated with maximum tumor diameter, extrathyroidal extension, and T and N stages. The area under the curve for MK/TG was 0.719 with a cutoff value of 55.57 ng/mg, while the area under the curve for MK/FT4 was 0.677 with a cutoff value of 0.11 μg/pmol. FNAC in combination with MK/FT4 had a higher sensitivity (95% vs. 91%) and accuracy (96% vs. 92%) than FNAC alone for cytologically indeterminate specimens, those of unknown significance, or those suspected of malignancy. Conclusions MK/FT4 and MK/TG may have diagnostic utility for evaluation of papillary thyroid carcinomas, particularly for cytologically indeterminate thyroid nodules.

Background Alcohol consumption and smoking are the leading risk factors for laryngeal cancer (LC). Understanding the variations in disease burden of LC attributable to alcohol use and smoking is critical for LC prevention. Methods Disease burden data of LC were retrieved from the Global Burden of Disease Study 2019. We used estimated average percentage change (EAPC) to measure the temporal trends of the age-standardized mortality rate (ASMR) of LC. Results Globally, while the ASMR of LC decreased by 1.49% (95% CI, 1.41–1.57%) per year between 1990 and 2019, the number of deaths from LC has increased 41.0% to 123.4 thousand in 2019. In 2019, 19.4 and 63.5% of total LC-related deaths were attributable to alcohol use and smoking worldwide, respectively. The ASMR of alcohol- and smoking-related LC decreased by 1.78 and 1.93% per year, whereas the corresponding death number has increased 29.2 and 25.1% during this period, respectively. The decreasing trend was more pronounced in developed countries. In some developing countries, such as Guinea and Mongolia, the LC mortality has shown an unfavorable trend. Conclusion The ubiquitous decrease in LC mortality was largely attributed to the smoking control and highlighted the importance of smoking control policies. However, the disease burden of LC remained in increase and more effective strategies are needed to combat the global increase of alcohol consumption.

AIM The aim of the study was to examine the cross-sectional association between serum albumin and hyperuricemia (HU). MATERIALS AND METHODS HU was defined as uric acid ≥ 420 umol/L for the male population and ≥ 357 umol/Lfor the female population. We reviewed the files of 216 consecutive patients with idiopathic membranous nephropathy treated at our hospital between 2010 and 2019. The correlation of serum albumin with hyperuricemia and the association between serum uric acid levels and the clinical of Idiopathic membranous nephropathy were assessed by statistical analysis. A multivariable logistic analysis model was applied to test the association after adjusting for a number of potential confounding factors. RESULTS Triglyceride and serum albumin were higher in the group with hyperuricemia than in the group without hyperuricemia (p = 0.020, p < 0.001, respectively). As serum albumin rose to 1 g/L, the probability for hyperuricemia increased to 17% (adjusted II OR = 1.17, 95% CI (1.02, 1.35), p = 0.0294). A unit increase in serum albumin was associated with an increase of 6.64 g/L in uric acid (adjusted II β = 6.64, p = 0.0135). Using tertile 1 (T1) for reference, the tertile 3 (T3) group was positively associated with both hyperuricemia (adjusted II OR = 44.21, 95% CI (12.76, 75.67), p = 0.0064) and uric acid (adjusted II β = 98.64, p = 0.0116). The interaction test showed significant interactions between serum albumin and the body mass index (BMI) when hyperuricemia or uric acid were used to determine the outcomes. The participants with a BMI ≥ 25 kg/m2 had a higher OR between serum albumin and hyperuricemia and had a higher β between serum albumin and uric acid than those with a BMI ≥ 25 kg/m2 (for hyperuricemia: OR = 1.01 vs. 1.18, p for interaction = 0.0056; for uric acid: β = 0.96 vs. 6.23, p for interaction = 0.0154). The area under the ROC curve (AUC) was 0.7615 in the participants with a BMI ≥ 25 kg/m2. The sensitivity and specificity of this point were 47.37% and 95.83%, respectively. CONCLUSION Our study showed that serum albumin was positively associated with hyperuricemia and uric acid, especially in obese subjects.

Background Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed cancer and third leading cause of cancer-related death worldwide in 2020. Exosomes derived from cancer-associated fibroblasts (CAFs-exo) can promote tumor progression in various human cancers. However, the underlying regulatory mechanism controlling how CAFs-exo can promote HCC progression remains poorly understood. Methods CAFs and para-cancer fibroblasts (PAFs) were isolated from HCC tissues and corresponding para-cancer tissues, then were cultured in vitro. CAFs and PAFs were characterized by immunofluorescence and western blot (WB) assays. Exosomes were isolated by ultracentrifugation, and characterized by transmission electron microscopy, nanoflow cytometry, and WB assay. The internalization of exosomes by HCC cells was observed under a fluorescence microscope. Cell Counting Kit-8 (CCK-8) assay was used to evaluate cell proliferation. Wound healing and transwell assays were used for migration and invasion experiments. RT-PCR assay was used to examine differentially expressed microRNAs (miRNAs) in exosomes and HCC cells. The TargetScan database was used to predict miRNA target genes. Hedgehog interacting protein (HHIP) expression analysis, prognostic analysis, and enrichment analysis of HHIP-related co-expressed genes were performed using the TIMER, UALCAN, Kaplan–Meier plotter, and LinkedOmics databases. Results CAFs-exo were internalized by HCC cells. CAFs-exo contributed to the aggressive phenotype of HCC cells, while inhibiting exosome secretion reversed these effects. Mechanistically, miRNAs in the DLK1-DIO3 imprinted region (miR-329-3p, miR-380-3p, miR-410-5p, miR-431-5p) were increased in HCC cells co-cultured with CAFs-exo compared with PAFs-exo. Expression of HHIP, a possible miR-431-5p target gene, was significantly downregulated in HCC cells. Low HHIP expression level in tumor tissues could predict poor prognosis in HCC patients. HHIP-related co-expressed genes were mainly associated with cell adhesion molecules. Conclusions CAFs-exo can promote HCC progression by delivering miRNAs in the DLK1-DIO3 imprinted region to HCC cells, subsequently inhibiting HHIP expression. HHIP is a potential prognostic biomarker in HCC.

When the world is recovering from the chaos that COVID-19 creates, the epidemic is still posing challenges to the public health system and communication. However, a case of information communication during the COVID-19 outbreak can provide a reference for the current information promulgate strategy in China. In January 2020, CCTV broadcasted the construction of two cabin hospitals on a 24-h Livestream (24H-LS), creating a remarkable viewing effect. We conducted a quantitative analysis based on the number of views, social media communication, and internet search index. We collected posts and comment data of the 24H-LS audience and related topics on Weibo, using sentiment classification and word frequency analysis to study the communication effect of 24H-LS from three perspectives: perception effect, psychology, and subject issue. The results show that, first, 24H-LS has attracted extensive public attention on the Internet and social media after its launch. Second, the public's perception of the risks of the COVID-19 outbreak and its uncertainty has decreased after watching the 24H-LS. At the same time, the positive emotions of the public have been enhanced to a certain extent. Third, through subject analysis, we found that the public had high participation and strong interaction in 24H-LS, which produced collective symbols and emotions. The study shows that through 24H-LS, a new information form, the media can effectively convey important information and resolve the public's fear and anxiety.

Ferulic acid (FA) is one of the most abundant bound phenolics in whole grains, partly contributing to its preventive effects on metabolic syndrome (MetS). The study aims to investigate if FA mediates MetS through the regulation of hepatic metabolisms and the insulin receptor related pathways in the palmitate-treated HepG2 cells (MetS model). We found that FA (50, 100, and 200 μM) dramatically ameliorated the lipid accumulation in the MetS model. FA significantly decreased the activities of the gluconeogenic enzymes, G6Pase and PEPCK, downregulated the lipogenic enzyme FAS-1, and upregulated the lipolytic enzyme CPT-1 by regulating a series of transcriptional factors including HNF4α, FOXO-1, SREBP-1c, and PPAR-γ. Notably, we found that FA's ability to alleviate MetS is achieved by activating the insulin receptor/PI3K/AKT pathway. Our results validated the effects of FA on mediating the metabolic disorders of lipid and glucose pathways and unveiled its potential intracellular mechanisms for the prevention of MetS.

Here, we present a protocol to characterize the antiviral ability of a protein of interest to SARS-CoV-2 infection in cultured cells, using MUC1 as an example. We use SARS-CoV-2 ΔN trVLP system, which utilizes transcription and replication-competent SARS-CoV-2 virus-like particles lacking nucleocapsid gene. We describe the optimized procedure to analyze protein interference of viral attachment and entry into cells, and qRT-PCR-based quantification of viral infection. The protocol can be applied to characterize more antiviral candidates and clarify their functioning stage. For complete details on the use and execution of this protocol, please refer to Lai et al. (2022).

Background Isolated sulfite oxidase deficiency (ISOD) caused by sulfite oxidase gene (SUOX) mutations is a rare neurometabolic disease associated with ectopia lentis (EL). However, few genotype–phenotype correlations have been established yet. Methods Potentially pathogenic SUOX mutations were screened from a Chinese cohort of congenital EL using panel-based next-generation sequencing and analyzed with multiple bioinformatics tools. The genotype–phenotype correlations were evaluated via a systematic review of SUOX mutations within our data and from the literature. Results A novel paternal missense mutation, c.205G > C (p.A69P), and a recurrent maternal nonsense mutation, c.1200 C > G (p.Y400*), of SUOX were identified in a 4-year-old boy from 312 probands. The biochemical assays manifested elevated urine sulfite and S-sulfocysteine accompanied by decreased homocysteine in the blood. The patient had bilateral EL and normal fundus, yet minimal neurological involvement and normal brain structure. Molecular modeling simulation revealed the p.A69P mutant had an unstable structure but an unchanged affinity for sulfite, while the truncated p.Y400* mutant showed decreased binding capacity. Genotype–phenotype analysis demonstrated patients with biallelic missense mutations had milder symptoms (P = 0.023), later age of onset (P P = 0.017) than other genotypes. No correlations were found regarding EL and other neurological symptoms. Conclusion The data from this study not only enrich the known mutation spectrum of SUOX but also suggest that missense mutations are associated with mild and atypical symptoms.

Protein tyrosine phosphatases function in dephosphorylating target proteins to regulate signaling pathways that control a broad spectrum of fundamental physiological and pathological processes. Detailed knowledge concerning the roles of classical PTPs in human cancer merits in-depth investigation. We comprehensively analyzed the regulatory mechanisms and clinical relevance of classical PTPs in more than 9000 tumor patients across 33 types of cancer. The independent datasets and functional experiments were employed to validate our findings. We exhibited the extensive dysregulation of classical PTPs and constructed the gene regulatory network in human cancer. Moreover, we characterized the correlation of classical PTPs with both drug-resistant and drug-sensitive responses to anti-cancer drugs. To evaluate the PTP activity in cancer prognosis, we generated a PTPscore based on the expression and hazard ratio of classical PTPs. Our study highlights the notable role of classical PTPs in cancer biology and provides novel intelligence to improve potential therapeutic strategies based on pTyr regulation.

HLA-B*35:251:02 has one nucleotide change from HLA-B*35:22:01:01 at nucleotide 363 changing Serine to Arginine at residue 97.

HLA-C*01:212 differs from HLA-C*01:02:01:01 by two non-synonmous nucleotide changes at positions 368 and 379 in exon 3.

Background To research the first-order features of apparent diffusion coefficient (ADC) values on diffusion-weighted magnetic resonance imaging (DWI) in maxillofacial malignant mesenchymal tumours. Methods The clinical data of 12 patients with rare malignant mesenchymal tumours of the maxillofacial region (6 cases of sarcoma and 6 cases of lymphoma) treated in the hospital from May 2018 to June 2020 and were confirmed by postoperative pathology were retrospectively analyzed. The patients were all examined by 1.5T magnetic resonance imaging. PyRadiomics were used to extract radiomics imaging first-order features. Group differences in quantitative variables were examined using independent-samples t-tests. Results The voxels number of ADCmean and ADCmedian of sarcoma tissues were 44.9124 and 44.2064, respectively, significantly higher than those in lymphoma tissues (ADCmean (− 68.8379) and ADCmedian (− 74.0045)), the difference considered statistically significant, so do the ADCkurt and ADCskew. Conclusions The statistical difference of ADCmean and ADCmedian is significant, it is consistent with the outcome of the manual measurement of the ADC mean value of the most significant cross-section of twelve cases of lymphoma. Development of tumour volume based on the ADC parameter map of DWI demonstrates that the first-order ADC radiomics features analysis can provide new imaging markers for the differentiation of maxillofacial sarcoma and lymphoma. Therefore, first-order ADC features of ADCkurt combined ADCskew may improve the diagnosis level.

BACKGROUND Intestinal barrier breakdown, a frequent complication of intestinal ischemia-reperfusion (I/R) including dysfunction and the structure changes of the intestine, is characterized by a loss of tight junction and enhanced permeability of the intestinal barrier and increased mortality. To develop effective and novel therapeutics is important for the improvement of outcome of patients with intestinal barrier deterioration. Recombinant human angiopoietin-like protein 4 (rhANGPTL4) is reported to protect the blood-brain barrier when administered exogenously, and endogenous ANGPTL4 deficiency deteriorates radiation-induced intestinal injury. AIM To identify whether rhANGPTL4 may protect intestinal barrier breakdown induced by I/R. METHODS Intestinal I/R injury was elicited through clamping the superior mesenteric artery for 60 min followed by 240 min reperfusion. Intestinal epithelial (Caco-2) cells and human umbilical vein endothelial cells were challenged by hypoxia/ reoxygenation to mimic I/R in vitro. RESULTS Indicators including fluorescein isothiocyanate-conjugated dextran (4 kilodaltons; FD-4) clearance, ratio of phosphorylated myosin light chain/total myosin light chain, myosin light chain kinase and loss of zonula occludens-1, claudin-2 and VE-cadherin were significantly increased after intestinal I/R or cell hypoxia/reoxygenation. rhANGPTL4 treatment significantly reversed these indicators, which were associated with inhibiting the inflammatory and oxidative cascade, excessive activation of cellular autophagy and apoptosis and improvement of survival rate. Similar results were observed in vitro when cells were challenged by hypoxia/reoxygenation, whereas rhANGPTL4 reversed the indicators close to normal level in Caco-2 cells and human umbilical vein endothelial cells significantly. CONCLUSION rhANGPTL4 can function as a protective agent against intestinal injury induced by intestinal I/R and improve survival via maintenance of intestinal barrier structure and functions.

The present study aimed to construct a novel methylation-related prognostic model based on microsatellite status that may enhance the prognosis of colorectal cancer (CRC) from methylation and microsatellite status perspective. DNA methylation and mRNA expression data with clinical information were downloaded from The Cancer Genome Atlas (TCGA) data set. The samples were divided into microsatellite stability and microsatellite instability group, and CIBERSORT was used to assess the immune cell infiltration characteristics. After identifying the differentially methylated genes and differentially expression genes using R packages, the methylation-driven genes were further identified. Prognostic genes that were used to establish the methylation-related risk score model were generated by the univariate and multivariate Cox regression model. Finally, we established and evaluated the methylation-related prognostic model for CRC patients. A total of 69 MDGs were obtained and three of these genes (MIOX, TH, DKFZP434K028) were selected to construct the prognostic model. Patients in the low-risk score group had a conspicuously better overall survival than those in the high-risk score group (p < .0001). The area under the receiver operating characteristic curve for this model was 0.689 at 3 years, 0.674 at 4 years, and 0.658 at 5 years. The Wilcoxon test showed that higher risk score was associated with higher T stage (p = .01), N stages (p = .0028), metastasis (p = .013), and advanced pathological stage (p = .0013). However, the more instability of microsatellite status, the lower risk score of CRC patients (p = .0048). Our constructed methylation-related prognostic model based on microsatellite status presents potential significance in assessing recurrence risk stratification, tumor staging, and immunotherapy for CRC patients.

Unfractionated heparin (UFH) is an anionic glycosaminoglycan that is widely used to prevent blood clotting. However, in certain cases, unwanted side effects can require it to be neutralized. Protamine sulfate (PS), a basic peptide rich in arginine, is the only approved antagonist for UFH neutralization. Many adverse reactions occur with the clinical application of PS, including systemic hypotension, pulmonary hypertension, and anaphylaxis. We previously described R15, a linear peptide composed of 15 arginine molecules, as a potential UFH antagonist. In this study, the in‐depth safety of R15 was explored to reveal its merits and associated risks in comparison with PS. In vitro safety studies investigated the interactions of R15 with erythrocytes, fibrin, complement, and rat plasma. In vivo safety studies explored potential toxicity and immunogenicity of R15 and the UFH–R15 complex. Results showed that both PS and R15 can induce erythrocyte aggregation, thicken fibrin fibers, activate complement, and cause anticoagulation in a concentration‐dependent manner. However, those influences weakened in whole blood or in live animals and were avoided when R15 was in a complex with UFH. We found dramatically enhanced complement activation when there was excess UFH in analyses involving UFH–PS complexes, and a slight increase in those involving UFH–R15 complexes. Within 2 h, R15 was degraded in rat plasma in vitro, whereas PS was not. Enhanced creatinine was found after a single intravenous injection of PS or R15 (900 U·kg−1, body weight), suggesting possible abnormal renal function. The UFH–PS complex, but not the UFH–R15 complex, exhibited obvious immunogenicity. In conclusion, R15 is nonimmunogenic and potentially safe at a therapeutic dose to reverse the effects of UFH., Safety studies of R15, a new heparin antagonist, were investigated in comparison with PS (protamine sulfate). R15 was degradable in plasma of rats within 2 h, whereas PS was not. Dramatically enhanced complement activation was observed for UFH–PS complex with excess UFH (unfractionated heparin). UFH–PS complex possessed immunogenicity that was completely absent for the UFH–R15 complex.

To explore the treatment of pediatric hepatic hemangioma and the role of the Hisense computer-assisted surgery (Hisense CAS) system in diagnosis and treatment. We collected the clinical and follow-up data of all pediatric hepatic hemangioma cases in our pediatric surgery department from March 2008 to March 2021 for retrospective analysis. The Hisense CAS system was used to create three-dimensional (3D) reconstructions based on computed tomography data. There were 71 patients, mainly infants (prenatal to 39 months). There were more males than females (42 vs. 29), and the alpha-fetoprotein level was significantly increased in 8 cases. 3D reconstruction by the Hisense CAS system showed that hepatic artery tracking was helpful for the differential diagnosis of pediatric hepatic hemangioma. Twenty-three children treated with propranolol showed significant differences in the tumour diameter, volume, and tumour-to-liver volume ratio after treatment (all P

Background Septic shock comprises a heterogeneous population, and individualized resuscitation strategy is of vital importance. The study aimed to identify subclasses of septic shock with non-supervised learning algorithms, so as to tailor resuscitation strategy for each class. Methods Patients with septic shock in 25 tertiary care teaching hospitals in China from January 2016 to December 2017 were enrolled in the study. Clinical and laboratory variables were collected on days 0, 1, 2, 3 and 7 after ICU admission. Subclasses of septic shock were identified by both finite mixture modeling and K-means clustering. Individualized fluid volume and norepinephrine dose were estimated using dynamic treatment regime (DTR) model to optimize the final mortality outcome. DTR models were validated in the eICU Collaborative Research Database (eICU-CRD) dataset. Results A total of 1437 patients with a mortality rate of 29% were included for analysis. The finite mixture modeling and K-means clustering robustly identified five classes of septic shock. Class 1 (baseline class) accounted for the majority of patients over all days; class 2 (critical class) had the highest severity of illness; class 3 (renal dysfunction) was characterized by renal dysfunction; class 4 (respiratory failure class) was characterized by respiratory failure; and class 5 (mild class) was characterized by the lowest mortality rate (21%). The optimal fluid infusion followed the resuscitation/de-resuscitation phases with initial large volume infusion and late restricted volume infusion. While class 1 transitioned to de-resuscitation phase on day 3, class 3 transitioned on day 1. Classes 1 and 3 might benefit from early use of norepinephrine, and class 2 can benefit from delayed use of norepinephrine while waiting for adequate fluid infusion. Conclusions Septic shock comprises a heterogeneous population that can be robustly classified into five phenotypes. These classes can be easily identified with routine clinical variables and can help to tailor resuscitation strategy in the context of precise medicine.

As an autoimmune disease affecting women of reproductive age, systemic lupus erythematosus (SLE) is linked to adverse fetal and maternal outcomes. However, the status of peripheral lymphocytes in SLE patients with different pregnancy outcomes is unclear. This retrospective cross-sectional study explored the relationship between lymphocyte subpopulations and pregnancy outcomes in married SLE female patients.The absolute numbers of peripheral T, helper T (Th)1, Th2, Th17, regulatory T (Treg), B, and natural killer (NK) cell subpopulations from 585 female SLE patients and 91 female healthy controls (HCs) were assessed. We compared the lymphocyte subpopulations in SLE patients with HCs and analyzed the absolute number and ratio of Treg cells according to pregnancy outcome in SLE patients.SLE patients had decreased numbers of T, B, NK, Th1, Th2, Th17, and Treg cells and an imbalance in pro- and anti-inflammatory cells (p .05), as well as adverse pregnancy outcomes. In abortion patients, the number of Treg cells (p = .008) decreased, leading to an imbalance in effector T and Treg cells. The ratio of Treg cells was higher in SLE patients with nulliparity than in those with one or two parities.The absolute numbers of lymphocyte subpopulations in SLE patients decreased, which was associated with abortion and parity (p .05). These results suggest that a loss of immune tolerance mediated by Tregs triggers pregnancy loss.

As an evolutionary success in life science, wearable biosensor systems, which can monitor human health information and quantify vital signs in real time, have been actively studied. Research in wearable biosensor systems is mainly focused on the design of sensors with various flexible materials. Among them, 2D materials with excellent mechanical, optical, and electrical properties provide the expected characteristics to address the challenges of developing microminiaturized wearable biosensor systems. This review summarizes the recent research progresses in 2D-materials-based wearable biosensors including e-skin, contact lens sensors, and others. Then, we highlight the challenges of flexible power supply technologies for smart systems. The latest advances in biosensor systems involving wearable wristbands, diabetic patches, and smart contact lenses are also discussed. This review will enable a better understanding of the design principle of 2D biosensors, offering insights into innovative technologies for future biosensor systems toward their practical applications.

Due to the lack of precise microstructure and functions of the two-dimensional culture model, the

Antibacterial hydrogels have gradually become a powerful weapon to treat bacterially infected wounds and accelerate healing. In this paper, we designed a small-molecule self-healing antibacterial hydrogel containing 100% drug-loaded benzyl 3β-amino-11-oxo-olean-12-en-30-oate (GN-Bn), which was governed by π-π stacking, hydrogen bonding, and van der Waals forces. Due to the carrier-free design concept, the problems of interbatch variability during sample preparation and carrier-related toxicity can be effectively avoided. Moreover, the GN-Bn hydrogel exhibited promising antibacterial activities against multidrug-resistant

α-1,6 Fucosyltransferase (FUT8) appears to play an essential role in the pathogenesis of renal fibrosis. However, it remained unknown whether FUT8 also contributed to renal fibrosis in immunoglobulin A nephropathy (IgAN). In the present study, we explored the association of serum FUT8 activity with renal tubulointerstitial injury in IgAN patients.Serum FUT8 activity was measured in 135 IgAN patients and 68 healthy controls from January 2016 to December 2018. The relationships of serum FUT8 activity with clinical and pathological features were analyzed.Relative to healthy controls, IgAN patients had significantly higher serum FUT8 activity and upregulation of renal FUT8 protein (p .05). Among IgAN patients, there was a positive correlation of serum FUT8 activity with renal FUT8 protein expression (p .05). Multivariable logistic regression analyses showed that serum FUT8 activity was significantly associated with serum creatinine and eGFR (p .05). Based on a cut-off value determined from ROC curve analysis, we divided IgAN patients into a low serum FUT8 activity group (≤12.2 pmol/h/mL, n = 40) and a high serum FUT8 activity group (12.2 pmol/h/ml, n = 95). The high serum FUT8 activity group had a higher Oxford T score, increased inflammatory cell infiltration, more severe fibrosis and poor renal function (p .05).Serum FUT8 activity was positive association with renal tubulointerstitial injury in IgAN patients.