Hollow Stair-Stepping Spherical High-Entropy Prussian Blue Analogue for High-Rate Sodium Ion Batteries.

Prussian blue analogues (PBAs) are considered to be one of the most suitable sodium storage materials, especially with the introduction of the high-entropy (HE) concept into their structure to further improve their various abilities. However, severe agglomeration of the HEPBA particles still limits the fast charging capabilities. Here, an HEPBA (Nax(FeMnCoNiCu)[Fe(CN)6]y□1-y·nH2O) with a hollow stair-stepping spherical structure has been prepared through the chemical etching process of the traditional cubic structure of HEPBA. Electrochemical characterization (sodium ion battery), kinetic analysis, and COMSOL Multiphysics simulations reveal that the nature of the high-entropy and the hollow stair-stepping spherical structure can greatly improve the diffusion behavior of Na+ ions. Moreover, the hollow structure effectively mitigates the volume change of HEPBA during SIBs operation, ultimately extending the lifespan. Consequently, the as-prepared HEPBA cathode exhibits excellent rate performance (126.5 and 76.4 mAh g-1 at 0.1 and 4.0 A g-1, respectively) and stable long-term capability (maintaining its 75.6% capacity after 1000 cycles) due to its unique structure. Furthermore, the waste of the etching process can easily be recycled to prepare more HEPBA product. This processing method holds great promise for designing nanostructures of advanced high-entropy Prussian blue analogues for sodium ion batteries.

Screening optimal candidates with operable, early-stage triple-negative breast cancer benefitting from capecitabine maintenance: A post-hoc analysis of the SYSUCC-001 study.

BACKGROUND: To explore whether specific clinicopathological covariates are predictive for a benefit from capecitabine maintenance in early-stage triple-negative breast cancer (TNBC) in the SYSUCC-001 phase III clinical trial. METHODS: Candidate covariates included age, menstrual status, type of surgery, postoperative chemotherapy regimen, Ki-67 percentage, histologic grade, primary tumor size, lymphovascular invasion, node status, and capecitabine medication. Their nonlinear effects were modeled by restricted cubic spline. The primary endpoint was disease-free survival (DFS). A survival prediction model was constructed using Cox proportional hazards regression analysis. RESULTS: All 434 participants (306 in development cohort and 128 in validation cohort) were analyzed. The estimated 5-year DFS in development and validation cohorts were 77.8 % (95 % CI, 72.9%-82.7 %) and 78.2 % (95 % CI, 70.9%-85.5 %), respectively. Age and node status had significant nonlinear effects on DFS. The prediction model constructed using four covariates (node status, lymphovascular invasion, capecitabine maintenance, and age) demonstrated satisfactory calibration and fair discrimination ability, with C-index of 0.722 (95 % CI, 0.662-0.781) and 0.764 (95 % CI, 0.668-0.859) in development and validation cohorts, respectively. Moreover, patient classification was conducted according to their risk scores calculated using our model, in which, notable survival benefits were reported in low-risk subpopulations. An easy-to-use online calculator for predicting benefit of capecitabine maintenance was also designed. CONCLUSIONS: The evidence-based prediction model can be readily assessed at baseline, which might help decision making in clinical practice and optimize patient stratification, especially for those with low-risk, capecitabine maintenance might be a potential strategy in the early-disease setting.

Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.

Induced Anionic Functional Group Orientation-Assisted Stable Electrode-Electrolyte Interphases for Highly Reversible Zinc Anodes.

Dendrite growth and other side-reaction problems of zinc anodes in aqueous zinc-ion batteries heavily affect their cycling lifespan and Coulombic efficiency, which can be effectively alleviated by the application of polymer-based functional protection layer on the anode. However, the utilization rate of functional groups is difficult to improve without destroying the polymer chain. Here, a simple and well-established strategy is proposed by controlling the orientation of functional groups (─SO3H) to assist the optimization of zinc anodes. Depending on the electrostatic effect, the surface-enriched ─SO3H groups increase the ionic conductivity and homogenize the Zn2+ flux while inhibiting anionic permeation. This approach avoids the destruction of the polymer backbone by over-sulfonation and amplifies the effect of functional groups. Therefore, the modified sulfonated polyether ether ketone (H-SPEEK) coating-optimized zinc anode is capable of longtime stable zinc plating/stripping, and moreover an enhanced cycling steadiness under high current densities is also detected in a series of Zn batteries with different cathode materials, which achieved by the inclusion of H-SPEEK coating without causing any harmful effects on the electrolyte and cathode. This work provides an easy and efficient approach to further optimize the plating/stripping of cations on metal electrodes, and sheds lights on the scale-up of high-performance aqueous zinc-ion battery technology.

Multifunctional dual-interface layer enables efficient and stable inverted perovskite solar cells.

Considering that the hydrophobicity of PTAA as the surface of an inverted perovskite solar cell (PSC) substrate directly influences the crystallization and top surface properties of perovskite films, dual-interface engineering is a significant strategy to obtain excellent PSCs. PFN-Br was inserted into the PTAA/perovskite interface to ensure close interfacial contact and achieve exceptional crystallization, and then the perovskite top surface was covered with 3-PyAI to further improve its interface property. The mechanism of interaction of PFN-Br and 3-PyAI with perovskites was analyzed through various characterization methods. The results showed that the introduction of a hydrophilic interface layer reduces voids and defects at the bottom of the film. Additionally, the existence of 3-PyAI reduces surface defects, optimizes energy level alignment, and decreases non-radiative recombination, which is beneficial for charge transfer. Consequently, the open circuit voltage (VOC) and fill factor (FF) of the optimized device were greatly enhanced, and the champion device showed a power conversion efficiency (PCE) of 22.07%. The unencapsulated device with PFN-Br&3-PyAI can retain 80% of its initial performance after aging in the air atmosphere (25 °C at a relative humidity (RH) of 25%) for 27 days. Moreover, the reverse bias stability of the device was improved, with the reverse breakdown voltage (VRB) reaching -2 V. This work recommends a dual-interface strategy for efficient and reliable PTAA-based PSCs.

Gasdermin D in macrophages drives orchitis by regulating inflammation and antigen presentation processes.

Inflammation in the testes induced by infection and autoimmunity contributes significantly to male infertility, a public health issue. Current therapies using antibiotics and broad-spectrum anti-inflammatory drugs are ineffective against non-bacterial orchitis and induce side effects. This highlights the need to explore the pathogenesis of orchitis and develop alternative therapeutic strategies. In this study, we demonstrated that Gasdermin D (GSDMD) was activated in the testes during uropathogenic Escherichia coli (UPEC)-induced acute orchitis, and that GSDMD in macrophages induced inflammation and affected spermatogenesis during acute and chronic orchitis. In testicular macrophages, GSDMD promoted inflammation and antigen presentation, thereby enhancing the T-cell response after orchitis. Furthermore, the pharmacological inhibition of GSDMD alleviated the symptoms of UPEC-induced acute orchitis. Collectively, these findings provide the first demonstration of GSDMD's role in driving orchitis and suggest that GSDMD may be a potential therapeutic target for treating orchitis.

Pyrotinib Combined with Vinorelbine in Patients with Previously Treated HER2-Positive Metastatic Breast Cancer: A Multicenter, Single-Arm, Prospective Study.

PURPOSE: This study aims to evaluate the efficacy and safety of a new combination treatment of vinorelbine and pyrotinib in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and provide higher level evidence for clinical practice. MATERIALS AND METHODS: This was a prospective, single-arm, phase 2 trial conducted at three institutions in China. Patients with HER2-positive MBC, who had previously been treated with trastuzumab plus a taxane or trastuzumab plus pertuzumab combined with a chemotherapeutic agent, were enrolled between March 2020 and December 2021. All patients received pyrotinib 400 mg orally once daily plus vinorelbine 25 mg/m2 intravenously or 60-80 mg/m2 orally on day 1 and day 8 of 21-day cycle. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival, and safety. RESULTS: A total of 39 patients were enrolled. All patients had been pretreated with trastuzumab and 23.1% (n=9) of them had accepted trastuzumab plus pertuzumab. The median follow-up time was 16.3 months (95% confidence interval [CI], 5.3 to 27.2), and the median PFS was 6.4 months (95% CI, 4.0 to 8.8). The ORR was 43.6% (95% CI, 27.8% to 60.4%) and the DCR was 84.6% (95% CI, 69.5% to 94.1%). The median PFS of patients with versus without prior pertuzumab treatment was 4.6 and 8.3 months (p=0.017). The most common grade 3/4 adverse events were diarrhea (28.2%), neutrophil count decreased (15.4%), white blood cell count decreased (7.7%), vomiting (5.1%), and anemia (2.6%). CONCLUSION: Pyrotinib plus vinorelbine showed promising efficacy and tolerable toxicity as second-line treatment in patients with HER2-positive MBC.

Timely assessment of 5-year relative survival for patients with thyroid cancer from Taizhou, eastern China: a period analysis.

BACKGROUND: While timely assessment of long-term survival in thyroid cancer patients is critical for assessing early detection and screening programs for thyroid cancer, those data are sorely lacking in China. We aimed to timely and accurately assess the long-term survival of thyroid cancer patients in eastern China. METHODS: Patients diagnosed with thyroid cancer during 2004-2018 from four cancer registries in Taizhou, eastern China were included. The 5-year relative survival was estimated by period analysis and stratified by sex, age at diagnosis, and region. The 5-year RS of thyroid cancer patients during 2019-2023 was also predicted using the model-based period analysis. RESULTS: During 2014-2018, the overall 5-year relative survival of thyroid cancer patients was 87.7%, 91.2% for women and 79.4% for men. The 5-year RS decreased along with increasing age at diagnosis, decreasing from 94.9% for age <45 years to 81.3% for age >74 years, while 5-year RS was higher in urban areas than in rural areas (93.2% vs. 86.1%). The 5-year RS for thyroid cancer patients improved greatly between 2004-2008 to 2014-2018. The predicted overall 5-year RS could reach 91.4% over the upcoming 2019-2023 period. CONCLUSION: We provided, for the first time in China using period analysis, the most up-to-date 5-year RS for thyroid cancer patients from Taizhou, eastern China, which has important implications for timely evaluation on early detection and screening programs for patients with thyroid cancer in eastern China.

Anti-Freezing Electrolytes in Aqueous Multivalent Metal-Ion Batteries: Progress, Challenges, and Optimization Strategies.

Aqueous rechargeable multivalent metal-ion batteries (ARMMBs) have attracted considerable attention due to their high capacity, high energy density, and low cost. However, their performance is often limited by low temperature operation, which requires the development of anti-freezing electrolytes. In this review, we summarize the anti-freezing mechanisms and optimization strategies of anti-freezing electrolytes for aqueous batteries (especially for Zn-ion batteries). Besides, we investigate the possible interactions and side reactions between electrolytes and electrodes. We also analyze the problems between electrolytes and electrodes at low temperature, and propose possible solutions. The research progress in the field of low temperature energy storage for aqueous Mg-ion, Ca-ion, and Al-ion batteries, and the challenges faced in their anti-freezing electrolytes are investigated in detail. Last but not least, the outlook on the energy storage applications of ARMMBs is provided to guide the future research.

Impact of early heparin therapy on outcomes in patients with solid malignancy associated sepsis: a marginal structural model causal analyse.

Background: Previous studies documented that heparin can inhibit the invasion and metastasis of tumors, but its role on outcomes in patients with solid malignancy complicated sepsis remains unclear. Methods: A retrospective cohort study was conducted in critically ill patients with solid malignancy associated sepsis from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary endpoint was intensive care unit (ICU) mortality, secondary outcomes were thrombosis and hospital mortality. Propensity score matching (PSM), marginal structural Cox model (MSCM), cox proportional hazards model, stratification analysis and E-value were used to account for baseline differences, time-varying confounding and unmeasured variables. Results: A total of 1,512 patients with solid malignancy complicated sepsis were enrolled, of which 683 in the heparin group with intensive care unit mortality, thrombosis rate and hospital mortality were 9.7%, 5.4%, 16.1%, and 829 in the non-heparin group with ICU mortality, thrombosis rate and hospital mortality were 14.6%, 12.5%, 22.6%. Similar results were observed on outcomes for patients with PSM (ICU mortality hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.41-0.92), thrombosis rate (HR 0.42, 95% confidence interval 0.26-0.68); hospital mortality HR 0.70, 95% CI 0.50-0.99). marginal structural Cox model further reinforced the efficacy of heparin in reducing ICU mortality (HR 0.48, 95% CI 0.34-0.68). Logistic regression and Cox regression model showed heparin use also markedly reduced thrombosis (HR 0.42; 95% CI 0.26-0.68; p < 0.001) and hospital mortality (HR 0.70; 95% CI 0.50-0.99; p = 0.043). Stratification analysis with the MSCM showed an effect only those with digestive system cancer (HR 0.33, 95% CI 0.16-0.69). Conclusion: Early heparin therapy improved outcomes in critically ill patients with solid malignancy complicated sepsis. These results are evident especially in those with digestive system cancer. A prospective randomized controlled study should be designed to further assess the relevant findings.

[Heterocyclic compounds and phenolic glycosides from flowers of Dendrobium officinale].

Eight heterocyclic compounds and twelve phenolic glycosides were separated from the water extract of Dendrobium officinale flowers through chromatographic techniques, such as Diaion HP-20 macroporous adsorption resin column chromatography(CC), silica gel CC, ODS CC, Sephadex LH-20 CC, and preparative high performance liquid chromatography(PHPLC). According to the spectroscopic analyses(MS, ~1H-NMR, and ~(13)C-NMR) and optical rotation data, the compounds were identified as dendrofurfural A(1), 2'-deoxyadenosine(2), 4-[2-formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl] butanoic acid(3), 4-[2-formyl-5-(methoxymethyl)-1H-pyrrol-1-yl] butanoic acid(4), 1-(2-hydroxyethyl)-5-(methoxymethyl)-1H-pyrrole-2-carbaldehyde(5), 5-(methoxymethyl)-1H-pyrrole-2-carbaldehyde(6), methyl 5-(hydroxymethyl)-furan-2-carboxylate(7),(S)-5-hydroxymethyl-5H-furan-2-one(8), 2-methoxyphenyl-1-O-ß-D-glucopyranoside(9), arbutin(10), isotachioside(11), 2,6-dimethoxy-4-hydroxyphenol-1-O-ß-D-glucopyranoside(12), orcinol glucoside(13), tachioside(14), gastrodin(15), 4-O-ß-D-glucopyranosylvanillyl alcohol(16), 2,6-dimethoxy-4-hydroxymethylphenol-1-O-ß-D-glucopyranoside(17), icariside D_2(18), 4-formylphenyl-ß-D-glucopyranoside(19), and vanillin-4-O-ß-D-glucopyranoside(20). Among them, compound 1 is a new furfural benzyl alcohol condensate, with the skeleton first found in Dendrobium. Compounds 2-9, 11, 13, and 19 are reported from Dendrobium for the first time, and compounds 14 and 18 are reported for the first time from D. officinale. Compounds 11 and 14 showed moderate DPPH radical scavenging capacity, and compounds 11-14 demonstrated potent ABTS radical scavenging capacity, possessing antioxidant activity.

Accurate diagnosis of pulmonary inflammatory myofibroblastic tumor by imaging technology before operation: A case report.

RATIONALE: Pulmonary inflammatory myofibroblastic tumor (IMT) is a rare borderline tumor, which has the potential of malignant including invasion of surrounding tissues, distant metastasis and recurrence. However, the preoperative diagnosis is difficult and it can also be difficult to distinguish from malignancy in small tissue samples. Preoperative accurate diagnosis has important clinical significance for patients to choose treatment measures and improve the quality of rehabilitation. We was examined by computed tomography (CT) plain scan plus enhanced scan, magnetic resonance diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) imaging technology in an adult female, compared with lung cancer and pulmonary cryptococcus infection for diagnosis of pulmonary IMT. PATIENT CONCERNS: A 32-year-old female patient was admitted to the hospital "physical examination revealed nodules in the right upper lung for 1 week". DIAGNOSES: The patient was diagnosed with Pulmonary inflammatory myofibroblastic tumor. INTERVENTIONS: Single-port thoracoscopic lobectomy was performed after multidisciplinary consultation. OUTCOMES: DWI and ADC improves the accuracy of preoperative diagnosis and well guides the formulation of treatment measures. The combined CT, DWI, and ADC magnetic resonance imaging technology has more important significance in the diagnosis and differential diagnosis of IMT and lung malignant tumors. LESSONS: Although accurate preoperative diagnosis of pulmonary IMT is difficult. Chest CT examination combined with DWI and ADC imaging technology has high clinical significance for the diagnosis of IMT.

Prognostic value and immune landscapes of TERT promoter methylation in triple negative breast cancer.

Background: Treatment options for patients with triple-negative breast cancer (TNBC) remain limited to mainstay therapies owing to a lack of efficacious therapeutic targets. Accordingly, there is an urgent need to discover and identify novel molecular targets for the treatment and diagnosis of this disease. In this study, we analyzed the correlation of telomerase reverse transcriptase (TERT) methylation status with TERT expression, prognosis, and immune infiltration in TNBC and identified the role of TERT methylation in the regulation TNBC prognosis and immunotherapy. Methods: Data relating to the transcriptome, clinicopathological characteristics and methylation of TNBC patients were obtained from The Cancer Genome Atlas (TCGA) database. TERT expression levels and differential methylation sites (DMSs) were detected. The correlations between TERT expression and DMSs were calculated. Kaplan-Meier curves was plotted to analyze the relationship between the survival of TNBC patients and the DMSs. The correlations of DMSs and TERT expression with several immunological characteristics of immune microenvironment (immune cell infiltration, immunomodulators, immune-related biological pathways, and immune checkpoints) were assessed. The results were validated using 40 TNBC patients from Sun Yat-sen University Cancer Center (SYSUCC). Results: Six DMSs were identified. Among them, four sites (cg11625005, cg07380026, cg17166338, and cg26006951) were within the TERT promoter, in which two sites (cg07380026 and cg26006951) were significantly related to the prognosis of patients with TNBC. Further validation using 40 TNBC samples from SYSUCC showed that the high methylation of the cg26006951 CpG site was associated with poor survival prognosis (P=0.0022). TERT expression was significantly correlated with pathological N stage and clinical stage, and cg07380026 were significantly associated with pathological T and N stages in the TCGA cohort. Moreover, the methylation site cg26006951, cg07380026 and TERT expression were significantly correlated with immune cell infiltration, common immunomodulators, and the level of the immune checkpoint receptor lymphocyte activation gene 3 (LAG-3) in TNBC patients. Conclusion: TERT promotertypermethylation plays an important role in TERT expression regulation and tumor microenvironment in TNBC. It is associated with overall survival and LAG-3 expression. TERT promoter hypermethylation may be a potential molecular biomarker for predicting response to the TERT inhibitors and immune checkpoint inhibitors in TNBC.

Serum myoglobin modulates kidney injury via inducing ferroptosis after exertional heatstroke.

Background and Objectives: Myoglobin released by rhabdomyolysis (RM) is considered to be involved in pathogenesis of kidney disease caused by crush injury, but whether high level of serum myoglobin predisposes patients to acute kidney injury (AKI) and its molecular mechanisms are still unclear in exertional heatstroke (EHS). We aimed to determine the association and potential mechanism of myoglobin and AKI, and further investigate the targeted therapeutic agents for myoglobinemia. Methods: Serum myoglobin concentrations in patients with EHS were measured at admission, 24 h and 48 h after admission and discharge. The risk of AKI at 48 h was the primary outcome; the secondary outcome was composite outcome events with myoglobin levels and AKI at discharge and death at 90 days. In experimental studies, we further investigated the mechanisms of human kidney proximal tubular (HK-2) cells that were exposed to human myoglobin under heat stress conditions and the effect of baicalein. Results: Our measurements showed that the highest myoglobin quartile (vs. the lowest) had an adjusted odds ratio (OR) of 18.95 (95% confidence interval [CI], 6.00-59.83) for AKI and that the OR (vs. quartile 2) was 7.92 (95% CI, 1.62-38.89) for the secondary outcome. The survival rate of HK-2 cells treated with myoglobin under heat stress was significantly decreased, and the production of Fe2+ and reactive oxygen species (ROS) was markedly increased, accompanied by changes in ferroptosis proteins, including increased p53, decreased SLC7A11 and GPX4, and alterations in endoplasmic reticulum stress (ERS) marker proteins. Treatment with baicalein attenuated HK-2 cell ferroptosis induced by myoglobin under heat stress through inhibition of ERS. Conclusions: High myoglobin was associated with AKI in the EHS, and its mechanisms involved ERS-associated ferroptosis. Baicalein may be a potential therapeutic drug for the treatment of AKI in patients with high myoglobin induced by rhabdomyolysis following EHS.

Retrospective analysis of pulmonary cryptococcosis and extrapulmonary cryptococcosis in a chinese tertiary hospital.

Cryptococcosis is an invasive fungal disease with increased morbidity in China over the past two decades. Cryptococci can infect immunocompromised hosts as well as immunocompetent ones. In this study, we reviewed data of 71 inpatients with cryptococcosis at Ningbo First Hospital from May 2010 to May 2020 and compared the clinical profiles of pulmonary cryptococcosis (PC) and extrapulmonary cryptococcosis (EPC). Of 71 patients (38 males, 33 females), 70 were non-HIV. The annual inpatient population increased dramatically, especially in the PC group. PC was confirmed in 77.46% (55/71) of cases by pathology. The rest were EPC including intracranial infection (15.49%, 11/71) and cryptococcemia (7.04%, 5/71). Compared with PC, a larger proportion of EPC patients were found to have immunocompromised conditions judged by predisposing factors (p < 0.01), or detectable humoral or cellular immunodeficiency. Fever and headache were more common in EPC patients (p < 0.001). Patients with EPC had lower serum sodium level (p = 0.041), lower monocyte counts (p = 0.025) and higher C-reactive protein (p = 0.012). In our study, the sensitivity of cryptococcus antigen detection for EPC was 100% regardless of sample type, while serum lateral flow assay (LFA) tested negative in 25% (5/20) of PC. Immunocompromised hosts are more likely to suffer from EPC than PC.

Inhibition of extranodal NK/T-cell lymphoma by Chiauranib through an AIF-dependent pathway and its synergy with L-asparaginase.

Extranodal NK/T-cell lymphoma (NKTL) is a rare and aggressive form of extranodal lymphoma with a poor prognosis. Currently, there are very limited treatment options for patients with advanced-stage disease or those with relapsed/recurrent disease. Here we show that Chiauranib, an orally small molecule inhibitor of select serine-threonine kinases (aurora B, VEGFRs, PDGFR, CSF1R, c-Kit), inhibited NKTL cell proliferation, induced cell cycle arrest, as well as suppressed the microvessel density in vitro and in vivo similar as in other types of cancer cells. Surprisingly, Chiauranib unfolded a new effect to induce apoptosis of NKTL cells by triggering AIF-dependent apoptosis other than the traditional cyt-c/caspase mitochondrial apoptosis pathway. The knockdown of AIF in vitro and in vivo dramatically blocked the efficacy of Chiauranib on NKTL. Mechanistically, the release of AIF from mitochondria is due to the upregulation of VDAC1 by the AKT-GSK3ß pathway and activation of calcium-dependent m-calpain, which promotes the cleavage of VDAC1 and therefore permits the release of AIF. Notably, the low expression of Bax in both NKTL cells and patient tissues restrained the cyt-c release. It resulted in the inhibition of cyt-c/caspase mitochondrial pathway, suggesting that drugs targeting this traditional pathway may not be effective in NKTL. Furthermore, we found that L-asparaginase triggered CD95 (Fas/Apo-1)-caspase 8-caspase 3 apoptotic pathway in NKTL cells, and combination of Chiauranib and L-asparaginase exhibited a synergistic effect, suggesting a feasibility to combine these two drugs for effective treatment of NKTL. This study demonstrates Chiauranib's positive efficacy toward NKTL through the activation of the AIF-dependent apoptosis pathway for the first time. The novel and multi-targets of Chiauranib and the synergistic effect with L-asparaginase may provide a promising therapy for NKTL patients.

Effectiveness of early heparin therapy on outcomes in critically ill patients with sepsis-induced coagulopathy.

Background: This study aimed to investigate whether early unfractionated heparin (UFH) administration provides a survival advantage for patients with sepsis-induced coagulopathy (SIC). Methods: Patients hospitalized with sepsis-induced coagulopathy from the Medical Information Mart for Intensive Care (MIMIC)-IV database were identified. Patients were divided into two groups, who received unfractionated heparin (UFH) subcutaneously within 24 h after intensive care unit (ICU) admission, and the control group, who received not. The primary endpoint was intensive care unit mortality, the secondary outcomes were 7, 14, and 28-day and hospital mortality. Propensity score matching (PSM) the marginal structural Cox model (MSCM) and E-value analysis were used to account for baseline differences, time-varying and unmeasured confounding factors. Results: A total of 3,377 patients with sepsis-induced coagulopathy were enrolled in the study, of which 815 in unfractionated heparin group and 2,562 in control group. There was significant effect on primary and secondary outcomes with unfractionated heparin after propensity score matching (intensive care unit mortality, hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.52-0.92; 7-day, HR 0.70, 95% CI 0.49-0.99; 14-day, HR 0.68.95% CI 0.50-0.92; 28-day, HR 0.72, 95% CI 0.54-0.96; hospital mortality, HR 0.74, 95% CI 0.57-0.96), marginal structural Cox model manifested unfractionated heparin associated with decreased intensive care unit mortality in all populations (HR 0.64, 95% CI 0.49-0.84), and stratification with the marginal structural Cox model indicated analysis further indicated the survival advantage only among patients with an sepsis-induced coagulopathy score of 4 (HR 0.56, 95% CI 0.38-0.81). Further analysis showed that treatment with 6,250-13750 IU/day of unfractionated heparin associated with a decreased risk of intensive care unit mortality. Similar results were replicated in subgroup analysis with propensity score matching only for patients with an sepsis-induced coagulopathy score of 4 (intensive care unit mortality, HR 0.51, 95% CI 0.34-0.76). Conclusion: This study found early unfractionated heparin therapy to patients with sepsis-induced coagulopathy appears to be associated with improved outcomes. Subgroup analysis further demonstrates heparin therapy decreased intensive care unit mortality primarily in patients only with SIC score of 4.

Advances on the Application of Wide Band-Gap Insulating Materials in Perovskite Solar Cells.

In recent years, the development of perovskite solar cells (PSCs) is advancing rapidly with their recorded photoelectric conversion efficiency reaching 25.8%. However, for the commercialization of PSCs, it is also necessary to solve their stability issue. In order to improve the device performance, various additives and interface modification strategies have been proposed. While, in many cases, they can guarantee a significant increase in efficiency, but not ensure improved stability. Therefore, materials that improve the device efficiency and stability simultaneously are urgently needed. Some wide band-gap insulating materials with stable physical and chemical properties are promising alternative materials. In this review, the application of wide band-gap insulating materials in PSCs, including their preparation methods, working roles, and mechanisms are described, which will promote the commercial application of PSCs.

Median effective dose of esketamine for intranasal premedication in children with congenital heart disease.

BACKGROUND: Esketamine is commonly used as a premedication for its sedation effect. However, the proper dosage for intranasal use in children with congenital heart disease (CHD) has not been determined. This study aimed to estimate the median effective dose (ED50) of esketamine for intranasal premedication in children with CHD. METHODS: Thirty-four children with CHD who needed premedication in March 2021 were enrolled. Intranasal esketamine was initiated at a dose of 1 mg/kg. Based on the outcome of sedation in the previous patient, the dose for the subsequent patient was either increased or reduced by 0.1 mg/kg, which was adjusted between each child. Successful sedation was defined as a Ramsay Sedation Scale score ≥ 3 and Parental Separation Anxiety Scale score ≤ 2. The required ED50 of esketamine was calculated using the modified sequential method. Non-invasive blood pressure, heart rate, saturation of peripheral oxygen, sedation onset time, and adverse reactions were recorded at 5 min intervals after drug administration. RESULTS: The 34 children enrolled had a mean age of 22.5 ± 16.4 (4-54) months and a mean weight of 11.2 ± 3.6 (5.5-20.5) kg; American Society of Anesthesiologists classification I-III. The ED50 of intranasal S(+)-ketamine (esketamine) required for preoperative sedation in pediatric patients with CHD was 0.7 (95% confidence interval: 0.54-0.86) mg/kg, and the mean sedation onset time was 16.39 ± 7.24 min. No serious adverse events, such as respiratory distress, nausea, and vomiting were observed. CONCLUSIONS: The ED50 of intranasal esketamine was 0.7 mg/kg, which was safe and effective for preoperative sedation in pediatric patients with CHD. TRIAL REGISTRATION: The trial was registered in the Chinese Clinical Trial Registry Network (ChiCTR2100044551) on 24/03/2021.

What is the appropriate genetic testing criteria for breast cancer in the Chinese population?-Analysis of genetic and clinical features from a single cancer center database.

BACKGROUND: Genetic testing plays an important role in guiding screening, diagnosis, and precision treatment of breast cancer (BC). However, the appropriate genetic testing criteria remain controversial. The current study aims to facilitate the development of suitable strategies by analyzing the germline mutational profiles and clinicopathological features of large-scale Chinese BC patients. METHODS: BC patients who had undergone genetic testing at the Sun Yat-sen University Cancer Center (SYSUCC) from September 2014 to March 2022 were retrospectively reviewed. Different screening criteria were applied and compared in the population cohort. RESULTS: A total of 1035 BC patients were enrolled, 237 pathogenic or likely pathogenic variants (P/LPV) were identified in 235 patients, including 41 out of 203 (19.6%) patients tested only for BRCA1/2 genes, and 194 out of 832 (23.3%) received 21 genes panel testing. Among the 235 P/LPV carriers, 222 (94.5%) met the NCCN high-risk criteria, and 13 (5.5%) did not. While using Desai's criteria of testing, all females diagnosed with BC by 60 years and NCCN criteria for older patients, 234 (99.6%) met the high-risk standard, and only one did not. The 21 genes panel testing identified 4.9% of non-BRCA P/LPVs and a significantly high rate of variants of uncertain significance (VUSs) (33.9%). The most common non-BRCA P/LPVs were PALB2 (11, 1.3%), TP53 (10, 1.2%), PTEN (3, 0.4%), CHEK2 (3, 0.4%), ATM (3, 0.4%), BARD1 (3, 0.4%), and RAD51C (2, 0.2%). Compared with BRCA1/2 P/LPVs, non-BRCA P/LPVs showed a significantly low incidence of NCCN criteria listed family history, second primary cancer, and different molecular subtypes. CONCLUSIONS: Desai's criteria might be a more appropriate genetic testing strategy for Chinese BC patients. Panel testing could identify more non-BRCA P/LPVs than BRCA1/2 testing alone. Compared with BRCA1/2 P/LPVs, non-BRCA P/LPVs exhibited different personal and family histories of cancer and molecular subtype distributions. The optimal genetic testing strategy for BC still needs to be investigated with larger continuous population studies.