Bioclay Enzyme with Bimetal Synergistic Sterilization and Infectious Wound Regeneration.

Bacteria invasion is the main factor hindering the wound-healing process. However, current antibacterial therapies inevitably face complex challenges, such as the abuse of antibiotics or severe inflammation during treatment. Here, a drug-free bioclay enzyme (Bio-Clayzyme) consisting of Fe2+-tannic acid (TA) network-coated kaolinite nanoclay and glucose oxidase (GOx) was reported to destroy harmful bacteria via bimetal antibacterial therapy. At the wound site, Bio-Clayzyme was found to enhance the generation of toxic hydroxyl radicals for sterilization via cascade catalysis of GOx and Fe2+-mediated peroxidase mimetic activity. Specifically, the acidic characteristics of the infection microenvironment accelerated the release of Al3+ from kaolinite, which further led to bacterial membrane damage and amplified the antibacterial toxicity of Fe2+. Besides, Bio-Clayzyme also performed hemostasis and anti-inflammatory functions inherited from Kaol and TA. By the combination of hemostasis and anti-inflammatory and bimetal synergistic sterilization, Bio-Clayzyme achieves efficient healing of infected wounds, providing a revolutionary approach for infectious wound regeneration.

Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Adding CDK4/6 inhibitor dalpiciclib to fulvestrant significantly prolonged progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer progressing after endocrine therapy. We aimed to assess the efficacy and safety of dalpiciclib plus letrozole or anastrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had no previous systemic therapy in the advanced setting. METHODS: DAWNA-2 is a randomised, double-blind, placebo-controlled, phase 3 trial done at 42 hospitals in China. Eligible patients were aged 18-75 years, of any menopausal status, had an ECOG performance status of 0-1, and had pathologically confirmed hormone receptor-positive, HER2-negative untreated advanced breast cancer. Patients were randomly assigned (2:1) to receive oral dalpiciclib (150 mg per day for 3 weeks, followed by 1 week off) or matching placebo. Both groups also received endocrine therapy: either 2·5 mg letrozole or 1 mg anastrozole orally once daily continuously. Randomisation was using an interactive web response system (block size of six) and stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting, and endocrine therapy partner. All investigators, patients, and the funders of the study were masked to group allocation. We present the results of the preplanned interim analyses for the primary endpoint of investigator-assessed progression-free survival, which was assessed in all randomly assigned patients who met the eligibility criteria by intention-to treat. Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. The superiority boundary was calculated as a one-sided p value of 0·0076 or less. This trial is registered with ClinicalTrials.gov, NCT03966898, and is ongoing but closed to recruitment. FINDINGS: Between July 19, 2019, and Dec 25, 2020, 580 patients were screened and 456 were eligible and randomly assigned to the dalpiciclib group (n=303) or placebo group (n=153). At data cutoff (June 1, 2022), median follow-up was 21·6 months (IQR 18·3-25·9), and 103 (34%) of 303 patients in the dalpiciclib group and 83 (54%) of 153 patients in the placebo group had disease progression or died. Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (30·6 months [95% CI 30·6-not reached] vs 18·2 months [16·5-22·5]; stratified hazard ratio 0·51 [95% CI 0·38-0·69]; one-sided log-rank p<0·0001). Adverse events of grade 3 or 4 were reported in 271 (90%) of 302 patients in the dalpiciclib group and 18 (12%) of 153 patients in the placebo group. The most common adverse events of grade 3 or 4 were neutropenia (259 [86%] in the dalpiciclib group vs none in the placebo group) and leukopenia (201 [67%] vs none). Serious adverse events were reported for 36 (12%) patients in the dalpiciclib group and ten (7%) patients in the placebo group. Two treatment-related deaths occurred, both in the dalpiciclib group (deaths from unknown causes). INTERPRETATION: Our findings suggest that dalpiciclib plus letrozole or anastrozole could be a novel standard first-line treatment for patients with hormone receptor-positive, HER2-negative advanced breast cancer, and is an alternative option to the current treatment landscape. FUNDING: Jiangsu Hengrui Pharmaceuticals and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Pyrotinib plus capecitabine for trastuzumab-resistant, HER2-positive advanced breast cancer (PICTURE): a single-arm, multicenter phase 2 trial.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer and primary resistance to trastuzumab have a poor clinical outcome and lack good evidence to inform clinical decision. This study investigated the efficacy and safety of pyrotinib plus capecitabine in this population. METHODS: This phase 2 trial was conducted at 16 sites in China. Patients received oral pyrotinib 400 mg once daily and capecitabine 1000 mg/m2 twice a day on days 1-14 of each 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: Between June 2019 and September 2021, 100 patients were enrolled with a median age of 51 years (range, 24-69). All patients had been treated with trastuzumab and 21 (21.0%) patients had prior use of pertuzumab. As of August 31, 2022, the median follow-up duration was 20.1 months (range, 1.3-38.2). The median PFS was 11.8 months (95% confidence interval [CI], 8.4-15.1), which crossed the pre-specified efficacy boundary of 8.0 months. The objective response rate was 70.0% (70/100), with a median duration of response of 13.8 months (95% CI, 10.2-19.3). The disease control rate was 87.0% (87/100). The median overall survival was not reached. The most common grade ≥ 3 treatment-emergent adverse event was diarrhea (24 [24.0%]). No treatment-related deaths occurred. CONCLUSIONS: Pyrotinib plus capecitabine can be considered to be a treatment option in HER2-positive advanced breast cancer patients who have shown primary resistance to trastuzumab. Even in the era of modern anti-HER2 treatments, this clinical setting warrants more investigations to meet unmet needs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04001621. Retrospectively registered on June 28, 2019.

Layered Clay Minerals in Cancer Therapy: Recent Progress and Prospects.

Cancer is one of the deadliest diseases, and current treatment regimens suffer from limited efficacy, nonspecific toxicity, and chemoresistance. With the advantages of good biocompatibility, large specific surface area, excellent cation exchange capacity, and easy availability, clay minerals have been receiving ever-increasing interests in cancer treatment. They can act as carriers to reduce the toxic side effects of chemotherapeutic drugs, and some of their own properties can kill cancer cells, etc. Compared with other morphologies clays, layered clay minerals (LCM) have attracted more and more attention due to adjustable interlayer spacing, easier ion exchange, and stronger adsorption capacity. In this review, the structure, classification, physicochemical properties, and functionalization methods of LCM are summarized. The state-of-the-art progress of LCM in antitumor therapy is systematically described, with emphasis on the application of montmorillonite, kaolinite, and vermiculite. Furthermore, the property-function relationships of LCM are comprehensively illustrated to reveal the design principles of clay-based antitumor systems. Finally, foreseeable challenges and outlook in this field are discussed.

Survival outcomes for breast conserving surgery versus mastectomy among elderly women with breast cancer.

PURPOSE: Elderly patients have different physical condition and tumor biology of breast cancer. Surgical choices for older patients are complicated and several studies have reported that breast conserving surgery (BCS) had better survival than mastectomy in different patient population. The major objective of this study was to compare the efficacy of BCS and mastectomy in the whole elderly cohort in SEER database. METHODS: Female patients aged over 70 years old and diagnosed with breast cancer between 2010 and 2015 were included from SEER database. Propensity score matching (PSM) was used to establish a cohort composing of similar characteristics. We compared the overall survival (OS) among patients undergoing BCS and mastectomy. Kaplan-Meier analysis and Cox proportional regression model were used to evaluate the associated factors of survival outcome. RESULTS: Of 44,755 eligible patients, 30,375 (67.9%) patients underwent BCS and 14,380 (32.1%) patients underwent mastectomy. After PSM, 7222 patients in each group were analyzed and there was no significant difference between BCS and mastectomy in terms of the OS rate (85.8% in BCS group and 85.0% in mastectomy group, p = 0.135). Multivariable analysis also indicated that no significant difference between two surgical procedures after adjusting for covariates in matched cohort (HR 1.062, 95% CI 0.997-1.132, p = 0.063). Subgroup analysis demonstrated that postoperative radiotherapy and chemotherapy contributed to the survival benefit of BCS compared to mastectomy (p < 0.05). CONCLUSION: For elderly breast cancer patients, BCS and mastectomy appeared to be comparable in terms of OS after being matched by clinicopathologic features. While our findings suggested that there was statistically survival benefit of BCS in some subsets of patients, including radiotherapy, chemotherapy, and 80-84 year-old subgroups, these results were likely to be related to selection bias and should be interpreted with caution. Thus, for this elderly patient population, BCS should be considered as an equivalent and less aggressive alternative to mastectomy.

Insight into the Pathogenic Mechanism of Mycoplasma pneumoniae.

Mycoplasma pneumoniae, an obligate parasitic pathogen without cell wall, can cause severe upper and lower respiratory tract symptoms. It is the pathogen of human bronchitis and walking pneumonia, and named community-acquired pneumonia. In addition to severe respiratory symptoms, there are clinical extrapulmonary manifestations in the skin, brain, kidney, musculoskeletal, digestive system, and even blood system after M. pneumoniae infection. Hereby, we comprehensively summarized and reviewed the intrapulmonary and extrapulmonary pathogenesis of M. pneumoniae infection. The pathogenesis of related respiratory symptoms caused by M. pneumoniae is mainly adhesion damage, direct damage including nutrient predation, invasion and toxin, cytokine induced inflammation damage and immune evasion effect. The pathogenesis of extrapulmonary manifestations includes direct damage mediated by invasion and inflammatory factors, indirect damage caused by host immune response, and vascular occlusion. The intrapulmonary and extrapulmonary pathogenic mechanisms of M. pneumoniae infection are independent and interrelated, and have certain commonalities. In fact, the pathogenic mechanisms of M. pneumoniae are complicated, and the specific content is still not completely clear, further researches are necessary for determining the detailed pathogenesis of M. pneumoniae. This review can provide certain guidance for the effective prevention and treatment of M. pneumoniae infection.

Hypomethylation-driven overexpression of HJURP promotes progression of hepatocellular carcinoma and is associated with poor prognosis.

Our previous studies have initially identified HJURP, which encodes a Holliday junction recognizing protein, as a hepatocellular carcinoma (HCC) susceptibility gene. In this report, we showed that the HJURP is highly expressed in HCC tissues compared to adjacent normal tissues. Overexpression of HJURP in HCC tissues is mainly due to the hypomethylation of HJURP promoter region. Clinically, high expression of HJURP is significantly associated with poor overall survival and disease-free survival of patients with HCC, as well as in multiple other types of cancer. Gain- and loss-of functional studies demonstrated that HJURP promotes HCC cell proliferation, clone formation, migration and invasion. Additionally, HJURP enhances HCC tumorigenesis via reducing G0/G1 arrest and apoptosis. Mechanistically, by gene set enrichment analysis (GSEA) analysis, HJURP was identified as a modulator involved in CENPA-mediated centromere maintenance. Our results provide evidence of HJURP as an important oncogene that promotes HCC progression, and the HJURP pathway may be a potential target for the treatment of HCC.

Medium- and long-term effects of endovascular treatments for severely stenotic basilar arteries supported by multimodal imaging.

BACKGROUND: To evaluate the medium-and long-term effect of intravascular interventional therapy for symptomatic severe basilar artery stenosis supported by multimodal imaging. METHOD: After strict screening of 67 patients with symptomatic severe basilar artery stenosis (70-99%) with atherosclerotic stenosis, 67 patients with symptomatic recurrence after intensive drug treatment were treated with intravascular balloon dilatation and Enterprise stent implantation. Any stroke or death within 30 days after operation and any stroke and restenosis during medium-and long-term follow-up were recorded. RESULTS: ①The mean age of 67 patients (67lesions) was 57 ± 8 years old, and the technical success rate was 100%; ②Preoperative angiography showed that the collateral circulation was poor, and TICI was 1-2a while postoperative angiography showed that TICI was significantly improved to 2b-3; ③The average preoperative stenosis rate was 82 ± 9%, and the postoperative stenosis rate was reduced to 17 ± 10%; ④Before surgery, abnormal perfusion was found in the posterior circulation CTP; After the postoperative re-examination, the posterior circulation of CTP perfusion was significantly improved; ⑤Postoperative symptoms and neurological conditions improved significantly; ⑥Complications of perforating branch event occurred in 1 case after operation, and symptoms were relieved after more than 1 month of medication treatment, and mild neurological dysfunction remained. 1 case developed subacute thrombosis in the stent, which improved after active intra-arterial thrombolysis, and there was no residual neurological dysfunction; and 1 case of micro-guide wire being trapped by the distal vasospasm. ⑦67 patients were followed up by telephone, WeChat or imaging for 36-66 months. CONCLUSIONS: In summary intravascular balloon dilation + Enterprise stent implantation is safe and effective for the treatment of symptomatic severe atherosclerotic stenosis of the basilar artery, with high technical success rate, low perioperative complications, and good mid-term and long-term effects.

Germline Duplication of SNORA18L5 Increases Risk for HBV-related Hepatocellular Carcinoma by Altering Localization of Ribosomal Proteins and Decreasing Levels of p53.

BACKGROUND & AIMS: Single nucleotide polymorphisms could affect risk for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We performed a germline copy number variation (CNV)-based genome-wide association study (GWAS) in populations of Chinese ancestry to search for germline CNVs that increase risk of HCC. METHODS: We conducted a CNV-based GWAS of 1583 HCC cases (persons with chronic HBV infection and HCC) and 1540 controls (persons with chronic HBV infection without HCC) in Chinese populations. Identified candidates were expressed in L-02, HepG2, or TP53-/- or wild-type HCT116 cells, and knocked down with short hairpin RNAs in HepG2, Bel-7402, and SMMC-7721 cells; proliferation, colony formation, and apoptosis were measured. Formation of xenograft tumors from cell lines was monitored in nude mice. Subcellular localization of ribosome proteins and levels or activity of p53 were investigated by co-immunoprecipitation, immunofluorescence, and immunoblot analyses. Levels of small nucleolar RNA H/ACA box 18-like 5 (SNORA18L5) were quantified by quantitative reverse transcription polymerase chain reaction. RESULTS: We identified a low-frequency duplication at chromosome 15q13.3 strongly associated with risk of HBV-related HCC (overall P = 3.17 × 10-8; odds ratio, 12.02). Copy numbers of the 15q13.3 duplication correlated with the expression of SNORA18L5 in liver tissues. Overexpression of SNORA18L5 increased HCC cell proliferation and growth of xenograft tumors in mice; knockdown reduced HCC proliferation and tumor growth. SNORA18L5 overexpression in HepG2 and SMMC-7721 cells inhibited p53-dependent cell cycle arrest and apoptosis. Overexpression of SNORA18L5 led to hyperactive ribosome biogenesis, increasing levels of mature 18S and 28S ribosomal RNAs and causing the ribosomal proteins RPL5 and RPL11 to stay in the nucleolus, which kept them from binding to MDM2. This resulted in increased MDM2-mediated ubiquitination and degradation of p53. Levels of SNORA18L5 were increased in HCC tissues compared with nontumor liver tissues and associated with shorter survival times of patients. CONCLUSIONS: In a CNV-based GWAS, we associated duplication at 15q13.3 with increased risk of HBV-related HCC. We found SNORA18L5 at this location to promote HCC cell proliferation and tumor growth in mice. SNORA18L5 increases ribosome biogenesis, facilitates ribosomal RNA maturation, and alters localization of RPL5 and RPL11, allowing for increased MDM2-mediated proteolysis of p53 and cell cycle arrest.

Oncofertility in patients with stage I epithelial ovarian cancer: fertility-sparing surgery in young women of reproductive age.

BACKGROUND: Fertility-sparing surgery is indicated for patients with stage I epithelial ovarian cancers. We sought to evaluate the clinical outcomes and oncofertility in a cohort of patients of reproductive age with stage I epithelial ovarian cancer (EOC). METHODS: Overall, 108 patients of reproductive age (≤ 40 years) diagnosed with stage I EOC who were treated at Peking Union Medical College Hospital between 1999 and 2013 were included in the study. The Kaplan-Meier model and Cox regression analyses were used for the survival analysis. RESULTS: The type of surgery included fertility-sparing surgery (FSS) (48.1%) and radical surgery (RS) (51.9%). After a median follow-up of 83 months, we observed that grade 3 or clear-cell carcinoma was the only independent risk factor for disease-free survival and tumor-specific survival in the multivariate analysis. Patients with grade 3 or clear-cell carcinoma tended to be older than 30 years, have endometriosis, and undergo RS (p < 0.05). Fertility-sparing surgery did not affect disease-free survival or tumor-specific survival among patients of reproductive age with stage I EOC and among high-risk patients with stage IC2-3, grade 3, or clear-cell carcinoma. Thirty-four out of 52 (65.4%) FSS patients attempted to get pregnant. Twenty-eight (82.4%) achieved a successful pregnancy with a full-term delivery. CONCLUSIONS: Grade 3 or clear-cell carcinoma was the only independent risk factor for survival of patients of reproductive age with stage I EOC. FSS can be safely performed on patients of reproductive age with grade 1-2, stage I EOC. The safety of FSS for grade 3 and clear-cell carcinoma warrants further investigation.

Single-Port vs Multiport Laparoscopic Hysterectomy: A Meta-Analysis of Randomized Controlled Trials.

Numerous studies have compared the surgical outcomes of single-port laparoscopic hysterectomy (LH) and conventional multiport LH, but the results are conflicting. The aim of this meta-analysis was to compare the safety and efficacy of single-port LH and multiport LH for benign gynecologic conditions based on published reports. PubMed, the Cochrane Central Register of Controlled Trials, and Embase were searched for relevant randomized controlled trials (RCTs). Outcome measures included intraoperative and postoperative complication rates, postoperative pain, conversion rate, operative time, estimated blood loss (EBL), and length of hospital stay. Pooled outcome measures (risk ratio [RR] and weighted mean difference [WMD]) were pooled with either a fixed-effects model or a random-effects model. Six RCTs encompassing 624 patients were included. There were no significant differences between single-port LH and multiport LH in terms of intraoperative complication rate (RR, 1.00; 95% confidence interval [CI], 0.14-7.05; p = .00), postoperative complication rate (RR, 0.95; 95% CI, 0.63-1.44; p = .82), postoperative pain (WMD, -0.42; 95% CI, -0.99 to 0.15; p = .15), conversion rate (p = .11), EBL (p = .51), or length of hospital stay (p = .27). However, single-port LH was associated with an average of 13.13 minutes longer operative time than multiport LH (p = .02). Our findings show that single-port LH is a safe and effective technique for benign gynecologic conditions, although it may require a longer operative time than multiport LH. Further large, prospective RCTs with long-term follow-up are needed to determine whether single-port LH really offers such benefits as better cosmetic outcome over multiport LH.

[Variation in Phosphorus Concentration and Flux at Zhutuo Section in the Yangtze River and Source Apportionment].

Phosphorus (P) is a pollutant of great concern in the Yangtze River Basin. The Xiangjiaba Reservoir and Xiluodu Reservoir on the lower reach of the Jinsha River began to operate in 2012 and 2013, respectively, which greatly changed the concentrations of suspended sediment and characteristics of P form and transport in the reservoirs and the downstream reach from Yibin to Jiangjin of the Yangtze River. The Zhutuo section is representative in the water quality of the Yibin-Jiangjin reach, which can not only reflect the comprehensive effects of the formation of the two reservoirs and changes in the aquatic environment in the Min-Tuo Rivers but also reflect the quality of water flowing into the Three Gorges Reservoir. The runoff, concentrations and fluxes of suspended sediments (SS), and P concentrations and fluxes at Zhutuo section were studied during 2002-2019, and the source of P was apportioned based on the principle of river base flow. The results showed that in the past 18 years, the concentrations and fluxes of total phosphorus (TP) and particulate phosphorus (PP) at Zhutuo section in the wet season were higher than those in the level and dry seasons; the rule of positive correlation between PP and SS concentrations remained unchanged. From 2002 to 2019, the concentrations and fluxes of TP, PP, and dissolved P (DP) generally increased first and then decreased, and the operation of the Xiangjiaba Reservoir was a time node for the trend turning. Compared with that in the period from 2002-2012, the SS concentration and flux decreased by 94% and 77%, TP and PP concentrations decreased by 46% and 70%, and TP and PP fluxes decreased by 58% and 74%, respectively, during 2014-2019. The decline mainly occurred in the wet season, followed by that in the level season. After the formation of the two reservoirs, the relationship between water and sediment and the form of P greatly changed, and the proportion of DP in TP increased significantly, whereas the proportion of PP was the opposite. The TP pool in overlying water in the dry and level seasons shifted from mainly particulate to mainly dissolved. The change in water and sediment conditions was the main driving force for the significant change in P concentration, flux, and form. Before the operation of the Xiangjiaba Reservoir, the Jinsha River was the maximum contributor to the whole and diffuse source part of the TP load at Zhutuo section among the contributing catchment sub-basins; however, the Minjiang River became the largest contributor after the operation. The average TP load at Zhutuo section from 2017-2019 was 3.575×104 t·a-1 (after deducting the natural background value), of which the contribution of diffuse sources and point sources accounted for 68% and 32%, respectively. The Minjiang River represented 49%, 43%, and 62% of the total TP load, diffuse source TP load, and point source TP load at Zhutuo section, respectively. Considering the load contribution and pollution intensity, the key area for P pollution control in the area upstream of the Three Gorges Reservoir was the Min-Tuo River Basin.

Efficacy, Safety, and Population Pharmacokinetics of MW032 Compared With Denosumab for Solid Tumor-Related Bone Metastases: A Randomized, Double-Blind, Phase 3 Equivalence Trial.

Importance: The bioequivalence of denosumab biosimilar has yet to be studied in a 53-week, multicenter, large-scale, and head-to-head trial. A clinically effective biosimilar may help increase access to denosumab in patients with solid tumor-related bone metastases. Objectives: To establish the biosimilarity of MW032 to denosumab in patients with solid tumor-related bone metastases based on a large-scale head-to-head study. Design, Setting, and Participants: In this 53-week, randomized, double-blind, phase 3 equivalence trial, patients with solid tumors with bone metastasis were recruited from 46 clinical sites in China. Overall, 856 patients were screened and 708 eligible patients were randomly allocated to receive either MW032 or denosumab. Interventions: Patients were randomly assigned (1:1) to receive MW032 or reference denosumab subcutaneously every 4 weeks until week 49. Main Outcomes and Measures: The primary end point was percentage change from baseline to week 13 of natural logarithmic transformed urinary N-telopeptide/creatinine ratio (uNTx/uCr). Results: Among the 701 evaluable patients (350 in the MW032 group and 351 in the denosumab group), the mean (range) age was 56.1 (22.0-86.0) years and 460 patients were women (65.6%). The mean change of uNTx/uCr from baseline to week 13 was -72.0% (95% CI, -73.5% to -70.4%) in the MW032 group and -72.7% (95% CI, -74.2% to -71.2%) in the denosumab group. These percent changes corresponded to mean logarithmic ratios of -1.27 and -1.30, or a difference of 0.02. The 90% CI for the difference (-0.04 to 0.09) was within the equivalence margin (-0.13 to 0.13); the mean changes of uNTx/uCr and bone-specific alkaline phosphatase (s-BALP) at each time point were also similar during 53 weeks. The differences of uNTx/uCr change were 0.015 (95% CI, -0.06 to 0.09), -0.02 (95% CI, -0.09 to 0.06), -0.05 (95% CI, -0.13 to 0.03) and 0.001 (95% CI, -0.10 to 0.10) at weeks 5, 25, 37, and 53, respectively. The differences of s-BALP change were -0.006 (95% CI, 0.06 to 0.05), 0.00 (95% CI, -0.07 to 0.07), -0.085 (95% CI, -0.18 to 0.01), -0.09 (95% CI, -0.20 to 0.02), and -0.13 (95% CI, -0.27 to 0.004) at weeks 5, 13, 25, 37 and 53, respectively. No significant differences were observed in the incidence of skeletal-related events (-1.4%; 95% CI, -5.8% to 3.0%) or time to first on-study skeletal-related events (unadjusted HR, 0.86; P = .53; multiplicity adjusted HR, 0.87; P = .55) in the 2 groups. Conclusions and Relevance: MW032 and denosumab were biosimilar in efficacy, population pharmacokinetics, and safety profile. Availability of denosumab biosimilars may broaden the access to denosumab and reduce the drug burden for patients with advanced tumors. Trial Registration: ClinicalTrials.gov Identifier: NCT04812509.

Structurally Tailoring Clay Nanosheets to Design Emerging Macrofibers with Tunable Mechanical Properties and Thermal Behavior.

Bio-derived nanomaterials are promising candidates for spinning high-performance sustainable textiles, but the inherent flammability of biomass-based fibers seriously limits their applications. There is still an urgent need to improve fiber flame retardancy while maintaining excellent mechanical performance. Here, inspired by the structural properties of layered nanoclay, we report a novel and efficient strategy to synthesize the strong, super tough, and flame-retardant nanocellulose/clay/sodium alginate (CRS) macrofibers via wet-spinning and directional drying. Benefiting from the precise modulation of arrangement and orientation of nanoclay in macrofibers, the new inorganic structure exhibits excellent mechanical and thermal functional properties. The anisotropic structure contributes to high toughness: the tensile strength was 373.3 MPa and the toughness was 26.92 MJ·m-3. Remarkably, rectorite nanosheets as a thermal and qualitative insulator significantly improve the flame retardancy of the CRS fibers with a heat release rate as low as 6.07 W/g, thermal conductivity of 90.5 mW/(m·K), and good temperature tolerance (ranging from -196 to 100 °C). This facile and high-efficiency strategy may have great scalability in manufacturing high-strength, super tough, and flame-retardant fibers for emerging biodegradable next-generation artificial fibers.

Unique ion rectifier intermediate enabled by ultrathin vermiculite sheets for high-performance Zn metal anodes.

Metallic Zn represents as a primary choice in fabricating various aqueous Zn-ion batteries (ZIBs), however challenging issues including dendrite growth and parasitic reactions at the anode/electrolyte interface, considerably hamper its practical implementation in large-scale energy storage. Herein, we report a low-cost multifunctional ion rectifier (IRT) as an artificial intermediate to reform Zn anode, which can practically eliminate the above issues. The hydrophobic shell (polyvinylidene difluoride) can suppress Zn interfacial corrosion with an inhibition efficiency of 94.8% by repelling water molecules from the bulk electrolyte. Additionally, negatively-charged ion channels inside the zincophilic core (ultrathin vermiculite sheets) induce de-solvating redistribution effect on Zn2+ ions flux, enabling a high ions transference number (0.79) for dendrite-free Zn deposition. This leads to exceptional Zn/Zn2+ reversibility in metallic Zn with IRT stabilization. The remarkable Coulombic efficiency (99.8%, 2000 cycles) for asymmetrical batteries, and a long lifespan (1600 h) with ultrahigh cumulative capacity of 2400 mAh cm-2 for symmetrical batteries, are successfully achieved. More encouragingly, the Zn//NH4V4O10 pouch cell retains 94.3% of its original capacity after 150 cycles at 1 A g-1. We believe that this low-cost and high-efficiency tactic could pave a promising path for anode surface modification.

HOXD9 aggravates the development of cervical cancer by transcriptionally activating HMCN1.

BACKGROUND: To detect HOXD9 levels in cervical cancer species and to explore the relationship between HOXD9 level and prognosis in cervical cancer patients. We also verify the influence of HOXD9 on metastatic abilities in cervical cancer. METHODS: HOXD9 levels in cervical cancer species were detected. Its influence on clinical features and prognosis in cervical cancer patients was analyzed. Regulatory effects of HOXD9 on migratory and invasive capacities in C33-A and HeLa cells were evaluated by Transwell assay. Subsequently, the downstream gene of HOXD9 was predicted by bioinformatics analysis and confirmed by luciferase assay. The involvement of HMCN1 in regulating metastatic ability in cervical cancer cells was finally explored by rescue experiments. RESULTS: HOXD9 was upregulated in cervical cancer species and its level was positively correlated to rates of lymphatic metastasis and distant metastasis. High level of HOXD9 in cervical cancer patients predicted a poor prognosis. Overexpression of HOXD9 promoted migratory and invasive capacities in cervical cancer cells. HMCN1 was identified to be the downstream gene binding HOXD9. It was responsible for HOXD9-regulated metastasis in cervical cancer. CONCLUSIONS: HOXD9 is upregulated in cervical cancer species. Its level is closely linked to metastasis rate and poor prognosis in cervical cancer patients. Through positively regulating HMCN1 level, HOXD9 stimulates migratory and invasive capacities in cervical cancer cells.

Prognostic value of long non-coding RNA MALAT1 in hepatocellular carcinoma: A study based on multi-omics analysis and RT-PCR validation.

Background: This study aimed to explore the relationship between MALAT1 and the prognosis of patients with hepatocellular carcinoma (HCC). Methods: We constructed a MALAT1 protein-protein interaction network using the STRING database and a network of competing endogenous RNAs (ceRNAs) using the StarBase database. Using data from the GEPIA2 database, we studied the association between genes in these networks and survival of patients with HCC. The potential mechanisms underlying the relationship between MALAT1 and HCC prognosis were studied using combined data from RNA sequencing, DNA methylation, and somatic mutation data from The Cancer Genome Atlas (TCGA) liver cancer cohort. Tumor tissues and 19 paired adjacent non-tumor tissues (PANTs) from HCC patients who underwent radical resection were analyzed for MALAT1 mRNA levels using real-time PCR, and associations of MALAT1 expression with clinicopathological features or prognosis of patients were analyzed using log-rank test and Gehan-Breslow-Wilcoxon test. Results: Five interacting proteins and five target genes of MALAT1 in the ceRNA network significantly correlated with poor survival of patients with HCC (p < 0.05). High MALAT1 expression was associated with mutations in two genes leading to poor prognosis and may upregulate some prognostic risk genes through methylation. MALAT1 was significantly co-expressed with various signatures of genes involved in HCC progression, including the cell cycle, DNA damage repair, mismatch repair, homologous recombination, molecular cancer m6A, exosome, ferroptosis, infiltration of lymphocyte (p < 0.05). The expression of MALAT1 was markedly upregulated in HCC tissues compared with PANTs. In Kaplan-Meier analysis, patients with high MALAT1 expression had significantly shorter progression-free survival (PFS) (p = 0.033) and overall survival (OS) (p = 0.023) than those with low MALAT1 expression. Median PFS was 19.2 months for patients with high MALAT1 expression and 52.8 months for patients with low expression, while the corresponding median OS was 40.5 and 78.3 months. In subgroup analysis of patients with vascular invasion, cirrhosis, and HBsAg positive or AFP positive, MALAT1 overexpression was significantly associated with shorter PFS and OS. Models for predicting PFS and OS constructed based on MALAT1 expression and clinicopathological features had moderate predictive power, with areas under the receiver operating characteristic curves of 0.661-0.731. Additionally, MALAT1 expression level was significantly associated with liver cirrhosis, vascular invasion, and tumor capsular infiltration (p < 0.05 for all). Conclusion: MALAT1 is overexpressed in HCC, and higher expression is associated with worse prognosis. MALAT1 mRNA level may serve as a prognostic marker for patients with HCC after hepatectomy.

Oncolytic adenoviruses synergistically enhance anti-PD-L1 and anti-CTLA-4 immunotherapy by modulating the tumour microenvironment in a 4T1 orthotopic mouse model.

Effective therapeutic strategies for triple-negative breast cancer (TNBC) are still lacking. Clinical data suggest that a large number of TNBC patients cannot benefit from single immune checkpoint inhibitor (ICI) treatment due to the immunosuppressive tumour microenvironment (TME). Therefore, combination immunotherapy is an alternative approach to overcome this limitation. In this article, we combined two kinds of oncolytic adenoviruses with ICIs to treat TNBC in an orthotopic mouse model. Histopathological analysis and immunohistochemistry as well as multiplex immunofluorescence were used to analyse the TME. The immunophenotype of the peripheral blood and spleen was detected by using flow cytometry. Oncolytic adenovirus-mediated immune activity in a coculture system of lytic supernatant and splenocytes supported the study of the mechanism of combination therapy in vitro. Our results showed that the combination of oncolytic adenoviruses with anti-programmed cell death-ligand 1 (anti-PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (anti-CTLA-4) (aPC) can significantly inhibit tumour growth and prolong survival in a TNBC model. The combination therapy synergistically enhanced the antitumour effect by recruiting CD8+ T and T memory cells, reducing the number of regulatory T cells and tumour-associated macrophages, and promoting the polarization of macrophages from the M2 to the M1 phenotype to regulate the TME. The rAd.GM regimen performed better than the rAd.Null treatment. Furthermore, aPC efficiently blocked oncolytic virus-induced upregulation of PD-L1 and CTLA-4. These findings indicate that oncolytic adenoviruses can reprogramme the immunosuppressive TME, while ICIs can prevent immune escape after oncolytic virus therapy by reducing the expression of immune checkpoint molecules. Our results provide a mutually reinforcing strategy for clinical combination immunotherapy.

Elimination of NH3 and odor from composting by biotrickling filter and preliminary exploration on molecular biology.

A biotrickling filter was focused on treatment of odorous NH(3) gas, along with volatile organic compounds (VOCs) and other odorous gases during cattle manure composting. The biotrickling filter could treat NH(3), the main composition, with removal efficiencies of close to 100% because NH(4)(+) was bio-oxidized in the biofilm to NO(3)(-) resulting final NO(3)(-) concentrations of about 1000 mg/L. Results of polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) revealed that ammonia-oxidizing bacteria, Nitrosospira sp, and nitrite-oxidizing bacteria, Nitrococcus mobilis, coexisted in the biofilm. There were 23 kinds of VOCs detected in the exhaust gas. A significant observation was that the biofilm itself of the biotrickling biofilter released VOCs. The odor concentrations of inlet and outlet gases were 1425 and 110, respectively, with removal efficiency of 92.2%, suggesting that the biotrickling filter was effective for treatment of odorous gases during composting.

[Proteomics of the colonic mucosa in sub-healthy people with shapeless stool].

OBJECTIVE: To establish the 2-dimensional electrophoresis (2-DE) map in colonic mucosa in sub-healthy people with shapeless stool and healthy people, to identify the differential proteins by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS), and to provide theoretical basis for the pathogenesis of intestinal mucosa in sub-healthy people with shapeless stool. METHODS: Two-DE was used to separate the total proteins from the intestinal mucosa in sub-healthy people (the sub-health group) with the shapeless stool and healthy volunteers (the control group). ImageMaster 2D Elite soft was applied to analyze the 2-DE images, and the differentially expressed protein spots between the 2 groups were identified by MALDI-TOF-MS, protein bank and information technique. RESULTS: We analyzed the average maps and obtained 517 protein spots in the sub-healthy group and 535 protein spots in the control group. Between the sub-healthy group and the control group, the mean of 366 protein spots was matched, and the matching rate was 70.79%. Ten differential protein spots were screened by MALDI-TOF-MS, and 8 were identified. Five out of the 8 spots were significantly decreased, while 3 out of the 8 were significantly increased. CONCLUSION: The proteomic expression in colonic mucosa of people with shapeless stool is significantly different from that of healthy people. Eight differential proteins such as aldehyde dehydrogenase 1A1 isoform 1, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 (mitochondrial), γ-actin, annexin A5 possibly involve in the pathogenesis of sub-healthy people with shapeless stool.