A case report of parotid gland epithelioid hemangioendothelioma.

Epithelioid hemangioendothelioma (EHE) is a rare low-grade malignant vascular tumor. It mainly occurs in the liver, lungs, bones, and other parts of the body. Reports of epithelioid hemangioendothelioma in the parotid gland are rare in both domestic and international literature. Here, we present a case report of a parotid gland epithelioid hemangioendothelioma, including its complete clinical course and imaging findings, to improve the diagnosis and treatment of this unusual disease. Case presentation: The patient, a 75-year-old female, presented with a swelling around the right ear for 2 months and pain for 20 days. Enhanced MRI of the parotid gland revealed a well-defined, round mass with homogeneous signal intensity. The mass showed low signal intensity on T1-weighted imaging, high signal intensity on T2-weighted imaging, nodular low signal intensity within, significant high signal intensity on DWI sequence, low signal intensity on ADC sequence, and heterogeneous enhancement in the arterial phase after intravenous injection of Gd-DTPA. Nodular non-enhancing low signal intensity was observed internally, and slight clearance was seen in the venous phase. The initial diagnosis before surgery was a benign lesion, but after histopathological and immunohistochemical examination, it was confirmed as epithelioid hemangioendothelioma. Intervention: Complete tumor resection was performed. Results: The patient experienced a favorable recovery, with meticulous follow-up conducted for up to 1 year revealing no signs of recurrence or metastasis. Continued patient surveillance is ongoing to substantiate and validate the long-term efficacy of the treatment. Conclusion: Due to the extreme rarity of parotid gland epithelioid hemangioendothelioma, it often leads to a high misdiagnosis rate. The most common misdiagnosis is salivary gland lymphoma, followed by epithelioid hemangiosarcoma. When the lesion is multifocal, fusiform, with internal necrosis, and shows punctate low signal intensity on T2-weighted imaging, significant enhancement in the arterial phase, particularly with more pronounced peripheral enhancement, and persistent enhancement in the venous and delayed phases, epithelioid hemangioendothelioma should be considered. However, the current clinical diagnosis of epithelioid hemangioendothelioma still primarily relies on immunohistochemical methods.

Tumor-derived extracellular vesicles as a biomarker for breast cancer diagnosis and metastasis monitoring.

It is imperative to explore biomarkers that are both precise and readily accessible in the comprehensive management of breast cancer. A multicenter cohort, including 512 breast cancer patients and 198 nonneoplastic individuals, was recruited to detect the level of tumor-derived extracellular vesicles using our method based on dual DNA tetrahedral nanostructures. The level of tumor-derived extracellular vesicles was significantly higher in newly diagnosed breast cancer patients than in nonneoplastic individuals at a cutoff value of 3.58 U/µL. For postoperative metastasis monitoring, the level of tumor-derived extracellular vesicles was significantly higher in breast cancer patients with metastasis than in those without metastasis at a cutoff value of 3.91 U/µL. Its efficacy of diagnosis and metastasis monitoring was superior to traditional tumor markers. Elevated level of tumor-derived extracellular vesicles served as a predictive biomarker for diagnosis and metastasis monitoring in breast cancer patients.

Temporal and spatial biosonar activity of the recently established uppermost Yangtze finless porpoise population downstream of the Gezhouba Dam: Correlation with hydropower cascade development, shipping, hydrological regime, and light intensity.

Numerous dams disrupt freshwater animals. The uppermost population of the critically endangered Yangtze finless porpoise has been newly formed below the Gezhouba Dam, however, information regarding the local porpoise is scarce. Passive acoustic monitoring was used to detect the behaviors of porpoises below the Gezhouba Dam. The influence of shipping, pandemic lockdown, hydrological regime, and light intensity on the biosonar activity of dolphins was also examined using Generalized linear models. Over the course of 4 years (2019-2022), approximately 848, 596, and 676 effective monitoring days were investigated at the three sites, from upstream to downstream. Observations revealed significant spatio-temporal biosonar activity. Proportion of days that are porpoise positive were 73%, 54%, and 61%, while porpoise buzz signals accounted for 78.49%, 62.35%, and 81.30% of all porpoise biosonar at the three stations. The biosonar activity of porpoises was much higher at the confluence area, particularly at the MZ site, during the absence of boat traffic, and during the Pandemic shutdown. Temporal trends of monthly, seasonal, and yearly variation were also visible, with the highest number of porpoises biosonar detected in the summer season and in 2020. Significant correlations also exist between the hydrological regime and light intensity and porpoise activity, with much higher detections during nighttime and full moon periods. Hydropower cascade development, establishment of a natural reserve, fish release initiatives, and implementation of fishing restrictions may facilitate the proliferation of the porpoise population downstream of the Gezhouba Dam within the Yichang section of the Yangtze River. Prioritizing restoration designs that match natural flow regimes, optimize boat traffic, and reduce noise pollution is crucial for promoting the conservation of the local porpoises.

ED-71 Improves Bone Mass in Ovariectomized Rats by Inhibiting Osteoclastogenesis Through EphrinB2-EphB4-RANKL/OPG Axis.

Purpose: Estrogen deficiency is the main reason of postmenopausal osteoporosis. Eldecalcitol (ED-71) is a new active vitamin D analogue clinically used in the treatment of postmenopausal osteoporosis. We aimed to investigate whether EphrinB2-EphB4 and RANKL/RANK/OPG signaling cooperate in mediating the process of osteoporosis by ED-71. Methods: In vivo, the ovariectomized (OVX) rats were administered orally with 30 ng/kg ED-71 once a day for 8 weeks. HE staining, Masson staining and Immunofluorescence staining were used to evaluate bone mass, bone formation, osteoclastogenesis associated factors and the expression of EphrinB2, EphB4, RANKL and OPG. In vitro, H2O2 stimulation was used to simulate the cell environment in osteoporosis. Immunofluorescence, quantitative real time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and Western Blot were applied to detect the expression of EphrinB2, EphB4, RANKL and OPG. In osteoblasts, EphB4 was knocked down by EphB4 small-interfering RNA (siRNA) transfection. LY294002 (PI3K inhibitor) or ARQ092 (AKT inhibitor) was used to block PI3K/AKT pathway. An indirect co-culture system of osteoblasts and osteoclasts was established. The mRNA and protein expression of osteoclastogenes is associated factors were tested by qRT-PCR and Western Blot. Results: ED-71 increased bone mass and decreased the number of osteoclasts in OVX rats. Moreover, ED-71 promoted the expression of EphrinB2, EphB4, and decreased the RANKL/OPG ratio in osteoblasts. Osteoclastogenesis was restrained when osteoclasts were indirectly co-cultured with ED-71-treated osteoblasts. After silencing of EphB4 expression in osteoblasts, ED-71 inhibited the expression of P-PI3K and P-AKT and increased the ratio of RANKL/OPG. This reversed the inhibitory effect of ED-71 on osteoclastogenes. Therefore, in ED-71-inhibited osteoclastogenes, EphB4 is a key factor affecting the secretion of RANKL and OPG by osteoblasts. EphB4 suppressed the RANKL/OPG ratio through activating PI3K/AKT signaling in osteoblasts. Conclusion: ED-71 inhibits osteoclastogenesis through EphrinB2-EphB4-RANKL/OPG axis, improving bone mass in ovariectomized rats. PI3K/AKT pathway is involved this process.

The combination of breast cancer PDO and mini-PDX platform for drug screening and individualized treatment.

The majority of advanced breast cancers exhibit strong aggressiveness, heterogeneity, and drug resistance, and currently, the lack of effective treatment strategies is one of the main challenges that cancer research must face. Therefore, developing a feasible preclinical model to explore tailored treatments for refractory breast cancer is urgently needed. We established organoid biobanks from 17 patients with breast cancer and characterized them by immunohistochemistry (IHC) and next generation sequencing (NGS). In addition, we in the first combination of patient-derived organoids (PDOs) with mini-patient-derived xenografts (Mini-PDXs) for the rapid and precise screening of drug sensitivity. We confirmed that breast cancer organoids are a high-fidelity three-dimension (3D) model in vitro that recapitulates the original tumour's histological and genetic features. In addition, for a heavily pretreated patient with advanced drug-resistant breast cancer, we combined PDO and Mini-PDX models to identify potentially effective combinations of therapeutic agents for this patient who were alpelisib + fulvestrant. In the drug sensitivity experiment of organoids, we observed changes in the PI3K/AKT/mTOR signalling axis and oestrogen receptor (ER) protein expression levels, which further verified the reliability of the screening results. Our study demonstrates that the PDO combined with mini-PDX model offers a rapid and precise drug screening platform that holds promise for personalized medicine, improving patient outcomes and addressing the urgent need for effective therapies in advanced breast cancer.

Trim14-IκBα Signaling Regulates Chronic Inflammatory Pain in Rats and Osteoarthritis Patients.

Chronic inflammatory pain is the highest priority for people with osteoarthritis when seeking medical attention. Despite the availability of NSAIDs and glucocorticoids, central sensitization and peripheral sensitization make pain increasingly difficult to control. Previous studies have identified the ubiquitination system as an important role in the chronic inflammatory pain. Our study displayed that the E3 ubiquitin ligase tripartite motif-containing 14 (Trim14) was abnormally elevated in the serum of patients with osteoarthritis and pain, and the degree of pain was positively correlated with the degree of Trim14 elevation. Furthermore, CFA-induced inflammatory pain rat model showed that Trim14 was significantly increased in the L3-5 spinal dorsal horn (SDH) and dorsal root ganglion (DRG), and in turn the inhibitor of nuclear factor Kappa-B isoform α (IκBα) was decreased after Trim14 elevation. After intrathecal injection of Trim14 siRNA to inhibit Trim14 expression, IκBα expression was reversed and increased, and the pain behaviors and anxiety behaviors of rats were significantly relieved. Overall, these findings suggested that Trim14 may contribute to chronic inflammatory pain by degrading IκBα, and that Trim14 may become a novel therapeutic target for chronic inflammatory pain.

The clinical application of V-Y advanced flap pedicled with freestyle perforator flap for repairing small range defects in the anterior knee region.

Introduction: This study aims to investigate the clinical efficacy of V-Y advanced flap pedicled with freestyle perforator flap for repairing small range defects in the anterior knee region. Methods: 8 patients with skin and soft tissue defect/necrosis in the anterior knee area admitted to the Changshu No.1 People's Hospital from January 2021 to January 2022 were selected, with a defect range of 4 cm × 3 cm-9 cm × 6 cm, designed a V-Y advanced flap pedicled with freestyle perforator flap to repair the wound in the anterior knee area. Adjust the size and position of the flap according to the number and position of perforating branches found during the surgery, with a cutting area of 6 cm × 5 cm-14 cm × 10 cm and the supply area was directly pulled and sutured. Results: 4 patients were repaired by flaps pedicled with 2 perforating branches, 2 patients were repaired by flaps pedicled with 1 perforating branch and 2 patients were repaired by flaps pedicled with 3 perforating branches. 4 patients were repaired by flaps pedicled with 2 perforating branches, 2 patients were repaired by flaps pedicled with 1 perforating branch and 2 patients were repaired by flaps pedicled with 3 perforating branches. All flaps survived and following up for 6-15 months, the blood supply, appearance, and color of the flap were satisfactory, and the functions of knee joint flexion and extension were well preserved. Discussion: The V-Y advancement flap pedicled with freestyle perforator flap has the advantages of reliable blood supply, simple surgical operation, texture and thickness similar to the skin of the anterior knee area, and direct suture of the donor area. It is a perforator flap with good repair effect for small scale defects in the anterior knee area.

Predictors of gastrointestinal bleeding in patients with acute coronary syndrome and the optimal duration of dual antiplatelet therapy.

Background: This study aims to estimate the risk factors of gastrointestinal (GI) bleeding in patients with acute coronary syndrome (ACS) and to evaluate the optimal duration of dual antiplatelet therapy (DAPT). Materials and Methods: We enrolled 1266 patients with ACS in a telephone follow-up program to determine whether any of the patients were hospitalized for GI bleeding. We collected baseline data, laboratory tests, electrocardiograms, and echocardiography covering all ACS patients. Multivariable regression was performed to adjust for confounders and predictors of GI bleeding. At the same time, the optimal duration of DAPT for ACS patients was evaluated. Results: A total of 1061 ACS patients were included in the study. After 13-68 months, 48 patients (4.5%) were hospitalized for GI bleeding. The risk of GI bleeding was significantly increased in patients treated with DAPT for more than 18 months (hazard ratio 12.792, 5.607-29.185, P < 0.01). Receiver Operating Characteristic curve showed that the duration of DAPT using a cutoff of 14.5 months resulted in a sensitivity of 66.7% and a specificity of 77%. Conclusion: In patients with ACS, DAPT time are the main risk factors of GI bleeding. The optimal duration of DAPT is 14.5 months.

The impact of ageing mechanisms on musculoskeletal system diseases in the elderly.

Ageing is an inevitable process that affects various tissues and organs of the human body, leading to a series of physiological and pathological changes. Mechanisms such as telomere depletion, stem cell depletion, macrophage dysfunction, and cellular senescence gradually manifest in the body, significantly increasing the incidence of diseases in elderly individuals. These mechanisms interact with each other, profoundly impacting the quality of life of older adults. As the ageing population continues to grow, the burden on the public health system is expected to intensify. Globally, the prevalence of musculoskeletal system diseases in elderly individuals is increasing, resulting in reduced limb mobility and prolonged suffering. This review aims to elucidate the mechanisms of ageing and their interplay while exploring their impact on diseases such as osteoarthritis, osteoporosis, and sarcopenia. By delving into the mechanisms of ageing, further research can be conducted to prevent and mitigate its effects, with the ultimate goal of alleviating the suffering of elderly patients in the future.

A novel LAG3 neutralizing antibody improves cancer immunotherapy by dual inhibition of MHC-II and FGL1 ligand binding.

LAG3 is an inhibitory immune checkpoint expressed on activated T and NK cells. Blocking the interaction of LAG3 with its ligands MHC-II and FGL1 renders T cells improved cytotoxicity to cancer cells. Current study generated a panel of LAG3 monoclonal antibodies (mAbs) through immunization of mice followed by phage display. Some of them bound to the D1-D2 domain of LAG3, which is known for the engagement of its ligands FGL1 and MHC-II. Three outperformers, M208, M226, and M234, showed stronger blocking activity than Relatlimab in the FGL1 binding. Furthermore, M234 showed dual inhibition of FGL1 (IC50 of 20.6 nM) and MHC-II binding (IC50 of 6.2 nM) to LAG3. In vitro functional tests showed that M234 significantly stimulated IFN-γ secretion from activated PBMC cells. In vivo studies in a mouse model of hepatocellular carcinoma xenografts demonstrated that combining M234 IgG with GPC3-targeted bispecific antibodies significantly improved efficacy. In addition, GPC3-targeted CAR-T cells secreting IL-21-M234 scFv fusion protein exhibited enhanced activity in inhibiting tumor growth and greatly increased the survival rate of mice. Taken together, M234 has potential in cancer immunotherapy and warrants further clinical trial.

[Antibiotic bone cement covered reconstruction plate for infected anterior pelvic ring fractures].

OBJECTIVE: To explore the clinical efficacy of antibiotic bone cement covered reconstruction steel plate in the treatment of infected anterior pelvic ring fracture. METHODS: From January 2017 to March 2022, 11 patients with infected anterior pelvic ring fracture were treated with antibiotic bone cement covered reconstruction steel plate including 7 males and 4 females and the age ranged from 27 to 49 years old. The pelvic fractures were classified according to the Tile typology: 4 cases of C1 type, 4 cases of C2 type, and 3 cases of C3 type. Among them, 2 cases of infected anterior ring were infected after internal fixation of anterior ring, and 9 patients were infected with infected anterior ring due to incomplete early debridement, which was classified as infected according to the injury severity score(ISS) for 24 to 38 scores. The anterior ring was internally fixed by extended debridement, irrigation, and antibiotic bone cement covered reconstruction plate, and the posterior ring fractures were all closed reduction and internally fixed with sacroiliac screws. RESULTS: All 11 cases obtained follow-up from 13 to 20 months. Among them, 2 patients had recurrence of postoperative infection, 1 case was re-dissected and replaced with antibiotic bone cement-coated internal fixation, and 1 case had a milder infection without accumulation of the medullary cavity, and the infection was controlled by retaining the plate and replacing the antibiotic bone cement only after dissecting. Two cases developed incisional oozing, which healed after removal of the internal fixation three months postoperatively. All patients did not show pelvic fracture redisplacement or reinfection during the follow-up period. All 11 cases eventually healed bony. At the final follow-up, according to the Matta score, the fracture reduction was excellent in 6 cases, good in 4, and possible in 1. According to the Majeed functional score, it was excellent in 6, good in 3, and possible in 2. CONCLUSION: Antibiotic bone cement covered reconstruction plate is effective in the treatment of infected anterior pelvic ring fracture, with high intraoperative safety and low recurrence rate of infection, which is conducive to the early postoperative rehabilitation and significantly shortens the course of the disease.

Exerkine FNDC5/irisin-enriched exosomes promote proliferation and inhibit ferroptosis of osteoblasts through interaction with Caveolin-1.

Postmenopausal osteoporosis is a prevalent metabolic bone disorder characterized by a decrease in bone mineral density and deterioration of bone microstructure. Despite the high prevalence of this disease, no effective treatment for osteoporosis has been developed. Exercise has long been considered a potent anabolic factor that promotes bone mass via upregulation of myokines secreted by skeletal muscle, exerting long-term osteoprotective effects and few side effects. Irisin was recently identified as a novel myokine that is significantly upregulated by exercise and could increase bone mass. However, the mechanisms underlying exercise-induced muscle-bone crosstalk remain unclear. Here, we identified that polyunsaturated fatty acids (arachidonic acid and docosahexaenoic acid) are increased in skeletal muscles following a 10-week treadmill exercise programme, which then promotes the expression and release of FNDC5/irisin. In osteoblasts, irisin binds directly to Cav1, which recruits and interacts with AMP-activated protein kinase α (AMPKα) to activate the AMPK pathway. Nrf2 is the downstream target of the AMPK pathway and increases the transcription of HMOX1 and Fpn. HMOX1 is involved in regulating the cell cycle and promotes the proliferation of osteoblasts. Moreover, upregulation of Fpn in osteoblasts enhanced iron removal, thereby suppressing ferroptosis in osteoblasts. Additionally, we confirmed that myotube-derived exosomes are involved in the transportation of irisin and enter osteoblasts through caveolae-mediated endocytosis. In conclusion, our findings highlight the crucial role of irisin, present in myotube-derived exosomes, as a crucial regulator of exercise-induced protective effects on bone, which provides novel insights into the mechanisms underlying exercise-dependent treatment of osteoporosis.

Tailoring amorphous boron nitride for high-performance two-dimensional electronics.

Two-dimensional (2D) materials have garnered significant attention in recent years due to their atomically thin structure and unique electronic and optoelectronic properties. To harness their full potential for applications in next-generation electronics and photonics, precise control over the dielectric environment surrounding the 2D material is critical. The lack of nucleation sites on 2D surfaces to form thin, uniform dielectric layers often leads to interfacial defects that degrade the device performance, posing a major roadblock in the realization of 2D-based devices. Here, we demonstrate a wafer-scale, low-temperature process (<250 °C) using atomic layer deposition (ALD) for the synthesis of uniform, conformal amorphous boron nitride (aBN) thin films. ALD deposition temperatures between 125 and 250 °C result in stoichiometric films with high oxidative stability, yielding a dielectric strength of 8.2 MV/cm. Utilizing a seed-free ALD approach, we form uniform aBN dielectric layers on 2D surfaces and fabricate multiple quantum well structures of aBN/MoS2 and aBN-encapsulated double-gated monolayer (ML) MoS2 field-effect transistors to evaluate the impact of aBN dielectric environment on MoS2 optoelectronic and electronic properties. Our work in scalable aBN dielectric integration paves a way towards realizing the theoretical performance of 2D materials for next-generation electronics.

Niraparib maintenance therapy using an individualised starting dose in patients with platinum-sensitive recurrent ovarian cancer (NORA): final overall survival analysis of a phase 3 randomised, placebo-controlled trial.

Background: Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline BRCA mutation (gBRCAm) status, in NORA. This analysis reports final data on overall survival (OS). Methods: This randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gBRCAm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gBRCAm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200 mg/day for patients with bodyweight <77 kg and/or platelet count <150 × 103/µL at baseline and 300 mg/day otherwise. OS was a secondary endpoint. Findings: Totally, 265 patients were randomised to receive niraparib (n = 177) or placebo (n = 88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8-61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4-58.9) versus 47.6 (33.3-not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60-1.23), in the overall population; 56.0 (36.1-NE) versus 47.6 (31.6-NE) months, with HR of 0.86 (95% CI, 0.46-1.58), in patients with gBRCAm; and 46.5 (41.0-NE) versus 46.9 (31.8-NE) months, with HR of 0.87 (95% CI, 0.56-1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients. Interpretation: Niraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gBRCAm status. Funding: Zai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019].

Senaparib as first-line maintenance therapy in advanced ovarian cancer: a randomized phase 3 trial.

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as maintenance therapy after first-line chemotherapy have improved progression-free survival in women with advanced ovarian cancer; however, not all PARP inhibitors can provide benefit for a biomarker-unselected population. Senaparib is a PARP inhibitor that demonstrated antitumor activity in patients with solid tumors, including ovarian cancer, in phase 1 studies. The multicenter, double-blind, phase 3 trial FLAMES randomized (2:1) 404 females with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV) and response to first-line platinum-based chemotherapy to senaparib 100 mg (n = 271) or placebo (n = 133) orally once daily for up to 2 years. The primary endpoint was progression-free survival assessed by blinded independent central review. At the prespecified interim analysis, the median progression-free survival was not reached with senaparib and was 13.6 months with placebo (hazard ratio 0.43, 95% confidence interval 0.32-0.58; P < 0.0001). The benefit with senaparib over placebo was consistent in the subgroups defined by BRCA1 and BRCA2 mutation or homologous recombination status. Grade ≥3 treatment-emergent adverse events occurred in 179 (66%) and 27 (20%) patients, respectively. Senaparib significantly improved progression-free survival versus placebo in patients with advanced ovarian cancer after response to first-line platinum-based chemotherapy, irrespective of BRCA1 and BRCA2 mutation status and with consistent benefits observed between homologous recombination subgroups, and was well tolerated. These results support senaparib as a maintenance treatment for patients with advanced ovarian cancer after a response to first-line chemotherapy. ClinicalTrials.gov identifier: NCT04169997 .

Stable Lithium Metal Batteries Enabled by Lithiophilic Core-Shell Nanowires on Copper Foam.

Lithium (Li) metal batteries have attracted considerable research attention due to their exceptionally high theoretical capacity. However, the commercialization of Li metal batteries faces challenges, primarily attributed to uncontrolled growth of Li dendrites, which raises safety concerns and lowers coulombic efficiency. To mitigate Li dendrites growth and attain dense Li deposition, the hybrid SiO2-Cu2O lithiophilic film applied to a 3D copper foam current collector is developed to regulate the interfacial properties for achieving even and dense Li deposition. The SiO2-Cu2O possesses strong Li+ trapping capability through strong lithiophilicity from Cu2O. Additionally, the SiO2-Cu2O enables uniform ion diffusion through the domain-limiting effect of the holes in the SiO2 layer, inducing an even and dense Li plating/stripping behavior at a large capacity. Furthermore, the SiO2 layer promotes the formation of an initial high inorganic content Solid Electrolyte Interphase (SEI) through selective preferential binding with anion and solvent molecules. When the SiO2-Cu2O@Li anode is coupled with a LiFePO4 (LFP) cathode, the resulting full cell exhibits superior cycling stability and rate performance. These results provide a facile approach to construct a lithiophilic current collector for practical Li metal anodes.

Coumarin-Furoxan Hybrid Suppressed the Proliferation and Metastasis of Triple-Negative Breast Cancer by Activating Mitochondrial Stress and Cell Apoptosis.

Triple-negative breast cancer (TNBC) typically manifests as higher invasive carcinoma correlated with a worse prognosis that primarily relies on chemotherapy. There is growing evidence that nitric oxide (NO) donor drugs have the potential for anticancer therapy. On this basis, we constructed and evaluated a novel coumarin-furoxan hybrid 4A93 as an effective antitumor candidate drug. 4A93 exhibits low IC50 values in three TNBC cell lines and inhibits colony formation and DNA synthesis, probably due to the release of high concentrations of NO in mitochondria, which induces oxidative stress, mitochondrial dysfunction, and apoptosis. Further research suggests that 4A93 might destroy mitochondria by opening the mitochondrial permeability transition pore (mPTP), depolarizing the mitochondrial membrane potential (MMP), and promoting the release of cytochrome c into the cytoplasm. Intrinsic apoptosis is induced finally, along with Akt/Erk signaling suppression. Additionally, 4A93 underregulates the Epithelial-mesenchymal transition process to inhibit cell migration and invasion. In 4T1 subcutaneous and hematogenous models of mice, 4A93 therapy suppresses the tumor growth and prevented lung metastasis with favorable biosafety. Our results provide insights into 4A93 in TNBC treatment and validate the contribution of NO donors in tumor therapy.

Design and analysis of a lower limb assistive exoskeleton robot.

BACKGROUND: In recent years, exoskeleton robot technology has developed rapidly. Exoskeleton robots that can be worn on a human body and provide additional strength, speed or other abilities. Exoskeleton robots have a wide range of applications, such as medical rehabilitation, logistics and disaster relief and other fields. OBJECTIVE: The study goal is to propose a lower limb assistive exoskeleton robot to provide extra power for wearers. METHODS: The mechanical structure of the exoskeleton robot was designed by using bionics principle to imitate human body shape, so as to satisfy the coordination of man-machine movement and the comfort of wearing. Then a gait prediction method based on neural network was designed. In addition, a control strategy according to iterative learning control was designed. RESULTS: The experiment results showed that the proposed exoskeleton robot can produce effective assistance and reduce the wearer's muscle force output. CONCLUSION: A lower limb assistive exoskeleton robot was introduced in this paper. The kinematics model and dynamic model of the exoskeleton robot were established. Tracking effects of joint angle displacement and velocity were analyzed to verify feasibility of the control strategy. The learning error of joint angle can be improved with increase of the number of iterations. The error of trajectory tracking is acceptable.

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer.

BACKGROUND: The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. METHODS: HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan-Meier method was utilised to analyse progression-free survival (PFS). RESULTS: This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5-22.1) versus 9.2 months (95% CI: 7.5-13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4-18.2) versus 22.2 months (95% CI: 18.3-NA)]. Conversely, positive PD-L1 expression on immune cells was associated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9-NA) versus 8.3 months (95% CI: 6.7-13.8)]. CONCLUSIONS: HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. TRIAL REGISTRATION: NCT03534453. Registered at May 23, 2018.

Assessment of efficacy and safety of MET tyrosine kinase inhibitors in non-small-cell lung cancer patients with MET alterations.

Background: While targeted therapy has become the standard treatment for certain non-small-cell lung cancer (NSCLC) patients with gene mutation positivity, there remains a lack of enough reports of the efficacy of mesenchymal-epithelial transition (MET) alterations in the real world. Objectives: We aimed to explore the efficacy and toxicity of targeted therapy in NSCLC patients with different types of MET alterations and hope to provide more clinical medication guidance. Design: Designed different subgroups to compare the efficacy and safety of targeted therapy in NSCLC patients with MET alterations. Methods: We conducted analyses on the efficacy and safety of mesenchymal-epithelial transition factor-tyrosine kinase inhibitor (MET-TKI) therapy in NSCLC patients with MET alterations. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors version 1.1 criteria, and both progression-free survival (PFS) and overall survival were determined using the Kaplan-Meier method. Results: Our study encompassed 116 NSCLC patients with MET alterations, including MET ex14 skipping mutation (n = 50), MET primary amplification (amp) (n = 25), and secondary amp (n = 41). Among treated patients, 34 achieved a partial response, while 52 exhibited stable disease. The overall response rate for the entire cohort was 29.31%, with a disease control rate of 74.14%. A significant difference was observed in the median PFS among patients with MET ex14 skipping mutation, MET primary amplification (amp), and secondary amp (10.4 versus 6.6 versus 4.5 months, p = 0.002). In all, 69 patients experienced drug-related adverse effects, with the most common being peripheral edema (35.34%), nausea and vomiting (21.55%), and fatigue (10.34%). In total, 29 patients (25%) encountered drug-related adverse reactions of grade 3 or higher. Conclusion: MET-TKI therapy works better for MET ex14 skipping mutation than other types of MET gene alteration. In the two MET amplified groups, the secondary amp was less effective. This study may provide more research support for the treatment of these patients.