PTP1B inhibitor alleviates deleterious septic lung injury through Src signaling.

Septic lung injury is an unmet clinical challenge due to its high mortality, and there is a lack of effective treatment. Accumulating evidence suggests that an uncontrolled pulmonary inflammatory response is important in the pathogenesis of lung injury in sepsis. Therefore, limiting excessive early inflammatory responses may be an effective strategy. We established a septic lung injury model using cecal ligation and puncture. Western blotting and immunofluorescence analyses were performed to assess the expression of PTP1B and endoplasmic reticulum (ER) stress and pyroptosis. Co-immunoprecipitation was used to analyze the binding of PTP1B and Src molecules. PTP1B is upregulated in both in vivo and in vitro models of septic lung injury. PTP1B directly binds to Src and aggravates inflammation by regulating the ER stress-pyroptosis axis. The inhibition of PTP1B alleviates inflammation and improves the prognosis of septic mice. Our study suggesting that PT1B inhibitors have clinical application value in the treatment of septic lung injury. This may provide a new strategy for the treatment of septic lung injury.

H9N2 Avian Influenza Virus Downregulates FcRY Expression in Chicken Macrophage Cell Line HD11 by Activating the JNK MAPK Pathway.

The H9N2 avian influenza virus causes reduced production performance and immunosuppression in chickens. The chicken yolk sac immunoglobulins (IgY) receptor (FcRY) transports from the yolk into the embryo, providing offspring with passive immunity to infection against common poultry pathogens. FcRY is expressed in many tissues/organs of the chicken; however, there are no reports investigating FcRY expression in chicken macrophage cells, and how H9N2-infected HD11 cells (a chicken macrophage-like cell line) regulate FcRY expression remains uninvestigated. This study used the H9N2 virus as a model pathogen to explore the regulation of FcRY expression in avian macrophages. FcRY was highly expressed in HD11 cells, as shown by reverse transcription polymerase chain reactions, and indirect immunofluorescence indicated that FcRY was widely expressed in HD11 cells. HD11 cells infected with live H9N2 virus exhibited downregulated FcRY expression. Transfection of eukaryotic expression plasmids encoding each viral protein of H9N2 into HD11 cells revealed that nonstructural protein (NS1) and matrix protein (M1) downregulated FcRY expression. In addition, the use of a c-jun N-terminal kinase (JNK) activator inhibited the expression of FcRY, while a JNK inhibitor antagonized the downregulation of FcRY expression by live H9N2 virus, NS1 and M1 proteins. Finally, a dual luciferase reporter system showed that both the M1 protein and the transcription factor c-jun inhibited FcRY expression at the transcriptional level. Taken together, the transcription factor c-jun was a negative regulator of FcRY, while the live H9N2 virus, NS1, and M1 proteins downregulated the FcRY expression through activating the JNK signaling pathway. This provides an experimental basis for a novel mechanism of immunosuppression in the H9N2 avian influenza virus.

Rim plate in the treatment of hyperextension tibial plateau fracture: surgical technique and a series of cases.

BACKGROUND: The existence of a "bare area" at the anterior plateau has been observed in cases where anteromedial and/or anterolateral proximal tibial locking plates are used for fixation in the treatment of hyperextension tibial plateau fractures (HTPF). The objective of this study is to introduce the rim plate fixation technique and evaluate its clinical efficacy. METHODS: A retrospective analysis was conducted on HTPF patients who underwent treatment with a combination of rim plate and proximal tibial locking plate at our hospital between April 2015 and December 2019. All patients were followed up for a minimum of one year. Open reduction and internal fixation were performed using anteromedial/posteromedial and/or anterolateral approaches for all cases. The surgical strategies employed for rim plate fixation were introduced, and both radiographic and clinical outcomes were assessed. RESULTS: Thirteen patients were enrolled in the study, with an average follow-up time of 4.3 years. Satisfactory reduction was achieved and radiographically maintained in all cases. Additionally, all patients exhibited satisfactory clinical functions, as evidenced by a mean hospital for special surgery (HSS) knee score of 96.2 ± 2.0 (range: 90-98). Furthermore, no wound complications or implant breakage were observed in this series. CONCLUSION: The combination of the rim plate and proximal tibial plate proved to be an effective fixation configuration, resulting in satisfactory clinical outcomes.

Standard: Human intestinal cancer organoids.

Intestinal cancer is one of the most frequent and lethal types of cancer. Modeling intestinal cancer using organoids has emerged in the last decade. Human intestinal cancer organoids are physiologically relevant in vitro models, which provides an unprecedented opportunity for fundamental and applied research in colorectal cancer. "Human intestinal cancer organoids" is the first set of guidelines on human intestinal organoids in China, jointly drafted and agreed by the experts from the Chinese Society for Cell Biology and its branch society: the Chinese Society for Stem Cell Research. This standard specifies terms and definitions, technical requirements, test methods for human intestinal cancer organoids, which apply to the production and quality control during the process of manufacturing and testing of human intestinal cancer organoids. It was released by the Chinese Society for Cell Biology on 24 September 2022. We hope that the publication of this standard will guide institutional establishment, acceptance and execution of proper practocal protocols, and accelerate the international standardization of human intestinal cancer organoids for clinical development and therapeutic applications.

CA916798 predicts poor prognosis and promotes Gefitinib resistance for lung adenocarcinoma.

BACKGROUND: Our previous studies have identified CA916798 as a chemotherapy resistance-associated gene in lung cancer. However, the histopathological relevance and biological function of CA916798 in lung adenocarcinoma (LUAD) remains to be delineated. In this study, we further investigated and explored the clinical and biological significance of CA916798 in LUAD. METHODS: The relationship between CA916798 and clinical features of LUAD was analyzed by tissue array and online database. CCK8 and flow cytometry were used to measure cell proliferation and cell cycle of LUAD after knockdown of CA916798 gene. qRT-PCR and western blotting were used to detect the changes of cell cycle-related genes after knockdown or overexpression of CA916798. The tumorigenesis of LUAD cells was evaluated with or without engineering manipulation of CA916798 gene expression. Response to Gefitinib was evaluated using LUAD cells with forced expression or knockdown of CA916798. RESULTS: The analysis on LUAD samples showed that high expression of CA916798 was tightly correlated with pathological progression and poor prognosis of LUAD patients. A critical methylation site in promoter region of CA916798 gene was identified to be related with CA916798 gene expression. Forced expression of CA916798 relieved the inhibitory effects of WEE1 on CDK1 and facilitated cell cycle progression from G2 phase to M phase. However, knockdown of CA916798 enhanced WEE1 function and resulted in G2/M phase arrest. Consistently, chemical suppression of CDK1 dramatically inhibited G2/M phase transition in LUAD cells with high expression of CA916798. Finally, we found that CA916798 was highly expressed in Gefitinib-resistant LUAD cells. Exogenous expression of CA916798 was sufficient to endow Gefitinib resistance with tumor cells, but interference of CA916798 expression largely rescued response of tumor cells to Gefitinib. CONCLUSIONS: CA916798 played oncogenic roles and was correlated with the development of Gefitinib resistance in LUAD cells. Therefore, CA916798 could be considered as a promising prognostic marker and a therapeutic target for LUAD.

Abbreviated perioperative fasting management for elective fresh fracture surgery: guideline adherence analysis.

BACKGROUND: Long-term fasting for elective surgery has been proven unnecessary based on established guidelines. Instead, preoperative carbohydrate loading 2 h before surgery and recommencing oral nutrition intake as soon as possible after surgery is recommended. This study was performed to analyze the compliance with and effect of abbreviated perioperative fasting management in patients undergoing surgical repair of fresh fractures based on current guidelines. METHODS: Patients with fresh fractures were retrospectively analyzed from the prospectively collected database about perioperative managements based on enhanced recovery of surgery (ERAS) from May 2019 to July 2019 at our hospital. A carbohydrate-enriched beverage was recommended up to 2 h before surgery for all surgical patients except those with contraindications. Postoperatively, oral clear liquids were allowed once the patients had regained full consciousness, and solid food was allowed 1 to 2 h later according to the patients' willingness. The perioperative fasting time was recorded and the patients' subjective comfort with respect to thirst and hunger was assessed using an interview-assisted questionnaire. RESULTS: In total, 306 patients were enrolled in this study. The compliance rate of preoperative carbohydrate loading was 71.6%, and 93.5% of patients began ingestion of oral liquids within 2 h after surgery. The median (interquartile range) preoperative fasting time for liquids and solids was 8 (5.2-12.9) and 19 (15.7-22) hours, respectively. The median postoperative fasting time for liquids and solids was 1 (0.5-1.9) and 2.8 (2.2-3.5) hours, respectively. A total of 70.3% and 74.2% of patients reported no thirst and hunger during the perioperative period, respectively. Logistic regression analysis showed that the preoperative fasting time for liquids was an independent risk factor for perioperative hunger. No risk factor was identified for perioperative thirst. No adverse events such as aspiration pneumonia or gastroesophageal reflux were observed. CONCLUSIONS: In this study of a real clinical practice setting, abbreviated perioperative fasting management was carried out with high compliance in patients with fresh fractures. The preoperative fasting time should be further shortened to further improve patients' subjective comfort.

Perioperative Protocol of Ankle Fracture and Distal Radius Fracture Based on Enhanced Recovery after Surgery Program: A Multicenter Prospective Clinical Controlled study.

Background: The enhanced recovery after surgery (ERAS) program is aimed to shorten patients' recovery process and improve clinical outcomes. This study aimed to compare the outcomes between the ERAS program and the traditional pathway among patients with ankle fracture and distal radius fracture. Methods: This is a multicenter prospective clinical controlled study consisting of 323 consecutive adults with ankle fracture from 12 centers and 323 consecutive adults with distal radial fracture from 13 centers scheduled for open reduction and internal fixation between January 2017 and December 2018. According to the perioperative protocol, patients were divided into two groups: the ERAS group and the traditional group. The primary outcome was the patients' satisfaction of the whole treatment on discharge and at 6 months postoperatively. The secondary outcomes include delapsed time between admission and surgery, length of hospital stay, postoperative complications, functional score, and the MOS item short form health survey-36. Results: Data describing 772 patients with ankle fracture and 658 patients with distal radius fracture were collected, of which 323 patients with ankle fracture and 323 patients with distal radial fracture were included for analysis. The patients in the ERAS group showed higher satisfaction levels on discharge and at 6 months postoperatively than in the traditional group (P < 0.001). In the subgroup analysis, patients with distal radial fracture in the ERAS group were more satisfied with the treatment (P=0.001). Furthermore, patients with ankle fracture had less time in bed (P < 0.001) and shorter hospital stay (P < 0.001) and patients with distal radial fracture received surgery quickly after being admitted into the ward in the ERAS group than in the traditional group (P=0.001). Conclusions: Perioperative protocol based on the ERAS program was associated with high satisfaction levels, less time in bed, and short hospital stay without increased complication rate and decreased functional outcomes.

Oligoadenylate synthetases-like is a prognostic biomarker and therapeutic target in pancreatic ductal adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) is fatal cancer that causes death. Early metastasis, resistance to chemotherapy, and lack of treatment contribute to a poor prognosis. Therefore, finding new therapeutic targets and biomarkers is a particularly urgent need to improve the survival of PDAC patients. Oligoadenylate synthetases-like (OASL), an antiviral enzyme produced by interferon (IFN), has been found to be associated with the occurrence and development of multiple cancers. However, its role in PDAC has been less well-studied. The value of OASL in PDAC was evaluated by bioinformatics and in vitro experiments. Methods: The expression of OASL was evaluated using the Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA) online websites. The survival time was also calculated by GEPIA. The correlation between OASL messenger RNA (mRNA) expression and immune infiltration was analyzed by the Tumor Immune Estimation Resource (TIMER) database. Clinical characteristics were revealed by The Cancer Genome Atlas (TCGA) data. A nomogram and forest plot were constructed based on univariate and multivariate Cox regression. Cell experiments [western blot assays, 3-(4,5-dimethylathiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, transwell assays, flow cytometry assays] were used to verify the value of OASL in PDAC cells (Panc-1, Mia paca-2, and Aspc-1). Results: A higher expression of OASL was observed in PDAC (P<0.05). Patients with increased expression of OASL had worse overall survival (OS; P<0.05) and disease-specific survival (DSS; P<0.05). The expression of OASL was correlated with T stage (P=0.030) and N stage (P=0.004), radiation therapy (P=0.013), primary therapy outcome (P<0.001), residual tumor (P=0.028), and tumor location (P=0.004) by univariate analysis, which also confirmed that OASL was an independent prognostic factor. Moreover, OASL expression was positively associated with neutrophils. In vitro experiments indicated that knockdown of OASL inhibited cell viability and invasion while increasing apoptosis rate. Conclusions: High expression of OASL is associated with poor prognosis. Targeting OASL delays PDAC tumor progression in vitro. We highlight that OASL is a novel prognostic biomarker and therapeutic target of PDAC.

Phenotypical screening on metastatic PRCC-TFE3 fusion translocation renal cell carcinoma organoids reveals potential therapeutic agents.

PURPOSE: Translocation renal cell carcinoma (tRCC) is a subtype that occurs predominantly in children and young individuals. Metastatic tRCC occurring in young patients is more aggressive than that occurring in older patients, and there are still no effective therapies. Organoids can mimic original tissues and be assessed by high-throughput screening (HTS). We aimed to utilize patient-derived organoids and HTS to screen drugs that can be repurposed for metastatic tRCC with PRCC-TFE3 fusion. METHODS: Tumor tissues were obtained from treatment-naïve metastatic tRCC patients who underwent surgery. Histopathology and fluorescence in situ hybridization (FISH) confirmed the tRCC. Organoids derived from the dissected tissues were cultured and verified by FISH and RNA-seq. HTS was performed to seek promising drugs, and potential mechanisms were explored by RNA-seq and cell-based studies. RESULTS: We successfully established a metastatic tRCC organoid with PRCC-TFE3 fusion, a common fusion subtype, and its characteristics were verified by histopathology, FISH, and RNA-seq. An HTS assay was developed, and the robustness was confirmed. A compound library of 1816 drugs was screened. Eventually, axitinib, crizotinib, and JQ-1 were selected for further validation and were found to induce cell cycle arrest and apoptosis. RNA-seq analyses of posttreatment organoids indicated that crizotinib induced significant changes in autophagy-related genes, consistent with the potential pathogenesis of tRCC. CONCLUSIONS: We established and validated organoids derived from tissues dissected from a patient with metastatic tRCC with PRCC-TFE3 fusion and achieved the HTS process for the first time. Crizotinib might be a targeted therapy worthy of exploration in the clinic for metastatic tRCC with PRCC-TFE3 fusion. Such organoid and HTS assays may represent a promising model system in translational research assisting in the development of clinical strategies.

Comprehensive omics analyses profile genesets related with tumor heterogeneity of multifocal glioblastomas and reveal LIF/CCL2 as biomarkers for mesenchymal subtype.

Rationale: Around 10%-20% patients with glioblastoma (GBM) are diagnosed with more than one tumor lesions or multifocal GBM (mGBM). However, the understanding on genetic, DNA methylomic, and transcriptomic characteristics of mGBM is still limited. Methods: In this study, we collected nine tumor foci from three mGBM patients followed by whole genome sequencing, whole genome bisulfite sequencing, RNA sequencing, and immunohistochemistry. The data were further examined using public GBM databases and GBM cell line. Results: Analysis on genetic data confirmed common features of GBM, including gain of chr.7 and loss of chr.10, loss of critical tumor suppressors, high frequency of PDGFA and EGFR amplification. Through profiling DNA methylome of individual tumor foci, we found that promoter methylation status of genes involved in detection of chemical stimulus, immune response, and Hippo/YAP1 pathway was significantly changed in mGBM. Although both CNV and promoter methylation alteration were involved in heterogeneity of different tumor foci from same patients, more CNV events than promoter hypomethylation events were shared by different tumor foci, implying CNV were relatively earlier than promoter methylation alteration during evolution of different tumor foci from same mGBM. Moreover, different tumor foci from same mGBM assumed different molecular subtypes and mesenchymal subtype was prevalent in mGBM, which might explain the worse prognosis of mGBM than single GBM. Interestingly, we noticed that LIF and CCL2 was tightly correlated with mesenchymal subtype tumor focus in mGBM and predicted poor survival of GBM patients. Treatment with LIF and CCL2 produced mesenchymal-like transcriptome in GBM cells. Conclusions: Together, our work herein comprehensively profiled multi-omics features of mGBM and emphasized that components of extracellular microenvironment, such as LIF and CCL2, contributed to the evolution and prognosis of tumor foci in mGBM patients.

Pyrotinib in Patients with HER2-Amplified Advanced Non-Small Cell Lung Cancer: A Prospective, Multicenter, Single-Arm Trial.

PURPOSE: In this study, we aimed to evaluate the efficacy and safety of pyrotinib, a pan-HER inhibitor, in patients with HER2-amplified non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: In this prospective, multicenter, single-arm trial (ChiCTR1800020262), patients with advanced NSCLC with HER2 amplification, as determined by next-generation sequencing, were enrolled and administered pyrotinib orally at 400 mg per day. The primary endpoint was 6-month progression-free survival (PFS) rate. Other endpoints included objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety. RESULTS: The enrolled cohort included 27 patients with HER2 amplification. The 6-month PFS rate was 51.9% [95% confidence interval (CI), 34.0-69.3]. The median PFS (mPFS) was 6.3 months (95% CI, 3.0-9.6 months), and median OS was 12.5 months (95% CI, 8.2-16.8 months). Pyrotinib elicited a confirmed ORR of 22.2% (95% CI, 10.6%-40.8%). Patients administered pyrotinib as first-line treatment achieved an mPFS of 12.4 months. Moreover, 30.8% of the patients who had progressed on EGFR tyrosine kinase inhibitor (TKI) responded to pyrotinib. Patients with brain metastases had an ORR of 40%. Treatment-related adverse events (TRAE) occurred in all patients (grade 3, 22.2%), but no grade 4 or higher TRAEs were documented. Diarrhea was the most frequent TRAE (all, 92.6%; grade 3, 7.4%). Loss of HER2 amplification was detected upon disease progression. CONCLUSIONS: Pyrotinib provided antitumor efficacy with a manageable safety profile in HER2-amplified patients with NSCLC.

Halofuginone Sensitizes Lung Cancer Organoids to Cisplatin via Suppressing PI3K/AKT and MAPK Signaling Pathways.

Lung cancer is the leading cause of cancer death worldwide. Cisplatin is the major DNA-damaging anticancer drug that cross-links the DNA in cancer cells, but many patients inevitably develop resistance with treatment. Identification of a cisplatin sensitizer might postpone or even reverse the development of cisplatin resistance. Halofuginone (HF), a natural small molecule isolated from Dichroa febrifuga, has been found to play an antitumor role. In this study, we found that HF inhibited the proliferation, induced G0/G1 phase arrest, and promoted apoptosis in lung cancer cells in a dose-dependent manner. To explore the underlying mechanism of this antitumor effect of halofuginone, we performed RNA sequencing to profile transcriptomes of NSCLC cells treated with or without halofuginone. Gene expression profiling and KEGG analysis indicated that PI3K/AKT and MAPK signaling pathways were top-ranked pathways affected by halofuginone. Moreover, combination of cisplatin and HF revealed that HF could sensitize the cisplatin-resistant patient-derived lung cancer organoids and lung cancer cells to cisplatin treatment. Taken together, this study identified HF as a cisplatin sensitizer and a dual pathway inhibitor, which might provide a new strategy to improve prognosis of patients with cisplatin-resistant lung cancer.

Intra-abdominal hypertension and increased acute kidney injury risk: a systematic review and meta-analysis.

OBJECTIVE: The present meta-analysis aimed to determine the relationship between intra-abdominal hypertension (IAH) and an increased prevalence of acute kidney injury (AKI) and identify the associated risk factors in various patient populations, regardless of whether they were admitted to an intensive care unit. METHODS: We used three databases for the following search terms: "IAH," "abdominal compartment syndrome," "AKI," "acute kidney failure," and others. The articles retrieved were compared to identify appropriate studies published until 7 May 2020. The main outcome was AKI. RESULTS: Six studies with 344 individuals were included. The patients were divided into two main groups: the IAH and non-IAH groups. Compared with patients without IAH, patients with IAH had a higher risk of AKI (odds ratio = 2.57, 95% confidence interval: 1.55-4.26). In the subgroup and meta-regression analyses, body mass index, age, the presence or absence of burns, and cardiac surgery did not affect the risk of AKI. CONCLUSION: IAH was associated with AKI risk, and this association was not influenced by age, body mass index, the presence or absence of burns, or cardiac surgery.

Clinical outcome of distal tibiofibular arthrodesis with plate fixation for the treatment of chronic frank syndesmosis instability.

BACKGROUND: Numerous treatment strategies have been reported for the treatment of chronic frank distal tibiofibular syndesmosis instability, including several small case series treated by syndesmosis arthrodesis. The aim of this study is to report the treatment of this condition using a specially contoured plate and the associated clinical outcomes. METHODS: Over a period of 8 years, patients presented in our institution with chronic frank distal tibiofibular syndesmosis instability were eligible to participate. All patients were managed with plating and screw fixation. The average follow-up period was 58 months (range, 12-99). Clinical outcome was evaluated using the American Orthopaedic Foot & Ankle Society ankle-hindfoot score. RESULTS: In total, 8 patients met the inclusion criteria and formed the basis of this study. All patients could tolerate full weightbearing 3 months after surgery. The mean Visual Analog Scale pain score and the American Orthopaedic Foot & Ankle Society ankle-hindfoot score were significantly improved at the last follow-up (P<0.05). All patients were satisfied with the result and 7 patients returned to sports. 4 patients had mild limitation of ankle range of motion compared with the unaffected side. CONCLUSION: Syndesmosis arthrodesis was a feasible method for the treatment of chronic frank syndesmosis instability according to our findings. Syndesmosis arthrodesis with plate and screw stabilization is another viable option to be considered into the surgeon's armamentarium. Larger scale studies are desirable to provide further evidence of this method of treatment.

The Involvement of the Chemokine RANTES in Regulating Luminal Acidification in Rat Epididymis.

Background: A complex interplay between different cell types in the epithelium leads to activation of the luminal acidifying capacity of the epididymis, a process that is crucial for sperm maturation and storage. Basal cells sense the luminal angiotensin II (ANG II) and stimulate proton secretion in clear cells through nitric oxide (NO). Our previous study has shown the chemokine regulated upon activation normal T-cell expressed and secreted (RANTES) was expressed in the F4/80 positive macrophages of human epididymis. The objective of this study was to explore the involvement of RANTES in regulating the luminal acidification in the rat epididymis. Methods: The role of RANTES was investigated by in vivo perfusion with recombinant RANTES, Met-RANTES, and PBS of different pH values. Furthermore, rats vasectomy was performed to alter the epididymal luminal pH. RIA was used to measure the tissue homogenate ANG II concentration. Real time-PCR and western blot were employed to examine the expression levels of AGTR2, RANTES, CCR1, CCR5, and iNOS in epididymis. Results: RANTES was restricted to the basal macrophages of epididymal ducts and co-localized with its receptors CCR1 and CCR5. Both V-ATPase and iNOS were up-regulated in the cauda epididymis after perfused with recombinant RANTES, while the antagonist Met-RANTES perfusion led to a complete abrogation of the increased expression of V-ATPase in the apical membrane of clear cells and iNOS in macrophages. Upon alkaline perfusion, RANTES expression was significantly increased and the apical accumulation of V-ATPase in the clear cells was induced in the cauda epididymis. The luminal pH in the cauda epididymis increased after vasectomy. The concentration of the ANG II and the expression levels of AGTR2, RANTES, CCR1, CCR5, and iNOS dropped in the cauda epididymis following vasectomy. Conclusion: Upon the activation of basal cells, RANTES might induce the NO release from macrophages by interacting with its receptors, which increases proton secretion by adjacent clear cells. Thus, RANTES is possible to participate in the crosstalk among basal cells, macrophages and clear cells for the fine control of an optimum acidic luminal environment that is critical for male fertility.

Hierarchical 0D-2D bio-composite film based on enzyme-loaded polymeric nanoparticles decorating graphene nanosheets as a high-performance bio-sensing platform.

Herein, we developed a hierarchical bio-composite sensing film by facile one-step electro-deposition of 0D enzyme-polymer nanoparticles (NPs) with 2D graphene oxide nanosheets as conductive supports and nanofillers, based on which an effective and robust enzymatic biosensor platform was constructed. Horseradish peroxidase (HRP) as a model enzyme was co-assembled with a photo-cross-linkable polypeptide of 2-hydroxyethyl methacrylate modified poly(γ-glutamic acid) (γ-PGA-HEMA), generating hybrid HRP@γ-PGA-HEMA nanoparticles (HRP@PGH NPs). Then HRP@PGH NPs and graphene oxide nanosheets (GO NSs) were simultaneously electrodeposited onto the electrode surface, obtaining a hierarchical 0D-2D bio-composite film. After subsequent electrochemical reduction of GO NSs into graphene nanosheets (GNSs) and following photo-cross-linking, the resultant nanostructured HRP@PGH/GNSs sensing film was successfully applied to construct an enzymatic biosensor for hydrogen peroxide (H2O2). The biosensor exerted high sensitivity, fast response, and good stability for H2O2 sensing. Satisfactory results were also demonstrated for its practical application in human serum samples, suggesting a promising application potential in biomedical diagnostics. The one-step generated 0D-2D bio-composite sensing film demonstrates synergetic effects from both the soft nanoparticles and hard conductive nanosheets, which would enlighten the innovative construction of composite nanomaterials and nanoarchitectonics for bio-sensing systems.

Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.

Aberrant activation of Bruton's tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematological malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclinical characterization of a potent, selective, and irreversible BTK inhibitor as our clinical candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compounds. Compound BGB-3111 (31a, Zanubrutinib) demonstrates (i) potent activity against BTK and excellent selectivity over other TEC, EGFR and Src family kinases, (ii) desirable ADME, excellent in vivo pharmacodynamic in mice and efficacy in OCI-LY10 xenograft models.

Solamargine inhibits gastric cancer progression by regulating the expression of lncNEAT1_2 via the MAPK signaling pathway.

Solamargine, a derivative from the steroidal solasodine in Solanum species, has exhibited anticancer activities in numerous types of cancer; however, its role in gastric cancer (GC) remains unknown. In the present study, it was demonstrated that Solamargine suppressed the viability of five gastric cancer cell lines in a dose­dependent manner and induced notable alterations in morphology. Treatment with Solamargine promoted cell apoptosis (P<0.01). Solamargine increased the expression of long noncoding RNA (lnc) p53 induced transcript and lnc nuclear paraspeckle assembly transcript 1 (NEAT1)_2 (P<0.01) in GC by reducing the phosphorylation of extracellular signal­regulated kinase (Erk)1/2 mitogen­activated protein kinase (MAPK). To gain insight into the potential mechanism, an Erk1/2 inhibitor (U0126) was applied. The results revealed that lncNEAT1_2 expression levels increased, which was consistent with the effects of Solamargine. Downregulation of lncNEAT1_2 in GC cells revealed no effect on the expression levels of total Erk1/2 and, and counteracted the effect of Solamargine. Solamargine was observed to increase the expression of lncNEAT1_2 via the Erk1/2 MAPK signaling pathway. Of note, the knockdown of lncNEAT1_2 reduced the inhibitory effect of Solamargine (P<0.05). Additionally, experiments in vivo and in primary GC cells from patients demonstrated that Solamargine significantly suppressed tumor growth (P<0.05). In vivo analysis of a xenograft mouse model further supported that Solamargine could induce the apoptosis of cancer cells in tumor tissue as observed by a terminal deoxynucleotidyl transferase­mediated dUTP­biotin nick end labeling and H&E staining (P<0.05). Experiments in primary GC cells from patients verified the anti­tumor effect of Solamargine. In summary, the findings of the present study indicated that Solamargine inhibited the progression of GC by regulating lncNeat1_2 via the MAPK pathway.

Does routinely repairing deltoid ligament injuries in type B ankle joint fractures influence long term outcomes?

Deltoid ligament reconstruction following type B ankle fractures continues to generate a vivid discussion amongst trauma surgeons. There is a difference of opinion as to whether operative or non operative treatment should prevail. We therefore conducted a prospective comparative cohort study to determine whether it is necessary to routinely repair the injured deltoid ligaments. 41 Type B ankle joint fracture patients were enrolled, all the patients were associated with deltoid ligament ruptures and lateral/posterior-lateral dislocation of talus. After fixation of the lateral malleolus fracture, 12 patients were treated by superficial deltoid ligaments repairing, 16 patients with deep components augmentation, 13 patients had no direct surgical intervention. In the deep components group, the planter and the dorsi flexion was 3.2° (0-10°) and 8.8° (0-15°) less than the normal side. In the superficial components group, plantar and dorsi flexion was 0.8° (0-5°) and 4.2° (0-15°) less than the normal side. In the non-repairing group, the plantar and dorsi flexion was 2.4° (0-10°) and 5.6° (0-20°) less than the normal side. Overall, no significant statistical difference was observed comparing the 3 groups. In addition, no statistically significant inter-group differences were evident in terms of measurement of the ankle medial clear space and the clinical and functional outcomes recorded. In conclusion, the results of this study do not support routine exposure and repairing of the injured deltoid ligaments.

A fusion protein composed of the DSL domain of Dll1 and RGD motif protects cryptic stem cells in irradiation injury.

Intestine is vulnerable to irradiation injury, which induces cell death and compromises regeneration of intestinal crypts. It is well accepted that cryptic stem cells, which are responsible for cryptic regeneration under physiological and pathological conditions, are controlled by multiple cell-intrinsic and environmental signals such as Notch signaling. Therefore, in the present study, we tested whether a soluble Notch ligand tethered to endothelial cells-mD1R-the Delta-Serrate-Lag2 (DSL) domain of mouse Notch ligand Delta-like1 fused with a RGD motif could protect cryptic cells from irradiation-induced intestinal injury. The result showed that administration of mD1R, which activated Notch signaling in intestinal cells, ameliorated loss of body weight and reduction of cryptic structures in intestine after total body irradiation (TBI) in mice. Histological staining showed that injection of mD1R after TBI promoted cryptic cell proliferation and reduced cell apoptosis in crypts. Immunofluorescence staining and reverse transcription (RT)-PCR showed that mD1R increased the level of Lgr5, Bmi1, Olfactomedin-4 (OLFM4), and IRIG1 in crypts, suggesting a protective effect on cryptic stem and progenitor cells after irradiation. Moreover, we found that administration of mD1R increased the number of Paneth cells and the mRNA level of Defa1, and the number Alcian Blue+ Goblet cells decreased first and then increased after irradiation, suggesting that mD1R promoted the maturation of the intestinal crypt after irradiation injury. Our data suggested that mD1R could serve as a therapeutic agent for the treatment of irradiation-induced intestinal injury.