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Programmed cell death ligand 1 (PD‐L1), inducing T cell exhaustion to facilitate immune escape of tumor cells, is upregulated by interleukin 6 (IL‐6) in T cell lymphoma and ovarian cancer. The purpose of this study is to investigate the expression of IL‐6 and PD‐L1 in thyroid cancer, and whether IL‐6 regulates PD‐L1 expression. As a result, IL‐6 and PD‐L1 were highly expressed in thyroid cancer tissues. Multivariate logistic analysis showed that tumor size, distant metastasis, and risk stratification were significantly associated with IL‐6 expression (P < .05), and multifocality, lymph node metastasis, distant metastasis, risk stratification, and IL‐6 expression were identified as the independent predictors of PD‐L1 expression (P < .05). The invasiveness of thyroid cancer was significantly enhanced after IL‐6 treatment or PD‐L1 overexpression. PD‐L1 positive rate correlated with IL‐6 expression in cancer tissues (P < .001), and after IL‐6 treatment, the PD‐L1 expression in TPC‐1 and BCPAP significantly increased. The mitogen‐activated protein kinase pathway (MAPK) and the Janus‐activated kinase (JAK)–signal transducers and activators of transcription 3 (STAT3) signaling pathways were activated by IL‐6, and the IL‐6–induced PD‐L1 expression decreased after treatment with these two signaling pathway inhibitors. Knockdown of transcription factors c‐Jun and stat3 suppressed the expression of PD‐L1 induced by IL‐6, and these two factors could bind to PD‐L1 gene promoter directly and promote its transcription. It is concluded that IL‐6 and PD‐L1 are overexpressed in thyroid cancer and are related to tumor invasiveness. IL‐6 upregulates PD‐L1 expression through the MAPK and JAK‐STAT3 signaling pathways, which function via transcription factors c‐Jun and stat3. IL‐6 and PD‐L1 are highly expressed in thyroid cancer and correlate with disease aggressiveness. IL‐6 activates the MAPK and JAK‐STAT3 signaling pathways in thyroid cancer. In addition, IL‐6 promotes PD‐L1 transcription through the MAPK and JAK‐STAT3 signaling pathways, which function via transcription factors c‐Jun and stat3.

Few studies have investigated the relationship between sarcopenia and mild to moderate renal decline. This study aimed to investigate the relationship between chronic kidney disease (CKD) and sarcopenia. In total, 123 patients hospitalized with CKD and 57 healthy volunteers who underwent physical examination during the same period (control group) were analyzed. Body compositions were measured by dual-energy X-ray absorptiometry, and the relative appendicular skeletal muscle index (RASMI) was calculated. Muscular strength was evaluated using hydraulic hand dynamometer. Walking speed within 6 m was measured for muscular function assessment. Single-photon emission computed tomography was performed to measure the glomerular filtration rate of CKD patients, who were then divided into CKD1 (55 patients in CKD stages 1 and 2) and CKD2 (68 patients in CKD stages 3–5). RASMI showed a downward trend with CKD progression ( P  = 0.001). Multivariate logistic regression analysis showed that age and CKD progression were independent risk factors for sarcopenia. The morbidity of sarcopenia was significantly greater in CKD patients than in healthy volunteers, and the degree of muscle loss was closely related to CKD progression.

2D heterostructures have garnered tremendous attention for potential applications in electronics and optoelectronics. Heterostructures can be constructed by assembling individual atomically thin layers of 2D materials into integrated devices, which involves three primary degrees of freedom (DOFs), i.e., Lego‐like basic building blocks, out‐of‐plane stacking order, and in‐plane twist‐angle alignment. By steering the DOFs of 2D materials, devices and structures such as artificial Shockley junction, quantum wells, and superlattices can be conveniently established based on well‐developed fabrication and/or assembly techniques, beneficial for next‐generation ultracompact information technologies. Herein, the recent progress on constructing the artificial atomic structures by taking advantage of three primary DOFs is overviewed. An outlook of the challenges and future developments is presented as well. Future advancements in the rational construction of complex devices and artificial heterostructures are also suggested. 2D atomic crystal materials are most attractive candidates for next‐generation optoelectronics because of their unique mechanical, electronic, and optical properties. Extraordinarily, the heterogeneous assembly of 2D material structures has evidenced plenty of intriguing physical properties. From the viewpoint of the precise fabrication, this review summarizes the most important degrees of freedom and their potential figures of merit. Finally, the review provides a future perspective on the artificial heterostructures of 2D atomic crystals.

Osteosarcoma (OS), which is the most common primary malignant bone tumor, has a high incidence of pulmonary metastasis. CCL18 (C-C motif chemokine ligand 18), which is secreted by tumor-associated macrophages (TAMs), has been found to be increased in various tumors and is associated with tumor metastasis. However, the role of CCL18 in OS remains unclear. Here, we evaluated the effect of CCL18 on the OS cell lines MG63 and 143B and explored its potential mechanisms. We found that CCL18 enhanced the proliferation and migration of OS cells and upregulated UCA1 through transcription factor EP300. Subsequently, we further revealed that the downstream Wnt/β-catenin signaling pathway participated in this process. In addition, the high expression of CCL18 in both tissue and serum from patients was closely related to pulmonary metastasis and poor survival in OS patients. The tumor xenograft models also showed that CCL18 promoted the metastasis of OS cells. Collectively, our study indicated that macrophage-derived CCL18 promotes OS proliferation and metastasis via the EP300/UCA1/Wnt/β-catenin pathway and that CCL18 may be used as a prognostic marker and therapeutic target of OS.Key messagesCCL18 promotes proliferation and migration of osteosarcoma cells by EP300/ UCA1/ Wnt/β-catenin pathway.CCL18+ TAMs are significantly correlated with pulmonary metastasis and poor survival in osteosarcoma patients.CCL18 may be used as a prognostic marker and therapeutic target for osteosarcoma.

IntroductionSevere septic cardiomyopathy (SCM) is one of the main causes of refractory septic shock (RSS), with a high mortality. The application of venoarterial extracorporeal membrane oxygenation (ECMO) to support the impaired cardiac function in patients with septic shock remains controversial. Moreover, no prospective studies have been taken to address whether venoarterial ECMO treatment could improve the outcome of patients with sepsis-induced cardiogenic shock. The objective of this study is to assess whether venoarterial ECMO treatment can improve the 30-day survival rate of patients with sepsis-induced refractory cardiogenic shock.Methods and analysisExtraCorporeal Membrane Oxygenation in the therapy for REfractory Septic shock with Cardiac function Under Estimated is a prospective, multicentre, non-randomised, cohort study on the application of ECMO in SCM. At least 64 patients with SCM and RSS will be enrolled in an estimated ratio of 1:1.5. Participants taking venoarterial ECMO during the period of study are referred to as cohort 1, and patients receiving only conventional therapy without ECMO belong to cohort 2. The primary outcome is survival in a 30-day follow-up period. Other end points include survival to intensive care unit (ICU) discharge, hospital survival, 6-month survival, quality of life for long-term survival (EQ-5D score), successful rate of ECMO weaning, long-term survivors’ cardiac function, the number of days alive without continuous renal replacement therapy, mechanical ventilation and vasopressor, ICU and hospital length of stay, the rate of complications potentially related to ECMO treatment.Ethics and disseminationThe trial has been approved by the Clinical Research and Application Institutional Review Board of the Second Affiliated Hospital of Guangzhou Medical University (2020-hs-51). Participants will be screened and enrolled from ICU patients with septic shock by clinicians, with no public advertisement for recruitment. Results will be disseminated in research journals and through conference presentations.Trial registration number NCT05184296.

Background In aged people, tendon injuries frequently occur during sporting and daily activities. In clinical practice, typical physiotherapeutic, pharmacotherapeutic, and surgical techniques do not result in the full recovery of injured tendons, which may lead to chronic degenerative disease. Methods We first isolated tendon stem cells (TSCs) from rats and transfected them with the TGFβ1 gene, resulting in TGFβ1 -TSCs. The proliferation of TSCs was detected using the Cell Counting Kit 8, and TSCs were identified by immunofluorescence analysis and differentiation capacity analysis. Aggrecan, COL2A1, alpha smooth muscle actin (α-SMA), and p-Smad2 expression levels were detected using western blotting and quantitative reverse transcription polymerase chain reaction. Additionally, a tendon injury model was generated to explore the effect of TGFβ1 on the repair of the tendon by TSCs. Results Compared with fibrinogen treatment, TSC + fibrinogen or TGFβ1 -TSC + fibrinogen treatment significantly promoted the fibrosis of injured tendons, as evidenced by histological analyses, with TGFβ1 -TSC + fibrinogen having a greater effect than TSC + fibrinogen. In TGFβ1 -TSCs, increased expression levels of aggrecan and COL2A1 indicated that TGFβ1 signaling induced chondrogenic differentiation. Meanwhile, the increased collagen and α-SMA protein levels indicated that TGFβ1 promoted fibrogenesis. Additionally, TGFβ1 stimulated the production of phosphorylated Smad2 in TSCs, which suggested that the chondrogenic and fibrogenic differentiation of TSCs, as well as tissue regeneration, may be associated with the TGFβ1/Smad2 pathway. Conclusion TGFβ1 -TSC therapy may be a candidate for effective tendon fibrosis.

IntroductionAcute kidney injury (AKI) is one of the most common organ dysfunction in sepsis, and increases the risk of unfavourable outcomes. Renal replacement therapy (RRT) is the predominant treatment for sepsis-associated AKI (SAKI). However, to date, no prospective randomised study has adequately addressed whether initiating RRT earlier will attenuate renal injury and improve the outcome of sepsis. The objective of the trial is to compare the early strategy with delayed strategy on the outcomes in patients with SAKI in the intensive care unit (ICU).Methods and analysisThis is a large-scale, multicentre, randomised controlled trial about SAKI. In total, 460 patients with sepsis and evidence of AKI stage 2 of Kidney Disease Improving Global Outcomes (KDIGO) will be recruited and equally randomised into the early group and the delay group in a ratio of 1:1. In the early group, continuous RRT (CRRT) will be started immediately after randomisation. In the delay group, CRRT will initiated if at least one of the following criteria was met: stage 3 of KDIGO, severe hyperkalaemia, pulmonary oedema, blood urea nitrogen level higher than 112 mg/dL after randomisation. The primary outcome is overall survival in a 90-day follow-up period (90-day all-cause mortality). Other end points include 28-day, 60-day and 1-year mortality, recovery rate of renal function by day 28 and day 90, ICU and hospital length of stay, the numbers of CRRT-free days, mechanical ventilation-free days and vasopressor-free days, the rate of complications potentially related to CRRT, CRRT-related cost, and concentrations of inflammatory mediators in serum.Ethics and disseminationThe trial has been approved by the Clinical Research and Application Institutional Review Board of the Second Affiliated Hospital of Guangzhou Medical University (2017–31-ks-01). Participants will be screened and enrolled from patients in the ICU with SAKI by clinicians, with no public advertisement for recruitment. Results will be disseminated in research journals and through conference presentations.Trial registrationNCT03175328.

Vacuolar protein sorting 33B (VPS33B) is important for intracellular vesicular trafficking process and protein interactions, which is closely associated with the arthrogryposis, renal dysfunction, and cholestasis syndrome. Our previous study has shown a crucial role of Vps33b in regulating metabolisms of bile acids and lipids in hepatic Vps33b deficiency mice with normal chow, but it remains unknown whether VPS33B could contribute to cholestatic liver injury. In this study we investigated the effects of hepatic Vps33b deficiency on bile acid metabolism and liver function in intrahepatic cholestatic mice. Cholestasis was induced in Vps33b hepatic knockout and wild-type male mice by feeding 1% CA chow diet for 5 consecutive days. We showed that compared with the wild-type mice, hepatic Vps33b deficiency greatly exacerbated CA-induced cholestatic liver injury as shown in markedly increased serum ALT, AST, and ALP activities, serum levels of total bilirubin, and total bile acid, as well as severe hepatocytes necrosis and inflammatory infiltration. Target metabolomics analysis revealed that hepatic Vps33b deficiency caused abnormal profiles of bile acids in cholestasis mice, evidenced by the upregulation of conjugated bile acids in serum, liver, and bile. We further demonstrated that the metabolomics alternation was accompanied by gene expression changes in bile acid metabolizing enzymes and transporters including Cyp3a11 , Ugt1a1 , Ntcp , Oatp1b1 , Bsep , and Mrp2 . Overall, these results suggest a crucial role of hepatic Vps33b deficiency in exacerbating cholestasis and liver injury, which is associated with the altered metabolism of bile acids.

Background Septic patients with cardiac impairment are with high mortality. Afterload-related cardiac performance (ACP), as a new tool for diagnosing septic cardiomyopathy (SCM), still needs to be evaluated for its impact on the prognosis for patients with septic shock. Methods In this retrospective study, 100 patients with septic shock undertaken PiCCO monitoring were included. The ability of ACP, cardiac index (CI), and cardiac power index (CPI) to discriminate between survivors and non-survivors was tested by comparing the area under the receiver operating characteristic curve (AUROC) analysis. Cox proportional hazards regression analyses were performed to assess the associations of ACP with day-28 mortality. Curve estimation was used to describe the relationship between the hazard ratio (HR) of death and ACP. Results ACP had a strong linear correlation with CI and CPI ( P < 0.001). ACP demonstrated significantly greater discrimination for day-28 mortality than CI before adjusted [AUROC 0.723 (95% CI 0.625 to 0.822) vs. 0.580 (95% CI 0.468 to 0.692), P = 0.007] and CPI after adjusted [AUROC 0.693 (95% CI 0.590 to 0.797) vs . 0.448 (0.332 to 0.565), P < 0.001]. Compared with ACP > 68.78%, HR for ACP ≤ 68.78% was 3.55 (1.93 to 6.54) ( P < 0.001). When adjusted with age, APACHE-II score, Vasoactive Inotropic Score, Lactate, CRRT, day-1 volume, fibrinogen and total bilirubin as possible confounders, and decrease ACP are still associated with increasing day-28 mortality ( P < 0.05). An exponential relationship was observed between ACP12h and HR of day-28 death. Conclusions Our results suggested thatACP could improve mortality predictions when compared to CI and CPI. Decreased ACP was still an independent risk factor for increased day-28 mortality.

A large number of colorectal cancers have a genetic background in China. However, due to insufficient awareness, the diagnostic rate remains low and merely 5-6% of colorectal cancer patients are diagnosed with hereditary colorectal cancer. Familial adenomatous polyposis (FAP) is an autosomal dominant genetic disease caused by mutations in the adenomatous polyposis coli (APC) gene. Different mutation sites in APC are associated with the severity of FAP, risks of carcinogenesis, and extraintestinal manifestations. We used next-generation sequencing (NGS) and capture techniques to screen suspected mutation points in the proband in this pedigree. Using modified Sanger sequencing, we identified members of the family who were carriers of this variant and whether this segregated well with disease occurrence. FAP family members had multiple adenomatous polyps in their gastrointestinal tracts, some of which developed into cancer with age. Two subjects presented a rare common bile duct polyp phenotype. No extraintestinal manifestations were observed. A heterozygous frameshift mutation in APC exon 16 (NM_000038.6) was observed in the proband and in other patients: c.3260_3261del (p.Leu1087GlnQfs∗31) (rs587782305); the variant call format was CCT/C. Due to the deletion of two bases, a stop codon appeared after 31 amino acids, and the protein was truncated prematurely, which affected the conformation of the protein. Pedigree genetic linkage analysis showed that the clinical phenotype cosegregated with the APC mutation p.L1087fs. This mutation may be the pathogenic in this FAP family and responsible for this rare common bile duct polyp.