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Previous fluid-structure interaction (FSI) studies on carotid bifurcation focused on the effect of wall compliance on the predicted hemodynamic features in normal or atherosclerotic carotid arteries. However, FSI study on patient-specific post-stent carotid model is still lacking, and to the authors knowledge no such a study has been reported so far. This study attempts to simulate the full-scale patient-specific post- stent carotid bifurcation geometry with the hope to understand the effect of wall compliance on hemodynamic quantities. The FSI model was based on patient-specific geometry consisting of three components i.e., the carotid artery wall and stent as the solid domain, and blood in the fluid domain. Full FSI simulations incorporating patient-specific boundary conditions at the inlet and outlets, and realistic homogenous incompressible carotid wall and stent were completed to evaluate the flow patterns and wall shear stress. The FSI simulation results were compared with the corresponding rigid-wall model. The quantitative difference in time-averaged wall shear stress (TAWSS) distribution between the FSI and rigid-wall models shows that FSI model predicted 8% less of the area in the low TAWSS band (

Acute kidney injury (AKI) is a common complication after cardiopulmonary bypass (CPB) for cardiac surgery, and there is no effective treatment. This study was aimed at constructing an early warning model of AKI after CPB in adults and investigating the performance of this model. Patients who underwent CPB in the Department of Cardiac Surgery, Shanghai Tenth People’s Hospital, from January 2018 to December 2019 were recruited into the present study. Blood and urine samples were collected preoperatively (0 h) and 2 h, 6 h, 12 h, 24 h, and 48 h after surgery, and the creatinine and activating transcription factor 3 (ATF3) were detected. According to the diagnostic criteria of AKI, patients were divided into the AKI group and the non-AKI group, and the risk factors for AKI after CPB were screened. The receiver operating characteristic (ROC) curve analysis was used to identify the optimal biomarkers for the establishment of early warning model of AKI after CPB. Finally, the performance of this model was further verified. A total of 83 patients were included in this study, 42 of whom developed AKI after surgery. After CPB, the serum and urine levels of creatinine and ATF3 increased to different degrees, and the increase in urine ATF3 was the most obvious in the AKI group. The area under ROC (AUC) of urine ATF3 at 12 h after surgery was 0.691 (95% CI: 0.576-0.807). When ATF3 was higher than 1216 pg/mL, the sensitivity and specificity of ATF3 in the diagnosis of AKI were 0.43 and 0.85, respectively. The height, conjugated bilirubin on the surgery day, urine ATF3 12 h after surgery, and serum creatinine 24 h after surgery were independent risk factors for postoperative AKI. Urine ATF3 and other factors were used to establish AKI warning model after CPB, which showed good fitting and accuracy. In conclusion, ATF3 is an early biomarker of post-CPB AKI. Addition of urine ATF3 to AKI risk factors can improve the accuracy of early AKI prediction.

This study aimed to examine changes in electrolytes and acid-base status in primary and secondary hypokalaemic periodic paralysis (HypoPP), which will help early differential diagnosis of HypoPP. A total of 64 HypoPP patients were enrolled and relevant data from clinical records was collected. Overall, 64 patients (mean age 28.2±7.3 years) of which 58(91%) were males, with 39, 11 and 14 patients, respectively, diagnosed as primary HypoPP, thyrotoxic HypoPP, and other secondary HypoPPs at discharge, were assessed. Those with HypoPP secondary to conditions other than hyperthyroidism were more likely to develop acid-base imbalance (p

Deep neural networks (DNNs) have been widely applied in various domains in artificial intelligence including computer vision and natural language processing. A DNN is typically trained for many epochs and then a validation dataset is used to select the DNN in an epoch (we simply call this epoch ``the last epoch") as the final model for making predictions on unseen samples, while it usually cannot achieve a perfect accuracy on unseen samples. An interesting question is ``how many test (unseen) samples that a DNN misclassifies in the last epoch were ever correctly classified by the DNN before the last epoch?". In this paper, we empirically study this question and find on several benchmark datasets that the vast majority of the misclassified samples in the last epoch were ever classified correctly before the last epoch, which means that the predictions for these samples were flipped from ``correct" to ``wrong". Motivated by this observation, we propose to restrict the behavior changes of a DNN on the correctly-classified samples so that the correct local boundaries can be maintained and the flipping error on unseen samples can be largely reduced. Extensive experiments on different benchmark datasets with different modern network architectures demonstrate that the proposed flipping error reduction (FER) approach can substantially improve the generalization, the robustness, and the transferability of DNNs without introducing any additional network parameters or inference cost, only with a negligible training overhead.

Primary liver cancer (PLC) is a major contributor to cancer-related deaths. Data on global and country-specific levels and trends of PLC are essential for understanding the effects of this disease and helping policymakers to allocate resources.To investigate the association between the burden of PLC and socioeconomic development status.Cancer mortality and incidence rates were obtained from the Global Burden of Disease (GBD) 2019, and the data were stratified by country and territory, sex, and the Socio-demographic Index (SDI) level. The association between the attributable etiology of PLC and socioeconomic development status, represented using the SDI, was described. The attributable etiology of PLC included hepatitis B, hepatitis C, alcohol use, and nonalcoholic steatohepatitis. The association between the attributable etiology of PLC and SDI was further stratified by sex and geographical location. A confidence analysis was also performed based on bootstrap draw.The age-standardized incidence rate of PLC was 6.5 [95% confidence intervals (CI): 5.9-7.2] per 100000 person-years, which decreased by -27.5% (-37.0 to -16.6) from 1990 to 2019. Several countries located in East Asia, South Asia, West Africa, and North Africa shouldered the heaviest burden of PLC in 2019. In terms of incidence rates, the first leading underlying cause of PLC identified was hepatitis B, followed by hepatitis C, alcohol use, and nonalcoholic steatohepatitis. Regarding stratification using the SDI, the incidence rate of PLC was the highest for high and middle SDI locations. Further, the leading attributable etiologies of PLC were hepatitis B for the middle and high middle SDI locations while hepatitis C and nonalcoholic steatohepatitis for the high SDI locations.The pronounced association between socioeconomic development status and PLC burden indicates socioeconomic development status affects attributable etiologies for PLC. GBD 2019 data are valuable for policymakers implementing PLC cost-effective interventions.

Objective. This study assessed the anti-arthritic effect and protection of Gedunin (GDN) on joint tissues and revealed the possible mechanism in suppressing rheumatoid arthritis (RA). Methods. LPS-induced macrophages and TNF-α-stimulated synovial fibroblasts (MH7A) or IL-1β-stimulated primary rheumatoid arthritis synovial fibroblasts (RASFs) were used to evaluate the antiinflammatory effect of GDN. In addition, CIA-induced arthritis was employed here to evaluate the anti-arthritic effect. MTT and BRDU assays were utilized to evaluate the cell viability and proliferation, Q-PCR was conducted to detect the mRNA expression of cytokines, FACS was adopted to monitor ROS production, while western blotting (WB) and siRNA interference were applied in confirming the anti-arthritic effects of GDN via the Nrf2 signaling. Results. In vitro, cell viability was inhibited in macrophages and MH7A cells, but not in RASFs; but the proliferation of RASFs was significantly suppressed in time- and dose-dependent manners. GDN suppressed cytokine levels in LPS-stimulated macrophages and TNF-α-stimulated MH7A cells or RASFs. GDN suppressed ROS expression. Furthermore, GDN treatment notably dose-dependently decreased the mRNA and protein expression of iNOS in LPS-induced macrophages. sip62 interference results showed that GDN cause the less expression of HO-1 and Keap1 and also fail to inhibit cytokines after sip62 interference. In vivo, GDN effectively inhibited paw swelling, arthritis score, and arthritis incidence and cytokines. Conclusions. Our study suggested that GDN exhibited strong antagonistic effect on arthritis both in vitro and in vivo via activation of Nrf2 signaling. Our work will provide a promising therapeutic strategy for RA.

Huang, Z-H, Ma, CZ-H, Wang, L-K, Wang, X-Y, Fu, S-N, and Zheng, Y-P. Real-time visual biofeedback via wearable ultrasound imaging can enhance the muscle contraction training outcome of young adults. J Strength Cond Res 36(4): 941-947, 2022-Real-time ultrasound imaging (RUSI) can serve as visual biofeedback to train deep muscle contraction in clinical rehabilitative settings. However, its effectiveness in resistance training in sports/fitness fields remains unexplored. This article introduced a newly developed wearable RUSI system that provided visual biofeedback of muscle thickening and movement and reported its effectiveness in improving the training outcomes of muscle thickness change (%) during dynamic contraction. Twenty-five healthy young men participated and performed pec fly exercise both with and without RUSI biofeedback. Statistical analysis was conducted to examine the reliability of the measurements and the immediate effects of (a) RUSI biofeedback of muscle contraction and (b) training intensity (50 vs. 80% of 1-repetition maximum [1RM]) on the pectoralis major (PMaj) thickness change measured by ultrasound images. In addition to significantly high inter-contraction reliability (ICC3,10.97), we observed significantly increased PMaj thickness change for both training intensities upon receiving biofeedback in subjects, compared with without biofeedback (p0.001). We also observed significantly larger PMaj thickness change at 80% of 1RM compared with 50% of 1RM (p = 0.023). The provision of visual biofeedback using RUSI significantly enlarged the magnitude of PMaj thickness change during pec fly exercises, potentially indicating that RUSI biofeedback could improve the ability of targeted muscle contraction of PMaj in healthy young adults. To our knowledge, this study has pioneered in applying RUSI as a form of biofeedback during weight training and observed positive effectiveness. Future iterations of the technique will benefit more subject groups, such as athletes and patients with neuromuscular disorders.

Background Previous studies have shown that monotherapy with apatinib, an oral tyrosine kinase inhibitor, has promising efficacy for treating recurrent or metastatic (RM) nasopharyngeal carcinoma (NPC) patients. In this study, we aimed to assess the efficacy and safety of apatinib combined with capecitabine as a second-line therapy or beyond for treating RM-NPC patients who failed the first-line platinum-based chemotherapy. Methods In this single-arm, phase II study, we enrolled RM-NPC patients who had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). The sample size was determined using Simon’s two-stage design. All patients were administered with apatinib 500 mg once daily and capecitabine 1000 mg/m2 twice per day on days 1–14 of each 21-day cycle. The primary endpoint was the objective response rate (ORR), and the secondary endpoints comprised disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results We enrolled 64 patients from September 2018 to August 2020. The ORR and DCR were 39.1% (95% CI, 27.1–52.1) and 85.9% (95% CI, 75.0–93.4), respectively. The median DoR was 14.4 months (95% CI, 7.8–21.0). As of April 20, 2021, the median follow-up duration was 12.0 months. The median PFS was 7.5 months (95% CI, 5.0–10.0) and the median OS was 15.7 months (95% CI, 11.3–20.1). The most common toxicities of any grade were anemia (75.0%), hand-foot syndrome (65.6%), and proteinuria (64.0%). Grade 3–4 toxicities were observed in 36 (56.3%) patients, with hypertension (14.1%), mucositis (12.4%), and fatigue (10.9%) most commonly observed. Conclusions Apatinib plus capecitabine shows promising efficacy as a second-line treatment option in pretreated platinum-refractory RM-NPC patients. Dose selection of this combination needs further investigation considering the toxicity. Trial registration Chi-CTR1800017229.

Derivatives of Scylla paramamosain heat-stable allergens TM and MLC could alleviate food allergy symptoms in mice, also ability to induce blocking IgG antibodies, which offer a promising new strategy in immunotherapy for crab-allergic subjects.

3-hydroxybutyrate (3OHB) has been proved to act as a neuroprotective molecule in multiple neurodegenerative diseases. Here, we employed a quantitative proteomics approach to assess the changes of the global protein expression pattern of neural cells upon 3OHB administration. In combination with a disease-related, protein-protein interaction network we pinpointed a hub marker, histone lysine 27 trimethylation, which is one of the key epigenetic markers in multiple neurodegenerative diseases. Integrative analysis of transcriptomic and epigenomic datasets highlighted the involvement of bivalent transcription factors in 3OHB-mediated disease protection and its alteration of neuronal development processes. Transcriptomic profiling revealed that 3OHB impaired the fate decision process of neural precursor cells by repressing differentiation and promoting proliferation. Our study provides a new mechanism of 3OHB’s neuroprotective effect, in which chromatin bivalency is sensitive to 3OHB alteration and drives its neuroprotective function both in neurodegenerative diseases and in neural development processes.

Sex pheromone-binding proteins (PBPs) play an important role in sex pheromone recognition in Lepidoptera. However, the mechanisms of chemical communication mediating the response to sex pheromones remain unclear in the diurnal moths of the superfamily Zygaenoidea. In this study, Phauda flammans (Walker) (Lepidoptera: Zygaenoidea: Phaudidae) was used as a model insect to explore the molecular mechanism of sex pheromone perception in the superfamily Zygaenoidea. Two novel pheromone-binding proteins (PflaPBP1 and PflaPBP2) from P. flammans were identified. The two pheromone-binding proteins were predominantly expressed in the antennae of P. flammans male and female moths, in which PflaPBP1 had stronger binding affinity to the female sex pheromones Z-9-hexadecenal and (Z, Z, Z)-9, 12, 15-octadecatrienal, PflaPBP2 had stronger binding affinity only for (Z, Z, Z)-9, 12, 15-octadecatrienal, and no apparent binding affinity to Z-9-hexadecenal. The molecular docking results indicated that Ile 170 and Leu 169 are predicted to be important in the binding of the sex pheromone to PflaPBP1 and PflaPBP2. We concluded that PflaPBP1 and PflaPBP2 may be responsible for the recognition of two sex pheromone components and may function differently in female and male P. flammans. These results provide a foundation for the development of pest control by exploring sex pheromone blocking agents and the application of sex pheromones and their analogs for insect pests in the superfamily Zygaenoidea.

BACKGROUND Tracheobronchial tuberculosis (TBTB) is a common subtype of pulmonary tuberculosis. Concomitant diseases often obscure the diagnosis of senile TBTB. AIM To characterize senile patients with TBTB and to identify the potential causes of misdiagnosis. METHODS One hundred twenty patients with senile TBTB who were admitted to the Anhui Chest hospital between May 2017 and May 2019 were retrospectively analyzed. Patients were classified as diagnosed group (n = 58) and misdiagnosed group (n = 62). Clinical manifestations, laboratory results, radiographic data, and endoscopic findings were compared between the two groups. RESULTS Patients in the misdiagnosed group were most commonly diagnosed as pulmonary tuberculosis (non-TBTB, 29/62, 46.8%), general pneumonia (9/62, 14.5%), chronic obstructive pulmonary disease (8/62, 12.9%), and tracheobronchial carcinoma (7/62, 11.3%). The time elapsed between disease onset and confirmation of diagnosis was significantly longer in the misdiagnosed group [median (first quartile, third quartile): 6.32 (4.94, 16.02) mo vs 3.73 (2.37, 8.52) mo]. The misdiagnosed group had lower proportion of patients who underwent bronchoscopy [33.87% (21/62) vs 87.93% (51/58)], chest computed tomography (CT) scan [69.35% (43/62) vs 98.28% (57/58)], and those who showed CT signs of tuberculosis [27.91% (12/62) vs 50% (29/58)] as compared to that in the diagnosed group (P < 0.05). There were no significant between-group differences with respect to age, gender, occupation, clinical manifestations, or prevalence of comorbid chronic diseases (P > 0.05). CONCLUSION Insufficient or inaccurate radiographic or bronchoscopic assessment was the predominant cause of delayed diagnosis of TBTB. Increased implementation and better interpretation of CT scan and early implementation of bronchoscopy can help reduce misdiagnosis of senile TBTB.

BACKGROUND Extramedullary plasmacytoma (EMP), a variant form of myeloma, is a rare solid plasma cell tumor that originates from the bone marrow hematopoietic tissue and accounts for about 3% of all plasma cell tumors. EMP can affect various tissues and organs, about 90% of which is found in the head and neck. However, EMP in the reproductive organs is rare, and is difficult to be distinguished from other primary or metastatic genital tumors according to clinical symptoms and imaging findings. CASE SUMMARY Herein, we report a case with coexistence of EMP and squamous cell carcinoma in the cervix. The first histopathological report of neoplasms on the surface of the cervix and vagina showed an EMP. Both ultrasound and pelvic enhanced magnetic resonance imaging (MRI) indicated that there was a tumor in the cervix. Thus, another cervical biopsy and pathological examination were performed, which indicated EMP combined with squamous cell carcinoma. Then, the patient underwent extensive total hysterectomy (type C1) + systemic lymph node dissection and received 25 external pelvic irradiations with a dose of 50 Gy following surgery. During 2-year follow-up, no recurrence was reported. CONCLUSION In conclusion, EMP involving the reproductive system is relatively rare. In this case, MRI, B-ultrasound, and cervical canal scraping were used to further determine the diagnosis of EMP combined with squamous cell carcinoma. The patient had improved prognosis after appropriate treatments.

Small cell lung cancer (SCLC) is one of the most malignant types of lung cancer. Cancer stem cell (CSC) and tumor immune evasion are critical for the development of SCLC. We previously reported that NDR1 enhances breast CSC properties. NDR1 might also have a role in the regulation of immune responses. In the current study, we explore the function of NDR1 in the control of CSC properties and evasion of phagocytosis in SCLC. We find that NDR1 enhances the enrichment of the ALDEFLUOR

The cytochrome P450s (CYP450s) include key oxidative enzymes involved in the metabolism of various carcinogens and anticancer drugs. Bioinformatic studies have demonstrated the association of CYP3A43 with liver cancer and ovarian cancer. However, the biological function of CYP3A43 in tumor progression remains unclear. To further reveal the role of CYP3A43 in tumor progression, we first analyzed the data from the UALCAN database and found that CYP3A43 was negatively correlated to the cancer staging and lymph node metastasis of lung adenocarcinoma (LUAD). We established stable CYP3A43-knockdown LUAD H1299 cell line and found that its knockdown enhanced cell proliferation, colony formation, and migration in vitro, and promoted the growth of tumor xenograft in vivo. Interestingly, when CYP3A43 was ectopically-expressed in the LUAD cell lines, decreased cell proliferation and ERK1/2 phosphorylation level were observed. Lastly, we also identified CYP3A43 co-expressed genes in LUAD from LinkedOmics database followed by GO and KEGG analyses. In conclusion, our results indicate the unprecedented role of CYP3A43 in the suppression of LUAD and provide new possibilities for targeted therapy of this life-threatening disease.

Risk-stratification of acute myeloid leukemia (AML) based on (cyto)genetic aberrations, including hotspot mutations, deletions and point mutations have evolved substantially in recent years. With the development of next-generation sequence technology, more and more novel mutations in the AML were identified. Thus, to unravel roles and mechanism of novel mutations would improve prognostic and predictive abilities. In this study, two novel germline JAK2 His608Tyr (H608Y) and His608Asn (H608N) mutations were identified and the molecular basis of these mutations in the leukemiagenesis of AML was elucidated. Our results indicated that JAK2 H608Y and H608N mutations disrupted the hydrogen bond between Q656 and H608 which reduced the JH2 domain's activity and abolished interactions between JH1 and JH2 domains, forced JAK2 into the active conformation, facilitated the entrance of substrates and thus caused JAK2 hyperactivation. Further studies suggested that JAK2 H608Y and H608N mutations enhanced the cell proliferation and inhibited the differentiation of Ba/F3 and MV4-11 cells via activating the JAK2-STAT5 signaling pathway. Moreover, rescue experiments demonstrated that mutations repaired the hydrogen bond between Q656 and H608 displayed opposite results. Thus, this study revealed the molecular basis of JAK2 H608Y and H608N mutations in the pathology of AML.

ATG4D, a member of autophagy-related protein 4 (ATG4) family, plays an interplay role between autophagy and apoptosis in cancers. However, the role of ATG4D in hepatocellular carcinoma (HCC) has not been defined. Herein, this study aimed to investigate the role and the underlying mechanism of ATG4D in regulating HCC cell apoptosis. ATG4D was silenced in MHCC-97L HCC cells, and then cell proliferation and apoptosis were examined. ATG4D expression was significantly upregulated in HCC tissues when compared with paired non-tumor tissues. In vitro assays revealed that silencing of ATG4D significantly suppressed cell proliferation, promoted cell apoptosis, and enhanced sensitivity to cisplatin of MHCC-97L cells. Furthermore, silencing of ATG4D decreased the phosphorylation of Akt and increased the protein level of caspase-3. Taken together, ATG4D may play an oncogenic role in HCC progression. These findings suggest that ATG4D may serve as a therapeutic target for HCC therapy.

Objective Circular RNAs (circRNAs) involve in the development and progression of tumour. The mechanism of circRNAs in oral squamous cell carcinoma (OSCC) has remained unclear. This study aimed to investigate the role of circular Yes-associated protein (circYap) in OSCC. Methods Quantification reverse transcription-polymerase chain reaction (qRT-PCR) was applied to measure circYap expression in patients with OSCC tissues and cells. Flow cytometry was performed to evaluate cell cycle. circYap interaction with CDK4 was detected by RNA immunoprecipitation (RIP) and RNA pull-down. The interaction of Cyclin D1 and CDK4 was determined using co-immunoprecipitation (co-IP). Results We showed that circYap expression was downregulated in OSCC tissues. Using small interfering circular (Si-circYap) and overexpression plasmid, we found that circYap overexpression inhibited proliferation and arrested cell cycle in OSCC cells, while, circYap knockdown yielded the opposite result. Cyclin D1/CDK4 complexes and nuclear translocation is essential for cell cycle progression. We found that CDK4 interacted with circYap was increased when circYap overexpression, meanwhile, Cyclin D1/CDK4 complexes and of nuclear distribution were decreased. Conclusions Our findings suggest that circYap impedes progression of OSCC. Overexpression of circYap suppresses proliferation and cell cycle through binding to CDK4 to block formation and nuclear translocation of Cyclin D1/CDK4 complexes. Thus, circYap may serves as a valuable therapeutic target for OSCC.

Background Gastrointestinal xanthomas are asymptomatic and infrequent non-neoplastic lesions that commonly occur in the stomach with Helicobacter pylori-associated gastritis and rarely in the esophagus. To date, there have been no reports of esophageal xanthoma combined with esophageal cancer. Herein, we present the first case in the literature of a diffuse xanthoma complicated with early esophageal cancer. Moreover, this combination makes the endoscopic diagnosis difficult if it is not in mind. Case summary A 68-year-old man visited our department with a 2-mo history of epigastric discomfort. He underwent surgery for gastric cancer 6 years ago. Esophagogastroduodenoscopy showed a semi-circumferential irregular yellowish-colored and granular lesion in the esophagus (30-35 cm from the incisors). Using magnifying endoscopy with narrow band imaging, aggregated minute and yellowish-colored spots with tortuous microvessels on the surface were observed, and background coloration was clearly seen in the lesion. As endoscopic biopsy suggested a histologically high-grade dysplasia; the lesion was completely resected en bloc by endoscopic submucosal dissection (ESD). The resected specimen was confirmed to be a squamous cell carcinoma in situ with extensive foamy cells in the superficial mucosal layer. Immunohistochemically, the observed foamy cells were strongly positive for CD68, which is characteristic of xanthoma. The clinical course was favorable, and no recurrence was observed 2 years and 7 mo after ESD. Conclusion Diffuse xanthoma concurrent with early esophageal cancer is extremely rare. The characteristic endoscopic features may assist endoscopists in diagnosing similar lesions.

Despite the empirical success in various domains, it has been revealed that deep neural networks are vulnerable to maliciously perturbed input data that much degrade their performance. This is known as adversarial attacks. To counter adversarial attacks, adversarial training formulated as a form of robust optimization has been demonstrated to be effective. However, conducting adversarial training brings much computational overhead compared with standard training. In order to reduce the computational cost, we propose an annealing mechanism, Amata, to reduce the overhead associated with adversarial training. The proposed Amata is provably convergent, well-motivated from the lens of optimal control theory and can be combined with existing acceleration methods to further enhance performance. It is demonstrated that on standard datasets, Amata can achieve similar or better robustness with around 1/3 to 1/2 the computational time compared with traditional methods. In addition, Amata can be incorporated into other adversarial training acceleration algorithms (e.g. YOPO, Free, Fast, and ATTA), which leads to further reduction in computational time on large-scale problems.

Furmonertinib was designed for the treatment of non-small cell lung cancer (NSCLC) patients with EGFR T790M mutation. In this study, we investigated the metabolic disposition and mass balance in humans and tissue distribution in rats. After a single oral administration of 97.9 μCi/81.5 mg [(14)C]-furmonertinib mesylate to six healthy male volunteers, the absorption process of furmonertinib was fast with a t(max) of total plasma radioactivity at 0.75 h. Afterward, furmonertinib was extensively metabolized, with the parent drug and active metabolite AST5902 accounting for 1.68% and 0.97% of total radioactivity in plasma. The terminal t(1/2) of total radioactivity in plasma was as long as 333 h, suggesting that the covalent binding of drug-related substances to plasma proteins was irreversible to a great extent. The most abundant metabolites identified in feces were desmethyl metabolite (AST5902), cysteine conjugate (M19), and parent drug (M0), which accounted for 6.28%, 5.52%, and 1.38% of the dose, respectively. After intragastric administration of 124 μCi/9.93 mg/kg [(14)C]-furmonertinib to rats, drug-related substances were widely and rapidly distributed in tissues within 4 h. The concentration of total radioactivity in the lung was 100-fold higher than that in rat plasma, which could be beneficial to the treatment of lung cancer. Mass balance in humans was achieved with 77.8% of the administered dose recovered in excretions within 35 days after administration, including 6.63% and 71.2% in urine and feces, respectively. In conclusion, [(14)C]-furmonertinib is completely absorbed and rapidly distributed into lung tissue, extensively metabolized in humans, presented mostly as covalent conjugates in plasma, and slowly eliminated mostly via fecal route.

Adenomyosis is a diffuse or localized disease. Our previous study has indicated that tanshinone IIA (TSIIA) inhibits the proliferation, migration, and induces apoptosis of ectopic endometrial stromal cells (EESCs) of adenomyosis. However, the complex molecular mechanism of TSIIA in adenomyosis remains unclear. The objective of this study was to explore the complex molecular mechanism of TSIIA on EESCs. In our present study, we used the proteomics approach iTRAQ (isobaric tags for relative and absolute quantitation) combined with LC–MS/MS (liquid chromatography–mass spectrometry) to investigate changes in the protein profile of EESCs treated with TSIIA. Differential proteins were analyzed by employing bioinformatics tools and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. In TSIIA treated EESCs, the protein expression levels of TNFRSF10D, PLEKHM1, FECH, and TPM1A were detected by western blotting. Quantitative results revealed 267 significantly differential proteins in TSIIA pretreated EESCs. Gene Ontology (GO) analysis presented an overview of dysregulated proteins in the biological process (BP), cell component (CC), and molecular function (MF) categories. Interestingly, we observed that differential proteins in the extracellular matrix (ECM)-receptor interaction pathway and estrogen signaling pathway were all involved in the focal adhesion pathway, which plays essential roles in the TSIIA-mediated inhibition of EESC proliferation and migration. Furthermore, some significantly differential proteins, which may be potential targets for the treatment of adenomyosis in the future, were validated by western blotting. Our study provides a useful method to detect the detailed mechanism underlying the efficacy of TSIIA on EESCs.

Objectives The value of using PET/CT for staging of stage I–II NPC remains unclear. Hence, we aimed to investigate the survival benefit of PET/CT for staging of early-stage NPC before radical therapy. Methods A total of 1003 patients with pathologically confirmed NPC of stages I–II were consecutively enrolled. Among them, 218 patients underwent both PET/CT and conventional workup ([CWU], head-and-neck MRI, chest radiograph, liver ultrasound, bone scintigraphy) before treatment. The remaining 785 patients only underwent CWU. The standard of truth (SOT) for lymph node metastasis was defined by the change of size according to follow-up MRI. The diagnostic efficacies were compared in 218 patients who underwent both PET/CT and CWU. After covariate adjustment using propensity scoring, a cohort of 872 patients (218 with and 654 without pre-treatment PET/CT) was included. The primary outcome was overall survival based on intention to treat. Results Retropharyngeal lymph nodes were metastatic based on follow-up MRI in 79 cases. PET/CT was significantly less sensitive than MRI in detecting retropharyngeal lymph node lesions (72.2% [62.3–82.1] vs. 91.1% [84.8–97.4], p = 0.004). Neck lymph nodes were metastatic in 89 cases and PET/CT was more sensitive than MRI (96.6% [92.8–100.0] vs. 76.4% [67.6–85.2], p < 0.001). In the survival analyses, there was no association between pre-treatment PET/CT use and improved overall survival, progression-free survival, local relapse-free survival, regional relapse-free survival, and distant metastasis-free survival. Conclusions This study showed PET/CT is of little value for staging of stage I–II NPC patients at initial imaging. Key Points • PET/CT was more sensitive than MRI in detecting neck lymph node lesions whereas it was significantly less sensitive than MRI in detecting retropharyngeal lymph node lesions. • No association existed between pre-treatment PET/CT use and improved survival in stage I–II NPC patients.

This study aimed to establish an effective nomogram to predict primary distant metastasis (DM) in patients with nasopharyngeal carcinoma (NPC) to guide the application of PET/CT. In total, 3591 patients with pathologically confirmed NPC were consecutively enrolled. The nomogram was constructed based on 1922 patients treated between 2007 and 2014. Multivariate logistical regression was applied to identify the independent risk factors of DM. The predictive value of the nomogram was evaluated using the concordance index (C-index), calibration curve, probability density functions (PDFs), and clinical utility curve (CUC). The results were validated in 1669 patients enrolled from 2015 to 2016. Net reclassification improvement (NRI) was applied to compare performances of the nomogram with other clinical factors. The best cut-off value of the nomogram chosen for clinical application was analyzed. A total of 355 patients showed primary DM among 3591 patients, yielding an incidence rate of 9.9%. Sex, N stage, EBV DNA level, lactate dehydrogenase level, and hemoglobin level were independent predictive factors for primary DM. C-indices in the training and validation cohort were 0.796 (95% CI, 0.76–0.83) and 0.779 (95% CI, 0.74–0.81), respectively. The NRI indices demonstrated that this model had better predictive performance than plasma EBV DNA level and N stage. We advocate for a threshold probability of 3.5% for guiding the application of PET/CT depending on the clinical utility analyses. This nomogram is a useful tool to predict primary DM of NPC and guide the clinical application of PET/CT individually at the initial staging.

Despite the significant advances in creating assembled structures from polymers, engineering the assembly of polymeric materials into framework structures remains an outstanding challenge. In this work, we present a facile strategy to construct polymeric molecular frameworks through the assembly of T-shape polymer-rod-sphere amphiphiles in the bulk state. Various frameworks are yielded as a result of delicate interplays among three components of the T-shape amphiphiles. The internal structure of frameworks was revealed by combining experimental investigations and computational simulations. The frameworks display good solution-processability, thermal stability, and uniform pore-forming capability, which endow the resultant frameworks with great potential in scalable fabrications.

BACKGROUND Immunosuppression is an important factor in the incidence of infections in transplant recipient. Few studies are available on the management of immunosuppression (IS) treatment in the liver transplant (LT) recipients complicated with infection. The aim of this study is to describe our experience in the management of IS treatment during bacterial bloodstream infection (BSI) in LT recipients and assess the effect of temporary IS withdrawal on 30 d mortality of recipients presenting with severe infection. AIM To assess the effect of temporary IS withdrawal on 30 d mortality of LT recipients presenting with severe infection. METHODS A retrospective study was conducted with patients diagnosed with BSI after LT in the Department of Liver Surgery, Renji Hospital from January 1, 2016 through December 31, 2017. All recipients diagnosed with BSI after LT were included. Univariate and multivariate Cox regression analysis of risk factors for 30 d mortality was conducted in the LT recipients with Gram-negative bacterial (GNB) infection. RESULTS Seventy-four episodes of BSI were identified in 70 LT recipients, including 45 episodes of Gram-positive bacterial (GPB) infections in 42 patients and 29 episodes of GNB infections in 28 patients. Overall, IS reduction (at least 50% dose reduction or cessation of one or more immunosuppressive agent) was made in 28 (41.2%) cases, specifically, in 5 (11.9%) cases with GPB infections and 23 (82.1%) cases with GNB infections. The 180 d all-cause mortality rate was 18.5% (13/70). The mortality rate in GNB group (39.3%, 11/28) was significantly higher than that in GPB group (4.8%, 2/42) (P = 0.001). All the deaths in GNB group were attributed to worsening infection secondary to IS withdrawal, but the deaths in GPB group were all due to graft-versus-host disease. GNB group was associated with significantly higher incidence of intra-abdominal infection, IS reduction, and complete IS withdrawal than GPB group (P < 0.05). Cox regression showed that rejection (adjusted hazard ratio 7.021, P = 0.001) and complete IS withdrawal (adjusted hazard ratio 12.65, P = 0.019) were independent risk factors for 30 d mortality in patients with GNB infections after LT. CONCLUSION IS reduction is more frequently associated with GNB infection than GPB infection in LT recipients. Complete IS withdrawal should be cautious due to increased risk of mortality in LT recipients complicated with BSI. IS

Development of liver fibrosis is associated with activation of quiescent hepatic stellate cells (HSCs) into myofibroblasts (activated HSCs), which produce excessive extracellular matrix. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) exerts protective effects on hepatic inflammation and fibrosis. The current study was to explore the function of PPAR-γ on HSC activation and progression of nonalcoholic steatohepatitis (NASH). Our study found that HSCs were gradually activated during the progression of methionine-choline-deficient (MCD) diet-induced NASH, accompanied by decreased PPAR-γ expression and activated TGF-β1/Smad signaling pathway in the liver. PPAR-γ agonist was found to inhibit primary HSCs and NIH/3T3 fibroblast activation and reverted their phenotypical morphology induced by TGF-β1 in vitro. In addition to this, PPAR-γ agonist decreased expression of TGF-β1 and phosphorylation of Smad2/3 while increased expression of Smad7. In vivo, rosiglitazone, a PPAR-γ agonist, inhibited HSC activation and alleviated liver fibrosis and inflammation similarly via inhibiting the activation of TGF-β1/Smad signaling pathway. In parallel, rosiglitazone alleviated hepatic lipid accumulation and peroxidation, beneficial to reverse of NASH. From these findings, it can be concluded that the gradual activation of HSCs is crucial to the progression of NASH and modulating PPAR-γ expression can affect HSC activation via TGF-β1/Smad signaling pathway and thereby influence hepatic fibrogenesis.

A novel, Gram-stain-positive, aerobic, non-spore-forming, non-motile and irregular rod-shaped bacterium designated Q22T was isolated from the rhizosphere soil of mangrove plant, Kandelia candel collected in Zhangzhou, Fujian province, China. Strain Q22T was able to grow at 10–40 °C (optimum 30 °C), pH 5.5–9.0 (optimum 7.0–8.0) and with 0–5.0% (w/v) NaCl (optimum 1.0 %). The genomic DNA G+C content was 71.9%. The average nucleotide identity, and in silico DNA–DNA hybridization values between strain Q22T and the reference strains were 79.7–88.9% and 22.6–37.4%, respectively. The predominant isoprenoid quinone was MK-12 and the major fatty acids were anteiso-C15:0, iso-C16:0 and anteiso-C17:0. The major polar lipids of strain Q22T were diphosphatidylglycerol, phosphatidylglycerol, one glycolipid and three unidentified lipids. The strain Q22T contained 2,4-diaminobutyric acid, alanine acid, glutamic acid and glycine in the peptidoglycans. The phylogenetic analysis and genotypic features, along with the phenotypic and chemotaxonomic characteristics, indicate that strain Q22T represents a novel species of the genus Agromyces , for which the name Agromyces kandeliae sp. nov. is proposed. The type strain is Q22T (=MCCC 1K03340T= KCTC 39961T).

Artificial intelligence (AI) is gradually changing the practice of surgery with technological advancements in imaging, navigation, and robotic intervention. In this article, we review the recent successful and influential applications of AI in surgery from preoperative planning and intraoperative guidance to its integration into surgical robots. We conclude this review by summarizing the current state, emerging trends, and major challenges in the future development of AI in surgery.

Copper based catalysts have high potential for the substituent of noble-metal based catalysts as their high selectivity and moderate activity for selective hydrogenation reaction; however, achieving further high catalytic stability is very difficult. In this work, the carbonization process of Cu-based organic frameworks was explored for the synthesis of highly-dispersed Cu supported by hierarchically porous carbon with high catalytic performance for selective hydrogenation of 1,3-butadiene. The porous hierarchy of carbon support and the dispersion of copper nanoparticles can be precisely tuned by controlling the carbonization process. The resultant catalyst carbonized at 600 °C exhibits a rather low reaction temperature at 75 °C for 100% butadiene conversion with 100% selectivity to butenes, due to its reasonable porous hierarchy and highly-dispersed copper sites. More importantly, unprecedentedly stability of the corresponding Cu catalyst was firstly observed for selective 1,3-butadiene hydrogenation, with both 100% butadiene conversion and 100% butenes selectivity over 120 h of reaction at 75 °C. This study verifies that a simply control the carbonization process of metal organic frameworks can be an effective way to obtain Cu-based catalysts with superior catalytic performance for selective hydrogenation reaction.

Lysophosphatidic acid (LPA), a ubiquitous phospholipid, plays a crucial role in the pathogenesis and pathophysiological process of neurological diseases, which constitute the pathological course after cerebral ischemia. Nevertheless, the molecular mechanisms associated with the pathogenic roles of LPA remain elusive. In this study, we evaluated the expression of the liver X receptor (LXR) and nuclear factor kappa B (NFκB) by Western blotting, quantified the levels of IL-1β, IL-6, TNF-α, and LPA by ELISA, and evaluated apoptosis and infarct by TUNEL (terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling) and TTC (triphenyltetrazolium chloride) staining respectively in Sprague-Dawley (SD) rats after middle cerebral artery occlusion (MCAO). The levels of LPA, an extracellular signaling molecule, increased after ischemia and caused neurological injury effect, decreased the expression level of LXR, and increased the expression level of inflammatory factors (IL-1β, IL-6, and TNF-α) via the NFκB signaling pathway. This elevated LPA-induced pathological process is one of the pathological reactions associated with ischemic brain injury. We present a direct or indirect connection between LPA and LXR in the pathophysiological process. In conclusion, we speculate that the inhibition of LPA generation and administration of LXR agonist may be explored as potential cerebral infarction treatment strategies.

Alflutinib (AST2818) is a third-generation epidermal growth factor receptor (EGFR) inhibitor that inhibits both EGFR-sensitive mutations and T790M mutations. Previous study has shown that after multiple dosages, alflutinib exhibits nonlinear pharmacokinetics and displays a time- and dose-dependent increase in the apparent clearance, probably due to its self-induction of cytochrome P450 (CYP) enzyme. In this study, we investigated the CYP isozymes involved in the metabolism of alflutinib and evaluated the enzyme inhibition and induction potential of alflutinib and its metabolites. The data showed that alflutinib in human liver microsomes (HLMs) was metabolized mainly by CYP3A4, which could catalyze the formation of AST5902. Alflutinib did not inhibit CYP isozymes in HLMs but could induce CYP3A4 in human hepatocytes. Rifampin is a known strong CYP3A4 inducer and is recommended by the FDA as a positive control in the CYP3A4 induction assay. We found that the induction potential of alflutinib was comparable to that of rifampin. The Emax of CYP3A4 induction by alflutinib in three lots of human hepatocytes were 9.24-, 11.2-, and 10.4-fold, while the fold-induction of rifampin (10 μM) were 7.22-, 19.4- and 9.46-fold, respectively. The EC50 of alflutinib-induced CYP3A4 mRNA expression was 0.25 μM, which was similar to that of rifampin. In addition, AST5902 exhibited much weak CYP3A4 induction potential compared to alflutinib. Given the plasma exposure of alflutinib and AST5902, both are likely to affect the pharmacokinetics of CYP3A4 substrates. Considering that alflutinib is a CYP3A4 substrate and a potent CYP3A4 inducer, drug–drug interactions are expected during alflutinib treatment.

Background The performance of lung cancer screening with low-dose computed tomography (CT) (LDCT) in China is uncertain. This study aimed to evaluate the performance of LDCT lung cancer screening in the Chinese setting. Methods In 2014, a screening cohort of lung cancer with LDCT was established in Gejiu, Yunnan Province, a screening center of the Lung Cancer Screening Program in Rural China (LungSPRC). Participants received a baseline screening and four rounds of annual screening with LDCT in two local hospitals until June 2019. We analyzed the rates of participation, detection, early detection, and the clinical characteristics of lung cancer. Results A total of 2006 participants had complete baseline screening results with a compliance rate of 98.4%. Of these, 1411 were high-risk and 558 were nonhigh-risk participants. During this period, 40 lung cancer cases were confirmed, of these, 35 were screen-detected, four were post-screening and one was an interval case. The positive rate of baseline and annual screening was 9.7% and 9.0%, while the lung cancer detection rate was 0.4% and 0.6%, respectively. The proportion of early lung cancer increased from 37.5% in T0 to 75.0% in T4. Adenocarcinoma was the most common histological subtype. Lung cancer incidence according to the criteria of LungSPRC and National Lung Cancer Screening Trial (NLST) was 513.31 and 877.41 per 100 000 person-years, respectively. Conclusions The program of lung cancer screening with LDCT showed a successful performance in Gejiu, Yunnan. However, further studies are warranted to refine a high-risk population who will benefit most from LDCT screening and reduce the high false positive results. Key points This study reports the results of lung cancer screening with LDCT in Gejiu, Yunnan, a high-risk area of lung cancer, and it demonstrates that lung cancer screening with LDCT is effective in detecting early-stage lung cancer. Our program provides an opportunity to explore the performance of LDCT lung cancer screening in the Chinese context.

Costunolide being a sesquiterpene lactone, is known to have anticancer properties. The present study investigated the anticancer effects of costunolide against the H1299 human non‑small‑cell lung cancer (NSCLC) cell line. Inhibition of cell viability by costunolide was assessed via a MTT assay. Furthermore, the apoptotic rate was detected using Annexin V/propidium iodide labeling. A colony forming cell assay was performed to investigate the antiproliferative effects of costunolide. Wound healing and Transwell assays were performed to determine the inhibitory effects of costunolide on migration and invasion, respectively. Western blot analysis was undertaken to determine protein expression, and reverse transcription‑quantitative PCR was performed to assess mRNA expression levels. The results demonstrated that costunolide inhibited the viability of H1299 cells, with a half maximal inhibitory concentration value of 23.93±1.67 µM and induced cellular apoptosis in a dose‑dependent manner. Furthermore, the colony formation, migrative and invasive abilities of the H1299 cells were inhibited in a dose‑ or time‑dependent manner. The protein expression levels of E‑cadherin increased and those of N‑cadherin decreased following treatment with costunolide, which suggested that costunolide inhibited epithelial‑to‑mesenchymal transition. The mRNA levels of B‑Raf, E‑cadherin, N‑cadherin, integrins α2 and β1, as well as matrix metalloproteinases 2 were also found to be regulated costunolide. These findings indicate the potential of costunolide in the treatment of NSCLC.

Hematologic and neurological expression 1 (HN1) has been reported to involved in certain cancers, but its role in hepatocellular carcinoma (HCC) is largely unknown. The contribution of HN1 to HCC progression was investigated in the present study. We found that HN1 was significantly up‐regulated in HCC tissues, compared with normal tissues, by analyzing the Oncomine and Human Protein Atlas database; and found that high expression of HN1 was markedly associated with worse overall survival, relapse‐free survival, progression‐ free survival and disease‐specific survival in HCC patients via exploring the Kaplan‐Meier plotter database. Functional assays revealed that HN1 knockdown by siRNA induced G1 cell cycle arrest, and inhibited the growth and migration of HCC cells; accordingly, HN1 over‐expression promoted HCC cells proliferation and migration. Further studies indicated that HN1 knockdown reduced the expression of cyclin D1 and CDK4, while upregulated the cell cycle inhibitor p21WAF1/Cip1. Moreover, HN1 knockdown decreased c‐Met (receptor tyrosine kinase of hepatocyte growth factor) expression, and suppressed ERK activation, which is a common downstream signaling pathway triggered by c‐Met; consistently, HN1 over‐expression reversed these effects. Meanwhile, down‐regulation of c‐Met partly eliminated the effect of HN1 over‐expression in HCC cells. Thus, the present findings suggested that HN1 promotes the progression of HCC to some extent by up‐regulating the expression of c‐Met, and may act as a potential biomarker and therapeutic target for the treatment of HCC.

BACKGROUND Mesenteric phlebosclerosis (MP) is a rare disease of the colon. The clinical manifestations of this disease are nonspecific and it may easily be misdiagnosed. We report a case of MP with amyloidosis in the colonic vessel walls in a patient with hypertension who had been consuming Chinese medicinal liquor for 10 years. We also review the relevant literature and summarize the characteristics of MP in patients in mainland China. CASE SUMMARY A 64-year-old man was referred to our department from his primary hospital because of abdominal pain, diarrhea, and fever for almost 10 d. Computed tomography showed colon wall thickening, with threadlike calcifications in the mesenteric vein in the transverse colon. Colonoscopy revealed purple-blue mucosa with multiple ulcers in the ascending and transverse colon. Biopsy showed thickening and calcification of the vein walls, perivascular and mucosal collagen degeneration, and amyloidosis. The patient had been consuming Chinese medicinal liquor, mainly that made from gardenia fruit, for 10 years. Based on these results, a diagnosis of MP with amyloidosis was made. After conservative treatment, the patient’s discomfort subsided and he was followed closely. The use of Chinese herbal medicine was suspected to play a role in the pathogenesis of MP. CONCLUSION The clinical manifestations of MP are nonspecific. Recognition of its typical imaging findings, including multiple calcifications on computed tomography and purple-blue mucosal discoloration on colonoscopy, is vital.

To assess whether the use of intravenous immunoglobulin (IVIG) in late-preterm and term newborns with haemolytic disease of the newborn (HDN) is associated with an increased risk of necrotizing enterocolitis (NEC).A retrospective cohort study was conducted in a tertiary centre. Infants with HDN during early neonatal period (7 days) who were of ≥34 weeks' gestation and born between January 2019 and October 2021 were included. Propensity score, interaction as well as univariate and multiple logistic regression analyses were employed.One-thousand two-hundred and fifty-nine infants with HDN were enrolled, of whom 192 (15.3%) received IVIG. NEC was diagnosed in 29 (2.3%) patients with 5 (2.6%) in the IVIG group and 24 (2.2%) in the non-IVIG group. No significant association between IVIG administration and confirmed NEC was observed using univariate analysis (p 0.05). The possible predictors of NEC, as assessed by multivariate analysis, were caesarean delivery, haemoglobin on admission130 g/L and patent ductus arteriosus (PDA). There was no interactive effect of IVIG against NEC for prematurity, low birth weight, caesarean delivery, haemoglobin on admission130 g/L and PDA.In late-preterm and term infants with HDN, there was no evidence that the early use of IVIG led to the development of NEC.

Diabetic neuropathic pain (DNP) is a common and devastating complication in patients with diabetes. The mechanisms mediating DNP are not completely elucidated, and effective treatments are lacking. A-fiber sensory neurons have been shown to mediate the development of mechanical allodynia in neuropathic pain, yet the molecular basis underlying the contribution of A-fiber neurons is still unclear. Here, we report that the orphan G protein–coupled receptor 177 (GPR177) in A-fiber neurons drives DNP via WNT5a-mediated activation of transient receptor potential vanilloid receptor-1 (TRPV1) ion channel. GPR177 is mainly expressed in large-diameter A-fiber dorsal root ganglion (DRG) neurons and required for the development of DNP in mice. Mechanistically, we found that GPR177 mediated the secretion of WNT5a from A-fiber DRG neurons into cerebrospinal fluid (CSF), which was necessary for the maintenance of DNP. Extracellular perfusion of WNT5a induced rapid currents in both TRPV1-expressing heterologous cells and nociceptive DRG neurons. Computer simulations revealed that WNT5a has the potential to bind the residues at the extracellular S5-S6 loop of TRPV1. Using a peptide able to disrupt the predicted WNT5a/TRPV1 interaction suppressed DNP- and WNT5a-induced neuropathic pain symptoms in rodents. We confirmed GPR177/WNT5A coexpression in human DRG neurons and WNT5A secretion in CSF from patients with DNP. Thus, our results reveal a role for WNT5a as an endogenous and potent TRPV1 agonist, and the GPR177-WNT5a-TRPV1 axis as a driver of DNP pathogenesis in rodents. Our findings identified a potential analgesic target that might relieve neuropathic pain in patients with diabetes.