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BACKGROUND AND AIMS: The associations between genetic factors and waist circumference (WC) with stroke risk have been evaluated in Western studies. However, evidence of this association has rarely been reported in the Chinese population. This study aimed to evaluate the association between WC and family history of stroke (FHS) with ischemic stroke (IS) risk among Chinese adults and to further explore the potential interaction of these associations. METHODS AND RESULTS: The China Kadoorie Biobank (CKB) study recruited 35,508 participants aged 30-79 years from the Qingdao urban area during 2004-2008. A total of 33,355 participants were included in study. Cox regression analysis was used to estimate the multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the independent and interactional associations between FHS and WC and IS risk. Participants with FHS had a 29% (HR = 1.29, 95% CI: 1.12-1.50) higher IS risk than those without FHS. Participants with excessive WC (85 cm for males and 80 cm for females) had a 78% (HR = 1.78, 95% CI: 1.51-2.10) higher IS risk than those with normal WC. The combined effect of FHS and excessive WC on IS was statistically significant (HR = 2.29, 95% CI: 1.84-2.86). The present study further found statistically significant multiplicative interactions of FHS and WC with IS risk (Pinteraction < 0.001). CONCLUSION: The present study indicated that FHS and WC were significantly associated with an increased risk of IS. The association between FHS and IS was associated with excessive WC.

Lihong Li, Heyu Meng, Xue Wang, Jianjun Ruan, Xiaomin Tian, Fanbo Meng Department of Cardiology, The Third Hospital of Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Fanbo Meng, Department of Cardiology, The Third Hospital of Jilin University, Changchun, People’s Republic of China, Tel +86-15948346855, Fax + 86-431-84995228, Email mengfb@jlu.edu.cnPurpose: ZCCHC9 is a zinc finger protein with a CCHC zinc finger structure and has important roles in several cellular processes. This study was conducted on an expanded number of samples to evaluate The usefulness of ZCCHC9 gene expression in peripheral blood as a molecular marker for the prediction of AMI (acute myocardial infarction) risk.Patients and Methods: Peripheral blood samples were collected from 117 patients with stable CAD (coronary atherosclerotic disease) and 126 patients with AMI. The mRNA level of the ZCCHC9 gene was assessed by qRT-PCR, and its protein level was determined by Western blotting.Results: The AMI group exhibited reduced expression of the ZCCHC9 gene, at both transcript and protein levels, than the stable CAD group. The low expression of the ZCCHC9 gene was not related to blood glucose level (P=0.635), blood lipid level, and troponin level (P=0.715), and may cause AMI through the MAPK signaling pathway. Compared with other patients, patients with low ZCCHC9 gene expression in their peripheral blood have a 2.597-fold higher risk of AMI.Conclusion: ZCCHC9 gene expression in peripheral blood was significantly lower in patients with AMI than in stable CAD patients. Individuals with low expression of ZCCHC9 in peripheral blood have higher a probability to develop AMI than those with stable CAD. Thus, lowered ZCCHC9 gene expression can act as an independent risk factor for AMI.Keywords: genetics, molecular marker, oxidative stress, MAPK

In this paper, the main aim is to consider the Spanne-type boundedness of the multiliinear fractional integral operator $\mathcal{I}_{\alpha,m}$ and multiliinear fractional maximal operator $\mathcal{M}_{\alpha,m}$ in the generalized Morrey spaces over some stratified Lie group $\mathbb{G}$., Comment: arXiv admin note: substantial text overlap with arXiv:2206.08340

Ti Wu,1,&ast; Haipeng Zhang,2,&ast; Xiaolin Tian,3 Yang Cao,2 Dianjun Wei,4 Xiangkun Wu4 1Department of Neurology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Department of Clinical Laboratory, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; 3Department of Neurology, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; 4Department of Clinical Laboratory, Hebei Yanda Hospital, Langfang, Hebei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiangkun Wu Tel +8615613682051Email wuxiangkun_2021@163.comPurpose: To evaluate the association between neutrophil-to-lymphocyte ratio (NLR) and stroke-associated pneumonia (SAP) in patients with acute ischemic stroke (AIS) without fever and to clarify whether NLR has an advantage over high-sensitivity C-reactive protein (hs-CRP) in predicting SAP.Patients and Methods: A total of 434 patients with AIS without fever were assessed in this study. Multivariable analysis was used to evaluate the relationship between NLR and SAP, and the receiver operating characteristic (ROC) curve was used to compare the predictive value of NLR and hs-CRP.Results: Among the total patients, 18 (4.1%) developed SAP. After adjusting for confounders, NLR (adjusted odds ratio [aOR] = 1.60; 95% confidence interval [CI], 1.30– 1.96; p < 0.001) remained independently associated with an increased risk of SAP. In addition, the area under the curve (AUC) of NLR (0.862 [0.826– 0.893]) was higher than that of hs-CRP (0.738 [0.694– 0.779]).Conclusion: We found that compared with hs-CRP, NLR was significantly associated with the occurrence of SAP in patients with AIS without fever and showed a more effective predictive value for SAP.Keywords: stroke, pneumonia, neutrophil, lymphocyte, high-sensitivity C-reactive protein, inflammation

Xue Tian,1,&ast; Feiyue Yang,2,&ast; Fenghu Li,1 Li Ran,1 Jianying Chang,1 Jiehui Li,1 Wei Hong,3 Lang Shan,1 Yanjun Du,1 Lili Hu,1 Fan Mei,1 Mingyuan He,1 Yongxia Li,1 Heran Wang,1 Kai Zuo,1 Bo Zhou,4 Shuying Chen,1 Wanli Mao1 1Department of Oncology, The Affiliated Hospital of Guizhou Medical University, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China; 2Department of Gynecologic Oncology, Guizhou Provincial People’s Hospital, Guiyang, 550004, People’s Republic of China; 3Department of Radiotherapy, The Affiliated Hospital of Guizhou Medical University, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China; 4Surgical Department of Gynecological Oncology, The Affiliated Hospital of Guizhou Medical University, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fenghu Li; Li Ran Email 769654418@qq.com; ranli171@hotmail.comPurpose: To examine the clinical significance of unoperated cervical cancer patients treated with different neoadjuvant chemotherapy (NACT) schemes followed by concurrent chemotherapy and radiotherapy (CCRT).Methods: This retrospective analysis included women with locally advanced cervical cancer treated with NACT-CCRT between September 2011 and September 2014. Neoadjuvant chemotherapy included paclitaxel plus cisplatin (TP group; 62 patients) or paclitaxel plus loplatin (TL group; 58 patients), which were administered three weekly, and cisplatin or loplatin, which were administered weekly for synchronous chemotherapy. External beam radiation therapy (50.4– 56.35 Gy/28 f, 180– 215 cGy/f, 5 f/w) was followed by intracavitary brachytherapy (5 Gy per fraction, mostly 5 fractions, Ir192 based).Results: One hundred twenty women were included in the analysis. The complete/partial response rate was 99.2% after treatment. The one-year, three-year, and five-year survival rates were 99.2%, 82.5%, and 70.8%, respectively. In the TP and TL groups, the three-year and five-year survival rates were 85.5% vs 77.6% and 75.8% vs 65.5%, respectively, with no significant difference. The 5-year overall survival (OS) rates between patients with stage IIB and stage IIIB disease were not significantly different (69.2% vs 64.7%). In the TP group, grade 3 or 4 digestive reactions were more frequent than those in the TL group. Leukopenia, neutropenia, and thrombocytopenia were more common in the TL group. No significant difference was found in anemia, radiation enteritis, radiation proctitis, or radiation cystitis between the groups.Conclusion: Lobaplatin may be used as an alternative drug for patients with severe digestive system reactions or contraindications to cisplatin, but hematological toxicity must be considered, particularly in dose-intensive schemes. Neoadjuvant chemotherapy followed by concurrent chemotherapy and radiotherapy (NACT-CCRT) warrants further prospective study in cervical cancer patients with a wide range of tumor invasion (eg, mass size ≥ 5 cm or stage IIIB).Keywords: cervical cancer, neoadjuvant chemotherapy, survival benefit, side effects

BACKGROUND: Innate lymphoid cells type 2 (ILC2s) play critical homeostatic functions in peripheral tissues. ILC2s reside in perivascular niches and limit atherosclerosis development. OBJECTIVES: ILC2s also reside in the pericardium but their role in postischemic injury is unknown. METHODS: We examined the role of ILC2 in a mouse model of myocardial infarction (MI), and compared mice with or without genetic deletion of ILC2. We determined infarct size using histology and heart function using echocardiography. We assessed cardiac ILC2 using flow cytometry and RNA sequencing. Based on these data, we devised a therapeutic strategy to activate ILC2 in mice with acute MI, using exogenous interleukin (IL)-2. We also assessed the ability of low-dose IL-2 to activate ILC2 in a double-blind randomized clinical trial of patients with acute coronary syndromes (ACS). RESULTS: We found that ILC2 levels were increased in pericardial adipose tissue after experimental MI, and genetic ablation of ILC2 impeded the recovery of heart function. RNA sequencing revealed distinct transcript signatures in ILC2, and pointed to IL-2 axis as a major upstream regulator. Treatment of T-cell-deficient mice with IL-2 (to activate ILC2) significantly improved the recovery of heart function post-MI. Administration of low-dose IL-2 to patients with ACS led to activation of circulating ILC2, with significant increase in circulating IL-5, a prototypic ILC2-derived cytokine. CONCLUSIONS: ILC2s promote cardiac healing and improve the recovery of heart function after MI in mice. Activation of ILC2 using low-dose IL-2 could be a novel therapeutic strategy to promote a reparative response after MI.

Accurate assessment of anthropogenic carbon dioxide (CO2) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere in a changing climate is critical to better understand the global carbon cycle, support the development of climate policies, and project future climate change. Here we describe and synthesize data sets and methodologies to quantify the five major components of the global carbon budget and their uncertainties. Fossil CO2 emissions (EFOS) are based on energy statistics and cement production data, while emissions from land-use change (ELUC), mainly deforestation, are based on land use and land-use change data and bookkeeping models. Atmospheric CO2 concentration is measured directly, and its growth rate (GATM) is computed from the annual changes in concentration. The ocean CO2 sink (SOCEAN) is estimated with global ocean biogeochemistry models and observation-based data products. The terrestrial CO2 sink (SLAND) is estimated with dynamic global vegetation models. The resulting carbon budget imbalance (BIM), the difference between the estimated total emissions and the estimated changes in the atmosphere, ocean, and terrestrial biosphere, is a measure of imperfect data and understanding of the contemporary carbon cycle. All uncertainties are reported as ±1σ. For the year 2021, EFOS increased by 5.1 % relative to 2020, with fossil emissions at 10.1 ± 0.5 GtC yr−1 (9.9 ± 0.5 GtC yr−1 when the cement carbonation sink is included), and ELUC was 1.1 ± 0.7 GtC yr−1, for a total anthropogenic CO2 emission (including the cement carbonation sink) of 10.9 ± 0.8 GtC yr−1 (40.0 ± 2.9 GtCO2). Also, for 2021, GATM was 5.2 ± 0.2 GtC yr−1 (2.5 ± 0.1 ppm yr−1), SOCEAN was 2.9 ± 0.4 GtC yr−1, and SLAND was 3.5 ± 0.9 GtC yr−1, with a BIM of −0.6 GtC yr−1 (i.e. the total estimated sources were too low or sinks were too high). The global atmospheric CO2 concentration averaged over 2021 reached 414.71 ± 0.1 ppm. Preliminary data for 2022 suggest an increase in EFOS relative to 2021 of +1.0 % (0.1 % to 1.9 %) globally and atmospheric CO2 concentration reaching 417.2 ppm, more than 50 % above pre-industrial levels (around 278 ppm). Overall, the mean and trend in the components of the global carbon budget are consistently estimated over the period 1959–2021, but discrepancies of up to 1 GtC yr−1 persist for the representation of annual to semi-decadal variability in CO2 fluxes. Comparison of estimates from multiple approaches and observations shows (1) a persistent large uncertainty in the estimate of land-use change emissions, (2) a low agreement between the different methods on the magnitude of the land CO2 flux in the northern extratropics, and (3) a discrepancy between the different methods on the strength of the ocean sink over the last decade. This living data update documents changes in the methods and data sets used in this new global carbon budget and the progress in understanding of the global carbon cycle compared with previous publications of this data set. The data presented in this work are available at https://doi.org/10.18160/GCP-2022 (Friedlingstein et al., 2022b).

Zhenwen Chen,1,2,&ast; Ning Zhao,1,&ast; Qi Wang,1 Yanfeng Xi,3 Xiaoai Tian,2 Huiwen Wu,1 Yirong Xu1,2 1Department of Pathology, Fenyang College of Shanxi Medical University, Fenyang, 032200, Shanxi Province, People’s Republic of China; 2Department of Pathology, Shanxi Fenyang Hospital, Fenyang, Shanxi Province, People’s Republic of China; 3Department of Pathology, Shanxi Cancer Hospital (Shanxi Institute of Oncology), Taiyuan, Shanxi Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huiwen Wu; Yirong XuDepartment of Pathology, Fenyang College of Shanxi Medical University, No. 16 Xueyuan Road, Fenyang, 032200, Shanxi Province, People’s Republic of ChinaTel +86 151 3588 2981Email yirongxu@163.comPurpose: To investigate PD-L1 protein expression and gene amplification in lung squamous cell carcinoma (LUSC) and analyse their correlation with the clinicopathological characteristics and prognosis of LUSC patients.Patients and Methods: Tissue samples from 164 LUSC patients were collected. PD-L1 protein was detected by immunochemistry (IHC), and PD-L1 gene amplification was investigated by fluorescence in situ hybridization in LUSC patients.Results: The positive expression rate of PD-L1 in LUSC was 47.6% (78/164), and the amplification rate of PD-L1 was 6.7% (11/164); both rates were higher than those of paratumor tissue. Both PD-L1 positive expression and gene amplification were correlated with clinical stage and lymph node metastasis (P< 0.05). PD-L1 protein expression, PD-L1 gene amplification, late stage, lymph node metastasis and distant metastasis were significantly correlated with the prognosis of patients. Among these factors, late stage, lymph node metastasis, PD-L1 protein expression and PD-L1 gene amplification were independent prognostic factors for LUSC.Conclusion: Positive PD-L1 protein expression and gene amplification are involved in the malignant progression and metastasis of LUSC. Both PD-L1 protein expression and gene amplification are associated with poor prognosis.Keywords: PD-L1 protein expression, PD-L1 gene amplification, lung squamous cell carcinoma, prognosis

Xiaoning Cen,1,&ast; Yunmei Huang,2,&ast; Zhuangnian Lu,3,&ast; Wenjun Shao,4 Chenyi Zhuo,1 Chongchan Bao,5 Shi Feng,5 Cheng Wei,5 Xiqiang Tang,5 Lijun Cen,5 Wenwen Guo,5 Xinru Tian,5 Qianli Tang,5 Xusen Huang1 1General Surgery, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China; 2Department of Pathology, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China; 3Department of Pediatrics, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China; 4Medical college of Soochow University, Suzhou, Jiangsu, 215000, People’s Republic of China; 5YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qianli TangYouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of ChinaEmail htmgx@163.comXusen HuangGeneral Surgery, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of ChinaEmail hxsfy@163.comBackground: LncRNAs play an important role in tumor initiation and development. However, the underlying involvement of lncRNA expression in colorectal carcinoma remains to be clarified.Methods: All analyses were performed in R software v4.0, SPSS v13.0, and GraphPad Prism 8. The “limma” package was used to identify differentially expressed lncRNAs between two groups with the threshold of |logFC| > 1 and P < 0.05. The “Survival” package was used to conduct survival analysis. HCT8 and SE480 cell lines were used to conduct further phenotype experiments, including transwell, wound-healing, CCK8 and colony formation assay. Gene set enrichment analysis was used to explore the biological pathway difference in high and low IGFL2-AS1 patients.Results: The lncRNA IGFL2-AS1 was highly expressed in colon adenocarcinoma (COAD) tissue and cell lines (HCT116, HCT8, HCT129, and SW480). The COAD patients with high IGFL2-AS1 were associated with a worse prognosis. Meanwhile, the knockdown of IGFL2-AS1 could significantly suppress the proliferation and invasion of COAD cells. Gene set enrichment analysis showed that the top five biological pathways involving IGFL2-AS1 were angiogenesis, epithelial–mesenchymal transition, KRAS signaling, myogenesis, and coagulation. Western blot results showed that the inhibition of IGFL2-AS1 could significantly reduce the N-cadherin, HIF1A and KRAS protein expression, yet increase the E-cadherin protein level. IGFL2-AS1 was also positively correlated with M0 macrophages, M2 macrophages, and neutrophils but negatively correlated with CD4+ memory T cells and CD8+ T cells.Conclusion: IGFL1-AS1 could seriously worsen patient outcomes and facilitate COAD progression, thus serving as an independent tumor marker.Keywords: IGFL2-AS1, lncRNA, colon cancer, immune

Xin Tian, Qiuxia Zhu, Zhenyong Zhang Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110022, People’s Republic of ChinaCorrespondence: Zhenyong ZhangDepartment of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110022, People’s Republic of ChinaEmail zhangzhenyongvip@163.comAbstract: Synchronous occurrences of gastric cancer positive for human epidermal growth factor receptor 2 (HER2+) and bladder cancer are rarely encountered in clinical practice. When and how to effectively treat both tumors, without compounding adverse effects, must be addressed. Herein, we describe an elderly man who presented with both gastric cancer (HER2+) and bladder cancer. Due to enlarged and fused lymph nodal metastasis, he was ill-suited for stomach resection. After transurethral resection of the bladder tumor, we administered both chemotherapy and the targeted agent trastuzumab. Gastric cancer showed partial response however bladder cancer recurred following two cycles of this regimen, the adverse effects were prohibitive, prompting refusal of further chemotherapy and radiotherapy. He then received the immune checkpoint inhibitor (ICI) nivolumab and trastuzumab in combination. This particular regimen successfully controlled both cancers and substantially improved the patient’s quality of life. Its long-term use did not intensify adverse reactions, enabling a progression-free survival of 21 months to date. We have also reviewed other published clinical strategies applied in rare instances of multiple primary malignancies as a reference for treating such patients.Keywords: immunotherapy, targeted therapy, synchronous cancer, HER2-positive gastric cancer, bladder cancer

Yifang Li, Yanzhen Chen, Xing Tian, Shanshan Zhang, Jian Jiao Department of Gastroenterolgy & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, 130033, People’s Republic of ChinaCorrespondence: Jian JiaoDepartment of Gastroenterology & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, People’s Republic of ChinaTel +86 13756009567Fax +86 0431-84995850Email jjian@jlu.edu.cnObjective: Non-alcoholic fatty liver disease (NAFLD), previously thought to predominantly affect obese individuals, has also been shown to occur in subjects who have a relatively normal body mass index (BMI). Due to the normal BMI, non-obese NAFLD are easily to be ignored and eventually lead to potential liver injuries.Methods: A population-based cross-sectional study was conducted on 1608 cases with normal serum alanine aminotransferase (ALT) levels who were divided into an obese group (BMI ≥ 25 kg/m2) and a non-obese group (BMI < 25 kg/m2). NAFLD was diagnosed by ultrasound and Fibro Scan examination. Non-obese populations were divided into NAFLD group (CAP ≥ 240 db/m) and non-NAFLD group (CAP < 240 db/m). The incidence of NAFLD in the obese and non-obese populations and constituent ratios of genders, age, and serum levels of triglycerides (TG), cholesterol (CHOL), and blood glucose were compared. Risk factors of NAFLD in non-obese people were analyzed by multivariate logistics regression.Results: The occurrence of NAFLD was higher in the obese group than in the non-obese group, regardless of gender (P < 0.001). In the non-obese group, the occurrence of NAFLD in female patients was lower than that in male (P=0.001). The occurrence of NAFLD increased with age, with 50– 59 years being the peak age of incidence in both male and female. The peak age of NAFLD occurrence in non-obese male patients was more delayed than that in obese male patients. BMI (OR=1.311, P=0.000) and TG (OR=2.545, P=0.000) were risk factors for NAFLD in the non-obese population.Conclusion: Compared with obese population, the incidence of NAFLD in non-obese population was relatively low and more frequently in male than in female, the peak age of NAFLD occurrence in non-obese male patients was also delayed. BMI and TG should still be controlled to avoid the occurrence of NAFLD although the BMI of such patients is normal.Keywords: obese, non-obese, non-alcoholic liver disease, gender, characteristic

Rongli Cui,* Zhiqiang Song,* Baojun Suo, Xueli Tian, Yan Xue, Lingmei Meng, Zhanyue Niu, Zhu Jin, Hejun Zhang, Liya Zhou Department of Gastroenterology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liya ZhouDepartment of Gastroenterology, Peking University Third Hospital, 49 Road Garden, Haidian District, Beijing, 100191, People’s Republic of ChinaTel +86-13911827827Fax +86-10-82265021Email zhouliya123456@163.comBackground: It has not been fully confirmed whether the detection of Helicobacter pylori resistance gene mutation can replace antibiotic drug sensitivity test to guide the clinical individualized treatment. Therefore, we have studied this aspect and discussed the application value of antibiotic sensitivity gene test.Materials and Methods: The biopsy specimen of gastric mucosa from the patients examined by endoscopy and positive for rapid urease test were collected continuously for histopathological analysis, H. pylori culture, antibiotic drug sensitivity test (E-test drug sensitivity test), and antibiotic sensitivity gene test (high-throughput nucleotide sequencing). The participants received triple plus bismuth solution eradication treatment (esomeprazole 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg, and bismuth potassium citrate 220 mg, twice daily for 14 days) for follow-up, and the eradication effect was determined.Results: The 551/602 subjects, who met the inclusion criteria, were subjected to culture for H. pylori and antibiotic drug sensitivity determination; among them 506 were cultured successfully. The results showed that the resistance rates of H. pylori were 38.9% for clarithromycin and 31.0% for levofloxacin. In 489 H. pylori strains, the mutations were detected in clarithromycin and levofloxacin resistance genes, indicating the genotype resistance. The resistance genes of clarithromycin and levofloxacin were consistent with phenotype resistance with respect to sensitivity (81.2% and 69.7% for clarithromycin and levofloxacin, respectively) and specificity (88.9% and 93.7% for clarithromycin and levofloxacin, respectively). The eradication rate of H. pylori in the clarithromycin-resistant group was significantly lower than that in the sensitive group (ITT: 52.1% vs 85.0%, P < 0.001).Conclusion: A correlation was established between the resistance genes of clarithromycin and levofloxacin and their phenotypic resistance and clinical efficacy. The detection of H. pylori resistance genes has a good clinical application prospect.Keywords: Helicobacter pylori, drug resistance, clarithromycin, levofloxacin, mutation, high-throughput nucleotide sequencing

Xiangkuo Zheng,1,* Renchi Fang,2,* Chong Wang,3 Xuebin Tian,4 Jie Lin,1 Weiliang Zeng,4 Tieli Zhou,1 Chunquan Xu1 1Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China; 2Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, People’s Republic of China; 3Department of Laboratory Medicine, Qingdao Municipal Hospital, Qingdao, 266000, People’s Republic of China; 4School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunquan Xu; Tieli ZhouDepartment of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of ChinaTel +86-577-5557-9725; +86-577-8668-9885Email 417242374@qq.com; wyztli@163.comBackground: Staphylococcus aureus (S. aureus) is a major contributor to nosocomial and community-acquired infections. S. aureus small colony variants (SCVs) which changed in relevant phenotype have made more limited and difficult for therapeutic options against S. aureus infections increasingly. Rifampicin is considered as the “last-resort” antibiotic against S. aureus. Our study investigated resistance profiles and biological characteristics of rifampicin-resistant S. aureus SCVs.Methods: We collected S. aureus SCVs that were selected from 41 rifampicin-resistant clinical isolates. Then, biological characteristics, resistance spectrum, and rifampicin resistance mechanisms of tested S. aureus SCVs and corresponding parental strains were investigated by classic microbiological methods, agar dilution method, polymerase chain reaction (PCR). Moreover, the fitness cost of S. aureus SCVs, including growth, biofilm formation ability, and virulence profile, was also determined by bacterial growth curve assay, biofilm formation assay, and Galleria mellonella infection model.Results: There were three S. aureus SCVs (JP310 SCVs, JP1450 SCVs, JP1486 SCVs) that were selected from 41 rifampicin-resistant S. aureus. S. aureus SCVs colonies were tiny, with decreased pigmentation, and the hemolysis circle was not obvious compared with corresponding parental strains. And SCVs could not be restored to normal-colony phenotype after hemin, menaquinone, or thymidine supplementation. Different rpoB mutations occurred in JP1486 SCVs. Antimicrobial susceptibility testing revealed MICs of SCVs were higher than corresponding parental strains. Besides, the growth ability and virulence of SCVs were lower, and biofilm formation ability of which increased compared with parental strains.Conclusion: S. aureus SCVs share the rifampicin resistance mechanisms with parental strains, although there were some differences in the position of rpoB mutations. Moreover, we found that the biological characteristics of SCVs were significantly different from corresponding parental strains. In contrast, decreased susceptibility to other antibiotics of SCVs was observed during phenotype switch. Furthermore, SCVs incur the fitness cost.Keywords: Staphylococcus aureus, small-colony variant, rifampicin resistance, resistance profile, biological characteristic

Guanghui Cao, Chan Zhang, Xiangyong Tian, Gaopeng Jing, Xiaolin Zhou, Tianzhong Yan Department of Urology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, Henan, 450003, People’s Republic of ChinaCorrespondence: Tianzhong YanDepartment of Urology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, No. 7, Weiwu Road, Jinshui District, Zhengzhou, Henan, 450003, People’s Republic of ChinaTel +86-15515920410Email yantianzhong74@126.comBackground: Dysregulation of circular RNAs (circRNAs) is associated with bladder cancer progression. Nevertheless, the mechanisms of circRNA centrosomal protein 128 (circCEP128) underlying bladder cancer progression remain poorly understood.Methods: The levels of circCEP128, microRNA-515-5p (miR-515-5p) and syndecan-1 (SDC1) were determined via reverse transcription-quantitative polymerase chain reaction or Western blot. The effects of circCEP128, miR-515-5p and SDC1 on bladder cancer progression were investigated via MTT and colony formation assays, flow cytometry and transwell analysis and subcutaneous xenograft experiments. The interactions between miR-515-5p and circCEP128 or SDC1 were examined through bioinformatics prediction and luciferase reporter assay.Results: circCEP128 and SDC1 were highly expressed and miR-515-5p was low expressed in bladder cancer tissues and cells. circCEP128 knockdown hindered cell proliferation, migration and invasion and promoted cell apoptosis in bladder cancer. circCEP128 loss increased miR-515-5p expression through direct interaction in bladder cancer cells. MiR-515-5p depletion mitigated the influences of circCEP128 knockdown on bladder cancer cell phenotypes. SDC1 was a direct target of miR-515-5p. circCEP128 positively regulated SDC1 expression via miR-515-5p. MiR-515-5p restrained the malignant progression of bladder cancer cells by decreasing SDC1 expression. circCEP128 knockdown hindered the growth of bladder cancer xenograft tumors by up-regulating miR-515-5p and down-regulating SDC1.Conclusion: circCEP128 knockdown hampered the tumorigenesis and progression of bladder cancer by regulating miR-515-5p/SDC1 axis in vitro and in vivo, deepening our understanding on the molecular mechanisms of circCEP128 in bladder cancer.Keywords: bladder cancer, circCEP128, microRNA-515-5p, SDC1

Jingjing Yuan, Qing Zhang, Shengsheng Wu, Suran Yan, Ran Zhao, Yajuan Sun, Xiaoxu Tian, Keshu Zhou Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, People’s Republic of ChinaCorrespondence: Keshu ZhouDepartment of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, People’s Republic of ChinaTel/Fax +86-371-65587513Email drzhouks77@163.comBackground: Mantle cell lymphoma (MCL) is an aggressive malignancy that accounts for 5– 10% of non-Hodgkin’s lymphoma. MiRNA-223-3p has been demonstrated to be down-regulated in MCL and is a useful prognostic factor. However, little is known about underlying molecular mechanism of miRNA-233-3p in MCL.Methods: The expression levels of miRNA-223-3p and CHUK mRNA in MCL cells were detected by real-time quantitative PCR (RT-qPCR). The effects of miRNA-223-3p/CHUK overexpression/knockdown on MCL cell proliferation and apoptosis were measured by CCK-8 assay and annexin V PE/7-AAD-based flow cytometry/TUNEL assay, respectively. A nude mouse subcutaneous xenograft model was used to further evaluate the potential effects in vivo. Dual-luciferase reporter assay was used to verify the inhibitory effect of miRNA-223-3p on CHUK. Furthermore, the regulatory function of miRNA-223-3p on the CHUK/NF-ƘB2 axis was assessed by RT-qPCR, western blot and immunofluorescence.Results: In the present study, miRNA-223-3p overexpression inhibited proliferation and accelerated apoptosis of MCL cells in vitro and in vivo. The results of Luciferase reporter assay showed that CHUK was a direct target of miRNA-223-3p in HEK293T cells. Furthermore, the results of RT-qPCR, western blot confirmed that CHUK was targeted and negatively regulated by miRNA-223-3p for repressing NF-ƘB2 pathway activation in MCL cells. Importantly, CHUK overexpression promoted proliferation and suppressed apoptosis of MCL cells, whereas CHUK knockdown reversed down-regulated miRNA-223-3p -accelerated cell proliferation in vitro.Conclusion: In conclusion, miRNA-223-3p affects MCL development by regulating the CHUK/NF-ƘB2 signaling pathway, which is crucial to provide a novel therapeutic strategy.Keywords: mantle cell lymphoma, miRNA-223-3p, CHUK, NF-ƘB2 signaling pathway, disease progression

Xiaoning Lin,1,* Rong Huang,2,* Yanlin Huang,1,* Kai Wang,3 Heng Li,1 Yiheng Bao,1 Chaohui Wu,4 Yi Zhang,5 Xinhua Tian,1 Xiaomin Wang6 1Department of Neurosurgery, Zhongshan Hospital Xiamen University, Xiamen, 361004, People’s Republic of China; 2Department of Child Health, Women and Children’s Hospital, Xiamen University, Xiamen, 361003, People’s Republic of China; 3School of Public Health, Xiamen University, Xiamen, 361102, People’s Republic of China; 4Department of Thoracic Surgery, Zhongshan Hospital Xiamen University, Xiamen, 361004, People’s Republic of China; 5Department of Breast Surgery, Xiamen TCM Hospital, Xiamen, 361001, People’s Republic of China; 6Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital Xiamen University, Xiamen, 361004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaomin WangFujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen University Affiliated Zhongshan Hospital, Xiamen, 361004, People’s Republic of ChinaEmail wxm2203@xmu.edu.cnXinhua TianDepartment of Neurosurgery, Zhongshan Hospital Xiamen University, Xiamen, 361004, People’s Republic of ChinaEmail txhmd@163.comIntroduction: Sonodynamic therapy (SDT) has good targeting and non-invasive advantages in the treatment of solid cancers, and checkpoint blockade immunotherapy is also a promising treatment to cure cancer. However, their antitumor effects are not sufficient due to some inherent factors. Some studies that combined SDT with immunotherapy or nanoparticles have managed to enhance its efficiency to treat cancers.Methods: In this work, an effective therapeutic strategy that can potentiate the antitumor efficacy of anti-PD-L1 antibody (aPD-L1) is developed by the use of cascade immuno-sonodynamic therapy (immuno-SDT). Titanium dioxide (TiO2), a nanostructured agent for SDT, sonosensitizer Chlorin e6 (Ce6), and immunological adjuvant CpG oligonucleotide (CpG ODN), are used to construct a multifunctional nanosonosensitizer (TiO2-Ce6-CpG). Then, we conducted in vitro and in vivo experiments to explore the antitumor effect of TiO2-Ce6-CpG under ultrasound (US) treatment.Results: The characterization tests showed that the nanosonosensitizers are polycrystalline structure with homogeneous sizes, resulting in a good drug loading efficiency. The innovative nanosonosensitizers (TiO2-Ce6-CpG) can not only effectively inhibit tumor growth but also stimulate the immune system to activate the adaptive immune responses, using the TiO2-Ce6 to augment SDT and the immune adjuvant CpG to enhance the immune response. After combined with the aPD-L1, the synergistic effect could not only efficiently inhibit the primary tumor growth but also lead to an inhibition of the non-irradiated pre-existing distant tumors by inducing a strong tumor-specific immune response.Conclusion: In this study, we present an effective strategy for tumor treatment by combining nanosonosensitizer-augmented SDT and aPD-L1 checkpoint blockade. This work provides a promising strategy and offers a new vision for treating malignant tumors.Keywords: cancer immunotherapy, sonodynamic therapy, titanium dioxide nanoparticles, sonosensitizer, checkpoint blockade

Ting Yang1 1, Yaqun Zhou1 1, Wen Zhang1 1, Longqing Zhang1 1, Shuping Chen1 1, Chao Chen1 1, Feng Gao1 1, Hui Yang1 1, Anne Manyande2 2, Jie Wang3 3, Yuke Tian1 1, Xuebi Tian1 1 1Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2School of Human and Social Sciences, University of West London, London, UK; 3State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Center for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Xuebi TianDepartment of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095#, Wuhan, Hubei, 430030, People’s Republic of ChinaTel +862783663423Fax +862783662853Email Tianxb@hust.edu.cnIntroduction: Cancer-induced bone pain (CIBP) is acknowledged as a multifactorial chronic pain that tortures advanced cancer patients, but existing treatment strategies for CIBP have not been satisfactory yet. Investigators have demonstrated that the activation of α 7-nAChRs exerts analgesic effects in some chronic pain models. However, the role of spinal α 7-nAChRs in CIBP remains unknown. This study was designed to investigate the role of α 7-nAChRs in a well-established CIBP model induced by Walker 256 rat mammary gland carcinoma cells.Methods: The paw withdrawal threshold (PWT) of the ipsilateral hind paw was measured using von Frey filament. The expressions of spinal α 7-nAChRs and NF-κB were measured with Western blotting analysis. Immunofluorescence was employed to detect the expression of α 7-nAChRs and co-expressed of α 7-nAChRs with NeuN or GFAP or Iba1.Results: Experiment results showed that the expression of spinal α 7-nAChRs was significantly downregulated over time in CIBP rats, and in both CIBP rats and sham rats, most of the α 7-nAChRs located in neurons. Behavioral data suggested PNU-282,987, a selective α 7-nAChRs agonist, dose-dependently produced analgesic effect and positive allosteric modulator could intensify its effects. Further, repeated administration of PNU-282,987 reversed the expression of α 7-nAChRs, inhibited the nuclear factor kappa B (NF-κB) signaling pathway, and attenuates CIBP-induced mechanical allodynia state as well.Conclusion: These results suggest that the reduced expression of spinal α 7-nAChRs contributes to the maintenance of CIBP by upregulating NF-κB expression, which implying a novel pharmacological therapeutic target for the treatment of CIBP.Keywords: cancer-induced bone pain, α 7-nAChR, NF-κB, PNU-282,987

Objectives ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- and older-onset patients are still incompletely understood. Methods We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We divided the population according to age at diagnosis: Results A total of 1338 patients with AAV were included: 66% had disease onset at Conclusion Within 6 months of diagnosis of AAV, patients >65 years of age display a different pattern of organ involvement and an increased risk of significant damage and mortality compared with younger patients.

Xiangyang Tian,1 Shuyuan Li,2 Guoyan Ge2 1Department of Oncology, Peace Hospital, Changzhi Medical College, Changzhi, Shanxi Province, 046000, People’s Republic of China; 2Department of Tumor Spleen and Stomach, Hospital of Traditional Chinese Medicine of Changzhi City, Changzhi, Shanxi Province, 046013, People’s Republic of ChinaCorrespondence: Xiangyang TianPeace Hospital, Changzhi Medical College, No. 110 Yan’an South Road, Luzhou District, Changzhi, Shanxi Province, 046000, People’s Republic of ChinaEmail xiangyangd@163.comBackground: Colorectal cancer (CRC) is a common digestive system malignancy. Ferroptosis, a new form of regulated cell death, plays a vital role in the pathogenesis and therapy of cancers.Objective: We aimed to study the role of apatinib in ferroptosis of CRC cells and its potential mechanisms.Materials and Methods: Human CRC HCT116 cells were exposed to apatinib. Cell viability was examined using a CCK-8 kit. The concentrations of intracellular iron and reactive oxygen species (ROS) were detected using kits. Additionally, Western blot analysis was used to determine the expression of ferroptosis-related proteins. Elongation of very long-chain fatty acids family member 6 (ELOVL6) was one of the targets of apatinib predicted by SwissTargetPrediction. Therefore, ELOVL6 expression was evaluated after treatment with apatinib. Subsequently, the effects of ELOVL6 overexpression on ferroptosis of HCT116 cells were investigated. Finally, STRING database was applied to predict the potential proteins interacting with ELOVL6, and co-immunoprecipitation (co-IP) assay was applied for confirmation.Results: Results indicated that apatinib decreased cell viability and increased the contents of intracellular iron ROS. Moreover, significantly upregulated ACSL4 expression was observed, accompanied by notable downregulation of GPx4 and FTH1 expression after apatinib exposure. Furthermore, ELOVL6 expression was remarkably enhanced in HCT116 cells, which was dramatically inhibited under apatinib intervention. ELOVL6 overexpression reversed the effects of apatinib on cell viability and ferroptosis of HCT116 cells. Moreover, ACSL4, a vital regulator of ferroptosis, could interact with ELOVL6 directly, which was confirmed by the result of co-IP.Conclusion: These findings demonstrated that apatinib promoted ferroptosis in CRC cells by targeting ELOVL6/ACSL4, providing a new mechanism support for apatinib application in the clinical treatment of CRC.Keywords: colorectal cancer, apatinib, ferroptosis, reactive oxygen species, ELOVL6

Liang Yan,1,* Xiuyun Tian,1,* Chunxiang Ye,1,2 Xiaoya Guan,1 Bin Dong,3 Min Zhao,4 Jianhui Wu,1 Chunyi Hao1 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 2Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Central Laboratory, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 4Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunyi HaoKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, People’s Republic of ChinaTel +86-10-88196182Fax +86-10-88196548Email haochunyi@bjmu.edu.cnPurpose: Pancreatic cancer is associated with a high mortality rate owing to insufficient approaches for early diagnosis and the invasive biological behavior of the cancer. CD26 is a membrane-anchored protein involved in multiple physiological and pathological processes. Here, we investigated correlations between CD26 expression and clinicopathological features in patients with pancreatic tumors.Methods: We collected 170 tumor tissue specimens and 138 paired paratumoral tissues from patients with pancreatic tumors and evaluated CD26 expression using immunohistochemistry.Results: CD26 was expressed in 79.4% of pancreatic tumors, which was significantly (P < 0.001) higher than that in paratumoral pancreatic tissues (23.2%). High expression of CD26 was correlated with ABO blood type (P = 0.035), malignancy degree (P = 0.001), CA199 (P = 0.01), and CA242 (P = 0.027). In pancreatic malignancies, CD26 expression was observed in 80.7% (130/161) of cases. Lower CD26 expression was correlated with longer disease-free survival (P = 0.048) and overall survival (P = 0.024) and was an independent predictor of overall survival (hazard ratio [HR]: 1.713; P = 0.042). Similar results were observed in pancreatic ductal adenocarcinoma (PDAC) tissues, and CD26 expression level (HR: 2.117; P = 0.008) was an independent predictor of overall survival in patients with PDAC. CD26 expression was significantly increased in pancreatic tumors and gradually increased with increasing malignancy degree, suggesting that CD26 may be involved in the tumorigenic proliferation of pancreatic tumors.Conclusion: Therefore, CD26 is a potential marker for early diagnosis and a promising therapeutic target in pancreatic tumors.Keywords: biomarker, CD26, immunohistochemistry, pancreatic cancer, prognosis

Background Post–percutaneous coronary intervention (PCI) fractional flow reserve ≥0.90 is an accepted marker of procedural success, and a cutoff of ≥0.95 has recently been proposed for post‐PCI instantaneous wave‐free ratio. However, stability of nonhyperemic pressure ratios (NHPRs) post‐PCI is not well characterized, and transient reactive submaximal hyperemia post‐PCI may affect their precision. We performed this study to assess stability and reproducibility of NHPRs post‐PCI. Methods and Results Fifty‐seven patients (age, 63.77±10.67 years; men, 71%) underwent hemodynamic assessment immediately post‐PCI and then after a recovery period of 10, 20, and 30 minutes and repeated at 3 months. Manual offline analysis was performed to derive resting and hyperemic pressure indexes (Pd/Pa resting pressure gradient, mathematically derived instantaneous wave‐free ratio, resting full cycle ratio, and fractional flow reserve) and microcirculatory resistances (basal microvascular resistance and index of microvascular resistance). Transient submaximal hyperemia occurring post‐PCI was demonstrated by longer thermodilution time at 30 minutes compared with immediately post‐PCI; mean difference of thermodilution time was 0.17 seconds (95% CI, 0.07–0.26 seconds; P =0.04). Basal microcirculatory resistance was also higher at 30 minutes than immediately post‐PCI; mean difference of basal microvascular resistance was 10.89 mm Hg.s (95% CI, 2.25–19.52 mm Hg.s; P =0.04). Despite this, group analysis confirmed no significant differences in the values of resting whole cycle pressure ratios (Pd/Pa and resting full cycle ratio) as well as diastolic pressure ratios (diastolic pressure ratio and mathematically derived instantaneous wave‐free ratio). Whole cardiac cycle NHPRs demonstrated the best overall stability post‐PCI, and 1 in 5 repeated diastolic NHPRs crossed the clinical decision threshold. Conclusions Whole cycle NHPRs demonstrate better reproducibility and clinical precision post‐PCI than diastolic NHPRs, possibly because of less perturbation from predominantly diastolic reactive hyperemia and left ventricular stunning. Registration URL: https://clinicaltrials.gov/ct2/show/NCT03502083 ; Unique identifier: NCT03502083 and URL: https://clinicaltrials.gov/ct2/show/NCT03076476 ; Unique identifier: NCT03076476.

Supplemental Digital Content is available in the text., Objective: NR4A orphan receptors have been well studied in vascular and myeloid cells where they play important roles in the regulation of inflammation in atherosclerosis. NR4A1 (nerve growth factor IB) is among the most highly induced transcription factors in B cells following BCR (B-cell receptor) stimulation. Given that B cells substantially contribute to the development of atherosclerosis, we examined whether NR4A1 regulates B-cell function during atherogenesis. Approach and Results: We found that feeding Ldlr−/− mice a Western diet substantially increased Nr4a1 expression in marginal zone B (MZB) cells compared with follicular B cells. We then generated Ldlr−/− mice with complete B- or specific MZB-cell deletion of Nr4a1. Complete B-cell deletion of Nr4a1 led to increased atherosclerosis, which was accompanied by increased T follicular helper cell–germinal center axis response, as well as increased serum total cholesterol and triglycerides levels. Interestingly, specific MZB-cell deletion of Nr4a1 increased atherosclerosis in association with an increased T follicular helper–germinal center response but without any impact on serum cholesterol or triglyceride levels. Nr4a1−/− MZB cells showed decreased PDL1 (programmed death ligand-1) expression, which may have contributed to the enhanced T follicular helper response. Conclusions: Our findings reveal a previously unsuspected role for NR4A1 in the atheroprotective role of MZB cells. Graphic Abstract: A graphic abstract is available for this article.

Jing Tang,1,2 Fengyong Liu,2 Hongjun Yuan,2 Xin Li,2 Xiaomei Tian,2 Kan Ji,2 Xueping Li,3 Wei Wang3 1Medical School of Chinese PLA, Beijing, People’s Republic of China; 2Department of Interventional Radiology, The First Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of China; 3Department of Radiology, The First Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Fengyong LiuDepartment of Interventional Radiology, The First Medical Center, Chinese PLA General Hospital, No. 28, Fuxing Road, Haidian District, Beijing 100853, People’s Republic of ChinaTel +8613371668617Fax +86-10-66939340Email liufengyong301@163.comPurpose: To evaluate whether the pretreatment apparent diffusion coefficient (ADC) measured with diffusion weighted imaging (DWI) of tumor can be used as an imaging biomarker for predicting prognosis in solitary large hepatocellular carcinomas (HCCs) treated with transcatheter arterial chemoembolization (TACE) immediately combined with radiofrequency ablation (RFA).Patients and Methods: In this single institution retrospective study, 40 solitary large HCCs that underwent treatment with TACE immediately combined with RFA were analyzed. All patients underwent abdominal dynamic contrast-enhanced magnetic resonance imaging within one month before treatment with DWI, and ADC values in the lesions were measured by two independent radiologists. Associations among patients’ preoperative ADC values and objective response (OR), progression-free survival (PFS) and overall survival (OS) were examined. Survival curves were drawn with the Kaplan–Meier method, and differences were determined with the Log rank test. The Cox proportional-hazards model was used for univariate and multivariate analyses of PFS and OS.Results: Forty solitary large HCCs (mean 9.54 cm, range 5.04– 16.06 cm) were successfully treated with TACE in immediate combination with RFA (OR 75%). The ADC values were significantly higher in the response group than the non-response group (1.51± 0.32× 10− 3 mm2/s vs 1.09± 0.17× 10− 3 mm2/s; P< 0.001). As predicted on the basis of the ADC values, the optimal cutoff value for the efficacy of TACE combined with RFA was 1.32× 10− 3 mm2/s, with a predictive sensitivity of 0.63 and a specificity of 1.00. Patients with high ADC had longer PFS than those with low ADC (14.9 months vs 5.3 months; P< 0.001) and had significantly longer survival rates (22.6 months vs 12.1 months; P=0.004).Conclusion: Preoperative ADC values < 1.32× 10− 3 mm2/s are an independent predictor of poorer prognosis in patients with solitary large HCCs who have undergone TACE immediately combined with RFA.Keywords: solitary large hepatocellular carcinoma, apparent diffusion coefficient, TACE, radiofrequency ablation

Xin Tian, Qian Wang, Weisong Cai Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110022, People’s Republic of ChinaCorrespondence: Weisong CaiDepartment of Clinical Oncology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Shenyang 110022, People’s Republic of ChinaEmail caiweisongvip@163.comAbstract: Colorectal cancer is a rare pediatric tumor. Pediatric patients with colorectal cancer present with more aggressive tumor biology and at later stages of the disease, higher proportions of signet ring and mucinous histology, and less differentiation. The effective treatment is same as that received by adults. The overall prognosis of pediatric colorectal cancer is generally poor. Genetic mutations have been identified as the cause of inherited cancer risk in some colorectal cancers. Here, we presented a case of a pediatric patient carrying a maternally derived, heterozygous MYH germline mutation (c.934– 2A>G,intron), the mutation was not reported in pediatric patients before. Also, the patient carried somatic mutations of proto-oncogene SMAD4 (R361C) and TP53 (Y234H). The patient underwent surgical resection, chemotherapy and targeted therapy, but the prognosis was not good. We also review the literature to summarize clinical features, gene mutations, management, and outcomes of pediatric colorectal cancer patient. Our results suggest that the genetic mutation of MYH together with somatic mutations of proto-oncogene SMAD4 and TP53 may lead to the early onset colorectal cancer of the patient. Although the overall prognosis of pediatric colorectal cancer is generally poor, the pathogenesis may be related to hereditary genetic mutations as was found with the MYH gene mutation in our case. Genetic screening can provide early diagnosis and improve prognosis.Keywords: pediatric, colorectal cancer, heredity, MYH, gene mutations

Xiumei Tian1 ,* Ao Zeng1 ,* Ziying Liu,1 Cunjing Zheng,2 Yuezi Wei,1 Peiheng Yang,1 Minru Zhang,1 Fanwen Yang,1 Fukang Xie1 1School of Basic Medical Sciences, Affiliated Stomatology Hospital, Guangzhou Medical University, Guangzhou 510182, People’s Republic of China; 2Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fukang Xie Tel +86 20 136 4231 6682Email 378141679@qq.comFanwen Yang Tel +86 20 135 0308 0690Fax +86 20 3710 3509Email yangfanwen@163.comBackground: Understanding the biocompatibility and biointeractions of nano-carbon quantum dots (nano-CQDs) in vitro and in vivo is important for assessing their potential risk to human health. In the previous research, the physical properties of CQDs synthesized by the laser ablation in liquid (LAL) method were analyzed in detail; however, possible bioapplications were not considered.Materials and Methods: CQDs were prepared by LAL and characterized by atomic force microscopy, fluorescence lifetime, absorption spectrum, Fourier-transform infrared spectroscopy, and dynamic light scattering. Their biocompatibility was evaluated in vitro using assays for cytotoxicity, apoptosis, and biodistribution and in vivo using immunotoxicity and the relative expression of genes. Cells were measured in vitro using fluorescence-lifetime imaging microscopy to analyze the biointeractions between CQDs and intracellular proteins.Results: There were no significant differences in biocompatibility between the CQDs and the negative control. The intracellular interactions had no impact on the optical imaging of CQDs upon intake by cells. Optical imaging of zebrafish showed the green fluorescence was well dispersed.Conclusion: We have demonstrated that the CQDs have an excellent biocompatibility and can be used as efficient optical nanoprobes for cell tracking and biomedical labeling except for L929 and PC-3M cells.Keywords: nanoprobe, immunotoxicity, biodistribution, biointeraction, optical imaging

Juan Li,1 Lei Zheng,2 Rongmei Wang,1 Deqing Sun,1 Shuang Liang,3 Jing Wu,1 Yongqing Liu,1 Xiaona Tian,1 Tingting Li,4 Yang Yang,5 Leiqiang Han1 1Department of Clinical Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, People’s Republic of China; 2Department of Pharmacy, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250031, People’s Republic of China; 3School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, People’s Republic of China; 4Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA; 5China National Center for Biotechnology Development, Beijing 100039, People’s Republic of ChinaCorrespondence: Leiqiang HanDepartment of Clinical Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Road, Jinan, Shandong 250033, People’s Republic of ChinaTel +86-531-85875083Fax +86-531-88962544Email hanlq007@sina.cnBackground: The development of paclitaxel (PTX) resistance seriously restricts its clinical efficacy. An attractive option for combating resistance is inhibiting the expression of P-glycoprotein (P-gp) in tumor cells. We have reported that flavokawain A (FKA) inhibited P-gp protein expression in PTX-resistant A549 (A549/T) cells, indicating that FKA combined with PTX may reverse PTX resistance. However, due to the variable pharmacokinetics of FKA and PTX, the conventional cocktail combination in clinics may cause uncertainty of treatment efficacy in vivo.Materials and Methods: To synergistically elevate the anti-cancer activity of PTX and FKA in vivo, the national medical products administration (NMPA) approved sodium aescinate (Aes) was utilized to stabilize hydrophobic PTX and FKA to form polymer-free twin like PTX-A nanoparticles (NPs) and FKA-A NPs.Results: The resulting nanoparticles prepared simply by nanoprecipitation possessed similar particle size, good stability and ultrahigh drug loadings of up to 50%. With the aid of Aes, these two drugs accumulated in tumor tissue by passive targeting and were efficiently taken up by A549/T cells; this resulted in significant suppression of tumor growth in A549/T homograft mice at a low PTX dose (2.5 mg·kg− 1). Synergistic effects and reversed PTX resistance were achieved by the combination of PTX-A NPs and FKA-A NPs by inhibiting P-gp expression in tumor cells.Conclusion: Using NMPA-approved Aes to prepare twin-like nanoparticles without introducing any new materials provides an efficient platform for combination chemotherapy and clinical translation.Keywords: paclitaxel resistance, flavokawain A, sodium aescinate, polymer-free nanoparticles, combination therapy

Jianjun Jia,1 Suiqun Guo,2 Dong Zhang,1 Xiaohui Tian,3 Xingmei Xie1 1Department of Obstetrics and Gynecology, The First Affiliated Hospital, Jinan University, Guangzhou City, Guangdong Province 510632, People’s Republic of China; 2Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Southern Medical University, Guangzhou City, Guangdong Province, People’s Republic of China; 3Department of Obstetrics and Gynecology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen City, Guangdong Province, People’s Republic of ChinaCorrespondence: Jianjun JiaDepartment of Obstetrics and Gynecology, The First Affiliated Hospital, Jinan University, No. 613, West Huangpu Avenue, Tianhe District, Guangzhou City, Guangdong Province 510632, People’s Republic of ChinaTel +86-20-38688357Email jiajianjun615@sohu.comPurpose: Long non-coding RNAs (lncRNAs) may act as oncogenes in several cancers, including endometrial carcinoma (EC). The purpose of the current study is to investigate the regulatory mechanism of exosomal-lncRNA deleted in lymphocytic leukemia1 (DLEU1) on EC.Methods: The expression levels of lncRNA DLEU1, microRNA-381-3p and E2F Transcription Factor 3 (E2F3) in EC tissues or cells were detected using quantitative reverse transcription–polymerase chain reaction (qRT-PCR). We then analysed the proliferation, migration, and invasion of EC cells by performing the MTT assay, wound healing assay, and transwell invasion assay, respectively. Identification of exosomes was detected using Western blot assay. The uptake of exosomes was detected by a confocal microscope. The effects of exosomes on EC cells were investigated by construction of cell co-culture system. The interactions among DLEU1, miR-381-3p and E2F3 were confirmed using the dual-luciferase reporter (DLR) assay.Results: LncRNA DLEU1 expression was highly up-regulated in EC tissues and cells. Knockdown of DLEU1 inhibited the proliferation, migration, and invasion of EC cells. Exosomes could be uptaken by the ambient EC cells. MiR-381-3p was a target of DLEU1 and was negatively modulated by DLEU1. Overexpression of miR-381-3p suppressed the proliferation, migration, and invasion of EC cells. Additionally, E2F3 was the target gene of miR-381-3p and was negatively modulated by miR-381-3p. Upregulation of miR-381-3p and down-regulation of E2F3 reversed the promoting effect of exosomal DLEU1 on EC cells.Conclusion: Exosomal DLEU1 accelerates the development of EC by regulating the miR-381-3p/E2F3 axis, thus DLEU1 may act as a possible therapeutic target for treating EC.Keywords: endometrial carcinoma, exosomes, lncRNA DLEU1, miR-381-3p, E2F3

Zhiqiang Wang,* Chaowei Zhang,* Junkai Chang, Xin Tian, Chaoyang Zhu, Weibo Xu Department of Urinary Surgery, Huaihe Hospital of Henan University, Kaifeng 475000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weibo XuDepartment of Urinary Surgery, Huaihe Hospital of Henan University, No. 8 Baobei Road, Kaifeng 475000, People’s Republic of ChinaTel/ Fax +86 371-23906691Email xuweibo_kf@126.comBackground: LncRNA EMX2OS (EMX2 opposite strand/antisense RNA) is notably downregulated in prostate cancer (PCa) tissues and may be regarded as a potential molecular biomarker for diagnosis and prognosis. However, its exact role in regulating the development of PCa is obscure.Methods: The EMX2OS expression was assessed in PCa tissues, paracancer tissues, PCa cells and normal prostate epithelial cells by qPCR. Gain- and loss-of-function experiments were performed to investigate the role of EMX2OS and FUS in cGMP-PKG (cyclic guanosine monophosphate-dependent protein kinase)-mediated proliferation, invasion, and migration in human PCa cell lines DU145 and PC3. Then, the interaction of transcription factor 12 (TCF12) with EMX2OS promoter was confirmed by using the dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. RNA binding protein immunoprecipitation and RNA pull-down assays were used to verify the interaction between EMX2OS and FUS protein. Finally, the role of EMX2OS and FUS in tumor growth in vivo was validated in a xenograft nude mouse model.Results: TCF12 and EMX2OS were both downregulated in PCa tissues and cells, and they negatively regulated cell proliferation, migration and invasion, and activated cGMP-PKG pathway in DU145 and PC3 cells. TCF12 was a transcription factor of EMX2OS. TCF12 and EMX2OS overexpression both down-regulated cell proliferation, migration and invasion, and activated cGMP-PKG pathway in DU145 and PC3 cells. Furthermore, EMX2OS directly bound with FUS protein and had a synergy effect with FUS protein on cGMP-PKG-mediated cell functions, which could be suppressed by (D)-DT-2 (a cGMP-PKG inhibitor). In addition, the overexpression of FUS or EMX2OS individually markedly decreased the volume and weight of tumors in vivo, and co-overexpression of them further inhibited tumor growth.Conclusion: EMX2OS, transcriptionally regulated by TCF12, played a synergy role with FUS protein in regulating the proliferation, migration and invasion of PCa cells by activating the cGMP-PKG pathway.Keywords: LncRNA EMX2OS, TCF12, FUS, cGMP-PKG pathway, prostate cancer

Sha Zhang,1 Liang Yan,1 Can Cui,2 Zhen Wang,1 Jianhui Wu,1 Ang Lv,1 Min Zhao,3 Bin Dong,4 Wenlong Zhang,5 Xiaoya Guan,1 Xiuyun Tian,1 Chunyi Hao1 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of China; 2Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of China; 3Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 4Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Central Laboratory, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 5Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Laboratory Animal, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of ChinaCorrespondence: Chunyi Hao; Xiuyun TianDepartment of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, People’s Republic of ChinaTel +86-10-88196182; +86-10-88196841Fax +86-10-88196548Email haochunyi@bjmu.edu.cn; xiuyunt@126.comBackground: Retroperitoneal liposarcoma (RLPS) is a rare tumor with high recurrence rate. Ribonucleotide reductase small subunit M2 (RRM2) protein is essential for DNA synthesis and replication. Our previous study has demonstrated that RRM2 downregulation inhibited the proliferation of RLPS cells, but further association between RRM2 and RLPS and relevant mechanisms remains to be explored.Methods: RRM2 expression was evaluated in RLPS tumor tissues and cell lines by using real-time PCR and immunohistochemical analysis. The effect of RRM2 downregulation on cell proliferation, apoptosis, cell cycle, cell migration and invasion was tested by lentivirus. The effect of RRM2 inhibition on tumor growth in vivo was assessed by using patient-derived tumor xenograft (PDX) of RLPS and RRM2 inhibitor. The underlying mechanisms of RRM2 in RLPS were explored by protein microarray and Western blotting.Results: The results showed that RRM2 mRNA expression was higher in RLPS tissues than in normal fatty tissues (P< 0.001). RRM2 expression was higher in the dedifferentiated, myxoid/round cell, and pleomorphic subtypes (P=0.027), and it was also higher in the high-grade RLPS tissues compared to that in the low-grade RLPS tissues (P=0.004). There was no correlation between RRM2 expression and overall survival (OS) or disease-free survival (DFS) in this group of RLPS patients (P> 0.05). RRM2 downregulation inhibited cell proliferation, promoted cell apoptosis, facilitated cell cycle from G1 phase to S phase and inhibited cell migration and invasion. Inhibition of RRM2 suppressed tumor growth in NOD/SCID mice. Protein microarray and Western blot verification showed that activity of Akt/mammalian target of rapamycin/eukaryotic translation initiation factor 4E binding protein 1 (Akt/mTOR/4EBP1) pathway was downregulated along with RRM2 downregulation.Conclusion: RRM2 was overexpressed in RLPS tissues, and downregulation of RRM2 could inhibit RLPS progression. In addition, suppression of RRM2 is expected to be a promising treatment for RLPS patients.Keywords: retroperitoneal liposarcoma, ribonucleotide reductase small subunit M2, tumor progression, Akt/mTOR/4EBP1 pathway

Xia Tian,* Meng Liu,* Xiaodong Huang, Qingxi Zhu, Weijie Liu, Wei Chen, Yanli Zou, Yishan Cai, Shasha Huang, Aifang Chen, Ting Zhan, Min Huang, Xiaoli Chen, Zheng Han, Jie Tan Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zheng Han; Jie Tan Email 422435466@qq.com; 549774892@qq.comBackground: Noscapine is an opium alkaloid that has recently been shown to potentiate anti-cancer therapeutic effects by inducing apoptosis in various malignant cells without any detectable toxicity. However, the mechanism by which noscapine induces apoptosis in colon cancer cells remains unclear.Materials and Methods: In this study, we explored the anti-cancer activity of noscapine in 5-fluorouracil (5-FU)-resistant human colon cancer cell lines HT29/5-FU and LoVo/5-FU and investigated the possible underlying mechanism. The apoptosis and mitochondrial morphology of cells were detected by TUNEL assay and transmission electron microscopy (TEM). The mitochondrial membrane potential (MMP) was determined using JC-1. The mitochondrial permeability transition pore (mPTP) opening was detected by the calcein-AM/cobalt assay. The levels of glucose, lactic, and ATP in cells were evaluated by ELISA kits. Relative protein expression levels were detected by Western blot.Results: We verified that PTEN was involved in noscapine-induced apoptosis in HT29/5-FU and LoVo/5-FU cells. Noscapine greatly increased mitochondrial damage by altering mitochondrial morphology, inducing mitochondrial membrane potential depolarization, and enabling mitochondrial permeability transition pore opening in HT29/5-FU and LoVo/5-FU cells. In addition, noscapine inhibited the Warburg effect by decreasing the levels of glucose, lactic acid, and ATP and inhibiting the protein expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in HT29/5-FU and LoVo/5-FU cells. However, PTEN interference counteracted the effect of noscapine on mitochondrial damage and the Warburg effect in HT29/5-FU and LoVo/5-FU cells by decreasing the activation of PI3K/mTOR signaling.Conclusion: These results indicated that noscapine induced the apoptosis of HT29/5-FU and LoVo/5-FU human colon cancer cells by regulating mitochondria damage and the Warburg effect via PTEN, and the process is closely related to the PI3K/mTOR signaling pathway.Keywords: colon cancer, noscapine, mitochondrial damage, PTEN, PI3K/mTOR

Nan Jiang,1,* Pingting Yang,2,* Shengyun Liu,3,* Hongbin Li,4 Lijun Wu,5 Xiaofei Shi,6 Yongfei Fang,7 Yi Zhao,8 Jian Xu,9 Zhenyu Jiang,10 Zhenbiao Wu,11 Xinwang Duan,12 Qian Wang,1 Xinping Tian,1 Mengtao Li,1 Xiaofeng Zeng1 1Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, People’s Republic of China; 2Department of Rheumatology and Immunology, First Affiliated Hospital, China Medical University, Shenyang, People’s Republic of China; 3Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 4Department of Rheumatology, Affiliated Hospital of Inner Mongolia Medical College, Hohhot, Inner Mongolia, People’s Republic of China; 5Department of Rheumatology and Immunology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Uygur Autonomous Region, People’s Republic of China; 6Department of Rheumatology and Immunology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, People’s Republic of China; 7Department of Rheumatology, Southwest Hospital, Third Military Medical University, Chongqing, People’s Republic of China; 8Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 9Department of Rheumatology and Immunology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 10Department of Rheumatology, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 11Department of Clinical Immunology and Rheumatology, Xijing Hospital Affiliated to the Fourth Military Medical University, Shanxi, People’s Republic of China; 12Department of Rheumatology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaofeng Zeng; Mengtao LiDepartment of Rheumatology, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing Ave, Beijing 100730, People’s Republic of ChinaTel/ Fax + 86-10-69158793Email zengxfpumc@163.com; mengtao.li@cstar.org.cnPurpose: Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by chronic destructive synovitis and possible multisystem involvement. This study aimed to survey the treatment satisfaction of physicians and patients with RA, and to explore the potential factors.Patients and Methods: This cross-sectional study was conducted in 12 centers across China between March 2018 and April 2018. The Treatment Satisfaction Questionnaire for Medication version II was used to assess the treatment satisfaction of patients and physicians. Multivariable regression analysis was used to determine the factors independently associated with treatment satisfaction of patients.Results: The patients’ satisfaction (n=335) with biological disease-modifying antirheumatic drugs (bDMARDs) was higher than physicians’ satisfaction (n=146) regarding the side effects (95.0± 14.3 vs 84.6± 15.7, P< 0.001) and convenience (74.6± 21.2 vs 69.1± 16.5, P=0.002). Among physicians, global satisfaction with bDMARDs was higher than that with conventional synthetic DMARDs (csDMARDs). The multivariable regression analysis showed that age was positively associated with satisfaction of patients, while college or above education and self-assessment of disease severity were inversely associated with satisfaction. Treatment satisfaction was associated positively with the quality of communication with the physician and inversely with treatment costs.Conclusion: For bDMARDs, the treatment satisfaction of patients with RA is generally higher than that of physicians’. Physicians’ satisfaction with bDMARDs is higher than with csDMARDs. Age, education, disease severity, communication with the physician, and treatment costs are independently associated with the treatment satisfaction among patients. Physician–patient communication should be improved in clinical practice. Treatment costs should be taken into account when physicians make decisions.Keywords: patient, physician, rheumatoid arthritis, treatment satisfaction, TSQM-II

Xin Tian, Ying Xuan, Rong Wu, Song Gao Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, People’s Republic of ChinaCorrespondence: Song GaoDepartment of Clinical Oncology, Shengjing Hospital of China Medical University, 36 San Hao Street, Shenyang 110004, People’s Republic of ChinaEmail gaogao0229@hotmail.comObjective: To investigate the curative and adverse effects (AEs) of additional use of nimotuzumab combined with induction chemotherapy and concurrent chemoradiotherapy in unresectable locoregionally advanced hypopharyngeal carcinoma.Patients and Methods: We retrospectively evaluated 36 patients with stage III or IVA hypopharyngeal carcinoma who received induction chemotherapy followed by concurrent chemoradiotherapy with or without nimotuzumab. The induction chemotherapy included two or three cycles of TPF regimen. The intensity-modulated radiation therapy (IMRT) dose was 70 Gy to the planning target volume. Concurrent with radiotherapy, patients received chemotherapy consisting of cisplatin q3w. Adjuvant chemotherapy consisting of TPF regimen was administered 1 month later after concurrent chemoradiotherapy. Nimotuzumab (200 mg day 1, q3w) was given to patients concurrently with induction chemotherapy and was administered concurrently with IMRT at a weekly dose of 200 mg.Results: After induction chemotherapy, the objective response rate in patients treated with nimotuzumab (group A) versus those treated without nimotuzumab (group B) was 91.7% versus 58.3% (p=0.029). After concurrent chemoradiotherapy, the objective response rate was 95.8% in group A versus 83.3% in group B (p=0.253). The median follow-up was 22.6 months (range 8.9– 39.5 months). The 2-year OS rate in group A and group B were 62.5% (95% CI 55– 70%) and 51.8% (95% CI 45– 59%), respectively, the 2-year OS rate in group A was better than group B, P< 0.05. PFS was 23 months (95% CI 19– 27) in group A versus 18 months (95% CI 12– 22) in group B, PFS was longer in group A than group B, P< 0.05. There was no significant difference in AEs between the two groups.Conclusion: Additional use of nimotuzumab combined with induction chemotherapy and concurrent chemoradiotherapy in unresectable locoregionally advanced hypopharyngeal carcinoma yielded better short-term efficacy, also may improve overall survival and progression-free survival than patients without using nimotuzumab. The toxicity was tolerable.Keywords: nimotuzumab, induction chemotherapy, chemoradiotherapy, unresectable, locoregionally advanced, hypopharyngeal carcinoma

Ye Xu,1 Xiangkuo Zheng,2 Weiliang Zeng,2 Tao Chen,1 Wenli Liao,1 Jiao Qian,1 Jie Lin,1 Cui Zhou,1 Xuebin Tian,2 Jianming Cao,2 Tieli Zhou1 1Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China; 2Department of Medical Laboratory Science, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Jianming Cao; Tieli Zhou Tel +86-577-88069595; +86-577-86689885Email wzcjming@163.com; wyztli@163.comBackground: Heteroresistance is a phenomenon that occurs in all bacteria and can cause treatment failure. Yet, the exact mechanisms responsible for heteroresistance still remain unknown. The following study investigated the mechanisms of imipenem-heteroresistance and -resistance in Pseudomonas aeruginosa clinical isolates from Wenzhou, China.Methods: Imipenem resistance was detected by the agar dilution method; heteroresistance was determined by population analysis profiles. Biofilm formation assay and modified carbapenem inactivation methods were also performed. Polymerase chain reaction (PCR) was conducted to detect oprD, and quantitative real-time PCR was used to determine expression levels of oprD, ampC and four efflux pump coding genes (mexB, mexD, mexE and mexY).Results: Six imipenem-heteroresistant and -resistant P. aeruginosa isolates were selected respectively. Deficient oprD was detected in all resistant isolates and two heteroresistant isolates. No strains produced carbapenemases. Expression levels of oprD were down-regulated in heteroresistant isolates. Transcription levels of the mexE and mexY were significantly increased in all heterogeneous subpopulations compared with their respective native ones. Compared with the susceptible group, increased mean relative expression levels of mexE and mexY or the decreased mean relative expression levels of oprD were observed in the resistant group (P < 0.05), whereas transcription levels of the mexB and mexD remained unchanged.Conclusion: Down-regulation of oprD contributed to the resistance and heteroresistance of imipenem in our P. aeruginosa clinical isolates. In addition, the marginal up-regulation of efflux systems may indirectly affect imipenem resistance. Contrarily, defective oprD was less common in our experimental heteroresistant strains than resistant strains.Keywords: Pseudomonas aeruginosa, imipenem, resistance, heteroresistance, molecular mechanism, oprD

Xuebin Tian, 1, 2 Xiangkuo Zheng, 2 Yao Sun, 1 Renchi Fang, 1 Siqin Zhang, 1 Xiucai Zhang, 1 Jie Lin, 1 Jianming Cao, 2 Tieli Zhou 1 1Department of Clinical Laboratory, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China; 2School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Tieli ZhouDepartment of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of ChinaTel +86-0577-86699370Email wyztli@163.com Jianming CaoSchool of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, People’s Republic of ChinaTel +86-0577-88069595Email wzcjming@163.comBackground: The emergence and spread of carbapenem-resistant Escherichia coli (E. coli) pose a serious threat to human health worldwide. This study aimed to investigate the molecular mechanisms underlying carbapenem resistance and their prevalence among E. coli in China.Methods: A collection of 5796 E. coli clinical isolates were collected from the First Affiliated Hospital of Wenzhou Medical University from 2002 to 2017. Sensitivity to antibiotics was determined using the agar dilution method. The detection of carbapenemases production and the prevalence of resistance-associated genes were investigated through modified carbapenem inactivation method (mCIM), PCR and sequencing. The mutations in outer membrane porins genes (ompC and ompF) were also analyzed by PCR and sequencing assays. The effect of efflux pump mechanism on carbapenem resistance was also tested. E. coli were typed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST).Results: A total of 58 strains (1.0%) of carbapenem-resistant E. coli were identified. The strains carrying blaKPC-2 and blaNDM accounted for 22.4% (13/58) and 51.7% (30/58), respectively. Among blaNDM- positive strains, 27 blaNDM genes were assigned to blaNDM-5, while the remaining three strains were blaNDM-1, whereas blaVIM, blaIMP, blaOXA-48, and blaSHV were not found. The CTX-M-type β-lactamase genes accounted for 96.6% (56/58). In addition, blaTEM-1 genes were identified in 58.6% of tested strains. In carbapenem-resistant isolates, mutations in OmpC (the majority of mutated sites were D192G and Q104_F141del, accounting for 54.5%) and OmpF (large deletions S75_V127del, W83_D135del and Q88_D135del) were detected. Of note, the antibiotic resistance was not associated with overexpression of efflux pump. Moreover, MLST categorized the 58 carbapenem-resistant isolates into 19 different sequence types. PFGE analysis revealed that homology among the carbapenem-resistant isolates was low and sporadic.Conclusion: The blaNDM was the principal resistance mechanism of carbapenem-resistant E. coli in the hospital. blaNDM-5 is becoming a new threat to public health and the alteration of outer membrane porins might help further increase the MIC of carbapenem.Keywords: Escherichia coli, carbapenem-resistant, carbapenemase, outer membrane porin, epidemiology

Ting Zhan, 1,* Qingxi Zhu, 1,* Zheng Han, 1 Jie Tan, 1 Meng Liu, 1 Weijie Liu, 1 Wei Chen, 1 Xiaoli Chen, 1 Xueting Chen, 2 Junsheng Deng, 2 Xia Tian, 1 Xiaodong Huang 1 1Department of Gastroenterology, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan 430060, People’s Republic of China; 2Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan 430060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaodong Huang; Xia Tian Tel +86 1388619054; +86 13871480868Email 13297056720@163.com; hcwy100@163.comBackground: Pancreatic cancer (PC) is a highly invasive tumor with a poor prognosis, short overall survival rate and few chemotherapeutic choices. Despite the importance of finding ways to treat pancreatic cancer, the mechanisms of tumor progression have not been fully elucidated. microRNA-455-3p (miR-455-3p) has been reported to play an important role in several cancers, but its function in pancreatic cancer remains unclear.Methods: To investigate the biological functions, miRNAs mimics or inhibitors were transfected into pancreatic cancer cells. Flow cytometry was used to detect cell apoptosis. Wound healing and Transwell assays were employed to observe cell invasion and migration abilities. The expression of Bcl-2, Bax, caspase-3, E-cadherin, N-cadherin, Snail, β-Catenin, c-Myc and Cyclin D1 were evaluated by qPCR and Western blot.Results: We confirmed that inhibition of miR-455-3p decreases cell apoptosis and increases cell migration, invasion and EMT of pancreatic cancer, whereas forced overexpression of miR-455-3p has the opposite effect. Furthermore, we demonstrated that the tumor suppression effects of miR-455-3p were partially reversed by TAZ overexpression. In addition, miR-455-3p led to inactivation of Wnt/β-catenin signaling in pancreatic cancer cells, and TAZ overexpression restored the inhibition of Wnt/β-catenin signaling.Conclusion: Taken together, our data demonstrated that miR-455-3p functions as an important tumor suppressor that suppresses the Wnt/β-catenin signaling pathway via TAZ to inhibit tumor progression in pancreatic cancer. We conclude that the miR-455-3p/TAZ/Wnt axis may be a potential therapeutic target for pancreatic cancer.Keywords: miR-455-3p, Wnt, apoptosis, metastasis, EMT

Xiaolang Tian, Changwu Huang, Xiaoli Ye, Hongyan Jiang, Rufang Zhang, Xiaofang Hu, Dongshuang Xu Department of Clinical Laboratory, University of Chinese Academy of Sciences Chongqing Renji Hospital (Fifth People’s Hospital of Chongqing), Chongqing, People’s Republic of ChinaCorrespondence: Dongshuang XuDepartment of Clinical Laboratory, University of Chinese Academy of Sciences Chongqing Renji Hospital (Fifth People’s Hospital of Chongqing), No. 24 Renji Road, Nanan District, Chongqing 400062, People’s Republic of ChinaTel +86 023-62895125Fax +86 023-62881980Email dongshuang_xu@163.comBackground: The emergence and spread of carbapenem-resistant Enterobacter cloacae (CR-ECL) have posed a serious threat to clinical management. This retrospective study assessed the epidemiological characteristics of CR-ECL to explore the risk factors and predictors of mortality in patients with CR-ECL infection.Methods: We performed a retrospective 1:2 case-control study of hospitalized patients from January 2014 to December 2017. A total of 85 consecutive unique CR-ECL strains comprised the case group, and 170 matched patients with carbapenem-susceptible Enterobacter cloacae (CS-ECL) infection at the same period as the control group. Isolates were screened for potential resistance genes by polymerase chain reaction (PCR) and molecular typing was performed by multilocus sequence typing (MLST).Results: The results of drug resistance gene detection showed that blaNDM-1 was the most common carbapenem resistance gene. The MLST results showed that ST51 was the predominant epidemic type, followed by ST88. ICU admission (P< 0.001), drainage tube (P=0.002), central venous catheter (P=0.005), and carbapenem exposure (P=0.003) were independent risk factors for CR-ECL infection. Significant predictors for 28-day mortality included solid tumours (P=0.005), septic shock (P=0.019), and mechanical ventilation (P=0.027).Conclusion: Our study indicated that ST51 and ST88, which are closely related, were the predominant epidemic types of CR-ECL producing blaNDM-1 in southwestern China. Strengthening the surveillance of patients with solid tumours, septic shock and mechanical ventilation is an urgent need.Keywords: carbapenem-resistant Enterobacter cloacae, epidemiological characteristics, risk factors, predictors of mortality

ObjectiveTo develop and validate revised classification criteria for eosinophilic granulomatosis with polyangiitis (EGPA).MethodsPatients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in five phases: (1) identification of candidate criteria items using consensus methodology, (2) prospective collection of candidate items present at the time of diagnosis, (3) data-driven reduction of the number of candidate items, (4) expert panel review of cases to define the reference diagnosis and (5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators.ResultsThe development set for EGPA consisted of 107 cases of EGPA and 450 comparators. The validation set consisted of an additional 119 cases of EGPA and 437 comparators. From 91 candidate items, regression analysis identified 11 items for EPGA, 7 of which were retained. The final criteria and their weights were as follows: maximum eosinophil count ≥1×109/L (+5), obstructive airway disease (+3), nasal polyps (+3), cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3–ANCA positivity (−3), extravascular eosinophilic predominant inflammation (+2), mononeuritis multiplex/motor neuropathy not due to radiculopathy (+1) and haematuria (−1). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having EGPA if the cumulative score was ≥6 points. When these criteria were tested in the validation data set, the sensitivity was 85% (95% CI 77% to 91%) and the specificity was 99% (95% CI 98% to 100%).ConclusionThe 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis with Polyangiitis demonstrate strong performance characteristics and are validated for use in research.

Accurate assessment of anthropogenic carbon dioxide (CO2) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere in a changing climate is critical to better understand the global carbon cycle, support the development of climate policies, and project future climate change. Here we describe and synthesize data sets and methodologies to quantify the five major components of the global carbon budget and their uncertainties. Fossil CO2 emissions (EFOS) are based on energy statistics and cement production data, while emissions from land-use change (ELUC), mainly deforestation, are based on land use and land-use change data and bookkeeping models. Atmospheric CO2 concentration is measured directly, and its growth rate (GATM) is computed from the annual changes in concentration. The ocean CO2 sink (SOCEAN) is estimated with global ocean biogeochemistry models and observation-based data products. The terrestrial CO2 sink (SLAND) is estimated with dynamic global vegetation models. The resulting carbon budget imbalance (BIM), the difference between the estimated total emissions and the estimated changes in the atmosphere, ocean, and terrestrial biosphere, is a measure of imperfect data and understanding of the contemporary carbon cycle. All uncertainties are reported as ±1σ. For the year 2021, EFOS increased by 5.1 % relative to 2020, with fossil emissions at 10.1 ± 0.5 GtC yr−1 (9.9 ± 0.5 GtC yr−1 when the cement carbonation sink is included), and ELUC was 1.1 ± 0.7 GtC yr−1, for a total anthropogenic CO2 emission (including the cement carbonation sink) of 10.9 ± 0.8 GtC yr−1 (40.0 ± 2.9 GtCO2). Also, for 2021, GATM was 5.2 ± 0.2 GtC yr−1 (2.5 ± 0.1 ppm yr−1), SOCEAN was 2.9 ± 0.4 GtC yr−1, and SLAND was 3.5 ± 0.9 GtC yr−1, with a BIM of −0.6 GtC yr−1 (i.e. the total estimated sources were too low or sinks were too high). The global atmospheric CO2 concentration averaged over 2021 reached 414.71 ± 0.1 ppm. Preliminary data for 2022 suggest an increase in EFOS relative to 2021 of +1.0 % (0.1 % to 1.9 %) globally and atmospheric CO2 concentration reaching 417.2 ppm, more than 50 % above pre-industrial levels (around 278 ppm). Overall, the mean and trend in the components of the global carbon budget are consistently estimated over the period 1959–2021, but discrepancies of up to 1 GtC yr−1 persist for the representation of annual to semi-decadal variability in CO2 fluxes. Comparison of estimates from multiple approaches and observations shows (1) a persistent large uncertainty in the estimate of land-use change emissions, (2) a low agreement between the different methods on the magnitude of the land CO2 flux in the northern extratropics, and (3) a discrepancy between the different methods on the strength of the ocean sink over the last decade. This living data update documents changes in the methods and data sets used in this new global carbon budget and the progress in understanding of the global carbon cycle compared with previous publications of this data set.

Cosmic rays were first discovered over a century ago, however the origin of their high-energy component remains elusive. Uncovering astrophysical neutrino sources would provide smoking gun evidence for ultrahigh energy cosmic ray production. The IceCube Neutrino Observatory discovered a diffuse astrophysical neutrino flux in 2013 and observed the first compelling evidence for a high-energy neutrino source in 2017. Next-generation telescopes with improved sensitivity are required to resolve the diffuse flux. A detector near the equator will provide a unique viewpoint of the neutrino sky, complementing IceCube and other neutrino telescopes in the Northern Hemisphere. Here we present results from an expedition to the north-eastern region of the South China Sea. A favorable neutrino telescope site was found on an abyssal plain at a depth of $\sim$ 3.5 km. Below 3 km, the sea current speed was measured to be $v_{\mathrm{c}}, Comment: 33 pages,16 figures. Correspondence should be addressed to D. L. Xu (donglianxu@sjtu.edu.cn)

Yingjian Song,1,* Huimin Liu,2,* Chunling Cui,3 Xiaonu Peng,1 Chaoyang Wang,1 Xudong Tian,4 Wenjun Li1 1Department of Thoracic Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong, People’s Republic of China; 2Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong, People’s Republic of China; 3Library, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong, People’s Republic of China; 4Department of Thoracic Surgery, Liaocheng People’s Hospital, Liaocheng 252000, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xudong TianDepartment of Thoracic Surgery, Liaocheng People’s Hospital, No. 67, Changxi Road, Liaocheng, Shandong 252000, People’s Republic of ChinaTel +86-15653112705Email zhangding553977@126.comWenjun LiDepartment of Thoracic Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhungding East Road, Zhifu District, Yantai 264000, Shandong, People’s Republic of ChinaTel +86-18653525277Email liwenjun90808@163.comObjective: To study the effect of peroxiredoxin 1 (PRDX1) on esophageal squamous carcinoma cells and determine whether it plays a role in regulating the PI3K/AKT signaling pathway.Methods: Three esophageal squamous cell carcinoma cell lines (Eca-109, EC9706, and KYSE150) and one normal cell line (human esophageal epithelial cells) were selected. The protein expression of peroxiredoxin 1 (PRDX1) and the activity of the PI3K/AKT pathway were detected via Western blotting. The proliferation ability of cells was detected through the MTT assay and cell clone formation. Apoptosis was detected using flow cytometry. Subsequently, cells were treated with a PI3K/AKT pathway inhibitor and activator, alone or in combination with silencing of PRDX1, and the above indicators were re-tested.Results: The expression of PRDX1 and activity of PI3K/AKT pathway-associated proteins were higher in esophageal cancer cells than in normal esophageal epithelial cells. Compared with normal human esophageal epithelial cells, the proliferation of the three types of esophageal cancer cells was increased, whereas their level of apoptosis was decreased (p

Xinyu Dai,1 Jingqing Yao,1 Yuejiao Zhong,2 Yuntao Li,3 Qianling Lu,4 Yan Zhang,1 Xue Tian,1 Zhirui Guo,5 Tingting Bai5 1Department of Neurology, Second Affiliated Hospital of Nanjing Medical University, Nanjing 210000, People’s Republic of China; 2Department of Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210000, People’s Republic of China; 3Department of General Practice, Second Affiliated Hospital of Nanjing Medical University, Nanjing 210000, People’s Republic of China; 4Department of Neurology, Third Affiliated Hospital of Nanjing Medical University, Nanjing 210000, People’s Republic of China; 5Department of Geratology, Second Affiliated Hospital of Nanjing Medical University, Nanjing 210000, People’s Republic of ChinaCorrespondence: Yuejiao ZhongDepartment of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Baiziting 42, Nanjing 210009, People’s Republic of ChinaEmail zhongyuejiao2019@163.com Yuntao LiDepartment of General Practice, Second Affiliated Hospital of Nanjing Medical University, No. 121 Jiangjiayuan Road, Nanjing, Jiangsu, People’s Republic of ChinaTel/Fax +86 25 5850 9989Email 18951762737@163.comBackground: Primary central nervous system lymphomas (PCNSL) are extranodal malignant non-Hodgkin lymphomas (NHL) that arise exclusively in central nervous system (CNS). Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype.Purpose: To evaluate whether nano drug-loading system-mediated magnetic-targeted thermochemotherapy could produce a better therapeutic effect than single chemotherapy while reducing the use of chemotherapeutic drugs.Methods: Six groups (control, Fe3O4, MTX, Fe3O4@MTX, Fe3O4 with hyperthermia and Fe3O4@MTX with hyperthermia) were set. Tumor cell apoptosis in each treatment group was detected by flow cytometry. Apoptosis-related gene expressions Caspase-3, Bax and Bcl-2 were detected by qPCR and Western blot; intracranial tumor model of PCNSL was established by intracranial injection of OCI-LY18 tumor cells into BALB/c-Nude mice. Magnetic resonance imaging (MRI) was used to monitor tumor progression and H&E staining was used to observe pathological changes of the tumor tissue.Results: In vitro, compared with chemotherapy alone, apoptosis rate of Fe3O4@MTX mediated thermochemotherapy group was significantly increased, and expression of apoptosis-inducing gene Caspase-3 and Bax were significantly upregulated in OCI-LY18 cells, while expression of apoptosis-inhibiting Bcl-2 gene was significantly downregulated. In vivo, MRI showed successful generation of intracranial tumor, and tumor volume was significantly smaller in combined thermochemotherapy group than in single chemotherapy group. H&E staining result of tumor tissues in each group was consistent with MRI; tumor cells were significantly reduced in thermochemotherapy group. Expression of apoptosis-related gene Caspase-3 and Bax were significantly upregulated in tumor tissues, while expression of Bcl-2 gene was significantly downregulated.Conclusion: These results demonstrated in vivo and in vitro that the combined thermochemotherapy of Fe3O4@MTX MNPs was superior to the single MTX chemotherapy with less dosage, which may promote apoptosis of DLBCL cells through the mitochondrial apoptotic pathway and provided a new way for the treatment of PCNSL.Keywords: primary central nervous lymphoma, PCNSL, Fe3O4@MTX magnetic nanoparticles, MNPs, hyperthermia, OCI-LY18 cells

This study included 93 patients with renal masses who underwent standard partial nephrectomy or tumor enucleation. After surgery, parenchymal mass loss caused by devascularization resulted in more damage to renal function than excised parenchymal mass loss. Surgeons should seek better techniques to decrease devascularization during reconstruction.To evaluate the importance of devascularized parenchymal mass(DPM) and excised parenchymal mass(EPM) in functional preservation after standard partial nephrectomy(SPN).Forty-one patients who underwent pure tumor enucleation(TE) and 52 patients who underwent SPN with necessary data were included. As no EPM was lost in TE, the TE samples were used to estimate the degree of volume shrinkage that occurred when the measurements were performed in vivo with blood flow versus ex vivo without, and the shrinkage ratio was calculated as specimen volume divided by tumor volume in vivo. In SPN, the specimen volume comprised tumor volume plus EPM. The EPM was calculated as specimen volume divided by shrinkage ratio minus tumor volume in vivo. The DPM was defined as total ipsilateral parenchymal mass loss minus EPM. T tests, χThe mean sizes of devascularized and excised parenchymal masses were 13.6 cmThe DPM comprises most of parenchymal mass loss after SPN and plays a more important role than EPM on functional outcomes. Surgeons should pay more attention to reducing devascularization during partial nephrectomy.

Introduction Fabry disease is a lysosomal storage disorder resulting in multisystemic effects due to deposition and accumulation of glycosphingolipids. Although an X linked disorder, it is recognised that female heterozygotes can express clinical manifestations. Cardiac expression in the female Fabry population remains incompletely understood. Data from the Fabry Outcome Survey suggests that up to a quarter of female patients demonstrate left ventricular hypertrophy (LVH) on echocardiography. Although LVH is the most commonly cited cardiac finding, other abnormalities from clinical surveillance can include electrocardiographic abnormalities, fibrosis and elevated troponin levels. Purpose To establish the prevalence and extent of cardiac involvement amongst our cohort of female Fabry patients. Methods Heterozygous females, confirmed by genetic testing, were identified in our single centre Fabry database. Data was collected retrospectively on their 12 lead ECG, high sensitivity troponin I level and echocardiography performed at their most recent cardiac Fabry clinic visit, along with the most recent cardiac magnetic resonance imaging (CMR). Values are expressed as mean ± SD. Results 51 female heterozygotes were identified, ranging from 23 to 83 years (mean age 49.3±15.4). 28 (54.9%) were established on enzyme replacement therapy. On echocardiography LVH of ≥13mm was identified in 14 (27.5%) patients (mean 14.6±1.9 mm). 44 patients had CMR and of these, 17 (38.6%) had findings in keeping with a Fabry cardiomyopathy (34.1% had fibrosis, 15.9% hypertrophy, 13.6% both). Of the 17 patients with abnormalities on CMR, 8 had normal left ventricular wall thickness on echocardiography. All patients had a high sensitivity troponin I measurement and this was above upper reference limits (>40ng/L) in 21 (41.1%) patients in the absence of chest pain. Of 21 patients with abnormal troponin I levels, 9 had normal left ventricular wall thickness on echocardiography. Abnormalities identified on 12 lead ECG are summarised in Table 1. All patients with ECG abnormalities listed in Table 1 had an abnormal troponin and/or abnormal imaging, except for 5 patients who had an isolated short PR interval. 6 patients had a permanent pacemaker and 1 had a primary prevention implantable cardioverter defibrillator. 25 (49%) of the 51 patients were classed as having cardiac involvement based on raised troponin levels and/or abnormal imaging findings. Conclusion Although Fabry disease is traditionally thought to be a male predominant disease, in our cohort nearly half of our female heterozygotes showed evidence of cardiac involvement. The use of CMR, cardiac biomarkers and 12 lead ECG are helpful adjuncts to identify cardiac involvement, which could otherwise be missed if stand-alone echocardiography was used. Timely identification and monitoring of cardiac involvement has clinical implication, especially with regards to prognosis and treatment. Funding Acknowledgement Type of funding sources: None.

BACKGROUND: Innate lymphoid cells type 2 (ILC2s) play critical homeostatic functions in peripheral tissues. ILC2s reside in perivascular niches and limit atherosclerosis development. OBJECTIVES: ILC2s also reside in the pericardium but their role in postischemic injury is unknown. METHODS: We examined the role of ILC2 in a mouse model of myocardial infarction (MI), and compared mice with or without genetic deletion of ILC2. We determined infarct size using histology and heart function using echocardiography. We assessed cardiac ILC2 using flow cytometry and RNA sequencing. Based on these data, we devised a therapeutic strategy to activate ILC2 in mice with acute MI, using exogenous interleukin (IL)-2. We also assessed the ability of low-dose IL-2 to activate ILC2 in a double-blind randomized clinical trial of patients with acute coronary syndromes (ACS). RESULTS: We found that ILC2 levels were increased in pericardial adipose tissue after experimental MI, and genetic ablation of ILC2 impeded the recovery of heart function. RNA sequencing revealed distinct transcript signatures in ILC2, and pointed to IL-2 axis as a major upstream regulator. Treatment of T-cell-deficient mice with IL-2 (to activate ILC2) significantly improved the recovery of heart function post-MI. Administration of low-dose IL-2 to patients with ACS led to activation of circulating ILC2, with significant increase in circulating IL-5, a prototypic ILC2-derived cytokine. CONCLUSIONS: ILC2s promote cardiac healing and improve the recovery of heart function after MI in mice. Activation of ILC2 using low-dose IL-2 could be a novel therapeutic strategy to promote a reparative response after MI.

Background Adenosine is used to treat no‐reflow in the infarct‐related artery (IRA) during ST‐segment–elevation myocardial infarction intervention. However, the physiological effect of adenosine in the IRA is variable. Coronary steal—a reduction of blood flow to the distal coronary bed—can occur in response to adenosine and this is facilitated by collaterals. We investigated the effects of adenosine on coronary flow reserve (CFR) in patients presenting with ST‐segment–elevation myocardial infarction to better understand the physiological mechanism underpinning the variable response to adenosine. Methods and Results Pressure‐wire assessment of the IRA after percutaneous coronary intervention was performed in 93 patients presenting with ST‐segment–elevation myocardial infarction to calculate index of microvascular resistance, CFR, and collateral flow index by pressure. Modified collateral Rentrop grade to the IRA was recorded, as was microvascular obstruction by cardiac magnetic resonance imaging. Coronary steal (CFR 1.1) after adenosine occurred in 19 (20%), 15 (16%), and 59 (63%) patients, respectively. Patients with coronary steal had higher modified Rentrop score to the IRA (1 [0, 1.75] versus 0 [0, 1], P P =0.004) than the hyperemic group. The coronary steal group also had significantly higher index of microvascular resistance (61.68 [28.13, 87.04] versus 23.93 [14.67, 37.00], P =0.006) and had more disease (stenosis >50%) in the donor arteries (52.63% versus 22.03%, P =0.02) than the hyperemic group. Conclusions Adenosine‐induced coronary steal may be responsible for a reduction in coronary flow reserve in a proportion of patients presenting with ST‐segment–elevation myocardial infarction. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03145194. URL: https://www.isrctn.com ; Unique identifier: ISRCTN3176727.

Effectively recycling spent perovskite solar modules will further reduce the energy inputs and environmental consequences induced by their production and deployment, thus facilitating their sustainable development. Here, through “cradle-to-grave” life cycle assessments on a variety of perovskite solar cell architectures, we report that the substrates with conducting oxide and energy-intensive heating processes are the largest contributors to the primary energy consumption, global warming potential, and other impact categories. We thus focus on these materials and processes when expanding to “cradle-to-cradle” analyses with recycling as the end-of-life scenario. Our results reveal that recycling strategies can lead to up to 72.6% shorter energy payback time and 71.2% reduction in greenhouse gas emission factor. We highlight that the best recycled module architecture can exhibit an extremely small energy payback time of 0.09 years and greenhouse gas emission factor as low as 13.4 g CO2-eq/kWh, such that it outcompetes all other rivals including the market-leading silicon at 1.3 - 2.4 years and 22.1 - 38.1 g CO2-eq/kWh. Finally, we use sensitivity analyses to highlight the importance of prolonging the device lifetime and quantify the impacts of uncertainty induced by the still immature manufacturing processes, changing operating conditions, and individual differences for each module.

BackgroundPsychopathic traits have been suggested to increase the risk of violations of socio-moral norms. Previous studies revealed that abnormal neural signatures are associated with elevated psychopathic traits; however, whether the intrinsic network architecture can predict psychopathic traits at the individual level remains unclear.MethodsThe present study utilized connectome-based predictive modeling (CPM) to investigate whether whole-brain resting-state functional connectivity (RSFC) can predict psychopathic traits in the general population. RS functional magnetic resonance imaging data were collected from 84 college students with varying psychopathic traits measured by the Levenson Self-Report Psychopathy Scale (LSRP).ResultsWe found that RSFC of the negative networks predicted individual differences in total LSRP and secondary psychopathy scores but not primary psychopathy score. Particularly, nodes with the most connections in the predictive connectome anchored in the prefrontal cortex (e.g., anterior prefrontal cortex and orbitofrontal cortex) and limbic system (e.g., anterior cingulate cortex and insula). In addition, the connections between the occipital network (OCCN) and cingulo-opercular network (CON) served as a significant predictive connectome for total LSRP and secondary psychopathy score.ConclusionCPM constituted by whole-brain RSFC significantly predicted psychopathic traits individually in the general population. The prefrontal cortex and limbic system at the anatomic level and the CON and OCCN at the functional network level plays a special role in the predictive model—reflecting atypical executive control and affective processing for individuals with elevated psychopathic traits. These findings may provide some implications for early detection and potential intervention of psychopathic tendency.

Salmonella Typhimurium is gram-negative flagellated bacteria that can cause food-borne gastroenteritis and diarrhea in humans and animals. The regenerating islet-derived family member 4 (Reg4) is overexpressed in the gastrointestinal tract during intestinal inflammation. However, the role of Reg4 in the intestinal inflammation induced by Salmonella Typhimurium is largely unknown. In this study, we reported for the first time that Reg4 has bactericidal activity against intestinal infection caused by Salmonella Typhimurium. In vivo, Reg4 could reduce the colonization of Salmonella Typhimurium and attenuate intestinal inflammation in the Salmonella Typhimurium-infected model. Additionally, the mice with the epithelial cell specific deletion of Reg4 (Reg4ΔIEC) exhibited more severe intestinal inflammation and more colonization of Salmonella Typhimurium. However, the administration of Reg4 could reverse these negative impacts. In vitro, Reg4 protein was showed to inhibit the growth of Salmonella Typhimurium. We further investigate the function motif of Reg4 and find that the “HDPQK” motif in Reg4 is essential to its bactericidal activity. Reg4 exerted the bactericidal effect by binding to the flagellin of Salmonella Typhimurium and suppressing its motility, adhesion, and invasion to the intestinal epithelia. In conclusion, our findings identify Reg4 as a novel antimicrobial peptide against infection by Salmonella Typhimurium and explore its possible mechanism, which may be of great significance for developing novel agents against flagellated micro pathogens.

BACKGROUND AND PURPOSE: Intraplaque hemorrhage within intracranial atherosclerotic plaques identified by high-resolution MR imaging has been studied as a potential marker of stroke risk. However, previous studies only examined intracranial arteries with high-grade stenosis (degree of stenosis, >50%). This study aimed to ascertain the clinical relevance of intraplaque hemorrhage in patients with low- and high-grade stenotic basilar artery plaques. MATERIALS AND METHODS: Patients with basilar artery stenosis (n = 126; mean age, 62 ± 10 years; 66 symptomatic and 60 asymptomatic) underwent high-resolution MR imaging. The relationship between imaging findings (intraplaque hemorrhage, contrast enhancement, degree of stenosis, minimal lumen area, and plaque burden) and symptoms was analyzed. RESULTS: Intraplaque hemorrhage was identified in 22 patients (17.5%), including 21 (31.8%) symptomatic patients and 1 (1.7%) asymptomatic patient. Multivariate analysis showed that intraplaque hemorrhage was the strongest independent marker of symptomatic status (odds ratio, 27.5; 95% CI, 3.4–221.5; P = .002). Contrast enhancement was also independently associated with symptomatic status (odds ratio, 9.9; 95% CI, 1.5–23.6; P = .016). Stenosis, minimal lumen area, and plaque burden were not correlated with symptoms (P > .05). Intraplaque hemorrhage was present in both low- and high-grade stenotic basilar arteries (11.3% versus 16.3%, P = .63). Diagnostic performance values of intraplaque hemorrhage for patients with acute/subacute symptomatic stroke were the following: specificity, 98.3%; sensitivity, 31.8%; positive predictive value, 95.5%; and negative predictive value, 56.7%. CONCLUSIONS: Intraplaque hemorrhage is present in both low- and high-grade stenotic basilar artery plaques and is independently associated with symptomatic stroke status. Intraplaque hemorrhage may identify high-risk plaque and provide new insight into the management of patient with stroke without significant stenosis.