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Guanglu Jiang,1,* Rongmei Liu,2,* Yi Xue,1 Qiping Ge,2 Lihui Nie,2 Zizheng Lv,2 Zhongshun Kong,2 Jin Shi,2 Hongmei Chen,2 Hua Li,2 Xiaoguang Wu,2 Li Xie,2 Yanhua Song,2 Hairong Huang,1 Mengqiu Gao2 1National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-Resistant Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mengqiu Gao; Hairong Huang, Email gaomqwdm@aliyun.com; huanghairong@tb123.orgBackground: Contezolid (CZD) is an analog of Linezolid (LZD) that has demonstrated potent in vitro and in vivo activity against tuberculosis (TB) while presenting a safer side-effect profile. In this study, we evaluated the early bactericidal activity (EBA) of CZD compared to LZD, with LZD serving as a control.Methods: Naive, smear-positive pulmonary TB patients were enrolled and randomly assigned to receive either a 14-day monotherapy regimen of 600 mg LZD once daily (QD) or 800 mg CZD twice daily (BID). Sputum samples were collected daily starting one day before treatment initiation and continuing throughout the treatment period. Each sample was processed for the enumeration of acid-fast bacilli (AFB) colonies, and time-to-positivity (TTP) during MGIT960 liquid culture was recorded.Results: A total of 10 eligible patients were enrolled in each treatment group, although one patient in the CZD group was later excluded from the analysis. The early bactericidal activity (EBA0-14) was 0.08 ± 0.12 log CFU/mL/day (95% CI: − 0.02 to 0.18 CFU/mL/day) in the CZD group, compared to 0.03 ± 0.10 log CFU/mL/day (95% CI: − 0.05 to 0.10 CFU/mL/day) in the LZD group. The increase in time-to-positivity (TTP0-14) was 38.6 ± 43.69 hours (95% CI: − 1.85 to 79 hours) in the CZD group and 27.7 ± 78.21 hours (95% CI: − 28.15 to 83.75 hours) in the LZD group. LZD showed rapid bacterial reduction in sputum during the first two days of treatment, whereas CZD demonstrated superior efficacy after a few days of treatment.Conclusion: 800 mg BID contezolid exhibited comparable efficacy to 600 mg QD LZD in treating pulmonary TB in this EBA study. While CZD showed slower initial bactericidal action compared to LZD, its efficacy surpassed that of LZD after a few days of treatment. Given its similar efficacy and superior safety profile, contezolid may serve as an alternative to linezolid for the treatment of tuberculosis.Keywords: contezolid, linezolid, early bactericidal activity, time-to-positivity

We report on the fabrication of single-mode channel waveguide structures produced by the vacuum assisted microfluidic soft lithography technique. The soft lithographic technique in conjunction with a specially designed photomask pattern and a synthesized UV curable epoxy resin can result in a high yield, cost-effective method for fabrication of channel waveguides. In particular, the use of the microfluidic technique allows for the production of freestanding high quality single-mode channel waveguides on various substrates. Notably, the introduction of sectional flow tapers allows for proper uniform filling of long length small cross-sectional waveguide structures that would ordinarily succumb to clogging at shorter distances during channel filling. The fabricated polymer waveguide was 30 mm in length with a cross section dimension of 7 × 7 µm. The single-mode waveguide propagation was confirmed with beam profiler measurement, and the measured propagation loss for this polymer waveguide was about 0.55 dB/cm.

Jiali Xia, Guan Jiang Department of Dermatology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, People’s Republic of ChinaCorrespondence: Guan Jiang, Department of Dermatology, The Affiliated Hospital of Xuzhou Medical University, 99 West Huai Hai Road, Xuzhou, Jiangsu, 221002, People’s Republic of China, Tel +86 181 6877 7336, Email dr.guanjiang@xzhmu.edu.cnAbstract: Eruptive pruritic papular porokeratosis (EPPP) is a subtype of porokeratosis (PK). EPPP is characterized by intense itching and challenging to treat in some cases. Herein, for the first time, a case of successful relief of EPPP treated with abrocitinib was reported. A 75-year-old male with a 60-year history of PK suddenly experienced severe itching in the past 6 months. The patient’s use of antihistamines, prednisone, vitamin A derivatives, vitamin D derivatives, and tripterygium wilfordii showed poor efficacy. Abrocitinib is a highly selective JAK1 inhibitor, and JAK1 appears to play a crucial role in pruritic diseases. Abrocitinib can quickly relieve itching within 24 hours. Before abrocitinib treatment, the visual analog scale (VAS) score was 10, the 12-item pruritus severity scale (12-PSS) score was 19, and the dermatology life quality index (DLQI) score was 18. Abrocitinib (100 mg) was taken orally once a day. After 1 month of oral administration of abrocitinib, the skin lesions gradually subsided, pruritus was relieved, and no adverse side effects occurred. The VAS, 12-PSS, and DLQI scores of the patient decreased to 2, 3, and 4, respectively. This report suggests a potential therapeutic benefit of abrocitinib in managing EPPP. However further investigations with larger sample sizes and controlled studies are necessary to validate its efficacy as a clinical therapy.Keywords: eruptive pruritic papular porokeratosis, porokeratosis, abrocitinib, pruritus, itch, JAK inhibitors

Guanghui Jiang,* Cuicui Sheng,* Luxia Yan,* Zipeng Wang, Qing Wang, Rui Chen, Ying Zhao Department of Neurology, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ying Zhao; Rui Chen, Email zhaoying772023@163.com; chenrui5980@163.comPurpose: To explore the relationship between the serum level of S100 calcium-binding protein, beta chain (S100β) and Parkinson’s disease (PD) with depression.Patients and Methods: A total of 145 patients with PD and 60 healthy controls matched for sex, age, and years of education in our hospital were selected. Fluorescence quantitative immunochromatography was used to quantify the level of S100β in serum. Clinical manifestations were assessed by Unified Parkinson’s Disease Rating Scale part-III (UPDRS-III), Hoehn & Yahr (H-Y) stage and 17-item Hamilton Rating Scale for Depression (HAMD-17). According to the results of HAMD-17, PD patients were divided into PD with depression group and PD without depression group. The relationship between serum S100β and HAMD-17 scores in PD patients with depression was investigated through correlation analysis and multivariate regression analysis, and receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of serum S100β.Results: The level of serum S100β in PD with depression group was significantly higher than that in PD without depression group and control group. In PD patients with depression, serum S100β level was positively correlated with UPDRS-III score, H-Y Scale and HAMD-17 score. The HAMD-17 score was positively correlated with the UPDRS-III and H-Y scales, and the increase in the HAMD-17 score was associated with women. Elevated serum S100β level and UPDRS-III score are independent risk factors for PD with depression. Analysis of receiver operating characteristic (ROC) curves showed that the serum S100β level with a cutoff of 0.28 ng/mL distinguished patients with PD with or without depression with an area under the ROC curve (AUC) of 0.742, sensitivity of 0.696, and specificity of 0.779.Conclusion: The serum S100β level could be a biomarker of PD with depression.Keywords: Parkinson’s disease, depression, S100β, risk factors

Xiaoxia Tang,1 Yizhuo Zhang,2 Xinyu Dong,2 Guixing Jiang,2 Defei Hong,2,* Xiaolong Liu2,* 1Operating Room, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2General Surgery, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaolong Liu; Defei Hong, Email hahapoint1234@sina.com; hongdefi@163.comAbstract: At present, the average five-year survival rate of liver cancer in China is only 12.1%. The reason for this association lies in the diagnosis at its middle or/and advanced stage of liver cancer for lacking special clinical symptoms in almost 70% of patients without the chance of effective surgical resection. Epidemiological studies have shown that there are only 30% of patients with an initial diagnosis of liver cancer have the opportunity to undergo radical surgery. Therefore, systematic and comprehensive treatment would play an important role in liver cancer treatment at its middle or/and advanced stage, and the related therapeutic schedule still needs further improvement and optimization. We applied a gene-targeted drug of Icaritin soft capsule in the treatment of a liver cancer patient at its advanced stage. And the level of AFP was found to decrease to 6.4ng/mL from 10.86ng/mL; meanwhile, MRI showed that the primary tumor significantly reduced in size, with shrinking of the hepatogastric space, hepatic aortic side, and renal artery side lymph nodes. After treatment with TACE and Icaritin, the patient had no discomfort and no longer experienced abdominal pain and bloating and gained three kilograms of weight. The therapeutic effect of Icaritin-targeted drugs was completely demonstrated during the later treatment follow-up. That is to say, the multiple anti-tumor characteristics of Icaritin with good safety were fully displayed in this case, and it can be used in combination with other drugs to treat hepatocellular carcinoma in the clinical setting. The results show that Icaritin can put some effects on the combined treatment of patients with liver cancer.Keywords: HCC, patient, systematic and comprehensive treatment, Icaritin, gene-targeted

The ecological threshold concept describes how changes in one or more factors at thresholds can result in a large shift in the state of an ecosystem. This concept focuses attention on limiting factors that affect the tolerance of systems or organisms and changes in them. Accumulating empirical evidence for the existence of ecological thresholds has created favorable conditions for practical application to wildlife conservation. Applying the concept has the potential to enhance conservation of two large carnivores, Amur tiger and leopard, and the knowledge gained could guide the construction of a proposed national park. In this review, ecological thresholds that result from considering a paradigm of bottom-up control were evaluated for their potential to contribute to the conservation of Amur tiger and leopard. Our review highlights that large carnivores, as top predators, are potentially affected by ecological thresholds arising from changes in climate (or weather), habitat, vegetation, prey, competitors, and anthropogenic disturbances. What's more, interactions between factors and context dependence need to be considered in threshold research and conservation practice, because they may amplify the response of ecosystems or organisms to changes in specific drivers. Application of the threshold concept leads to a more thorough evaluation of conservation needs, and could be used to guide future Amur tiger and leopard research and conservation in China. Such application may inform the conservation of other large carnivores worldwide.

Yuhong Tang,1,* Jun Cao,1,* Rui Peng,1 Xingkang Mao,1 Bingbing Su,1 Hao Tang,1 Daoyuan Tu,1 Jie Zhou,1 Guoqing Jiang,1 Shengjie Jin,1 Qian Wang,1 Chen Zhang,2 Renjie Liu,1 Chi Zhang,1,3 Dousheng Bai1,3 1Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China; 2The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China; 3General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dousheng Bai; Chi Zhang, Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, 98 West Nantong Road, Yangzhou, 225000, People’s Republic of China, Email drbaidousheng@yzu.edu.cn; zc17212850@163.comIntroduction: Immune checkpoint therapy (ICIs) effectively improves the prognosis of advanced (stage III/IV) hepatocellular carcinoma (HCC) patients. However, its objective response rate (ORR) is below 20%, significantly limiting ICI use in advanced HCC patients. The level of tumour immune infiltration influences ICI response rate. Recent studies have found ubiquitinase to be an important factor that regulates tumour immune infiltration. Therefore, the aim of this study is to explore the key ubiquitination genes that regulate immune infiltration in advanced HCC and further validate them.Methods: A biotechnological process was performed as a means of classifying 90 advanced HCC patients into three immune subtypes and identifying associations with immune infiltration in the co-expressed modules. Ubiquitination-related genes were then screened with WGCNA. Gene enrichment analysis was performed for the target module and 30 hub genes were screened out by protein–protein interaction network (PPI). ssGSEA, single-gene sequencing and the MCP counter were used for exploring immune infiltration. TIDE score was applied for predicting drug efficacy and GSEA was used for exploring potential pathways. Finally, GRB2 expression in HCC tissue was validated by in vitro experiments.Results: GRB2 expression was found to have a significant correlation with the pathological stage and prognosis of HCC patients and a positive correlation with immune infiltration and tumour mutation burden (TMB). In addition, significant correlations with the efficacy of ICIs, sorafenib and transarterial chemoembolization (TACE) were identified. GRB2 was found to be most significantly associated with the JAK-STAT signalling pathway and cytosolic DNA sensing pathway. Finally, it was found that GRB2 expression is closely related to the prognosis, tumour size and TMN stage.Conclusion: A significant association was observed between the ubiquitinated gene GRB2 and the prognosis and immune infiltration of advanced HCC patients and it may potentially be used for predicting therapy efficacy in advanced HCC patients in the future.Keywords: ubiquitination, growth factor receptor-binding protein 2, liver cancer, tumour-infiltrating immune cells

Lu Liu,1,&ast; Xiaojiu Zhang,1,2,&ast; Nan Jiang,3,&ast; Yufeng Liu,1 Qing Wang,1 Guanghui Jiang,1 Xuejing Li,4 Liandong Zhao,1 Qijin Zhai1 1Department of Neurology, Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, People’s Republic of China; 2Department of Neurology, Hongze People’s Hospital, Huai’an, Jiangsu, People’s Republic of China; 3Department of Neurology, Lianshui PEople’s Hospital Affiliated to Kangda College of Nanjing Medical University, Huai’an, Jiangsu, People’s Republic of China; 4Rehabilitation Centre, Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liandong Zhao; Qijin Zhai, Email zld18796201519@163.com; qjzhai1983@163.comPurpose: The plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory biomarker of cerebral microbleeds (CMBs) and may be related to the occurrence, development, and prognosis of cognitive impairment. The present study aimed to investigate the impact of plasma Lp-PLA2 level on the cognitive impairment in patients with CMBs.Methods: In this study, 213 patients with CMBs confirmed by 3.0 T brain magnetic resonance imaging (MRI) were analyzed. Lp-PLA2 levels were determined by magnetic particle chemiluminescence immunoassay technology, and cognitive function was assessed using the Montreal Cognitive Assessment Scale (MoCA). The cognitive functions of patients with CMBs were divided into three groups according to the MoCA scale, including normal cognition (NC), mild cognitive impairment (MCI), and moderate-severe cognitive impairment (MSCI). Clinical, laboratory and radiological data of the three groups were analysed. The relationship between plasma Lp-PLA2 and MoCA score in patients with CMBs was investigated through rank correlation analysis and multivariate regression analysis, and receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of Lp-PLA2.Results: CMBs were detected in 213 (30.2%) of 705 patients who underwent 3.0 T MRI. Multiple comparisons showed that plasma Lp-PLA2 in patients with CMBs with normal cognitive scores was significantly lower than that in the other two groups with cognitive impairment (p < 0.05). In the single factor correlation analysis, high level of plasma Lp-PLA2 was negatively correlated with the decrease of MoCA score in patients with CMBs (r =− 0.389, p < 0.01). Multivariate regression analysis showed that high plasma Lp-PLA2 was an independent risk factor for a low MoCA score in patients with CMBs (odds ratio [OR]=1.014; 95% confidence interval [CI], 1.002– 1.026; p=0.025).Conclusion: A high level of plasma Lp-PLA2 is positively correlated with the generation of cognitive impairment in patients with CMBs and negatively correlated with the degree of impairment. Plasma Lp-PLA2 is an important indicator of cognitive impairment in patients with CMBs and may provide a therapeutic target for preventing CMB-induced cognitive impairment.Keywords: cerebral microbleeds, lipoprotein-associated phospholipase A2, cognitive impairment, risk factors, cerebral small vessel disease

Tao Wang,1,2 Zhandong Wang,1 Wenxia Qi,1 Ganggang Jiang,1 Gang Wang2 1Gansu University of Chinese Medicine, Lanzhou, 730020, People’s Republic of China; 2Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, 730020, People’s Republic of ChinaCorrespondence: Gang Wang, Email wanggangyishi6565@gszy.edu.cnAbstract: Rheumatoid arthritis (RA) is a persistent systemic autoimmune disease with the hallmarks of swelling of the joint, joint tenderness, and progressive joint destruction, which may cause synovial inflammation and pannus as a basic pathological change, resulting in joint malformations and serious disorders. At present, the precise etiology and mechanism of pathogenesis of RA are unknown. The imbalance of immune homeostasis is the origin of RA. Hippo pathway is widely expressed in a range of cell lineages and plays a fundamental role in maintaining the immune steady state and may be involved in the pathogenic mechanism of RA. This study reviews the progress of Hippo pathway and its main members in the pathogenesis of RA from three aspects: regulating the maintenance of autoimmune homeostasis, promoting the pathogenicity of synovial fibroblasts and regulating the differentiation of osteoclasts. The study also presents a new way to recognize the pathogenesis of rheumatoid arthritis, which is favorable for finding a new way for treating the rheumatoid arthritis.Keywords: Hippo pathway, rheumatoid arthritis, pathogenesis, immune cell

Yuyuan Zhang,1,&ast; Zaoqu Liu,1,&ast; Jie Li,1 Xin Li,1 Mengjie Duo,2 Siyuan Weng,1 Peijie Lv,3 Guozhong Jiang,4 Caihong Wang,5 Yan Li,6 Shichao Liu,6 Zhen Li1 1Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Department of Radiology, Zhengzhou University First Affiliated Hospital, Zhengzhou, Henan, People’s Republic of China; 4Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 5Department of Magnetic Resonance Imaging, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 6Department Cardiology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhen Li, Email lzlyct620@163.comIntroduction: Mutation patterns have been extensively explored to decipher the etiologies of hepatocellular carcinoma (HCC). However, the study and potential clinical role of mutation patterns to stratify high-risk patients and optimize precision therapeutic strategies remain elusive in HCC.Methods: Using exon-sequencing data in public (n=362) and in-house (n=30) cohorts, mutation signatures were extracted to decipher relationships with the etiology and prognosis in HCC. The proteomics (n=159) and cell-line transcriptome data (n=1019) were collected to screen the implication of sensitive drugs. A novel multi-step machine-learning framework was then performed to construct a classification predictor, including recognizing stable reversed gene pairs, establishing a robust prediction model, and validating the robustness of the predictor in five independent cohorts (n=900).Results: Two heterogeneous mutation signature clusters were identified, and a high-risk prognosis cluster was recognized for further analysis. Notably, mutation signature cluster 1 (MSC1) was featured by activated anti-tumor immune and metabolism dysfunctional states, higher genomic instability (high TMB, SNV neoantigen, indel neoantigens, and total neoantigens), and a dismal prognosis. Notably, MSC performed as an independent risk factor than clinical traits (eg, stage, vascular invasion). Additionally, afatinib and canertinib were recognized which might have potential therapeutic implications in MSC1, and the targets of these drugs presented a higher expression in both gene and protein levels in HCC.Discussion: Our studies may provide a promising platform for improving prognosis and tailoring therapy in HCC.Keywords: hepatocellular carcinoma, mutation signature, gene pairs, precision therapy, machine learning, prognosis

Hua Xiao,&ast; Xia Yu,&ast; Yuanyuan Shang, Ruyan Ren, Yi Xue, Lingling Dong, Liping Zhao, Guanglu Jiang, Hairong Huang National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory for Drug Resistant Tuberculosis Research; Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hairong Huang, Beijing Key Laboratory for Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, No. 97 Ma Chang, Tongzhou District, Beijing, 101149, People’s Republic of China, Tel +86-10-89509159, Fax +86-10-89509160, Email huanghairong@tb123.orgBackground: Sudapyridine (WX-081) has exhibited equivalent efficacy than its counterpart parent drug bedaquiline (BDQ) but better safety profile against Mycobacterium tuberculosis (Mtb). Our study was aimed to evaluate in vitro activity of WX-081 against the clinical isolates of Mtb with different drug-resistance profiles and the intracellular bactericidal activity against the reference strain.Methods: The minimum inhibitory concentrations (MICs) of WX-081 and BDQ were tested against 114 Mtb clinical isolates. The intracellular activity of WX-081 and BDQ against the Mtb reference strain H37Rv in THP-1 cells was also evaluated in parallel.Results: The MICs for WX-081 of the enrolled isolates ranged from 0.0156 μg/mL to 1 μg/mL. The MIC50 and MIC90 of WX-081 were, respectively, 0.25 μg/mL and 0.5 μg/mL, with 95.6% of the enrolled strains having MICs ≤ 0.25 μg/mL. For a given strain, the MIC value of WX-081 was generally equivalent to or 2-fold than MIC of BDQ. The intracellular bacterial killing was acquired with the tested drug concentrations that were presumed attainable during clinical usage.Conclusion: WX-081 exhibited potent efficacy against the clinical isolates in vitro. The intracellular killing effect of sudapyridine against the reference strain supports its potential efficacy in treating TB patients.Keywords: tuberculosis, sudapyridine, bedaquiline, antibacterial activity

Xin Zhang,1– 3 Xiangbo Bu,4 Wenyu Jia,1,2 Yu Ying,1,2 Shanrong Lv,1,2 Guan Jiang1,2 1Department of Dermatology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People’s Republic of China; 2Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China; 3Department of Dermatology, Xuzhou Children’s Hospital, Xuzhou Medical University, Xuzhou, Jiangsu, 221000, People’s Republic of China; 4Department of Orthopaedics, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, 221009, People’s Republic of ChinaCorrespondence: Guan Jiang, Email dr.guanjiang@xzhmu.edu.cnIntroduction: Nanophototherapy has emerged as a novel and promising therapeutic strategy for cancer treatment; however, its efficacy in dermatological tumors and precancerous lesions remains severely limited. This study aimed to use the gas-liquid injection technique to fully utilize the synergistic photodynamic therapy (PDT)/photothermal therapy (PTT) of nanomaterials to enhance the antitumor effect.Methods: A novel oxygen-generating nanocomposite (TSL-IR820-CAT) was synthesized by encapsulating the photosensitizer IR820 and catalase (CAT) using a matrix encapsulation method based on thermosensitive liposomes (TSL).–The liquid injection technology enhances the treatment of cutaneous squamous cell carcinoma (cSCC). The combined PDT/PTT therapeutic effect of TSL-IR820-CAT on cSCC was investigated using in vivo and in vitro experiments.Results: TSL-IR820-CAT, with good stability, efficient drug release, and photothermal conversion ability, was successfully developed. Nanoparticles injected through a needle-free syringe efficiently accumulate in the tumor tissue. As TSL-IR820-CAT was consumed by A431 cells, some of it localized to the mitochondria and produced oxygen to relieve hypoxia, thereby enhancing the efficacy of PDT. PDT/PTT combination therapy resulted in irreversible apoptosis and inhibited cSCC growth. TSL-IR820-CAT coupled with gas-liquid injection was free from apparent systemic side effects.Conclusion: This article discusses new strategies and ideas for treating skin tumors and has significant application value.Keywords: skin squamous cell carcinoma, nanoparticles, gas-liquid injection technology, photodynamic therapy, photothermal therapy

Danfeng Wang,1,2 Shuhui Min,1,2 Xiao Lin,1,2 Guan Jiang1,2 1Department of Dermatology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China; 2First Clinical Medical College, Xuzhou Medical University, Xuzhou, People’s Republic of ChinaCorrespondence: Guan Jiang, Department of Dermatology, Affiliated Hospital of Xuzhou Medical University; First Clinical Medical College, Xuzhou Medical University, Xuzhou, People’s Republic of China, Email dr.guanjiang@xzhmu.edu.cnObjective: The aim of the present study was to investigate the association of single-nucleotide polymorphisms (SNPs) in the macrophage migration inhibiting factor (MIF), interferon-induced Helicase C domain 1 (IFIH1), interleukin-6 (IL6) genes, circulating levels with non-segmental vitiligo (NSV) susceptibility in the Chinese population, and to analyze the relationships between gene polymorphisms and clinical characteristics of vitiligo.Methods: In this study, genotyping was conducted in 155 patients with NSV and 117 unaffected controls using polymerase chain reaction and snapshot technique. Serum concentrations were determined by ELISA kit.Results: There were strong associations between IFIH1 H843R and IL6-572G/C polymorphisms and NSV susceptibility (p = 0.013; p = 0.009). In contrast to previous studies, we found no significant difference in the MIF-173G/C polymorphism between the two groups. In addition, the frequency of allelic distribution for MIF-173G/C in patients with active NSV was significantly higher than stable NSV (p = 0.011), and IFIH1 H843R with early-onset (≤ 20), active or family history of NSV was significantly higher than late-onset (> 20), stable or no family history of NSV (p = 0.033; p = 0.045; p = 0.039). Serum concentrations of MIF were higher in patients with active NSV, serum IFIH1 and IL6 concentrations were related to the presence of polymorphisms in patients with NSV (p = 0.009; p = 0.011).Conclusion: Our results suggested that IFIH1 H843R and IL6-572G/C gene polymorphisms and expression levels are obviously correlated with the onset of NSV. MIF-173G/C allele and serum concentrations may be associated with active NSV, and IFIH1 H843R allele may be associated with youth, active or family history of NSV.Keywords: vitiligo, MIF, IFIH1, IL6, single nucleotide polymorphism

Chunlong Li,1 Yuexia Liu,2 Ning Yang,3 Zhihong Lan,4 Shumei Huang,3 Yunfan Wu,3 Xiaofen Ma,3 Guihua Jiang3 1Department of Medical Imaging, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’ s Republic of China; 2Department of Ultrasound, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’ s Republic of China; 3Department of Medical Imaging, Guangdong Second Provincial General Hospital, Guangzhou, People’s Republic of China; 4Department of Medical Imaging, Zhuhai City People’s Hospital, Zhuhai, People’s Republic of ChinaCorrespondence: Guihua Jiang; Xiaofen Ma, Email GH.jiang2002@163.com; xiaofenma12@163.comIntroduction: In recent years, people have gained a profound understanding of chronic insomnia disorder (CID), but the pathophysiological mechanism of CID is still unclear. There is some evidence that the locus coeruleus (LC) is involved in the regulation of wakefulness in CID, but there have been few studies using brain functional imaging. The purpose of this study was to evaluate the resting-state functional connectivity (FC) between the LC and other brain voxels in CID and whether these abnormal FC are involved in the regulation of wakefulness.Methods: A total of 49 patients with chronic insomnia disorder and 47 healthy controls (HC) matched for gender, age, and education were examined with rs-fMRI in this study. The LC was selected as the region of interest, and then seed-based analysis was conducted on the LC and other voxels to obtain the brain regions with abnormal FC. The correlation between the FC value of the abnormal connection area and the clinical scale score was analyzed.Results: Compared with the HC, the FC between the LC and right precuneus, right posterior cingulate cortex, left middle temporal gyrus, left calcarine, and right superior orbitofrontal cortex was significantly enhanced (p < 0.05, FDR correction), and the functional connectivity signal value between the locus coeruleus and left middle temporal gyrus was positively correlated with the Self-Rating Depression Scale (p = 0.021).Conclusion: The abnormal FC between the LC and multiple brain regions may contribute to a better understanding of the neurobiological mechanism of CID.Keywords: chronic insomnia disorder, default mode network, functional connectivity, locus coeruleus, seed-based analysis

Shoujun Xu,1,&ast; Meng Li,2,&ast; Chunlan Yang,3 Xiangling Fang,4 Miaoting Ye,4 Yunfan Wu,2 Binrang Yang,4 Wenxian Huang,4 Peng Li,1 Xiaofen Ma,2 Shishun Fu,2 Yi Yin,2 Junzhang Tian,2 Yungen Gan,1 Guihua Jiang2 1Department of Radiology, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China; 2Department of Medical Imaging, Guangdong Second Provincial General Hospital, Guangzhou, People’s Republic of China; 3Department of Hematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China; 4Department of Department of Children Healthcare, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China&ast;These authors have contributed equally to this workCorrespondence: Guihua Jiang; Yungen Gan, Email jianggh@gd2h.org.cn; gdszgyg-1@126.comPurpose: This study used the graph-theory approach, degree centrality (DC) to analyze whole-brain functional networks at the voxel level in children with ASD, and investigated whether DC changes were correlated with any clinical variables in ASD children.Methods: The current study included 86 children with ASD and 54 matched healthy subjects Aged 2– 5.5 years. Next, chloral hydrate induced sleeping-state functional magnetic resonance imaging (ss-fMRI) datasets were acquired from these ASD and healthy subjects. For a given voxel, the DC was calculated by calculating the number of functional connections with significantly positive correlations at the individual level. Group differences were tested using two-sample t-tests (p < 0.01, AlphaSim corrected). Finally, relationships between abnormal DCs and clinical variables were investigated via Pearson’s correlation analysis.Results: Children with ASD exhibited low DC values in the right middle frontal gyrus (MFG) (p

Suting Chen,&ast; Fen Wang,&ast; Yi Xue, Fengmin Huo, Junnan Jia, Lingling Dong, Liping Zhao, Guanglu Jiang, Hairong Huang National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory for Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China&ast;These authors contributed equally to this workCorrespondence: Hairong Huang, Email huanghairong@tb123.org; Guanglu Jiang, guanglu0725@126.comBackground: Nontuberculous mycobacteria (NTM) and their associated diseases remain neglected. Through minor modifications in our diagnostic algorithm, we observed an unexpected higher number of cultivable NTM isolates. Therefore, a retrospective study was performed thoroughly to investigate the effect of changed laboratory procedures on NTM isolation in a specialized tuberculosis hospital.Methods: NTM isolation rates and composition of NTM species were compared for the two diagnostic algorithms: (1) by using traditional p-nitrobenzoic acid (PNB) selective medium as a preliminary test to identify NTM isolates among the positive cultures (procedure I) and (2) by using the MPT64 antigen detection method to distinguish between Mycobacterium tuberculosis complex (MTBC) isolates and possible NTM isolates after a positive MGIT960 liquid culture (procedure II).Results: The NTM isolation rate in procedure II was significantly higher than the procedure I (18.08% vs 9.71%; P< 0.001). A noticeable increase in the ratio of NTM isolates among the identified mycobacteria was observed over the studied years (ie, from 58.18% in 2019 to 72.93% in 2021), which indicated a more precise prescription of species identification test after prompt information was provided in procedure II. In addition, the consistency of the identified species using multiple specimens from the same patient did not present a significant difference between the procedures.Conclusion: According to our study, NTM infection might be far more underestimated than it is. A diagnostic procedure combining MGIT960 culture and MPT64 antigen detection could timely and easily identify clues of NTM isolates and improve the diagnosis of NTM infections.Keywords: tuberculosis, nontuberculous mycobacteria, p-nitrobenzoic acid, MPT64 antigen, species

Jian-guo Zhang,1– 3,&ast; Shang-miao Fu,1,&ast; Fen Liu,1 Jian-guo Wan,4 Shu-bing Wu,4 Guang-hui Jiang,4 Wen-qiang Tao,1 Wen Zhou,4 Ke-jian Qian1 1Department of Critical Care Medicine, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Infection, First Affiliated Hospital of Nanchang University, Nanchang, Jianxi, People’s Republic of China; 3Department of Critical Care Medicine, Linyi People’s Hospital, Linyi, Shandong, People’s Republic of China; 4Department of Critical Care Medicine, First Hospital of Nanchang, Nanchang, Jiangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ke-jian Qian, Department of Critical Care Medicine, First Affiliated Hospital of Nanchang University, No. 17 YongwaiZheng Street, Nanchang, Jiangxi, 330006, People’s Republic of China, Email 361439919072@email.ncu.edu.cn Wen Zhou, Department of Critical Care Medicine, First Hospital of Nanchang, No. 128 Xiangshan North Road, Nanchang, Jiangxi, 330006, People’s Republic of China, Email doctor20210428@163.comPurpose: To investigate the correlation and prognostic significance of low triiodothyronine (T3) syndrome and norepinephrine dosage in patients with sepsis and septic shock.Methods: This single-center, retrospective, cohort study enrolled 169 patients with sepsis and septic shock that were admitted to the intensive care unit of First Hospital of Nanchang, Nanchang, China from June 2017 to July 2019. All included patients were followed up for 28 days or died, whichever was earlier. Patients with free T3 (FT3) of < 3.1 pmol/L were considered with low T3 syndrome. The correlation and prognostic significance of the FT3 and maximum dosage of norepinephrine (MDN) within 72 h, as well as other clinical indicators, were analyzed by using correlation analysis, principal component analysis, receiver operating characteristic curve, Youden index, and logistic regression.Results: A total of 138 patients were allocated to the low T3 group. FT3 inversely correlated with the Sequential Organ Failure Assessment (SOFA) score within 24 h, fluid resuscitation volume within 24 h, and lactic acid levels, and positively correlated with the mean arterial pressure. The critical values of age, SOFA, and MDN for predicting the 28-day mortality were 79.5 years, 8.5 points, and 0.61 μg/kg/min, respectively. The mortality of the low T3 and normal T3 groups was similar. Considering the MDN of 0.61 μg/kg/min as the cutoff value, the mortality between the two groups was significantly different.Conclusion: Among patients with sepsis and septic shock, FT3 was inversely correlated with the disease severity. An MDN ≥ 0.61 μg/kg/min within 72 h may be an important prognostic indicator.Keywords: euthyroid sick syndromes, low T3 syndrome, non-thyroidal illness syndrome, norepinephrine, sepsis, septic shock

Topological insulators (TIs) in the Bi2Se3 family manifest helical Dirac surface states that span the topologically ordered bulk band gap. Recent scanning tunneling microscopy measurements have discovered additional states in the bulk band gap of Bi2Se3 and Bi2Te3, localized at one-dimensional step edges. Here numerical simulations of a TI surface are used to explore the phenomenology of edge state formation at the single-quintuple layer step defects found ubiquitously on these materials. The modeled one-dimensional edge states are found to exhibit a stable topological connection to the two-dimensional surface state Dirac point.

Xiaochen Yang,1,2 Yangjing Zhao,3 Qixiang Shao,3 Guoqin Jiang1 1Department of Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu Province, People’s Republic of China; 2Department of Thyroid and Breast Surgery, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, 215300, Jiangsu Province, People’s Republic of China; 3Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu Province, People’s Republic of ChinaCorrespondence: Guoqin JiangDepartment of Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215004, People’s Republic of ChinaTel/Fax +86-512-67784797Email jiang_guoqin@suda.edu.cnQixiang ShaoJiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, 212013, People’s Republic of ChinaTel +86-511-80961661Fax +86-511-86102010Email shao_qx@ujs.edu.cnPurpose: Cytochrome b561 (CYB561) is a transmembrane protein and participates in ascorbate recycling and iron homeostasis. However, its role in breast cancer remains unclear.Patients and Methods: In this study, we explored the expression pattern and prognostic value of CYB561 in breast cancer through The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), PrognoScan and Kaplan–Meier Plotter and confirmed its mRNA expression in human breast cell lines. LinkedOmics, Metascape and Gene Expression Profiling Interactive Analysis (GEPIA2) databases were applied to investigate the co-expression genes and construct microRNA (miRNA) networks associated with CYB561. The correlations between CYB561 and immune infiltration cells and genes were also illustrated.Results: The CYB561 expression was upregulated in breast cancer tissues and cell lines and significantly correlated with the clinical features of breast cancer patients. High CYB561 expression was associated with poor survival and was an independent risk factor for overall and disease-specific survival. Functional enrichment analysis showed that CYB561 and its co-expressed genes were mainly enriched in lipid biosynthetic process, Wnt signaling pathway, Hippo signaling pathway, etc. The miRNA network analysis suggested that hsa-miR-497 was negatively correlated with CYB561 expression and was predicted to direct target CYB561. CYB561 expression was positively correlated with infiltrating levels of CD4+ T cells, neutrophils and dendritic cells in breast cancer. Subsequent analysis found that B cells could predict the outcome of breast cancer. Also, CYB561 showed strong correlations with diverse immune marker sets in breast cancer.Conclusion: CYB561 may serve as a potential prognostic biomarker and target for breast cancer. Our findings laid foundation for future research on molecular mechanisms of CYB561 in breast cancer.Keywords: cytochrome b561, breast cancer, prognosis, biomarker, immune infiltrates

Xia Yu,&ast; Fengmin Huo,&ast; Fen Wang,&ast; Shu’an Wen, Guanglu Jiang, Yi Xue, Lingling Dong, Liping Zhao, Rui Zhu, Hairong Huang National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory for Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hairong HuangBeijing Key Laboratory for Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beiguan St, No. 9, Tongzhou Qu, Beijing, 101149, People’s Republic of ChinaEmail huanghairong@tb123.orgBackground: The antimicrobial activities of some new oxazolidinones against slowly growing mycobacteria (SGM) have never been well evaluated.Methods: We evaluate the in vitro susceptibility of 20 reference strains and 157 clinical isolates, pertaining different SGM species, against four oxazolidinones, ie, delpazolid, sutezolid, tedizolid and linezolid. In addition, the association of linezolid resistance and mutations in 23srRNA, rplC, rplD were also tested.Results: Sutezolid presented the strongest antimicrobial activity against the clinical isolates of M. intracellulare than the other oxazolidinones, with MIC50 at 2 μg/mL and MIC90 at 4 μg/mL. MICs of sutezolid were usually 4- to 8-fold lower than these of linezolid against M. intracellulare and M. avium. The tested isolates of M. kansasii were susceptible to all of the four oxazolidinones. According to the multiple sequence alignment, novel 23srRNA mutations (A2267C and A2266G) in M. intracellulare and rplD mutations (Thr147Ala) in M. avium were identified in this study which have plausible involvement in rendering resistance against linezolid.Conclusion: This study showed that sutezolid harbors the strongest inhibitory activity against M. intracellulare, M. avium and M. kansasii in vitro, which provided important insights on the potential clinical application of oxazolidinones for treating SGM infections.Keywords: slowly growing mycobacteria, delpazolid, sutezolid, tedizolid, linezolid, antimicrobial activity

Qin Li,1,&ast; Jie Ren,2,&ast; Wei Liu,3 Guoqin Jiang,2 Rongkuan Hu1 1GenePharma Co., Ltd., Suzhou, 215125, Jiangsu, People’s Republic of China; 2Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, People’s Republic of China; 3Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guoqin JiangDepartment of General Surgery, The Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, People’s Republic of ChinaTel +86-512-67784797Email jiang_guoqin@163.comRongkuan HuGenePharma Co., Ltd., 199 Dongping Street, Suzhou, 215125, Jiangsu, People’s Republic of ChinaTel +86-512-86668828Email rkhu@mail.ustc.edu.cnPurpose: The purpose of our research was to identify and evaluate synthetic phosphorothioate-modified CPG oligodeoxynucleotides (CPG-ODNs) activating innate and adaptive immune responses. Furthermore, combined treatment with CpG and an mRNA cancer vaccine was evaluated in melanoma models as a therapeutic approach.Methods: A molecular assay was used to screen new CpG molecules; mouse modeling and pathological analysis were used to confirm the antitumor effect of CpG alone or in combination with an mRNA vaccine. Finally, safety was assessed by monitoring blood biochemistry.Results: We first screened and identified a new CpG-B class ODN (CpG2018B) that effectively stimulated type II interferons in both mouse plasmacytoid dendritic cells (pDCs) and human peripheral blood mononuclear cells (PBMCs). In addition, CpG2018B promoted cytokine production mainly via toll-like receptor 9 (TLR9) pathways. We further demonstrated that intratumoral (IT) injection of CpG2018B inhibited melanoma growth in syngeneic models and could turn “cold” tumors into “hot” tumors. Then, CpG2018B and an mRNA-based neoantigen cancer vaccine were encapsulated in lipid nanoparticles (LNPs) and intratumorally injected into melanoma mouse models. Interestingly, vaccination with CpG or the mRNA vaccine alone could inhibit tumor growth, while combination of CpG with the mRNA vaccine enhanced the antitumor effect. Finally, we described the long-term safety and tolerability of CpG2018B and mRNA therapy in mice model.Conclusion: We identified a novel CpG-B class ODN to promote the immune response, and CpG combined with mRNA cancer vaccines is an attractive candidate approach for immunostimulatory sequence (ISS)-based therapeutic strategies.Keywords: CpG, IFN-γ, TLR9, mRNA vaccine, neoantigen

Global biodiversity conservation has recently focused on the roles of land management strategies of land sharing vs. land sparing. However, few studies have evaluated the roles of social and ecological interactions in modifying the effectiveness of land management for top predator conservation. Using a 65-year dataset from northeastern China, we evaluated the roles of government social policies in resolving human-wildlife conflicts and improving human livelihood. From 1998 to 2015, both big cat populations and their habitats have increased. Concurrently, regional human population density decreased by 59.6%, forest volume logged was reduced by 62.6%. Consequently, increases of key prey species were observed during the same periods. Although populations remained small, the annual finite rate of increase was 1.04 for the Amur tiger population and 1.08 for Amur leopards from 1999 to 2015. Habitat areas occupied by big cats increased significantly. Overexploitation of forest resources and big cat declines under previous unsustainable land use are progressively being reversed under land sparing. Large economic investment and intense human-relocation projects coupled with efforts to reduce poaching and illegal hunting and trapping demonstrate a complex social and ecological synergy in big cat conservation in China.

Yilan Xing,1,2 Shishun Fu,3 Meng Li,3 Xiaofen Ma,3 Mengchen Liu,3 Xintong Liu,2 Yan Huang,2 Guang Xu,2 Yonggang Jiao,2 Hong Wu,2 Guihua Jiang,1,3 Junzhang Tian1,3 1The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Neurology of Guangdong Second Provincial General Hospital, Guangzhou, People’s Republic of China; 3Department of Medical Imaging of Guangdong Second Provincial General Hospital, Guangzhou, People’s Republic of ChinaCorrespondence: Junzhang Tian; Guihua JiangDepartment of Medical Imaging of Guangdong Second Provincial General Hospital, No. 466, Xingang Road, Guangzhou, People’s Republic of ChinaTel +86 20 89168701; +86 18620120333Email tianjunzhang2015@163.com; GH.jiang2002@163.comPurpose: The aim of this study was to compare regional homogeneity (ReHo) changes in Parkinson’s disease mild cognitive impairment (PD-MCI) patients with respect to normal controls (NC) and those with cognitively normal PD (PD-CN). Further, the study investigated the relationship between ReHo changes in PD patients and neuropsychological variation.Patients and Methods: Thirty PD-MCI, 19 PD-CN, and 21 NC subjects were enrolled. Resting state functional magnetic resonance imaging data of all subjects were collected, and regional brain activity was measured for ReHo. Analysis of covariance for ReHo was determined between the PD-MCI, PD-CN, and NC groups. Spearman rank correlations were assessed using the ReHo maps and data from the neuropsychological tests.Results: In comparison with NC, PD-CN patients showed significantly higher ReHo values in the right middle frontal gyrus (MFG) and lower ReHo values in the left supramarginal gyrus, bilateral inferior parietal lobule (IPL), and the right postcentral gyrus (PCG). In comparison with PD-CN patients, PD-MCI patients displayed significantly higher ReHo values in the right PCG, left middle occipital gyrus (MOG) and IPL. No significant correlation between ReHo indices and the neuropsychological scales was observed.Conclusion: Our finding revealed that decreases in ReHo in the default mode network (DMN) may appear before PD-related cognitive impairment. In order to preserve executive attention capacity, ReHo in the right MFG in PD patients lacking cognition impairment increased for compensation. PD-MCI showed increased ReHo in the left MOG, which might have been caused by visual and visual-spatial dysfunction, and increased ReHo in the left IPL, which might reflect network disturbance and induce cognition deficits.Keywords: Parkinson’s disease, mild cognitive impairment, ReHo, fMRI, DMN

Guiying Jiang,1,* Xueqian Wang,1,* Ying Zhou,1 Chenming Zou,2,3 Ling Wang,1 Wei Wang,1 Danya Zhang,1 Hanjie Xu,1 Jie Li,1 Fei Li,1 Danfeng Luo,1 Xiangyi Ma,1 Ding Ma,1 Songwei Tan,2 Rui Wei,1 Ling Xi1 1Department of Obstetrics & Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei Province, People’s Republic of China; 2Tongji School of Pharmacy, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei Province, People’s Republic of China; 3School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ling Xi; Rui WeiDepartment of Obstetrics & Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, People’s Republic of ChinaTel/Fax +86 27 83662688Email lxi@tjh.tjmu.edu.cn; weirui2018@tjh.tjmu.edu.cnBackground and Purpose: Cisplatin–paclitaxel (TP) combination chemotherapy as the first-line therapy for numerous cancers is hindered by its inadequate accumulation in tumors and severe side effects resulting from non-specific distribution. The aim of this study is to explore whether TMTP1-modified, cisplatin and paclitaxel prodrugs co-loaded nanodrug could improve cervical cancer chemotherapy and relieve its side effects through active and passive tumor targeting accumulation and controlled drug release.Methods: TDNP, with capacities of active targeting for tumors and controlled drug release, was prepared to co-deliver cisplatin and paclitaxel prodrugs. The characteristics were investigated, including the diameter, surface zeta potential, stability and tumor microenvironment (TME) dependent drug release profiles. Cellular uptake, cytotoxicity, drug accumulation in tumors, antitumor effects and safety analysis were evaluated in vitro and in vivo.Results: The oxidized cisplatin and the paclitaxel linked to the polymer achieved a high loading effciency of over 80% and TME-dependent sustained drug release. Moreover, TMTP1 modification enhanced cellular uptake of TDNP and further improved the cytotoxicity of TDNP in vitro. In vivo, TDNP showed an extended blood circulation and increased accumulation in SiHa xenograft models with the aid of TMTP1. More importantly, TDNP controlled tumor growth without life-threatening side effects.Conclusion: Our study provided a novel TP co-delivery platform for targeted chemotherapy of cervical cancer, which was promising to improve the therapeutic effcacy of TP and may also have application in other tumors.Keywords: TME-responsive, targeted co-delivery, combined chemotherapy, cervical cancer

Suting Chen,1,* Tianlu Teng,1,2,* Zhuman Zhang,1 Yuanyuan Shang,1,2 Hua Xiao,1 Guanglu Jiang,1 Fen Wang,1 Junnan Jia,1 Lingling Dong,1 Liping Zhao,1 Naihui Chu,2 Hairong Huang1 1National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory for Drug Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, People’s Republic of China; 2Department of Tuberculosis; Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hairong Huang; Naihui Chu Tel +86-10-89509159; +86-10-89509301Email nclhuang@ccmu.edu.cn; dongchu1994@sina.comObjective: Treatment choices for Mycobacterium abscessus (M. abscessus) infections are very limited, and the prognosis is generally poor. Effective new antibiotics or repurposing existing antibiotics against M. abscessus infection are urgently needed. Carbonyl cyanide 3-chlorophenylhydrazone (CCCP), a member of the lipophilic weak acid class, is known as an efflux pump inhibitor for Mycobacterium tuberculosis. The aim of this study was to determine the inhibitory activity of CCCP as a potential novel antibiotic against M. abscessus.Methods: A total of 47 reference strains of different mycobacterial species and 60 clinical isolates of M. abscessus were enrolled. In vitro inhibitory activity of CCCP was accessed using microplates alamar blue method with the reference and clinical isolates. The activity of CCCP against intracellular M. abscessus residing within macrophage was also evaluated by intracellular colony numerating assay.Results: CCCP exhibited good activity against M. abscessus clinical isolates in vitro, the minimum inhibitory concentration (MIC) ranged from 0.47 μg/mL to 3.75 μg/mL, with a MIC50 of 1.875 μg/mL and MIC90 of 3.75 μg/mL. At concentrations safe for the cells, CCCP exhibited highly intracellular bactericidal activities against M. abscessus and M. massiliense reference strains, with inhibitory rates of 84.8%± 8.8% and 72.5%± 13.7%, respectively. CCCP demonstrated bactericidal activity against intracellular M. abscessus that was comparable to clarithromycin, and concentration-dependent antimicrobial activity against M. abscessus in macrophages was observed. In addition, CCCP also exhibited good activities against most reference strains of rapidly growing mycobacterial species.Conclusion: CCCP could be a potential candidate of novel antimicrobiological agent to treat M. abscessus infection.Keywords: Mycobacterium abscessus, carbonyl cyanide 3-chlorophenylhydrazone, minimum inhibitory concentration, intracellular bactericidal activity

Sun J, Chen C, Jiang G, Tian W, Li Y, Sun S. Int J Nanomedicine. 2014;9(1):1339–1346. An error during the preparation of Figure 3 for publishing led to the inadvertent creation of a duplicate region in figure part 3A on page 1342. The journal wishes to apologise for this error. The correct version of Figure 3 is shown below. Figure 3 The different Ki67 expressions detected by QD-IHC (A and C) and IHC (B and D) in the same specimens.Abbreviations: IHC, immunohistochemistry; QD-IHC, quantum dot-immunohistochemistry.Notes: (A and B) are the same specimens; (C and D) are the same specimens. Scale bar: 25 μm.

The Nonlinear autoregressive exogenous (NARX) model, which predicts the current value of a time series based upon its previous values as well as the current and past values of multiple driving (exogenous) series, has been studied for decades. Despite the fact that various NARX models have been developed, few of them can capture the long-term temporal dependencies appropriately and select the relevant driving series to make predictions. In this paper, we propose a dual-stage attention-based recurrent neural network (DA-RNN) to address these two issues. In the first stage, we introduce an input attention mechanism to adaptively extract relevant driving series (a.k.a., input features) at each time step by referring to the previous encoder hidden state. In the second stage, we use a temporal attention mechanism to select relevant encoder hidden states across all time steps. With this dual-stage attention scheme, our model can not only make predictions effectively, but can also be easily interpreted. Thorough empirical studies based upon the SML 2010 dataset and the NASDAQ 100 Stock dataset demonstrate that the DA-RNN can outperform state-of-the-art methods for time series prediction.

HIV targets the gut mucosa early in infection, causing immune and epithelial barrier dysfunction and disease progression. However, gut mucosal sensing and innate immune signaling through mucosal pattern recognition receptors (PRRs) during HIV infection and disease progression are not well defined. Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model of AIDS, we found a robust increase in PRRs and inflammatory cytokine gene expression during the acute SIV infection in both peripheral blood and gut mucosa, coinciding with viral replication. PRR expression remained elevated in peripheral blood following the transition to chronic SIV infection. In contrast, massive dampening of PRR expression was detected in the gut mucosa, despite the presence of detectable viral loads. Exceptionally, expression of Toll-like receptor 4 (TLR4) and TLR8 was downmodulated and diverged from expression patterns for most other TLRs in the gut. Decreased mucosal PRR expression was associated with increased abundance of several pathogenic bacterial taxa, including Pasteurellaceae members, Aggregatibacter and Actinobacillus, and Mycoplasmataceae family. Early antiretroviral therapy led to viral suppression but only partial maintenance of gut PRRs and cytokine gene expression. In summary, SIV infection dampens mucosal innate immunity through PRR dysregulation and may promote immune activation, gut microbiota changes, and ineffective viral clearance.

Qidong Zhou,1,2 Weihong Ding,1,2 Zhiyu Qian,1,2 Guangliang Jiang,3 Chuanyu Sun,1,2 Ke Xu1,2 1Department of Urology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Department of Urology, Ruijin Hospital, Medical School of Shanghai Jiao Tong University, Shanghai, People’s Republic of ChinaCorrespondence: Ke XuDepartment of Urology, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai 200040, People’s Republic of ChinaTel/Fax +86 21 52887080Email drkexu@163.comObjective: Chronic psychological stress is common in patients with bladder cancer. An increasing number of evidence demonstrated that psychiatric disorder leads to worse prognostic outcomes in bladder cancer. This study was to investigate the effects of chronic psychological stress on the growth of bladder cancer and its potential mechanisms.Methods: A xenograft mouse model was established by subcutaneously implanting the human bladder cancer cell line T24 into nude mice. All of the tumor-bearing mice (N=20) were randomly separated into two groups. Mice in the control group were subjected to normal feeding conditions, while in another group, a chronic unpredictable mild stress (CUMS) model was established, in which mice were exposed to various types of stressors. Various analyses were performed on parameters including the tumor volume, tumor weight, expression of Caspase-3 and VEGF, proportion of Ki-67 positive cells (Ki-67 index), microvessel density (MVD) and serum concentrations of epinephrine and cortisol.Results: In the CUMS group, the growth of transplanted tumors was distinctly accelerated, with the weight of removed tumors at the end of experiment increased by 34.07% compared to that of the control. Serum levels of epinephrine and cortisol determined by ELISA were significantly increased by CUMS. Immunohistochemistry and Western blot analysis showed that the expression of Caspase-3 was downregulated, whereas the expression of VEGF was upregulated in the CUMS group. Meanwhile, CUMS could increase the Ki-67 index and MVD.Conclusion: Our research supports the hypothesis that CUMS could affect the growth of bladder cancer in nude mice, indicating that the intervention of chronic psychological stress may be a possible therapeutic strategy for bladder cancer.Keywords: bladder cancer, chronic unpredictable mild stress, tumor growth, cell proliferation, angiogenesis

Xiaoyang Hou,1,* Yingkai Tao,1,* Xinxin Li,1,* Yanyu Pang,1 Chunsheng Yang,2 Guan Jiang,1 Yanqun Liu1 1Department of Dermatology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, People’s Republic of China; 2Department of Dermatology, The Affiliated Huai’an Hospital of Xuzhou Medical University, The Second People’s Hospital of Huai’an, Huai’an 223002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guan Jiang; Yanqun LiuDepartment of Dermatology, The Affiliated Hospital of Xuzhou Medical University, 99 West Huai Hai Road, Xuzhou, Jiangsu 221002, People’s Republic of ChinaEmail dr.guanjiang@xzhmu.edu.cn; xyfylyq@sohu.comObjective: Nanotechnology-based photodynamic therapy (PDT) is a relatively new anti-tumor strategy. However, its efficacy is limited by the hypoxic state in the tumor microenvironment. In the present study, a poly(lactic-co-glycolic acid) (PLGA) nanoparticle that encapsulated both IR820 and catalase (CAT) was developed to enhance anti-tumor therapy.Materials and Methods: HA-PLGA-CAT-IR820 nanoparticles (HCINPs) were fabricated via a double emulsion solvent evaporation method. Dynamic light scattering (DLS), transmission electron microscopy (TEM), laser scanning confocal microscopy, and an ultraviolet spectrophotometer were used to identify and characterize the nanoparticles. The stability of the nanoparticle was investigated by DLS via monitoring the sizes and polydispersity indexes (PDIs) in water, PBS, DMEM, and DMEM+10%FBS. Oxygen generation measurement was carried out via visualizing the oxygen bubbles with ultrasound imaging system and an optical microscope. Inverted fluorescence microscopy and flow cytometry were used to measure the uptake and targeting effect of the fluorescent-labeled nanoparticles. The live-dead method and tumor-bearing mouse models were applied to study the HCINP-induced enhanced PDT effect.Results: The results showed that the HCINPs could selectively target melanoma cells with high expression of CD44, and generated oxygen by catalyzing H2O2, which increased the amount of singlet oxygen, ultimately inhibiting tumor growth significantly.Conclusion: The present study presents a novel nanoplatform for melanoma treatment.Keywords: catalase, hyaluronic acid, IR820, photodynamic therapy, tumor hypoxia

Meiying Cui,1 Pan Li,1 Ying Mao,1 Lan Zhang,1 Peiyi Xia,1 Enjie Liu,1 Weiwei Wang,1 Jianying Zhang,2 Guozhong Jiang,1 Wencai Li1 1Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, Mainland China; Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Wencai Li; Guozhong JiangDepartment of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450002, People’s Republic of ChinaEmail liwencai@zzu.edu.cn; guozhongjiang@zzu.edu.cnBackground: Microsatellite instability (MSI) has been a hot topic in cancer research. Determining MSI status greatly aids tumor prognosis and treatment plans. However, MSI data for Asian cancer patients with prognostic information are scarce. Here, our aim was to clarify MSI status and its prognostic value in a large Chinese cohort with different tumors.Patients and Methods: Tissue samples from 600 Chinese cases, including 150 endometrial cancers, 150 colorectal cancers, 150 liver cancers and 150 gastric cancers, were used for IHC and MSI examinations. Two mononucleotide and three dinucleotide markers were used to analyze MSI status.Results: In total,17.3% (26/150) of endometrial cancer patients showed positive MSI,10.0% (15/150) in colorectal cancer, 2.7% (4/150) in liver cancer, and 2.7% (4/150) in gastric cancer. Tumor location (P < 0.001 for colorectal cancer) and clinical stage (P =0.038 for gastric cancer) showed significant correlations with MSI status in gastrointestinal carcinogenesis. The mismatch repair (MMR) deficiency was observed in 20 colorectal cases (13.3%) and was significantly more frequent in the MSI-positive group (P < 0.001). Interestingly, the prevalence of MSI-H was mostly occurred in early-stage tumors, and none was in late stage (stage IV). Meanwhile, low clinicopathological stage had significant correlation with longer survival in multiple cancers here.Conclusion: The incidence of microsatellite instability varies among different cancer types. And the prevalence of MSI-H mostly occurred early clinicopathological stage. In addition, our study provided a large Asian cohort screened by five loci PCR method and significantly increased knowledge on the prognostic significance of MSI in Asia.Keywords: microsatellite instability, endometrial cancer, colorectal cancer, liver cancer, gastric cancer

Yuru Guo,1 Yan Liu,2 Zehui Zhang,1 Menghan Chen,1 Dexian Zhang,1 Chunlian Tian,1 Mingchun Liu,1 Guotuo Jiang2 1Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, Liaoning, People’s Republic of China; 2Dalian Sanyi Animal Medicine Co., Ltd., Dalian, Liaoning, People’s Republic of ChinaCorrespondence: Mingchun Liu; Guotuo Jiang Tel/Fax +86 024 8848 7156; +86 411 6688 6289Email liumingchun@syau.edu.cn; jgt600@sina.comPurpose: This research aimed to investigate the antibacterial activity and potential mechanism of luteolin against T. pyogenes.Materials and Methods: The broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) of luteolin against various T. pyogenes strains. The potential mechanism of action of luteolin was elucidated through testing and analysing the luteolin-induced alterations of T. pyogenes in several aspects, including cell wall, cell membrane, protein expression, nucleic acid content, topoisomerase activity and energy metabolism.Results: The MIC values of luteolin against various T. pyogenes isolates and ATCC19411 were 78 μg/mL. The increased cell membrane permeability, destruction of cell wall integrity and TEM images after exposure to luteolin showed that the cell wall and membrane were damaged. The content of total protein and nucleic acid in T. pyogenes decreased significantly after treatment with luteolin (1/2 MIC) for 12, 24, and 36 h. Moreover, a hypochromic effect was observed in the absorption spectrum of luteolin when deoxyribonucleic acid (DNA) was added. In addition, after treatment with luteolin, a decrease in nicked or relaxed DNA content, which was catalysed by T. pyogenes-isolated DNA topoisomerase, was observed. In addition, the adenosine triphosphate (ATP) content in cells and the activity of succinate dehydrogenase (SDH) both decreased when T. pyogenes was exposed to different concentrations (1/4 MIC, 1/2 MIC, 1 MIC, 2 MIC) of luteolin for 1 h.Conclusion: Luteolin showed distinct antibacterial activity against T. pyogenes by multiple actions, which mainly include destroying the integrity of the cell wall and cell membrane, influencing the expression of proteins, inhibiting nucleic acid synthesis, and interfering with energy metabolism.Keywords: luteolin, Trueperella pyogenes, antibacterial activity, antibacterial mechanism

Jingjing Ge,1,2 Jingjing Yang,3 Jingjing Song,1 Guangyu Jiang,1,2 Yong Zheng1 1Faculty of Psychology, Southwest University, Chongqing, People’s Republic of China; 2Department of Humanities and Management, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, People’s Republic of China; 3Department of Public Health and Management, Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Yong ZhengFaculty of Psychology, Southwest University, Chongqing, People’s Republic of ChinaTel +86 13667636167Fax + 86 23 68254139Email zhengy@swu.edu.cnPurpose: Past-negative time perspective (PNTP) can affect our everyday lives and is associated with negative emotions, unhealthy behaviors, rumination, anxiety, depression, and post-traumatic stress disorder (PTSD). Dispositional mindfulness may be able to reduce the negative effects of PNTP; however, few studies have investigated their relationship. Thus, the purpose of this study was to explore the effect dispositional mindfulness has on PNTP, as well as the mediating role of resilience and inner peace in this regard.Methods: This study investigated the cross-sectional relationship between self-reported mindfulness, resilience, inner peace, and PNTP. In order to further explore the relationship between mindfulness and PNTP, this study specially selected and analyzed the samples of 185 meditators and 181 non-meditators.Results: Correlation analysis revealed that mindfulness is significantly positively correlated with resilience and inner peace. Conversely, PNTP is significantly negatively correlated with mindfulness, resilience, and inner peace. Structural equation model analysis revealed that resilience and inner peace partially mediated the relationship between mindfulness and PNTP. Furthermore, a multi-group analysis showed that the mediating effects are different between meditators and non-meditators. For meditators, the effect of mindfulness on PNTP was fully mediated by resilience and inner peace. For non-meditators, the effect of mindfulness on PNTP was only partially mediated by resilience and inner peace.Conclusion: Based on the significant differences between the mediational models of meditators and non-meditators, we believe that dispositional mindfulness can negatively predict PNTP, and practicing meditation consistently improves dispositional mindfulness, resilience and inner peace and effectively reduces PNTP. Our findings indicate that a combination of mindfulness and PNTP could be used to design new psychological interventions to reduce the symptoms of mental health concerns such as negative bias, rumination, depression, anxiety, and PTSD.Keywords: psychological intervention, resilience, meditation, past-negative time perspective, unhealthy behaviors, inner peace