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Dongjing Xie,1,&ast; Junfang Wan,2,3,&ast; Changwei Guo,1 Jie Yang,1 Jiacheng Huang,1 Zhouzhou Peng,1 Jiandi Huang,1 Linyu Li,1 Shitao Fan,1 Dahong Yang,1 Wenzhe Sun,1 Wenjie Zi,1 Fengli Li,1 Feng Peng,4 Jinrong Hu,1 Qingwu Yang1 1Department of Neurology, Xinqiao Hospital and The Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, People’s Republic of China; 2Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Anesthesiology, Xinqiao Hospital and The Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, People’s Republic of China; 4Department of Neurology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qingwu Yang; Jinrong Hu, Department of Neurology, Xinqiao Hospital and The Second Affiliated Hospital, Army Medical University (Third Military Medical University), No. 183 Xinqiao Main Street, Shapingba District, Chongqing, 400037, People’s Republic of China, Tel +86 23 68774270 ; +86 15183089810, Email yangqwmlys@tmmu.edu.cn; hujinrong1108@163.comBackground and Purpose: Many patients who gained successful recanalization by endovascular treatment (EVT) with acute large vessel occlusion (LVO) did not have the favorable outcome. The study aimed to assess the association between H-type hypertension and clinical prognosis in patients with LVO after receiving EVT.Methods: Our study enrolled patients from the Endovascular Treatment With versus Without Tirofiban for Stroke Patients with Large Vessel Occlusion (RESCUE BT) Trial. H-type hypertension is defined as patients with hypertension and homocysteine (Hcy) ≥ 10μmol/L. The primary outcome was a favorable functional outcome, defined as a score of 0– 2 on the modified Rankin Scale (mRS) at 90 days. The secondary outcomes were mortality, successful recanalization, futile recanalization, and symptomatic intracerebral hemorrhage (sICH).Results: The plasma homocysteine level was recorded for 215 patients with hypertension in our study. Among those patients, 172 patients (80%) were founded with Hcy ≥ 10μmol/L (H-type hypertension), and 43 patients (20%) with Hcy < 10μmol/L (non-H-type hypertension). The probability of favorable outcome decreased with homocysteine increasing in patients with hypertension. H-type hypertension was associated with a low probability of favorable outcome (adjusted odds ratio (aOR), 0.38 [95% confidence interval (CI), 0.18– 0.80]; p = 0.01) at 90 days. The effects of H-type hypertension on mortality (aOR, 1.90 [95% CI, 0.67– 5.39]; p = 0.23) and sICH (aOR, 0.55 [95% CI, 0.13– 2.29]; p = 0.41) were not significant.Conclusion: Our findings suggest that patients with H-type hypertension have a lower likelihood of achieving favorable outcomes but do not have an increased mortality rate within 90 days.Keywords: H-type hypertension, clinical prognoses, large vessel occlusion

Fengyi Yang,1,2,&ast; Qiaoyan Dong,3,&ast; Zhuo Chen,1,2,&ast; Benjian Gao,1,2,&ast; Dongning Zheng,1,2 Rui Wang,1,2 Shu Qin,1,2 Fangyi Peng,1,2 Ming Luo,1,2 Jin Yang,1,2 Mengmei Nie,4 Bo Li,1,2 Xiaoli Yang1,2 1Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 2Academician (Expert) Workstation of Sichuan Province, Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 3Luzhou Senior High School, Luzhou, 646000, People’s Republic of China; 4Department of Urological Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bo Li; Xiaoli Yang, Email liboer2002@126.com; 344920646@qq.comPurpose: The efficacy of systemic therapy for hepatocellular carcinoma (HCC) is limited mainly by the complex tumor defense mechanism and the severe toxic side-effects of drugs. The efficacy of apatinib (Apa), a key liver cancer treatment, is unsatisfactory due to inadequate targeting and is accompanied by notable side-effects. Leveraging nanomaterials to enhance its targeting represents a crucial strategy for improving the effectiveness of liver cancer therapy.Patients and Methods: A metal polyphenol network-coated apatinib-loaded metal-organic framework-based multifunctional drug-delivery system (MIL-100@Apa@MPN) was prepared by using metal-organic frameworks (MOFs) as carriers. The nanoparticles (NPs) were subsequently characterized using techniques such as X-ray diffraction (XRD), transmission electron microscopy (TEM), zeta potential measurements, and particle size analysis. In vitro experiments were conducted to observe the drug release kinetics and cytotoxic effects of MIL-100@Apa@MPN on HepG2 cells. The in vivo anti-tumor efficacy of MIL-100@Apa@MPN was evaluated using the H22 tumor-bearing mouse model.Results: The formulated MIL-100@Apa@MPN demonstrates remarkable thermal stability and possesses a uniform structure, with measured drug-loading (DL) and encapsulation efficiency (EE) rates of 28.33% and 85.01%, respectively. In vitro studies demonstrated that HepG2 cells efficiently uptake coumarin-6-loaded NPs, and a significant increase in cumulative drug release was observed under lower pH conditions (pH 5.0), leading to the release of approximately 73.72% of Apa. In HepG2 cells, MIL-100@Apa@MPN exhibited more significant antiproliferative activity compared to free Apa. In vivo, MIL-100@Apa@MPN significantly inhibited tumor growth, attenuated side-effects, and enhanced therapeutic effects in H22 tumor-bearing mice compared to other groups.Conclusion: We have successfully constructed a MOF delivery system with excellent safety, sustained-release capability, pH-targeting, and improved anti-tumor efficacy, highlighting its potential as a therapeutic approach for the treatment of HCC.Keywords: metal-organic frameworks nanoparticles, apatinib, drug-targeting delivery, ferroptosis therapy, hepatocellular carcinoma

Qingxiang Liu,1,&ast; Fei Peng,1,&ast; Haitao Liu,2,&ast; Qin Sun,1 Hui Chen,1 Xinyi Xu,1 Zihan Hu,1 Xing Zhou,1 Kai Jin,1 Jianfeng Xie,1 Yingzi Huang,1 Wei Huang,1 Yi Yang1 1Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, People’s Republic of China; 2School of Life Science, Fudan University, Shanghai, 200000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Huang; Yi Yang, Email whuang@seu.edu.cn; yiyiyang2004@163.comBackground: Natural killer (NK) cells are key regulators of immune defense in sepsis-induced acute respiratory distress syndrome (ARDS), yet the characteristics of NK cell clusters in ARDS remain poorly understood.Methods: A prospective and observational study enrolled septic patients with ARDS or not was conducted to determine the percentage of NK cells via flow cytometry. The transcriptomes of peripheral blood mononuclear cells (PBMCs) from healthy controls, patients with sepsis only, and patients with sepsis-induced ARDS were profiled. Vitro experiments were performed to confirm the mechanism mediating MX1+NK cell infiltration.Results: A total of 115 septic patients were analyzed, among whom 63 patients developed ARDS and 52 patients did not. Decreased NK percentages were found in sepsis with ARDS patients (%, 7.46± 4.40 vs 11.65± 6.88, P=0.0001) compared with sepsis-only patients. A lower percentage of NK cells showed a significant increase in 28-day mortality. Single-cell sequencing analysis revealed distinct characteristics of NK cells in sepsis-induced ARDS, notably the identification of a unique cluster defined as MX1+NK cells. Flow cytometry analysis showed an elevated percentage of MX1+NK cells specifically in individuals with sepsis-induced ARDS, compared with patients with sepsis only. Pseudo-time analysis showed that MX1+NK cells were characterized by upregulation of type I interferon-induced genes and other pro-inflammatory genes. MX1+NK cells can respond to type I interferons and secrete type I interferons themselves. Ligand–receptor interaction analysis also revealed extensive interaction between MX1+NK cells and T/B cells, leading to an uncontrolled inflammatory response in ARDS.Conclusion: MX1+NK cells can respond to type I interferons and secrete type I interferons themselves, promoting the development of sepsis-induced ARDS. Interfering with the infiltration of MX1+NK cells could be a therapeutic approach for this disease. Due to the limited sample size, a larger sample size was needed for further exploration.Keywords: ARDS, inflammation, natural killer cells, sepsis

Qing Zhang,1,&ast; Wenjun Hu,1,&ast; Mingxue Guo,1 Xinyu Zhang,1 Qin Zhang,1 Fengqi Peng,1 Liwen Yan,1 Zucheng Hu,1 Jakkree Tangthianchaichana,2 Yan Shen,3 Haiyan Hu,4 Shouying Du,1 Yang Lu1 1School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of China; 2Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, 12120, Thailand; 3School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China; 4School of Pharmacy, Beijing Health Vocational College, Beijing, 101100, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haiyan Hu, School of Pharmacy, Beijing Health Vocational College, Beijing, 101100, People’s Republic of China, Email yxyhhy@163.com Yang Lu, School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of China, Email luyang@bucm.edu.cnIntroduction: Responsive drug delivery systems hold great promise for tumor treatment as they focus on therapeutic agents directly, thus minimizing systemic toxicities and drug leakage. In this study, we covalently bound a matrix metalloproteinases-2 (MMP-2) enzyme-sensitive peptide to a tissue-penetrating peptide to rationally design a MMP-2 responsive multifunctional peptide hydrogel platform (aP/IR@FMKB) for cancer photothermal-chemo-immunotherapy. The constructed aP/IR@FMKB with bufalin (BF) loaded in trimethyl chitosan nanoparticles (TB NPs), photothermal agent IR820, and immune checkpoint inhibitor aPD-L1 by self-assembly could be dissociated in the presence of MMP-2 enzyme, triggering content release.Methods: TB NPs, IR820, and aPD-L1 were encapsulated by intermolecular self-assembly and enzyme-sensitive nanogels (aP/IR@FMKB) were constructed. The in vitro cytotoxicity of the blank gels and their ability to induce immunogenic cell death (ICD) in aP/IR@FMKB were evaluated using 4T1 cells. The promotion of deep tumor penetration and enzyme responsiveness was analyzed using a 3D cell model. The retention and antitumor activity at the tumor sites were examined using the primary tumor model. To assess the antitumor effect of aP/IR@FMKB induced by the immune response and its mechanism of action, recurrent tumor and distal tumor models were constructed.Results: This hydrogel system demonstrated exceptional photothermal performance and displayed prolonged local retention. Furthermore, the induction of ICD through IR820 and TB NPs sensitized the PD-L1 blockade, resulting in a remarkable 3.5-fold and 5.2-fold increase in the frequency of intratumor-infiltrating CD8+ T-cells in the primary tumor and distal tumor, respectively. Additionally, this system demonstrated remarkable efficacy in suppressing primary, distal, and recurrent tumors, underscoring its potential as a highly potent therapeutic strategy.Conclusion: This innovative design of the responsive hydrogel can effectively modulate the tumor immune microenvironment while also demonstrating sensitivity to the PD-1/PD-L1 blockade. This significant finding highlights the promising potential of this hydrogel in the field of multimodal tumor therapy.Keywords: responsive drug delivery systems, peptide hydrogels, immunogenic cell death, PD-1/PD-L1 blockade

Cheng-Yi Hu,1 Wen-Shuai Cui,1 Yi Lei,1 Yu-Wen Tang,1 Yan-Yan Zhang,1 Qi-Min Su,1 Fang Peng,2 Yun-Fei Zeng,1 Jia-Lin Song,1 Cheng-Na Luo,1 Yan Zhou,1 Xin-Yan Li,1 Zhu-Xiang Zhao1 1Department of Infectious Diseases, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China; 2Department of Critical Care Medicine, the Third Affiliated Hospital of Guang Zhou Medical University, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Zhu-Xiang Zhao, Department of Infectious Diseases, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, 510515, People’s Republic of China, Email zhaozhuxiang@126.comPurpose: To compare the effectiveness of azvudine and nirmatrelvir/ritonavir for the treatment of coronavirus disease (COVID-19).Patients and Methods: We conducted a retrospective analysis of data from 576 patients with COVID-19, comprising 195 patients without antiviral therapy, 226 patients treated with azvudine, 114 patients treated with nirmatrelvir/ritonavir, and 41 patients were treated with azvudine and nirmatrelvir/ritonavir concurrently. We compared their symptoms, mortality rates, and the length and cost of hospitalization.Results: The incidence of symptoms was similar in patients treated with azvudine and in those treated with nirmatrelvir/ritonavir. However, among patients experiencing weakness, the duration of weakness was significantly shorter in the azvudine group than in the nirmatrelvir/ritonavir group (P=0.029). Mortality did not differ significantly between the azvudine group and the nirmatrelvir/ritonavir group (18.14% vs.10.53%, P=0.068). Among “severe patients”, the mortality rate was markedly lower in patients treated with nirmatrelvir/ritonavir than in patients treated with azvudine (16.92% vs.32.17%, P=0.026). In patients with hepatic insufficiency, those treated with nirmatrelvir/ritonavir had substantially lower mortality than those treated with azvudine (15.09% vs.34.25%, P=0.016). In addition, patients treated with nirmatrelvir/ritonavir had longer hospital stays (P=0.002) and higher hospital costs (P< 0.001) than those receiving azvudine. Compared with patients treated with nirmatrelvir/ritonavir or azvudine alone, patients taking nirmatrelvir/ritonavir and azvudine concurrently had no significant improvement in survival (P> 0.05), length of stay (P> 0.05), or hospital costs (P> 0.05).Conclusion: Azvudine is recommended for patients with non-severe COVID-19 with weakness. Nirmatrelvir/ritonavir is recommended for patients with severe COVID-19, to reduce mortality, and it could be the best choice for patients with hepatic insufficiency. The concurrent use of nirmatrelvir/ritonavir and azvudine in patients with COVID-19 could be not recommended.Keywords: azvudine, nirmatrelvir/ritonavir, COVID-19, SARS-CoV-2

Peng Zhang,1,&ast; Hui Lin,1,&ast; Yan Guo,2 Fang Peng,1 Liping Meng1 1Department of Cardiology, Shaoxing People’s Hospital, Shaoxing, Zhejiang, 312000, People’s Republic of China; 2Department of Cardiology, Zhuji hospital of Traditional Chinese Medicine, Shaoxing, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liping Meng; Fang Peng, Department of Cardiology, Shaoxing People’s Hospital, No. 568 Zhongxing North Road, Shaoxing, 312000, Zhejiang, People’s Republic of China, Email mengliping@zju.edu.cn; sxrmyypf@126.comPurpose: Atherosclerosis is still a global public problem with increasing incidence rate and mortality. It has been found that gender factors play an important role in the progression of atherosclerosis. However, few people explore gender related atherosclerosis at the level of genes and immune cells. The purpose of this study was to determine genetic and immune cell differences between male and female samples.Patients and Methods: This study aims to identify differential genes between male and female samples in the GSE43292 dataset. The focus will be on identifying immune-related genes (IRGs) among these differentially expressed genes. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis will be employed to explore the enrichment of IRGs in biological processes, molecular functions, cellular components, and pathways. Furthermore, a protein-protein interaction (PPI) network for the IRGs will be constructed using Cytoscape software. To estimate the degree of immune cell infiltration, single-sample gene set enrichment analysis (ssGSEA) will be conducted. Moreover, the identified IRGs will be validated using GSE28829 dataset. Finally, we validated in atherosclerotic mice.Results: Seven IRGs (CCL13, IL1RN, FPR2, S100A8, CCL19, CXCL1, CXCL8) were identified as being overexpressed in male atherosclerosis. GO and KEGG analysis revealed that these IRGs are primarily enriched in inflammatory response pathways, cytokine signaling pathways, and cytokine- cytokine receptor interactions. Notably, when compared to females, there was a significant infiltration of immune cells in male specimens. Importantly, all seven IRGs demonstrated high diagnostic value in GSE28829 dataset. The use of animal samples supports our results.Conclusion: This study demonstrates the effectiveness of seven IRGs and reveal sex differences in atherosclerosis. Notably, there is a significant presence of immune cells within the atherosclerotic plaque of men compared to women. These findings have potential implications for the development of personalized treatment approaches targeting gender-related atherosclerosis.Keywords: atherosclerosis, immune related genes, sex related atherosclerosis, bioinformatics, immune infiltration

Zihan Hu,1,&ast; Danjiang Dong,2,&ast; Fei Peng,1,&ast; Xing Zhou,1 Qin Sun,1 Hui Chen,1,3 Wei Chang,1 Qin Gu,2,&ast; Jianfeng Xie,1,&ast; Yi Yang1,&ast; 1Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, People’s Republic of China; 2Department of Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China; 3Department of Critical Care Medicine, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianfeng Xie; Qin Gu, Department of Critical Care Medicine, Zhongda Hospital, School of medicine, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, People’s Republic of China, Tel/Fax +00862583262500, Email xie820405@126.com; guqinicu012323@126.comPurpose: Immune dysfunction plays a pivotal role in sepsis pathogenesis. Previous studies have revealed the crucial role of T cells and human leukocyte antigen-DR (HLA-DR) in sepsis. However, the function of natural killer (NK) cells remains unclear. This study aimed to investigate whether NK cells are associated with sepsis prognosis. In addition, we aimed to explore the interrelation and influence between NK and other immunological features in patients with sepsis.Patients and Methods: This retrospective, observational study included patients with sepsis from two hospitals in mainland China. The clinical characteristics and immune results during the early phase were collected. Patients were classified according to the level of immune cells to analyze the relationship between immunological features and 28-day mortality.Results: A total of 984 patients were included in this study. Non-survivors were older and had lower levels of lymphocytes, monocytes, NK cells, HLA-DR, and T cells. Patients were classified into eight groups according to their levels of NK cells, HLA-DR, and T cells. Only patients with decreased NK and T cell counts showed a significant increase in 28-day mortality. An increase in CD8+ T cells was correlated with the alleviation of 28-day mortality only among patients with high NK cell levels.Conclusion: This study provides novel insights into the association between NK cells and 28-day mortality as well as the interrelation between NK cells and other immune cells in sepsis. The relationship between CD8+ T cells and 28-day mortality in sepsis is dependent on NK cell count.Keywords: sepsis, immune dysfunction, natural killer cell, HLA-DR, T cell

Abstract Frailty, as measured by the modified frailty index-5 (mFI-5), and older age are associated with increased mortality in the setting of spinal cord injury (SCI). However, there is limited evidence demonstrating an incremental prognostic value derived from patient mFI-5. We conducted a retrospective cohort study to evaluate in-hospital mortality among adult complete cervical SCI patients at participating centers of the Trauma Quality Improvement Program from 2010 to 2018. Logistic regression was used to model in-hospital mortality, and the area under the receiver operating characteristic curve (AUROC) of regression models with age, mFI-5, or age with mFI-5 was used to compare the prognostic value of each model. 4733 patients were eligible. We found that both age (80 y versus 60 y: OR 3.59 95% CI [2.82 4.56], P

Abstract Odontoid fractures are increasingly prevalent in older adults and associated with high morbidity and mortality. Optimal management remains controversial. Our study aims to investigate the association between surgical management of odontoid fractures and in-hospital mortality in a multi-center geriatric cohort. We identified patients 65 years or older with C2 odontoid fractures from the Trauma Quality Improvement Program database. The primary study outcome was in-hospital mortality. Secondary outcomes were in-hospital complications and hospital length of stay. Generalized estimating equation models were used to compare outcomes between operative and non-operative cohorts. Among the 13,218 eligible patients, 1100 (8.3%) were treated surgically. The risk of in-hospital mortality did not differ between surgical and non-surgical groups, after patient and hospital-level adjustment (OR: 0.94, 95%CI: 0.55–1.60). The risks of major complications and immobility-related complications were higher in the operative cohort (adjusted OR: 2.12, 95%CI: 1.53–2.94; and OR: 2.24, 95%CI: 1.38–3.63, respectively). Patients undergoing surgery had extended in-hospital length of stay compared to the non-operative group (9 days, IQR: 6–12 days vs. 4 days, IQR: 3–7 days). These findings were supported by secondary analyses that considered between-center differences in rates of surgery. Among geriatric patients with odontoid fractures surgical management was associated with similar in-hospital mortality, but higher in-hospital complication rates compared to non-operative management. Surgical management of geriatric patients with odontoid fractures requires careful patient selection and consideration of pre-existing comorbidities.

Fen Peng,1 Tian-Bao Xia2 1Department of Dermatology, Peking University Third Hospital, Beijing, People’s Republic of China; 2Department of Dermatology, People’s Liberation Army Strategic Support Force Characteristic Medical Center, Beijing, People’s Republic of ChinaCorrespondence: Tian-Bao Xia, Department of Dermatology, People’s Liberation Army Strategic Support Force Characteristic Medical Center, No. 9th Anxiang Beili Road, Chaoyang District, Beijing, 100101, People’s Republic of China, Email xtb78@163.comBackground: Postherpetic neuralgia (PHN), which represents the most common chronic complication of herpes zoster, is characterized by intense pain and is difficult to treat. In fact, no treatments are currently available that can effectively reduce the pain associated with PHN. Recent evidence has been presented indicating that Botulinum toxin (BoNT-A) can serve as an effective and safe treatment for peripheral neuropathic pain.Objective: The effects of intradermal BoNT-A injections on herpes zoster related neuralgia were investigated in this study.Methods: Patients diagnosed with herpes zoster related acute neuralgia (N=13 – acute group) and those diagnosed with postherpetic neuralgia (N=17 - PHN group) were enrolled in this study. The two groups were treated with intradermal injections of BoNT-A at the site of their affected pain areas and were then assessed at 1 day, 1 week, 2 weeks, 1 month, 2 months and 3 months after their BoNT-A treatments.Results: When compared with pre-treatment values, Visual Analogue Scores (VAS) in all patients were all significantly decreased at all times tested following BoNT-A injection. Before treatment, PHN patients had significantly higher VAS than those in the acute group. However, after 1 day of treatment, there was no difference in VAS between the two groups. None of the patients in the acute phase treated with BoNT-A developed PHN.Conclusion: BoNT-A injections significantly reduced herpetic-related pain and proved to be a more effective treatment for the PHN versus acute pain group. Moreover, an early application of BoNT-A can alleviate the probability of developing PHN.Keywords: herpes zoster, postherpetic neuralgia, botulinum toxin

Fen Peng,1,&ast; Haiyang He,2,&ast; Tianbao Xia,2 Shichao Lv2 1Department of Dermatology, Peking University Third Hospital, Beijing, People’s Republic of China; 2Department of Dermatology, Special Medical Center of Strategic Support Force of PLA, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tianbao Xia; Shichao Lv, Department of Dermatology, Special Medical Center of Strategic Support Force of PLA, No. 9 Anxiang Beili Road, Chaoyang District, Beijing, 100101, People’s Republic of China, Email xtb78@163.com; lvshichao@sina.comBackground: Herpes zoster (HZ) is an acute herpetic skin disease resulting from the varicella-zoster virus. Typically, this condition is treated with a one-week administration of antiviral drugs, including famciclovir, which can effectively control the symptoms during the acute phase and prevent the occurrence of postherpetic neuralgia (PHN).Objective: To investigate whether a longer, two-week, regimen would enhance the capacity for famciclovir to reduce pain and prevent the occurrence of postherpetic neuralgia.Methods: HZ patients were randomly divided into two groups who were treated with famciclovir for either a one- or two-week period. Following their respective famciclovir treatments, patients were assessed for potential differences in pain intensity as evaluated at 1, 2, 4, 8 and 12 weeks post-treatment. In addition, the occurrence of postherpetic neuralgia at three months after treatment was compared between the two groups.Results: Of the 86 patients initially enrolled, 80 completed the study with N=40 randomly assigned to each of the two groups. Pain scores decreased significantly at 1, 2, 4, 8 and 12 weeks after famciclovir treatments. There were no significant differences in pain scores, and the incidence of postherpetic neuralgia occurrence between the two groups. There were no statistically significant differences in reducing pain intensity or frequency of postherpetic neuralgia between the one-week and two-week treatment protocols.Conclusion: It suggests that longer administration of famciclovir has no further benefit in the treatment of herpes zoster in our study.Keywords: herpes zoster, postherpetic neuralgia, famciclovir

Fei Peng,1 Jing Liu,1,2 Yujun Zhang,1,2 Guoyan Zhao,1,2 Deying Gong,1,2 Liu He,1,2 Wensheng Zhang,1,2 Feng Qiu1,2 1Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Feng Qiu; Wensheng Zhang, Email fengqiu@scu.edu.cn; zhang_ws@scu.edu.cnIntroduction: Ropivacaine as a conventional local anesthetic has been used more and more frequently in the treatment of postoperative pain, but its analgesic effect can only last for several hours. In order to fulfill the clinic requirement for long-term analgesia, a long-acting ropivacaine nanocrystal formulation was fabricated through the interaction between ropivacaine and a self-assembling peptide.Methods: Transmission electron microscopy, dynamic light scattering, circular dichroism and fluorescence spectrometry were used to examine the structural changes caused by the interaction between ropivacaine and the peptide. Scanning electron microscopy, dynamic light scattering, Fourier transform infrared spectrometry, X-ray diffraction and optical microscopy were used to characterize the ropivacaine-peptide nanocrystal. In vitro drug release and pharmacokinetics study were conducted to evaluate the slow-release profile of the nanocrystal formulation. A rodent cutaneous trunci muscle reflex model was used to evaluate the nociceptive blockade effects, and histological analysis was used to evaluate the local toxicity. A rodent plantar incisional pain model was used to evaluate the analgesic effect.Results: Soluble ropivacaine monomers interacted with the Q11 peptide through π-π stacking and remolded its self-assembling structure, leading to the formation of drug/peptide nanoparticles which could be mineralized to form drug/peptide nanocrystals by adjusting the pH. Under physiological condition, the nanocrystals could release free ropivacaine slowly. As evaluated in rodent models, the anesthetic and analgesic effects of this formulation were significantly extended without causing toxicity.Conclusion: Based on the interaction between ropivacaine and Q11, a controllable biomineralization process could be induced to obtain homogeneous nanocrystals, which could be used as an injectable long-acting analgesic formulation. This crystallization strategy utilizing the peptide-drug interaction also provided a promising pathway to fabricate long-acting formulations for many other small molecular drugs.Keywords: self-assembling peptide, nanocrystal, local anesthetics, π-π stacking, slow release, long-acting analgesia

Fang Peng,1 Hao Yuan,1 Yi-Feng Zhou,2 Si-Xian Wu,1 Zhen-Yi Long,1 Ya-Meng Peng1 1Department of Clinical Laboratory, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, People’s Republic of China; 2Operating Room, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, People’s Republic of ChinaCorrespondence: Hao Yuan, Department of Clinical Laboratory, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, People’s Republic of China, Tel +8613677366519, Email yuanhao666@hunnu.edu.cnPurpose: We aimed to explore the clinical diagnostic value of combined detection via protein induced by vitamin K absence or antagonist II (PIVKA-II), alpha-fetoprotein (AFP), and D-dimer (D-D) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).Materials and Methods: We analyzed PIVKA-II, AFP, and D-D levels in 291 subjects comprising liver cirrhosis (LC) patients (n = 143) and HCC patients (n = 148). Receiver operating characteristic (ROC) curves were used to analyze and compare the clinical diagnostic value of the three biomarkers for HBV-related HCC alone and in combination.Results: The levels of PIVKA-II, AFP, and D-D were positively correlated with tumor size in HCC patients. The levels of PIVKA-II and AFP in early-stage HCC, advanced HCC, HBV DNA+ HCC, and HBV DNA- HCC patients were higher than those in LC patients, while the levels of D-D were lower. The area under the curve for combined detection was greater than that for single-index detection in early-stage HCC, advanced HCC, HBV DNA+ HCC, and HBV DNA- HCC patients.Conclusion: D-D may be a useful biomarker for the diagnosis of HBV-related HCC. The combined detection of PIVKA-II, AFP, and D-D had better diagnostic value for different types of HCC than the detection of individual biomarkers.Keywords: PIVKA-II, alpha-fetoprotein, D-dimer, biomarker, hepatocellular carcinoma, hepatitis B virus

Jun Chen,1,&ast; Hongli Wang,2,&ast; Fang Peng,3,&ast; Haiyan Qiao,1 Linfeng Liu,1 Liang Wang,1 Bingbing Shang4 1Laboratory Animal Center, Dalian Medical University, Dalian, 116044, Liaoning Province, People’s Republic of China; 2Cardiology Department, The Second Hospital of Dalian Medical University, Dalian, 116023, Liaoning Province, People’s Republic of China; 3Pathology Department, The Second Hospital of Dalian Medical University, Dalian, 116023, Liaoning Province, People’s Republic of China; 4Emergency Department, The Second Hospital of Dalian Medical University, Dalian, 116023, Liaoning Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bingbing Shang; Liang Wang, Tel +86-17709875175 ; +86-13332225676, Email shangbingbing@dmu.edu.cn; wangliang-dy@dmu.edu.cnBackground: Anoctamin 1 (ANO1) has been observed to be overexpressed in gastrointestinal and pulmonary epithelial cells, as well as in a number of cancers. Although Ano1 is involved in the prognosis of colorectal cancer (CRC), its mechanism of action in metastatic CRC has not been fully elucidated.Methods: The expression of Ano1 was assessed in samples obtained from The Cancer Genome Atlas (TCGA) database. Then, we used Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, Gene set enrichment analysis (GSEA), Gene set variation analysis (GSVA), and Weighted Correlation Network Analysis (WGCNA) to determine the functions of Ano1. Additionally, random survival forest, Cox multivariate analysis, Kaplan Meier analysis, and ROC were used to determine the predictive value of Ano1 on clinical outcomes in CRC patients. Finally, HE staining, immunohistochemical (IHC) analysis and qRT-PCR were used to explore the expression of the Ano1 gene in CRC tissue.Results: The expression level of Ano1 in CRC was significantly elevated, and the prognosis was poor. The modules with a higher proportion of upregulated genes tended to be positively correlated with Ano1-high. KNG1, GNG4, F2, POSTN, THBS2, SPP1 and FGA were identified as hub proteins of the PPI network. The heatmap showed that the expression level of the Ano1-high group was significantly negatively correlated with immune infiltrate. The overexpression of the Ano1 gene in CRC tissue samples was also confirmed by HE staining, immunohistochemical (IHC) analysis and qRT-PCR.Conclusion: High expression of Ano1 is closely related to a poor prognosis in patients with colorectal cancer. Ano1 may participate in the metastasis and progression, as well as the immune regulation of CRC. In summary, Ano1 can act as a potential prognostic biomarker and a novel target for CRC therapy.Keywords: ANO1, biomarker, colorectal cancer, prognosis, Immune infiltration

Fei Peng,1 Si Lei,1 Quan Zhang,1 Yanjun Zhong,2 Shangjie Wu1 1Department of Respiratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 2Department of Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, People’s Republic of ChinaCorrespondence: Yanjun ZhongDepartment of Critical Care Medicine, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, People’s Republic of China, Email zhongyanjun@csu.edu.cnShangjie WuDepartment of Respiratory Medicine, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, People’s Republic of China, Email wushangjie@csu.edu.cnBackground: Triglyceride to high density lipoprotein cholesterol ratio (TG/HDL-c) is crucial when researching metabolic and vascular diseases, and its involvement in COVID-19 was sparsely elaborated on. The purpose of the study was to explore the inflammatory associations between the TG/HDL-c ratio and COVID-19 prognosis.Methods: A total of 262 COVID-19 patients consisting of 244 survivors and 18 non-survivors were retrospectively investigated. The clinical features and baseline hematological parameters were recorded and analyzed. The receiver operating characteristic curve (ROC) was used to explore the role of TG/HDL-c in predicting the mortality of COVID-19, the Spearman’s rank correlation coefficients were used to measure the correlation between TG/HDL-c and inflammatory indicators, and the Kaplan–Meier (KM) curve was used to estimate the survival of COVID-19 patients with high and low TG/HDL-c ratio. Logistic regression analyses were performed to investigate the role of TG/HDL-c ratio on mortality of COVID-19 with no underlying diseases.Results: Compared with the survivors, the non-survivors of COVID-19 had significantly higher levels of white blood cells (4.7 vs 13.0 × 109/L; P < 0.001), neutrophils (3.0 vs 11.6 × 109/L; P < 0.001), C-reactive proteins (15.7 vs 76.7 mg/L; P < 0.001) and TG/HDL-c ratio (1.4 vs 2.5; P = 0.001). The ROC curve [area under the curve (AUC), 0.731; 95% confidence interval (CI), 0.609– 0.853; P = 0.001] suggested that the TG/HDL-c ratio could predict the mortality of COVID-19. The TG/HDL-c ratio was positively correlated with white blood cells (r = 0.255, P < 0.001), neutrophils (r = 0.243, P < 0.001) and C-reactive proteins (r = 0.170, P < 0.006). Patients with high TG/HDL-c ratio showed a worse survival compared with those with low TG/HDL-c ratio (Log rank P = 0.003). Moreover, TG/HDL-c ratio was an independent factor in predicting the mortality of COVID-19 patients with no underlying diseases.Conclusion: Our study demonstrated that TG/HDL-c ratio might potentially be a predictive marker for mortality in COVID-19 patients.Keywords: COVID-19, triglyceride, high density lipoprotein cholesterol, inflammation, viral infection, triglyceride-to-high-density lipoprotein cholesterol ratio, mortality

Zhen-Yi Long,1,&ast; Yi-Feng Zhou,2,&ast; Hao Yuan,1 Ya-Meng Peng,1 Si-Xian Wu,1 Fang Peng1 1Department of Clinical Laboratory, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, People’s Republic of China; 2Operating Room, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hao YuanDepartment of Clinical Laboratory, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, People’s Republic of ChinaTel +86-13677366519Fax +86-731-82278012Email yuanhao666@hunnu.edu.cnPurpose: We explored the expression levels of IgG4 and interleukin (IL)-21 in the serum and ankle joints of collagen-induced arthritis (CIA) rats at different disease stages.Materials and Methods: Wistar rats were randomly divided into normal and model groups, and the latter group was administered bovine type II collagen to induce arthritis. Enzyme-linked immunosorbent assay was performed at 21, 28, 35, and 42 days to detect IgG4 and IL-21 in the serum, followed by histological and immunohistochemical analyses of IgG4 and IL-21r in the ankle joint of rats.Results: The contents of IgG4 and IL-21 in the serum of the CIA model group were positively correlated and increased with disease progression. The expression of IgG4 and IL-21 receptors in the ankle joint of the CIA model group was significantly higher than that in the control group. These proteins were closely related to the pathological score. The serum IL-21 level in the model group was closely related to the level of IL-21 receptor in the ankle joint.Conclusion: IL-21 may promote the occurrence and development of rheumatoid arthritis by combining with IL-21r to regulate the content of IgG4.Keywords: rheumatoid arthritis, immunoglobulin, interleukin, interleukin receptor

Lei Yu,1,&ast; Xiaofang Xie,1,&ast; Xiaoyu Cao,1 Junren Chen,1 Guanru Chen,1 Yan Chen,1 Gangmin Li,1 Junyuan Qin,1 Fu Peng,2 Cheng Peng1 1State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 2Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fu PengDepartment of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, People’s Republic of ChinaTel/Fax +86 28-61800018Email fujing126@yeah.netCheng PengState Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People’s Republic of ChinaTel/Fax +86 28-61800231Email cdtcmpengcheng@126.comAbstract: Cancer is still an insurmountable problem for humans and critically attacking human health. In recent years, natural products have gained increasing attention in the field of anti-tumor due to their extensive sources and minimal side effects. Maslinic acid (MA), a pentacyclic triterpene acid mainly derived from the olive tree (Olea europaea L.) has been confirmed to possess great anti-cancer effects. This paper reviewed the inhibitory effect of MA and its derivatives on lung cancer, colon cancer, ovarian cancer, gastric cancer, lymphatic, leukemia, breast cancer, pancreatic cancer, melanoma, prostate cancer, renal cell carcinoma, gallbladder cancer, and bladder cancer, among others. MA inhibited the proliferation of various tumor cells and showed lower IC50 values in melanoma 518A2 cells and gastric cancer MKN28 cells compared with other cell lines. A series of semi-synthetic derivatives obtained by modifying MA chemical structure have been shown to have high cytotoxicity to human tumor cell lines, but low cytotoxicity to non-malignant cells, which is conducive to developing its potential as a chemotherapeutic agent. These studies suggest that MA derivatives have broad prospects in the development of antitumor therapeutics in the future and warrant further study.Keywords: maslinic acid, tumor, mechanism, derivatives

Shengyi Long,1,&ast; Fang Peng,1,&ast; Baohui Song,1,&ast; Liang Wang,2 Jun Chen,2 Bingbing Shang1 1The Second Hospital of Dalian Medical University, Dalian, Liaoning Province, People’s Republic of China; 2Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Chen Email chenjun@dmu.edu.cnBingbing Shang Email shangbingbing@dmu.edu.cnBackground: Hepatocellular carcinoma (HCC) is one of the most serious malignancies. The main features of HCC are vascular invasion and drug resistance. Ferroptosis is a novel cell program that is involved in several diseases, such as cancer. Heat shock protein beta 1 (HSPB1) is a major component of heat shock proteins. A recent study showed that HSPB1 could be a new therapeutic target for colorectal cancer with 5-fluorouracil-acquired resistance. However, the functional role of HSPB1 in HCC remains unclear.Aim: The aim of this study is to clarify HSPB1 expression in HCC and its potential therapeutic and prognostic value.Methods: We collected data on HSPB1 expression levels in HCC and normal liver tissues from The Cancer Genome Atlas and Gene Expression Omnibus databases. We then validated it using immunohistochemistry (IHC). Receiver operating characteristic and Kaplan–Meier survival curves were used to investigate the role of HSPB1 in the prognosis analysis of HCC. Further, we used the online Search Tool for the Retrieval of Interacting Genes/Proteins website, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes to conduct enrichment analysis and identify the predictive signaling pathways. Meanwhile, we used the TIMER and GSVA package of R (v3.6.3) to analyze the association between HSPB1 and immunocyte infiltration.Results: Compared to normal tissues, there was differential expression of HSPB1 in pan-cancers. HSPB1 expression was higher in HCC tissues than in normal tissues (p< 0.05). There was an evident significant difference between HSPB1 mRNA levels and histologic grade, vascular invasion, and alpha-fetoprotein level (all p values< 0.05). Univariate analysis indicated that HCC patients with high HSPB1 levels had shorter overall survival rates than those with low HSPB1 levels (p< 0.05). MAPK14, HSPA8, MAPKAPK3, MAPKAPK5, and MAPKAPK2 are essential proteins that interact with HSPB1. There was a significant correlation between HSPB1 expression levels and immune cell infiltration, including CD4+ T cells (r=0.203, p< 0.05).Conclusion: High HSPB1 expression is closely associated with a worse prognosis in HCC patients, and HSPB1 may be a target of immunotherapy in HCC.Keywords: hepatocellular carcinoma, ferroptosis, HSPB1, immune cells infiltration, bioinformatics analysis

Jing Liu,1,2 Fei Peng,1,2 Yi Kang,1,2 Deying Gong,1,2 Jing Fan,1,2 Wensheng Zhang,1,2 Feng Qiu1,2 1Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Feng Qiu; Wensheng Zhang Email fengqiu@scu.edu.cn; zhang_ws@scu.edu.cnPurpose: Typical hydrophobic amino acids (HAAs) are important motifs for self-assembling peptides (SAPs), but they lead to low water-solubility or compact packing of peptides, limiting their capacity for encapsulating hydrophobic drugs. As an alternative, we designed a peptide GQY based on atypical HAAs, which could encapsulate hydrophobic drugs more efficiently. Although hydrophobic general anesthetics (GAs) have been formulated as lipid emulsions, their lipid-free formulations have been pursued because of some side effects inherent to lipids. Using GAs as targets, potential application of GQY as a carrier for hydrophobic drugs was evaluated.Methods: Thioflavin-T (ThT) binding test, dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to examine the self-assembling ability of GQY. Pyrene and 8-Anilino-1-naphthalenesulfonic acid (ANS) were used to confirm formation of hydrophobic domain in GQY nanoparticles. Using pyrene as a model, GQY’s capacity to encapsulate hydrophobic drugs was evaluated. GAs including propofol, etomidate and ET26 were encapsulated by GQY. Loss of righting reflex (LORR) test was conducted to assess the anesthetic efficacy of these lipid-free formulations. Paw-licking test was used to evaluate pain-on-injection of propofol-GQY (PROP-GQY) formulation. Hemolytic and cytotoxicity assay were used to evaluate biocompatibility of GQY.Results: Stable nanoparticles containing plenty of hydrophobic cavities could be formed by GQY, which could encapsulate hydrophobic drugs at very high concentration and form stable suspensions. Propofol, etomidate and ET26 formulated by GQY showed anesthetic efficacy comparable to their currently available formulations. Unlike clinic lipid emulsion, PROP-GQY formulation did not cause pain-on-injection in rats. Neither obvious cytotoxicity nor hemolytic activity of GQY was observed.Conclusion: GQY could encapsulate GAs to obtain stable and effective formulations. As a lipid-free carrier, GQY exhibited considerable biocompatibility and other side benefits such as reducing pain-on-injection. More SAPs based on atypical HAAs could be designed as promising carriers for hydrophobic drugs.Keywords: self-assembling peptides, nanoparticles, hydrophobic drugs, lipid-free formulations, general anesthetics

Chen Gao, Fenghua Peng, Xubiao Xie, Longkai Peng Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People’s Republic of ChinaCorrespondence: Longkai PengDepartment of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People’s Republic of ChinaEmail penglongkai@csu.edu.cnBackground: Circulating interleukin (IL)-10 is associated with adverse cardiovascular events in chronic kidney disease (CKD). Whether IL-10 predicts cardiovascular and all-cause mortality after kidney transplantation (KT) is unknown.Methods: The association between plasma IL-10 and cardiovascular and all-cause mortality was analyzed in a prospective cohort, which included 418 stable kidney transplant recipients, at a median of 3.6 (range=1.2– 8.4) years after transplantation. Multivariate Cox regression models were performed to adjusting related confounding factors.Results: Median level of IL-10 in KT patient was 22.3 pg/mL. Multivariate Cox regression analysis revealed that serum levels IL-10 were significantly and independently associated with cardiovascular mortality after adjusting for age, gender, BMI, current smoker, current drinker, cause of kidney disease, systolic and diastolic BP, laboratory indexes and medication (HR=1.26, 95% CI 1.19– 2.08, P-trend< 0.001). The multivariate Cox analysis also suggested that serum levels IL-10 were independently associated with all-cause mortality (HR=1.25, 95% CI 1.11– 1.8, P-trend=0.023) after controlling these same related confounding factors. Sensitivity and stratified analysis showed that the significant association can be affected by history of acute rejection.Conclusion: Plasma IL-10 is independently and significant associated with cardiovascular and all-cause mortality after kidney transplantation. The significant association is independent of cardiovascular risk factors and other related confounding factors.Keywords: IL-10, kidney transplantation, cardiovascular mortality, all-cause mortality, Cox regression, prognosis

Hui Ye,1,* Xiaoying Chu,1,* Zhensheng Cao,2,* Xuanxuan Hu,1,* Zihan Wang,2 Meiqi Li,1 Leyu Wan,2 Yongping Li,3 Yongge Cao,4 Zhanqiu Diao,2 Fengting Peng,2 Jinsong Liu,2 Lihua Xu5 1School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China; 2School of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China; 3Department of Surgery, Chengdu Shuangliu District Maternal and Child Health Hospital, ChengDu, Sichuan, 610200, People’s Republic of China; 4Department of Stomatology, Haiyuan College, Kunming, Yunnan, 650106, People’s Republic of China; 5Department of General Medicine, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui YeSchool of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of ChinaEmail wmcyh@wmu.edu.cnLihua XuDepartment of General Medicine, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, ChinaEmail lihuaxu@wmu.edu.cnBackground: This study was aimed to prepare a novel magnetic thermosensitive cationic liposome drug carrier for the codelivery of Oxaliplatin (OXA) and antisense lncRNA of MDC1 (MDC1-AS) to Cervical cancer cells and evaluate the efficiency of this drug carrier and its antitumor effects on Cervical cancer.Methods: Thermosensitive magnetic cationic liposomes were prepared using thin-film hydration method. The OXA and MDC1-AS vectors were loaded into the codelivery system, and the in vitro OXA thermosensitive release activity, efficiency of MDC1-AS regulating MDC1, in vitro cytotoxicity, and in vivo antitumor activity were determined.Results: The codelivery system had desirable targeted delivery efficacy, OXA thermosensitive release, and MDC1-AS regulating MDC1. Codelivery of OXA and MDC1-AS enhanced the inhibition of cervical cancer cell growth in vitro and in vivo, compared with single drug delivery.Conclusion: The novel codelivery of OXA and MDC1-AS magnetic thermosensitive cationic liposome drug carrier can be applied in the combined chemotherapy and gene therapy for cervical cancer.Keywords: magnetic thermosensitive cationic liposome, oxaliplatin, antisense lncRNA of MDC1, targeted therapy, cervical cancer

Miaoxia Liu,1,2,* Ruihong Wu,1,3,* Xu Liu,1 Hongqin Xu,1 Xiumei Chi,1,3 Xiaomei Wang,1 Mengru Zhan,1 Bao Wang,1 Fei Peng,1 Xiuzhu Gao,1,3 Ying Shi,1 Xiaoyu Wen,1 Yali Ji,2 Qinglong Jin,1 Junqi Niu1 1Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People’s Republic of China; 2Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People’s Republic of China; 3Phase I Clinical Research Center, First Hospital of Jilin University, Changchun, Jilin Province 130021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qinglong JinDepartment of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun 130021, People’s Republic of ChinaTel/Fax +86-431-81875103Email jinql2016@163.comPurpose: GALAD is a statistical model for estimating the likelihood of having hepatocellular carcinoma (HCC) based on gender, age, AFP, AFP-L3, and PIVKA-II. We aimed to assess its performance and build new models in China, where hepatitis B virus (HBV) is the leading etiology of HCC.Patients and Methods: We built the GALAD-C model with the same five variables in GALAD, and the GAAP model with gender, age, AFP, and PIVKA-II, using logistic regression based on 242 patients with HCC and 283 patients with chronic liver disease (CLD). We also collected 50 patients with other malignant liver tumors (OMTs) and 50 healthy controls (HCs). A test dataset (169 patients with HCC and 139 with CLD) was used to test the performance of GAAP.Results: The GALAD-C and GAAP models achieved comparable performance (area under the receiver operating characteristic curve [AUC], 0.922 vs 0.914), and both were superior to GALAD, PIVKA-II, AFP, and AFP-L3% (AUCs, 0.891, 0.869, 0.750, and 0.711) for discrimination of HCC from CLD for the entire dataset. The AUCs of the GALAD, GALAD-C and GAAP models were excellent for the hepatitis C virus (HCV) subgroup (0.939, 0.958 and 0.954), and for discrimination HCC from HCs (0.988, 0.982, and 0.979), but were relatively lower for the HBV subgroup (0.855, 0.904, and 0.894), and for HCC within Milan Criteria (0.810, 0.841, and 0.840). They were not superior to AFP (0.873) for discrimination of HCC from OMT (0.873, 0.809, and 0.823). GAAP achieved an AUC of 0.922 in the test dataset.Conclusion: GALAD was excellent for discrimination of HCC from CLD in the HCV subgroup of a cohort of Chinese patients. The GAAP and GALAD-C models achieved better performance compared with GALAD. These three models exhibited better performance in patients with an HCV etiology than those with HBV.Keywords: hepatocellular carcinoma, alpha-fetoprotein, PIVKA-II, GALAD

Fangxing Peng,1,2 Yao Liu1,2 1Gastrointestinal Surgery, No. 2 Affiliated Hospital of North Sichuan Medical College, Mianyang, Sichuan Province 621000, People’s Republic of China; 2Gastrointestinal Surgery, Sichuan Mianyang 404 Hospital, Mianyang, Sichuan Province 621000, People’s Republic of ChinaCorrespondence: Fangxing Peng Tel +8618990181928Email pfx120@126.comAbstract: In recent years, the diagnosis and treatment of gastrointestinal stromal tumors (GISTs) of the small intestine have been a hot topic due to their rarity and non-specific clinical manifestations. With the development of gene and imaging technology, surgery, and molecular targeted drugs, the diagnosis and treatment of GISTs have achieved great success. For a long time, radical resection was prioritized to treat GISTs of the small intestine. At present, preoperative tumor staging is a novel treatment for unresectable malignant tumors. In addition, karyokinesis exponent is the sole independent predictor of progression-free survival of GISTs. The DNA, miRNA, and protein of exosomes have also been found to be biomarkers with prognostic implications. The research on the treatment of GISTs has become a focus in the era of precision medicine, ushering in the use of standardized, normalized, and individualized treatment.Keywords: gastrointestinal stromal tumors, GISTs, small intestine, novel treatment, preoperative tumor staging, karyokinesis exponent, exosomes

Panpan Zhai,1–3 Qian Li,1–3 Ali Hassan Gillani,4 Khezar Hayat,1–3,5 Li Shi,1–3 Siyi Wang,1–3 Fei Peng,1–3 Sen Xu,1–3 Qianqian Du,1–3 Zeyu Cao,1–3 Donald E Morisky,6 Yu Fang1–31Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmacy, Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2Center for Drug Safety and Policy Research, Xi’an, People’s Republic of China; 3Shaanxi Center for Health Reform and Development Research, Xi’an Jiaotong University, Xi’an, People’s Republic of China; 4Department of Pharmacy, Yusra Institute of Pharmaceutical Sciences, Islamabad, Pakistan; 5Institute of Pharmaceutical Sciences, University of Veternary and Animal Sciences, Lahore, Pakistan; 6Department of Community Health Sciences, UCLA Fielding School of Public Health, Los Angeles, CA 90095-1772, USAPurpose: Hypertension prevalence is mounting at a great pace in the People’s Republic of China and poses a serious threat to health care systems. Medication nonadherence is one of the key factors in controlling high blood pressure. Our study uses two-arm cluster randomized controlled trial to investigate whether personal consultation by postgraduate pharmacy students and short message services (SMS) is effective in improving medication adherence and blood pressure control.Patients and methods: The trial will involve 384 treated patients in 8 community health care centers (CHCs). The 8 CHCs will be randomly assigned to intervention and control group in a ratio of 1:1. Patients in the intervention group will receive a personal consultation which identifies the barriers to medication adherence and SMS reminders which will be sent at 3-day intervals while patients in the control group will receive standard pharmaceutical care. Personal consultation by pharmacy students will be delivered at months 0 and 3. SMS messages will include educational information about normal blood pressure, complications of hypertension, salt intake, healthy diet, smoking cessation, regular exercise, weight control, antihypertensive medication schedule and treatment. Both groups will be followed for 6 months in order to compare their medication adherence and blood pressure at months 0, 3 and 6. The primary clinical outcome is the change in mean blood pressure and medication adherence measured at baseline, months 3 and 6. Secondary outcome is the proportion of patients reaching controlled blood pressure at months 3 and 6.Discussion: Pharmacy students led consultation will be conducted in the process of physical examination and SMS reminders which is at low cost, may be a feasible way to address the high prevalence of hypertension in the People’s Republic of China.Keywords: medication adherence, hypertension, blood pressure, SMS reminders, personal consultation, community health care centers

Xiaomin Dai, Li Zhao, Fang Peng Department of Pathology, Zhejiang Hospital, Xihu District, Hangzhou, Zhejiang, China Abstract: Clear cell carcinoma arising from the thymus is considered exceedingly rare. It shows aggressive clinical behavior and demonstrates frequent local recurrences as well as widespread metastasis. The detailed clinical data of one patient with thymic clear cell carcinoma were compiled, and a review of relevant reported studies was performed. We summarized the clinical characteristics, pathological diagnosis of the patient and other reported cases. The analysis showed that older male patients were more likely to suffer, and the manifestations included chest pain and dyspnea. Some patients are asymptomatic, with the tumor being discovered during physical examination. Histologically, thymic clear cell carcinoma is composed of lobulated structures arranged in hyperchromatic fibrous stroma; the tumor cells are uniform with obvious nucleoli and clear cytoplasm. To establish the correct diagnosis, consideration and exclusion of metastasis and other original tumors in the ­differential diagnosis by immunohistochemistry, clinical and radiologic correlation is important. Keywords: thymic carcinoma, clear cell carcinoma, differential diagnosis

Juan Zhou,1,* Wen-Wen Zhang,2,* Fang Peng,3 Jia-Yuan Sun,2 Zhen-Yu He,2 San-Gang Wu4 1Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, Xiamen 361003, People’s Republic of China; 2Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, People’s Republic of China; 3Department of Radiation Oncology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, People’s Republic of China; 4Department of Radiation Oncology, Xiamen Cancer Hospital, the First Affiliated Hospital of Xiamen University, Xiamen 361003, People’s Republic of China *These authors contributed equally to this work Introduction: Although some circRNAs have been found to regulate the progression of malignancies, their functions and coupled molecular mechanisms are still unclear. In our study, we sought to assess the underlying molecular mechanisms of circRNAs in breast cancer and therefore explored the differentially expressed circRNAs and co-expression networks, followed by in vitro experiments. Materials and methods: High-throughput RNA sequencing was performed to obtain an unbiased profile of circRNA expression. CircRNA-miRNA-mRNA co-expression networks were predicted, and sequence analyses were carried out. The MTT, transwell migration and invasion assay was conducted in Michigan Cancer Foundation-7 cells that had been transfected with si-circRNA and si-negative control (si-NC). Results: A total of 152 circRNAs were differentially expressed in breast cancer tissues, among which 85 were upregulated and 67 downregulated. Out of these, hsa_circ_0011946 was selected and the subsequent bioinformatics analysis predicted that hsa_circ_0011946 sponging miR-26a/b directly targeted replication factor C subunit 3 (RFC3) and that its knockdown could inhibit RFC3 mRNA and protein expression. Furthermore, hsa_circ_0011946 loss-of-function significantly suppressed the migration and invasion of Michigan Cancer Foundation-7 cells. Conclusion: Together, these results indicate that hsa_circ_0011946 and RFC3 comprise a novel pathway involved in the progression of breast cancer. Keywords: hsa_circ_0011946, MCF-7, RFC, breast cancer, high-throughput sequencing

Yanbo Lv, Shuangyan Lin, Fang Peng Department of Pathology, Zhejiang Hospital, Hangzhou City, Zhejiang, China Objective: Lung cancer, which is the leading cause of cancer death worldwide, is influenced by a wide variety of environmental and genetic risk factors. The silent information regulator 1 (SIRT1) gene is located on the long arm of chromosome 10 (10q21.3) and has been shown to play crucial roles in lung cancer development in previous studies. In this study, we determined whether variation in the SIRT1 gene is associated with lung cancer in Chinese population.Methods: The case–control study comprised 246 controls and 257 non-small cell lung cancer patients, comprising 79 squamous cell carcinoma patients and 124 adenocarcinoma patients. All subjects were from Zhejiang, China. Four single-nucleotide polymorphisms of SIRT1 gene were analyzed: rs12778366 (C/T, lies in the 5′ upstream), rs3758391 (C/T, lies in the 5′ upstream), rs2273773 (C/T, lies in the coding) and rs4746720 (C/T, lies in the 3′ untranslated region).Results: No significant difference of allele and genotype frequencies was observed between the different groups. Haplotype association analysis carried out on the four single-nucleotide polymorphisms within the case–control cohort also did not reveal a significant association with lung cancer (P>0.05).Conclusion: The results suggest the tested SIRT1 gene polymorphisms may not contribute to lung cancer. Further studies are warranted to demonstrate the functional roles of the SIRT1 polymorphism in lung cancer. Keywords: SIRT1, SNP, non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma

Fei Gao,1–3 Jinming Zhang,3 Chaomei Fu,3 Xiaoming Xie,4 Fu Peng,1–3 Jieshu You,1,2 Hailin Tang,1,2,4 Zhiyu Wang,5 Peng Li,6 Jianping Chen1–3 1School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, 2Shenzhen Institute of Research and Innovation, University of Hong Kong, Shenzhen, 3College of Pharmacy, Chengdu University of Chinese Medicine, Chengdu, 4Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 5Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 6State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, People’s Republic of China Abstract: Isoliquiritigenin (ISL), a natural anti-breast cancer dietary compound, has poor delivery characteristics and low bioavailability. In order to promote the therapeutic outcome of ISL, a tumor-targeting lipid–polymer hybrid nanoparticle (NP) system modified by tumor-homing iRGD peptides has been developed. The hybrid NPs were prepared by a modified single-step nanoprecipitation method to encapsulate ISL. iRGD peptides were anchored on the surface by a postinsertion method (ISL-iRGD NPs). The stable lipid–polymer structure of ISL-iRGD NPs, with high encapsulation and loading efficiency, was confirmed. Compared to free ISL and non-iRGD-modified counterparts, ISL-iRGD NPs showed higher cytotoxicity and cell apoptosis against the different type of breast cancer cells. This was attributable to higher cellular accumulation mediated by the iRGD-integrin recognition and the nanoscale effect. More importantly, based on the active tumor-tissue accumulation by iRGD peptides and the prolonged in vivo circulation by the stealth nanostructure, ISL-iRGD NPs displayed higher tumor-growth inhibition efficiency in 4T1-bearing breast-tumor mouse models. Therefore, the constructed iRGD modified lipid–polymer hybrid NPs would provide a promising drug-delivery strategy to improve ISL in anti-breast cancer efficacy. Keywords: isoliquiritigenin, iRGD, lipid–polymer hybrid NPs, breast cancer

Wendian Zhang,1 Fangqi Peng,1 Taotao Zhou,1 Yifei Huang,2 Li Zhang,3 Peng Ye,4 Miao Lu,1 Guang Yang,5 Yongkang Gai,1 Tan Yang,1 Xiang Ma,1 Guangya Xiang1 1School of Pharmacy, Tongji Medical College, 2Department of Pharmacy, 3Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 4Department of Pharmacy, Wuhan University, Renmin Hospital, 5School of Medicine, Jianghan University, Wuhan, People’s Republic of China Abstract: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death. Gene therapy was established as a new strategy for treating HCC. To explore the potential delivery system to support the gene therapy of HCC, negatively charged liposomal delivery system was used to deliver miR-221 antisense oligonucleotide (anti-miR-221) to the transferrin (Tf) receptor over expressed HepG2 cells. The liposome exhibited a mean particle size of 122.5 nm, zeta potential of -15.74 mV, anti-miR-221 encapsulation efficiency of 70%, and excellent colloidal stability at 4°C. Anti-miR-221-encapsulated Tf-targeted liposome demonstrated a 15-fold higher delivery efficiency compared to nontargeted liposome in HepG2 cells in vitro. Anti-miR-221 Tf-targeted liposome effectively delivered anti-miR-221 to HepG2 cells, upregulated miR-221 target genes PTEN, P27kip1, and TIMP3, and exhibited greater silencing efficiency over nontargeted anti-miR-221 liposome. After intravenous injection into HepG2 tumor-bearing xenografted mice with Cy3-labeled anti-miR-221 Tf-targeted liposome, Cy3-anti-miR-221 was successfully delivered to the tumor site and increased the expressions of PTEN, P27kip1, and TIMP3. Our results demonstrate that the Tf-targeted negatively charged liposome could be a potential therapeutic modality in the gene therapy of human HCC. Keywords: transferrin, gene, HCC, target delivery system, anionic liposome

Cong Zhang,1 Fan Peng,1 Wei Liu,1 Jiangling Wan,1 Chunxi Wan,1 Huibi Xu,1,2 Christopher Waikei Lam,2 Xiangliang Yang1,2 1National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 2State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, People's Republic of China Abstract: After oral administration in rodents, triptolide (TP), a diterpenoid triepoxide compound, active as anti-inflammatory, immunosuppressive, anti-fertility, anti-cystogenesis, and anticancer agent, is rapidly absorbed into the blood circulation (from 5.0 to 19.5 minutes after dosing, depending on the rodent species) followed by a short elimination half-life (from about 20 minutes to less than 1 hour). Such significant and rapid fluctuations of TP in plasma likely contribute to its toxicity, which is characterized by injury to hepatic, renal, digestive, reproductive, and hematological systems. With the aim of prolonging drug release and improving its safety, TP-loaded nanostructured lipid carriers (TP-NLCs), composed of Compritol® 888 ATO (solid lipid) and Capryol™ 90 (liquid lipid), were developed using a microemulsion technique. The formulated TP-NLCs were also characterized and in vitro release was evaluated using the dialysis bag diffusion technique. In addition, the pharmacokinetics and toxicology profiles of TP-NLCs were compared to free TP and TP-loaded solid lipid nanoparticles (TP-SLNs; containing Compritol 888 ATO only). Results demonstrate that TP-NLCs had mean particle size of 231.8 nm, increased drug encapsulation with a 71.6% efficiency, and stable drug incorporation for over 1-month. TP-NLCs manifested a better in vitro sustained-release pattern compared to TP-SLNs. Furthermore, TP-NLCs prolonged mean residence time (MRT)0–t (P

This study examined the drag reduction properties of cylindrical flows across various asymmetric notched structures through numerical simulation and particle image velocimetry. The focus was on investigating the influence of the number of asymmetric grooves on the drag characteristics, including the mean drag, spectral characteristics, time-averaged streamlines, separation point prediction, time-averaged pressure, wake vortex strength, Reynolds stress, and turbulent kinetic energy. The results showed that the presence of asymmetric grooves significantly influenced these flow parameters. Notably, the improvement was optimal in the four-groove configuration, evidenced by the lowest mean drag coefficient (0.804), vortex shedding frequency (2.74 Hz), recirculation area length (1.208D), and pressure difference across the cylinder (81.76). Moreover, this configuration resulted in the weakest trailing vortex, a 45% reduction in the maximum Reynolds stress (0.011), and a 40.5% decrease in the maximum turbulent kinetic energy (0.05). Thus, the presence of asymmetric grooves had a significant positive effect on the cylindrical flow properties, though the degree of improvement decreased with further increase in the number of grooves. [ABSTRACT FROM AUTHOR]

Meigan cai and zao cai are two important traditional fermented vegetables in Fujian Province, China. However, there is little information on the bacterial community of these two fermented vegetables. In the present work, we evaluated and compared the physicochemical characteristics and bacterial communities of meigan cai and zao cai. Results revealed that Firmicutes and Proteobacteria were the main dominant phyla, and Lactobacillus and Serratia were the main genera. Principal coordinate and significance analysis showed that the bacterial communities were similar between meigan cai and zao cai. Except for glucose, there was no significant difference in the physicochemical characteristics between meigan cai and zao cai. Our study provided information on the bacterial communities of meigan cai and zao cai, and a guide for the production of these two fermented vegetables. [ABSTRACT FROM AUTHOR]