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Yinghong Wang,1,2 Xuan Long,1 Min Tan,1 Xiaolian Song1 1Department of Respiratory and Critical Care Medicine, Shanghai Tenth People’s Hospital, Shanghai, People’s Republic of China; 2Department of Clinical Medicine, Tongji University, Shanghai, People’s Republic of ChinaCorrespondence: Min Tan; Xiaolian Song, Department of Respiratory and Critical Care Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Middle Yanchang Road 301, Shanghai, 200072, People’s Republic of China, Email mylikes_tm@163.com; 18901601547@163.comBackground: The platelet to high-density lipoprotein cholesterol ratio (PHR) is a novel biomarker for inflammation and hypercoagulability. This study aimed to explore the potential association between PHR and prevalence of chronic obstructive pulmonary disease (COPD).Methods: Participants aged between 40 and 85 years from the 1999– 2018 US National Health and Nutrition Examination Survey with COPD were included. Multivariable logistic regression and restricted cubic spline analysis were applied to evaluate the associations between PHR and COPD. Propensity score matching (PSM) was performed to reduce the impact of potential confounding factors.Results: A total of 25751 participants, including 753 with COPD, at a mean age of 57.19 years and 47.83% men, were included. The multivariable-adjusted model showed that the odds ratio (OR) and 95% confidence interval (CI) for PHR to predict COPD was 1.002 (1.001– 1.003). Compared with the lowest quartile, the ORs and 95% CIs for the Q2, Q3, and Q4 PHR quartile were 1.162 (0.874– 1.546), 1.225 (0.924– 1.625), and 1.510 (1.102– 2.069), respectively (P for trend = 0.012). Restricted cubic spline analysis demonstrated a linear association between PHR and COPD prevalence both before and after PSM. Significant association between PHR and COPD prevalence was observed only in participants without hypertension. Receiver-operating characteristic curves showed significantly higher area under the curve for distinguishing COPD from non-COPD by PHR than platelet count and high-density lipoprotein cholesterol.Conclusion: PHR is significantly associated with COPD prevalence in US adults aged 40 to 85 years without hypertension, supporting the effectiveness of PHR as a potential biomarker for COPD.Keywords: chronic obstructive pulmonary disease, high-density lipoprotein cholesterol, NHANES, platelet, platelet/HDL ratio

Dongdong Chen,1,2,* Surong Qian,3,* Wenjun Qian,3 Miao Wu,3 Xinlong Wang,3 Haitao Shen,1 Xianming Long,4 Ming Ye,1 Yan Gong,3 Gang Chen1 1Department of Neurosurgery& Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, People’s Republic of China; 2Department of Neurosurgery, The Affiliated Hospital of Jiang Nan University, Wuxi, Jiangsu, 214000, People’s Republic of China; 3Department of Rehabilitation Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital Rehabilitation Medical Center, Gusu School, Suzhou, Jiangsu, 215000, People’s Republic of China; 4Department of Rheumatology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Gong; Ming Ye, Email gongyan200605@126.com; yeming@suda.edu.cnBackground: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that shows promise for the treatment of Parkinson’s disease (PD). However, there is still limited understanding of the optimal stimulation frequencies and whether rTMS can alleviate PD symptoms by regulating the CaMKII-CREB-BMAL1 pathway.Methods: A PD mouse model was induced intraperitoneally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated with 1 Hz, 5 Hz, and 10 Hz rTMS. The neurological function, survival of dopaminergic neurons, and protein levels of Tyrosine hydroxylase (TH), α-synuclein(α-syn), and brain-derived neurotrophic factor (BDNF) in the striatum were measured to determine the optimal stimulation frequencies of rTMS treatment in PD mice. The levels of melatonin, cortisol, and the circadian rhythm of Brain and muscle ARNT-like 1 (BMAL1) in PD model mice were detected after optimal frequency rTMS treatment. Additionally, KN-93 and Bmal1siRNA interventions were used to verify that rTMS could alleviate PD symptoms by regulating the CaMKII-CREB-BMAL1 pathway.Results: Administration of 10 Hz rTMS significantly improved neurological function, increased the protein levels of TH and BDNF, and inhibited abnormal aggregation of a-syn. Furthermore, administration of 10 Hz rTMS regulated the secretion profile of cortisol and melatonin and reversed the circadian arrhythmia of BMAL1 expression. After the KN-93 intervention, the MPTP+rTMS+KN-93 group exhibited decreased levels of P- Ca2+/calmodulin-dependent protein kinase II (CaMKII)/CaMKII, P-cAMP-response-element-binding protein (CREB)/CREB, BMALI, and TH. After Bmal1siRNA intervention, the protein levels of BMAL1 and TH were significantly reduced in the MPTP+10 Hz+ Bmal1siRNA group. At the same time, there were no significant changes in the proportions of P-CaMKIIα/CaMKIIα and P-CREB/CREB expression levels. Finally, immunohistochemical analysis showed that the number of TH-positive neurons was high in the MPTP+10 Hz group, but decreased significantly after KN-93 and Bmal1siRNA interventions.Conclusion: Treatment with 10 Hz rTMS alleviated MPTP-induced PD symptoms by regulating the CaMKII-CREB-BMAL1 pathway. This study provides a comprehensive perspective of the therapeutic mechanisms of rTMS in PD.Keywords: Parkinson’s disease, transcranial magnetic stimulation, brain and muscle ARNT-like 1, Ca2+/calmodulin-dependent protein kinase II, cAMP-response-element-binding protein

Bowen Xing,1 Zhengyu Li,1,2 Yuyan Liu,1 Chen Ling,1 Xiaolin Long,1 Hui Xie,3 Fang Feng1 1The First People’s Hospital of Chenzhou City, Chenzhou City, People’s Republic of China; 2Hunan University of Chinese Medicine, Changsha City, People’s Republic of China; 3Chenzhou Municipal Hospital of Traditional Chinese Medicine, Chenzhou City, People’s Republic of ChinaCorrespondence: Hui Xie, Chenzhou Municipal Hospital of Traditional Chinese Medicine, Chenzhou City, 423000, People’s Republic of China, Email 568694981@qq.com Fang Feng The First People’s Hospital of Chenzhou City, Chenzhou City, 423000, People’s Republic of China, Email 272874387@qq.com

Xinyi Long,1 Fangfang Li,1 Sishi Tang,1 Jing Liu,1 Yunfeng Fu,2 Yanhui Feng3 1Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, 410013, People’s Republic of China; 2Department of Blood Transfusion, The Third Xiangya Hospital of Central South University, Changsha, 410013, People’s Republic of China; 3Department of Oncology, The Third Xiangya Hospital of Central South University, Changsha, 410013, People’s Republic of ChinaCorrespondence: Yanhui Feng, Department of Oncology, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Yuelu District, Hexi, Changsha, Hunan Province, People’s Republic of China, Tel +86-13549656766, Email fengyanhui900@sohu.comPurpose: Immunological regimens are an important area of research for treating multiple myeloma (MM). Plasma cells play a crucial role in immunotherapy.Patients and Methods: In our study, we used both single-cell RNA sequencing (scRNA-seq) and bulk sequencing techniques to analyze MM patients. We analyzed each sample using gene set variation analysis (GSVA) based on immune-related gene sets. We also conducted further analyses to compare immune infiltration, clinical characteristics, and expression of immune checkpoint molecules between the H-S100A9 and L-S100A9 groups of MM patients.Results: We identified eight subpopulations of plasma cells, with S100A9 plasma cells being more abundant in patients with 1q21 gain and 1q21 diploid. CellChat analysis revealed that GAS and HGF signaling pathways were prominent in intercellular communication of S100A9 plasma cells. We identified 14 immune-related genes in the S100A9 plasma cell population, which allowed us to classify patients into the H-S100A9 group or the L-S100A9 group. The H-S100A9 group showed higher ESTIMATE, immune and stroma scores, lower tumor purity, and greater immune checkpoint expression. Patients with 1q21 gain and four or more copies had the lowest ESTIMATE score, immune score, stroma score, and highest tumor purity. Drug sensitivity analysis indicated that the H-S100A9 group had lower IC50 values and greater drug sensitivity compared to the L-S100A9 group. Quantitative reverse transcription (RT-q) PCR showed significantly elevated expression of RNASE6, LYZ, S100A8, S100A9, and S100A12 in MM patients compared to the healthy control group.Conclusion: Our study has identified a correlation between molecular subtypes of S100A9 plasma cells and the response to immunotherapy in MM patients. These findings improve our understanding of tumor immunology and provide guidance for developing effective immunotherapy strategies for this patient population.Keywords: multiple myeloma, single-cell sequencing, bulk transcription, tumor immune microenvironment, S100A9

Xiaoling Long,1,* Huan Zeng,1,* Yun Zhang,1 Qiulong Lu,1 Zhao Cao,2 Hong Shu1 1Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, People’s Republic of China; 2Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong Shu, Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Qingxiu District, Nanning, Guangxi, 530021, People’s Republic of China, Tel +86 7715640296, Email shuhong@gxmu.edu.cn Zhao Cao, Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Qingxiu District, Nanning, Guangxi, 530021, People’s Republic of China, Tel +86 7715356724, Email river_79@126.comPurpose: Developing a high-value, convenient, and validated differential diagnosis model to differentiate alpha-fetoprotein (AFP) negative hepatic occupying lesions and assist clinicians in early identification and intervention.Patients and Methods: A total of 340 patients with AFP-negative hepatic occupying lesions who were admitted to the Guangxi Medical University Cancer Hospital between August 2021 and April 2023 were included in the final retrospective analysis. The data were randomly divided into training and validation sets in a 7:3 ratio after performing multiple interpolations. In the training set, laboratory variables and models were screened using least absolute shrinkage and selection operator regression analysis, comparison of five machine learning algorithms, and univariate, as well as multivariate logistic regression analysis. A diagnostic prediction nomogram model was developed. We evaluated and validated the model using the receiver operating characteristic (ROC) curve analysis, calibration curve analysis, and decision curve analysis (DCA).Results: We identified six significant predictive factors from the results of multivariate logistic analysis in the training set and incorporated them into the nomogram model for diagnosing AFP-negative hepatic malignant occupying lesions (HMOL). The diagnostic nomogram, including gender, age, des-gamma-carboxy prothrombin (DCP), serum ferritin (SF), AFP, and hepatitis B surface antigen (HBsAg), achieved an area under the curve of 0.905 discriminated patients with HMOL from those with benign occupying lesions. Additionally, calibration curves demonstrated the close alignment between the nomogram predictions and the ideal curve, along with the consistency between predictions and actual results. Moreover, the DCA curves illustrated indicated benefit for all patients. These finding were confirmed by the validation set.Conclusion: The GADSAH model specifically targets the discrimination of malignant and benign liver lesions in AFP-negative patients. It offers a noninvasive, cost-effective, and efficient approach for diagnosing such cases.Keywords: hepatic occupying lesions, alpha-fetoprotein-negative, nomogram, diagnostic model

Xingtao Long,1 Qingming Jiang,2 Rengui Li,1 Dong Wang,1 Dongling Zou1 1Department of Gynaecological Oncology, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China; 2Department of Pathology, Chongqing University Cancer Hospital, Chongqing, People’s Republic of ChinaCorrespondence: Dongling Zou, Department of Gynaecological Oncology, Chongqing University Cancer Hospital, 181 Hanyu Road, Shapingba District, Chongqing, 400000, People’s Republic of China, Tel +8613657690699, Fax +8602365075612, Email cqzl_zdl@163.comIntroduction: Alveolar soft part sarcoma (ASPS) is a rare and distinct subtype of soft tissue sarcoma. This study aims to describe the unique presentation of ASPS in the female genital tract.Methods: Prognostic factors for cancer-specific overall survival (CSS) were evaluated using multivariate analyses.Results: In our case series, we identified a novel TFE3-PRCC gene fusion in a 24-year-old unmarried patient with cervical ASPS who underwent fertility-sparing surgery and remained recurrence-free for 41 months. The other two patients underwent radical hysterectomy and bilateral salpingo-oophorectomy. At the time of writing, the two patients had been disease-free for 49 and 71 months, fluorescence in situ hybridization showed break-apart signals for the ASPL-TFE3 gene. Among the 55 cases with available information from the PubMed/Medline database, most presented with localized disease, and at the last follow-up, all patients were alive and 45 patients showed no evidence of disease. The 5-year CSS rate in the female genital tract cohort from SEER database was 86.2%. Multivariate analysis revealed that older age was associated with a 1.042-fold increased risk of cancer-specific mortality (HR=1.042, 95% CI 1.022– 1.063, P < 0.001), involvement of soft tissue including the heart was associated with a 4.786-fold higher risk (HR=4.7868, 95% CI 1.681– 13.623, P= 0.003), and regional infiltration and distant metastasis were associated with approximately 8.6-fold and 18-fold higher risk of cancer-specific mortality compared to local disease, respectively (HR=8.652, 95% CI 2.529– 29.63, P = 0.001; HR=18.366, 95% CI 6.153– 54.817, P< 0.001). Patients who underwent radical excision did not show reduced cancer-specific mortality compared to those who underwent local excision (HR=0.492, 95% CI 0.224– 1.081, P = 0.078).Discussion: Previously unrecognized genetic diversity exists in ASPS. Patients with ASPS in the female genital tract have the lowest likelihood of presenting with a distant disease and are associated with a more favorable survival outcome.Keywords: ASPSCR1, TFE3, alveolar soft part sarcoma, fusion

Xiaoying Zhu,1,2 Fengqin Tian,2 Yulei Li,2 Qunfeng Lu,3 Qinqin Long,2 Xidai Long,1,2 Demin Cao2 1Medical College, Guangxi University, Nanning, Guangxi, People’s Republic of China; 2Clinical Pathological Diagnosis & Research Center, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, People’s Republic of China; 3School of Medical Laboratory Sciences, Youjiang Medical University for Nationalities, Baise, Guangxi, People’s Republic of ChinaCorrespondence: Demin Cao; Xidai Long, Email caodm@ymun.edu.cn; sjtulongxd@ymun.edu.cnBackground: Recent research highlights the contribution of co-infections to elevated disease severity and mortality among COVID-19 patients. Given China’s decision to ease epidemic prevention policies in December 2022, a comprehensive exploration of the risks and characteristics of co-infections with respiratory pathogens becomes imperative.Methods: We conducted a retrospective analysis of 716 COVID-19 patients admitted to a primary hospital in China. The detection of twelve respiratory pathogens was conducted using qPCR, and the potential risk factors were analyzed through Cox regression analysis.Results: Within this cohort, 76.82% of cases exhibited co-infection involving eleven distinct pathogens. Among these, bacterial co-infections were observed in 74% of cases, with Streptococcus pneumoniae and Haemophilus influenzae emerging as the most prevalent bacterial co-infection agents. Additionally, 15% of cases presented with viral co-infections, predominantly involving influenza A virus and respiratory syncytial virus. Nevertheless, our investigation suggested that there might be some inappropriate antibiotic use in treatments. Furthermore, risk analysis unveiled dyspnea, hypoproteinemia, low lymphocyte counts, and co-infection with Mycoplasma pneumoniae as prominent risk factors for COVID-19 inpatients.Conclusion: Our findings underscore a significant occurrence of co-infections among COVID-19 patients during the epidemic, emphasizing the need for enhanced antibiotic stewardship. Effective management strategies should encompass respiratory status, nutritional aspects, and vigilance towards co-infections involving M. pneumoniae during COVID-19 treatment. This study underscores the significance of comprehensive management protocols to address the multifaceted challenges presented by co-infections in COVID-19 patients.Keywords: COVID-19, co-infection, respiratory pathogens, risk factors

Xuda Ma,1,&ast; Jiuzuo Huang,1,&ast; Yu Chen,2 Xiaojun Wang,1 Xiao Long1 1Department of Plastic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiao Long, Department of Plastic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, People’s Republic of China, Tel +86 135 1616 6205, Fax +86 10 6915 8730, Email pumclongxiao@126.comAbstract: In this study, we report a rare case of en coup de sabre with hyperplasia of the left frontal bone beneath skin lesion, which is detected during magnetic resonance imaging screening and preoperative evaluation. A 27-year-old woman with 13-year history of progressive soft tissue depression in the forehead and scalp, and was treated by traditional Chinese herb before the disease went into stationary stage. The patient underwent serial long-pulsed laser treatments and autologous fat grafting with satisfactory outcome. To our knowledge, this is the first time that bony hyperplasia beneath the soft tissue lesion was found in a patient with en coup de sabre.Keywords: localized scleroderma, morphea, autologous fat grafting, magnetic resonance imaging, computed tomography

Lijuan Xiong,1,&ast; Xu Long,1,&ast; Lijun Ni,2,&ast; Lili Wang,2 Yang Zhang,1 Lili Cui,1 Jian Guo,2 Chunying Yang1 1Department of Laboratory Medicine, the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guizhou, People’s Republic of China; 2Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian Guo, Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 1800 Yuntai Road, Pudong New Area, Shanghai, People’s Republic of China, Tel +86-17701810639, Email guojian1110@126.com Chunying Yang, Department of Laboratory Medicine, the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 83 Feishan Street, Yunyan District, Guiyang City, Guizhou Province, People’s Republic of China, Tel +86-13658504875, Email 2590470591@qq.comPurpose: Matrix-assisted laser desorption-ionization-time of flight mass spectrometry (MALDI-TOF) has recently been widely used in clinical microbiology laboratories, with the advantages of being reliable, rapid, and cost-effective. Here, we reported the performance of two MALDI-TOF MS instruments, EXS3000 (Zybio, China) and Autof ms1000 (Autobio, China), which are commonly used in clinical microbiology field.Methods: A total of 209 common clinical common isolates, including 70 gram-negative bacteria strains, 58 gram-positive bacteria strains, 33 yeast strains, 15 anaerobic bacteria strains, and 33 mold strains, and 19 mycobacterial strains were tested. All strains were identified by EXS3000 (Zybio, China) and Autof ms1000 (Autobio, China). Sequence analysis of 16S rRNA or ITS regions was used to verify all strains.Results: Current study found that species-level discrimination was found to be 191 (91.39%) and 190 (90.91%) by EXS3000 and Autof ms1000, respectively. Genus-level discrimination was 205 (98.09%) by the EXS3000 and 205 (98.09%) by the Autof ms1000, respectively. The correct results at species level of the EXS3000 were 91.43% (64/70) for gram-negative bacteria, 93.1% (54/58) for gram-positive cocci, 93.94% (31/33) for yeast, 100% (15/15) for anaerobes and 81.82% (27/33) for filamentous fungi. The correct results at species level of the Autof ms1000 were 92.86% (65/70) for gram-negative bacteria, 91.38% (53/58) for gram-positive cocci, 93.94% (31/33) for yeast, 100% (15/15) for anaerobes and 78.79% (26/33) for filamentous fungi.Conclusion: Although the results show that the EXS3000 and Autof ms1000 systems are equally good choices in terms of analytical efficiency for routine procedures, the test result of EXS3000 is slightly better than Autof ms1000. It’s worth mentioning that the target plate of the EXS 3000 instrument is reusable, but the target plate of the Autof ms1000 is disposable, making the EXS3000 more effective in reducing costs.Keywords: evaluation, MALDI-TOF mass spectrometry, EXS3000, Autof ms1000, clinical isolates, identification, gram-negative bacteria, gram-positive bacteria, mycobacteria, yeast, anaerobic bacteria

Jie Shen,1,2,&ast; Xiao Long,3,&ast; Qi Jiang,1 Hao Xu,2 Qinming Wei,1 Qingmiao Shi,2 Yi Liu,2 Shanshan Xu,1 Xiaolu Ma,1 Lanjuan Li2 1Department of Medical Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Department of Orthopedics, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lanjuan Li, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China, Tel +86-571-87236458, Fax +86-571-87236459, Email ljli@zju.edu.cnPurpose: In China, vancomycin-resistant enterococci (VRE) was not a common occurrence, and research on the genetic context and transmission mechanism of vanA-plasmid was scarce. The aim of this study was to molecularly characterise a vancomycin-resistant Enterococcus faecium isolate from a bloodstream infection and determine the genetic environment and delivery pattern of the plasmid carrying vancomycin-resistant gene.Materials and Methods: In May 2022, a vancomycin-resistant strain of Enterococci was identified during routine screening for VRE bacteria at the First Affiliated Hospital, Zhejiang University School of Medicine. Utilizing matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), the isolate was accurately identified. Antimicrobial susceptibility and whole-genome sequencing (WGS) were employed to perform phenotypic and genomic analysis, respectively. Further bioinformatics analyses was carried out to characterize the vanA-bearing plasmid.Results: The antimicrobial susceptibility test showed that SJ2 strain was resistant to multiple antimicrobials, including ampicillin, benzylpenicillin, ciprofloxacin, erythromycin, levofloxacin, streptomycin, and vancomycin. Whole-genome analysis revealed that SJ2 strain carries several antimicrobial resistance genes and virulence determinants. MLST analysis found that SJ2 strain belongs to an unknown ST type. Plasmid analysis confirmed that the vanA gene was located on a variant of ~50 kb rep2 plasmid.Conclusion: Our study found that vanA-bearing rep2 plasmid is a potential source of dissemination and outbreak, and continuous surveillance is necessary to control its spread in Hangzhou, China.Keywords: vancomycin-resistant Enterococcus faecium, vanA, whole genome sequencing, rep2

Dehua Zhao, Xiaoqing Long, Jisheng Wang Department of Clinical Pharmacy, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, Sichuan, People’s Republic of ChinaCorrespondence: Dehua Zhao; Jisheng Wang, Email zhaoyaoshi0566@163.com; wangjishengyaoshi@163.comAbstract: Poly (ADP-ribose) polymerase (PARP) inhibitors are small-molecule inhibitors of PARP enzymes (including PARP1, PARP2, and PARP3) that exhibit activity against tumor cells with defects in DNA repair. In recent years, five PARP inhibitors, olaparib, niraparib, rucaparib, talazoparib and veliparib, have been developed for the treatment of solid tumors, particularly in patients with breast-related cancer antigen (BRCA) 1/2 mutations, or those without a functional homologous recombination repair pathway. These novel treatments exhibit improved efficacy and toxicity when compared to conventional chemotherapy agents. The five PARP inhibitors are eliminated primarily via the liver and kidneys, hepatic or renal impairment may significantly affect their pharmacokinetics (PK). Therefore, it is important to know the effects of hepatic or renal impairment on the PK and safety of PARP inhibitors. In this review, we characterize and summarize the effects of hepatic and renal function on the PK of PARP inhibitors and provide specific recommendations for clinicians when prescribing PARP inhibitors in patients with hepatic or renal impairment.Keywords: PARP inhibitors, cancer, hepatic impairment, renal impairment, PK

Yixin Sun,1,* Runzhu Liu,1,* Nanze Yu,1 Dingyue Zhang,2 Juan Chen,3 Jiuzuo Huang,1 Xiao Long1 1Division of Plastic Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Clinical Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 3Institute of Medical Information/Medical Library, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiuzuo Huang; Xiao Long, Division of Plastic Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, No. 1, Shuaifuyuan, Dongcheng District, Beijing, 100730, People’s Republic of China, Tel/Fax +86-1069158730, Email hjz1983@126.com; pumclongxiao@126.comPurpose: Incisional double eyelid blepharoplasty is the most common cosmetic operation in East Asia. Although numerous articles on surgical techniques have been published, complications, such as fold loss, asymmetry, and visible scars, still exist. To create a stable and dynamic double-eyelid crease, the author has introduced a modified technique of double-eyelid blepharoplasty.Patients and Methods: The authors introduced a new surgical technique to reduce complications and create reliable and dynamic double eyelids. The orbicularis oculi muscle of the lower flap was anchored on the tarsus and sutured with the distal part of the septal flap. The skin incision was closed by skin–septal flap–skin suture. Postoperative evaluations were assessed at the twelfth postoperative month.Results: One hundred ninety-three patients underwent double eyelidplasty with the TOS fixation technique. The mean follow-up duration was 18.6 months (range, 12– 30 months). In the aesthetic outcome evaluation, 88 (45.6%) patients had very much improved results, 56 (29.0%) had much improved results, 29 (15.0%) had improved results, 8 (4.1%) had no change and 12 (6.2%) had worse results. Complications included crease asymmetry (n=7, 3.6%), partial fold loss (n=8, 4.1%) and complete fold loss (n =5, 2.6%).Conclusion: Tarsus-orbicularis-septum (TOS) fixation is a reliable and flexible surgical technique for creating stable and dynamic double-eyelid creases.Keywords: double eyelidplasty, primarily blepharoplasty, orbital septum, tarsus

Xialing Huang,1 Xiaoping Long,2 Jun Zi,3 Ping Liu4 1Department of Infectious Diseases, Leiyang People’s Hospital, Leiyang, Hunan, 421800, People’s Republic of China; 2Pulmonary and Critical Care Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan, 421001, People’s Republic of China; 3Department of Pediatrics, Leiyang, Hunan, 421800, People’s Republic of China; 4Department of Emergency, People’s Hospital of Leiyang City, Leiyang, Hunan, 421800, People’s Republic of ChinaCorrespondence: Xiaoping LongPulmonary and Critical Care Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan, 421001, People’s Republic of ChinaTel +8613975403734Email xiaopinglong88@sina.comAbstract: The patient had several close contacts with friends from Wuhan, the epicenter of the epidemic. His mother and father had close contact with him. His father was later diagnosed with COVID-19 infection after a positive reverse transcription PCR test for SARS-CoV-2 RNA. The patient and his mother were diagnosed as suspected cases of COVID-19 based on a history of exposure, clinical manifestation, and imaging examination. However, the patient was tested more than three times with the reverse transcription PCR test for SARS-CoV-2 RNA, and the results were negative each time. COVID-19 should be suspected, regardless of SARS-CoV-2 test negativity, for recent close contact with a confirmed case and respiratory symptoms.Keywords: COVID-19, respiratory symptoms, suspected, negative, cluster

Xianrong Zhou,1– 4,&ast; Hang-Hang Du,5,&ast; Xingyao Long,1– 3 Yanni Pan,1– 3 Jian Hu,6 Jianjun Yu,6 Xin Zhao1– 3 1Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Chongqing, People’s Republic of China; 2Chongqing Engineering Research Center of Functional Food, Chongqing University of Education, Chongqing, People’s Republic of China; 3Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing, People’s Republic of China; 4Department of Food and Nutrition, College of Medical and Life Sciences, Silla University, Busan, South Korea; 5Department of Plastic Surgery, Chongqing Huamei Plastic Surgery Hospital, Chongqing, People’s Republic of China; 6R&D Department, Effepharm (Shanghai) Co., Ltd, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin ZhaoChongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Xuefu Main Street 9, Chongqing, 400067, People’s Republic of ChinaEmail zhaoxin@cque.edu.cnJianjun YuR&D Department, Effepharm (Shanghai) Co., Ltd, Room 201, Building 12, No. 1, Wangdong Middle Road, Sijing Town, Shanghai, 201601, People’s Republic of ChinaEmail jianjun.yu@effepharm.comObjective: Ultraviolet light is an important environmental factor that induces skin oxidation, inflammation, and other diseases. Nicotinamide mononucleotide (NMN) has the effect of anti-oxidation and improving various physiological processes. This study explores the protective effect of NMN monomers given via intraperitoneal injection on UVB-induced photodamage.Methods: We used a murine model of UVB-induced photodamage to evaluate the effect of an NMN monomer on photoaging skin by assessing skin and liver tissue sections, serum and skin oxidative stress levels, inflammatory markers, mRNA expression, and protein expression of skin- and liver-related genes.Results: The results showed that NMN treatment blocked UVB-induced photodamage in mice, maintaining normal structure and amount of collagen fibers, normal thickness of epidermis and dermis, reducing the production of mast cells, and maintaining complete organized skin structure. NMN intraperitoneal injection also maintained the normal morphology of the mouse liver after UVB exposure. Meanwhile, NMN intraperitoneal injection was found to increase antioxidant ability and regulate the proinflammatory response of the skin and liver to UVB irradiation by enhancing the activity of antioxidant enzymes, release of anti-inflammatory cytokines, reduction of hydrogen peroxide production (H2O2), and decreased inflammatory cytokines. Furthermore, RT-qPCR results indicated that NMN reduced oxidative stress of skin and liver by promoting the activation of the AMP-activated protein kinase (AMPK) signaling pathway and further increasing the expression of downstream antioxidant genes of AMPK. RT-qPCR results also revealed that NMN treatment could downregulate the mRNA expression of interleukin (IL)-6, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α, and upregulate NF-kappa-B inhibitor-α (IκB-α) and interleukin (IL)-10 by inhibiting the activation of nuclear factor-κBp65 (NFκB-p65). Finally, NMN upregulated AMPK, IκB-α, SOD1, and CAT in the skin and downregulated NF-κBp65 protein expression, which is in line with the RT-qPCR results.Conclusion: Based on the above results, NMN monomer treatment with intraperitoneal injection also block the photodamage caused by UVB irradiation in mice by regulating the oxidative stress response and inflammatory response.Keywords: nicotinamide mononucleotide, UVB, antioxidant, NF-κBp65 signaling pathway, AMP-activated protein kinase signaling pathway

Ying Zhang, Ruiqiu Zhao, Zhenzhen Zhang, Quanbo Liu, Aihua Zhang, Qiaoli Ren, Siyuan Li, Xiaoru Long, Hongmei Xu Department of Infection, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, The Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Xiaoru Long; Hongmei Xu Tel +86 2368370396; +86 2368370385Email 2387207074@qq.com; xuhongm0095@hospital.cqmu.edu.cnObjective: Pediatric tuberculosis (TB) is one of the top ten causes of death in children. Our study was to analyze influencing factors of multidrug-resistant tuberculosis (MDR-TB) and validation of whole-genome sequencing (WGS) used in children with drug-resistant TB (DR-TB).Methods: All Mycobacterium tuberculosis (Mtb) strains were isolated from patients aged below 18 years old of Children’s Hospital of Chongqing Medical University, China. A total of 208 Mtb isolates were tested for eight anti-TB drugs with phenotypic drug susceptibility test (DST) and for genetic prediction of the susceptible profile with WGS. The patients corresponding to each strain were grouped according to drug resistance and genotype. Influencing factors of MDR-TB and DR-TB were analyzed.Results: According to the phenotypic DST and WGS, 82.2% of Mtb strains were susceptible to all eight drugs, and 6.3% were MDR-TB. Using the phenotypic DSTs as the gold standard, the kappa value of WGS to predict isoniazid, rifampin, ethambutol, rifapentine, prothionamide, levofloxacin, moxifloxacin and amikacin was 0.84, 0.89, 0.59, 0.86, 0.89, 0.82, 0.88 and 1.00, respectively. There was significant difference in the distribution of severe TB, diagnosis, treatment and outcome between MDR and drug-susceptible group (P< 0.05). The distribution of severe TB and treatment between DR and drug-susceptible group was statistically different (P< 0.05). The results of binary logistic regression showed that Calmette–Guérin bacillus (BCG) vaccine is the protective factor for MDR-TB (OR=0.19), and MDR-TB is the risk factor for PTB and EPTB (OR=17.98).Conclusion: The BCG vaccine is a protective factor for MDR-TB, and MDR-TB might not be confined to pulmonary infection, spreading to extrapulmonary organs in children. MDR-TB had more severe cases and a lower recovery rate than drug-susceptible TB. WGS could provide an accurate prediction of drug susceptibility test results for anti-TB drugs, which are needed for the diagnosis and precise treatment of TB in children.Keywords: tuberculosis, whole-genome sequencing, children, consistency test, multidrug-resistant tuberculosis, clinical feature

Heming Lu,1,&ast; Yuying Wu,2,&ast; Xu Liu,1 Huixian Huang,1 Hailan Jiang,1 Chaohua Zhu,1 Yuping Man,3 Pei Liu,4 Xianglong Li,1 Zhaohong Chen,1 Xianfeng Long,1 Qiang Pang,1 Shan Deng,1 Junzhao Gu1 1Department of Radiation Oncology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, People’s Republic of China; 2Department of Gynecology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, People’s Republic of China; 3Department of Radiology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, People’s Republic of China; 4Department of Oncology, Youjiang Medical University for Nationalities, Baise, 533000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Heming LuDepartment of Radiation Oncology, People’s Hospital of Guangxi Zhuang Autonomous Region, No. 6 Taoyuan Road, Nanning, 530021, People’s Republic of ChinaTel +86-771-218-6806Email luhming3632@163.comPurpose: To evaluate the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in predicting early treatment response.Materials and Methods: Patients with locally advanced cervical cancer (LACC) treated with concurrent chemoradiotherapy (CCRT) were enrolled. Pelvic DCE-MRI scans were performed before RT (pre-RT), in the middle of RT (mid-RT), and at the end of RT (post-RT), separately. Parameters (ie, Ktrans, Kep, and Ve) were measured. Pre-, mid-, and post-RT Ktrans were denoted as Ktrans-preTx, Ktrans-midTx, and Ktrans-postTx, respectively. And the same denoting rule also went for Kep and Ve. Difference for the same parameter such as Ktrans measured between two consecutive time points was calculated as second Ktrans value minus first Ktrans value. The differences in Ktrans between pre-RT and post-RT, between pre-RT and mid-RT, and between mid-RT and post-RT were denoted as ΔKtrans-post-preTx, ΔKtrans-mid-preTx, and ΔKtrans-post-midTx, respectively, and the same denoting rule was also applied to Kep and Ve.Results: A total of 57 patients were enrolled. After the treatment, 31 patients had complete response (CR group). The remaining 26 patients had partial response (NCR group). Significant differences were found in Ktrans-postTx, Kep-postTx, Ve-midTx, ΔKtrans-post-preTx, ΔKtrans-post-midTx, ΔKep-post-preTx, ΔKep-mid-preTx and ΔKep-post-midTx between the two groups. Receiver operating characteristic (ROC) analysis for their performances in predicting treatment response showed an area under curve (AUC) of 0.656– 0.849, sensitivity of 61.3– 93.5%, specificity of 46.1– 73.1%, and maximal Youden Index of 36.5– 66.6. Among those parameters, Kep-postTx was the best, and its AUC, sensitivity, specificity, maximal Youden Index, and cutoff value were 0.849, 87.1%, 73.1%, 60.2, and 0.341, respectively. These combined parameters showed an AUC of 0.952, with sensitivity of 87.1%, specificity of 96.1%, and maximal Youden Index of 83.2.Conclusion: DCE-MRI parameters can predict early treatment outcome. Among those parameters, Kep-postTx is the best predictor. The combination of multi-parameters can increase the predictive potency.Keywords: cervical cancer, locally advanced disease, dynamic contrast-enhanced magnetic resonance imaging, concurrent chemoradiotherapy, prognosis prediction

Chen Xu,1,&ast; Junli Fan,1,&ast; Yi Luo,1,&ast; Ziwu Zhao,1,&ast; Peng Tang,1,&ast; Gui Yang,1 Yunbao Pan,1 Shuang Guo,1 Yingjuan Liu,1 Yong Xiong,2 Wen Xie,1 Xinghua Long1 1Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Department of infectious diseases, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinghua Long; Wen XieDepartment of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of ChinaEmail zhoulongxinghua@qq.com; whxw007@126.comObjective: Patients with rheumatic immune diseases were more likely to develop severe or critical COVID-19. We aimed to determine whether rheumatoid factor antibodies were present in COVID patients and the level and type of rheumatoid factor antibodies produced in COVID-19 patients were related to the degree of the patient’s condition. The study also aimed to determine the prevalence and characteristics of rheumatoid factor antibodies in patients with COVID-19.Methods: Sera collected from 129 patients with COVID-19 were tested for rheumatoid factor antibodies by ELISA. Five patients were tracked for several months to monitor dynamic changes of these antibodies.Results: Rheumatoid-associated autoantibodies were detected in 20.16% of patients (26/129) following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, IgM-RF was primarily present in critically ill patients, while IgA-RF was mainly present in mild patients. Five patients were able to track for several months to monitor dynamic changes of these antibodies. Rheumatoid factor antibodies peaks in the later phase of the disease and last for longer time. Anti-Jo-1 antibody was found in one of the five patients.Conclusion: This was the case series report that rheumatoid-associated autoantibodies are present in patients with COVID-19. The clinical significance of these antibodies was not fully understood and needed further characterization. These autoantibodies are related to the severity of the patient’s disease and exist for a long time in the patient’s body, while their impact on the patient’s health is unknown.Keywords: rheumatoid factor, IgA-RF, IgG-RF, IgM-RF, anti-Jo-1, COVID-19, SARS-CoV-2

Qian Tan,1,2,* Jing Hu,3,* Yujing Zhou,1,2 Yunxiao Wan,1,2 Chuanlan Zhang,1,2 Xin Liu,1,2 Xingyao Long,1,4 Fang Tan,5 Xin Zhao1 1Chongqing Collaborative Innovation Center for Functional Food, Chongqing Engineering Research Center of Functional Food, Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing, 400067, People’s Republic of China; 2College of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, People’s Republic of China; 3Department of Pharmacy, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, People’s Republic of China; 4Department of Food Science and Biotechnology, Cha University, Seongnam, 13488, South Korea; 5Department of Public Health, Our Lady of Fatima University, 838 Valenzuela, Philippines*These authors contributed equally to this workCorrespondence: Xin ZhaoChongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Xuefu Main Street 9, Chongqing, 400067, People’s Republic of ChinaTel +86-23-6265-3650Email zhaoxin@cque.edu.cnFang TanDepartment of Public Health, Our Lady of Fatima University, 120 McArthur Highway, 838 Valenzuela, PhilippinesTel +86-23-6265-3650Email tanfang@foods.ac.cnAim: The naturally fermented yak yogurt of pastoralists in the Tibetan Plateau, China, because of its unique geographical environment and the unique lifestyle of Tibetan pastoralists, is very different from other kinds of sour milk, and the microorganisms it contains are special. Lactococcus lactis subsp. lactis HFY14 (LLSL-HFY14) is a new lactic acid bacterium isolated from naturally fermented yak yogurt. The purpose of this study was to study the inhibitory effect of the bacterium on constipation.Methods: Constipation was induced in ICR mice with diphenoxylate, and the constipated mice were treated with LLSL-HFY14. The weight and feces of the mice were visually detected. Colonic tissues were observed on hematoxylin and eosin-stained sections. Serum indices were detected with kits. mRNA expression in the colon was determined by quantitative polymerase chain reaction assay.Results: Constipation caused weight loss, the number of defecation granules, defecation weight, fecal water content decreased, and the first black stool excretion time increased. LLSL-HFY14 alleviated these symptoms, and the effects were similar to those of lactulose (drug). The pathological examination revealed that constipation caused pathological changes in the colon, and LLSL-HFY14 effectively alleviated the disease. LLSL-HFY14 increased serum levels of motilin, gastrin, endothelin, substance P, acetylcholinesterase, and vasoactive intestinal peptide (VIP) and decreased serum levels of somatostatin in constipated mice. In addition, LLSL-HFY14 upregulated VIP, cAMP, protein kinase A, and aquaporin 3 expression in colonic tissues of constipated mice in a dose-dependent manner.Conclusion: LLSL-HFY14 inhibited constipation, similar to lactulose, and has the potential to become a biological agent.Keywords: yak yogurt, lactic acid bacterium, diphenoxylate, constipation, mice

Ya Wu,1,2,* Jing Hu,3,* Xingyao Long,1,4 Yanni Pan,1,4 Jianfei Mu,1 Kun-Young Park,1,4 Xin Zhao1 1Chongqing Collaborative Innovation Center for Functional Food, Chongqing Engineering Research Center of Functional Food, Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing, 400067, People’s Republic of China; 2College of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, People’s Republic of China; 3Department of Pharmacy, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, People’s Republic of China; 4Department of Food Science and Biotechnology, Cha University, Seongnam, 13488, South Korea*These authors contributed equally to this workCorrespondence: Kun-Young Park; Xin Zhao Tel +86-23-6265-3650Email kunypark@foods.ac.cn; zhaoxin@cque.edu.cnAim: Gastric mucosal injury is a typical characteristic of gastric diseases. The prevalence of gastric mucosal injury caused by alcohol has been on the rise, which has been considered a serious problem. The purpose of this study is to explore the protective effect on gastric injury of Lactobacillus plantarum ZS62 (LP-ZS62) isolated from naturally fermented yak yoghurt.Methods: We established a gastric injury model through alcohol and evaluated the protective effect of LP-ZS62 on gastric injury in mice. The injury to the gastric mucosa, histopathological sections, related biochemical indicators, and related genes were examined to evaluate the protective effect of LP-ZS62.Results: LP-ZS62 effectively alleviated alcohol-induced gastric injury according to visual observations of gastric tissue and pathological tissue sections. The experimental results revealed that LP-ZS62 decreased malondialdehyde (MDA) level, and elevated superoxide dismutase (SOD) and glutathione (GSH) levels in gastric tissues. Additionally, LP-ZS62 increased glutathione peroxidase (GSH-Px), prostaglandin E2 (PGE2), and somatostatin (SS) levels. LP-ZS62 also decreased inflammatory cytokines interleukin (IL)-1β, tumor necrosis factor-α (TNF-α) and IL-6 levels, and increased the anti-inflammatory cytokine IL-10 level. The quantitative polymerase chain reaction results showed that LP-ZS62 upregulated mRNA expression of nuclear factor E2-related factor 2 (Nrf2), copper/zinc superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2), catalase (CAT), gamma-glutamylcysteine synthetase (GSH1), and glutathione peroxidase (GSH-Px).Conclusion: This study confirmed that LP-ZS62 alleviated alcohol-induced gastric injury by regulating antioxidant capacity. Therefore, LP-ZS62 could be developed as a probiotic product to treat alcoholic gastric injury.Keywords: Lactobacillus plantarum ZS62, alcohol-induced gastric injury, inflammation, antioxidant

Defeng Qing,1,* Yuying Wu,2,* Xu Liu,1,* Hailan Jiang,1,* Chaohua Zhu,1,* Pei Liu,3 Junming Dang,4 Xianglong Li,1 Zhaohong Chen,1 Xianfeng Long,1 Qiang Pang,1 Luxing Peng,1 Shan Deng,1 Junzhao Gu,1 Renfeng Zhao,2 Changyi Chen,2 Heming Lu1 1Department of Radiation Oncology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, People’s Republic of China; 2Department of Gynecology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, People’s Republic of China; 3Department of Radiation Oncology, Youjiang Medical University for Nationalities, Baise 533000, People’s Republic of China; 4Department of Oncology, Guangxi University of Chinese Medicine, Nanning 530001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Heming LuDepartment of Radiation Oncology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning City 530021, People’s Republic of ChinaTel +86-771-218-6504Email luhming3632@163.comPurpose: We aimed to evaluate the long-term survival outcomes of concurrent chemoradiotherapy (CCRT) combined with nimotuzumab followed by surgery in patients with locally advanced cervical cancer (LACC).Patients and Methods: Patients received whole pelvic intensity-modulated radiation therapy (IMRT) and concomitantly with weekly cisplatin (40 mg/m2) or nedaplatin (30 mg/m2) and weekly nimotuzumab (200 mg). After assessment of the treatment response, patients then underwent radical surgery.Results: Between June 2013 and July 2016, 33 patients with FIGO IB2–IIIB cervical cancer were recruited. Clinical complete response and partial response were observed in 8 (24.3%) and 23 patients (69.7%), respectively. Twenty-seven patients (81.8%) were successfully treated with radical hysterectomy and pelvic lymphadenectomy: 9 (33.3%) showed pathological complete response; 10 (37.1%) showed partial response and 8 (29.6%) presented with persistent macroscopic/microscopic residual carcinoma. For the intention-to-treat population, the median follow-up time was 53.7 months. Locoregional recurrence and distant metastases were observed in three and seven patients, respectively. The 5-year overall survival, progression-free survival, locoregional recurrence-free survival, and distant metastasis-free survival were 81.5%, 72.7%, 90.9%, and 78.3%, respectively. Both acute and late toxicities were manageable and mainly limited to grade 1 or 2.Conclusion: Concurrent chemoradiotherapy combined with nimotuzumab followed by surgery for patients with LACC is safe and results in excellent long-term treatment outcomes. Further randomized controlled studies are warranted to confirm the findings.Keywords: locally advanced cervical cancer, neoadjuvant chemotherapy, intensity-modulated radiotherapy, anti-EGFR monoclonal antibody, radical surgery

Xin Long,1,* Zhanguo Zhang,1,* Wenbin Zou,2,* Jianmin Ling,3 Donghui Li,3 Liang Jing,3 Shanshan Yu,3 Xiaojing Zou,3 Yi Bian,3 Wenjuan Wu,4 Shusheng Li,3 Minghao Fang3 1Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China; 2Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China; 3Department of Intensive Care Unit, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China; 4Department of Intensive Care Unit, Jinyintan Hospital, Wuhan 430023, People’s Republic of China*These authors contributed equally to this workCorrespondence: Minghao Fang Tel +86 15071157405Email fangmh@tjh.tjmu.edu.cnBackground: SARS-CoV-2 infection activates coagulation and stimulates innate immune system. Little is known about coagulopathy and response of inflammation and infection in ICU patients with COVID-19. Derangement of coagulation and markers of infection and inflammation induced by SARS-CoV-2 infection, as well as their correlations were elucidated.Methods: One hundred eight ICU patients with COVID-19 (28 survivors and 80 non-survivors) in Tongji hospital and Wuhan Jinyintan hospital, in Wuhan, China were included. Coagulation parameters, infectious and inflammatory markers were dynamically analysed. The correlation between coagulopathy of patients and infectious and inflammatory markers was verified.Results: SARS-CoV-2-associated coagulopathy occurred in most cases of critical illness. Raised values of d-dimer and FDP were measured in all patients, especially in non-survivors, who had longer PT, APTT, INR, as well as TT, and lower PTA and AT compared to survivors. SIC and DIC mostly occurred in non-survivors. CRP, ESR, serum ferritin, IL-8, and IL-2R increased in all patients, and were much higher in non-survivors who had significantly higher levels of IL-6 and IL-10. D-dimer was positively associated with CRP, serum ferritin (p = 0.02), PCT (p < 0.001), and IL-2R (p = 0.007). SIC scores were positively correlated with CRP (p = 0.006), PCT (p = 0.0007), IL-1β (p = 0.048), and IL-6 (p = 0.009). DIC scores were positively associated with CRP (p < 0.0001), ESR (p = 0.02), PCT (p < 0.0001), serum ferritin (p < 0.0001), IL-10 (p = 0.02), and IL-2R (p = 0.0005).Conclusion: Prothrombotic state, SIC, and DIC are the characteristics of coagulation in ICU patients with COVID-19. CRP, ESR, serum ferritin, IL-8, IL-2R, IL-6, and PCT were stimulated by SARS-CoV-2 infection. CRP, PCT, serum ferritin, and IL-2R indicate the coagulopathy severity of patients with COVID-19.Keywords: SARS-CoV-2, COVID-19, coagulopathy, markers of infection and inflammation, correlation

Zefeng Chen,1– 5 Yulan Bai,1– 5 Xinyang Long,1– 5 Qianqian Luo,1– 5 Zheng Wen,1– 5 Yuanfan Li,1– 5 Shengzhu Huang,1– 5 Yunkun Yan,1– 5 Zengnan Mo1– 4,6 1Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China; 2Guangxi Key Laboratory for Genomic and Personalized Medicine, Nanning 530021, Guangxi, People’s Republic of China; 3Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning 530021, Guangxi, People’s Republic of China; 4Guangxi Key Laboratory of Colleges and Universities, Nanning 530021, Guangxi, People’s Republic of China; 5School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China; 6Institute of Urology and Nephrology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of ChinaCorrespondence: Zengnan MoCenter for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, People’s Republic of ChinaTel +86771-5353342Email mozengnan@gxmu.edu.cnPurpose: The associations of adiponectin with type 2 diabetes mellitus (T2DM), glucose homeostasis (including β-cell function index (HOMA-β), insulin resistance (HOMA-IR), fasting insulin (FI) and fasting glucose (FG)) have reported in epidemiological studies. However, the previous observational studies are prone to biases, such as reverse causation and residual confounding factors. Herein, a Mendelian Randomization (MR) study was conducted to determine whether causal effects exist among them.Materials and and Methods: Two-sample MR analyses and multiple sensitivity analyses were performed using the summary data from the ADIPOGen consortium, MAGIC Consortium, and a meta-analysis of GWAS with a considerable sample of T2DM (62,892 cases and 596,424 controls of European ancestry). We got eight valid genetic variants to predict the causal effect among adiponectin and T2DM and glucose homeostasis after excluding the probable invalid or pleiotropic variants.Results: Adiponectin was not associated with T2DM (odds ratio (OR) = 1.004; 95% confidence interval (CI): 0.740, 1.363) when using MR Egger after removing the invalid SNPs, and the results were consistent when using the other four methods. Similar results existed among adiponectin and HOMA-β, HOMA-IR, FI, FG.Conclusion: Our MR study revealed that adiponectin had no causal effect on T2DM and glucose homeostasis and that the associations among them in observational studies may be due to confounding factors.Keywords: GWASs, adiponectin, Mendelian randomization, T2DM, glucose homeostasis

Dehua Zhao,1 Jing Chen,1 Mingming Chu,2 Xiaoqing Long,1 Jisheng Wang1 1Department of Clinical Pharmacy, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang 621000, People’s Republic of China; 2Department of Clinical Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, People’s Republic of ChinaCorrespondence: Jisheng Wang; Dehua Zhao Email wangjishengyaoshi@163.com; zhaodehua1000@163.comAbstract: Anaplastic lymphoma kinase (ALK) inhibitors are important treatment options for non-small-cell lung cancer (NSCLC), associated with ALK gene rearrangement. Patients with ALK gene rearrangement show sensitivity to and benefit clinically from treatment with ALK tyrosine kinase inhibitors (ALK-TKIs). To date, crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, and entrectinib have received approval from the US Food and Drug Administration and/or the European Medicines Agency for use during the treatment of ALK-gene-rearrangement forms of NSCLC. Although the oral route of administration is convenient and results in good compliance among patients, oral administration can be affected by many factors, such as food, intragastric pH, cytochrome P450 enzymes, transporters, and p-glycoprotein. These factors can result in increased risks for serious adverse events or can lead to reduced therapeutic effects of ALK-TKIs. This review characterizes and summarizes the pharmacokinetic parameters and drug–-drug interactions associated with ALK-TKIs to provide specific recommendations for oncologists and clinical pharmacists when prescribing ALK-TKIs.Keywords: ALK, TKIs, NSCLC, PK, drug–drug interactions

Qianqian Luo,1–5,* Zheng Wen,1–5,* Yuanfan Li,1–5 Zefeng Chen,1–5 Xinyang Long,1–5 Yulan Bai,1–5 Shengzhu Huang,1–4 Yunkun Yan,1–4 Rui Lin,1–5 Zengnan Mo1–4,6 1Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China; 2Guangxi Key Laboratory for Genomic and Personalized Medicine, Nanning 530021, Guangxi, People’s Republic of China; 3Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning 530021, Guangxi, People’s Republic of China; 4Guangxi Key Laboratory of Colleges and Universities, Nanning 530021, Guangxi, People’s Republic of China; 5School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China; 6Institute of Urology and Nephrology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zengnan Mo; Rui LinCenter for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, People’s Republic of ChinaTel/Fax +86771-5353342; +86771-5641040Email mozengnan@gxmu.edu.cn; linrui@gxmu.edu.cnPurpose: Although increasing lines of evidence showed associations between serum uric acid (UA) levels and schizophrenia, the causality and the direction of the associations remain uncertain. Thus, we aimed to assess whether the relationships between serum UA levels and schizophrenia are causal and to determine the direction of the association.Patients and Methods: Two-sample bidirectional Mendelian randomization (MR) analyses and various sensitivity analyses were performed utilizing the summary data from genome-wide association studies within the Global Urate Genetics Consortium and the Psychiatric Genomics Consortium. Secondary MR analyses in both directions were conducted within summary data using genetic risk scores (GRSs) as instrumental variables.Results: Three MR methods provided no causal relationship between serum UA and schizophrenia. Furthermore, GRS approach showed similar results in the three MR methods after adjustment for heterogeneity. By contrast, inverse variance weighted method, weighted median and GRS approach suggested a causal effect of schizophrenia risk on serum UA after adjustment for heterogeneity (per 10-symmetric percentage increase in schizophrenia risk, beta: − 0.039, standard error (SE): 0.013, P = 0.003; beta: − 0.036, SE: 0.018, P = 0.043; beta: − 0.039, SE: 0.013, P = 0.002; respectively). Moreover, in both directions’ analyses, the heterogeneity and sensitivity tests suggested no strong evidence of bias due to pleiotropy.Conclusion: Schizophrenia may causally affect serum UA levels, whereas the causal role of serum UA concentrations in schizophrenia was not supported by our MR analyses. These findings suggest that UA may be a useful potential biomarker for monitoring treatment or diagnosis of schizophrenia rather than a therapeutic target for schizophrenia.Keywords: schizophrenia, uric acid, Mendelian randomization, genetic risk score, causality

Lei Zhang, Zhan-Guo Zhang, Xin Long, Fei-Long Liu, Wan-Guang Zhang Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of ChinaCorrespondence: Wan-Guang ZhangHepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, People’s Republic of ChinaTel +86-27-83665213Fax +86-27-83662851Email wgzhuang@medmail.com.cnBackground: Splenomegaly/hypersplenism is one of the most common complications of portal hypertension. Splenic artery embolization (SAE) has been increasingly used for treatment of splenomegaly/hypersplenism. However, few studies focused on the severe complications after embolization. In this paper, we reported 16 cases of severe complications after SAE for portal hypertension.Methods: From February 2011 to January 2019, 16 cirrhotic patients were diagnosed with severe complications after embolization. The clinical symptoms, therapies and prognosis were analyzed.Results: In these patients, the splenic embolization volume was between 50% and 70%. Among 16 cases, 7 patients were diagnosed with splenic abscess and/or left subphrenic abscess, suffered from the insistent fever, and eventually underwent the surgical therapy; 6 patients with left refractory pleural effusion, suffered from severe chest distress, and underwent repeated thoracocentesis or thoracic closed drainage; 3 patients with thrombosis in portal vein needed oral warfarin therapy.Conclusion: In cirrhotic patients, the severe complications after SAE are not uncommon after the procedure. It causes more suffering, prolonged hospital stay and more medical cost in these patients. It was debatable whether this technique was an appropriate technique for portal hypertension due to liver cirrhosis, patients contraindicated for the treatment should be carefully identified to avoid the complications.Keywords: portal hypertension, hypersplenism, splenic artery embolization, complication

Ganhua You, 1, 2 Xiangshu Long, 3, 4 Fang Song, 3, 4 Jing Huang, 3, 4 Maobo Tian, 3, 4 Yan Xiao, 3, 4 Shiyan Deng, 3, 4 Qiang Wu 3, 4 1Guizhou University School of Medicine, Guiyang 550025, People’s Republic of China; 2Guizhou Institute for Food and Drug Control, Guiyang 550004, People’s Republic of China; 3Department of Cardiology, Guizhou Provincial People’s Hospital, Guiyang 550002, People’s Republic of China; 4Department of Cardiology, People’s Hospital of Guizhou University, Guiyang 550002, People’s Republic of ChinaCorrespondence: Qiang WuDepartment of Cardiology, Guizhou Provincial People’s Hospital, 83 Zhongshan East Road, Guiyang, Guizhou, People’s Republic of ChinaTel +86-0851-85937194Fax +86-0851-85924943Email wqgz0851@126.comBackground: Metformin has been shown to inhibit the proliferation and migration of vascular wall cells. However, the mechanism through which metformin acts on atherosclerosis (AS) via the long non-coding RNA taurine up-regulated gene 1 (lncRNA TUG1) is still unknown. Thus, this research investigated the effect of metformin and lncRNA TUG1 on AS.Methods: First, qRT-PCR was used to detect the expression of lncRNA TUG1 in patients with coronary heart disease (CHD). Then, the correlation between metformin and TUG1 expression in vitro and their effects on proliferation, migration, and autophagy in vascular wall cells were examined. Furthermore, in vivo experiments were performed to verify the anti-AS effect of metformin and TUG1 to provide a new strategy for the prevention and treatment of AS.Results: qRT-PCR results suggested that lncRNA TUG1 expression was robustly upregulated in patients with CHD. In vitro experiments indicated that after metformin administration, the expression of lncRNA TUG1 decreased in a time-dependent manner. Metformin and TUG1 knockdown via small interfering RNA both inhibited proliferation and migration while promoted autophagy via the AMPK/mTOR pathway in vascular wall cells. In vivo experiments with a rat AS model further demonstrated that metformin and sh-TUG1 could inhibit the progression of AS.Conclusion: Taken together, our data demonstrate that metformin might function to prevent AS by activating the AMPK/mTOR pathway via lncRNA TUG1.Keywords: metformin, taurine up-regulated gene 1, AMPK/mTOR, autophagy, atherosclerosis

Jingyi Ye,1,* Huiyi Wu,1,* Chuanli Huang,1 Wanting Lin,2 Caifeng Zhang,1 Bei Huang,2 Banyi Lu,2 Hongyu Xu,2 Xiaoling Li,3 Xiaoying Long1,41Department of Pharmaceutics, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, People’s Republic of China; 2Department of Pharmacy of Chinese Materia Medica, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, People’s Republic of China; 3Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA 95211, USA; 4Department of Oral Delivery, Guangdong Engineering and Technology Research Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou 510006, People’s Republic of China*These authors contributed equally to this workPurpose: The objective of this study was to compare the in vitro Fick’s first law, in vitro lipolysis, and in vivo rat assays for oral absorption of Biopharmaceutical Classification Systems Class II (BCS II) drugs in self-nanoemulsifying drug delivery system (SNEDDS), and studied drugs and oils properties effects on the absorption.Methods: The transport abilities of griseofulvin (GRI), phenytoin (PHE), indomethacin (IND), and ketoprofen (KET) in saturated water solutions and SNEDDS were investigated using the in vitro Madin-Darby canine kidney cell model. GRI and cinnarizine (CIN) in medium-chain triglycerides (MCT)-SNEDDS and long-chain triglycerides (LCT)-SNEDDS were administered in the in vivo SD rat and in vitro lipolysis models to compare the oral absorption and the distribution behaviors in GIT and build an in vitro-in vivo correlation (IVIVC).Results: In the cell model, the solubility of GRI, PHE, IND, and KET increased 6–8 fold by SNEDDS, but their permeability were only 18%, 4%, 8%, and 33% of those of their saturated water solutions, respectively. However, in vivo absorption of GRI-SNEDDS was twice that of the GRI suspension and those of CIN-SNEDDS were 15–21 fold those of the CIN suspension. In the lipolysis model, the GRI% in aqueous and pellet phases of MCT were similar to that in LCT. In contrast, the CIN% in the aqueous and pellet phases were decreased but that of the lipid phase increased. In addition, an IVIVC was found between the CIN% in the lipid phase and in vivo relative oral bioavailability (Fr).Conclusion: The in vitro cell model was still a suitable tool to study drug properties effects on biofilm transport and SNEDDS absorption mechanisms. The in vitro lipolysis model provided superior oral absorption simulation of SNEDDS and helped to build correlation with in vivo rats. The oral drug absorption was affected by drug and oil properties in SNEDDS.Keywords: SNEDDS, MDCK cell model, in vivo rat model, in vitro lipolysis, in vitro-in vivo correlation

Huixia Qiu,1 Frederic Flament,2 Xiaohui Long,1 Jun Wu,1 Mengzhi Xu,1 Didier Saint Leger,2 Helene Meaudre,2 Jerome Senee,1 Bertrand Piot,2 Roland Bazin2 1L’Oréal Research and Innovation, Shanghai, People’s Republic of China; 2L’Oréal Research and Innovation, Chevilly, France Abstract: The facial skin tone of two groups of Chinese women from Shanghai was compared using standard colorimetric space techniques during a 6-month interval between January and July 2011. During the study period, one group of women (n = 40) applied a potent sun-protective cosmetic product daily, while the other group (n = 40) did not use any sun protection. The results, based on images taken using a standardized digital camera coupled to a spectroradiometer, showed that sun protection largely mitigated changes in the components of skin tone, ie, lightness, melanization, and individual typology angle parameters. The skin darkening process appeared to be reduced or prevented in the sun-protected group when compared with the control group. The sun-protected women had participated in an earlier study in 2008, which confirmed that seasonal skin darkening occurs from winter through summer in Shanghaiese women. Comparing the data obtained in the winters of 2008 and 2011, we were able to identify better the impact of 3 years of aging on the components of skin tone. Comparing data between seasons on the same women with (2011 study) and without (2008 study) sun protection highlights the role of the test product in preventing skin darkening. Keywords: skin tone, skin seasonal darkening, sun protection, aging

Brine-dependent recovery, which involves injected water ionic composition and strength, has seen much global research efforts in the past two decades because of its benefits over other oil recovery methods. Several studies, ranging from lab coreflood experiments to field trials, indicate the potential of recovering additional oil in sandstone and carbonate reservoirs. Sandstone and carbonate rocks are composed of completely different minerals, with varying degree of complexity and heterogeneity, but wettability alteration has been widely considered as the consequence rather than the cause of brine-dependent recovery. However, the probable cause appears to be as a result of the combination of several proposed mechanisms that relate the wettability changes to the improved recovery. This paper provides a comprehensive review on laboratory and field observations, descriptions of underlying mechanisms and their validity, the complexity of the oil-brine-rock interactions, modeling works, and comparison between sandstone and carbonate rocks. The improvement in oil recovery varies depending on brine content (connate and injected), rock mineralogy, oil type and structure, and temperature. The brine ionic strength and composition modification are the two major frontlines that have been well-exploited, while further areas of investigation are highlighted to speed up the interpretation and prediction of the process efficiency.

Organometallic halides are great candidates for optoelectronics. As an important family of semiconductors, understanding their thermoelectric transport properties is also important. This has been a challenging task as many of such compounds are highly intrinsic. In this work, we synthesized two halides, CH3NH3PbI3 and (CH3NH3)3Bi2I9, using a solvent-free method. We found an extraordinarily high Seebeck coefficient of +2600 ± 200 μV/K in (CH3NH3)3Bi2I9. For CH3NH3PbI3, our synthesis method led to a negative Seebeck coefficient of -1350 ± 50 μV/K, in contrast to positive values observed in solvent synthesized samples. We also found the thermal conductivity of CH3NH3PbI3 to be 0.38 W/m K, largely independent of temperature from 300 K to 450 K, despite a tetragonal-to-cubic phase transition. (CH3NH3)3Bi2I9 has an even lower thermal conductivity of 0.21 W/m K (also temperature independent) which is due to its soft phonon dispersion and weak bonds.

Ultracold atoms, produced by laser cooling and trapping, have led to recent advances in quantum information, quantum chemistry, and quantum sensors. A lack of ultraviolet narrow-band lasers precludes laser cooling of prevalent atoms such as hydrogen, carbon, oxygen, and nitrogen. Broadband pulsed lasers can produce high power in the ultraviolet, and we demonstrate that the entire spectrum of an optical frequency comb can cool atoms when used to drive a narrow two-photon transition. This multiphoton optical force is also used to make a magneto-optical trap. These techniques may provide a route to ultracold samples of nature's most abundant building blocks for studies of pure-state chemistry and precision measurement.