Publications by authors named "Ying Zheng"

931 Publications

Organ-on-a-chip systems for vascular biology.

J Mol Cell Cardiol 2021 Jun 9;159:1-13. Epub 2021 Jun 9.

Department of Bioengineering, University of Washington, 3720 15th Ave NE, Seattle, WA 98105, USA; Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98195, USA. Electronic address:

Organ-on-a-chip (OOC) platforms involve the miniaturization of cell culture systems and enable a variety of novel experimental approaches. These range from modeling the independent effects of biophysical forces on cells to screening novel drugs in multi-organ microphysiological systems, all within microscale devices. As in living systems, the incorporation of vascular structure is a key feature common to almost all organ-on-a-chip systems. In this review we highlight recent advances in organ-on-a-chip technologies with a focus on the vasculature. We first present the developmental process of the blood vessels through which vascular cells assemble into networks and remodel to form complex vascular beds under flow. We then review self-assembled vascular models and flow systems for the study of vascular development and biology as well as pre-patterned vascular models for the generation of perfusable microvessels for modeling vascular and tissue function. We finally conclude with a perspective on developing future OOC approaches for studying different aspects of vascular biology. We highlight the fit for purpose selection of OOC models towards either simple but powerful testbeds for therapeutic development, or complex vasculature to accurately replicate human physiology for specific disease modeling and tissue regeneration.
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http://dx.doi.org/10.1016/j.yjmcc.2021.06.002DOI Listing
June 2021

Acupoint injection combined with pelvic floor rehabilitation in the treatment of postpartum pelvic floor disorders: A protocol of randomized controlled trial.

Medicine (Baltimore) 2021 Jun;100(23):e25511

Chongqing Ninth People's Hospital.

Background: Female pelvic floor dysfunction is one of the common chronic diseases affecting women's physical and mental health. Pregnancy and delivery are one of the main causes. Pelvic floor rehabilitation is a common method for the treatment of postpartum pelvic floor dysfunction, but it has some defects. Acupoint injection has advantages in the treatment of postpartum pelvic floor dysfunction, but there is a lack of standard clinical research to verify it. Therefore, the purpose of this randomized controlled trial is to evaluate the efficacy and safety of acupoint injection combined with pelvic floor rehabilitation in the treatment of postpartum pelvic floor disorders.

Methods: This is a prospective randomized controlled trial to study the efficacy and safety of acupoints injection combined with pelvic floor rehabilitation. And it is approved by the Ethics Committee of Clinical Research of our hospital. Patients were randomly divided into observation group (acupoint injection combined with pelvic floor rehabilitation group) or control group (pelvic floor rehabilitation group alone). The patients were followed up for 8 weeks after 12 weeks of treatment. The observation indexes included: pelvic organ prolapse degree, pelvic floor muscle strength, urinary incontinence score, adverse reactions, among others. Data were analyzed using the statistical software package SPSS version 18.0.

Conclusions: This study will evaluate the efficacy and safety of acupoint injection combined with pelvic floor rehabilitation in the treatment of postpartum pelvic floor dysfunction, and provide reliable reference for the clinical application of this project.

Trial Registration: OSF Registration number: DOI 10.17605/OSF.IO/VC65Z.
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http://dx.doi.org/10.1097/MD.0000000000025511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202566PMC
June 2021

Cytoplasmic and nuclear Sw-5b NLR act both independently and synergistically to confer full host defense against tospovirus infection.

New Phytol 2021 Jun 7. Epub 2021 Jun 7.

Key Laboratory of Plant Immunity, Department of Plant Pathology, College of Plant Protection, Nanjing Agricultural University, Nanjing, 210095, P. R. China.

Plant intracellular nucleotide binding-leucine-rich repeat (NLR) receptors play critical roles in mediating host immunity to pathogen attack. We use tomato Sw-5b::tospovirus as a model system to study the specific role of the compartmentalized plant NLR in dictating host defense against virus at different infection steps. We demonstrated here that tomato NLR Sw-5b distributes to cytoplasm and nucleus, respectively, to play different roles in inducing host resistances against tomato spotted wilt orthotospovirus (TSWV) infection. The cytoplasmic-enriched Sw-5b induces a strong cell death response to inhibit TSWV replication. This host response is, however, insufficient to block viral intercellular and long-distance movement. The nuclear-enriched Sw-5b triggers a host defense that weakly inhibits viral replication but strongly impedes virus intercellular and systemic movement. Furthermore, the cytoplasmic and nuclear Sw-5b act synergistically to dictate a full host defense of TSWV infection. We further demonstrated that the extended N-terminal Solanaceae domain (SD) of Sw-5b plays critical roles in cytoplasm/nucleus partitioning. Sw-5b nucleotide-binding leucine-rich repeat (NB-LRR) controls its cytoplasm localization. Strikingly, the SD but not coil-coil (CC) domain is crucial for Sw-5b receptor to import into nucleus to trigger the immunity. The SD was found to interact with importins. Silencing both importin α and β expression disrupted Sw-5b nucleus import and host immunity against TSWV systemic infection. Collectively, our findings suggest that Sw-5b bifurcates disease resistances by cytoplasm/nucleus partitioning to block different infection steps of TSWV. The findings also identified a new regulatory role of extra domain of a plant NLR in mediating host innate immunity.
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http://dx.doi.org/10.1111/nph.17535DOI Listing
June 2021

MicroRNA expression profiling involved in doxorubicin-induced cardiotoxicity using high-throughput deep-sequencing analysis.

Oncol Lett 2021 Jul 26;22(1):560. Epub 2021 May 26.

Department of Cardiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, P.R. China.

MicroRNAs (miRNAs/miRs) are sensitive biomarkers and endogenous repressors of gene expression by decreasing mRNA stability and interfering with mRNA translation. Despite a number of investigations revealing the dysregulation of miRNA expression associated with cardiotoxicity induced by doxorubicin (Dox), perturbation of miRNAs directly resulting from Dox at early stage in cardiomyocytes and the target gene interaction remain largely unknown. In the present study, high-throughput deep-sequencing was used to analyze changes in global miRNA expression in H9c2 cardiomyocytes exposed to 5 µg/ml Dox for 0, 12 or 24 h. Compared with the 0-h time point, the expression levels of 386 unique miRNAs were altered. Based on miRNA expression and fold-change, the target genes of 76 selected miRNAs were further analyzed using gene interaction networks and pathway enrichment analysis. These miRNAs were involved in the regulation of different pathways, whose functions included apoptosis, cell proliferation, extracellular matrix remodeling, oxidative stress and lipid metabolism. These differentially expressed miRNAs included let-7 family, miR-29b-3p, miR-378-3/5p, miR-351-3p, miR-664-3p, miR-455-3p, miR-298-3p, miR-702-5p, miR-128-1-5p, miR-671 and miR-421-5p. The present data indicated that global wide miRNA profiling in Dox-induced cardiomyocytes may provide a novel mechanistic insight into understanding Dox-induced heart failure and cardiotoxicity, as well as novel biomarkers and therapeutic targets.
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http://dx.doi.org/10.3892/ol.2021.12821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170198PMC
July 2021

WNT5A from the fetal liver vascular niche supports human fetal liver hematopoiesis.

Stem Cell Res Ther 2021 Jun 5;12(1):321. Epub 2021 Jun 5.

Department of Bioengineering, University of Washington, Seattle, WA, USA.

The human fetal liver is a critical organ for prenatal hematopoiesis, the study of which offers insights into niche signals that regulate the fates of hematopoietic stem and progenitor cells (HSPCs) during fetal development. Here, we demonstrate that human fetal liver endothelium uniquely supports the maturation and expansion of multilineage HSPCs. Specifically, co-culture of fetal liver-derived immature CD43CD45 hematopoietic cells with human fetal liver endothelial cells (ECs) led to a profound increase in the numbers of phenotypic CD45CD34 HSPCs and multilineage colony-forming progenitors generated in vitro, when compared to co-culture with ECs derived from other organs. We further identified a supportive role for EC-derived WNT5A in this process via gain- and loss-of-function studies within ECs. Our study emphasizes the importance of the organ-specific endothelial niche in supporting hematopoietic development and provides novel insight into signals that may facilitate HSPC expansion in vitro for clinical applications.
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http://dx.doi.org/10.1186/s13287-021-02380-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180064PMC
June 2021

Sentinel lymph Node mapping versus systematic pelvic lymphadenectomy on the prognosis for patients with intermediate-high-risk Endometrial Cancer confined to the uterus before surgery: trial protocol for a non-inferiority randomized controlled trial (SNEC trial).

J Gynecol Oncol 2021 Jul;32(4):e60

Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.

Background: Sentinel lymph node (SLN) mapping has been recommended as an alternative staging approach to lymphadenectomy for apparent uterine-confined endometrial cancer (EC). However, the prognostic value of SLN mapping alone instead of systematic lymphadenectomy on EC patients remains unclear.

Methods: A multi-center, open label, non-inferiority randomized controlled trial has been designed to identify if SLN mapping alone is not inferior to pelvic lymphadenectomy on prognosis of patients with intermediate-high-risk EC clinically confined to uterus. Eligible patients will be 1:1 randomly assigned to accept SLN mapping or pelvic lymphadenectomy. The primary endpoint is the 2-year progression-free survival (PFS). The second points are the 5-year PFS, 5-year overall survival, surgery-related adverse events and life quality. A total of 780 patients will be enrolled from 6 hospitals in China within 3-year period and followed up for 5 years.

Trial Registration: ClinicalTrials.gov Identifier: NCT04276532.
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http://dx.doi.org/10.3802/jgo.2021.32.e60DOI Listing
July 2021

Involvement of circRNAs in Proinflammatory Cytokines-Mediated -Cell Dysfunction.

Mediators Inflamm 2021 4;2021:5566453. Epub 2021 May 4.

Center for Medical Research, The Second Xiangya Hospital, Central South University, Changsha, 410011 Hunan, China.

Aim: During the initial stage of type 1 diabetes, prolonged exposure of pancreatic -cell to proinflammatory cytokines such as IL-1, TNF-, and IFN- results in a decreased capacity to produce and release insulin, as well as cell loss by apoptosis. Circular RNAs (circRNAs) are a new class of endogenous noncoding RNAs (ncRNAs) with closed loop with no free ends. circRNAs have been reported to be participated in the development of many diseases. As little is known about their role in insulin-secreting cells, this study is aimed at evaluating their contribution in the process of inflammation-induced -cell damage.

Methods: circRNA expression profile of MIN6 cells stimulated with a mix of cytokines, including IL-1, IFN-, and TNF-, was detected by circRNA microarrays. Four dysregulated circRNAs were validated by qRT-PCR. The involvement of the selected circRNAs in -cell dysfunction was tested after their inhibition in MIN6 cells. MicroRNA target prediction software and multiple bioinformatic approaches were used to predict the targeting genes of circRNAs and analyze possible functions of the circRNAs.

Results: 1020 upregulated and 902 downregulated circRNAs were identified in cytokines-treated -cells. Inhibition of circRNAs 000286 and 017277 in -cells could promote -cell apoptosis and affect insulin biosynthesis and secretion. GO analysis enriched terms such as regulation of transcription and regulation of gene expression and KEGG analysis enriched top pathways included TGF- and MAPK signaling pathways.

Conclusions: The data shows that circRNAs may be involved in proinflammatory cytokines-mediated -cell dysfunction and suggests the involvement of circRNAs in the development of type 1 diabetes.
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http://dx.doi.org/10.1155/2021/5566453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112919PMC
May 2021

Nitroso-Caged Rhodamine: A Superior Green Light-Activatable Fluorophore for Single-Molecule Localization Super-Resolution Imaging.

Anal Chem 2021 Jun 24;93(22):7833-7842. Epub 2021 May 24.

State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China.

The evolution of super-resolution imaging techniques, especially single-molecule localization microscopy, demands the engineering of switchable fluorophores with labeling functionality. Yet, the switching of these fluorophores depends on the exterior conditions of UV light and enhancing buffers, which is bioincompatible for living-cell applications. Herein, to surpass these limitations, a nitroso-caging strategy is employed to cage rhodamines into leuco forms, which for the first time, is discovered to uncage highly bright zwitterions by green light. Further, clickable construction grants the specificity and versatility for labeling various components in living cells. The simultaneous photoactivation and excitation of these novel probes allow for single-laser super-resolution imaging without any harmful additives. Super-resolution imaging of microtubules in fixed cells or mitochondria and the distribution of glycans and H2B proteins in living cells are achieved at a molecular scale with robust integrity. We envision that our nitroso-caging probes would set a platform for the development of future visible-activatable probes.
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http://dx.doi.org/10.1021/acs.analchem.1c00175DOI Listing
June 2021

Near-Complete Genome Sequence of GI-17 Lineage Infectious Bronchitis Virus, Circulating in Iowa.

Microbiol Resour Announc 2021 May 20;10(20). Epub 2021 May 20.

Department of Veterinary Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames, Iowa, USA

Avian infectious bronchitis virus (AvIBV) is the causative agent of a highly contagious respiratory disease in chickens which results in significant economic losses in the poultry industry. Here, we report a near-complete genome sequence of the strain, designated IA1162/2020, identified in tracheal swabs from chickens in Iowa in 2020.
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http://dx.doi.org/10.1128/MRA.01406-20DOI Listing
May 2021

Assessing Individual Risk for High-Risk Early Colorectal Neoplasm for Pre-Selection of Screening in Shanghai, China: A Population-Based Nested Case-Control Study.

Cancer Manag Res 2021 12;13:3867-3878. Epub 2021 May 12.

Department of Cancer Prevention, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China.

Objective: To identify people with high-risk early colorectal neoplasm is highly desirable for pre-selection in colorectal cancer (CRC) screening in low-resource countries. We aim to build and validate a risk-based model so as to improve compliance and increase the benefits of screening.

Patients And Methods: Using data from the Shanghai CRC screening cohort, we conducted a population-based nested case-control study to build a risk-based model. Cases of early colorectal neoplasm were extracted as colorectal adenomas and stage 0-I CRC. Each case was matched with five individuals without neoplasm (controls) by the screening site and year of enrollment. Cases and controls were then randomly divided into two groups, with two thirds for building the risk prediction model and the other one third for model validation. Known risk factors were included for risk prediction models using logistic regressions. The area under the receiver operating characteristic curve (AUC) and Hosmer-Lemeshow chi-square statistics were used to evaluate model discrimination and calibration. The predicted individual risk probability was calculated under the risk regression equation.

Results: The model incorporating age, sex, family history and lifestyle factors including body mass index (BMI), smoking status, alcohol, regular moderate-to-intensity physical activity showed good calibration and discrimination. When the risk cutoff threshold was defined as 17%, the sensitivity and specificity of the model were 63.99% and 53.82%, respectively. The validation data analysis also showed well discrimination.

Conclusion: A risk prediction model combining personal and lifestyle factors was developed and validated for high-risk early colorectal neoplasm among the Chinese population. This risk-based model could improve the pre-selection for screening and contribute a lot to efficient population-based screening in low-resource countries.
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http://dx.doi.org/10.2147/CMAR.S301185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126801PMC
May 2021

Transvaginal natural orifice transluminal endoscopic surgery (vNOTES) as treatment for upper vaginal leiomyoma: A case report.

Medicine (Baltimore) 2021 May;100(20):e25969

Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University.

Introduction: Transvaginal natural orifice transluminal endoscopic surgery (vNOTES) is an emerging technique in the area of minimally invasive surgery. Vaginal leiomyoma is a rare benign tumor, with only a few cases being reported in the literature. we demonstrate a novel approach for excision of a vaginal leiomyoma via vNOTES. To ensure reproducibility and replicability akin to a standardized procedure, we have provided a step-by-step video description of the use of vNOTES for upper anterior vaginal myomectomy.

Patient Concerns: A 35-year-old female (G2P0A2) presented with a tumor in the upper anterior vaginal wall, which gradually increased in size.

Diagnosis: A vaginal examination revealed a swollen area approximately 3-cm in diameter on the upper anterior vaginal wall. The swelling was mobile and solid. All other vitals were normal. Transvaginal ultrasound detected a 3.0 × 3.4 cm hypoechogenic mass on the superior vaginal wall, and a preoperative diagnosis of the vaginal tumor was confirmed.

Interventions: The upper vaginal leiomyoma treated using transvaginal natural orifice transluminal endoscopic surgery.

Outcomes: The procedure lasted for 20 min, and the postoperative course was uneventful.

Conclusions: vNOTES can be a promising alternative to traditional vaginal surgery for upper vaginal disease due to advantages such as excellent exposure, easy access and precise suturing. However, more studies are needed to assess its long-term efficacy.
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http://dx.doi.org/10.1097/MD.0000000000025969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137015PMC
May 2021

Uptake and trafficking of different sized PLGA nanoparticles by dendritic cells in imiquimod-induced psoriasis-like mice model.

Acta Pharm Sin B 2021 Apr 20;11(4):1047-1055. Epub 2020 Nov 20.

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.

Psoriasis is an autoimmune inflammatory disease, where dendritic cells (DCs) play an important role in its pathogenesis. In our previous work, we have demonstrated that topical delivery of curcumin-loaded poly (lactic--glycolic acid) (PLGA) nanoparticles (NPs) could treat Imiquimod (IMQ)-induced psoriasis-like mice. The objective of this study is to further elucidate biofate of PLGA NPs after intradermal delivery including DCs uptake, and their further trafficking in psoriasis-like mice model by using fluorescence probes. Two-sized DiO/DiI-loaded PLGA NPs of 50 ± 4.9 nm (S-NPs) and 226 ± 7.8 nm (L-NPs) were fabricated, respectively. cellular uptake results showed that NPs could be internalized into DCs with intact form, and DCs preferred to uptake larger NPs. Consistently, study showed that L-NPs were more captured by DCs and NPs were firstly transported to skin-draining lymph nodes (SDLN), then to spleens after 8 h injection, whereas more S-NPs were transported into SDLN and spleens. Moreover, FRET imaging showed more structurally intact L-NPs distributed in skins and lymph nodes. In conclusion, particle size can affect the uptake and trafficking of NPs by DCs in skin and lymphoid system, which needs to be considered in NPs tailing to treat inflammatory skin disease like psoriasis.
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http://dx.doi.org/10.1016/j.apsb.2020.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105876PMC
April 2021

The role of caveolin-1 in the biofate and efficacy of anti-tumor drugs and their nano-drug delivery systems.

Acta Pharm Sin B 2021 Apr 28;11(4):961-977. Epub 2020 Nov 28.

Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Science, Peking University, Beijing 100191, China.

As one of the most important components of caveolae, caveolin-1 is involved in caveolae-mediated endocytosis and transcytosis pathways, and also plays a role in regulating the cell membrane cholesterol homeostasis and mediating signal transduction. In recent years, the relationship between the expression level of caveolin-1 in the tumor microenvironment and the prognostic effect of tumor treatment and drug treatment resistance has also been widely explored. In addition, the interplay between caveolin-1 and nano-drugs is bidirectional. Caveolin-1 could determine the intracellular biofate of specific nano-drugs, preventing from lysosomal degradation, and facilitate them penetrate into deeper site of tumors by transcytosis; while some nanocarriers could also affect caveolin-1 levels in tumor cells, thereby changing certain biophysical function of cells. This article reviews the role of caveolin-1 in tumor prognosis, chemotherapeutic drug resistance, antibody drug sensitivity, and nano-drug delivery, providing a reference for the further application of caveolin-1 in nano-drug delivery systems.
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http://dx.doi.org/10.1016/j.apsb.2020.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105775PMC
April 2021

Editorial of Special Issue "The Biological Fate of Drug Nanocarriers".

Acta Pharm Sin B 2021 Apr 1;11(4):850-851. Epub 2021 May 1.

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.

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http://dx.doi.org/10.1016/j.apsb.2021.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105767PMC
April 2021

Extracellular Vesicle Application as a Novel Therapeutic Strategy for Ischemic Stroke.

Transl Stroke Res 2021 May 13. Epub 2021 May 13.

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Research Building N22, Avenida da Universidade, Taipa, Macao, 999078, SAR, China.

Ischemic stroke (IS) accounts for most of the cases of stroke onset, and due to short therapeutic time window for thrombolysis and numerous limited treatment measures and contraindications, lots of patients cannot receive satisfying therapeutic effects resulting in high disability and mortality worldly. In recent years, extracellular vesicles (EVs), as nanosized membrane-structured vesicles secreted from almost all cells, especially from stem/progenitor cells, have been reported to exert significant beneficial effects on IS from multiple approaches and notably ameliorate neurological outcome. Moreover, based on nano-size and lipid bilayer structure, EVs can easily penetrate the blood-brain barrier and migrate into the brain. In this review, we mainly systematically summarize the therapeutic effects of EVs on IS and explore their potential applications. Simultaneously, we also discuss administration routines, dosages, experimental observation time, and some key issues of EV application during IS treatment. It contributes to a comprehensive understanding of the progress of EV treatment for IS and providing confident evidence for further EV clinical application widely.
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http://dx.doi.org/10.1007/s12975-021-00915-3DOI Listing
May 2021

Lycium barbarum mitigates radiation injury via regulation of the immune function, gut microbiota, and related metabolites.

Biomed Pharmacother 2021 Jul 3;139:111654. Epub 2021 May 3.

Tianjin University of Traditional Chinese Medicine, Tianjin, China; Beijing Institute of Radiation Medicine, Beijing, China. Electronic address:

Previous studies have suggested that Lycium barbarum (L. barbarum) has a radioprotective function, although more in-depth investigation is still required. We investigated the radioprotective efficacy of extract of the fruits of L. barbarum (LBE) and its radioprotective mechanisms. Mice were exposed to 8.5 Gy, 5.5 Gy, or 6.0 Gy total body irradiation (TBI), and the survival rate, lymphocyte percentage, amount of cytokines, and viability of the irradiated cells, as well as the gut microbiome and fecal metabolomics were studied. LBE enhanced the survival of the mice exposed to 8.5 Gy γ-ray TBI or 5.5 Gy X-ray TBI. After 6.0 Gy γ-ray TBI, LBE exhibited good immunomodulatory properties, mainly characterized by the accelerated recovery of lymphocyte percentages, and the enhanced expression of immune-related cytokines. LBE reconstituted the gut microbiota of irradiated mice, increased the relative abundance of potentially beneficial genera (e.g., Turicibacter, Akkermansia), and decreased the relative abundance of potentially harmful bacterial genera (e.g., Rikenellaceae_RC9_gut_group). Beneficial regulatory effects of LBE on the host metabolites were also noted, and the major upregulated metabolites induced by LBE, such as Tetrahydrofolic acid and N-ornithyl-L-taurine, were positively correlated with the immune factor interleukin (IL)-6. In vitro, LBE also increased the vitality of rat small intestinal epithelial cells (IEC-6) after 4.0 Gy γ-ray irradiation and promoted the growth of Akkermansia muciniphila. These results confirmed a radioprotective function of LBE and indicated that the radioprotective mechanism may be due to immunomodulation and the synergistically modulating effect on the gut microbiota and related metabolites.
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http://dx.doi.org/10.1016/j.biopha.2021.111654DOI Listing
July 2021

The Impact of Adverse Events on Health Care Resource Utilization, Costs, and Mortality Among Patients Treated with Immune Checkpoint Inhibitors.

Oncologist 2021 May 5. Epub 2021 May 5.

Emmanuel Merck, Darmstadt Serono, Inc., Rockland, Massachusetts, USA.

Background: We investigated the association between adverse events (AEs) suspected to be immune-related and health care resource utilization, costs, and mortality among patients receiving programmed cell death 1/programmed cell death ligand 1 immune checkpoint inhibitor (ICI) monotherapy for urothelial carcinoma, renal cell carcinoma, non-small cell lung cancer, or Merkel cell carcinoma.

Patients And Methods: We conducted a retrospective cohort study using medical and pharmacy claims and enrollment information from U.S. commercial and Medicare Advantage with Part D enrollees in the Optum Research Database from March 1, 2014, through April 30, 2019. Claims were linked with mortality data from the Social Security Death Index and the National Death Index. Eligible patients had at least one ICI claim between September 1, 2014, and April 30, 2019.

Results: After adjusting for potential confounding variables, we found patients with AEs had more than double the risk of an inpatient stay (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.9-2.5) and an 80% higher risk of an emergency visit (HR, 1.8; 95% CI, 1.6-2.1) than patients without AEs. Adjusted 6-month total costs were $24,301 higher among patients with an AE versus those without ($99,037 vs. $74,736; 95% CI, $18,828-29,774; p < .001). Mean ± SD AE-related medical costs averaged $2,359 ± $7,496 per patient per month, driven by inpatient visits, which accounted for 89.9% of AE-related costs. Adjusted risk of mortality was similar in patients with and without AEs.

Conclusion: Patients with AEs had higher risks of hospitalizations, emergency room visits, and higher health care costs, driven by inpatient stays, than patients without AEs. The adjusted risk of mortality was similar between the two cohorts.

Implications For Practice: Patients taking immune checkpoint inhibitors (ICIs) who had adverse events (AEs) had significantly higher health care costs and utilization, driven by inpatient stays, compared with patients who did not. Given this high cost associated with AEs and the differences in the side effect profile of ICIs versus traditional chemotherapy, it is important for physicians to be cognizant of these differences when treating patients with ICIs. Ongoing evaluation, earlier recognition, and more effective, multidisciplinary management of AEs may improve patient outcomes and reduce the need for costly inpatient stays.
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http://dx.doi.org/10.1002/onco.13812DOI Listing
May 2021

Mus musculus Barrier-To-Autointegration Factor 2 (Banf2) is Not Essential for Spermatogenesis or Fertility.

Cytogenet Genome Res 2021 May 5:1-11. Epub 2021 May 5.

Department of Histology and Embryology, School of Medicine, Yangzhou University, Yangzhou, China.

The barrier-to-autointegration factor (BAF) is widely expressed in most human tissues and plays a critical role in chromatin organization, nuclear envelope assembly, gonadal development, and embryonic stem cell self-renewal. Complete loss of BAF has been shown to lead to embryonic lethality and gonadal defects. The BAF paralog, namely, barrier-to-autointegration factor 2 (BANF2), exhibits a testis-predominant expression pattern in both humans and mice. Unlike BAF, it may cause isolated male infertility. Therefore, we used the CRISPR/Cas9 system to generate Banf2-knockout mice to further study its function in spermatogenesis. Unexpectedly, knockout mice did not show any detectable abnormalities in histological structure of the testis, epididymis, ovary, and other tissues, and exhibited normal fertility, indicating that Banf2 is not essential for mouse spermatogenesis and fertility.
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http://dx.doi.org/10.1159/000513850DOI Listing
May 2021

Time-varying effect of sex on prognosis of lung adenocarcinoma surgical patients in China.

Thorac Cancer 2021 Jun 3;12(11):1699-1707. Epub 2021 May 3.

Department of Cancer Prevention, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: Little is known about the prognostic advantage of sex for pulmonary adenocarcinoma among Chinese patients. In this study, we aimed to investigate the true sex differences in prognosis by adjusting for confounders and to explore whether the differences were time-varying.

Methods: We identified 4438 lung adenocarcinoma patients who underwent surgery at a regional Cancer Center of China from 2008 to 2016, retrospectively. Sex, age group, smoking history, year of diagnosis and pathological stage were collected. Time-dependent Cox regression models with inverse probability of treatment weighting (IPTW) based on propensity score were used to assess the effect of sex and account for confounders. Landmark analyses were conducted to assess survival before, and after, five years.

Results: Of these patients, 1761 (39.7%) were men and 2677 (60.3%) were women. Median follow-up time was 52.6 months. After IPTW adjustment, women were found to have significantly better survival than men varying with time in both crude and IPTW models (hazard ratio [HR] [t] = 0.453*1.015 , where t is the length of time from treatment and its unit is month, p < 0.001). Women had significantly better survival than men within 0-5 years after surgery (HR = 0.763, 95% CI: 0.649-0.897, p = 0.001), whereas there was no difference after five years (HR = 1.135, 95% CI: 0.803-1.605, p = 0.472). In subgroup analysis, women in the 61-71+ age group, in the more than 20 year packs group, pathological stage 0-IB group, and 2013-2016 diagnosis period group revealed the same prognostic pattern.

Conclusions: Compared with men, women had better survival after surgical resection of lung adenocarcinoma, especially those who were older and nonsmokers or heavy-smokers and were pathological stage 0-IB in early years, while the advantage for women diminished with time.
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http://dx.doi.org/10.1111/1759-7714.13959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169287PMC
June 2021

Polymorphic Phase Formation of Liquid Crystals Distributed in Semicrystalline Polymers: An Indicator of Interlamellar and Interspherulitic Segregation.

J Phys Chem Lett 2021 May 3;12(18):4378-4384. Epub 2021 May 3.

State Key Laboratory of Chemical Engineering, College of Chemical and Biological Engineering, Zhejiang University, 38 Zheda Road, Hangzhou 310027, China.

Amorphous and melted components can segregate into the interlamellar or interspherulitic regions of polymer crystals in their blends/mixtures; this phase behavior strongly influences the physical properties and functions of materials. However, it is experimentally difficult to evaluate the spatial distributions of the other components in polymer crystals. Herein, we use a small-molecule liquid crystal (LC) as a probe and find that it forms different solid phases when mixed with the semicrystalline polymer poly(l-lactic acid) (PLLA). The LC can form the metastable phase at the lower PLLA crystallization temperature but the stable phase at the higher PLLA crystallization temperature in the PLLA/LC mixture. The formation of LC metastable and stable phases is attributed to the segregation of the LC material in the interlamellar and interspherulitic regions of polymer crystals, respectively. This study provides a potential way to evaluate the spatial segregation in the crystallization-induced microphase separation of polymer blends/mixtures.
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http://dx.doi.org/10.1021/acs.jpclett.1c01092DOI Listing
May 2021

Genome-Wide Analysis of Terpene Synthase Gene Family in and Catalytic Activity Analysis of a Single Terpene Synthase.

Genes (Basel) 2021 Apr 2;12(4). Epub 2021 Apr 2.

College of Forest, Nanjing Forestry University, Nanjing 210037, China.

Terpenoids are a wide variety of natural products and terpene synthase (TPS) plays a key role in the biosynthesis of terpenoids. plants are rich in essential oils, whose main components are terpenoids, and their biosynthetic pathways have been basically elucidated. However, there is a lack of systematic identification and study of TPS in plants. In this work, we genome-widely identified and analyzed the gene family in , a model plant for functional genomic research in the genus . A total of 63 genes were identified in the genome sequence assembly, which could be divided into six subfamilies. The subfamily had the largest number of genes, which might be related to the abundant monoterpenoids in plants. The subfamily had 18 members and showed a significant species-specific expansion compared with other sequenced Lamiaceae plant species. The 63 genes could be mapped to nine scaffolds of the genome sequence assembly and the distribution of these genes is uneven. Tandem duplicates and fragment duplicates contributed greatly to the increase in the number of genes in . The conserved motifs (RR(X)8W, NSE/DTE, RXR, and DDXXD) were analyzed in TPSs, and significant differentiation was found between different subfamilies. Adaptive evolution analysis showed that were subjected to purifying selection after the species-specific expansion, and some amino acid residues under positive selection were identified. Furthermore, we also cloned and analyzed the catalytic activity of a single terpene synthase, , which belongs to the subfamily. could encode a limonene synthase and catalyze the biosynthesis of limonene, an important precursor of essential oils from the genus . This study provides useful information for the biosynthesis of terpenoids in the genus .
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http://dx.doi.org/10.3390/genes12040518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066702PMC
April 2021

Risk factors for venous thromboembolism in patients with spinal cord injury: A systematic review and meta-analysis.

J Spinal Cord Med 2021 Apr 23:1-13. Epub 2021 Apr 23.

Department of Spinal Cord Injury Rehabilitation, China Rehabilitation Research Center, Beijing, People's Republic of China.

Context: Patients with spinal cord injury (SCI) are at high risk for venous thromboembolism (VTE). The risk factors for VTE in patients with SCI are complex.

Objective: This meta-analysis was conducted to clarify the risk factors for VTE in patients with SCI.

Methods: The Cochrane Library, PubMed, EBSCO, Web of Science, China National Knowledge Infrastructure (CNKI), China Biomedical Literature Database (CBM), Wanfang Med Data Database, and VIP Database were searched to identify studies reporting on risk factors for VTE in patients with SCI.

Results: The meta-analysis included 25 studies. Findings showed that risk of VTE in patients with SCI was significantly associated with middle- and old-age (OR = 2.08, 95%CI, 1.47, 2.95), male sex (OR = 1.41, 95%CI, 1.26, 1.59), complete paralysis (OR = 3.69, 95%CI, 2.60, 5.24), personal/family history of venous thrombosis (OR = 1.95, 95%CI, 1.35, 2.81), history of smoking (OR = 2.67, 95%CI, 1.79, 3.98), lack of compression therapy (OR = 2.44, 95%CI, 1.59, 3.73), presence of lower limb/pelvic fracture (OR = 3.47, 95%CI, 1.79, 6.75), paraplegia (OR = 1.81, 95%CI, 1.49, 2.19), and diabetes (OR = 4.24, 95%CI, 2.75, 6.52).

Conclusion: The meta-analysis identified 9 risk factors for VTE in patients with SCI. Healthcare providers should be aware of the risk factors for VTE when rehabilitating patients with SCI.
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http://dx.doi.org/10.1080/10790268.2021.1913561DOI Listing
April 2021

DNA Functionality with Photoswitchable Hydrazone Cytidine*.

Chemistry 2021 Jun 7;27(32):8372-8379. Epub 2021 May 7.

Department of Chemistry, University at Albany, State University of New York, 1400 Washington Ave., Albany, NY, 1222, USA.

A new family of hydrazone modified cytidine phosphoramidite building block was synthesized and incorporated into oligodeoxynucleotides to construct photoswitchable DNA strands. The E-Z isomerization triggered by the irradiation of blue light with a wavelength of 450 nm was investigated and confirmed by H NMR spectroscopy and HPLC in the contexts of both nucleoside and oligodeoxynucleotide. The light activated Z form isomer of this hydrazone-cytidine with a six-member intramolecular hydrogen bond was found to inhibit DNA synthesis in the primer extension model by using Bst DNA polymerase. In addition, the hydrazone modification caused the misincorporation of dATP together with dGTP into the growing DNA strand with similar selectivity, highlighting a potential G to A mutation. This work provides a novel functional DNA building block and an additional molecular tool that has potential chemical biology and biomedicinal applications to control DNA synthesis and DNA-enzyme interactions using the cell friendly blue light irradiation.
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http://dx.doi.org/10.1002/chem.202100742DOI Listing
June 2021

Perceptions of lung cancer screening and smoking behavior change among Chinese immigrants: A systematic review.

Authors:
Fang Lei Ying Zheng

Tob Induc Dis 2021 16;19:30. Epub 2021 Apr 16.

Shenzhen Nanshan Medical Group Headquarter, Shenzhen, China.

Introduction: Lung cancer is the leading cause of cancer death among Chinese immigrants in the US. Smoking cessation and lung cancer screening are effective ways to decrease lung cancer mortality. This study aims to investigate Chinese immigrants' perceptions of lung cancer screening and to explore the factors/barriers associated with their smoking behavior/cessation.

Methods: A systematic review design with narrative methods was used. Electronic literature databases, including PubMed, CINAHL and Google Scholar were searched.

Results: A total of 11 articles met the search criteria. Methodological rigor of the studies was evaluated by Bowling's checklist and Critical Appraisal Skills Program checklist. Data search revealed that a limited amount of research has been done on Chinese immigrants' perceptions of lung cancer screening. Factors influencing their smoking behavior included personal characteristics, psychological status, acculturation, and cues from external environment. Barriers to their smoking cessation behavior included language barriers, individual's unwillingness to use smoking cessation assistance methods, healthcare environment's insufficiency to counter pro-smoking norms, lack of social support, and wrong personal beliefs.

Conclusions: Findings from this study could help healthcare providers to design culturally tailored lung cancer screening programs and smoking cessation projects to decrease morbidity and mortality rates of lung cancer among Chinese immigrants.
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http://dx.doi.org/10.18332/tid/133579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051433PMC
April 2021

Real-World Outcomes Among US Veterans Health Administration Patients Newly Diagnosed with Metastatic Renal Cell Carcinoma and Treated with First-Line Monotherapy.

Adv Ther 2021 05 17;38(5):2644-2661. Epub 2021 Apr 17.

EMD Serono Inc., Rockland, MA, USA; an affiliate of Merck KGaA, Darmstadt, Germany.

Introduction: Substantial unmet needs exist among patients with metastatic renal cell carcinoma (mRCC). This retrospective study evaluated treatment patterns as well as clinical and economic outcomes associated with first-line monotherapy among patients with mRCC in the USA.

Methods: Newly diagnosed patients with mRCC initiating at least one first-line therapy (1L) from 1 October 2013 to 31 March 2018 (index date = 1L start date) were identified from the US Veterans Health Administration database. Treatment patterns, clinical outcomes (time to next treatment [TNT] defined by earliest of switch to non-index therapy or re-initiation of index therapy after a more than 90-day gap, time to treatment discontinuation [TTD], overall survival [OS]), and costs were evaluated among patients treated with tyrosine kinase inhibitors (TKI), mammalian target of rapamycin inhibitors (mTOR), immune checkpoint inhibitors (ICI), and other monotherapies. Standard descriptive statistics were presented. The Kaplan-Meier method was used to evaluate clinical outcomes.

Results: Of 759 patients (median age 68.0 years), 85.0%, 8.0%, 4.3%, and 2.6% were treated with TKI, mTOR, ICI, or other therapy in 1L, respectively. Advancement rates (to second-line [2L] therapy) ranged from 10.0 (ICI) to 45.1 per 100 person years (TKI). The 12-month OS rates ranged from 47.4% (TKI) to 67.7% (mTOR). The median TNT ranged from 3.8 (mTOR) to 9.6 months (ICI), and median TTD ranged from 2.3 (mTOR) to 4.7 months (TKI). Total all-cause mean costs per patient per month ranged from $12,466 (mTOR) to $19,812 (ICI).

Conclusion: These results indicate high unmet medical needs among patients with mRCC treated with 1L monotherapies. Novel combination therapies (e.g., ICI + ICI, ICI + TKI) may improve front-line outcomes for patients with poor prognoses.
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http://dx.doi.org/10.1007/s12325-021-01657-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107174PMC
May 2021

Corrigendum to "Decreased expression of DEAD-Box Helicase 5 inhibits esophageal squamous cell carcinomas by regulating endoplasmic reticulum stress and autophagy".

Biochem Biophys Res Commun 2021 May 6;555:210-211. Epub 2021 Apr 6.

Department of Digestive Disease and Gastrointestinal Motility Research Room, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Province, China. Electronic address:

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http://dx.doi.org/10.1016/j.bbrc.2021.03.050DOI Listing
May 2021

Angiogenic Actions of Paeoniflorin on Endothelial Progenitor Cells and in Ischemic Stroke Rat Model.

Am J Chin Med 2021 7;49(4):863-881. Epub 2021 Apr 7.

Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, P. R. China.

Ischemic stroke is one of the major diseases with high morbidity, mortality, and disability rate all over the world. Chinese herb-derived active components would provide valuable candidate compounds for ischemic stroke therapy. Paeoniflorin (PF) is an active ingredient from Paeoniae Radix which possesses neurovascular effect after ischemia. However, so far, few studies are reported on the efficacy and mechanism of PF from angiogenesis aspects. Results from our studies showed that the ability for proliferation, migration, and tube formation in bone marrow-derived endothelial progenitor cells (BM-EPCs) was promoted by coculturing with PF (100 [Formula: see text]M). Furthermore, to investigate the angiogenic effects of PF , we constructed an ischemic stroke model in rats and found that PF could reduce cerebral infarction, alleviate pathological injury, and increase the secretion of pro-angiogenic factors and cerebral vascular density after intraperitonially administration of 40 mg ⋅ kg[Formula: see text] ⋅ day[Formula: see text] for 14 days. Up-regulating the expression of VEGF/VEGF-R might be the mechanism of PF's angiogenic action. In conclusion, the present study provides evidence that PF is an active monomer of Traditional Chinese Medicine which shows angiogenic actions on endothelial progenitor cells and in ischemic stroke rat model.
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http://dx.doi.org/10.1142/S0192415X21500415DOI Listing
April 2021

[Diagonistic and prognostic analysis of olfactory neuroblastoma].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2021 Mar;35(3):224-228

Department of Otolaryngology Head and Neck Surgery,Affiliated Hospital of Qingdao University,Qingdao,266003,China.

To explore the therapeutic effect and prognostic risk factors of olfactory neuroblastoma. Retrospective analysis of clinical data of 31 patients with olfactory neuroblastoma. The Kaplan-Meier method was used for survival analysis to calculate the overall survival rate and progress-free survival rate. All 31 patients underwent surgical treatment and 7 patients died, of which 4 patients died of simple intracranial invasion and 3 patients died of concurrent distant metastasis (lung and spinal cord). The average death time was 40.7 (20-57) months. Statistical analysis showed that craniocerebral invasion (=0.035), age ≥60 years (=0.042), and Ki-67≥20%(=0.018) were closely related to the poor prognosis. It is speculated that the increase of T staging and modified Kadish staging are also predictors of poor prognosis. The 1-year and 5-year overall survival rates were 100.0% and 72.5%, and the 1-year and 5-year progress-free survival rates were 87.8% and 33.6% after first surgery. Conclusion:Surgery combined with radiotherapy and chemotherapy are the main treatments for olfactory neuroblastoma, but postoperative recurrence and metastasis are common. About 22.6% of the patients died during the follow-up. Advanced age, intracranial invasion and Ki-67≥20% are closely related to poor prognosis. The tumor was completely removed by the initial surgery and restricted in nasal cavity and sinuses are the key factors for a good prognosis.
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http://dx.doi.org/10.13201/j.issn.2096-7993.2021.03.007DOI Listing
March 2021

17β-Estradiol Promotes Apoptosis of HepG2 Cells Caused by Oxidative Stress by Increasing Foxo3a Phosphorylation.

Front Pharmacol 2021 15;12:607379. Epub 2021 Mar 15.

Clinical Laboratory, First Affiliated Hospital/School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China.

Liver cancer is associated with high mortality, particularly in patients infected with the hepatitis B virus. Treatment methods remain very limited. Here, we explored the effects of 17β-estradiol (E2) on apoptosis of various liver cell lines (LO2, HepG2, and HepG2.2.15 cells). Within a certain concentration range, 17β-estradiol induced oxidative stress and apoptosis of HepG2 cells, downregulated ERα-36 expression, and increased Akt and Foxo3a phosphorylation. -Foxo3a became localized around the nucleus but did not enter the organelle. The levels of mRNAs encoding manganese superoxide dismutase (MnSOD) and catalase, to the promoters of which Foxo3a binds to trigger gene expression, were significantly reduced in HepG2 cells. 17β-estradiol had no obvious effects on LO2 or HepG2.2.15 cells. We speculate that 17β-estradiol may induce oxidative stress in HepG2 cells by increasing Foxo3a phosphorylation, thus promoting apoptosis. This may serve as a new treatment for hepatocellular carcinoma.
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http://dx.doi.org/10.3389/fphar.2021.607379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005602PMC
March 2021

Clinical Outcomes, Costs, and Healthcare Resource Utilization in Patients with Metastatic Merkel Cell Carcinoma Treated with Immune Checkpoint Inhibitors vs Chemotherapy.

Clinicoecon Outcomes Res 2021 23;13:213-226. Epub 2021 Mar 23.

Pfizer Inc., New York, NY, USA.

Purpose: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with poor prognosis. This study compared patient characteristics, comorbidities, adverse events (AEs), treatment persistence, healthcare resource utilization (HRU) and costs in patients with metastatic MCC (mMCC) treated with immune checkpoint inhibitors (ICIs) or recommended chemotherapy per 2018 National Comprehensive Cancer Network (NCCN) Guidelines.

Patients And Methods: A retrospective, observational study was conducted using data from 3/1/2015 through 12/31/2017 from the Premier Healthcare Database, a US hospital discharge database. The study included patients aged ≥12 years with International Classification of Diseases Codes for MCC and metastasis, categorized by their first treatment (index) during the study period (ICI or NCCN-recommended chemotherapy [chemotherapy]). Patient, hospital, and visit characteristics were assessed at the index date and Charlson Comorbidity Index (CCI) score and comorbidities during a 6-month look-back period. Clinical outcomes, including AEs and treatment persistence were assessed over 90 days and HRU and costs over 180 days post-index.

Results: Of 75 patients with mMCC receiving ICIs (n=37) or chemotherapy (n=38), mean age was ≈73 years, and 21.3% had a history of immune-related (IR) conditions. Overall, ICI- and chemotherapy-treated patients were similar in most baseline characteristics, IR comorbidities, and CCI score. However, more ICI patients (46%) than chemotherapy patients (26%) persisted on treatment over 90-day follow-up, odds ratio (95% CI): 2.04 (0.93, 4.47), =0.07. Over 180-day follow-up, 33% of patients had an inpatient admission with mean length of stay (LOS) ≈2 days shorter for ICI vs chemotherapy (not statistically significant). Total costs, primarily driven by pharmacy costs, were higher for ICIs than chemotherapy; other departmental costs were similar between treatment groups.

Conclusion: In a real-world setting, patients with mMCC receiving ICIs had higher treatment persistence over 90 days, shorter inpatient LOS and similar departmental cost (excluding pharmacy cost) than those receiving chemotherapy.
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http://dx.doi.org/10.2147/CEOR.S290768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001053PMC
March 2021