Publications by authors named "Dawei Chen"

418 Publications

Live Birth with or without Preimplantation Genetic Testing for Aneuploidy.

N Engl J Med 2021 11;385(22):2047-2058

From the Center for Reproductive Medicine, Cheeloo College of Medicine, Key Laboratory of Reproductive Endocrinology of the Ministry of Education, and the National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Shandong Key Laboratory of Reproductive Medicine, and Shandong Provincial Clinical Research Center for Reproductive Health, Jinan (J.Y., Y.Q., H.Z., D.W., J.L., T.N., W.Z., K.W., Y.G., Y.S., Z.-J.C.), the Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics (Y.S., Z.-J.C., Y.L., T.Z.), and the Obstetrics and Gynecology Hospital of Fudan University, Shanghai JIAI Genetics and IVF Institute, Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital of Fudan University (X.S., J.F.), Shanghai, the Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, and Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha (F.G., H.M.), the Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, National Clinical Research Center for Obstetrics and Gynecology, Key Laboratory of Assisted Reproduction, Ministry of Education, and Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing (R.L.), the Department of Reproductive Medicine, the Affiliated Obstetrics and Gynecology Hospital with Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital (X.L., J.Z.), and the Department of Reproductive Medicine, First Affiliated Hospital of Nanjing Medical University-Jiangsu Province Hospital (X.M., W.W.), Nanjing, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou (H.L., Q.M.), the Center for Reproductive Medicine of Yantai Yuhuangding Hospital, Yantai (C.H.), the Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Key Laboratory of Reproductive Dysfunction Diseases and Fertility Remodeling of Liaoning Province, Shenyang (J.T.), the Center for Reproductive Medicine, Wuhan University, Wuhan (J.Y.), the Department of Reproductive Endocrinology, Key Laboratory of Reproductive Genetics, Ministry of Education, Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou (Y.Z.), the Department of Reproductive Health and Infertility, Guangdong Women and Children Hospital, Guangzhou (F.L.), and the Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei (D.C.) - all in China; the Department of Biostatistics, Yale University School of Public Health, New Haven, CT (H.Z.); and the Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, PA (R.S.L.).

Background: Embryo selection with preimplantation genetic testing for aneuploidy (PGT-A) may improve pregnancy outcomes after initial embryo transfer. However, it remains uncertain whether PGT-A improves the cumulative live-birth rate as compared with conventional in vitro fertilization (IVF).

Methods: In this multicenter, randomized, controlled trial, we randomly assigned subfertile women with three or more good-quality blastocysts to undergo either PGT-A or conventional IVF; all the women were between 20 and 37 years of age. Three blastocysts were screened by next-generation sequencing in the PGT-A group or were chosen by morphologic criteria in the conventional-IVF group and then were successively transferred one by one. The primary outcome was the cumulative live-birth rate after up to three embryo-transfer procedures within 1 year after randomization. We hypothesized that the use of PGT-A would result in a cumulative live-birth rate that was no more than 7 percentage points higher than the rate after conventional IVF, which would constitute the noninferiority margin for conventional IVF as compared with PGT-A.

Results: A total of 1212 patients underwent randomization, and 606 were assigned to each trial group. Live births occurred in 468 women (77.2%) in the PGT-A group and in 496 (81.8%) in the conventional-IVF group (absolute difference, -4.6 percentage points; 95% confidence interval [CI], -9.2 to -0.0; P<0.001). The cumulative frequency of clinical pregnancy loss was 8.7% and 12.6%, respectively (absolute difference, -3.9 percentage points; 95% CI, -7.5 to -0.2). The incidences of obstetrical or neonatal complications and other adverse events were similar in the two groups.

Conclusions: Among women with three or more good-quality blastocysts, conventional IVF resulted in a cumulative live-birth rate that was noninferior to the rate with PGT-A. (Funded by the National Natural Science Foundation of China and others; ClinicalTrials.gov number, NCT03118141.).
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http://dx.doi.org/10.1056/NEJMoa2103613DOI Listing
November 2021

Preimplantation genetic diagnosis for a carrier with m.3697G > A mitochondrial DNA mutation.

J Assist Reprod Genet 2021 Nov 21. Epub 2021 Nov 21.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei, 230022, Anhui, China.

Objective: To explore inheritance of the m.3697G > A mitochondrial DNA (mtDNA) mutation and the effectiveness of preimplantation genetic diagnosis (PGD) for the carrier.

Methods: The study encompassed a pedigree of m.3697G > A mtDNA mutation, including one asymptomatic patient who pursued for PGD treatment. Twelve cumulus oocyte complexes (COCs) were collected in the first PGD cycle and 11 COCs in the second cycle. The efficiency of cumulus cells, polar bodies, and trophectoderm (TE) in predicting the m.3697G > A heteroplasmy of embryos was analyzed.

Results: From 23 COCs, 20 oocytes were fertilized successfully. On day 5 and 6 post-fertilization, 15 blastocysts were biopsied. The m.3697G > A mutation load of TE biopsies ranged from 15.2 to 100%. In the first cycle, a blastocyst with mutation load of 31.7% and chromosomal mosaicism was transferred, but failed to yield a clinical pregnancy. In the second cycle, a euploid blastocyst with mutation load of 53.9% was transferred, which gave rise to a clinical pregnancy. However, the pregnancy was terminated due to fetal cleft lip and palate. The mutation loads of different tissues (47.7 ± 1.8%) from the induced fetus were comparable to that of the biopsied TE and amniotic fluid cell (49.7%). The mutation load of neither cumulus cells (R = 0.02, p = 0.58) nor polar bodies (R = 0.33, p = 0.13) correlated with TE mutation load which was regarded as a gold standard.

Conclusions: The m.3697G > A mutation showed a random pattern of inheritance. PGD could be used to reduce the risk of inheritance of a high mutation load. Cumulus cells are not a suitable predictor of blastocyst mutation load.
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http://dx.doi.org/10.1007/s10815-021-02354-3DOI Listing
November 2021

Binary regulation of the tumor microenvironment by a pH-responsive reversible shielding nanoplatform for improved tumor chemo-immunotherapy.

Acta Biomater 2021 Nov 16. Epub 2021 Nov 16.

School of Pharmacy, Shenyang Pharmaceutical University. Shenyang, 110016, PR China. Electronic address:

The limited infiltration of specific T cells in an immunosuppressive microenvironment is a major challenge for cancer immunotherapy. Reversing tumor microenvironment and inducing an antitumor immune response are crucial for cancer therapy. Here, phenylboronic acid (PBA) derivative-stabilized ultrasmall platinum nanoparticles (PBA-Pt) and dextran-coated BLZ-945 nanoparticles (DNPs) were co-assembled through a pH-responsive borate ester bond to construct a versatile reversible shielding multifunctional nanoplatform ([email protected]) for the first time. [email protected] dissociated into two individual components, namely PBA-Pt and DNPs, in the tumor acid microenvironment. Both in vitro and in vivo studies revealed that [email protected] induced immunogenic cell death (ICD) (through multimechanisms involving Pt release and a multienzyme catalytic process by PBA-Pt) and relieved immunosuppressive microenvironment (depletion of tumor-associated macrophages by BLZ-945), which led to tumor-associated antigen release, maturation of dendritic cells, and infiltration of cytotoxic T cells for efficient antitumor immune response against both primary tumor and pulmonary metastatic tumor nodules. Therefore, [email protected] is a promising option for cancer chemo-immunotherapy. STATEMENT OF SIGNIFICANCE: A versatile reversible shielding multifunctional nanoplatform ([email protected]) was engineered for the first time for combinational cancer chemo-immunotherapy. Multimechanisms involving induction of immunogenic cell death by PBA-Pt and sufficient TAM depletion by DNPs could efficiently relieve tumor immunosuppressive microenvironment and activate the antitumor immune response. The synergistic effect not only increased the infiltration of specific T cells in primary tumor, but it also induced a strong immune response against pulmonary metastatic nodules. Collectively, this nanoplatform may represent a promising strategy for combinational chemo-immunotherapy for cancers.
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http://dx.doi.org/10.1016/j.actbio.2021.11.017DOI Listing
November 2021

Resolving the difference between left-sided and right-sided colorectal cancer by single-cell sequencing.

JCI Insight 2021 Nov 18. Epub 2021 Nov 18.

Department of Physiology, Shandong University, Jinan, China.

Colorectal cancers (CRCs) exhibit differences in incidence, pathogenesis, molecular pathways and outcome depending on the location of the tumor. The transcriptomes of 27,927 single human CRC cells, from three left-sided and three right-sided CRC patients were profiled by scRNA-seq. Right-sided CRC harbors a significant proportion of exhausted CD8 T cells of a highly migratory nature. One cluster of cells from left-sided CRC exhibiting states preceding exhaustion and a high ratio of "pre-exhausted" to exhausted T cells were favorable prognostic markers. Notably, we identified a novel RBP4+ NTS+ subpopulation of cancer cells that exclusively expands in left-sided CRC. Tregs from left-sided CRC showed higher levels of immunotherapy-related genes than those from right-sided CRC, indicating that left-sided CRC may have increased responsiveness to immunotherapy. Antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) induced by M2-like macrophages were more pronounced in left-sided CRC and correlated with a good prognosis in CRC.
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http://dx.doi.org/10.1172/jci.insight.152616DOI Listing
November 2021

KIF15 knockdown suppresses gallbladder cancer development.

Eur J Cell Biol 2021 Nov 5;100(7-8):151182. Epub 2021 Nov 5.

Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch, Shanghai, China. Electronic address:

Gallbladder cancer (GBC) is commonly regarded as one of the most lethal malignant tumor types with poor prognosis. Kinesin family member 15 (KIF15) is reported to be tightly related with progression of multiple cancer types which, however, has not been clarified in GBC so far. KIF15 was significantly up-regulated in clinical GBC tissues compared with that in para-carcinoma tissues and the expression level was also correlated with tumor malignancies. In addition to tissues, GBC cells also exhibited a high expression abundance of KIF15. After down-regulating KIF15 via lentiviral transfection, GBC cell proliferation and migration were both inhibited, while cell apoptosis was promoted markedly. Likewise, silencing KIF15 significantly interfered the growth of nude mouse xenografts. Our experiments in GBC cell lines also demonstrated that KIF15 overexpression accelerated cell proliferation but lessened cell apoptosis in both GBC-SD and SGC-996 cells. Further investigation of the mechanism occurring in GBC inhibition mediated by KIF15 knockdown revealed that KIF15 deficiency led to decreased activity of several signaling pathways (TNF, PI3K/AKT and MAPK), a reduction of CDK6 expression regulated by enhanced p21, and HSP60 absence. Following the treatment of shCtrl- and shKIF15-transfected cells with AKT activator, we found that anti-tumor effects resulting from KIF15 deficiency could be relieved by AKT activator in both experimental cells. Overall, for the first time, we demonstrated that KIF15 was overexpressed in GBC and displayed a close relationship between KIF15 levels and GBC clinical stages. Furthermore, low expression of KIF15 resulted in obvious anti-tumor effects.
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http://dx.doi.org/10.1016/j.ejcb.2021.151182DOI Listing
November 2021

The epidemiology of concurrent extrapulmonary tuberculosis in inpatients with extrapulmonary tuberculosis lesions in China: a large-scale observational multi-center investigation.

Int J Infect Dis 2021 Nov 12. Epub 2021 Nov 12.

Chang Chun Infectious Diseases Hospital, Changchun, Jilin, China.

Aims: A high proportion of all tuberculosis (TB) cases present with extrapulmonary tuberculosis (EPTB), including concurrent EPTB involving more than one extrapulmonary lesion site within the body. However, previous reports only characterised lesions of single-site EPTB cases. This study aimed to investigate epidemiological characteristics and association rules of concurrent EPTB cases in China.

Methods: An observational multi-centre study was carried out in China from Jan 2011 to Dec 2017 that included a total of 208,214 patients with EPTB lesions. Multivariable logistic regression analysis was used to identify associations between gender and age with concurrent EPTB. Association rules were analysed for significance using the Apriori algorithm.

Results: The most prevalent form of EPTB lesion was tuberculous pleurisy (49.8%), followed by bronchial tuberculosis (14.8%) and tuberculous meningitis (7.6%). The most predominant concurrent EPTB case type was tuberculous pleurisy concurrent with tuberculous peritonitis (1.80%). Altogether 22 association rules were identified that included 20 strong association rules, among which highest confidence rates were found for tuberculous myelitis concurrent with tuberculous meningitis and sacral TB concurrent with lumbar vertebral TB. Moreover, association rules of EPTB concurrent with other EPTB types were found to vary with gender and age. The confidence rate of tuberculous myelitis concurrent with tuberculous meningitis was higher in females (83.67%) than males and highest in patients of ages 25-34 years (87.50%).

Conclusions: Many types of concurrent EPTB were found. Thus, greater awareness of concurrent EPTB disease characteristics is needed to ensure timely clinical diagnosis and treatment of this disease.
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http://dx.doi.org/10.1016/j.ijid.2021.11.019DOI Listing
November 2021

Thymic B Cells as a New Player in the Type 1 Diabetes Response.

Front Immunol 2021 21;12:772017. Epub 2021 Oct 21.

Centre for Experimental Medicine and Biomedicine, Hull York Medical School, University of York, York, United Kingdom.

Type 1 diabetes (T1d) results from a sustained autoreactive T and B cell response towards insulin-producing β cells in the islets of Langerhans. The autoreactive nature of the condition has led to many investigations addressing the genetic or cellular changes in primary lymphoid tissues that impairs central tolerance- a key process in the deletion of autoreactive T and B cells during their development. For T cells, these studies have largely focused on medullary thymic epithelial cells (mTECs) critical for the effective negative selection of autoreactive T cells in the thymus. Recently, a new cellular player that impacts positively or negatively on the deletion of autoreactive T cells during their development has come to light, thymic B cells. Normally a small population within the thymus of mouse and man, thymic B cells expand in T1d as well as other autoimmune conditions, reside in thymic ectopic germinal centres and secrete autoantibodies that bind selective mTECs precipitating mTEC death. In this review we will discuss the ontogeny, characteristics and functionality of thymic B cells in healthy and autoimmune settings. Furthermore, we explore how approaches may help decipher the complex cellular interplay of thymic B cells with other cells within the thymic microenvironment leading to new avenues for therapeutic intervention.
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http://dx.doi.org/10.3389/fimmu.2021.772017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566354PMC
October 2021

Effectiveness and Safety of Rituximab for Refractory Myasthenia Gravis: A Systematic Review and Single-Arm Meta-Analysis.

Front Neurol 2021 13;12:736190. Epub 2021 Oct 13.

Department of Neurology, Air Force Medical Center of PLA, Beijing, China.

Myasthenia gravis (MG) is an autoimmune neuromuscular disease. Nearly 10-30% of patients with MG are refractory to conventional therapy. Rituximab (RTX), a monoclonal antibody targeting CD20, is increasingly used in autoimmune disorders. We performed a systematic review and meta-analysis to evaluate the effectiveness and safety of RTX for refractory MG. Studies published between January 1, 2000 and January 17, 2021 were searched in PubMed, EMBASE, Cochrane Library, and ClincalTrails.gov. Primary outcomes included proportion of patients achieving minimal manifestation status (MMS) or better and quantitative MG (QMG) score change from baseline. Secondary outcomes were glucocorticoids (GC) doses change from baseline and proportion of patients discontinuing oral immunosuppressants. A total of 24 studies involving 417 patients were included in the meta-analysis. An overall 64% (95% confidence interval, 49-77%) of patients achieved MMS or better. The estimated reduction of QMG score was 1.55 (95% confidence interval, 0.88-2.22). The mean reduction of GC doses was 1.46 (95% confidence interval, 1.10-1.82). The proportion of patients discontinuing oral immunosuppressants was 81% (95% confidence interval, 66-93%). Subgroup analyses showed that the proportion of patients achieving MMS or better and discontinuing oral immunosuppressants was higher in MuSK-MG group than those in AChR-MG group. Improvement was more pronounced in patients with mild to moderate MG compared to those with severe MG. Moreover, the efficacy appeared to be independent of the dose of RTX. 19.6% of patients experienced adverse events, most of which were mild to moderate. Only one patient developed progressive multifocal leukoencephalopathy. RTX can alleviate the symptom of weakness, decrease QMG score and reduce the doses of steroids and non-steroid immunosuppressive agents in refractory MG. It is well-tolerated with few severe adverse events. Randomized controlled trials are urgently needed to study the efficacy of RTX in treating refractory MG and to identify the characteristics of patients who might respond well to RTX.
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http://dx.doi.org/10.3389/fneur.2021.736190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548630PMC
October 2021

Combined treatment of non-small cell lung cancer using radiotherapy and immunotherapy: challenges and updates.

Cancer Commun (Lond) 2021 Nov 17;41(11):1086-1099. Epub 2021 Oct 17.

Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong, 250117, P. R. China.

The efficacy of immunotherapy for advanced non-small cell lung cancer (NSCLC) remains unsatisfactory, as the majority of patients either do not experience an objective response or acquire secondary resistance. As a result, several methods to enhance the systemic efficacy of immunotherapy have been investigated, including a large area of active research by combining immunotherapy with radiation therapy (RT). Given the rapidly burgeoning concept of combining immunotherapy and RT for increasing therapeutic benefit, we review the progress in this field thus far and explore further avenues for enhancing this combination. This review commences with a discussion of the only two existing randomized trials (and a pooled analysis) showing that the addition of RT to immunotherapy improves the abscopal response rate, progression-free survival, and overall survival in metastatic NSCLC patients. We then discussed factors and biomarkers that may be associated with a proportionally greater benefit to additional RT, such as low programmed cell death protein ligand 1 (PD-L1) status, tumor mutational burden (TMB), and patient's immune function. Next, the implementation of RT to overcome immunotherapy resistance is discussed, including a mechanistic discussion and methods with which these mechanisms could be exploited. Lastly, the emerging role of low-dose RT is discussed, which may help to overcome inhibitory signals in the tumor stroma that limit T-cell infiltration. Taken together, given the current state of this rapidly expanding realm, these futuristic strategies may be reflected upon to further enhance the efficacy of immunotherapy for a wider group of patients.
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http://dx.doi.org/10.1002/cac2.12226DOI Listing
November 2021

Synthesis and Anti-Influenza Virus Effects of Novel Substituted Polycyclic Pyridone Derivatives Modified from Baloxavir.

J Med Chem 2021 Oct 22;64(19):14465-14476. Epub 2021 Sep 22.

Joint Key State Laboratory of Tumor Chemogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, P. R. China.

In this work, a series of novel substituted polycyclic pyridone derivatives were designed and synthesized as potent anti-influenza agents. The cytopathic effect (CPE) assay and cytotoxicity assay indicated that all of the compounds possessed potent anti-influenza virus activity and relatively low cytotoxicity; some of them inhibited the replication of influenza A virus (IAV) at picomolar concentrations. Further studies revealed that, at a concentration of 3 nM, three compounds (, , and ) could significantly reduce the RNA amounts and M2 protein expression of IAV and inhibit the activity of RNA-dependent RNA polymerase (RdRp). Among them, ()-12-(5-dibenzo[,][7]annulen-5-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1-[1,4]oxazino[3,4-]pyrido[2,1-][1,2,4]triazine-6,8-dione () was found to be a promising anti-influenza drug candidate with good human liver microsomal stability, as well as with better selectivity index and oral bioavailability than Baloxavir.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00979DOI Listing
October 2021

Downregulation of miR-23b by transcription factor c-Myc alleviates ischemic brain injury by upregulating Nrf2.

Int J Biol Sci 2021 26;17(13):3659-3671. Epub 2021 Aug 26.

Jilin University, Changchun 130000, P. R. China.

Ischemic brain injury (IBI) is a common acute cerebral vessel disease that occurs secondary to blockage in arteries, mainly characterized by insufficient blood supply to the brain. The transcription factor c-Myc in IBI continues to be implicated in numerous studies. This study was conducted with emphasis placed on the underlying mechanism of c-Myc in IBI. Clinical samples were collected from IBI patients. Middle cerebral artery occlusion (MCAO) was induced in mice by inserting a suture from the external carotid artery to the anterior cerebral artery through the internal carotid artery to mechanically block the blood supply at the origin of the middle cerebral artery, and cortical neurons from mice were exposed to oxygen glucose deprivation (OGD) conditions for IBI model construction. RT-qPCR was performed to determine microRNA-23b (miR-23b) expression. TUNEL staining and Western blot analysis was conducted to detect apoptosis. The regulatory relationship was analyzed by dual-luciferase reporter gene assay. After loss- and gain-of-function assays, triphenyltetrazolium chloride staining was carried out to detect the area of cerebral infarction, after which the spatial memory in mice was evaluated with Morris water maze test. As per our findings, miR-23b was upregulated in the serum of IBI patients and OGD-treated murine primary neurons. Silencing of miR-23b resulted in reduced OGD-induced neuronal apoptosis. miR-23b inversely targeted nuclear factor erythroid 2-related factor 2 (Nrf2) and c-Myc negatively regulated miR-23b expression. Overexpression of c-Myc and inhibition of miR-23b led to reduced neurological scores of infarction area, neuronal apoptosis, shortened platform arrival time and significantly increased the time spent on the platform quadrant and the times of crossing the platform . Collectively, downregulated miR-23b by c-Myc might alleviate IBI by upregulating Nrf2.
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http://dx.doi.org/10.7150/ijbs.61399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416714PMC
August 2021

Variation of bitter components of the asparagus juices during lactic acid bacteria fermentation.

Biosci Biotechnol Biochem 2021 Oct;85(11):2300-2310

Key Lab of Dairy Biotechnology and Safety Control, College of Food Science and Engineering, Yangzhou University, Jiangsu, China.

To investigate the bitterness status of asparagus juices during lactic acid fermentation, Limosilactobacillus fermentum Xd, Lacticaseibacillus paracasei Yd, Lactiplantibacillus plantarum 5-7-3, and their various combinations were used for single and mixed fermentation of asparagus juices. The fermentation characteristics and variation of the main bitter substances were studied. For the single and cofermented samples, the viable counts, pH value, and acidity were ranged from 8.33-8.65 lg CFU/mL, 3.58-3.86, and 6.29-6.52 g/kg, respectively. By sensory evaluation, the bitterness of every fermented sample was continuously reduced by at least 77% during fermentation, and the corresponding content of total saponins, flavonoids, and 9 bitter amino acids showed varying degrees of declination. These results suggested that it was feasible to develop novel low-bitter asparagus juices fermented by the lactic acid bacteria used in this study.
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http://dx.doi.org/10.1093/bbb/zbab158DOI Listing
October 2021

Pulsed Radiation Therapy to Improve Systemic Control of Metastatic Cancer.

Front Oncol 2021 23;11:737425. Epub 2021 Aug 23.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Radiation therapy (RT) is emerging as an interventional modality in the cancer-immunity cycle, augmenting the activation of an adaptive immune response against tumors. RT, particularly in combination with immunotherapy, can enhance immune memory effects and shape the tumor-directed T-cell populations. However, a single cycle of RT delivered to a limited number of polymetastatic lesions is rarely sufficient to achieve systemic control. We hypothesize that several rounds of RT, akin to several rounds of immunotherapeutic drugs, is likely to provide greater clinical benefit to patients with metastatic disease. We propose that the repeated exposure to tumor antigens released by "pulsed-RT" (i.e., treating 2-4 tumor lesions with 3 irradiation cycles given one month apart) may amplify the adaptive immune response by expanding the tumor-specific T-cell receptor repertoire, the production of high-affinity tumor antibodies, and the generation of memory lymphocytes and thereby improve immune control of systemic disease.
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http://dx.doi.org/10.3389/fonc.2021.737425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419338PMC
August 2021

Role of mitochondrial dysfunction and PINK1/Parkin-mediated mitophagy in Cd-induced hepatic lipid accumulation in chicken embryos.

Life Sci 2021 Nov 1;284:119906. Epub 2021 Sep 1.

Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, PR China. Electronic address:

The present study was performed to investigate the effects of Cd exposure on lipid metabolism and mitochondrial dysfunction and to explore the role of mitophagy in Cd-induced dysregulation of lipid metabolism in chicken embryo liver tissues and hepatocytes. To this end, seven-day-old chicken embryos were exposed to different concentrations of Cd for 7 days, and primary chicken embryo hepatocytes were treated with Cd at four different concentrations for 6 h. Furthermore, the mitophagy inhibitor cyclosporine A (CsA) was used to investigate the role of mitophagy in Cd-induced disruption of lipid metabolism. Lipid accumulation, the expression levels of genes involved in lipid metabolism, mitochondrial dysfunction, and mitophagy were measured. The results demonstrated that Cd exposure increases hepatic triglyceride (TG) accumulation and the expression levels of lipogenic genes while decreasing those of lipolytic genes. Furthermore, Cd exposure was observed to alter mitochondrial morphology in terms of reduced size, excessive mitochondrial damage, and the formation of mitophagosomes. The co-localization of lysosome-associated membrane glycoprotein 2 and LC3 puncta was significantly increased in primary chicken embryo hepatocytes after Cd exposure. Moreover, Cd exposure increased LC3, PINK1, and Parkin protein expression levels. CsA effectively alleviated Cd-induced mitochondrial dysfunction, blocked mitochondrial membrane potential collapse, and suppressed PINK1/Parkin-mediated mitophagy. Furthermore, CsA treatment reversed the Cd-induced TG accumulation in liver tissues but further increased it in hepatocytes. Taken together, our findings demonstrate (for the first time) the importance of mitochondrial dysfunction and mitophagy via the PINK1/Parkin pathway in Cd-induced disruption of lipid metabolism.
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http://dx.doi.org/10.1016/j.lfs.2021.119906DOI Listing
November 2021

Construction of Hierarchical-Targeting pH-Sensitive Liposomes to Reverse Chemotherapeutic Resistance of Cancer Stem-like Cells.

Pharmaceutics 2021 Aug 5;13(8). Epub 2021 Aug 5.

School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.

Cancer stem-like cells (CSLCs) have been considered to be one of the main problems in tumor treatment owing to high tumorigenicity and chemotherapy resistance. In this study, we synthesized a novel mitochondria-target derivate, triphentlphosphonium-resveratrol (TPP-Res), and simultaneously encapsulated it with doxorubicin (Dox) in pH-sensitive liposomes (PSL (Dox/TPP-Res)), to reverse chemotherapeutic resistance of CSLCs. PSL (Dox/TPP-Res) was approximately 165 nm in size with high encapsulation efficiency for both Dox and TPP-Res. Cytotoxicity assay showed that the optimal synergistic effect was the drug ratio of 1:1 for TPP-Res and Dox. Cellular uptake and intracellular trafficking assay indicated that PSL (Dox/TPP-Res) could release drugs in acidic endosomes, followed by mitochondrial targeting of TPP-Res and nucleus transports for Dox. The mechanisms for reversing the resistance in CSLCs were mainly attributed to a synergistic effect for reduction of mitochondrial membrane potential, activation of caspase cascade reaction, reduction of ATP level and suppression of the Wnt/β-catenin pathway. Further, in vivo assay results demonstrated that the constructed liposomes could efficiently accumulate in the tumor region and possess excellent antineoplastic activity in an orthotopic xenograft tumor model with no evident systemic toxicity. The above experimental results determined that PSL (Dox/TPP-Res) provides a new method for the treatment of heterogenecity tumors.
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http://dx.doi.org/10.3390/pharmaceutics13081205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399523PMC
August 2021

Laser/GSH-Activatable Oxaliplatin/Phthalocyanine-Based Coordination Polymer Nanoparticles Combining Chemophotodynamic Therapy to Improve Cancer Immunotherapy.

ACS Appl Mater Interfaces 2021 Aug 16;13(33):39934-39948. Epub 2021 Aug 16.

School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, P.R. China.

There are two severe obstacles in cancer immunotherapy. The first is that the low response rate challenges the immune response owing to the immunosuppressive tumor microenvironment (ITM) and poor immunogenicity of the tumor. The second obstacle is that the dense and intricate pathophysiology barrier seriously restricts deep drug delivery in solid tumors. A laser/glutathione (GSH)-activatable nanosystem with tumor penetration for achieving highly efficient immunotherapy is reported. The core of the nanosystem was synthesized by coordinating zinc ions with GSH-activatable oxaliplatin (OXA) prodrugs and carboxylated phthalocyanine. Such an OXA/phthalocyanine-based coordination polymer nanoparticle (OPCPN) was wrapped by a phospholipid bilayer and NTKPEG. NTKPEG is a PEGylated indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor prodrug containing a thioketal (TK) linker, which was modified on the OPCPN ([email protected]). Upon the laser irradiation tumor site, ROS production of the [email protected] triggers cleavage of NTKPEG by degradation of TK for promoted tumor penetration and uptake. OXA, phthalocyanine, and IDO1 inhibitor were released by the intracellular high-level GSH. OXA inhibits cell growth and is combined with photodynamic therapy (PDT) to induce immunogenic cell death (ICD). The IDO1 inhibitor reversed the ITM by suppressing IDO1-mediated Trp degradation and exhaustion of cytotoxic T cells. Laser/GSH-activatable drug delivery was more conducive to enhancing ICD and reversing ITM in deep tumors. Chemo-PDT with [email protected] significantly regressed tumor growth and reduced metastasis by improved cancer immunotherapy.
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http://dx.doi.org/10.1021/acsami.1c11327DOI Listing
August 2021

M6A methylation of DEGS2, a key ceramide-synthesizing enzyme, is involved in colorectal cancer progression through ceramide synthesis.

Oncogene 2021 Oct 6;40(40):5913-5924. Epub 2021 Aug 6.

Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

N6-methyladenosine (m6A) is the most prevalent RNA epigenetic regulator in cancer. However, the understanding of m6A modification on lipid metabolism regulation in colorectal cancer (CRC) is very limited. Here, we observed that human CRCs exhibited increased m6A mRNA methylation mediated by dysregulation of m6A erasers and readers. By performing methylated RNA-immunoprecipitation sequencing (MeRIP-seq) and transcriptomic sequencing (RNA-seq), we identified DEGS2 as a downstream target of m6A dysregulation. Overexpression or knockdown of DEGS2 confirmed the role of DEGS2 in proliferation, invasion and metastasis of CRC both in vitro and in vivo. Mechanistic studies identified the specific m6A modification site within DEGS2 mRNA, and mutation of this target site was found to drastically enhance the proliferative and invasive ability of CRC cells in vitro and promote tumorigenicity in vivo. Lipidome analysis showed that lipid metabolism was dysregulated in CRC. Moreover, ceramide synthesis was suppressed due to DEGS2 upregulation mediated by m6A modification in CRC tissues. Our findings highlight that the function of DEGS2 m6A methylation in CRC and extend the understanding of the importance of RNA epigenetics in cancer biology.
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http://dx.doi.org/10.1038/s41388-021-01987-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497269PMC
October 2021

THADA drives Golgi residency and upregulation of PD-L1 in cancer cells and provides promising target for immunotherapy.

J Immunother Cancer 2021 08;9(8)

Zhongshan-Xuhui Hospital, Shanghai Xuhui Central Hospital, Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Fudan University, Shanghai, China

Background: The abnormal upregulation of programmed death-ligand 1 (PD-L1) in cancer cells inhibits T cell-mediated cytotoxicity, but the molecular mechanisms that drive and maintain PD-L1 expression are still incompletely understood.

Methods: Combined analyses of genomes and proteomics were applied to find potential regulators of PD-L1. In vitro experiments were performed to investigate the regulatory mechanism of PD-L1 by thyroid adenoma associated gene (THADA) using human colorectal cancer (CRC) cells. The prevalence of THADA was analyzed using CRC tissue microarrays by immunohistochemistry. T cell killing assay, programmed cell death 1 binding assay and MC38 transplanted tumor models in C57BL/6 mice were developed to investigate the antitumor effect of THADA.

Results: THADA is critically required for the Golgi residency of PD-L1, and this non-redundant, coat protein complex II (COPII)-associated mechanism maintains PD-L1 expression in tumor cells. THADA mediated the interaction between PD-L1 as a cargo protein with SEC24A, a module on the COPII trafficking vesicle. Silencing THADA caused absence and endoplasmic reticulum (ER) retention of PD-L1 but not major histocompatibility complex-I, inducing PD-L1 clearance through ER-associated degradation. Targeting THADA substantially enhanced T cell-mediated cytotoxicity, and increased CD8+ T cells infiltration in mouse tumor tissues. Analysis on clinical tissue samples supported a potential role of THADA in upregulating PD-L1 expression in cancer.

Conclusions: Our data reveal a crucial cellular process for PD-L1 maturation and maintenance in tumor cells, and highlight THADA as a promising target for overcoming PD-L1-dependent immune evasion.
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http://dx.doi.org/10.1136/jitc-2021-002443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330570PMC
August 2021

PPM1G promotes the progression of hepatocellular carcinoma via phosphorylation regulation of alternative splicing protein SRSF3.

Cell Death Dis 2021 07 21;12(8):722. Epub 2021 Jul 21.

Department of Hepatopancreatobiliary Surgery, Jiangyin People's Hospital, School of Medicine, Southeast University, No. 163, Shoushan Road, Jiangyin, 214400, Jiangsu Province, China.

Emerging evidence has demonstrated that alternative splicing has a vital role in regulating protein function, but how alternative splicing factors can be regulated remains unclear. We showed that the PPM1G, a protein phosphatase, regulated the phosphorylation of SRSF3 in hepatocellular carcinoma (HCC) and contributed to the proliferation, invasion, and metastasis of HCC. PPM1G was highly expressed in HCC tissues compared to adjacent normal tissues, and higher levels of PPM1G were observed in adverse staged HCCs. The higher levels of PPM1G were highly correlated with poor prognosis, which was further validated in the TCGA cohort. The knockdown of PPM1G inhibited the cell growth and invasion of HCC cell lines. Further studies showed that the knockdown of PPM1G inhibited tumor growth in vivo. The mechanistic analysis showed that the PPM1G interacted with proteins related to alternative splicing, including SRSF3. Overexpression of PPM1G promoted the dephosphorylation of SRSF3 and changed the alternative splicing patterns of genes related to the cell cycle, the transcriptional regulation in HCC cells. In addition, we also demonstrated that the promoter of PPM1G was activated by multiple transcription factors and co-activators, including MYC/MAX and EP300, MED1, and ELF1. Our study highlighted the essential role of PPM1G in HCC and shed new light on unveiling the regulation of alternative splicing in malignant transformation.
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http://dx.doi.org/10.1038/s41419-021-04013-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295330PMC
July 2021

Correlation between exopolysaccharide biosynthesis and gastrointestinal tolerance of Lactiplantibacillus plantarum.

J Appl Microbiol 2021 Jul 14. Epub 2021 Jul 14.

College of Food Science and Technology, Yangzhou University, Yangzhou, China.

Aim: This study aimed to investigate the correlation between the level of exopolysaccharide (EPS) biosynthesis and gastrointestinal tolerance of 12 Lactiplantibacillus plantarum strains.

Methods And Results: In this study, the EPS production and survival rate of 12 strains of L. plantarum under gastrointestinal stress were determined. Results showed that the EPS biosynthesis level of L. plantarum in semi-defined medium ranged from 9.84 to 26.05 mg/L. The survival rates of all strains in simulated gastric juice at pH 3.0 ranged from 43.52% to 112.73%. Among them, eight strains were higher than 90%, while only one strain was lower than 50%. The survival rates of all strains in simulated intestinal juice ranged from 50.36% to 125.39%, among which eight strains were higher than 80%. The survival rates of all strains under 0.1% bile salt stress ranged from 3.39% to 109.34%, among which four strains were higher than 80% and three strains were lower than 60%. Besides, the survival rates of all strains under 0.5% bile salt stress ranged from 0.42% to 95.34%. The results indicated that the 12 L. plantarum strains had good tolerance to simulated gastric juice at pH 3.0, simulated intestinal juice and 0.1% bile salt. Notably, it was observed that the survival rates of L. plantarum strains under simulated gastric juice at pH 3.0 and simulated intestinal juice were significantly positively correlated with EPS biosynthesis (p < 0.01).

Conclusion: The yield of EPS of L. plantarum was related to simulated gastric juice and simulated intestinal juice environment.

Significance And Impact Of Study: It was speculated that the production of EPS may be one of the strategies for L. plantarum to adapt to the part of gastrointestinal environment. In the future, we could analyse the protection mechanism of EPS from the gene level.
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http://dx.doi.org/10.1111/jam.15213DOI Listing
July 2021

The m6A Reader IGF2BP2 Regulates Macrophage Phenotypic Activation and Inflammatory Diseases by Stabilizing TSC1 and PPAR.

Adv Sci (Weinh) 2021 07 3;8(13):2100209. Epub 2021 May 3.

Department of Physiology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University Jinan Shandong 250012 China.

Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment. Currently, little is known about how the intrinsic regulators modulate proinflammatory (M1) versus prohealing (M2) macrophages activation. Here, it is observed that insulin-like growth factor 2 messenger RNA (mRNA)-binding protein 2 (IGF2BP2)-deleted macrophages exhibit enhanced M1 phenotype and promote dextran sulfate sodium induced colitis development. However, the IGF2BP2 macrophages are refractory to interleukin-4 (IL-4) induced activation and alleviate cockroach extract induced pulmonary allergic inflammation. Molecular studies indicate that IGF2BP2 switches M1 macrophages to M2 activation by targeting tuberous sclerosis 1 via an N6-methyladenosine (mA)-dependent manner. Additionally, it is also shown a signal transducer and activators of transcription 6 (STAT6)-high mobility group AT-hook 2-IGF2BP2-peroxisome proliferator activated receptor- axis involves in M2 macrophages differentiation. These findings highlight a key role of IGF2BP2 in regulation of macrophages activation and imply a potential therapeutic target of macrophages in the inflammatory diseases.
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http://dx.doi.org/10.1002/advs.202100209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261491PMC
July 2021

Radiation Therapy Enhanced by NBTXR3 Nanoparticles Overcomes Anti-PD1 Resistance and Evokes Abscopal Effects.

Int J Radiat Oncol Biol Phys 2021 11 6;111(3):647-657. Epub 2021 Jul 6.

Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas. Electronic address:

Purpose: Radiation combined with PD1 blockade offers significant treatment benefits in several tumor types; however, anti-PD1 resistance precludes such benefits in many cases. Here we attempted to overcome anti-PD1 resistance by combining localized radiation with a radioenhancing nanoparticle (NBTXR3) and systemic anti-PD1 treatment to achieve abscopal effects in an anti-PD1-resistant mouse model of lung cancer.

Methods And Materials: Female 129Sv/Ev mice were inoculated with 344SQ anti-PD1-resistant (344SQR) or anti-PD1-sensitive (344SQP) metastatic lung cancer cells in the right leg on day 0 ("primary" tumor) and the left leg on day 4 ("secondary" tumor). Primary tumors were injected intratumorally with NBTXR3 on day 7 and were irradiated with 12 Gy on days 8, 9, and 10. Mice were given 6 intraperitoneal injections of anti-PD1. T cell receptor repertoire was analyzed in tumor samples with RNA sequencing, infiltration of CD8 T cells with immunohistochemical staining, and activities of various immune pathways with NanoString analysis.

Results: The triple combination of NBTXR3 with localized radiation and systemic anti-PD1 significantly delayed the growth of both irradiated and unirradiated tumors in both 344SQP and 344SQR tumor models. NBTXR3 remodeled the immune microenvironment of unirradiated tumors by triggering the activation of various immune pathways, increasing the number of CD8 T cells, and modifying the T cell receptor repertoire in the 344SQR tumor model.

Conclusions: The ability of NBTXR3 to evoke significant abscopal effects in both anti-PD1-sensitive and anti-PD1-resistant lung cancers could open the possibility of its use for treating patients with metastatic lung cancer regardless of sensitivity (or resistance) to immunotherapies.
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http://dx.doi.org/10.1016/j.ijrobp.2021.06.041DOI Listing
November 2021

High-dose irradiation in combination with non-ablative low-dose radiation to treat metastatic disease after progression on immunotherapy: Results of a phase II trial.

Radiother Oncol 2021 09 5;162:60-67. Epub 2021 Jul 5.

Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA.

Aim: To report early findings from a phase II trial of high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer.

Methods: Eligible patients had metastatic disease that progressed on immunotherapy within 6 months. Patients were given either HD-RT (20-70 Gy total; 3-12.5 Gy/f), or HD-RT + LD-RT (0.5-2 Gy/f up to 1-10 Gy total) to separate lesions, with continued immunotherapy. Radiographic response was assessed per RECIST 1.1 and Immune-Related Response Criteria (irRC). Primary endpoints: (1) 4-month disease control (DCR, complete/partial response [CR/PR] or stable disease [SD]) or an overall response (ORR, CR/PR) at any point in ≥10% of patients, per RECIST 1.1; (2) dose-limiting toxicity within 3 months not exceeding 30%. Secondary endpoint was lesion-specific response.

Results: Seventy-four patients (NSCLC, n = 38; melanoma n = 21) were analyzed (39 HD-RT and 35 HD-RT + LD-RT). The median follow-up time was 13.6 months. The primary endpoint was met for 72 evaluable patients, with a 4-month DCR of 42% (47% [16/34] vs. 37% [14/38] in HD-RT + LD-RT vs. HD-RT, P = 0.38), and 19% ORR at any time (26% [9/34] vs. 13% [5/38] in HD-RT + LD-RT vs. HD-RT, P = 0.27). Three patients had toxicity ≥grade 3. LD-RT lesion response (53%) was improved compared to nonirradiated lesions in HD-RT + LD-RT (23%, P = 0.002) and HD-RT (11%, P < 0.001). T- and NK cell infiltration was enhanced in lesions treated with LD-RT.

Conclusions: HD-RT plus LD-RT safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment.
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http://dx.doi.org/10.1016/j.radonc.2021.06.037DOI Listing
September 2021

Discovery of the PARP (poly ADP-ribose polymerase) inhibitor 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide for the treatment of cancer.

Bioorg Chem 2021 09 26;114:105026. Epub 2021 May 26.

Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China; Joint Key State Laboratory of Tumor Chemogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, PR China. Electronic address:

In this work, two series of cyclic amine-containing benzimidazole carboxamide derivatives were designed and synthesized as potent anticancer agents. PARP1/2 inhibitory activity assays indicated that most of the compounds showed significant activity. The in vitro antiproliferative activity of these compounds was investigated against four human cancer cell lines (MDA-MB-436, MDA-MB-231, MCF-7 and CAPAN-1), and several compounds exhibited strong cytotoxicity to tumor cells. Among them, 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide (17d) was found to be effective PARP1/2 inhibitors (IC = 4.30 and 1.58 nM, respectively). In addition, 17d possessed obvious selective antineoplastic activity and noteworthy microsomal metabolic stability. What's more, further studies revealed that 17d was endowed with an excellent ADME profile. These combined results indicated that 17d could be a promising candidate for the treatment of cancer.
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http://dx.doi.org/10.1016/j.bioorg.2021.105026DOI Listing
September 2021

Vehicle routing problem of contactless joint distribution service during COVID-19 pandemic.

Transp Res Interdiscip Perspect 2020 Nov 1;8:100233. Epub 2020 Oct 1.

School of Traffic and Transportation Engineering, Central South University, Changsha 410075, China.

In order to prevent the further spread of the COVID-19 virus, enclosed management of gated communities is necessary. The implementation of contactless food distribution for closed gated communities is an urgent issue. This paper proposes a contactless joint distribution service to avoid contact between couriers. Then a multi-vehicle multi-trip routing problem for contactless joint distribution service is proposed, and a mathematical programming model for this problem is established. The goal of the model is to increase residents' satisfaction with food distribution services. To solve this model, a PEABCTS algorithm is developed, which is the enhanced artificial bee colony algorithm embedded with a tabu search operator, using a progressive method to form a solution of multi-vehicle distribution routings. Finally, a variety of numerical simulations were carried out for statistical research. Compared with the two distribution services of supportive supply and on-demand supply, the proposed contactless joint distribution service can not only improve residents' satisfaction with the distribution service but also reduce the contact frequency between couriers. In addition, compared with various algorithms, it is found that the PEABCTS algorithm has better performance.
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http://dx.doi.org/10.1016/j.trip.2020.100233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528749PMC
November 2020

Stimuli-Responsive and Highly Penetrable Nanoparticles as a Multifunctional Nanoplatform for Boosting Nonsmall Cell Lung Cancer siRNA Therapy.

ACS Biomater Sci Eng 2021 07 17;7(7):3141-3155. Epub 2021 Jun 17.

School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, Liaoning Province 110016, P. R. China.

In cancer therapy, it is acknowledged that large-size nanoparticles stay in the circulation system for a long time, but their permeability to tumor tissues is poor. To address the conflicting need for prolonging circulation time and favorable tumor tissue penetration ability, a charge conversional multifunctional nanoplatform was strategically designed to improve the efficacy of small interfering RNA (siRNA) therapy against nonsmall cell lung cancer (NSCLC). The development of nanodrug delivery systems (NDDSs) was constructed by loading siRNA on polyamidoamine (PAMAM) dendrimers to build small-sized PAM/siRNA electrostatic interaction and then capped with a pH-triggered copolymer poly(ethylene glycol) methyl ether (mPEG)-poly-l-lysine (PLL)-2,3-dimethylmaleic anhydride (DMA) (shorted as PLM) under physiological conditions. While in the tumor microenvironment, the acidic reaction of the PLM copolymer changes from negative charge to positive charge due to the cleavable amide bond between mPEG-PLL and DMA, leading to large-size nanoparticles (NPs) with a negative charge that turns into a positive charge and small NPs with a high tumor-penetrating ability. All of the and studies validated that PLM/PAM/siRNA NPs possess desirable features including excellent biocompatibility, a prolonged circulation time, significant pH sensitivity, high tumor tissue penetration ability, and sufficient endo-/lysosomal escape. Taken together, all results suggest tremendous potential of the gene therapy based on the stimuli-sensitive PLM/PAM/siRNA NPs, providing a profound application prospective treatment strategy in cancer gene therapy.
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http://dx.doi.org/10.1021/acsbiomaterials.1c00582DOI Listing
July 2021

Considerations for Clinical Trials Testing Radiotherapy Combined With Immunotherapy for Metastatic Disease.

Semin Radiat Oncol 2021 Jul;31(3):217-226

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Metastatic cancer is inherently heterogeneous, and patients with metastatic disease can experience vastly different oncologic outcomes depending on several patient- and disease-specific characteristics. Designing trials for such a diverse population is challenging yet necessary to improve treatment outcomes for metastatic-previously thought to be incurable-disease. Here we review core considerations for designing and conducting clinical trials involving radiation therapy and immunotherapy for patients with metastatic cancer.
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http://dx.doi.org/10.1016/j.semradonc.2021.02.005DOI Listing
July 2021

An insight into the exploration of proliferation of antibiotic resistance genes in high-fat diet induced obesity mice.

Genomics 2021 Jul 2;113(4):2503-2512. Epub 2021 Jun 2.

Laboratory of Nutrition and Development,Beijing Pediatric Research Institute,Key Laboratory of Major Diseases in Children,Ministry of Education,Beijing Children's Hospital,Capital Medical University,National Center for Children's Health, Beijing 100045, PR China. Electronic address:

Using mice as an animal model, we first demonstrated the significant proliferation of ARGs and the change of mobile genetic elements (MGEs) in high-fat diet induced obesity (DIO) mice, which the ermB and tnpA-03 genes mostly increased, illuminating that DIO could enrich the abundance of ARGs. Additionally, Lactobacillus sharply increased in the DIO mice and might contribute to the proliferation of ARGs and dramatical change of MGEs in the HFD groups. Finally, procrustes analysis showed the explanatory variables of the MGEs, the metabolites, and the microbial communities for the ARGs accounted for 94.3%, 53.4%, and 68.1%, respectively, and implying that MGEs might be the most direct factor affecting ARGs, and microbiota could be the main driver of the proliferation of ARGs in the DIO mice.
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http://dx.doi.org/10.1016/j.ygeno.2021.05.041DOI Listing
July 2021

A new approach for investigating the relative contribution of basal glucose and postprandial glucose to HbA1.

Nutr Diabetes 2021 06 4;11(1):14. Epub 2021 Jun 4.

Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China.

To develop an accurate method for evaluating the relative contributions of basal glucose (BG) and postprandial glucose (PPG) to glycated haemoglobin (HbA1c) in subjects with hyperglycaemia using a Continuous Glucose Monitoring System (CGMS®). The subjects were divided into the normal glucose tolerance (NGT), impaired glucose tolerance (IGT), newly-diagnosed type 2 diabetes (NDDM), and drug-treated type 2 diabetes (T2DM) groups. We evaluated the relative contributions of BG and PPG to HbA1c in patients with hyperglycaemia according to three different baseline values. Subjects (n = 490) were grouped as follows: 92 NGT, 36 IGT, 131 NDDM, and 231 T2DM. The relative contributions of PPG to HbA1c were calculated using baseline values of 6.1 mmol/L, 5.6 mmol/L, and the 24-h glucose curve of the NGT group. The relative contribution of PPG to HbA1c decreased progressively from the IGT group to the T2DM group. Compared with the 24-h glucose curve as the baseline, the relative contribution of PPG was overestimated in 9.04% and 1.76% of the subjects when 6.1 mmol/L and 5.6 mmol/L were used as baselines, respectively (P < 0.01), in T2DM patients. The 24-h glucose curve of NGT is more suitable for studying the relative contributions of BG and PPG to HbA1c and it is more precise, as it considers physiological fluctuations in NGT after meals. However, 5.6 mmol/L can be used when the 24-h glucose curve for NGT is unavailable; using 6.1 mmol/L as a baseline value may overestimate the contribution to the HbA1c. There is no unified standard for assessing the contributions of basal glucose (BG) and postprandial glucose (PPG) to HbA1c. The 24-h glucose curve of NGT is more suitable for studying the relative contributions of BG and PPG to HbA1c, as it considers physiological fluctuations in NGT after meals. However, 5.6 mmol/L can be used when the 24-h glucose curve for NGT is unavailable; using 6.1 mmol/L as a baseline value may overestimate the contribution to the HbA1c.
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http://dx.doi.org/10.1038/s41387-021-00156-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178390PMC
June 2021

Charge-switchable nanoparticles enhance Cancer immunotherapy based on mitochondrial dynamic regulation and immunogenic cell death induction.

J Control Release 2021 07 29;335:320-332. Epub 2021 May 29.

Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, PR China. Electronic address:

Cancer immunotherapy has emerged as a promising option for various malignant tumors therapy. Unfortunately, the existence of an immunosuppressive tumor microenvironment (ITM) and the absence of an effective delivery strategy limit its further application. To reverse the ITM and exploit a favorable delivery system for cancer immunotherapy, twin-like charge-switchable nanoparticles (shMFN1-NPs + DOX-NPs, termed as MIX-NPs) were developed to selectively target tumor-associated macrophages (TAMs) and cancer cells, respectively. The shMFN1-NPs (150 nm) and DOX-NPs (160 nm) both had uniform spherical-shaped structures and showed favorable tumor tissue accumulation. Based on the pH-responsive core-shell separation, the nanoparticles obtained an excellent balance between the circulation time and cellular uptake. Mitochondrial dynamics are involved in macrophage polarization by regulating a novel signaling network, involving the modulation from fusion (M2-TAMs) to mitochondrial fission (M1-TAMs). M2-TAMs targeting nanoparticles shMFN1-NPs were fabricated to deliver shMFN1 for repolarization of TAMs from the M2 to M1 phenotype by inhibiting mitochondrial fusion. Moreover, DOX-NPs effectively triggered the immunogenic cell death (ICD) of cancer cells, and the succeeding maturation of dendritic cells (DCs) promoted the infiltration and activation of CD8 T cells. MIX-NPs displayed the strongest antitumor efficacy (TIR = 83%) in the subcutaneous 4T1 tumor model. MIX-NPs suppressed the myeloid-derived suppressor cells (MDSCs) and regulatory T lymphocytes (Tregs) to further remodel the ITM. Taken together, our developed drug delivery strategy reversed the ITM and activated the antitumor immune response, providing a profound prospective treatment strategy in cancer immunotherapy.
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http://dx.doi.org/10.1016/j.jconrel.2021.05.036DOI Listing
July 2021
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