Publications by authors named "Junjun Zhao"

32 Publications

Effect of the Hypoxia Inducible Factor on Sorafenib Resistance of Hepatocellular Carcinoma.

Front Oncol 2021 7;11:641522. Epub 2021 Jul 7.

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China.

Sorafenib a multi-target tyrosine kinase inhibitor, is the first-line drug for treating advanced hepatocellular carcinoma (HCC). Mechanistically, it suppresses tumor angiogenesis, cell proliferation and promotes apoptosis. Although sorafenib effectively prolongs median survival rates of patients with advanced HCC, its efficacy is limited by drug resistance in some patients. In HCC, this resistance is attributed to multiple complex mechanisms. Previous clinical data has shown that HIFs expression is a predictor of poor prognosis, with further evidence demonstrating that a combination of sorafenib and HIFs-targeted therapy or HIFs inhibitors can overcome HCC sorafenib resistance. Here, we describe the molecular mechanism underlying sorafenib resistance in HCC patients, and highlight the impact of hypoxia microenvironment on sorafenib resistance.
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http://dx.doi.org/10.3389/fonc.2021.641522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292964PMC
July 2021

Erratum: Long noncoding RNA LINC01123 promotes the proliferation and invasion of hepatocellular carcinoma cells by modulating the miR-34a-5p/TUFT1 axis: Erratum.

Int J Biol Sci 2021 8;17(9):2336-2337. Epub 2021 Jun 8.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.

[This corrects the article DOI: 10.7150/ijbs.45457.].
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http://dx.doi.org/10.7150/ijbs.61069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241735PMC
June 2021

Deferoxamine enhances the migration of dental pulp cells via hypoxia-inducible factor 1α.

Am J Transl Res 2021 15;13(5):4780-4787. Epub 2021 May 15.

Department of General Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology Shanghai, China.

In previous studies, we found that deferoxamine (DFO) improved the migration of dental pulp cells (DPCs). The present study aimed to determine whether the effects of DFO on the migration of DPCs were regulated via hypoxia-inducible factor 1α (HIF-1α). Recombinant adenovirus vectors carrying short hairpin RNA (shRNA) targeting the human HIF-1α gene (pAd-GFP-shRNA-HIF-1α) and green fluorescent protein (GFP) were constructed. The expression of HIF-1α was inhibited by pAd-GFP-shRNA-HIF-1α at messenger RNA and protein levels. The secretion of stromal cell-derived factor 1α (SDF-1α) or vascular endothelial growth factor (VEGF) in DPCs treated with 10 μM DFO was higher than that in the control condition. The migration of DPCs was enhanced by 10 μM DFO. However, the effects of DFO on DPCs were partially reversed by silencing the HIF-1α gene in enzyme-linked immunosorbent assay or migration assay. Cumulatively, we conclude that DFO upregulated the secretion of SDF-1α or VEGF in DPCs and improved the migration of DPCs through HIF-1α.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205705PMC
May 2021

HIF-1α-activated TM4SF1-AS1 promotes the proliferation, migration, and invasion of hepatocellular carcinoma cells by enhancing TM4SF1 expression.

Biochem Biophys Res Commun 2021 Aug 10;566:80-86. Epub 2021 Jun 10.

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China. Electronic address:

Long non-coding RNAs (lncRNAs) are essential drivers or suppressors in human hepatocellular carcinoma (HCC) by participating in controlling transcription, translation, mRNA stability, and protein degradation protein-protein interaction. TM4SF1-AS1 is recently identified as a tumor-promoting factor in lung cancer. Nevertheless, its function in HCC and related molecular mechanisms remain unknown. Here, our data indicated that either hypoxia or hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (DMOG) induced the upregulation of TM4SF1-AS1 in HCC cells. HIF-1α knockdown rather than HIF-2α silencing remarkably abrogated hypoxia-upregulated TM4SF1-AS1 expression. Furthermore, we confirmed the elevated expression of TM4SF1-AS1 in HCC tissue samples and cell lines. The silencing of TM4SF1-AS1 prominently inhibited the proliferative, migratory, and invasive abilities of HCC cells. TM4SF1-AS1 depletion significantly blocked hypoxia-enhanced Hep3B cell proliferation and mobility. Interfering TM4SF1-AS1 remarkably reduced TM4SF1 mRNA and protein levels in HCC cells. But TM4SF1-AS1 knockdown did not impact the stability of TM4SF1 mRNA. Hypoxia enhanced the expression of TM4SF1 mRNA, which was subsequently decreased by TM4SF1-AS1 knockdown in HCC cells. We confirmed the positive correlation between TM4SF1 mRNA and TM4SF1-AS1 expression in HCC specimens. Finally, TM4SF1 prominently reversed the inhibitory role of TM4SF1-AS1 depletion in Hep3B cells. In summary, hypoxia-responsive TM4SF1-AS1 was overexpressed in human HCC and contributed to the malignant behaviors of tumor cells by enhancing TM4SF1-AS1 expression.
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http://dx.doi.org/10.1016/j.bbrc.2021.06.011DOI Listing
August 2021

Erratum: Long noncoding RNA LINC01123 promotes the proliferation and invasion of hepatocellular carcinoma cells by modulating the miR-34a-5p/TUFT1 axis: Erratum.

Int J Biol Sci 2021 20;17(7):1742-1743. Epub 2021 Apr 20.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.

[This corrects the article DOI: 10.7150/ijbs.45457.].
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http://dx.doi.org/10.7150/ijbs.61130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120462PMC
April 2021

Psychological Impact of the COVID-19 Pandemic on Emergency Dental Care Providers on the Front Lines in China.

Int Dent J 2021 Jun 9;71(3):197-205. Epub 2020 Dec 9.

Department of General Dentistry, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai, China. Electronic address:

Coronavirus disease 2019 (COVID-19) is an infectious disease that emerged at the end of 2019. On 30 January 2020, the World Health Organization (WHO) classified it as a pandemic. To examine the psychological effects on dental care providers in China in the midst of the COVID-19 outbreak and factors closely associated with those effects, we conducted a cross-sectional study online with 4 widely used self-administered questionnaires: the Patient Health Questionnaire-9, the General Anxiety Disorder-7, the Perceived Stress Scale-10, and the Acute Stress Disorder Scale. Univariate and multivariate analyses were performed to evaluate the variables that potentially affected the mental health of emergency dental care providers. As a result, 969 out of 1035 questionnaires were included in the analysis, with 642 respondents reporting more than 1 symptom (66.3%). The symptom of perceived stress was reported by the largest proportion of the respondents (66.2%, n = 641), and anxiety the least (7.1%, n = 69). After adjustment for confounders, it was found that dental practitioners with preexisting physical health conditions were at higher risk of depression (odds ratio [OR], 1.972; 95% CI, 1.128-3.448; P = .017), and perceived stress (odds ratio, 2.397 95% CI, 1.283-4.478; P = .006). Additionally, feelings of fear, helplessness, or terror resulting from the possibility of contracting COVID-19 were significantly associated with the prevalence of all the 4 psychological symptoms observed (P < .05). In the present study, we found that dental care providers suffered psychological depression, stress, anxiety, and posttraumatic stress disorder (PTSD) during COVID-19, which indicates the importance of psychological support at times of major epidemic outbreaks. Chinese Clinical Trial Registry number: ChiCTR2000031538.
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http://dx.doi.org/10.1016/j.identj.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831395PMC
June 2021

Th17 Cells in Inflammatory Bowel Disease: Cytokines, Plasticity, and Therapies.

J Immunol Res 2021 22;2021:8816041. Epub 2021 Jan 22.

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.

Autoimmune diseases (such as rheumatoid arthritis, asthma, autoimmune bowel disease) are a complex disease. Improper activation of the immune system or imbalance of immune cells can cause the immune system to transform into a proinflammatory state, leading to autoimmune pathological damage. Recent studies have shown that autoimmune diseases are closely related to CD4+ T helper cells (Th). The original CD4 T cells will differentiate into different T helper (Th) subgroups after activation. According to their cytokines, the types of Th cells are different to produce lineage-specific cytokines, which play a role in autoimmune homeostasis. When Th differentiation and its cytokines are not regulated, it will induce autoimmune inflammation. Autoimmune bowel disease (IBD) is an autoimmune disease of unknown cause. Current research shows that its pathogenesis is closely related to Th17 cells. This article reviews the role and plasticity of the upstream and downstream cytokines and signaling pathways of Th17 cells in the occurrence and development of autoimmune bowel disease and summarizes the new progress of IBD immunotherapy.
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http://dx.doi.org/10.1155/2021/8816041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846404PMC
January 2021

Hypoxia-Inducible Ubiquitin Specific Peptidase 13 Contributes to Tumor Growth and Metastasis via Enhancing the Toll-Like Receptor 4/Myeloid Differentiation Primary Response Gene 88/Nuclear Factor-κB Pathway in Hepatocellular Carcinoma.

Front Cell Dev Biol 2020 19;8:587389. Epub 2020 Oct 19.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. The activation of the toll-like receptor 4/myeloid differentiation primary response gene 88/nuclear factor-κB (TLR4/MyD88/NF-κB) pathway contributes to the development and progression of HCC. The ubiquitin-proteasome system regulates TLR4 expression. However, whether ubiquitin specific peptidase 13 (USP13) stabilizes TLR4 and facilitates HCC progression remains unclear. Here, quantitative real-time PCR (qRT-PCR) and immunohistochemistry analysis revealed that USP13 expression in HCC tissues was higher than in non-tumor liver tissues. Moreover, the elevated expression of USP13 was detected in HCC cells (SK-HEP-1, HepG2, Huh7, and Hep3B) compared to LO2 cells. Interestingly, the positive staining of USP13 was closely correlated with tumor size ≥ 5 cm and advanced tumor stage and conferred to significantly lower survival of HCC patients. Next, USP13 knockdown prominently reduced the proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion of Hep3B and Huh7 cells, while USP13 overexpression enhanced these biological behaviors of HepG2 and LO2 cells. The silencing of USP13 significantly restrained the growth and lung metastasis of HCC cells . Mechanistically, the USP13 depletion markedly inhibited the TLR4/MyD88/NF-κB pathway in HCC cells. USP13 interacted with TLR4 and inhibited the ubiquitin-mediated degradation of TLR4. Significantly, TLR4 re-expression remarkably reversed the effects of USP13 knockdown on HCC cells. USP13 expression was markedly upregulated in HCC cells under hypoxia conditions. Notably, USP13 knockdown repressed hypoxia-induced activation of the TLR4/MyD88/NF-κB pathway in HCC cells. In conclusion, our study uncovered that hypoxia-induced USP13 facilitated HCC progression via enhancing TLR4 deubiquitination and subsequently activating the TLR4/MyD88/NF-κB pathway.
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http://dx.doi.org/10.3389/fcell.2020.587389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604352PMC
October 2020

Geniposide inhibits proliferation and induces apoptosis of diffuse large B-cell lymphoma cells by inactivating the HCP5/miR-27b-3p/MET axis.

Int J Med Sci 2020 23;17(17):2735-2743. Epub 2020 Sep 23.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.

Diffuse large B-cell lymphoma (DLBCL) is commonly treated with R-CHOP, but ~30 to 50% of the patients are poorly responsive to this strategy. Geniposide, an extract from the Ellis, plays antitumor roles in human gastric cancer, hepatocellular carcinoma, and oral squamous carcinoma. However, the effects of geniposide treatment on DLBCL cells, as well as its underlying mechanism, are still unknown. Here, we found that geniposide inhibited the proliferation of OCI-LY7 and OCI-LY3 cells in a dose-dependent manner. Furthermore, geniposide increased the percentage of apoptotic cells and upregulated the levels of cleaved PARP and cleaved caspase-3 in DLBCL cells. Interestingly, geniposide treatment significantly reduced the expression of the long noncoding RNA HLA complex P5 (lncRNA HCP5) in DLBCL cells. HCP5 expression was revealed to be upregulated in DLBCL tissues and cell lines. Moreover, HCP5 knockdown resulted in proliferation inhibition and apoptosis in OCI-LY7 and OCI-LY3 cells. miR-27b-3p was predicted as a potential target of HCP5 using the lnCAR web tool. Both HCP5 silencing and geniposide treatment increased the level of miR-27b-3p in DLBCL cells. Accordingly, a luciferase reporter assay identified miR-27b-3p as a direct target of HCP5. The expression of miR-27b-3p was upregulated and inversely correlated with the HCP5 level in DLBCL tissues. HCP5 knockdown reduced MET protein expression, which was subsequently rescued by miR-27b-3p silencing in DLBCL cells. Importantly, the restoration of MET partially reversed the geniposide-induced proliferation inhibition and apoptosis of DLBCL cells. In conclusion, geniposide inhibits the proliferation and induces the apoptosis of DLBCL cells at least partially by regulating the HCP5/miR-27b-3p/MET axis, indicating a potential strategy for DLBCL treatment.
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http://dx.doi.org/10.7150/ijms.51329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645330PMC
August 2021

Safety and feasibility of laparoscopic versus open liver resection with associated lymphadenectomy for intrahepatic cholangiocarcinoma.

Biosci Trends 2020 Nov 11;14(5):376-383. Epub 2020 Sep 11.

Department of Hepatobiliary and Pancreatic Surgery & Minimally Invasive Surgery, Zhejiang Provincial People's Hospital & Hangzhou Medical College affiliated People's Hospital, Hangzhou, Zhejiang, China.

The safety and feasibility of laparoscopic versus open liver resection (LLR vs. OLR) associated lymphadenectomy for intrahepatic cholangiocarcinoma (ICC) are still controversial. The aim of the present study was to compare short and long-term outcomes. We reviewed data on 43 consecutive patients who underwent curative liver resection with associated lymphadenectomy for ICC. The short-term outcomes including postoperative morbidity and mortality, and the long-term outcomes including overall survival (OS) and recurrence-free survival (RFS) were compared. The median survival, 1- and 3-year OS in LLR and OLR groups were 22.5 months, 76.9% and 47.1%, and 12.1 months, 43.1% and 20.0%, respectively. The median survival, 1- and 3-year RFS in LLR and OLR groups were 10.3 months, 27.8% and 0%, and 8.1 months, 24.0% and 4.0%, respectively. The results showed that LLR obviously reduced intraoperative blood loss (median, 375 vs. 500ml, p = 0.016) and postoperative hospital stay (median, 6 vs. 9 days, p = 0.016). Moreover, there was no significant difference in short-term outcomes including postoperative morbidity (including wound infection, bile leakage, liver failure and pneumonia) and mortality within 30 days, and long-term outcomes including OS and RFS between LLR and OLR. (all p > 0.05). Multivariate analysis showed that CA19-9 level, TNM stage, and tumor differentiation were independent risk factors for OS and RFS. LLR for ICC is safety and feasibility compared with OLR. The advantage of LLR was to reduce intraoperative blood loss and postoperative hospital stay.
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http://dx.doi.org/10.5582/bst.2020.03293DOI Listing
November 2020

[EGFR tyrosine kinase inhibitor HS-10296 induces autophagy and apoptosis in triplenegative breast cancer MDA-MB-231 cells].

Nan Fang Yi Ke Da Xue Xue Bao 2020 Jul;40(7):981-987

School of Pharmacy, Bengbu Medical College//Anhui Provincial Engineering Technology Research Center of Biochemical Pharmaceuticals, Bengbu 233030, China.

Objective: To investigate the inhibitory effect of epidermal growth factor receptor tyrosine kinase inhibitor (EGFRTKI) HS-10296 on the proliferation of triple-negative breast cancer (TNBC) MDA-MB-231 cells and explore the possible molecular mechanism.

Methods: MDA-MB-231 cells were treated with HS-10296 for 24, 48, or 72 h, and CCK-8 assay was used to assess the changes in the cell viability. The inhibitory effect of HS-10296 on cell proliferation was determined by clonogenic assay. JC-1 and flow cytometry were employed for analyzing the cell apoptosis, and the ultrastructure of the cells was observed under electron microscope. After pretreatment with autophagy inhibitor chloroquine (CQ), MDA-MB-231 cells were divided into control group, CQ treatment group, HS-10296 (4 and 6 μmol/L) treatment groups and combined treatment groups, and the sensitivity of the treated cells to HS-10296 was determined using CCK-8 assay. The effects of HS-10296 on EGFR pathway and apoptosis- and autophagy-related proteins in MDA-MB-231 cells were investigated using Western blotting.

Results: HS-10296 significantly inhibited the proliferation of MDA-MB-231 cells with IC values at 24, 48 and 72 h of 8.393, 2.777 and 2.016 μmol/L, respectively. JC-1 and flow cytometry showed that HS-10296 induced obvious apoptosis of MDA-MB-231 cells, which showed an apoptosis rate of (21.63 ± 2.97)% following treatment with 8 μmol/L HS-10296. Autophagy vesicles were observed in the cells treated with HS-10296 under electron microscope. In MDA-MB-231 cells pretreated with CQ, inhibition of autophagy significantly enhanced HS-10296-induced cell death. Western blotting showed that the apoptosis-related protein caspase-3 was activated after HS-10296 treatment to cut its substrate PARP. The expression of autophagy-related protein light chain 3B (LC3B) was significantly enhanced after HS-10296 treatment ( < 0.01), which also resulted in inhibited phosphorylation of EGFR and AKT proteins in the cells.

Conclusions: HS-10296 can inhibit the proliferation and induce autophagy and apoptosis of MDA-MB-231 cells by inhibiting the EGFR/PI3K/AKT signaling pathway.
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http://dx.doi.org/10.12122/j.issn.1673-4254.2020.07.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386211PMC
July 2020

Long noncoding RNA LINC01123 promotes the proliferation and invasion of hepatocellular carcinoma cells by modulating the miR-34a-5p/TUFT1 axis.

Int J Biol Sci 2020 5;16(13):2296-2305. Epub 2020 Jun 5.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.

Hepatocellular carcinoma (HCC), one of the main causes of cancer-related deaths globally, is characterized by rapid growth and high invasiveness. Accumulating evidence demonstrates that long noncoding RNAs (lncRNAs) play critical roles in the growth and metastasis of HCC. Recently, lncRNA LINC01123 has been found to contribute to cell proliferation and aerobic glycolysis in lung cancer. However, the function of LINC01123 in HCC, as well as the underlying mechanism of its action, remain unclear. Here, we found that the expression of LINC01123 was clearly upregulated in HCC tissues compared to nontumor tissues. Furthermore, expression of LINC01123 in HCC cells was significantly higher than in LO2 cells. Importantly, the upregulated level of LINC01123 was related to unfavorable clinical features and poor prognosis of HCC. Next, we demonstrated that LINC01123 knockdown suppressed the proliferation, migration and invasion of HCC cells . Depletion of LINC01123 inhibited HCC xenograft growth . Conversely, ectopic expression of LINC01123 facilitated HCC cell proliferation and invasion. Mechanistically, LINC01123 acted as a molecular sponge for miR-34a-5p in HCC cells. Tuftelin1 (TUFT1) was identified as the target gene of miR-34a-5p. LINC01123 positively regulated TUFT1 level by targeting of miR-34a-5p in HCC cells. Notably, TUFT1 restoration can abolish miR-34a-5p-induced inhibitory effects on HCC cell proliferation, migration and invasion. In conclusion, LINC01123 was overexpressed in HCC and accelerated cancer cell proliferation and invasion by regulating the miR-34a-5p/TUFT1 axis.
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http://dx.doi.org/10.7150/ijbs.45457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378647PMC
June 2020

The significance of multidisciplinary classifications based on transbronchial pathology in possible idiopathic interstitial pneumonias.

Medicine (Baltimore) 2020 Jul;99(28):e20930

Department of Respiratory.

Surgical lung biopsy is regarded as the golden standard for the diagnosis of idiopathic interstitial pneumonias (IIPs). Here, we attempted to show the diagnostic accuracy of multidisciplinary classifications based on transbronchial pathology including transbronchial lung cryobiopsy (TBLC) , bronchoalveolar lavage fluid (BALF) and endobronchial ultrasound-guided transbronchial needle aspiration biopsy (EBUS-TBNA).Patients with suspected interstitial lung diseases admitted from June 1, 2016 to December 31, 2018 were involved. Patients with known causes of interstitial lung diseases and typical idiopathic pulmonary fibrosis diagnosed through clinical, radiological information were excluded. Patients with atypical idiopathic pulmonary fibrosis and possible IIPs accepted transbronchial pathological evaluation. Initial multidisciplinary diagnosis (MDD) classifications were made depending on clinical, radiological and transbronchial pathological information by a multidisciplinary team (MDT). The final MDD classifications were confirmed by subsequent therapeutic effects. All patients were followed up for at least 6 months.A total of 70 patients were finally involved. The samples of lung parenchyma extracted through TBLC were enough for confirmation of pathological diagnoses in 68.6% (48/70) cases. Samples of 6 cases were extracted by EBUS-TBNA. Bacteriological diagnoses were positive in 1 case by BALF. Pathological diagnoses of 77.1% (54/70) cases were achieved through TBLC, EBUS-TBNA and BALF. During the follow up study, the pulmonary lesions of 60% patients were improved, 11.43% were relapsed when glucocorticoid was reduced to small dose or withdrawal, 14.29% were leveled off and 8.57% were progressed. The diagnoses of 4 patients with progressed clinical feature were revised. As a result, 94.3% initial MDD classifications based on transbronchial pathology were consistent with the final MDD, and the difference of diagnostic yield wasn't significant between initial and final MDD (Z = -1.414, P = .157).Classifications of IIPs based on transbronchial pathology were useful and quite agreed with final MDD.
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http://dx.doi.org/10.1097/MD.0000000000020930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360311PMC
July 2020

Application of nomogram containing log odds of metastatic lymph node in gallbladder cancer patients.

Ann Transl Med 2020 May;8(10):655

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China.

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http://dx.doi.org/10.21037/atm-2020-91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290604PMC
May 2020

Cystic fibrosis transmembrane conductance regulator-dependent bicarbonate entry controls rat cardiomyocyte ATP release via pannexin1 through mitochondrial signalling and caspase activation.

Acta Physiol (Oxf) 2020 09 19;230(1):e13495. Epub 2020 Jun 19.

School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.

Aim: Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in the heart, but its function there is unclear. CFTR regulates an ATP release pore in many tissues, but the identity and regulatory mechanism of the pore are unknown. We investigated the role of CFTR in ATP release from primary cardiomyocytes and ventricular wall in vivo.

Methods: Proteins involved in the signalling pathway for ATP release during simulated ischaemia (lactic acid treatment) were investigated using inhibitors and siRNA; colocalization was identified by coimmunofluorescence and proximity ligation assays; changes in near-membrane pH and calcium were identified with total internal reflection microscopy; in vivo ATP release was investigated using interstitial microdialysis of rat heart.

Results: Lactic acid-induced CFTR-dependent ATP release from cultured cardiomyocytes and left ventricle in vivo. Lactic acid entry elevated near-membrane calcium, which involved Na/H- and Na/Ca-exchangers colocalized with CFTR. Calcium entry-induced CFTR activation, which involved cAMP, protein kinase A, FAK, Pyk2 and Src. Removal of extracellular bicarbonate abolished cardiomyocyte ATP release induced by lactic acid or CFTR activators. Bicarbonate stimulated cytochrome c expression, cytochrome c release and ATP release from isolated cardiomyocyte mitochondria. Pannexin 1 (Panx1) colocalized with CFTR. Lactic acid increased cardiomyocyte caspase activity: caspase inhibitors or Panx1 siRNA abolished cardiomyocyte ATP release, while pannexin inhibition abolished cardiac ATP release in vivo.

Conclusion: During simulated ischaemia, CFTR-dependent bicarbonate entry stimulated ATP and cytochrome c release from mitochondria; in the cytoplasm, cytochrome c-activated caspase 3, which in turn activated Panx1, and ATP was released through the opened Panx1 channel.
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http://dx.doi.org/10.1111/apha.13495DOI Listing
September 2020

The genetic association between type 2 diabetic and hepatocellular carcinomas.

Ann Transl Med 2020 Mar;8(6):380

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China.

Background: Type 2 diabetes mellitus (T2DM) and hepatocellular carcinoma (HCC) are both major health problems throughout the world. It has been reported that T2DM is an independent risk factor for HCC, although the pathophysiology is still unclear.

Methods: In order to identify differentially expressed genes (DEGs) in T2DM and HCC, gene expression datasets for T2DM (GSE15653), HCC (GSE60502) and metformin-treated cells (GSE69850) were obtained from the Gene Expression Omnibus database repository. Protein-protein interaction (PPI) networks for the DEGs were constructed and gene clusters selected for functional enrichment analysis. Ten genes with the highest degree of connectivity were selected as hub genes and prognostic analysis together with analysis of gene expression and protein distribution were performed for these genes. Lastly, we investigated associations between the hub genes and genes associated with metformin treatment in hepatocarcinoma cells.

Results: In total, 256 common DEGs, including 155 up-regulated genes and 101 down-regulated genes, were identified. Enrichment analyses showed that the genes of the major module were largely associated with the cell cycle. All of the 10 hub genes ( and ) have a strong association with lower overall survival in liver cancer patients and four genes ( and ) have reduced expression in metformin-treated samples.

Conclusions: This study identified a number of genes that may play important roles in the association of T2DM and HCC, including four genes which may be the target of metformin treatment for diabetes and HCC. The specific mechanisms involved remain to be identified.
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http://dx.doi.org/10.21037/atm.2020.02.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186634PMC
March 2020

A new nomogram from the SEER database for predicting the prognosis of gallbladder cancer patients after surgery.

Ann Transl Med 2019 Dec;7(23):738

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China.

Background: To study the prognostic significance in gallbladder cancer (GBC) patients of the four N stage methods of log odds of positive lymph nodes (LODDS), lymph node ratio (LNR), and N stage in the 7th and 8 editions of the American Joint Committee on Cancer (AJCC), and to establish a prognostic model of GBC based on LODDS.

Methods: Data of 1,321 patients with GBC who underwent surgical resection of lymph nodes from 2010 to 2014 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. We then randomly divided these data into a training set (n=925) and a validation set (n=396). C-index, Akaike information criterion (AIC), and area under the curve (AUC) were calculated to evaluate the accuracy of LODDS, LNR, and N stage in the 7 and 8 editions of the AJCC. Cox multivariate analysis was performed to determine whether LODDS was an independent prognostic factor, and a nomogram model was established. C-index was used to evaluate the accuracy of the nomogram. A receiver operating characteristic (ROC) curve was drawn and the area under the AUC was calculated to evaluate the accuracy of the nomogram in predicting patients' 1-, 3-, and 5-year overall survival (OS).

Results: Univariate analysis showed that the four methods were all correlated with OS. Through C-index, AIC and AUC, We found that LODDS had the best accuracy of the four methods. C-index and AUC analysis revealed that the nomogram based on LODDS had excellent prognostic ability. All the results were verified in the validation set.

Conclusions: LODDS is an independent prognostic factor for GBC patients, and it is the best N stage in the SEER database. This new nomogram-containing LODDS system is a great model to predict the prognosis of GBC patients.
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http://dx.doi.org/10.21037/atm.2019.11.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989982PMC
December 2019

DNA methylation-based prognostic biomarkers of acute myeloid leukemia patients.

Ann Transl Med 2019 Dec;7(23):737

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China.

Background: Acute myeloid leukemia (AML) is a heterogeneous clonal disease that prevents normal myeloid differentiation with its common features. Its incidence increases with age and has a poor prognosis. Studies have shown that DNA methylation and abnormal gene expression are closely related to AML.

Methods: The methylation array data and mRNA array data are from the Gene Expression Omnibus (GEO) database. Through the GEO data, we identified differential genes from tumors and normal samples. Then we performed Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses on these differential genes. Protein-protein interaction (PPI) network construction and module analysis were performed to screen the highest-scoring modules. Next, we used SurvExpress software to analyze the genes in the highest-scoring module and selected potential prognostic genes by univariate and multivariate Cox analysis. Finally, the three genes screened by SurvExpress software were analyzed using the methylation analysis site MethSurv to explore AML associated methylation biomarkers.

Results: We found three genes that can be used as independent prognostic factors for AML. These three genes are the low expression/methylation genes ATP11A and ITGAM, and the high expression/low methylation gene ZNRF2.

Conclusions: In this study, we performed a comprehensive analysis of DNA methylation and gene expression to identify key epigenetic genes in AML.
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http://dx.doi.org/10.21037/atm.2019.11.122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989983PMC
December 2019

The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors.

PLoS Genet 2020 01 31;16(1):e1008587. Epub 2020 Jan 31.

School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.

Perturbation of synapse development underlies many inherited neurodevelopmental disorders including intellectual disability (ID). Diverse mutations on the human TBC1D24 gene are strongly associated with epilepsy and ID. However, the physiological function of TBC1D24 in the brain is not well understood, and there is a lack of genetic mouse model that mimics TBC1D24 loss-of-function for the study of animal behaviors. Here we report that TBC1D24 is present at the postsynaptic sites of excitatory synapses, where it is required for the maintenance of dendritic spines through inhibition of the small GTPase ARF6. Mice subjected to viral-mediated knockdown of TBC1D24 in the adult hippocampus display dendritic spine loss, deficits in contextual fear memory, as well as abnormal behaviors including hyperactivity and increased anxiety. Interestingly, we show that the protein stability of TBC1D24 is diminished by the disease-associated missense mutation that leads to F251L amino acid substitution. We further generate the F251L knock-in mice, and the homozygous mutants show increased neuronal excitability, spontaneous seizure and pre-mature death. Moreover, the heterozygous F251L knock-in mice survive into adulthood but display dendritic spine defects and impaired memory. Our findings therefore uncover a previously uncharacterized postsynaptic function of TBC1D24, and suggest that impaired dendritic spine maintenance contributes to the pathophysiology of individuals harboring TBC1D24 gene mutations. The F251L knock-in mice represent a useful animal model for investigation of the mechanistic link between TBC1D24 loss-of-function and neurodevelopmental disorders.
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http://dx.doi.org/10.1371/journal.pgen.1008587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015432PMC
January 2020

Specific depletion of the motor protein KIF5B leads to deficits in dendritic transport, synaptic plasticity and memory.

Elife 2020 01 21;9. Epub 2020 Jan 21.

School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.

The kinesin I family of motor proteins are crucial for axonal transport, but their roles in dendritic transport and postsynaptic function are not well-defined. Gene duplication and subsequent diversification give rise to three homologous kinesin I proteins (KIF5A, KIF5B and KIF5C) in vertebrates, but it is not clear whether and how they exhibit functional specificity. Here we show that knockdown of KIF5A or KIF5B differentially affects excitatory synapses and dendritic transport in hippocampal neurons. The functional specificities of the two kinesins are determined by their diverse carboxyl-termini, where arginine methylation occurs in KIF5B and regulates its function. KIF5B conditional knockout mice exhibit deficits in dendritic spine morphogenesis, synaptic plasticity and memory formation. Our findings provide insights into how expansion of the kinesin I family during evolution leads to diversification and specialization of motor proteins in regulating postsynaptic function.
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http://dx.doi.org/10.7554/eLife.53456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028368PMC
January 2020

PD-L1 expression in pleural effusions of pulmonary adenocarcinoma and survival prediction: a controlled study by pleural biopsy.

Sci Rep 2018 07 25;8(1):11206. Epub 2018 Jul 25.

Department of Respiratory, Dalian Municipal Central Hospital affiliated with Dalian Medical University, Dalian, 116033, China.

PD-L1 expression in pleural effusions (PE) of lung adenocarcinoma (ADC) was compared with pleural biopsies and the positive expression in PE was correlated with survival time. The matched slices from same patient's pleura and PE were collected which both were pathologically verified positive. Immunohistochemistry (IHC) was used to detect PD-L1 expression. A total of 51 eligible cases were enrolled, including 30 males and 21 females. The average age was (67.06 ± 12.10) years. PD-L1 expression wasn't statistically significant in pleura and cell masses (P > 0.05) and the correlation was statistically significant (r = 0.585, P = 0.000). Using an IHC scores of 5 point as a cutoff, positive PD-L1 expression in the pleura was 11.63% and that in the cell masses was 23.26%, and difference was significant (P < 0.05). The correlation coefficient was 0.605. Among 35 cases underwent systemic anti-tumor treatment, the mean survival time with positive PD-L1 expression in PE was 17.370 ± 1.827 months, which was significantly shorter than that with the negative (29.944 ± 2.671 months) (χ = 4.507, P = 0.034). Positive PD-L1 expression in PE is higher than in the pleura and their correlation is well. It may predict the short survival time after systemic anti-tumor treatment.
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http://dx.doi.org/10.1038/s41598-018-29156-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060157PMC
July 2018

MicroRNA Contents in Matrix Vesicles Produced by Growth Plate Chondrocytes are Cell Maturation Dependent.

Sci Rep 2018 02 26;8(1):3609. Epub 2018 Feb 26.

Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, VA, USA.

Chondrocytes at different maturation states in the growth plate produce matrix vesicles (MVs), membrane organelles found in the extracellular matrix, with a wide range of contents, such as matrix processing enzymes and receptors for hormones. We have shown that MVs harvested from growth zone (GC) chondrocyte cultures contain abundant small RNAs, including miRNAs. Here, we determined whether RNA also exists in MVs produced by less mature resting zone (RC) chondrocytes and, if so, whether it differs from the RNA in MVs produced by GC cells. Our results showed that RNA, small RNA specifically, was present in RC-MVs, and it was well-protected from RNase by the phospholipid membrane. A group of miRNAs was enriched in RC-MVs compared RC-cells, suggesting that miRNAs are selectively packaged into MVs. High throughput array and RNA sequencing showed that ~39% miRNAs were differentially expressed between RC-MVs and GC-MVs. Individual RT-qPCR also confirmed that miR-122-5p and miR-150-5p were expressed at significantly higher levels in RC-MVs compared to GC-MVs. This study showed that growth plate chondrocytes at different differentiation stages produce different MVs with different miRNA contents, further supporting extracellular vesicle miRNAs play a role as "matrisomes" that mediate the cell-cell communication in cartilage and bone development.
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http://dx.doi.org/10.1038/s41598-018-21517-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826934PMC
February 2018

miR-501 is upregulated in cervical cancer and promotes cell proliferation, migration and invasion by targeting CYLD.

Chem Biol Interact 2018 Apr 23;285:85-95. Epub 2018 Feb 23.

Department of Pathology and Forensics, Dalian Medical University, Dalian 116044, China. Electronic address:

Background: Cervical cancer is the common gynecological deadly malignancy worldwide. Here we attempted to evaluate the effects and mechanisms of microRNA-501-5p (miR-501) on the cell proliferation, migration, invasion and the clinical significance in the cervical cancer.

Methods: Cervical cancer HeLa cells were transfected with miR-501 mimic or inhibitor or siRNA against Cylindromatosis (CYLD) using Lipofectamine 2000. miR-501 expression was assessed in HeLa cells and cervical cancer specimens by real-time qRT-PCR. The functional roles of miR-501 were determined by CCK-8, colony formation, scratch wound healing and transwell assays. The apoptosis rate was detected by flow cytometry assay. CYLD, BCL-2, BAX, NF-κB p65 and phosphorylated p65 (p-p65) proteins were examined by Western blotting. CYLD expression was evaluated by immunohistochemistry in cervical cancer tissues.

Results: miR-501 was upregulated, whereas CYLD protein was downregulated in cervical cancer tissues compared to normal cervical tissues. miR-501 overexpression and CYLD protein downregulation were positively correlated with poor differentiation, tumor size, International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis. CYLD was downregulated by miR-501 at both mRNA and protein levels in HeLa cells. miR-501 promoted cell proliferation, migration and invasion in cervical cancer, while inhibited the apoptosis. This is possibly due to the downregulation of CYLD and subsequent activation of NF-κB p65.

Conclusions: miR-501 upregulation and CYLD downregulation are associated with the development and progression of cervical cancer. miR-501 promotes cervical cancer cell proliferation, migration and invasion possibly via downregulating CYLD and subsequently activating NF-κB p65. miR-501 might be a potential therapeutic target for cervical cancer.
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http://dx.doi.org/10.1016/j.cbi.2018.02.024DOI Listing
April 2018

Novel [1,2,4] Triazol [4,3-a] Pyridine Derivatives as Potential Selective c-Met Inhibitors with Improved Pharmacokinetic Properties.

Anticancer Agents Med Chem 2017 ;17(8):1102-1112

Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.

Aims: Total twenty-nine [1,2,4]triazolo[4,3-a]pyrazine derivatives were designed and synthesized.

Method: The target compounds, especially 4aa, showed potent activity to inhibit c-Met both in an enzyme assay and a cellular assay. The comprehensive screening for the inhibition of 60 different kinases revealed that 4aa could selectively inhibit c-Met while had no effect on other kinases, indicating 4aa is an excellent c-Met selective inhibitor.

Result: The flow cytometry studies found that 4aa had a similar behavior to the positive control SGX-523 in terms of causing the tumor cell apoptosis and blocking cell-cycle progression. More importantly, 4aa showed much better pharmacokinetic properties than SGX-523. Altogether, the findings suggested the target compounds may be potential anti-tumor drug candidates.
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http://dx.doi.org/10.2174/1871520616666161031142619DOI Listing
September 2017

Molecular basis of reactive oxygen species-induced inactivation of α4β2 nicotinic acetylcholine receptors.

Free Radic Biol Med 2016 08 18;97:520-530. Epub 2016 Jul 18.

Department of Neurobiology, Beijing Institute of Brain Disorders, Capital Medical University, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Center of Neural Regeneration and Repair, Beijing Key Laboratory of Brain Major Disorders-State Key Lab Incubation Base, Beijing Neuroscience Disciplines, Beijing 100069, China. Electronic address:

The α4β2 neuronal nicotinic acetylcholine receptors (nAChRs) are the most widespread heteromeric nAChR subtype in the brain, mediating fast synaptic transmission. Previous studies showed that α4β2 nAChRs could be inactivated by reactive oxygen species (ROS), but the underlying mechanism is still obscure. We found that H2O2 induced the rundown of ACh-evoked currents in human α4β2 nAChRs and the replacement of the conserved cysteine in the M1-M2 linker of either α4 Cys245 or β2 Cys237 with an alanine residue could prevent the current rundown. Structurally, α4 Cys245 and β2 Cys237 are hypothesized to be in close proximity when the receptor is activated. Western blotting results showed that α4 and β2 subunits were cross-linked when the agonist-bound receptor encountered H2O2, which could be prevented by the substitution of the conserved cysteine in the M1-M2 linker to an alanine. Thus, when agonist bound to the receptor, α4 Cys245 and β2 Cys237 came close to each other and ROS oxidized these conserved cysteines, leading subunits to be cross-linked and trapping α4β2 nAChRs into the inactivation state. In addition, we mimicked an experimental Parkinson's disease (PD) model in PC12 cells and found that ROS, generated by 6-hydroxydopamine (6-OHDA), could cause the current rundown in α4β2 nAChRs, which may play a role in PD.
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http://dx.doi.org/10.1016/j.freeradbiomed.2016.07.012DOI Listing
August 2016

Synthesis and biological evaluation of new [1,2,4]triazolo[4,3-a]pyridine derivatives as potential c-Met inhibitors.

Bioorg Med Chem 2016 08 30;24(16):3483-93. Epub 2016 May 30.

Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China. Electronic address:

A series of [1,2,4]triazolo[4,3-a]pyrazine derivatives (4a-4i) were designed, synthesized and evaluated for their c-Met kinase inhibition and antitumor activity against SNU5 gastric cell line in vitro. Among these compounds, 4d was found to show the highest activity against c-Met and high selectivity against the tumor cells which are believed to be dependent on the c-Met oncogene amplification, because 4d selectively inhibited c-Met while had no effect on other 59 kinases. In vivo efficacy study on human gastric (MKN-45) and human non-small cell lung (NCI-H1993) tumor xenograft in nude mouse demonstrated that 4d·CH3SO3H had a better inhibiting activity than SGX-523 in a dose-dependent manner. When tested in mice, compound 4d·CH3SO3H was found to have biological half-lives and plasma exposure values higher than those of JNJ-38877605, and its long-term toxicity and acute toxicity turned out to be acceptable, all of which indicates that 4d·CH3SO3H is a desirable drug candidate.
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http://dx.doi.org/10.1016/j.bmc.2016.05.057DOI Listing
August 2016

Chicken egg yolk antibodies (IgY) modulate the intestinal mucosal immune response in a mouse model of Salmonella typhimurium infection.

Int Immunopharmacol 2016 Jul 21;36:305-314. Epub 2016 May 21.

School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China; Ministry of Education Center for Food Safety of Animal Origin, Dalian 116620, China. Electronic address:

This study determined the effects of chicken egg yolk antibodies (IgY) on immune responses in the intestinal mucosal of mice infected with Salmonella typhimurium. Sixty, 28-day-old mice were divided into 4 groups and treated with streptomycin or sterile water for 2days followed by 1day without treatment. The control group was unchallenged whereas the mice in the other three groups were treated twice with 10(9)CFUmL(-1)S. typhimurium. For the next 3days, control mice continued to receive no treatment whereas the mice in the remaining three groups were orally administered with 20mgmL(-1) of specific IgY, 20mgmL(-1) of nonspecific IgY or PBS. S. typhimurium activated gut-associated lymphoid tissue, increasing the release of IFN-γ and TNF-α in the mucosa and increased the number of activated T-lymphocytes and cytotoxic T-γδ. Specific IgY attenuated the increase in IFN-γ and TNF-α and the decrease in IL-10. S. typhimurium induced mobilization of CD8(+) and CD8(+) TCRγδ T cells in the epithelium and CD4(+) and CD8(+) T cells in the lamina propria reflecting an inflammatory process that was attenuated by IgY. These results suggest that specific IgY modulates intestinal mucosal immune responses during a S. typhimurium infection.
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http://dx.doi.org/10.1016/j.intimp.2016.04.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106048PMC
July 2016

Selective enrichment of microRNAs in extracellular matrix vesicles produced by growth plate chondrocytes.

Bone 2016 07 12;88:47-55. Epub 2016 Apr 12.

Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, VA, United States; Department of Periodontics, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.

Matrix vesicles (MVs) are membrane organelles found in the extracellular matrix of calcifying cells, which contain matrix processing enzymes and regulate the extracellular environment via action of these enzymes. It is unknown whether MVs are also exosomic mediators of cell-cell communication via transfer of RNA material, and specifically, microRNA (miRNA). We investigated the presence of RNA in MVs isolated from cultures of costochondral growth zone chondrocytes. Our results showed that the average yield of MV RNA was 1.93±0.78ng RNA/10(4) cells, which was approximately 0.1% of the parent cell's total RNA. MV RNA was well-protected from RNase by the lipid membrane and was highly enriched in small RNA molecules compared to cells. Moreover, coding and non-coding small RNAs in MVs were in proportions that differed from parent cells. Enrichment of specific miRNAs was consistently observed in all three miRNA detection platforms that we used, suggesting that miRNAs are selectively packaged into MVs. MV-enriched miRNAs were related to different signaling pathways associated with bone formation. This study suggests a significant role for MVs as "matrisomes" in cell-cell communication in cartilage and bone development via transfer of specific miRNAs.
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http://dx.doi.org/10.1016/j.bone.2016.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899086PMC
July 2016

Oxidative Modification and Its Implications for the Neurodegeneration of Parkinson's Disease.

Mol Neurobiol 2017 03 3;54(2):1404-1418. Epub 2016 Feb 3.

Department of Neurobiology, Beijing Institute of Brain Disorders, Capital Medical University, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Center of Neural Regeneration and Repair, Beijing Key Laboratory of Brain Major Disorders-State Key Lab Incubation Base, Beijing Neuroscience Disciplines, Beijing, 100069, China.

Parkinson's disease (PD) is the second most common neurodegenerative disease. The major characteristics of PD include the loss of dopaminergic neurons in the substantia nigra and Lewy body depositions. Genetic defects, environment toxicants, and aging have been recognized as risk factors for the development of PD. Currently, although the pathogenesis of PD is still obscure, overwhelming evidence demonstrates that oxidative stress plays a central role in the progress of PD. Reactive oxygen species (ROS) function mainly through chemical reactions with atomic targets that lead to covalent oxidative modifications. Through the oxidative modification of ions, amino acids, amines, and nucleic acids, ROS exert augmented effects on the structures and functions of multiple macromolecules. These oxidative modifications can affect nucleic acid stability by oxidizing RNA, increasing mitochondrial DNA (mtDNA) mutation, and launching translesion synthesis (TLS); disturb protein homeostasis by accelerating α-synuclein aggregation, parkin aggregation, and proteasome dissociation; modulate dopamine release by activating ATP-sensitive potassium channels (K) and inactivating neuronal nicotinic acetylcholine receptors (nAChRs); and influence cellular self-defenses by promoting the cytoprotective effects of DJ-1 and PTEN-induced putative kinase 1 (PINK1) while inducing Akt dysregulation. Based on the above facts, we propose that various oxidative modifications may affect nucleic acid stability, protein homeostasis, the functionality of ion channels, and cellular self-defenses and that these processes lead to protein misfolding, dopamine depletion, and further neuronal death in PD.
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http://dx.doi.org/10.1007/s12035-016-9743-3DOI Listing
March 2017

Statistical inference for extended or shortened phase II studies based on Simon's two-stage designs.

BMC Med Res Methodol 2015 Jun 7;15:48. Epub 2015 Jun 7.

Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 639 Zhi Zao Ju Road200011, P.R. China.

Background: Simon's two-stage designs are popular choices for conducting phase II clinical trials, especially in the oncology trials to reduce the number of patients placed on ineffective experimental therapies. Recently Koyama and Chen (2008) discussed how to conduct proper inference for such studies because they found that inference procedures used with Simon's designs almost always ignore the actual sampling plan used. In particular, they proposed an inference method for studies when the actual second stage sample sizes differ from planned ones.

Methods: We consider an alternative inference method based on likelihood ratio. In particular, we order permissible sample paths under Simon's two-stage designs using their corresponding conditional likelihood. In this way, we can calculate p-values using the common definition: the probability of obtaining a test statistic value at least as extreme as that observed under the null hypothesis.

Results: In addition to providing inference for a couple of scenarios where Koyama and Chen's method can be difficult to apply, the resulting estimate based on our method appears to have certain advantage in terms of inference properties in many numerical simulations. It generally led to smaller biases and narrower confidence intervals while maintaining similar coverages. We also illustrated the two methods in a real data setting.

Conclusions: Inference procedures used with Simon's designs almost always ignore the actual sampling plan. Reported P-values, point estimates and confidence intervals for the response rate are not usually adjusted for the design's adaptiveness. Proper statistical inference procedures should be used.
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http://dx.doi.org/10.1186/s12874-015-0039-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535394PMC
June 2015
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