Publications by authors named "Aiguo Liu"

62 Publications

Pulse therapy with vincristine and dexamethasone for childhood acute lymphoblastic leukaemia (CCCG-ALL-2015): an open-label, multicentre, randomised, phase 3, non-inferiority trial.

Lancet Oncol 2021 09 27;22(9):1322-1332. Epub 2021 Jul 27.

Department of Hematology/Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, China.

Background: Vincristine plus dexamethasone pulses are generally used throughout maintenance treatment for childhood acute lymphoblastic leukaemia. However, previous studies remain inconclusive about the benefit of this maintenance therapy and the absence of randomised, controlled trials in patients with low-risk or high-risk acute lymphoblastic leukaemia provides uncertainty. We therefore aimed to determine if this therapy could be safely omitted beyond 1 year of treatment without leading to an inferior outcome in any risk subgroup of childhood acute lymphoblastic leukaemia.

Methods: This open-label, multicentre, randomised, phase 3, non-inferiority trial involved 20 major medical centres across China. We enrolled patients who were aged 0-18 years with newly diagnosed acute lymphoblastic leukaemia that was subsequently in continuous remission for 1 year after initial treatment. Patients with secondary malignancy or primary immunodeficiency were excluded. Eligible patients were classified as having low-risk, intermediate-risk, or high-risk acute lymphoblastic leukaemia based on minimal residual disease and immunophenotypic and genetic features of leukaemic cells. Randomisation and analyses were done separately for the low-risk and intermediate-to-high-risk cohorts. Randomisation was generated by the study biostatistician with a block size of six. Stratification factors included participating centre, sex, and age at diagnosis; the low-risk cohort was additionally stratified for ETV6-RUNX1 status, and the intermediate-to-high-risk cohort for cell lineage. Patients in each risk cohort were randomly assigned (1:1) to either receive (ie, the control group) or not receive (ie, the experimental group) seven pulses of intravenous vincristine (1·5 mg/m) plus oral dexamethasone (6 mg/m per day for 7 days) during the second year of treatment. The primary endpoint was difference in 5-year event-free survival between the experimental group and the control group for both the low-risk and intermediate-to-high-risk cohorts, with a non-inferiority margin of 0·05 (5%). The analysis was by intention to treat. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-IPR-14005706.

Findings: Between Jan 1, 2015, and Feb 20, 2020, 6141 paediatric patients with newly diagnosed acute lymphoblastic leukaemia were registered to this study. Approximately 1 year after diagnosis and treatment, 5054 patients in continuous remission were randomly assigned, including 2923 (1442 in the control group and 1481 in the experimental group) with low-risk acute lymphoblastic leukaemia and 2131 (1071 control, 1060 experimental) with intermediate-to-high risk acute lymphoblastic leukaemia. Median follow-up for patients who were alive at the time of analysis was 3·7 years (IQR 2·8-4·7). Among patients with low-risk acute lymphoblastic leukaemia, no difference was observed in 5-year event-free survival between the control group and the experimental group (90·3% [95% CI 88·4-92·2] vs 90·2% [88·2-92·2]; p=0·90). The one-sided 95% upper confidence bound for the difference in 5-year event-free survival probability was 0·024, establishing non-inferiority. Among patients with intermediate-to-high-risk acute lymphoblastic leukaemia, no difference was observed in 5-year event-free survival between the control group and the experimental group (82·8% [95% CI 80·0-85·7] vs 80·8% [77·7-84·0]; p=0·90), but the one-sided 95% upper confidence bound for the difference in 5-year event-free survival probability was 0·055, giving a borderline inferior result for those in the experimental group. In the low-risk cohort, we found no differences in the rates of infections, symptomatic osteonecrosis, or other complications during the second year of maintenance treatment between patients in the control and experimental groups. Patients with intermediate-to-high-risk acute lymphoblastic leukaemia in the control group were more likely to develop grade 3-4 pneumonia (26 [2·4%] of 1071 vs ten [0·9%] of 1060) and vincristine-related peripheral neuropathy (17 [1·6%] vs six [0·6%]) compared with the experimental group. Incidence of grade 5 fatal infection was similar between the control group and the experimental group in both the low-risk cohort (two [0·1%] of 1442 vs five [0·3%] of 1481) and intermediate-to-high risk cohort (six [0·6%] of 1071 vs five [0·5%] of 1060).

Interpretation: Vincristine plus dexamethasone pulses might be omitted beyond 1 year of treatment for children with low-risk acute lymphoblastic leukaemia. Additional studies are needed for intermediate-to-high-risk acute lymphoblastic leukaemia.

Funding: VIVA China Children's Cancer Foundation, the National Natural Science Foundation of China, the China fourth round of Three-Year Public Health Action Plan (2015-2017), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, US National Cancer Institute, St Baldrick's Foundation, and the American Lebanese Syrian Associated Charities.

Translation: For the Chinese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1470-2045(21)00328-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416799PMC
September 2021

Excellent Early Outcomes of Combined Chemotherapy With Arsenic Trioxide for Stage 4/M Neuroblastoma in Children: A Multicenter Nonrandomized Controlled Trial.

Oncol Res 2021 Sep 15;28(7):791-800. Epub 2021 Apr 15.

Pediatric Hematology/Oncology, Sun Yet-Sen Memorial Hospital, Sun Yet-Sen UniversityGuangzhouP.R. China.

This nonrandomized, multicenter cohort, open-label clinical trial evaluated the efficacy and safety of combined chemotherapy with arsenic trioxide (ATO) in children with stage 4/M neuroblastoma (NB). We enrolled patients who were newly diagnosed with NB and assessed as stage 4/M and received either traditional chemotherapy or ATO combined with chemotherapy according to their own wishes. Twenty-two patients were enrolled in the trial group (ATO combined with chemotherapy), and 13 patients were enrolled in the control group (traditional chemotherapy). Objective response rate (ORR) at 4 weeks after completing induction chemotherapy was defined as the main outcome, and adverse events were monitored and graded in the meantime. Data cutoff date was December 31, 2019. Finally, we found that patients who received ATO combined with chemotherapy had a significantly higher response rate than those who were treated with traditional chemotherapy (ORR: 86.36% vs. 46.16%, =0.020). Reversible cardiotoxicity was just observed in three patients who were treated with ATO, and no other differential adverse events were observed between the two groups. ATO combined with chemotherapy can significantly improve end-induction response in high-risk NB, and our novel regimen is well tolerated in pediatric patients. These results highlight the superiority of chemotherapy with ATO, which creates new opportunity for prolonging survival. In addition, this treatment protocol minimizes therapeutic costs compared with anti-GD2 therapy, MIBG, and proton therapy and can decrease the burden to families and society. However, we also need to evaluate more cases to consolidate our conclusion.
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http://dx.doi.org/10.3727/096504021X16184815905096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420893PMC
September 2021

TWIN BROTHERS WITH VARIABLE PHENOTYPES OF HAEMOPHILIA A RESULTING FROM MATERNAL MOSAICISM OF ARG550CYS OF F8.

J Paediatr Child Health 2021 02;57(2):307-309

Department of Paediatric Haematology and Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

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http://dx.doi.org/10.1111/jpc.15282DOI Listing
February 2021

miR-133b has protective effect on rats with acute lung injury caused by severe acute pancreatitis through targeting sp1 gene.

Int J Clin Exp Pathol 2021 1;14(1):86-96. Epub 2021 Jan 1.

Department of Emergency, The Affiliated Hospital of Qingdao University Qingdao, Shandong Province, China.

Objective: We aimed to investigate the regulatory mechanism of miR-133b and Sp1 in rats with severe acute pancreatitis complicated by acute lung injury.

Methods: The rats were divided into normal, NC, model, si-Sp1, miR-133b mimic, miR-133b inhibitor, and miR-133b inhibitor + si-Sp1 group and received different treatments.

Results: Compared with normal mice, model mice had a lower miR-133b expression, but higher levels of Sp1 expression, W/D of lung tissue, myeloperoxidase activities, and higher levels of interleukin(IL)-6, tumor necrosis factor (TNF)-α and IL-1β, cell apoptosis rate and Notch-1, and Hes-1, nuclear factor (NF)-κB P65 expressions in lung tissue. Compared with model mice, mice in the si-Sp1 group and the miR-133b mimic group had significantly lower W/D of lung tissue, myeloperoxidase activities, lower levels of IL-6, TNF-α and IL-1β, cell apoptosis rate and Notch-1, Hes-1, and NF-κB P65 expressions in lung tissue. Mice treated by miR-133b inhibitor showed opposite results in all above parameters, which were similar with those in the model group. The negative effects of miR-133b inhibitor could be reversed by the combination use of si-Sp1.

Conclusion: Overexpression of miR-133b could inhibit Sp1 expression, thereby improving severe acute pancreatitis in rats and playing a protective role in acute lung injury.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847488PMC
January 2021

The Possible Role of Sclerostin in the Pathogenesis of Tympanosclerosis.

Audiol Neurootol 2021 28;26(2):102-110. Epub 2021 Jan 28.

Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China,

Objective: The aim of this study was to investigate sclerostin (SOST) expression in a rat model of experimental tympanosclerosis (TS) and its possible role in the formation of TS.

Materials And Methods: Thirty-four SD rats were randomly divided into 2 groups: experimental group (n = 17) and normal group (n = 17). The left tympanic cavities in the experimental group were inoculated with methicillin-resistant Staphylococcus aureus. The changes of tympanic membranes were examined and recorded under otoendoscope. Haematoxylin-eosin staining was adopted to detect the morphological changes in the tympanic membrane and middle ear mucosa. Immunohistochemistry and Western blot analysis were used to observe the expression of SOST, Wnt3a, β-catenin, and P-ERK1/2.

Results: In the experimental group, sclerotic lesions were observed in 54.5% ears in the end of 6 weeks. Morphological changes such as mucosa incrassation, inflammatory cells infiltration, fibrous tissue proliferation, and interstitial tissue incrassation prominently appeared in the tympanic membrane and middle ear mucosa. SOST protein was mainly distributed in the cytoplasm of epithelial cells and gland cells, the expression of which increased significantly in the calcified experimental ears. In addition, expression levels of Wnt3a, β-catenin, and P-ERK1/2 increased significantly in the calcified group too.

Conclusion: The upregulated expression level of SOST may be involved in the formation of TS, first, through the pro-phosphorylation of ERK1/2 in the inflammatory stage, and then through the enhancement of Wnt3a in the osteogenic stage.
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http://dx.doi.org/10.1159/000508692DOI Listing
June 2021

MicroRNA-374b inhibits breast cancer progression through regulating CCND1 and TGFA genes.

Carcinogenesis 2021 Apr;42(4):528-536

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.

Emerging evidence indicates that microRNAs (miRNAs) play a critical role in breast cancer development. We recently reported that a higher expression of miR-374b in tumor tissues was associated with a better disease-free survival of triple-negative breast cancer (TNBC). However, the functional significance and molecular mechanisms underlying the role of miR-374b in breast cancer are largely unknown. In this current study, we evaluated the biological functions and potential mechanisms of miR-374b in both TNBC and non-TNBC. We found that miR-374b was significantly downregulated in breast cancer tissues, compared to adjacent tissues. MiR-374b levels were also lower in breast cancer cell lines, as compared to breast epithelial cells. In vitro and in vivo studies demonstrated that miR-374b modulates the malignant behavior of breast cancer cells, such as cell proliferation in 2D and 3D, cell invasion ability, colony-forming ability and tumor growth in mice. By using bioinformatics tools, we predicted that miR-374b plays a role in breast cancer cells through negatively regulating cyclin D1 (CCND1) and transforming growth factor alpha (TGFA). We further confirmed that CCND1 and TGFA contribute to the malignant behavior of breast cancer cells in vitro and in vivo. Our rescue experiments showed that overexpressing CCND1 or TGFA reverses the phenotypes caused by miR-374b overexpression. Taken together, our studies suggest that miR-374b modulates malignant behavior of breast cancer cells by negatively regulating CCND1 and TGFA genes. The newly identified miR-374b-mediated CCND1 and TGFA gene silencing may facilitate a better understanding of the molecular mechanisms of breast cancer progression.
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http://dx.doi.org/10.1093/carcin/bgab005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086770PMC
April 2021

Competition between two phosphatases fine-tunes Hedgehog signaling.

J Cell Biol 2021 02;220(2)

Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China.

Hedgehog (Hh) signaling is essential for embryonic development and adult homeostasis. How its signaling activity is fine-tuned in response to fluctuated Hh gradient is less known. Here, we identify protein phosphatase V (PpV), the catalytic subunit of protein phosphatase 6, as a homeostatic regulator of Hh signaling. PpV is genetically upstream of widerborst (wdb), which encodes a regulatory subunit of PP2A that modulates high-level Hh signaling. We show that PpV negatively regulates Wdb stability independent of phosphatase activity of PpV, by competing with the catalytic subunit of PP2A for Wdb association, leading to Wdb ubiquitination and subsequent proteasomal degradation. Thus, regulated Wdb stability, maintained through competition between two closely related phosphatases, ensures graded Hh signaling. Interestingly, PpV expression is regulated by Hh signaling. Therefore, PpV functions as a Hh activity sensor that regulates Wdb-mediated PP2A activity through feedback mechanisms to maintain Hh signaling homeostasis.
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http://dx.doi.org/10.1083/jcb.202010078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774589PMC
February 2021

CD44 as a tumor biomarker and therapeutic target.

Exp Hematol Oncol 2020 Dec 10;9(1):36. Epub 2020 Dec 10.

Department of Pediatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

CD44, a complex transmembrane glycoprotein, exists in multiple molecular forms, including the standard isoform CD44s and CD44 variant isoforms. CD44 participates in multiple physiological processes, and aberrant expression and dysregulation of CD44 contribute to tumor initiation and progression. CD44 represents a common biomarker of cancer stem cells, and promotes epithelial-mesenchymal transition. CD44 is involved in the regulation of diverse vital signaling pathways that modulate cancer proliferation, invasion, metastasis and therapy-resistance, and it is also modulated by a variety of molecules in cancer cells. In addition, CD44 can serve as an adverse prognostic marker among cancer population. The pleiotropic roles of CD44 in carcinoma potentially offering new molecular target for therapeutic intervention. Preclinical and clinical trials for evaluating the pharmacokinetics, efficacy and drug-related toxicity of CD44 monoclonal antibody have been carried out among tumors with CD44 expression. In this review, we focus on current data relevant to CD44, and outline CD44 structure, the regulation of CD44, functional properties of CD44 in carcinogenesis and cancer progression as well as the potential CD44-targeting therapy for cancer management.
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http://dx.doi.org/10.1186/s40164-020-00192-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727191PMC
December 2020

[Short-term postoperative outcome of laser-assisted stapedotomy in patients with otosclerosis].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2020 Dec;34(12):1074-1078

Department of Otolaryngology Head and Neck Surgery,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China.

To assess the short-term efficacy of laser-assisted stapedotomy in patients with otosclerosis. The clinical data of twenty-one patients with otosclerosis who underwent laser-assisted stapedotomy were retrospectively analyzed . Preoperative and 3-month postoperative standardized audiometric evaluations were carried out in all patients. The occurrence of surgical complications was observed. The mean preoperative and postoperative air conduction (AC) thresholds were (58.2±12.7) dB HL and (43.0±23.1)dB HL respectively; the postoperative AC threshold decreased by 15.2 dB HL which was statistically significant at 0.5, 1, 2, and 4 kHz (<0.01). The mean preoperative and postoperative bone conduction (BC) thresholds were (31.4±10.3)dB HL and (33.3±16.6)dB HL, and there was not significant difference between them as well as BC thresholds at each frequency. Overclosure >10 dB HL was occured in 3 ears (14.3%) while sensorineural hearing loss>10 dB HL was found in 2 ears (9.5%). The mean ABG decreased by 17.4 dB HL (<0.01) from preoperative (27.0±9.1) dB HL to postoperative (9.6±9.9) dB HL, and the ABG at each frequency had significant decrease. Fourteen ears (66.7%) had postoperative ABG of ≤10 dB HL while 18 ears (85.7%) had postoperative ABG of ≤20 dB HL. Sensorineural hearing loss occurred in 2 ears (9.5%) after surgery, tinnitus in 15 ears (71.4%) and vertigo in 3 ears (14.3%). But all were relieved on the third day after operation. Laser-assisted stapedotomy is a safe and effective treatment of otosclerosis. Although BC thresholds was slightly increased after surgery, it did not affect the overall hearing outcomes.
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http://dx.doi.org/10.13201/j.issn.2096-7993.2020.12.005DOI Listing
December 2020

Management of haemophilia patients in the COVID-19 pandemic: Experience in Wuhan and Tianjin, two differently affected cities in China.

Haemophilia 2020 Nov 6;26(6):1031-1037. Epub 2020 Sep 6.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Hematological Disorders, Institute of Hematology & Blood Diseases Hospital, Tianjin Laboratory of Blood Disease Gene Therapy, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.

Objective: To identify lessons learned from haemophilia care experience in Wuhan (COVID-19 outbreak epicenter in China) and Tianjin (with relatively low COVID-19 incidence) in the pandemic.

Methods: We compared the challenges in haemophilia management attributed to local COVID-19 containment policies, healthcare resource availability, clotting factors supply, daily living restrictions and coping strategies employed.

Results: Wuhan was in lockdown with strict traffic controls, enforced quarantine and overwhelmed resources. Tianjin was in relatively relaxed countermeasures to COVID-19. In Wuhan, haemophilia treatment (for bleeding, prophylaxis, multidisciplinary team care, immune tolerance induction) and patient education were severely affected, while the challenges in Tianjin were less. In both cities, patients' fear for COVID-19 infection also affected their management. Coping strategy in Wuhan included channelling of clotting factors supply from hospitals to nine pharmacies; timely transfers of in-need patients to healthcare facilities by a volunteer service network jointly coordinated by the government, hospitals and the community. Although factor concentrate supply in each city was adequate, patients still worried whether there would be enough supply to last through the pandemics. Consequently, many downgraded their treatment regimens resulting in increased bleeding episodes. In both cities, telemedicine was promoted for patient care and education.

Conclusions: The COVID-19 pandemic had varying adverse impacts on haemophilia care depending on the local infection incidence. Our experience suggests that haemophilia management strategies in the pandemic need to be established according to the local virus containment/mitigation policies, daily living restrictions and resource availability.
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http://dx.doi.org/10.1111/hae.14108DOI Listing
November 2020

Prevention of COVID-19 infection in a pediatric oncology ward in Wuhan.

Pediatr Blood Cancer 2020 10 11;67(10):e28424. Epub 2020 Aug 11.

Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Objective: To assess the screening and isolation measures for preventing coronavirus disease 2019 (COVID-19) infection from newly admitted patients into a pediatric oncology ward.

Methods: We retrospectively analyzed 44 patients with established hematologic malignancies admitted for chemotherapy from January 23 to March 27, 2020 in the Department of Pediatric Hematology of Tongji Hospital, Wuhan. Every patient and their caregivers were well educated on personal protection and put it into effect at home and in hospital. Screening for COVID-19 of all the patients and caregivers before admission was performed. Both clinical features and screening results including chest computerized tomography (CT); nucleic acid testing of nasopharyngeal, oropharyngeal or anal swabs; and quantitative antibodies (IgM and IgG) detecting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) of these patients were described.

Results: The results of nucleic acid and antibodies (IgM and IgG) testing of all the 44 inpatients and their caregivers were negative. Abnormal chest CT images were observed in six symptomatic patients, while chest CT images of their caregivers did not show the changes related to viral pneumonia. These symptomatic patients all recovered after antibacterial combined with antifungal treatment, but without any antiviral agents.

Conclusions: COVID-19 infection could be prevented in pediatric patients with malignancies if proper protective measures were implemented. For patients presenting suspicious symptoms, comprehensive examinations should be carried out.
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http://dx.doi.org/10.1002/pbc.28424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435353PMC
October 2020

Clinical findings in a patient with haemophilia A affected by COVID-19.

Haemophilia 2020 Jul 13;26(4):e214-e216. Epub 2020 Apr 13.

Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.

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http://dx.doi.org/10.1111/hae.14000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228272PMC
July 2020

Silencing of AURKA augments the antitumor efficacy of the AURKA inhibitor MLN8237 on neuroblastoma cells.

Cancer Cell Int 2020 7;20. Epub 2020 Jan 7.

2Department of Pediatrics of Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030 China.

Background: Aurora kinase A (AURKA) has been implicated in the regulation of cell cycle progression, mitosis and a key number of oncogenic signaling pathways in various malignancies including neuroblastoma. Small molecule inhibitors of AURKA have shown potential, but still not as good as expected effects in clinical trials. Little is known about this underlying mechanism. Here, we evaluated the inhibitory effects of AURKA inhibitor MLN8237 on neuroblastoma cells to understand the potential mechanisms responsible for tumor therapy.

Methods: MLN8237 treatment on neuroblastoma cell line IMR32 was done and in vivo inhibitory effects were investigated using tumor xenograft model. Cellular senescence was evaluated by senescence-associated β-gal Staining assay. Flow cytometry was used to tested cell cycle arrest and cell apoptosis. Senescence-associated signal pathways were detected by western blot. CD133 microbeads and microsphere formation were used to separate and enrich CD133 cells. AURKA small interfering RNA transfection was carried to downregulate AURKA level. Finally, the combination of MLN8237 treatment with AURKA small interfering RNA transfection were adopted to evaluate the inhibitory effect on neuroblastoma cells.

Results: We demonstrate that MLN8237, an inhibitor of AURKA, induces the neuroblastoma cell line IMR32 into cellular senescence and G2/M cell phase arrest. Inactivation of AURKA results in MYCN destabilization and inhibits cell growth in vitro and in a mouse model. Although MLN8237 inhibits AURKA kinase activity, it has almost no inhibitory effect on the AURKA protein level. By contrast, MLN8237 treatment leads to abnormal high expression of AURKA in vitro and in vivo. Knockdown of AURKA reduces cell survival. The combination of MLN8237 with AURKA small interfering RNA results in more profound inhibitory effects on neuroblastoma cell growth. Moreover, MLN8237 treatment followed by AURKA siRNA forces senescent cells into apoptosis via suppression of the Akt/Stat3 pathway.

Conclusions: The effect of AURKA-targeted inhibition of tumor growth plays roles in both the inactivation of AURKA activity and the decrease in the AURKA protein expression level.
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http://dx.doi.org/10.1186/s12935-019-1072-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947931PMC
January 2020

The association between vitamin deficiency and otolaryngologic diseases: A therapeutic target.

Med Hypotheses 2020 Feb 23;135:109448. Epub 2019 Oct 23.

The Third Hospital of Wuhan City, Wuhan, China. Electronic address:

Vitamins are indispensable nutrients for metabolism. Adequate vitamin intake plays vital role in physiological processes including embryonic development, cellular and immunity proliferation and differentiation, DNA synthesis and oxidative response. In contrast, insufficient vitamin levels usually lead to a large number of clinical manifestations including xerophthalmia, nyctalopia, hyperpigmentation, vitiligo, jaundice, megaloblastic anemia, glossitis, scurvy, stroke, cancer, coronary heart disease, Alzheimer's disease, multiple sclerosis and Parkinson's disease. In recent years, more and more researches have focused on the relationship between vitamin family and otorhinolaryngologic diseases. This review will summarize the current knowledge of vitamin family and vitamin-mediated regulating role in those related otorhinolaryngologic diseases.
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http://dx.doi.org/10.1016/j.mehy.2019.109448DOI Listing
February 2020

Mutation of Factor IX Cys178 is intolerant and may cause severe hemophilia B.

Thromb Res 2019 Nov 20;183:108-110. Epub 2019 Oct 20.

Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2019.10.016DOI Listing
November 2019

Hereditary elliptocytosis with variable expression and incomplete penetrance in a Chinese family.

Br J Haematol 2019 09 5;186(5):e159-e162. Epub 2019 Jun 5.

Department of Paediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

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http://dx.doi.org/10.1111/bjh.15999DOI Listing
September 2019

Sudden Sensorineural Hearing Loss in Children: Clinical Characteristics, Etiology, Treatment Outcomes, and Prognostic Factors.

Otol Neurotol 2019 04;40(4):446-453

Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Objective: To investigate the clinical characteristics, etiology, treatment outcomes, and prognostic factors of sudden sensorineural hearing loss (SSNHL) in children to guide the clinical diagnosis and treatment of SSNHL in the pediatric population.

Study Design: Retrospective case review.

Setting: Tertiary referral center.

Patients: Patients diagnosed with SSNHL from November 2011 to December 2017 with relatively complete clinical data.

Intervention: Diagnosis and systemic treatment of SSNHL.

Main Outcome Measures: Patients' clinical characteristics, etiology, laboratory tests, imaging, pure-tone audiometry at admission, and discharge were analyzed.

Results: A total of 25 children and 149 adults with SSNHL were included. Recent or previous viral infection rates (81.8%) and fasting blood glucose level (5.23 + 1.47 mmol/L) in children with SSNHL were lower than those in adult SSNHL patients (p = 0.033, p = 0.033). Autoimmune abnormalities (90.0%) and plasma fibrinogen abnormalities (27.3%) were higher in children with SSNHL than those in adult SSNHL patients (40.0%, 8.8%, respectively, p < 0.05). The recovery rate in children (38.4%) with SSNHL is comparable to that in adults (22.6%), but children have a higher complete rate compared to adults (26.9%, 11.3%, respectively, p < 0.05). Children with a profound audiometric curve had a worse prognosis in comparison to other types of audiometric curves (p = 0.041).

Conclusions: Children with SSNHL have a lower rate of viral infection in comparison to adults with SSNHL. Fasting blood glucose levels, complement C3, C4, and fibrinogen may be closely related to childhood SSNHL. The recovery rate in children with SSNHL is comparable to that in adults, but children have a higher complete rate compared to adults. A profound hearing curve is an unfavorable prognostic factor in both children and adults with SSNHL.
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http://dx.doi.org/10.1097/MAO.0000000000002190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426351PMC
April 2019

Novel compound heterozygous mutations in the SPTA1 gene, causing hereditary spherocytosis in a neonate with Coombs‑negative hemolytic jaundice.

Mol Med Rep 2019 Apr 8;19(4):2801-2807. Epub 2019 Feb 8.

Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.

Hereditary spherocytosis (HS) is a common heterogeneous type of inherited hemolytic anemia characterized by jaundice and splenomegaly. Diagnosis of HS in neonates is considered unreliable, and is generally based on positive family history, spherocytes in peripheral smears, increased osmotic fragility, and jaundice. In the present study, routine laboratory tests, next‑generation sequencing, and Sanger sequencing were applied to diagnose a neonatal patient with Coombs‑negative hemolytic jaundice. The neonate had no family history of HS; however, spherocytes were observed in peripheral smears, and the patient exhibited Coombs‑negative and severe hemolytic jaundice, normal mean corpuscular hemoglobin concentration (MCHC) and mean corpuscular volume (MCV), normal glucose‑6‑phosphate dehydrogenase activity, negative thalassemia genetic mutation screening results, and negative autoimmune antibody tests. Novel compound heterozygous mutations in the spectrin‑α, erythrocytic 1 (SPTA1) gene (c.3897‑1G>C and c.5029G>A) were identified. The SPTA1 c.3897‑1G>C mutation in intron 27‑1, which disrupted the consensus splice site, was inherited from his asymptomatic mother, and the SPTA1 c.5029G>A (p.Gly1677Arg) mutation in trans with the SPTA1 c.3897‑1G>C mutation was inherited from his asymptomatic father. Sanger sequencing of mRNA reverse transcribed into cDNA identified a deletion of the first 10 nucleotides of exon 28, confirming the splicing mutation. In conclusion, the present study reports a rare case of autosomal‑recessive HS with a severe clinical phenotype, but normal MCHC and MCV.
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http://dx.doi.org/10.3892/mmr.2019.9947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423610PMC
April 2019

Whole-exome sequencing identifies a novel missense variant within LOXHD1 causing rare hearing loss in a Chinese family.

BMC Med Genet 2019 02 13;20(1):30. Epub 2019 Feb 13.

Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Background: Deafness, autosomal recessive 77 (DFNB77) is a rare non-syndromic hearing loss (NSHL) worldwide, which is caused by deleterious variants within lipoxygenase homology domains 1 (LOXHD1). Here we identified that a novel missense variant of LOXHD1 was associated with NSHL in a Chinese family under consanguineous marriage.

Case Presentation: A 28-year-old woman suffered a bilateral profound NSHL. Impedance audiometry, temporal bone computerized tomography (TBCT) scans and magnetic resonance imaging-inner ear hydrography (MRI-IEH) did not find any obvious abnormality of middle or inner ear. Routine genetic detection did not find pathogenic variants in common HL-associated genes. Therefore, we performed a whole-exome sequencing (WES) in this family. By trio-WES, co-segregation validation and bioinformatics analysis, we revealed that a novel homozygous variant in this patient, LOXHD1: c.5948C > T (p.S1983F), might be the pathogenic factor. Her parents (heterozygotes) and brother (wild-type) were asymptomatic.

Conclusions: We successfully identified a novel variant of LOXHD1 associated with a rare NSHL from a Chinese family. Our finds highlight the effectiveness of trio-WES for molecular diagnosis of rare NHSL, and expand the genotypic spectrum of DFNB77.
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http://dx.doi.org/10.1186/s12881-019-0758-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373029PMC
February 2019

Patients' sense of responsibility to healthcare providers and its predictors: A national cross-sectional survey in China.

PLoS One 2018 5;13(12):e0207361. Epub 2018 Dec 5.

Department of Social Medicine and Health Management, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Objectives: To evaluate patients' sense of responsibility to healthcare providers and to determine its predictors using on a national sample in China.

Methods: We conducted a national cross-sectional survey in China with a stratified cluster sample of patients treated in 77 hospitals between July 2014 and April 2015. Patients' sense of responsibility to healthcare providers was measured with four questions assessing patients' perceptions regarding their responsibilities to respect doctors, respect nurses, coordinate with health professionals, and comply with hospital rules. Predictors included patient sociodemographic characteristics and their past hospitalization experience.

Results: Small proportions of respondents reported that they perceived having no responsibility to respect doctors (8.9%), respect nurses (7.9%), comply with hospital rules (6.7%), or coordinate with health professionals (6.3%). Multivariate regression analyses showed that the strongest predictor of patients' sense of responsibility to healthcare providers was patinets' trust in health professionals, followed by patients' education level. Familiarity with healthcare professionals and past hospitalization frequency were inversely associated with patients' sense of responsibility to healthcare providers.

Conclusions: Although only a small proportion of the patients reported feeling no or low sense of responsibility to healthcare providers, the lack of respect and collaboration from these patients can negatively affect patient-provider relationships. Healthcare administrators need to communicate clearly with the patients and the public about the role of patients and the limitations of medicine in order to instill a sense of patients' responsibility.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207361PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281211PMC
May 2019

Dickkopf-1: Current knowledge and related diseases.

Life Sci 2018 Sep 10;209:249-254. Epub 2018 Aug 10.

Department of Otorhinolaryngology, Head and Neck Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Dickkopf-1(DKK-1) has been identified as a secretory protein that can inhibit the Wnt signaling transduction pathway. It is well known that the Wnt signaling pathway plays an important role in embryogenesis, organogenesis and homeostasis. This signaling cascade is essential for many normal physiological processes such as cellular proliferation, tissue regeneration, embryonic development and many other systemic and local effects, and it can be regulated at different levels. Therefore, defects in the pathway may lead to some complicated effects. In addition, it has been demonstrated that defects in this pathway are closely linked to some diseases including cancer, rheumatism, bone disease, diabetes, and Alzheimer disease. Since DKK-1 is an antagonist of the Wnt pathway, it may be related to these diseases; in fact, many studies have identified this fact. This review will summarize the current knowledge of DKK-1 and DKK-1-mediated regulation of Wnt signaling in the development of these related diseases.
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http://dx.doi.org/10.1016/j.lfs.2018.08.019DOI Listing
September 2018

Identification and genetic analysis of Kadipiro virus isolated in Shandong province, China.

Virol J 2018 04 6;15(1):64. Epub 2018 Apr 6.

State Key Laboratory of Infectious Disease Prevention and Control, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China.

Background: Kadipiro virus (KDV) belongs to the Reoviridae family, which consists of segmented, non-enveloped, double-stranded RNA viruses. It has previously been isolated from Culex, Anopheles, Armigeres and Aedes mosquitoes in Indonesia and China. Here, we describe the isolation and characterization of SDKL1625 from Anopheles sinensis mosquitoes in Shandong province, China.

Methods: In this study, we isolated Kadipiro virus in Aedes albopictus C6/36 cell culture and the complete genome sequencing was made by next generation sequencing.

Results: We isolated and characterized a Kadipiro virus from Anopheles sinensis mosquitoes in 2016 in Shandong province, China. Nucleotide and amino acid homology analysis of SDKL1625 showed higher levels of sequence identity with QTM27331 (Odonata, China, 2016) than with JKT-7075 (Culex fuscocephalus, Indonesia, 1981). The SDKL1625 has 86-97% amino acid identity with the JKT-7075, 88-99% amino acid identity with the QTM27331. Among the 12 fragments, VP1, VP2, VP4, VP6, VP7, VP9 and VP12 showed high amino acid identity (> 90%) and VP5 showed the lowest identity (86% and 88%).

Conclusions: This is the first identification of KDV from mosquito in China. Virus morphology and genome organization were also determined, which will further enrich our understanding of the molecular biological characteristics of KDV and seadornaviruses.
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http://dx.doi.org/10.1186/s12985-018-0966-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889548PMC
April 2018

Hearing Loss in Type 2 Diabetes in Association with Diabetic Neuropathy.

Arch Med Res 2017 10 9;48(7):631-637. Epub 2018 Feb 9.

Department of Internal Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China. Electronic address:

Background: Reports assessing hearing abnormalities in diabetes are debated. We aimed to evaluated auditory alterations and their possible associations with vascular and neurological dysfunction in 160 Type 2 diabetes mellitus individuals and 100 age and sex-matched healthy controls.

Methods: Participants underwent pure tone audiometry (PTA). Associations with demographic, metabolic and neuropathic variables were assessed.

Results: Compared with healthy controls, diabetic patients had higher mean hearing thresholds at each frequency, with statistical significance at 2-8 kHz (p <0.05). Prevalence of hearing loss in diabetics was 67.5% (108/160), including high-frequency (72.22%, 78/108), and low/mid- and high-frequency (27.78%, 30/108). The mild hearing loss was predominant in diabetics with high-frequency impairment (52.56%), while the moderate/severe hearing loss was high in individuals with both low-and high-frequency hearing loss (80.00%). Multiple logistic regression analysis of PTA parameters showed that higher Semmes Weinstein Monofilament (OR 1.24, 95% CI 1.02-1.52), Michigan Neuropathy Screening Instrument score (OR 1.38, 95% CI 1.14-1.68), and vibration perception threshold (OR 1.19, 95% CI 1.05-1.34) were independent risk factors for hearing impairment in diabetics after adjusting for potential covariates.

Conclusions: These findings suggest that hearing loss is common in T2DM subjects, with predominantly high frequency involved. Diabetic neuropathic factors may explain the underlying mechanism of the association between diabetes and hearing loss.
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http://dx.doi.org/10.1016/j.arcmed.2018.02.001DOI Listing
October 2017

Transauricular vagus nerve stimulation at auricular acupoints Kindey (CO10), Yidan (CO11), Liver (CO12) and Shenmen (TF4) can induce auditory and limbic cortices activation measured by fMRI.

Hear Res 2018 03 24;359:1-12. Epub 2017 Dec 24.

Department of Otorhinolaryngology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

The purpose of this study was to explore the central mechanism of transauricular vagus nerve stimulation (taVNS) to human by fMRI and to find a suitable taVNS site for potential tinnitus treatment. 24 healthy subjects aged between 28 and 38 years were enrolled in the experiment. 8 subjects were stimulated in the auricular acupoints Kindey (CO10), Yidan (CO11), Liver (CO12) and Shenmen (TF4) in the left ear, 8 subjects were stimulated at the anterior wall of the auditory canal and left lower limb as an anterior stimulation group; 8 persons who were arranged in a sham group received taVNS at the left ear lobe and tail of the helix. Functional magnetic resonance imaging (fMRI) data from the cortices was collected and an Alphasim analysis was performed. We found that taVNS at auricular acupoints CO10-12, TF4 can instantly and effectively generate blood oxygenation level dependent (BOLD) signal changes in the prefrontal, auditory and limbic cortices of healthy subjects by fMRI. When comparing the acupoints group and the sham group in the left brain, the signals from the prefrontal cortex, the auditory ascending pathway including superior temporal gyrus, middle temporal gyrus, thalamus and limbic system regions such as putamen, caudate, posterior cingulate cortex, amygdala and parahippocampal gyrus were increased under our stimulation. The difference of the BOLD signal in the left brain between acupoints group and anterior group was in the superior temporal gyrus. We could also find signal differences in several regions of right brain among the groups. In conclusion, taVNS at acupoints CO10-12, TF4 could activate the prefrontal, auditory and limbic cortices of healthy brain and this scheme could be a promising tool for tinnitus treatment.
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http://dx.doi.org/10.1016/j.heares.2017.12.003DOI Listing
March 2018

Stress2TF: a manually curated database of TF regulation in plant response to stress.

Gene 2018 Jan 30;638:36-40. Epub 2017 Sep 30.

College of Information and Computer science, Anhui Agricultural University, Hefei 230036, China. Electronic address:

Considerable studies demonstrate that plant transcription factors (TFs) play key regulatory roles in abiotic/biotic stress conditions, such as drought and pathogen attack. However, there is no effort dedicated to curate experimentally validated stress-TF regulatory relationships from these individual reports into a central database, which put an obstacle in the exploration of stress-TF regulations in plants. To address this issue, we presented a literature-curated database 'Stress2TF' that currently documented 1533 regulatory relationships between 71 abiotic/biotic stresses and 558 TFs in 47 plant species. Each entry in Stress2TF contains detailed information about a stress-TF relationship such as plant name, stress name, TF and brief description of stress-TF relationship. Stress2TF provided a user-friendly interface for entry browse, search and download. In addition, a submission page and several useful tools (e.g., BLAST, network visualization) were integrated. Stress2TF may be a valuable resource for the research of stress-TF regulatory mechanisms in plants. Stress2TF is available at http://csgenomics.ahau.edu.cn/Stress2TF.
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http://dx.doi.org/10.1016/j.gene.2017.09.067DOI Listing
January 2018

[Retracted] Cathepsin B inhibition attenuates cardiac dysfunction and remodeling following myocardial infarction by inhibiting the NLRP3 pathway.

Mol Med Rep 2017 11 20;16(5):7873. Epub 2017 Sep 20.

Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, P.R. China.

An interested reader drew to our attention the fact that Figs. 4 and 5 in the above-mentioned article had already been published as Figs. 4 and  5 in the following paper [Boyle AJ, Kelly DJ, Zhang Y, Cox AJ, Gow RM, Way K, Itescu S, Krum H and Gilbert RE: Inhibition of protein kinase C reduces left ventricular fibrosis and dysfunction following myocardial infarction. J Mol Cell Cardiol 39: 213-221, 2005]. Following an investigation, the Journal was able to confirm that this accusation of plagiarism is well-founded. On those grounds, the Editorial Board has decided to retract this paper. Every effort was made to contact the authors in this regard, but without success. The Editor deeply regrets any inconvenience that this retraction has caused to the readership of the Journal [the original article was published in Molecular Medicine Reports 8: 361-366, 2013; DOI: 10.3892/mmr.2013.1507].
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http://dx.doi.org/10.3892/mmr.2017.7551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865890PMC
November 2017

Expression of Prostaglandin E Receptors in Acquired Middle Ear Cholesteatoma.

Clin Exp Otorhinolaryngol 2018 Mar 26;11(1):17-22. Epub 2017 Aug 26.

Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Objectives: To investigate the expression of prostaglandin E receptor subtypes, E-prostanoid (EP) 1-4 receptors, in acquired cholesteatoma and its possible role in the pathologic process of this disorder.

Methods: Specimens of human acquired cholesteatoma were obtained from 29 patients and 19 skin biopsies of normal external auditory canal were as controls. The mRNA and protein expression of EP receptors was assessed by quantitative real-time polymerase chain reaction, immunohistochemistry and Western blot.

Results: In acquired cholesteatoma, EP1-EP4 receptors were mainly expressed on squamous epithelium and subepithelial infiltrated inflammatory cells. In external auditory canal skin, EP1-EP4 receptors were mainly expressed on squamous epithelium and glandular epithelium. The expression of EP4 receptor on mRNA and protein levels were significant lower in acquired cholesteatoma compared with controls. EP1-EP3 receptors had no significant difference between the experimental and control group.

Conclusion: Low expression of EP4 may play a crucial role in the pathologic process of inflammation reaction and bone destruction in acquired cholesteatoma, but not EP1, EP2, or EP3 receptors.
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http://dx.doi.org/10.21053/ceo.2017.00304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831662PMC
March 2018

MicroRNA-218 functions as a tumor suppressor in lung cancer by targeting IL-6/STAT3 and negatively correlates with poor prognosis.

Mol Cancer 2017 08 22;16(1):141. Epub 2017 Aug 22.

Department of Pediatrics of Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, People's Republic of China.

Background: Aberrant expression of microRNAs in different human cancer types has been widely reported. MiR-218 acts as a tumor suppressor in diverse human cancer types impacting regulation of multiple genes in oncogenic pathways. Here, we evaluated the expression and function of miR-218 in human lung cancer and ALDH positive lung cancer cells to understand the potential mechanisms responsible for disease pathology. Also, the association between its host genes and the target genes could be useful towards the better understanding of prognosis in clinical settings.

Methods: Publicly-available data from The Cancer Genome Atlas (TCGA) was mined to compare the levels of miR-218 and its host gene SLIT2/3 between lung cancer tissues and normal lung tissues. Transfection of miR-218 to investigate its function in lung cancer cells was done and in vivo effects were determined using miR-218 expressing lentiviruses. Aldefluor assay and Flow cytometry was used to quantify and enrich ALDH positive lung cancer cells. Levels of miR-218, IL-6R, JAK3 and phosphorylated STAT3 were compared in ALDH1A1 positive and ALDH1A1 negative cells. Overexpression of miR-218 in ALDH positive cells was carried to test the survival by tumorsphere culture. Finally, utilizing TCGA data we studied the association of target genes of miR-218 with the prognosis of lung cancer.

Results: We observed that the expression of miR-218 was significantly down-regulated in lung cancer tissues compared to normal lung tissues. Overexpression of miR-218 decreased cell proliferation, invasion, colony formation, and tumor sphere formation in vitro and repressed tumor growth in vivo. We further found that miR-218 negatively regulated IL-6 receptor and JAK3 gene expression by directly targeting the 3'-UTR of their mRNAs. In addition, the levels of both miR-218 host genes and the components of IL-6/STAT3 pathway correlated with prognosis of lung cancer patients.

Conclusions: MiR-218 acts as a tumor suppressor in lung cancer via IL-6/STAT3 signaling pathway regulation.
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http://dx.doi.org/10.1186/s12943-017-0710-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567631PMC
August 2017

Association between the p.V37I variant of GJB2 and hearing loss: a pedigree and meta-analysis.

Oncotarget 2017 Jul;8(28):46681-46690

Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

Pathogenic variants in the gap junction protein beta-2 (GJB2) gene are the most common cause of hearing loss. Of these, the p.V37I variant of GJB2 has a high allele frequency (up to 10%) in East Asians. Characterization of the phenotypic spectrum associated with p.V37I, as well as the role of this variant in the onset of hearing loss could have a remarkable effect on future diagnostic strategies. Here, we performed a pedigree analysis of unrelated families exhibiting various hearing phenotypes, and then conducted a meta-analysis to comprehensively assess the association between the p.V37I and the risk of hearing loss. Pedigree analyses showed that both homozygous p.V37I variants, as well as compound heterozygous p.V37I with other GJB2 pathogenic variants, contributed to various phenotypes of hearing loss. Meanwhile, meta-analysis demonstrated that, compared with those in the wild type group, both p.V37I homozygotes and compound heterozygous p.V37I variants were at significantly higher risk of developing hearing loss (odds ratios = 7.14 and 3.63; 95% confidence intervals = 3.01-16.95 and 1.38-9.54, respectively). Conversely, heterozygous p.V37I variants alone did not increase the risk of hearing loss. Given the high allele carriage rate of p.V37I (up to 10%) within the general population, our work not only provides information that might influence future genetic screening policies, but also offers insight into clinical risk evaluation and genetic counseling regarding hearing loss.
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http://dx.doi.org/10.18632/oncotarget.17325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542302PMC
July 2017

The exon junction complex regulates the splicing of cell polarity gene dlg1 to control Wingless signaling in development.

Elife 2016 08 18;5. Epub 2016 Aug 18.

State Key Laboratory of Membrane Biology and Minstry of Education Key Laboratory of Cell Proliferation and Differentiation, Peking University, Beijing, China.

Wingless (Wg)/Wnt signaling is conserved in all metazoan animals and plays critical roles in development. The Wg/Wnt morphogen reception is essential for signal activation, whose activity is mediated through the receptor complex and a scaffold protein Dishevelled (Dsh). We report here that the exon junction complex (EJC) activity is indispensable for Wg signaling by maintaining an appropriate level of Dsh protein for Wg ligand reception in Drosophila. Transcriptome analyses in Drosophila wing imaginal discs indicate that the EJC controls the splicing of the cell polarity gene discs large 1 (dlg1), whose coding protein directly interacts with Dsh. Genetic and biochemical experiments demonstrate that Dlg1 protein acts independently from its role in cell polarity to protect Dsh protein from lysosomal degradation. More importantly, human orthologous Dlg protein is sufficient to promote Dvl protein stabilization and Wnt signaling activity, thus revealing a conserved regulatory mechanism of Wg/Wnt signaling by Dlg and EJC.
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http://dx.doi.org/10.7554/eLife.17200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008907PMC
August 2016
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