Publications by authors named "Shuyun Xu"

71 Publications

Eight months follow-up study on pulmonary function, lung radiographic, and related physiological characteristics in COVID-19 survivors.

Sci Rep 2021 07 5;11(1):13854. Epub 2021 Jul 5.

Department of Respiratory and Critical Care MedicineTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

To describe the long-term health outcomes of patients with COVID-19 and investigate the potential risk factors. Clinical data during hospitalization and at a mean (SD) day of 249 (15) days after discharge from 40 survivors with confirmed COVID-19 (including 25 severe cases) were collected and analyzed retrospectively. At follow-up, severe cases had higher incidences of persistent symptoms, DLCO impairment, and higher abnormal CT score as compared with mild cases. CT score at follow-up was positively correlated with age, LDH level, cumulative days of oxygen treatment, total dosage of glucocorticoids used, and CT peak score during hospitalization. DLCO% at follow-up was negatively correlated with cumulative days of oxygen treatment during hospitalization. DLCO/VA% at follow-up was positively correlated with BMI, and TNF-α level. Among the three groups categorized as survivors with normal DLCO, abnormal DLCO but normal DLCO/VA, and abnormal DLCO and DLCO/VA, survivors with abnormal DLCO and DLCO/VA had the lowest serum IL-2R, IL-8, and TNF-α level, while the survivors with abnormal DLCO but normal DLCO/VA had the highest levels of inflammatory cytokines during hospitalization. Altogether, COVID-19 had a greater long-term impact on the lung physiology of severe cases. The long-term radiological abnormality maybe relate to old age and the severity of COVID-19. Either absent or excess of inflammation during COVID-19 course would lead to the impairment of pulmonary diffusion function.
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http://dx.doi.org/10.1038/s41598-021-93191-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257634PMC
July 2021

Colloidal gold immunochromatographic assay (GICA) is an effective screening method for identifying detectable anti-SARS-CoV-2 neutralizing antibodies.

Int J Infect Dis 2021 Jul 6;108:483-486. Epub 2021 Jun 6.

Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing 100191, China. Electronic address:

Introduction: A large number of COVID-19 patients are in recovery, and millions of people are vaccinated for COVID-19 globally. This calls for a rapid screening strategy of SARS-CoV-2 protective antibodies, generated in rehabilitated and vaccinated populations.

Methods: Serum samples collected over a follow-up period of six months from 306 COVID-19 cases discharged from Wuhan Tongji Hospital were analyzed. Anti-S Abs were detected by colloidal gold immunochromatographic assay (GICA), and neutralizing antibodies (nAbs) were detected by chemiluminescent microparticle immunoassay (CMIA).

Results: Most COVID-19 survivors tested positive for anti-S Abs (83.7%) and nAbs (98.0%) 6 months after being discharged from the hospital, and the levels of anti-S Abs in the blood were highly positively correlated with nAbs (r = 0.652, P < 0.0001). The positivity rate of nAbs for patients with anti-S Abs positive was 100%.

Conclusions: There is a good agreement between anti-S Abs detected by GICA and nAbs detected by CMIA. It indicates that anti-S Abs detected by GICA may be used as a cheaper screening strategy for detectable SARS-CoV-2 nAbs in COVID-19 convalescent individuals.
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http://dx.doi.org/10.1016/j.ijid.2021.05.080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180344PMC
July 2021

Nickel complexes based on BIAN ligands: transformation and catalysis on ethylene polymerization.

Dalton Trans 2021 Jun;50(21):7356-7363

College of Chemistry, Jilin University, Changchun, China.

Treatment of bis(arylimino)acenaphthene (ArBIAN) with Ni(COD)2 in toluene afforded dmpBIANNi(COD) (2a, dmp = 2,6-Me2C6H3) and dippBIANNi(COD) (2b, dipp = 2,6-iPrC6H3), respectively, in moderate yields. Complexes 2a and 2b can be oxidized by a small amount of oxygen at low temperature leading to oxygen-bridged dinuclear Ni(ii) complexes (dmpBIANNi)2(μ-O)2 (4a) and (dippBIANNi)2(μ-O)2 (4b), respectively, as a purple powder. The reaction of ArBIAN with 0.5 equiv of Ni(COD)2 or Ni(Ph3P)4 gave bisligated complexes (dmpBIAN)2Ni (3a) and (dippBIAN)2Ni (3b), which can be considered as Ni(0) complexes supported by two neutral BIAN ligands. Oxidation of the bisligated nickel complexes 3a and 3b with [Cp2Fe][B(C6F5)4] afforded cationic Ni(i) complexes [(dmpBIAN)2Ni][B(C6F5)4] (5a) and [(dippBIAN)2Ni][B(C6F5)4] (5b), respectively, in which the Ni(i) centre is chelated by two neutral Ar-BIAN ligands. These complexes were characterized by NMR and IR spectroscopy and DFT calculation, and the molecular structures of 3b, 4b, and 5b were well established by X-ray diffraction analysis. These complexes were evaluated as catalysts for ethylene polymerization in which 2b showed high activity in the presence of AlMe3. 13C NMR analysis of polymers showed that the 2b/AlMe3 catalytic system gave less-branched polymers when compared to that obtained with dippBIANNiBr2 under the same conditions.
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http://dx.doi.org/10.1039/d1dt00649eDOI Listing
June 2021

One delayed diagnosis of paragonimiasis case and literature review.

Respirol Case Rep 2021 May 28;9(5):e00750. Epub 2021 Apr 28.

Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China.

Human paragonimiasis has been appearing all over the world due to increased human migration, international travel, and worldwide food trading. However, delayed and missed diagnosis rates are also increasing due to atypical clinical manifestations and the lack of disease understanding by clinical workers. We describe the case of a 43-year-old man, who was hospitalized with cough and chest pain for two months. Chest computed tomography (CT) revealed bilateral emphysema, left pleural effusion, and bilateral atelectasis. The hypereosinophilia gave us a clue; ultimately, the diagnosis of paragonimiasis was made through a diet history and a positive result of serum sp. immunoglobulin (Ig) G antibody. Moreover, 27 misdiagnosed paragonimiasis cases in the past decade have been reported. We draw conclusions by summarizing their characteristics for suspicious eosinophilic paragonimiasis patients; we should inquire diet history carefully, test serum IgG antibodies, and try to detect eggs. Once diagnosed, praziquantel is preferred for treatment.
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http://dx.doi.org/10.1002/rcr2.750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080295PMC
May 2021

High levels of soluble CD25 in COVID-19 severity suggest a divergence between anti-viral and pro-inflammatory T-cell responses.

Clin Transl Immunology 2021 15;10(2):e1251. Epub 2021 Feb 15.

The University of Queensland Diamantina Institute Faculty of Medicine The University of Queensland Brisbane QLD Australia.

Objectives: We aimed to gain an understanding of the paradox of the immunity in COVID-19 patients with T cells showing both functional defects and hyperactivation and enhanced proliferation.

Methods: A total of 280 hospitalised patients with COVID-19 were evaluated for cytokine profiles and clinical features including viral shedding. A mouse model of acute infection by lymphocytic choriomeningitis virus (LCMV) was applied to dissect the relationship between immunological, virological and pathological features. The results from the mouse model were validated by published data set of single-cell RNA sequencing (scRNA-seq) of immune cells in bronchoalveolar lavage fluid (BALF) of COVID-19 patients.

Results: The levels of soluble CD25 (sCD25), IL-6, IL-8, IL-10 and TNF-α were higher in severe COVID-19 patients than non-severe cases, but only sCD25 was identified as an independent risk factor for disease severity by multivariable binary logistic regression analysis and showed a positive association with the duration of viral shedding. In agreement with the clinical observation, LCMV-infected mice with high levels of sCD25 demonstrated insufficient anti-viral response and delayed viral clearance. The elevation of sCD25 in mice was mainly contributed by the expansion of CD25CD8 T cells that also expressed the highest level of PD-1 with pro-inflammatory potential. The counterpart human CD25PD-1 T cells were expanded in BALF of COVID-19 patients with severe disease compared to those with modest disease.

Conclusion: These results suggest that high levels of sCD25 in COVID-19 patients probably result from insufficient anti-viral immunity and indicate an expansion of pro-inflammatory T cells that contribute to disease severity.
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http://dx.doi.org/10.1002/cti2.1251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883478PMC
February 2021

Application of acid-fast staining combined with GeneXpert MTB/RIF in the diagnosis of non-tuberculous mycobacteria pulmonary disease.

Int J Infect Dis 2021 Mar 15;104:711-717. Epub 2021 Jan 15.

Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of the Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Electronic address:

Objective: To evaluate the clinical diagnostic value of positive acid-fast staining combined with negative GeneXpert MTB/RIF in the diagnosis of non-tuberculous mycobacteria pulmonary disease (NTM-PD).

Methods: A total of 133 inpatients with confirmed NTM-PD were included consecutively between January 1, 2018 and December 31, 2019, at Tongji Hospital and Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, in Wuhan, China. One hundred patients with confirmed pulmonary tuberculosis (PTB) were randomly included as the control group.

Results: The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of positive acid-fast staining combined with a negative GeneXpert MTB/RIF result were 51.13% (95% confidence interval (CI) 42.52-59.73%), 97.00% (95% CI 93.60-100.40%), 95.78% (95% CI 90.98-100.57%), and 59.88% (95% CI 52.25-67.51%), respectively. When subjects were limited to patients with positive acid-fast staining, the sensitivity of a negative GeneXpert MTB/RIF result was 88.31% (95% CI 80.97-95.65%). When acid-fast staining was conducted ≥3 times, the sensitivity of this combination diagnosis method increased to 61.67% (95% CI 49.00-74.33%).

Conclusions: Positive acid-fast staining combined with a negative GeneXpert MTB/RIF result could be an effective and time-saving method for the diagnosis of NTM-PD.
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http://dx.doi.org/10.1016/j.ijid.2020.12.091DOI Listing
March 2021

ATF-3 expression inhibits melanoma growth by downregulating ERK and AKT pathways.

Lab Invest 2021 05 9;101(5):636-647. Epub 2020 Dec 9.

Department of Pathology, Program in Dermatopathology, Brigham and Women's Hospital, Boston, MA, USA.

Activating transcription factor 3 (ATF-3), a cyclic AMP-dependent transcription factor, has been shown to play a regulatory role in melanoma, although its function during tumor progression remains unclear. Here, we demonstrate that ATF-3 exhibits tumor suppressive function in melanoma. Specifically, ATF-3 nuclear expression was significantly diminished with melanoma progression from nevi to primary to metastatic patient melanomas, correlating low expression with poor prognosis. Significantly low expression of ATF-3 was also found in cultured human metastatic melanoma cell lines. Importantly, overexpression of ATF-3 in metastatic melanoma cell lines significantly inhibited cell growth, migration, and invasion in vitro; as well as abrogated tumor growth in a human melanoma xenograft mouse model in vivo. RNA sequencing analysis revealed downregulation of ERK and AKT pathways and upregulation in apoptotic-related genes in ATF-3 overexpressed melanoma cell lines, which was further validated by Western-blot analysis. In summary, this study demonstrated that diminished ATF-3 expression is associated with melanoma virulence and thus provides a potential target for novel therapies and prognostic biomarker applications.
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http://dx.doi.org/10.1038/s41374-020-00516-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091967PMC
May 2021

Long-Term Existence of SARS-CoV-2 in COVID-19 Patients: Host Immunity, Viral Virulence, and Transmissibility.

Virol Sin 2020 Dec 6;35(6):793-802. Epub 2020 Nov 6.

Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

COVID-19 patients can recover with a median SARS-CoV-2 clearance of 20 days post initial symptoms (PIS). However, we observed some COVID-19 patients with existing SARS-CoV-2 for more than 50 days PIS. This study aimed to investigate the cause of viral clearance delay and the infectivity in these patients. Demographic data and clinical characteristics of 22 long-term COVID-19 patients were collected. The median age of the studied cohort was 59.83 ± 12.94 years. All patients were clinically cured after long-term SARS-CoV-2 infection ranging from 53 to 112 days PIS. Peripheral lymphocytes counts were normal. The ratios of interferon gamma (IFN-γ)-secreting cells to total CD4 and CD8 cells were normal as 24.68% ± 9.60% and 66.41% ± 14.87% respectively. However, the number of IFN-γ-secreting NK cells diminished (58.03% ± 11.78%). All patients presented detectable IgG, which positively correlated with mild neutralizing activity (Mean value neutralisation antibodies titers = 157.2, P = 0.05). No SARS-CoV-2 virus was isolated in Vero E6 cells inoculated with nasopharyngeal swab samples from all patients 50 days PIS, and the cytopathic effect was lacking. But one sample was positive for SARS-CoV-2 nucleic acid test in cell supernatants after two passages. Genome sequencing revealed that only three synonymous variants were identified in spike protein coding regions. In conclusion, decreased IFN-γ production by NK cells and low neutralizing antibodies might favor SARS-CoV-2 long-term existence. Further, low viral load and weak viral pathogenicity were observed in COVID-19 patients with long-term SARS-CoV-2 infection.
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http://dx.doi.org/10.1007/s12250-020-00308-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644793PMC
December 2020

Risk Factors for Poor Outcomes of Diabetes Patients With COVID-19: A Single-Center, Retrospective Study in Early Outbreak in China.

Front Endocrinol (Lausanne) 2020 24;11:571037. Epub 2020 Sep 24.

Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Diabetes has been found to increase severity and mortality under the current pandemic of coronavirus disease of 2019 (COVID-19). Up to date, the clinical characteristics of diabetes patients with COVID-19 and the risk factors for poor clinical outcomes are not clearly understood. The study was retrospectively carried out on enrolled diabetes patients with laboratory confirmed COVID-19 infection from a designated medical center for COVID-19 from January 25th, 2020 to February 14th, 2020 in Wuhan, China. The medical record was collected and reviewed. Univariate and multivariate analyses were performed to assess the risk factors associated with the severe events which were defined as a composite endpoint of admission to intensive care unit, the use of mechanical ventilation, or death. A total of 52 diabetes patients with COVID-19 were finally included in the study. 21 (40.4%) patients had developed severe events in 27.50 (IQR 12.25-35.75) days follow-up, 15 (28.8%) patients experienced life-threatening complications and 8 patients died with a recorded mortality rate of 15.4%. Only 13 patients (41.9%) were in optimal glycemic control with HbA1c value of <7.0%. In addition to general clinical characteristics of COVID-19, the severe events diabetes patients showed higher counts of white blood cells and neutrophil, lower lymphocytes (40, 76.9%), high levels of hs-CRP, erythrocyte sedimentation rate (ESR) and procalcitonin (PCT) as compared to the non-severe diabetes patients. Mild higher level of cardiac troponin I (cTNI) (32.0 pg/ml; IQR 16.80-55.00) and D-dimer (1.70 μg/L, IQR 0.70-2.40) were found in diabetes patients with severe events as compared to the non-severe patients (cTNI:20.00 pg/ml, IQR5.38-30.00, = 0.019; D-dimer: 0.70 μg/L, IQR 0.30-2.40, = 0.037). After adjusting age and sex, increased level of cTNI was found to significantly associate with the incidence of severe events (HR: 1.007; 95% CI: 1.000-1.013; = 0.048), Furthermore, using of α-glucosidase inhibitors was found to be the potential protectant for severe events (HR: 0.227; 95% CI: 0.057-0.904; = 0.035). Diabetes patients with COVID-19 showed poor clinical outcomes. Vigorous monitoring of cTNI should be recommended for the diabetes patients with COVID-19. Usage of α-glucosidase inhibitors could be a potential protectant for the diabetes patients with COVID-19.
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http://dx.doi.org/10.3389/fendo.2020.571037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543084PMC
November 2020

Airway-invasion-associated pulmonary computed tomography presentations characteristic of invasive pulmonary Aspergillosis in non-immunocompromised adults: a National Multicenter Retrospective Survey in China.

Respir Res 2020 Jul 7;21(1):173. Epub 2020 Jul 7.

Department of Respiratory and Critical Care Medicine, Clinical Microbiology and Infectious Disease Lab, China-Japan Friendship Hospital, Beijing, 100029, China.

Background: The European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria are widely used in the diagnosis of invasive pulmonary aspergillosis (IPA), but they only apply to immunocompromised patients. We here aimed to identify clinical characteristics helpful to the diagnosis of IPA in non-immunocompromised patients.

Methods: This is a multicenter retrospective study. Data were collected from adult patients with IPA admitted to 15 tertiary hospitals in China from 2010 to 2016.

Results: We included 254 patients in the study, of whom 66 (26.0%) were immunocompromised, and 188 (74.0%) were not. Airway-invasion-associated computed tomography (CT) signs including patchy exudation along the airway (67.6% vs. 45.5%, P = 0.001) and thickened airway wall (42.0% vs. 16.7%, P < 0.001) were more common in non-immunocompromised patients than in immunocompromised ones, and angio-invasive CT signs were more common in immunocompromised patients (55.3% vs.72.7%, P = 0.013). Typical angio-invasive CT signs were delayed in non-immunocompromised IPA patients, whereas airway-invasive signs appear earlier. Host immunocompromised condition was associated with ICU admission and/or intubation (OR 1.095; 95% CI 1.461-6.122; P = 0.003). Poor prognosis (35.5% vs. 21.1%, P = 0.005) was more common in immunocompromised patients.

Conclusion: Airway-invasion-associated CT presentations at early stages of the disease are characteristic of IPA in non-immunocompromised hosts.
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http://dx.doi.org/10.1186/s12931-020-01424-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341597PMC
July 2020

Gendered effects on inflammation reaction and outcome of COVID-19 patients in Wuhan.

J Med Virol 2020 11 19;92(11):2684-2692. Epub 2020 Jun 19.

Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: The rapid outbreak of coronavirus disease 2019 (COVID-19) has turned into a public health emergency of international concern. Epidemiological research has shown that sex is associated with the severity of COVID-19, but the underlying mechanism of sex predisposition remains poorly understood. We aim to study the gendered differences in inflammation reaction, and the association with severity and mortality of COVID-19.

Methods: In this retrospective study, we enrolled 548 COVID-19 inpatients from Tongji Hospital from 26 January to 5 February 2020, and followed up to 3 March 2020. Epidemiological, demographic and clinical features, and inflammatory indexes were collected and compared between males and females. The Cox proportional hazard regression model was applied to identify the gendered effect on mortality of COVID-19 after adjusting for age, comorbidity, and smoking history. The multiple linear regression method was used to explore the influence of sex on inflammation reaction.

Results: Males had higher mortality than females did (22.2% vs 10.4%), with an hazard ratio of 1.923 (95% confidence interval, 1.181-3.130); elder age and comorbidity were significantly associated with decease of COVID-19 patients. Excess inflammation reaction was related to severity of COVID-19. Male patients had greater inflammation reaction, with higher levels of interleukin 10, tumor necrosis factor-α, lactose dehydrogenase, ferritin, and hyper-sensitive C-reactive protein, but a lower lymphocyte count than females adjusted by age and comorbidity.

Conclusions: Sex, age, and comorbidity are critical risk factors for mortality of COVID-19. Excess innate immunity and proinflammation activity, and deficiency in adaptive immunity response promote males, especially elder males, to develop a cytokine storm, causing potential acute respiratory distressed syndrome, multiple organ failure and decease.
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http://dx.doi.org/10.1002/jmv.26137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300463PMC
November 2020

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan.

J Allergy Clin Immunol 2020 Jul 12;146(1):110-118. Epub 2020 Apr 12.

Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Respiratory Diseases, National Ministry of Health of the People's Republic of China and National Clinical Research Center for Respiratory Disease, Wuhan, China. Electronic address:

Background: In December 2019, the coronavirus disease 2019 (COVID-19) outbreak occurred in Wuhan. Data on the clinical characteristics and outcomes of patients with severe COVID-19 are limited.

Objective: We sought to evaluate the severity on admission, complications, treatment, and outcomes of patients with COVID-19.

Methods: Patients with COVID-19 admitted to Tongji Hospital from January 26, 2020, to February 5, 2020, were retrospectively enrolled and followed-up until March 3, 2020. Potential risk factors for severe COVID-19 were analyzed by a multivariable binary logistic model. Cox proportional hazard regression model was used for survival analysis in severe patients.

Results: We identified 269 (49.1%) of 548 patients as severe cases on admission. Older age, underlying hypertension, high cytokine levels (IL-2R, IL-6, IL-10, and TNF-α), and high lactate dehydrogenase level were significantly associated with severe COVID-19 on admission. The prevalence of asthma in patients with COVID-19 was 0.9%, markedly lower than that in the adult population of Wuhan. The estimated mortality was 1.1% in nonsevere patients and 32.5% in severe cases during the average 32 days of follow-up period. Survival analysis revealed that male sex, older age, leukocytosis, high lactate dehydrogenase level, cardiac injury, hyperglycemia, and high-dose corticosteroid use were associated with death in patients with severe COVID-19.

Conclusions: Patients with older age, hypertension, and high lactate dehydrogenase level need careful observation and early intervention to prevent the potential development of severe COVID-19. Severe male patients with heart injury, hyperglycemia, and high-dose corticosteroid use may have a high risk of death.
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http://dx.doi.org/10.1016/j.jaci.2020.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152876PMC
July 2020

Reply to Comments on 'Co-infection of SARS-CoV-2 and HIV in a patient in Wuhan city, China'.

J Med Virol 2020 09 9;92(9):1417-1418. Epub 2020 Jun 9.

Department of Respiratory and Critical Care Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

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http://dx.doi.org/10.1002/jmv.25838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262272PMC
September 2020

Co-infection of SARS-CoV-2 and HIV in a patient in Wuhan city, China.

J Med Virol 2020 06 11;92(6):529-530. Epub 2020 Mar 11.

Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

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http://dx.doi.org/10.1002/jmv.25732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228399PMC
June 2020

Loss of the Epigenetic Mark 5-hmC in Psoriasis: Implications for Epidermal Stem Cell Dysregulation.

J Invest Dermatol 2020 06 11;140(6):1266-1275.e3. Epub 2019 Dec 11.

Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Epigenetic regulation has a profound influence on stem cell fate during normal development in maintenance of physiologic tissue homeostasis. Here we report diminished ten-eleven translocation (TET) methylcytosine dioxygenase expression and loss of the DNA hydroxymethylation mark 5-hydroxymethylcytosine (5-hmC) in keratinocyte stem cells and transit amplifying cells in human psoriasis and in imiquimod-induced murine psoriasis. Loss of 5-hmC was associated with dysregulated keratinocyte stem cell kinetics, resulting in accumulation of nestin and FABP5-expressing transit amplifying cells to produce classic psoriatic epidermal architecture. Moreover, 5-hmC loss was accompanied by diminished TET1 and TET2 mRNA expression. Genome-wide mapping of epidermal 5-hmC in murine psoriasis revealed loci-specific loss of 5-hmC in genes regulating stem cell homeostasis, including MBD1, RTN1, STRN4, PRKD2, AKT1, and MAPKAP2, as well as those associated with RAR and Wnt/β-catenin signaling pathways. In vitro restoration of TET expression by ascorbic acid was accomplished in cultured human keratinocyte stem cells to show similar Ca-induced differentiation, resulting in increased 5-hmC levels and reduced nestin expression. To our knowledge, an epigenetic deficiency in psoriasis with relevance to stem cell dysregulation has not been previously reported. This observation raises the possibility that epigenetic modifiers that impact on the TET-5-hmC pathway may be a relevant approach of heretofore unappreciated therapeutic utility.
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http://dx.doi.org/10.1016/j.jid.2019.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931370PMC
June 2020

Thrombo-inflammatory prognostic score improves qSOFA for risk stratification in patients with sepsis: a retrospective cohort study.

Clin Chem Lab Med 2020 03;58(4):625-634

Department of Emergency Medicine, Laboratory of Emergency Medicine, West China Hospital, and Disaster Medical Center, Sichuan University, Sichuan, P.R. China.

Background Both the thrombo-inflammatory prognostic score (TIPS) and the quick sequential (sepsis-related) organ failure assessment (qSOFA) are quick prognostic scores for sepsis during the early phase, while either of two scores has limited prognostic value for sepsis patients. This study aimed to evaluate whether TIPS adds more information of sepsis risk stratification for qSOFA. Methods This was a retrospective cohort study of patients with sepsis in the emergency department (ED). We performed a receiver-operating characteristic curve, integrated discrimination improvement (IDI), net reclassification improvement (NRI) and decision-curve analysis (DCA) analyses to investigate whether TIPS can improve qSOFA for risk prediction in patients with sepsis. The primary endpoint was mortality and the secondary endpoints were mechanical ventilation and admission to the intensive care unit (ICU) during the 28-day follow-up. Results We identified 821 patients with sepsis. We randomly assigned the patients' data to a derivation group (n = 498; n = 112 died during the 28-days follow-up) or to a validation group (n = 323; n = 61). The addition of TIPS to qSOFA (T-qSOFA) improved the area under the curve (AUC) from 0.724 to 0.824 (p < 0.001) for predicting 28-day mortality. The discrimination improvement was confirmed by an IDI of 0.092 (p < 0.001). Addition of TIPS to the qSOFA resulted in a NRI of 0.247 (p < 0.001). The DCA showed that the net benefit of T-qSOFA was higher than that of TIPS or qSOFA for any threshold probabilities. Conclusions The prognostic value of qSOFA for patients with sepsis was enhanced by adding the TIPS score on admission for risk prediction in patients with sepsis during early phases in the ED.
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http://dx.doi.org/10.1515/cclm-2019-0864DOI Listing
March 2020

Intestinal dysbiosis promotes epithelial-mesenchymal transition by activating tumor-associated macrophages in ovarian cancer.

Pathog Dis 2019 03;77(2)

Heze Municipal Hospital of Shandong Province, No 2888 Caozhou West Road, Heze 274000, Shandong, China.

We aimed to investigate the relationship of intestinal dysbiosis (IDB) and ovarian cancer progression, and understand its underlying signaling mechanisms. IDB was induced with high dose antibiotics. The xenograft mouse model was used to assess the tumor progression. Real-time polymerase chain reaction and immunoblotting are commonly used quantitative methods, and they were used to quantify epithelial-mesenchymal transition (EMT) markers in this paper. Meanwhile, cellular proliferation was also measured. First, IDB could promote the growth of xenograft tumors and induce the EMT. Serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 also increased remarkably. In addition, the production and secretion of TNF-α and IL-6 in macrophages isolated from IDB model mice were observably higher. In vitro, conditioned medium could significantly stimulate the development of EMT in ovarian cancer cells. Loss of macrophages completely offset the pro-tumor effects of IDB. IDB can stimulate the activation of tumor-associated macrophages in ovarian cancer, which is achieved by secreting pro-inflammatory cytokines IL-6 and TNF-α, and ultimately induces the development of EMT.
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http://dx.doi.org/10.1093/femspd/ftz019DOI Listing
March 2019

Reversal of TET-mediated 5-hmC loss in hypoxic fibroblasts by ascorbic acid.

Lab Invest 2019 07 5;99(8):1193-1202. Epub 2019 Mar 5.

Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Hypoxia resulting in hypoxia-inducible factor-1 alpha (HIF-1α) induction is known to drive scar formation during cutaneous wound healing, and may be responsible for excessive fibrosis inherent to hypertrophic scars and keloids. Because epigenetic pathways play an important role in regulation of fibrosing processes, we evaluated patient scars for DNA hydroxymethylation (5-hydroxymethylcytosine; 5-hmC) status and documented a significant decrease in scar fibroblasts. To test this finding in vitro, human fibroblasts were cultured with cobalt chloride (CoCl), a known stimulant of HIF-1α. HIF-1α induced so resulted in loss of 5-hmC similar to that seen in naturally occurring scars and was associated with significant downregulation of one of the 5-hmC converting enzymes-ten-eleven translocation 3 (TET3)-as well as increased expression of phosphorylated focal adhesion kinase (p-FAK), which is important in wound contracture. These changes were partially reversed by exposure to ascorbic acid, a recognized epigenetic regulator potentially capable of minimizing excessive scar formation and promoting a more regenerative healing response. Our results provide a novel and translationally relevant mechanism whereby epigenetic regulation of scar formation may be manipulated at the level of fibroblast DNA hydroxymethylation.
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http://dx.doi.org/10.1038/s41374-019-0235-8DOI Listing
July 2019

MSK2 promotes proliferation and tumor formation in squamous cervical cancer via PAX8/RB-E2F1/cyclin A2 axis.

J Cell Biochem 2019 Feb 12. Epub 2019 Feb 12.

Department of Obstetrics and Gynecology, Heze Municipal Hospital, Heze, Shandong, China.

Patients with cervical cancer have abnormal cell proliferation and invasion after many years of latency. However, the precise mechanisms remain unclear. Mitogen- and stress-activated kinase 2 (MSK2) is a serine/threonine kinase which displays a phenotype that promotes tumor growth and metastasis in many different types of tumors. The aim of the present study was to determine the effects of MSK2 on the proliferation of cervical cancer cells and elucidate the signaling pathways through which MSK2 exerts its effects in the pathogenesis of squamous cell carcinoma (SCC). Our results confirmed that MSK2 expression was significantly upregulated in cervical cancer cells both in vivo and in vitro. We further found that the expression patterns of paired-box gene 8 (PAX8) and MSK2 were positively correlated in cervical cancer specimens. Moreover, MSK2 knockdown inhibited the phosphorylation of PAX8 and retinoblastoma protein (RB), and suppressed the sequential expressions of cell proliferation factors E2F1 and cyclin A2, resulting in the inhibition of SCC cell proliferation and tumor formation. Thus, this study demonstrates that MSK2 has oncogenic effects in the formation and development of SCC via the PAX8/RB-E2F1/cyclin A2 axis.
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http://dx.doi.org/10.1002/jcb.28421DOI Listing
February 2019

Mucin 1 downregulation impairs the anti-necroptotic effects of glucocorticoids in human bronchial epithelial cells.

Life Sci 2019 Mar 7;221:168-177. Epub 2019 Feb 7.

Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei 430030, China. Electronic address:

Aims: To investigate whether mucin 1 (MUC1) downregulation reduced the sensitivity of tumor necrosis factor-alpha (TNF-α)-induced bronchial epithelial cells to glucocorticoid-mediated necroptosis and explore the underlying mechanisms.

Main Methods: The human lung bronchial epithelial cell line (16HBE) was transfected with small interfering RNA (siRNA) against MUC1 and then stimulated by TNF-α, where some cells were pretreated with dexamethasone. Flow cytometry was performed to analyze necroptosis in 16HBE cells, and western blot analysis was used to detect protein expression levels of MUC1, glucocorticoid receptor (GR)α, GRβ, NF-κB p65, phospho-p65 (p-p65), and histone deacetylase-2 (HDAC2). Additionally, nuclear translocation of MUC1 and GRα was assessed by immunofluorescence.

Key Findings: We observed that MUC1 downregulation by siRNA significantly augmented TNF-α-induced necroptosis in 16HBE cells, and that dexamethasone showed impaired anti-necroptotic effects of MUC1 downregulation. Furthermore, we found that GRα nuclear translocation was inhibited in 16HBE cells with MUC1 downregulation, and that dexamethasone-mediated inhibition of p65 phosphorylation was lower in cells transfected with MUC1-siRNA compared to those transfected with negative control siRNA.

Significance: Impaired GRα nuclear translocation and inhibited p-p65 expression might contribute to glucocorticoid resistance caused by MUC1 deficiency in TNF-α-induced necroptosis in 16HBE cells, and should be considered as a potential target for the development of novel therapeutics for asthma.
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http://dx.doi.org/10.1016/j.lfs.2019.02.013DOI Listing
March 2019

MUC1 downregulation promotes TNF-α-induced necroptosis in human bronchial epithelial cells via regulation of the RIPK1/RIPK3 pathway.

J Cell Physiol 2019 Jan 21. Epub 2019 Jan 21.

Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.

MUC1 (mucin 1), a membrane-tethered mucin glycoprotein, is highly expressed on the surface of respiratory epithelial cells and plays a key role in anti-inflammatory and antiapoptotic responses against infections. However, little is known about the link between MUC1 and necroptosis in asthma. This study aimed to investigate the effects of MUC1 on TNF-α-induced necroptosis in human bronchial epithelial (16HBE) cells and the underlying molecular mechanism. Negative control and MUC1-siRNA cells were treated with TNF-α in the presence or absence of necrostatin-1 (Nec-1). Necroptosis was investigated using flow cytometry analyses, and the protein expression levels of MUC1, receptor-interacting protein kinase-1 (RIPK1), RIPK3, and phosphorylated RIPK1 were detected by western blot analysis. In addition, the interactions between RIPK and MUC1 were analyzed by coimmunoprecipitation. The results demonstrated that TNF-α could induce necroptosis of 16HBE cells, and MUC1 expression was increased upon treatment with TNF-α. The coimmunoprecipitation outcomes showed that MUC1 interacted with RIPK1 but not with RIPK3 in 16HBE cells, and the interaction was augmented by TNF-α. Furthermore, MUC1 downregulation obviously increased the TNF-α-induced necroptosis of 16HBE cells and enhanced the expression of p-RIPK1-Ser166 and RIPK3, whereas these phenomena were partially attenuated by Nec-1. These results may provide a new insight into the mechanism of severe asthma-related necroptosis and lay a foundation for the future development of new anti-inflammatory drugs for asthma.
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http://dx.doi.org/10.1002/jcp.28148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590293PMC
January 2019

Chronic rejection of human face allografts.

Am J Transplant 2019 04 10;19(4):1168-1177. Epub 2018 Nov 10.

Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.

Face vascularized composite allografts (FVCAs) have helped patients with severe facial disfigurement, with acute rejection now largely controlled through iatrogenic immunosuppression. However, little is known regarding the incidence and mechanism(s) of more long-term pathologic alterations in FVCAs that may affect function and graft durability. Protocol surveillance biopsy specimens for up to an 8-year interval in 7 patients who received FVCAs at our institution revealed histopathologic evidence of chronic rejection. Clinical manifestations included features of premature aging, mottled leukoderma accentuating suture lines, telangiectasia, and dryness of nasal mucosa. Pathologic changes consisted of epidermal thinning accompanied by discrete foci of lymphocyte-mediated cytotoxicity, hyperkeratosis, follicular plugging, vascular ectasia, and sclerosis beneath the epidermal layer associated with collagen type I deposition. Genomic interrogation and immunohistochemistry of sclerotic zones revealed upregulation of the AP-1 pathway components, JunB and c-Fos, previously implicated in overproduction of type I dermal collagen in the setting of systemic sclerosis. We conclude that some patients develop chronic rejection in FVCAs with striking similarities to alterations seen in certain autoimmune cutaneous disorders (lupus erythematosus and scleroderma/chronic sclerodermoid graft-versus-host disease). Identification of relevant pathways and genes, such as JunB and c-Fos, may provide new targets for preventative therapies for chronic immune-mediated changes in vascularized composite allografts.
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http://dx.doi.org/10.1111/ajt.15143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433509PMC
April 2019

Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer.

Nature 2018 07 18;559(7715):637-641. Epub 2018 Jul 18.

Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Diabetes is a complex metabolic syndrome that is characterized by prolonged high blood glucose levels and frequently associated with life-threatening complications. Epidemiological studies have suggested that diabetes is also linked to an increased risk of cancer. High glucose levels may be a prevailing factor that contributes to the link between diabetes and cancer, but little is known about the molecular basis of this link and how the high glucose state may drive genetic and/or epigenetic alterations that result in a cancer phenotype. Here we show that hyperglycaemic conditions have an adverse effect on the DNA 5-hydroxymethylome. We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo. Treatment with the anti-diabetic drug metformin protects AMPK-mediated phosphorylation of serine 99, thereby increasing TET2 stability and 5hmC levels. These findings define a novel 'phospho-switch' that regulates TET2 stability and a regulatory pathway that links glucose and AMPK to TET2 and 5hmC, which connects diabetes to cancer. Our data also unravel an epigenetic pathway by which metformin mediates tumour suppression. Thus, this study presents a new model for how a pernicious environment can directly reprogram the epigenome towards an oncogenic state, offering a potential strategy for cancer prevention and treatment.
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http://dx.doi.org/10.1038/s41586-018-0350-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430198PMC
July 2018

Comparison of Clinical Features and Prognostic Factors of Cryptococcal Meningitis Caused by Cryptococcus neoformans in Patients With and Without Pulmonary Nodules.

Mycopathologia 2019 Feb 8;184(1):73-80. Epub 2018 May 8.

Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, People's Republic of China.

Whether the clinical features of cryptococcal meningitis (CM) patients vary with the coexistence of pulmonary nodules is not clear. This study aimed to compare the clinical features of CM in patients with and without pulmonary nodules detected by chest computed tomography (CT). The medical records of CM patients hospitalized in Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology from January 1, 2010, to December 31, 2016, were retrospectively reviewed. Baseline demographics, laboratory and radiographic findings, clinical managements, and outcomes were analyzed. A total of 90 CM patients were enrolled. Forty (44.4%) patients had pulmonary nodules (PN-positive), and 50 (55.6%) patients had no pulmonary nodules (PN-negative). Compared with PN-negative patients, PN-positive patients had higher cerebrospinal fluid (CSF)/serum albumin ratios, higher rates of CSF protein > 1000 mg/L, CSF glucose < 2.5 mmol/L, worse overall treatment response, higher rates of abnormal head CT and magnetic resonance imaging manifestations, and more unfavorable clinical outcomes. Multivariate analysis showed that immunocompromise (p = 0.037) and CSF glucose < 2.5 mmol/L (p = 0.044) indicated poor outcome in PN-positive patients, while CSF glucose < 2.5 mmol/L (p = 0.025) also indicated poor outcome in PN-negative patients. Amphotericin B in the initial therapy was a protective factor for PN-negative patients (p = 0.008). Certain clinical features showed significant differences between CM patients with and without pulmonary nodules, and several independent contributing factors impacted the clinical outcomes for CM patients. Future studies should be performed to further examine these factors.
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http://dx.doi.org/10.1007/s11046-018-0263-8DOI Listing
February 2019

Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer.

Clin Cancer Res 2018 03 20;24(6):1389-1401. Epub 2017 Dec 20.

Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation. We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically. This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in patients newly diagnosed with HGSOC. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy and , decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum-resistant disease. Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951622PMC
March 2018

Osteogenesis effects of strontium-substituted hydroxyapatite coatings on true bone ceramic surfaces in vitro and in vivo.

Biomed Mater 2017 12 20;13(1):015018. Epub 2017 Dec 20.

Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, People's Republic of China.

To develop bioactive bone graft materials that can induce rapid bone regeneration, a novel biomaterial was synthesized by coating true bone ceramic (TBC) substrates with strontium-substituted nano-hydroxyapatites (SrHA) (Sr concentrations of 0%, 10%, 40%, 100%) through a sol-gel dip-coating approach. All coated TBC scaffolds retained the inherent natural trabecular structure, porosity, compressive strength and simultaneously possessed a micro/nanotopography SrHA layer on the substrate surface. The dimension of the deposited crystal increased and the density of the deposited apatite particles became sparse with increasing Sr content, but a unique HA crystalline phase was observed under all conditions. The modified TBC scaffolds significantly enhanced the adhesion, proliferation, and osteogenic differentiation of MC3T3-E1 osteoblasts in vitro. Particularly, the Sr10-TBC group (10 mol% Sr in apatite coating) revealed the highest osteogenic efficacy over the other groups. Three-dimensional CT imaging and histological evaluations on a bilateral critical-sized rabbit radial defect model for 12 weeks showed significant bone formation in the Sr10-TBC implants. The new bone area ratios of the Sr10-TBC group were significantly higher than that of the TBC group. Additionally, Sr10-TBC implants showed faster degradability compared with raw TBC implants during the 12 weeks of implantation. The results indicate that TBC modification with 10% SrHA coating stimulated osteogenesis and could be a promising biomaterial for future bone defect regeneration.
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http://dx.doi.org/10.1088/1748-605X/aa89afDOI Listing
December 2017

Biological significance of 5-hydroxymethylcytosine in oral epithelial dysplasia and oral squamous cell carcinoma.

Oral Surg Oral Med Oral Pathol Oral Radiol 2018 Jan 16;125(1):59-73.e2. Epub 2017 Jun 16.

Department of Oral Medicine and Dentistry, Brigham and Women's Hospital, Harvard School of Dental Medicine, Boston, MA, USA. Electronic address:

Objectives: The aim of this study was to determine the levels of 5-hydroxylmethylcytosine (5-hmC) in oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC) compared with those in benign, reactive inflammatory lesions and to explore whether DNA hydroxymethylation may serve as a novel biomarker for early diagnosis and prognosis of OSCC.

Study Design: The study included normal mucosa from uninvolved margins of 9 fibromas, 10 oral lichen planus, 15 OED, and 23 OSCC. Cultured human keratinocyte lines from benign oral mucosa, OED, and OSCC, as well as a murine model in which OSCC was induced with 4-nitroquinoline-1-oxide, were also evaluated.

Results: Progressive loss of 5-hmC from benign oral mucosal lesions to OED and OSCC was documented in patient samples. Decreased levels in 5-hmC that typify OED and OSCC were also detectable in human cell lines. Moreover, we characterized similar alterations in 5-hmC in an animal model of OED/OSCC.

Conclusions: This study demonstrated that 5-hmC distinguishes OED and OSCC from benign lesions with high sensitivity and specificity. Consequently, loss of 5-hmC may be useful for the diagnosis of OED with potential implications for therapy of OSCC.
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http://dx.doi.org/10.1016/j.oooo.2017.06.006DOI Listing
January 2018

Cyclic peptide *CRRETAWAC* attenuates fibronectin-induced cytokine secretion of human airway smooth muscle cells by inhibiting FAK and p38 MAPK.

J Cell Mol Med 2017 10 12;21(10):2535-2541. Epub 2017 Apr 12.

Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.

α5β1 integrin is highly expressed in airway smooth muscle cells and mediate the adhesion of airway smooth muscle cells to fibronectin to regulate airway remodelling in asthma. This study aimed to investigate the effects of synthetic cyclic peptide *CRRETAWAC* on fibronectin-induced cytokine secretion of airway smooth muscle cells and the underlying mechanism. Human airway smooth muscle cells were isolated and treated with fibronectin, IL-13, *CRRETAWAC* peptide, α5β1 integrin-blocking antibody, FAK inhibitor or p38 MAPK inhibitor. The transcription and secretion of eotaxin-1 and RANTES were detected by real-time PCR and ELISA, respectively. The phosphorylation of FAK and MAPKs including p38, ERK1/2 and JNK1/2 was detected by Western blot analysis. The transcription and secretion of eotaxin-1 and RANTES increased in airway smooth muscle cells cultured in fibronectin-coated plates. However, α5β1 integrin-blocking antibody, *CRRETAWAC* peptide, FAK inhibitor or p38 MAPK inhibitor significantly reduced mRNA levels and the secretion of eotaxin-1 and RANTES in airway smooth muscle cells cultured in fibronectin-coated plates. In addition, the phosphorylation of FAK and p38 MAPK was significantly increased in airway smooth muscle cells cultured in fibronectin-coated plates compared to the cells cultured in uncoated plates and was significantly reduced in airway smooth muscle cells treated with *CRRETAWAC* peptide. Fibronectin induces cytokine synthesis and secretion of airway smooth muscle cells. Peptide *CRRETAWAC* antagonizes fibronectin-induced cytokine synthesis and secretion of airway smooth muscle cells via the inhibition of FAK and p38 MAPK, and is a potential agent for the therapy of asthma.
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http://dx.doi.org/10.1111/jcmm.13174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618697PMC
October 2017

5-Hydroxymethylcytosine is a nuclear biomarker to assess biological potential in histologically ambiguous heavily pigmented melanocytic neoplasms.

J Cutan Pathol 2017 Mar 6;44(3):249-255. Epub 2017 Feb 6.

Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Background: 5-Hydroxymethylcytosine (5-hmC) is an epigenetic marker detectable through immunohistochemistry (IHC) that has been shown to distinguish benign nevi from melanoma with high sensitivity and specificity. The purpose of the study was to explore its diagnostic utility in a subset of histologically challenging, heavily pigmented cutaneous melanocytic neoplasms.

Methods: 5-hmC IHC was performed on 54 heavily pigmented melanocytic tumors. Semi-quantitative analysis of immunoreactivity was correlated with clinical, pathologic and follow-up data.

Results: Benign melanocytic neoplasms (4 of 4 blue nevi with epithelioid change; 12 of 12 combined nevi; 5 of 5 deep penetrating nevi, DPN) exhibited strong 5-hmC nuclear reactivity. Eight heavily pigmented blue nevus-like melanomas and 7 of 8 pigmented epithelioid melanocytomas (PEM) showed significant 5-hmC loss. Five of 7 atypical DPN cases and 8 of 10 melanocytic tumors of uncertain malignant potential (MELTUMP) showed low to intermediate 5-hmC immunoreactivity. These differences were statistically significant (P-value <.0001).

Conclusions: Loss of 5-hmC may be helpful in differentiating benign, diagnostically challenging, heavily pigmented melanocytic tumors from those with malignant potential. The intermediate to low 5-hmC immunoreactivity in atypical DPNs, PEMs and so-called MELTUMP categories further underscores the need to consider these neoplasms as having some potential for lethal biological behavior.
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http://dx.doi.org/10.1111/cup.12880DOI Listing
March 2017

Gene expression profiling of anti-CTLA4-treated metastatic melanoma in patients with treatment-induced autoimmunity.

Lab Invest 2017 02 5;97(2):207-216. Epub 2016 Dec 5.

Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.

Ipilimumab (IPI) is a monoclonal antibody that targets the inhibitory CTLA4 receptor of T cells, enhancing T-cell-driven antitumor responses. IPI therapy in metastatic melanoma results in significant improvement in disease-free and overall survival, although after initial responses disease progression generally ensues. Identification of specific responses in tissue where melanoma tumor cells are subjected to IPI-driven immune attack may reveal mechanisms of treatment efficacy or resistance, permitting refinement of targeted therapeutic approaches. We used NanoString digital barcoding chemistry to identify changes in the transcriptome of metastatic melanoma cells before and after IPI treatment using two comprehensive panels containing a total of 1330 unique genes. Only patients who developed autoimmune disorders following treatment, signifying a robust immune response, were included. Despite evidence of an enhanced immune response, most patients eventually exhibited disease progression. Overall, data from five pre-IPI tumors and four post-IPI tumor samples (from three patients) permitted identification of several candidate genes that showed increased expression based on normalized counts after therapy. These included TTK (~3.1-fold, P=1.18e-4), which encodes a dual-specificity protein tyrosine kinase, a known cell cycle regulator, and BIRC5 (~3.0-fold, P=9.36e-4), which encodes the antiapoptotic protein survivin. Both TTK (MPS1) and survivin are targetable proteins against which a number of pharmacologic agents have been developed. CDK1, which encodes a protein tyrosine kinase known to phosphorylate survivin, was also upregulated (~3.2-fold, P=2.80-3). Tumor cell expression of TTK and survivin proteins was confirmed using immunohistochemistry in an expanded patient cohort. Differences in gene expression for several commonly encountered immune antigens, such as CD3, CD4, CD8, and CTLA4, were not statistically significant, likely reflecting the long length of time (average 323 days) between the last IPI dose and post-treatment biopsies. Although our sample size is limited, these results for the first time identify targetable genes that are significantly altered by interaction between a highly activated, IPI-treated immune system and melanoma cells.
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http://dx.doi.org/10.1038/labinvest.2016.126DOI Listing
February 2017
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