Publications by authors named "Huang Huang"

286 Publications

Recurrent abdominal pain due to small bowel volvulus after transabdominal preperitoneal hernioplasty: A case report and review of literature.

World J Clin Cases 2021 May;9(15):3696-3703

Department of Hernia Surgery, Tianjin Union Medical Centre, Tianjin 300000, China.

Background: Compared with open mesh repair, transabdominal preperitoneal (TAPP) hernioplasty results in less chronic postoperative inguinal pain and faster postoperative recovery. However, it may still lead to rare but serious complications. Here we report a case of intestinal volvulus with recurrent abdominal pain as the only clinical symptom, which occurred 3 mo after TAPP repair for bilateral inguinal hernia.

Case Summary: A 50-year-old male patient underwent laparoscopic TAPP for bilateral inguinal hernias. After the operation, he experienced recurring pain in his lower right abdomen around the surgical area, which was relieved after symptomatic treatment. Three months after the surgery, the abdominal pain became severe and was aggravated over time. The whirlpool sign of the mesentery was seen on contrast-enhanced computed tomography (CT). Laparoscopic exploration confirmed that a barb of the V-Loc™ suture penetrated the peritoneum, which caused the adhesion of the small intestinal wall to the site of peritoneal injury, forming intestinal volvulus. Since there was no closed-loop obstruction or intestinal ischemia, recurrent abdominal pain became the only clinical manifestation in this case. After laparoscopic lysis of adhesions and reduction of intestinal volvulus, the patient recovered and was discharged.

Conclusion: The possibility of intestinal volvulus should be considered in patients who experience recurrent abdominal pain following TAPP surgery during which barbed V-Loc sutures are used for closing the peritoneum. Contrast-enhanced CT and active laparoscopic exploration can confirm the diagnosis and prevent serious complications.
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http://dx.doi.org/10.12998/wjcc.v9.i15.3696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130073PMC
May 2021

Impact of Ionic Liquids on Effectiveness of Tuning the Emissivity of Multilayer Graphene.

ACS Appl Mater Interfaces 2021 Jun 24;13(22):26256-26263. Epub 2021 May 24.

College of Physical Science and Technology, Xiamen University, Xiamen, Fujian 361000, China.

Multilayer graphene has been employed as a functional material for tuning the emissivity in mid- and long-infrared range, which shows great potential for various applications, such as radiative cooling and thermal camouflage. However, the stability of the multilayer graphene is not sufficient for practical applications yet. Even though it is reported that the integrity of the multilayer graphene is compromised by ion intercalation, the detailed mechanism is rather unclear. Here, a set of ionic liquids is deployed as sources of electronic charges for tuning the emissivity of multilayer graphene. It is found that the emissivity modulator using 1-ethyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide ([EMIm]NTf) as the ionic liquid provides a modulation depth of about 0.52 (i.e., about 21% larger than the best-reported value) while maintaining a reasonable device lifetime. The microscopic structures of the multilayer graphene in an operational and failure modulator are investigated by scanning electron microscopy, Raman spectroscopy, X-ray diffraction. The results indicate that the modulation depth of emissivity is negatively correlated with the initial voltage, which represents the reaction potential between the ionic liquid and graphene. Furthermore, not only the chemical reactivity but also the size of both anion and cation in the ionic liquids play important roles in maintaining stability of the modulator. Therefore, a set of criteria (e.g., low initial voltage and small size of anion and cation) is proposed to select proper ionic liquids for emissivity modulation. This not only sheds light on the underlying physics of the modulator but also promotes its practical applications.
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http://dx.doi.org/10.1021/acsami.0c22167DOI Listing
June 2021

Nanoparticle-enabled innate immune stimulation activates endogenous tumor-infiltrating T cells with broad antigen specificities.

Proc Natl Acad Sci U S A 2021 May;118(21)

Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305;

Tumors are often infiltrated by T lymphocytes recognizing either self- or mutated antigens but are generally inactive, although they often show signs of prior clonal expansion. Hypothesizing that this may be due to peripheral tolerance, we formulated nanoparticles containing innate immune stimulants that we found were sufficient to activate self-specific CD8 T cells and injected them into two different mouse tumor models, B16F10 and MC38. These nanoparticles robustly activated and/or expanded antigen-specific CD8 tumor-infiltrating T cells, along with a decrease in regulatory CD4 T cells and an increase in Interleukin-17 producers, resulting in significant tumor growth retardation or elimination and the establishment of immune memory in surviving mice. Furthermore, nanoparticles with modification of stimulating human T cells enabled the robust activation of endogenous T cells in patient-derived tumor organoids. These results indicate that breaking peripheral tolerance without regard to the antigen specificity creates a promising pathway for cancer immunotherapy.
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http://dx.doi.org/10.1073/pnas.2016168118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166076PMC
May 2021

Enhanced formation of dichloroacetamide and dichloroacetonitrile during chloramination of drinking water and model organic matters in the presence of copper corrosion products.

Sci Total Environ 2021 Sep 22;785:147242. Epub 2021 Apr 22.

Petrochina North China Gas Marketing Company, Beijing 100029, PR China.

The formation of nitrogenous disinfection byproducts (N-DBPs) occurs in chloraminated water in drinking water distribution systems and may be affected by metal pipe materials and their corrosion products. The effect of copper corrosion products, including Cu, CuO, and CuO, on the formation of dichloroacetonitrile (DCAN) and dichloroacetamide (DCAcAm) was investigated during chloramination of natural organic matter (NOM), model precursors (carboxylic acids and amino acids), and real water samples. Copper corrosion products enhanced DCAN and DCAcAm formation during chloramination of NOM by 33%-72% and 11%-80%, respectively. Addition of N-labeled monochloramine showed that the copper corrosion products primarily enhanced the formation of DCAN using organic nitrogen and monochloramine as nitrogen sources, and the formation of DCAcAm using monochloramine as the nitrogen source, but had a limited impact on the formation of DCAcAm using organic nitrogen as the nitrogen source. A distinct N-DBP formation pathway in the presence of Cu and CuO was observed using tyrosine as a model compound, which included the formation of 1,4-benzoquinone as a dominant intermediate. On reaction with monochloramine, the 1,4-benzoquinone greatly contributed to enhancement of DCAN and DCAcAm formation using monochloramine as the nitrogen source. During chloramination of real water samples, Cu and CuO enhanced DCAN formation by 9-40% and DCAcAm formation by 16-33%. This study increases our knowledge of copper catalyzed DCAN and DCAcAm formation in copper pipes, which will be meaningful for water safety in distribution systems using chloramine disinfection.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147242DOI Listing
September 2021

Formation mechanism of chloropicrin from amines and free amino acids during chlorination: A combined computational and experimental study.

J Hazard Mater 2021 Apr 6;416:125819. Epub 2021 Apr 6.

Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science & Bioengineering, Beijing University of Technology, Beijing 100124, China.

Chloropicrin as one of the most frequently detected N-DBPs has drawn great attention due to its high toxicity. However, our understanding of its formation mechanism is still very limited. A combined computational and experimental approach was used in this study to reveal chloropicrin formation mechanism during chlorination. Ethylamine, n-propylamine, alanine and tryptophan along with the above two amines and their four derivatives substituted by -OH or/and -NO groups were chosen as computational and experimental model precursors, respectively. The results indicate that primary amines and free amino acids are more likely to share the same chloropicrin formation pathway including N-chlorination, imidization, β-C-alcoholization, N-nitration, α-C-chlorination and dealdehydation processes. Moreover, elimination of hydrochloric acid from N,N-dichloro-amine and electrophilic addition of N-chloroalkylimide with hypochlorous acid were found to be the rate-limiting steps among all the elementary reactions. By skipping over both of the above rate-limiting steps, RCH(OH)CHNO and RCH(OH)CHNH(OH) compounds were proposed to be potent chloropicrin precursors, and experiments confirmed that 2-nitroethanol and N-methylhydroxylamine have the highest chloropicrin yields in the chlorination among all the precursors reported to date. The findings of this work are helpful for expanding the knowledge of chloropicrin formation mechanisms and predicting the potential chloropicrin precursors.
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http://dx.doi.org/10.1016/j.jhazmat.2021.125819DOI Listing
April 2021

O-GlcNAcylation promotes the migratory ability of hepatocellular carcinoma cells via regulating FOXA2 stability and transcriptional activity.

J Cell Physiol 2021 Apr 12. Epub 2021 Apr 12.

School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China.

O-GlcNAcylation is a posttranslational modification that regulates numerous nuclear and cytoplasmic proteins and is emerging as a key regulator of various biological processes, such as transcription, signal transduction, and cell motility. Although increasing evidence has shown that elevated levels of global O-GlcNAcylation are linked to the metastasis in hepatocellular carcinoma (HCC) cells, the underlying mechanism is still ambiguous. In this study, we demonstrated that forkhead box protein A2 (FOXA2), an essential transcription factor for liver homeostasis and HCC developing, was O-GlcNAcylated by O-GlcNAc transferase (OGT) and regulates HCC cells migration and invasion. Opposite FOXA2 and OGT expression tendency were observed in HCC tissues, and lower FOXA2 levels predicted a poor prognosis in HCC patients. The reduction of FOXA2 in HCC cells was found to be inversely correlated with the cellular O-GlcNAcylation and cell migratory ability. Notably, we found that FOXA2 was modified by O-GlcNAcylation and that O-GlcNAcylation activated the ubiquitination degradation of FOXA2 in highly metastatic HCC cells. Although this modification did not affect FOXA2 nuclear localization capability, O-GlcNAcylation on FOXA2 was key for attenuating FOXA2-mediated transcription. O-GlcNAcylation decreased the transcription of FOXA2 downstream target gene E-cadherin and it ultimately promoted O-GlcNAcylation-mediated HCC cell migration and invasion. The results provide insights into the role of O-GlcNAcylation in regulating FOXA2 activity and suggest its important implications in HCC metastasis.
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http://dx.doi.org/10.1002/jcp.30385DOI Listing
April 2021

Effect of "drip-and-ship" and "drip-and-drive" on endovascular treatment of acute ischemic stroke with large vessel occlusion: a single-center retrospective study.

Acta Radiol 2021 Apr 7:2841851211006897. Epub 2021 Apr 7.

Department of Interventional Radiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China.

Background: Patients with acute ischemic stroke (AIS) caused by large vessel occlusion (LVO) were usually transferred from a primary stroke center (PSC) to a comprehensive stroke center (CSC) for endovascular treatment (drip-and-ship [DS]), while driving the doctor from a CSC to a PSC to perform a procedure is an alternative strategy (drip-and-drive [DD]).

Purpose: To compare the efficacy and prognosis of the two strategies.

Material And Methods: From February 2017 to June 2019, 62 patients with LVO received endovascular treatment via the DS and DD models and were retrospectively analyzed from the stroke alliance based on our CSC. Primary endpoint was door-to-reperfusion (DTR) time. Secondary endpoints included puncture-to-recanalization (PTR) time, modified Thrombolysis in Cerebral Infarction (mTICI) rates at the end of the procedure, and modified Rankin Scale (mRS) at 90 days.

Results: Forty-one patients received the DS strategy and 21 patients received the DD strategy. The DTR time was significantly longer in the DS group compared to the DD group (315.5 ± 83.8 min vs. 248.6 ± 80.0 min;  < 0.05), and PTR time was shorter (77.2 ± 35.9 min vs. 113.7 ± 69.7 min;  = 0.033) compared with the DD group. Successful recanalization (mTICI 2b/3) was achieved in 89% (36/41) of patients in the DS group and 86% (18/21) in the DD group ( = 1.000). Favorable functional outcomes (mRS 0-2) were observed in 49% (20/41) of patients in the DS group and 71% (15/21) in the DD group at 90 days ( = 0.089).

Conclusion: Compared with the DS strategy, the DD strategy showed more effective and a trend of better clinical outcomes for AIS patients with LVO.
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http://dx.doi.org/10.1177/02841851211006897DOI Listing
April 2021

Lack of association between single nucleotide polymorphisms in TCF7L2 and T2DM in the Chinese Yao population: A case-control study.

Medicine (Baltimore) 2021 Mar;100(12):e25326

Department of Endocrinology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China.

Abstract: Single-nucleotide polymorphisms (SNPs) in the transcription factor 7-like 2 (TCF7L2) gene have been identified to be associated with the susceptibility to type 2 diabetes mellitus (T2DM) in various populations worldwide, but the results in Chinese are conflicting, and no data are available about the Liannan Yao population. Therefore, this study aimed to investigate the association of the TCF7L2 gene polymorphisms (rs12255372, rs7903146, rs7901695, rs11196205, and rs7895340) with T2DM in the Yao population living in the rural areas in the Liannan Yao Autonomous County.This was a case-control study of 28 subjects with T2DM or prediabetes and 52 non-T2DM controls, all from the Chinese Yao population and recruited between January 2019 and June 2020. Patients with T2DM and prediabetes were grouped as the case group. The five SNPs (rs12255372, rs7903146, rs7901695, rs11196205, and rs7895340) were examined by polymerase chain reaction and direct genomic DNA sequencing in case and control groups.The subjects in case group were older than the controls (55±14 vs 48 ± 15 years, P = .047), had higher FBG levels (9.31 ± 5.43 vs 4.09 ± 0.81, P < .001), higher TC (5.79 ± 1.29 vs 5.13 ± 1.18 mmol/L, P = .025), and higher triglycerides (2.94 ± 2.04 vs 1.86 ± 1.39 mmol/L, P = .003). The genotypic distribution for each of the SNPs was in agreement with the Hardy-Weinberg equilibrium. There were no statistically significant differences in the distributions of genotypes or alleles at all five SNPs of the TCF7L2 gene between the case and control groups (all P > .05).TCF7L2 SNPs were not associated with T2DM in the Liannan Yao population.
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http://dx.doi.org/10.1097/MD.0000000000025326DOI Listing
March 2021

Lichtenstein inguinal hernia repairs with porcine small intestine submucosa: a 5- year follow-up. a prospective randomized controlled study.

Regen Biomater 2021 Feb 4;8(1):rbaa055. Epub 2021 Jan 4.

Department of General Surgery, China-Japan Friendship Hospital, Sakura Garden East Street, Chaoyang District, Beijing 100029, China.

Porcine small intestine submucosa (SIS) biologic patch has been used in inguinal hernia repair. However, there are little data available to assess the long-term effect after repair. This study aimed to explore the long-term effect of SIS patch in open inguinal hernia repair. Sevent-six patients with unilateral inguinal hernia were treated with Lichtenstein tension-free hernia repair using SIS patch (Beijing Datsing Bio-Tech Co., Ltd.) and Surgisis patch (COOK, USA) in Tianjin Union Medical Center and China-Japan Friendship Hospital. In the trial, the long-term efficacy of the treatment group and the control group were compared. A total of 66 patients in both groups received long-term follow-up (> 5 years) after surgery, with a follow-up rate of 86.8%. During the follow-up period, there was one case of recurrence, one case of chronic pain in the control group. There was no statistically significant difference ( > 0.05) in terms of recurrence, chronic pain, foreign body sensation and infection between the two groups of patients. After long-term observations, it has been found that the porcine small intestinal submucosa (SIS) biological patch is safe and effective for inguinal hernia Lichtenstein repair, and has a low recurrence rate and complication rate.
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http://dx.doi.org/10.1093/rb/rbaa055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947568PMC
February 2021

Additive value of texture analysis based on breast MRI for distinguishing between benign and malignant non-mass enhancement in premenopausal women.

BMC Med Imaging 2021 Mar 12;21(1):48. Epub 2021 Mar 12.

Department of Radiology, Guangdong Women and Children Hospital, No.521, Xingnan Road, Panyu District, Guangzhou, 511400, China.

Background: Non-mass enhancement (NME) is a diagnostic dilemma and highly reliant on the experience of the radiologists. Texture analysis (TA) could serve as an objective method to quantify lesion characteristics. However, it remains unclear what role TA plays in a predictive model based on routine MRI characteristics. The purpose of this study was to explore the value of TA in distinguishing between benign and malignant NME in premenopausal women.

Methods: Women in whom NME was histologically proven (n = 147) were enrolled (benign: 58; malignant: 89) was retrospective. Then, 102 and 45 patients were classified as the training and validation groups, respectively. Scanning sequences included Fat-suppressed T2-weighted and fat-suppressed contrast-enhanced T1-weighted which were acquired on a 1.5T MRI system. Clinical and routine MR characteristics (CRMC) were evaluated by two radiologists according to the Breast Imaging and Reporting and Data system (2013). Texture features were extracted from all post-contrast sequences in the training group. The combination model was built and then assessed in the validation group. Pearson's chi-square test and Mann-Whitney U test were used to compare categorical variables and continuous variables, respectively. Logistic regression analysis and receiver operating characteristic curve were employed to assess the diagnostic performance of CRMC, TA, and their combination model in NME diagnosis.

Results: The combination model showed superior diagnostic performance in differentiating between benign and malignant NME compared to that of CRMC or TA alone (AUC, 0.887 vs 0.832 vs 0.74). Moreover, compared to CRMC, the model showed high specificity (72.5% vs 80%). The results obtained in the validation group confirmed the model was promising.

Conclusions: With the combined use of TA and CRMC could afford an improved diagnostic performance in differentiating between benign and malignant NME.
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http://dx.doi.org/10.1186/s12880-021-00571-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953679PMC
March 2021

SEDT2/METTL14-mediated m6A methylation awakening contributes to hypoxia-induced pulmonary arterial hypertension in mice.

Aging (Albany NY) 2021 02 26;13(5):7538-7548. Epub 2021 Feb 26.

Department of Cardiac Surgery, The First Affiliated Hospital, Nanchang University, Nanchang 330006, Jiangxi, China.

Pulmonary arterial hypertension (PAH) is a fatal disease whose molecular mechanism is unknown. The trimethylation of lysine 36 on histone 3 (H3K36me3) catalyzed by SETD2 and the modification of N6-methyladenine (mA) mRNA mediated by METTL14 play important roles in a variety of normal and pathological biological processes. However, the role of these epigenetic controls in the pathogenesis of PAH remains unclear. In this study, the expression of SETD2 and METTL14 was elevated in pulmonary artery smooth muscle cells (PASMCs) of hypoxia-induced PAH mice. We further constructed a mouse model with SETD2 specific knockout in smooth muscle cells (SETD2). Our results suggest that the lack of SETD2 in SMCs protected mice from hypoxia-induced PAH and significantly reduced right ventricular systolic pressure (RVSP), right ventricular/left ventricular plus septum [RV/(LV+S)] weight ratio, and pulmonary median width. In addition, the absence of SETD2 in SMCs alleviates the level of METTL14 expression and the mA RNA methylation level in PAH SMCs. These results obtained from mice suggest that strategies that target the inhibition of SETD2/METTL14 activity may be a viable treatment for PAH in a clinical setting.
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http://dx.doi.org/10.18632/aging.202616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993666PMC
February 2021

Cooking stoves and risk of birth defects in urban China.

Environ Res 2021 03 13;194:110731. Epub 2021 Jan 13.

National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address:

Introduction: Birth defects are a leading cause of infant death. Pregnant women spend a large amount of time indoors, and little research from population-based studies has investigated the association between indoor air pollution and birth defects. We aimed to examine whether using coal, biomass, or electromagnetic stoves for cooking is associated with risk of birth defects compared to using gas stoves.

Methods: A birth cohort study was conducted from 2010 to 2012 in Lanzhou, China. Cases (n = 264) were singleton births with birth defects, which were defined as abnormalities of structure or function, including metabolism, presented at birth based on the International Classification of Diseases (ICD)-10 codes. Controls (n = 9926) were defined as singleton live births without birth defects. Unconditional logistic regression models were employed to estimate the association adjusting for confounding variables.

Results: Compared to gas stoves for cooking, biomass (OR = 2.66, 95%CI: 1.38-5.13), and electromagnetic stove (OR = 1.90, 95%CI: 1.26-2.88) for cooking were associated with an increased risk of birth defects. The significant associations remained among non-congenital heart disease (CHD) defects but not CHDs.

Conclusions: Using biomass or electromagnetic stoves for cooking during pregnancy was associated with an increased risk of birth defects. Additional studies are warranted to confirm these novel findings. Studies with larger sample size or greater statistical power are also warranted to better estimate the associations for individual birth defects.
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http://dx.doi.org/10.1016/j.envres.2021.110731DOI Listing
March 2021

Antigen-specific T Cell Activation Distinguishes Between Recent and Remote Tuberculosis Infection.

Am J Respir Crit Care Med 2021 Jan 6. Epub 2021 Jan 6.

University of Cape Town, 37716, South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, , Cape Town, South Africa;

Rationale: Current diagnostic tests fail to identify individuals at higher risk of progression to tuberculosis disease, such as those with recent Mycobacterium tuberculosis infection, who should be prioritized for targeted preventive treatment.

Objectives: To define a blood-based biomarker, measured with a simple flow cytometry assay, that can stratify different stages of tuberculosis infection to infer risk of disease.

Methods: South African adolescents were serially tested with QuantiFERON-TB Gold to define recent (QuantiFERON-TB conversion <6 months) and persistent (QuantiFERON-TB+ for >1 year) infection. We defined the ΔHLA-DR median fluorescence intensity biomarker as the difference in HLA-DR expression between IFN-γ+TNF+ Mycobacterium tuberculosis-specific and total CD3+ T cells. Biomarker performance was assessed by blinded prediction in untouched test cohorts with recent versus persistent infection or tuberculosis disease, and unblinded analysis of asymptomatic adolescents with tuberculosis infection who remained healthy (non-progressors) or who progressed to microbiologically-confirmed disease (progressors).

Measurements And Main Results: In the test cohorts, frequencies of Mycobacterium tuberculosis-specific T cells differentiated between QuantiFERON-TB- (n=25) and QuantiFERON-TB+ (n=47) individuals (area under the ROC curve and 95% confidence intervals: 0.94; 0.87-1.00). ΔHLA-DR significantly discriminated between recent (n=20) and persistent (n=22) QuantiFERON-TB+ (0.91; 0.83-1.00); persistent QuantiFERON-TB+ and newly diagnosed tuberculosis (n=19, 0.99; 0.96-1.00); and tuberculosis progressors (n=22) and non-progressors (n=34, 0.75; 0.63-0.87). However, ΔHLA-DR MFI could not discriminate between recent QuantiFERON-TB+ and tuberculosis (0.67; 0.50-0.84).

Conclusion: The ΔHLA-DR biomarker can identify individuals with recent QuantiFERON-TB conversion and those with disease progression, allowing targeted provision of preventive treatment to those at highest risk of tuberculosis. Further validation studies of this novel immune biomarker in various settings and populations at risk are warranted.
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http://dx.doi.org/10.1164/rccm.202007-2686OCDOI Listing
January 2021

Distribution and removal characteristics of microplastics in different processes of the leachate treatment system.

Waste Manag 2021 Feb 10;120:240-247. Epub 2020 Dec 10.

Shanghai Engineering Research Center of Biotransformation of Organic Solid Waste, School of Ecological and Environmental Sciences, East China Normal University, Shanghai 200241, China; Shanghai Key Lab for Urban Ecological Processes and Eco-Restoration, School of Ecological and Environmental Sciences, East China Normal University, Shanghai 200241, China; Shanghai Institute of Pollution Control and Ecological Security, Shanghai 200092, China. Electronic address:

Microplastics (MPs) in environments are widely concerned in recent years due to the widely occurrence and potential risk to environments. With a large amount of plastic waste discarded into the landfills, leachate generated from landfills was found to be an important pollution source of MPs. However, the removal efficiency and characteristics of MPs in leachate treatment system were not clear. In this study, the concentration variation and the removal performance of MPs in leachate treatment system with the process of pretreatment + biotreatment + advanced treatment were investigated. The results showed that 58.33% of MPs were removed during the leachate treatment process. The Ultrafiltration had the highest efficiency of removing MPs, but the advanced treatment technologies (Nanofiltration and Reverse Osmosis) did not contribute to the removal of MPs. Furthermore, the removal performance of MPs in leachate treatment process was determined by MPs properties, such as size, shape and polymer type. The whole leachate treatment process had higher removal efficiencies for particle MPs compared to fiber MPs, and only 50% of fiber MPs were removed in biological treatment and advanced treatment. Ultrafiltration had better removal effect on microplastics with the size of less than 1 mm, and MPs less than 0.5 mm were almost removed by advanced treatment but accumulated in the sludge with the abundance of 0.893 ± 0.252 items/g. The results showed that a considerable amount of MPs (10 items/day) discharged with the effluent (3200 t/d), and most removed MPs from leachate accumulated in sludge, which would cause potential risk to the environments.
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http://dx.doi.org/10.1016/j.wasman.2020.11.025DOI Listing
February 2021

Association of Race/Ethnicity with Surgical Route and Perioperative Outcomes of Hysterectomy for Leiomyomas.

J Minim Invasive Gynecol 2020 Nov 23. Epub 2020 Nov 23.

Department of Environmental Health Services, Yale School of Public Health, New Haven, Connecticut (Ms. Huang, Ms. Zhuo, and Dr. Zhang); Department of Surgery, Yale School of Medicine, New Haven, Connecticut (Dr. Zhang).

Study Objective: To evaluate the associations among race/ethnicity, route of surgery, and perioperative outcomes for women undergoing hysterectomy for uterine leiomyomas.

Design: Retrospective cohort study.

Setting: Multistate.

Patients: Women who underwent hysterectomies for leiomyomas from the American College of Surgeons National Surgical Quality Improvement Program database, 2014 to 2017.

Interventions: None. Exposures of interest were race/ethnicity and route of surgery.

Measurements And Main Results: Racial/ethnic variation in route of surgery and perioperative outcomes. Propensity score matching was employed to control for possible confounders. We identified 20 133 women who underwent nonemergent abdominal hysterectomy (AH), laparoscopic hysterectomy (LH), or vaginal hysterectomy (VH) for leiomyomas. We defined minimally invasive hysterectomy (MIH) as LH or VH. Black women were more likely to have open surgery (AH vs MIH adjusted odds ratio [aOR], 2.22; 95% confidence interval [CI], 2.07-2.38; AH vs VH aOR, 1.79; 95% CI, 1.54-2.08; AH vs LH aOR, 2.27; 95% CI, 2.13-2.44) than white women. Likewise, Hispanic women were more likely to have open surgery (AH vs MIH aOR, 1.76; 95% CI, 1.58-1.96; AH vs LH aOR, 1.82; 95% CI, 1.61-2.00) than white women. Black women were more likely to experience any complication after hysterectomy (AH aOR, 1.54; 95% CI, 1.31-1.80; VH aOR, 1.65; 95% CI, 1.02-2.68; LH aOR, 1.37; 95% CI, 1.13-1.66) than white women. Hispanic women were less likely than white women to experience major complications after VH (aOR, 0.28; 95% CI, 0.08-0.98). Compared with white women, the mean length of stay was longer for black women who underwent AH or LH. The mean total operation time was higher for all minority groups (except for Asian/other undergoing AH) regardless of surgical approach.

Conclusion: Women of minority race/ethnicity were more likely to undergo abdominal rather than MIH for leiomyomas. Even when controlling for route of surgery, they were more likely to experience perioperative complications.
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http://dx.doi.org/10.1016/j.jmig.2020.11.008DOI Listing
November 2020

ppGalNAc-T4-catalyzed O-Glycosylation of TGF-β type Ⅱ receptor regulates breast cancer cells metastasis potential.

J Biol Chem 2020 Dec 3;296:100119. Epub 2020 Dec 3.

School of Life Science & Pharmacy, Dalian University of Technology, Panjin, China. Electronic address:

GalNAc-type O-glycosylation, initially catalyzed by polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts), is one of the most abundant and complex posttranslational modifications of proteins. Emerging evidence has proven that aberrant ppGalNAc-Ts are involved in malignant tumor transformation. However, the exact molecular functions of ppGalNAc-Ts are still unclear. Here, the role of one isoform, ppGalNAc-T4, in breast cancer cell lines was investigated. The expression of ppGalNAc-T4 was found to be negatively associated with migration of breast cancer cells. Loss-of-function studies revealed that ppGalNAc-T4 attenuated the migration and invasion of breast cancer cells by inhibiting the epithelial-mesenchymal transition (EMT) process. Correspondingly, transforming growth factor beta (TGF-β) signaling, which is the upstream pathway of EMT, was impaired by ppGalNAc-T4 expression. ppGalNAc-T4 knockout decreased O-GalNAc modification of TGF-β type Ⅰ and Ⅱ receptor (TβR Ⅰ and Ⅱ) and led to the elevation of TGF-β receptor dimerization and activity. Importantly, a peptide from TβR Ⅱ was identified as a naked peptide substrate of ppGalNAc-T4 with a higher affinity than ppGalNAc-T2. Further, Ser31, corresponding to the extracellular domain of TβR Ⅱ, was identified as the O-GalNAcylation site upon in vitro glycosylation by ppGalNAc-T4. The O-GalNAc-deficient S31 A mutation enhanced TGF-β signaling activity and EMT in breast cancer cells. Together, these results identified a novel mechanism of ppGalNAc-T4-catalyzed TGF-β receptors O-GalNAcylation that suppresses breast cancer cell migration and invasion via the EMT process. Targeting ppGalNAc-T4 may be a potential therapeutic strategy for breast cancer treatment.
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http://dx.doi.org/10.1074/jbc.RA120.016345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948473PMC
December 2020

A prediction model for outcome in patients with HBV-ACLF based on predisposition, injury, response and organ failure.

Sci Rep 2020 11 19;10(1):20176. Epub 2020 Nov 19.

Medical School of Chinese PLA, Beijing, China.

We aimed to develop a prediction model based on the PIRO concept (Predisposition, Injury, Response and Organ failure) for patients with Hepatitis B Virus (HBV) related acute-on-chronic liver failure (ACLF). 774 patients with HBV related ACLF defined in the CANONIC study were analyzed according to PIRO components. Variables associated with mortality were selected into the prediction model. Based on the regression coefficients, a score for each PIRO component was developed, and a classification and regression tree was used to stratify patients into different nodes. The prediction model was then validated using an independent cohort (n = 155). Factors significantly associated with 90-day mortality were: P: age, gender and ACLF type; I: drug, infection, surgery, and variceal bleeding; R: systemic inflammatory response syndrome (SIRS), spontaneous bacteria peritonitis (SBP), and pneumonia; and O: the CLIF consortium organ failure score (CLIF-C OFs). The areas under the receiver operating characteristics curve (95% confidence interval) for the combined PIRO model for 90-day mortality were 0.77 (0.73-0.80). Based on the scores for each of the PIRO components and the cut-offs estimated from the classification and regression tree, patients were stratified into different nodes with different estimated death probability. Based on the PIRO concept, a new prediction model was developed for patients with HBV related ACLF, allowing stratification into different clusters using the different scores obtained in each PIRO component. The proposed model will likely help to stratify patients at different risk, defining individual management plans, assessing criteria for specific therapies, and predicting outcomes.
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http://dx.doi.org/10.1038/s41598-020-77235-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677318PMC
November 2020

Assessment of Age, Period, and Birth Cohort Effects and Trends in Merkel Cell Carcinoma Incidence in the United States.

JAMA Dermatol 2021 01;157(1):59-65

Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut.

Importance: Merkel cell carcinoma is an aggressive, cutaneous, neuroendocrine cancer that is increasing in incidence. Understanding why the incidence of Merkel cell carcinoma is increasing through underlying factors, such as age effects, calendar period of diagnosis effects, and birth cohort effects, can help guide resource allocation and design of screening programs.

Objectives: To evaluate the associations of patient age, calendar period of diagnosis, and birth cohort with the increasing incidence of Merkel cell carcinoma and to provide new incidence projections to 2030.

Design, Setting, And Participants: A cross-sectional retrospective study with age-period-cohort analysis and incidence projection modeling using data from the Surveillance, Epidemiology, and End Results Program database of 9 registries from 1987 to 2016 was conducted among 3720 patients with Merkel cell carcinoma. Statistical analysis was conducted from October 20, 2019, to July 29, 2020.

Exposures: Age effects (ie, physiology), period of diagnosis effects (ie, changes in diagnostics and clinical awareness), and birth cohort effects (ie, environmental risk factors) over time were assessed.

Main Outcomes And Measures: Incidence rates of Merkel cell carcinoma.

Results: Among the 3720 patients in the study (2200 male patients [59.1%]; median age, 77 years [interquartile range, 68-84 years]), during the period from 2012 to 2016, the age-adjusted Merkel cell carcinoma incidence rate was 0.66 per 100 000 (95% CI, 0.62-0.70), which represented a 3.5-times (95% CI, 3.0-4.2) increase from 1987 to 1991. The incidence of Merkel cell carcinoma increased with patient age across calendar periods and birth cohorts; the highest incidence rate was observed for those aged 85 years or older, with an age-adjusted rate from 2012 to 2016 of 14.6 per 100 000 for men and 5.5 per 100 000 for women. Although the birth cohort effect has continued to increase over time, the calendar period of diagnosis effect has started to plateau. It is projected that there will be 3023 new cases of Merkel cell carcinoma in 2020 and 5130 new cases in 2030, increased from an estimated 1933 cases in 2010.

Conclusions And Relevance: The slowing down of the period effect (ie, changes in diagnostics and awareness) found in this longitudinal cohort study suggests that part of the initial increased incidence of Merkel cell carcinoma was associated with increased detection. However, the projected increase in incidence rate is likely associated with the aging population and increasing risk factor exposure in more recent birth cohorts.
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http://dx.doi.org/10.1001/jamadermatol.2020.4102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643047PMC
January 2021

Prognostic Factors for COVID-19 Pneumonia Progression to Severe Symptoms Based on Earlier Clinical Features: A Retrospective Analysis.

Front Med (Lausanne) 2020 5;7:557453. Epub 2020 Oct 5.

Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China.

Approximately 15-20% of COVID-19 patients will develop severe pneumonia, and about 10% of these will die if not properly managed. Earlier discrimination of potentially severe patients basing on routine clinical and laboratory changes and commencement of prophylactical management will not only save lives but also mitigate the otherwise overwhelming healthcare burden. In this retrospective investigation, the clinical and laboratory features were collected from 125 COVID-19 patients who were classified into mild (93 cases) or severe (32 cases) groups according to their clinical outcomes after 3-7 days post-admission. The subsequent analysis with single-factor and multivariate logistic regression methods indicated that 17 factors on admission differed significantly between mild and severe groups but that only comorbidity with underlying diseases, increased respiratory rate (>24/min), elevated C-reactive protein (CRP >10 mg/L), and lactate dehydrogenase (LDH >250 U/L) were independently associated with the later disease development. Finally, we evaluated their prognostic values with receiver operating characteristic curve (ROC) analysis and found that the above four factors could not confidently predict the occurrence of severe pneumonia individually, though a combination of fast respiratory rate and elevated LDH significantly increased the predictive confidence (AUC = 0.944, sensitivity = 0.941, and specificity = 0.902). A combination consisting of three or four factors could further increase the prognostic value. Additionally, measurable serum viral RNA post-admission independently predicted the severe illness occurrence. In conclusion, a combination of general clinical characteristics and laboratory tests could provide a highly confident prognostic value for identifying potentially severe COVID-19 pneumonia patients.
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http://dx.doi.org/10.3389/fmed.2020.557453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571455PMC
October 2020

Venetoclax plus bendamustine-rituximab or bendamustine-obinutuzumab in chronic lymphocytic leukemia: final results of a phase 1b study (GO28440).

Haematologica 2020 10 29;Online ahead of print. Epub 2020 Oct 29.

Hospices Civils de Lyon, Université de Lyon, Pierre-Bénite, France.

Venetoclax (Ven), an orally administered, potent BCL-2 inhibitor, has demonstrated efficacy in chronic lymphocytic leukaemia (CLL) in combination with rituximab (R) or obinutuzumab (G). Our aim was to investigate the addition of bendamustine (B) to these Ven-containing regimens in relapsed/refractory (R/R) or first-line (1L) CLL. This multi-arm, non-randomized, open-label, phase 1b study was designed to evaluate the maximum tolerated dose (MTD) and safety/tolerability of Ven with BR/BG, with 3+3 dose-escalation followed by safety expansion. Patients received Ven (schedule A) or BR/BG first (schedule B) to compare safety and determine dose/schedule for expansion. Six Ven-BR/-BG cycles were to be administered, then Ven monotherapy until disease progression (R/R) or fixed-duration 1-year treatment (1L). Overall, 33 R/R and 50 1L patients were enrolled. No dose-limiting toxicities were observed (doses 100-400-mg), and the MTD was not reached. Safety was similar between schedules; no tumour lysis syndrome (TLS) occurred during dose-finding. Schedule B and Ven 400-mg were chosen for expansion. The most frequent grade 3-4 toxicity was neutropenia: R/R 64%, 1L Ven-BR 85%, 1L Ven-BG 55%. Grade 3-4 infection rate was: R/R 27%, 1L Ven-BR 0%, 1L Ven-BG 27%. During expansion, one clinical and two laboratory TLS cases occurred. Fewer than half the patients completed six combination therapy cycles with all study drugs; rates of bendamustine discontinuation were high. Overall response rate was 91% in R/R and 100% in 1L patients (16/49 1L patients received Ven for >1 year). In conclusion, addition of bendamustine to Ven-R/-G increased toxicity without apparent efficacy benefit.
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http://dx.doi.org/10.3324/haematol.2020.261107DOI Listing
October 2020

Tetracycline antibiotics as precursors of dichloroacetamide and other disinfection byproducts during chlorination and chloramination.

Chemosphere 2021 May 14;270:128628. Epub 2020 Oct 14.

School of Environmental Science and Engineering, Sun Yat-sen University, Guangzhou, 510275, Guangdong, PR China; Guangdong Provincial Key Laboratory of Environmental Pollution Control and Remediation Technology, Guangzhou, 510275, Guangdong, PR China.

Pollution of natural water and even source water with pharmaceuticals is problematic worldwide and raises concern about the possibility of disinfection byproduct (DBP) formation during subsequent water treatment. In this study, the formation of DBPs, especially dichloroacetamide (DCAcAm), was investigated during chlorination and chloramination of tetracyclines, which are a class of broad-spectrum antibiotics. DBPs including DCAcAm were formed during chlorination and chloramination of tetracycline (TC). Although the concentrations and theoretical cytotoxicity of the DBPs formed from TC were affected by the contact time, disinfectant dose, and pH, DCAcAm was the main contributor determining the yields and cytotoxicity of the measured DBPs. The DCAcAm yields from four tetracycline antibiotics ranged from 0.43% to 54.26% for chlorination. For chloramination, the DCAcAm yields reached 44.57%, and the nitrogen in DCAcAm mainly came from tetracycline antibiotics rather than chloramines. ClO pre-oxidation and UV photolysis decreased DCAcAm formation during chlorination and chloramination of TC. The high yields observed in this study suggest that tetracycline antibiotics are possible precursors of DCAcAm.
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http://dx.doi.org/10.1016/j.chemosphere.2020.128628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556226PMC
May 2021

Reduced expression of ppGalNAc-T4 promotes proliferation of human breast cancer cells.

Cell Biol Int 2021 Feb 31;45(2):320-333. Epub 2020 Oct 31.

School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China.

Breast cancer, one of the most frequently diagnosed and aggressive malignancies, is the major cause of cancer-related death greatly threatening women health. Polypeptide N-acetylgalactosaminyltransferase 4 (ppGalNAc-T4), responsible for the initial step of mucin-type O-glycosylation, has been reported to be implicated in diverse types of human tumors. However, the biological role of ppGalNAc-T4 in breast cancer is still undetermined. In this study, we investigate the effects and mechanism of ppGalNAc-T4 to breast cancer cell proliferation. From analysis of high throughput RNA sequencing datasets of Gene Expression Omnibus and ArrayExpress, a positive correlation between ppGalNAc-T4 and the recurrence-free survival was observed in multigroup of human breast cancer datasets. Moreover, transcriptomes analysis using RNA-sequencing in MCF7 cells revealed that cell cycle-related genes induced the effects of ppGalNAc-T4 on breast cancer cell proliferation. Additionally, investigations showed that ppGalNAc-T4 impaired cell proliferation in MCF-7 and MDA-MB-231 breast cells. Furthermore, our results suggested that the ppGalNAc-T4 knockout activated Notch signaling pathway and enhanced cell proliferation. Collectively, our data indicated that ppGalNAc-T4 affected the proliferation of human breast cancer cells, which appears to be a novel target for understanding the underlying molecular mechanism of breast cancer.
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http://dx.doi.org/10.1002/cbin.11488DOI Listing
February 2021

Exposure to polychlorinated biphenyls and organochlorine pesticides and thyroid cancer in connecticut women.

Environ Res 2021 01 14;192:110333. Epub 2020 Oct 14.

Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA; Department of Surgical Outcomes, Yale School of Medicine, New Haven, CT, USA.

Background: Thyroid cancer incidence has increased substantially over the past decades, and environmental risk factors have been suggested to play a role. Polychlorinated biphenyls (PCB) and organochlorine pesticides (OCP) are established thyroid hormone disruptors, but their relationship to thyroid cancer is not known.

Methods: We investigated the relationship between serum PCB and OCP concentrations and papillary thyroid cancer (PTC) in 250 incident female PTC cases and 250 female controls frequency-matched on age, all residing in Connecticut. Interviews and serum samples were collected from 2010 to 2013. Samples were analyzed for 32 different chemicals using gas chromatography with isotope dilution high resolution mass spectrometry. We calculated odds ratios (OR) and 95% confidence intervals (CI) using single pollutant logistic regression models for concentrations (per interquartile range) of individual PCB/OCP and summed groups of structurally or biologically similar PCB/OCP, adjusted for education, family history of cancer, alcohol consumption, age, and body mass index. Sub-analyses included stratification by tumor size (≤ and >1 cm) and birth before or during peak PCB production (born in 1960 or earlier and born after 1960), as exposures during early life may be important. We also applied three multi-pollutant approaches (standard multi-pollutant regression, hierarchical Bayesian modeling, principal components regression analysis) to investigate associations with co-exposures to multiple PCB/OCPs.

Results: No PCB/OCPs were positively associated with PTC in primary analyses. Statistically significant associations were observed for 9 of the 32 chemicals and 3 summed groups of similar chemicals in the those born during peak production based on single-pollutant models. Multi-pollutant analyses suggested null associations overall.

Conclusions: Our results using single and multi-pollutant modeling do not generally support an association between PCB or OCP exposure and PTC, but some associations in those born during peak production suggest that additional investigation into early-life exposures and subsequent thyroid cancer risk may be warranted.
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http://dx.doi.org/10.1016/j.envres.2020.110333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736223PMC
January 2021

A Complex Stiffness Human Impedance Model With Customizable Exoskeleton Control.

IEEE Trans Neural Syst Rehabil Eng 2020 11 6;28(11):2468-2477. Epub 2020 Nov 6.

The natural impedance, or dynamic relationship between force and motion, of a human operator can determine the stability of exoskeletons that use interaction-torque feedback to amplify human strength. While human impedance is typically modelled as a linear system, our experiments on a single-joint exoskeleton testbed involving 10 human subjects show evidence of nonlinear behavior: a low-frequency asymptotic phase for the dynamic stiffness of the human that is different than the expected zero, and an unexpectedly consistent damping ratio as the stiffness and inertia vary. To explain these observations, this article considers a new frequency-domain model of the human joint dynamics featuring complex value stiffness comprising a real stiffness term and a hysteretic damping term. Using a statistical F-test we show that the hysteretic damping term is not only significant but is even more significant than the linear damping term. Further analysis reveals a linear trend linking hysteretic damping and the real part of the stiffness, which allows us to simplify the complex stiffness model down to a 1-parameter system. Then, we introduce and demonstrate a customizable fractional-order controller that exploits this hysteretic damping behavior to improve strength amplification bandwidth while maintaining stability, and explore a tuning approach which ensures that this stability property is robust to muscle co-contraction for each individual.
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http://dx.doi.org/10.1109/TNSRE.2020.3027501DOI Listing
November 2020

Liver X receptor β is required for the survival of single-positive thymocytes by regulating IL-7Rα expression.

Cell Mol Immunol 2020 Sep 22. Epub 2020 Sep 22.

Institute of Immunology, College of Basic Medical Sciences, Third Military Medical University, Chongqing, 400038, China.

Liver X receptors (LXRs) are known as key transcription factors in lipid metabolism and have been reported to play an important role in T-cell proliferation. However, whether LXRs play a role in thymocyte development remains largely unknown. Here, we demonstrated that LXRβ deficiency caused a reduction in single-positive (SP) thymocytes, whereas the transitions from the double-negative to SP stage were normal. Meanwhile, LXRβ-null SP thymocytes exhibited increased apoptosis and impairment of the IL-7Rα-Bcl2 axis. In addition, the LXR agonist T0901317 promoted the survival of SP thymocytes with enhanced IL-7Rα expression in wild-type mice but not in LXRβ-deficient mice. Mechanistically, LXRβ positively regulated the expression of IL-7Rα via direct binding to the Il7r allele in SP thymocytes, and forced expression of IL-7Rα or Bcl2 restored the survival of LXRβ-defective SP thymocytes. Thus, our results indicate that LXRβ functions as an important transcription factor upstream of IL-7Rα to promote the survival of SP thymocytes.
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http://dx.doi.org/10.1038/s41423-020-00546-yDOI Listing
September 2020

Breakpoint mapping of a t(9;22;12) chronic myeloid leukaemia patient with e14a3 BCR-ABL1 transcript using Nanopore sequencing.

J Gene Med 2021 Jan 1;23(1):e3276. Epub 2020 Oct 1.

Department of Haematology, The Affiliated Zhuzhou Hospital, XiangYa Medical College, Central South University, Zhuzhou, Hunan, China.

Background: The genetic changes in chronic myeloid leukaemia (CML) have been well established, although challenges persist in cases with rare fusion transcripts or complex variant translocations. Here, we present a CML patient with e14a3 BCR-ABL1 transcript and t(9;22;12) variant Philadelphia (Ph) chromosome.

Methods: Cytogenetic analysis and fluorescence in situ hybridization (FISH) was performed to identify the chromosomal aberrations and gene fusions. Rare fusion transcript was verified by a reverse transcription-polymerase chain reaction (RT-PCR). Breakpoints were characterized and validated using Oxford Nanopore Technologies (ONT) (Oxford, UK) and Sanger sequencing, respectively.

Results: The karyotype showed the translocation t(9;22;12)(q34;q11.2;q24) [20] and FISH indicated 40% positive BCR-ABL1 fusion signals. The RT-PCR suggested e14a3 type fusion transcript. The ONT sequencing analysis identified specific positions of translocation breakpoints: chr22:23633040-chr9:133729579, chr12:121567595-chr22:24701405, which were confirmed using Sanger sequencing. The patient achieved molecular remission 3 months after imatinib therapy.

Conclusions: The present study indicates Nanopore sequencing as a valid strategy, which can characterize breakpoints precisely in special clinical cases with atypical structural variations. CML patients with e14a3 transcripts may have good clinical course in the tyrosine kinase inhibitor era, as reviewed here.
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http://dx.doi.org/10.1002/jgm.3276DOI Listing
January 2021

Covalent inhibition of NSD1 histone methyltransferase.

Nat Chem Biol 2020 12 31;16(12):1403-1410. Epub 2020 Aug 31.

Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

The nuclear receptor-binding SET domain (NSD) family of histone methyltransferases is associated with various malignancies, including aggressive acute leukemia with NUP98-NSD1 translocation. While NSD proteins represent attractive drug targets, their catalytic SET domains exist in autoinhibited conformation, presenting notable challenges for inhibitor development. Here, we employed a fragment-based screening strategy followed by chemical optimization, which resulted in the development of the first-in-class irreversible small-molecule inhibitors of the nuclear receptor-binding SET domain protein 1 (NSD1) SET domain. The crystal structure of NSD1 in complex with covalently bound ligand reveals a conformational change in the autoinhibitory loop of the SET domain and formation of a channel-like pocket suitable for targeting with small molecules. Our covalent lead-compound BT5-demonstrates on-target activity in NUP98-NSD1 leukemia cells, including inhibition of histone H3 lysine 36 dimethylation and downregulation of target genes, and impaired colony formation in an NUP98-NSD1 patient sample. This study will facilitate the development of the next generation of potent and selective inhibitors of the NSD histone methyltransferases.
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http://dx.doi.org/10.1038/s41589-020-0626-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669657PMC
December 2020

Spatial and temporal clusters of avian influenza a (H7N9) virus in humans across five epidemics in mainland China: an epidemiological study of laboratory-confirmed cases.

BMC Infect Dis 2020 Aug 26;20(1):630. Epub 2020 Aug 26.

Prevention and Health Section, Affiliated Hospital, Chengdu University, Chengdu, Sichuan, China.

Background: Avian influenza A (H7N9) virus was first reported in mainland China in 2013, and alarming in 2016-17 due to the surge across a wide geographic area. Our study aimed to identify and explore the spatial and temporal variation across five epidemics to reinforce the epidemic prevention and control.

Methods: We collected spatial and temporal information about all laboratory-confirmed human cases of A (H7N9) virus infection reported in mainland China covering 2013-17 from the open source. The autocorrelation analysis and intensity of cases were used to analyse the spatial cluster while circular distribution method was used to analyse the temporal cluster.

Results: Across the five epidemics, a total of 1553 laboratory-confirmed human cases with A (H7N9) virus were reported in mainland China. The global Moran's I index values of five epidemic were 0.610, 0.132, 0.308, 0.306, 0.336 respectively, among which the differences were statistically significant. The highest intensity was present in the Yangtze River Delta region and the Pearl River Delta region, and the range enlarged from the east of China to inner provinces and even the west of China across the five epidemics. The temporal clusters of the five epidemics were statistically significant, and the peak period was from the end of January to April with the first and the fifth epidemic later than the mean peak period.

Conclusions: Spatial and temporal clusters of avian influenza A (H7N9) virus in humans are obvious, moreover the regions existing clusters may enlarge across the five epidemics. Yangtze River Delta region and the Pearl River Delta region have the spatial cluster and the peak period is from January to April. The government should facilitate the tangible improvement for the epidemic preparedness according to the characteristics of spatial and temporal clusters of patients with avian influenza A (H7N9) virus.
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http://dx.doi.org/10.1186/s12879-020-05345-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449057PMC
August 2020

ClO pre-oxidation impacts the formation and nitrogen origins of dichloroacetonitrile and dichloroacetamide during subsequent chloramination.

Water Res 2020 Nov 18;186:116313. Epub 2020 Aug 18.

School of Environmental Science and Engineering, Sun Yat-sen University, Guangzhou 510275, Guangdong, P.R. China; Guangdong Provincial Key Laboratory of Environmental Pollution Control and Remediation Technology, Guangzhou 510275, Guangdong, P.R. China.

Chlorine dioxide (ClO) can be used as a pre-oxidant when chloramination is performed in water treatment plants. However, the effects of ClO pre-oxidation on the formation of nitrogenous disinfection by-products, such as dichloroacetonitrile (DCAN) and dichloroacetamide (DCAcAm), during chloramination are not well understood. In this study, the effects of ClO pre-oxidation on the formation of DCAN and DCAcAm during chloramination of 28 model compounds and seven real water samples were investigated. The sources of nitrogen for DCAN and DCAcAm formation were investigated using N-labeled monochloramine. ClO pre-oxidation affected DCAN and DCAcAm formation during chloramination of model compounds in different ways. ClO pre-oxidation increased unlabeled and N-labeled DCAN and DCAcAm formation during chloramination of six amino acids and peptides and five indoles and tertiary amines. ClO pre-oxidation decreased DCAN formation but increased DCAcAm formation during chloramination of three hydroxybenzamide compounds, but had the opposite effects for four tetracyclines. ClO pre-oxidation generally decreased DCAN and DCAcAm formation during chloramination of the phenolic compounds that are precursors not containing nitrogen. 2-Aminoacetophenone, formamid-trans-muconic acid, and unsaturated ketones were found to be transformation products of ClO oxidation of 3-methylindole, salicylamide, and resorcinol, respectively. Possible DCAN and DCAcAm formation pathways during chloramination after ClO oxidation were identified. For most of the water samples, ClO pre-oxidation decreased the amounts of DCAN and DCAcAm formed during chloramination by 36%-70% and 11%-59%, respectively. This may have been caused by ClO oxidation destroying phenolic precursors and macromolecular proteins rather than amino acids in the water samples.
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http://dx.doi.org/10.1016/j.watres.2020.116313DOI Listing
November 2020

Clinical characteristics and corticosteroids application of different clinical types in patients with corona virus disease 2019.

Sci Rep 2020 08 13;10(1):13689. Epub 2020 Aug 13.

Fifth Medical Center of PLA General Hospital, Beijing, China.

To describe the epidemiological and clinical characteristics of patients with Corona Virus Disease 2019 (COVID-19) in Beijing. To analyze the application of corticosteroids in patients with severe pneumonia. We collected information on demographic characteristics, exposure history, clinical characteristics, corticosteroids use, and outcomes of the 65 confirmed cases of COVID-19 at Fifth Medical Center of PLA General Hospital from Jan 20 to Feb 23, 2020. The final follow-up date observed was April 15th, 2020. The number of patients with mild, general, severe, and critical type were 10 (15.38%), 32 (49.23%), 8 (12.31%), and 15 (23.08%), respectively. The median incubation period was 6 days. Notable outliers were 1 patient at 16 days and 1 patient at 21 days. In lymphocyte subgroup analysis, decreases in total, T, CD4, and CD8 lymphocytes were more common as the disease worsened (All P < 0.05). Methylprednisolone (mPSL) was applied to 31 (47.69%) patients with pneumonia, including 10 (31.25%) general, 8 (100%) severe, and 13 (86.67%) critical patients, respectively. Corticosteroids inhibited Interleukin-6(IL-6) production (P = 0.0215) but did not affect T lymphocyte (P = 0.0796). There was no significant difference between patients using lower dose (≤ 2 mg/kg day) and higher dose (> 2 mg/kg day) mPSL in inhibiting IL-6 production (P = 0.5856). Thirty of 31 patients (96.77%) had stopped mPSL due to improvement of pneumonia. Virus RNA clearance time lengthened with disease progression (P = 0.0001). In general type, there was no significant difference in virus clearance time between patients with (15, 12-19 days) and without (14.5, 11-18 days) (P = 0.7372) mPSL use. Lymphocyte, especially T lymphocyte, in severe and critical patients showed a dramatic decrease. Application of lower dose corticosteroids (≤ 2 mg/kg day) could inhibit IL-6 production (a representative of cytokines) as effectively as a higher dose. Proper use corticosteroids in general type patients did not delay virus clearance.
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http://dx.doi.org/10.1038/s41598-020-70387-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426825PMC
August 2020