Publications by authors named "Hui Pan"

637 Publications

An Optimized Pathway for the Differential Diagnosis of ACTH-Dependent Cushing's Syndrome Based on Low-Dose Dexamethasone Suppression Test.

Front Endocrinol (Lausanne) 2021 2;12:720823. Epub 2021 Sep 2.

Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Centre, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

Context: Traditionally, low-dose dexamethasone suppression test (LDDST) was used to confirm the diagnosis of Cushing's syndrome (CS), and high-dose dexamethasone suppression test (HDDST) was used to differentiate Cushing's disease (CD) and ectopic adrenocorticotropin (ACTH) syndrome (EAS), but some studies suggested that HDDST might be replaced by LDDST. For the differential diagnosis of CS, dexamethasone suppression test was usually combined with other tests such as bilateral petrosal sinus sampling (BIPSS) and pituitary magnetic resonance imaging, but the optimal pathway to incorporate these tests is still controversial.

Objectives: To develop an optimized pathway for the differential diagnosis of CD and EAS based on LDDST.

Design And Setting: Single-center retrospective study (2011-2019).

Patients: Two hundred sixty-nine CD and 29 EAS patients with pathological diagnosis who underwent consecutive low- and high-dose DST.

Results: For the differential diagnosis of CD and EAS, the area under curve (AUC) of LDDST using urine free cortisol (0.881) was higher than that using serum cortisol (0.685) (p < 0.001) in head-to-head comparison among a subgroup of 108 CD and 10 EAS. The AUC of LDDST (0.883) was higher than that of HDDST (0.834) among all the included patients. With the cutoff of <26%, the sensitivity and specificity of LDDST were 39.4% and 100%. We designed a new pathway in which BIPSS was only reserved for those patients with unsuppressed LDDST and adenoma <6mm, yielding an overall sensitivity of 97.7% and specificity of 86.7%.

Conclusion: LDDST had similar value to HDDST in differentiating CD and EAS using the specific cutoff point. The pathway that combined LDDST and BIPSS could differentiate CD and EAS accurately.
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http://dx.doi.org/10.3389/fendo.2021.720823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445331PMC
September 2021

Effectiveness and safety of bevacizumab in extensive-disease small cell lung cancer: a systemic review and meta-analysis.

Ann Transl Med 2021 Aug;9(16):1285

Department of Thoracic Surgery, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Background: Small cell lung cancer (SCLC) is highly invasive and poorly prognostic. The effects of chemotherapy with bevacizumab are promising on other tumors but unclear in extensive-disease SCLC (ED-SCLC). A systemic review and meta-analysis were performed to investigate the efficacy and toxicity in ED-SCLC patients.

Methods: A review of current studies was performed on electronic databases and other sources to identify publications of ED-SCLC patients who received bevacizumab. Endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and complications.

Results: Nine relevant articles with six single-arm and three two-arm studies were identified. Four hundred seventy-six patients were included, of which 368 and 108 were untreated and relapse patients. Most patients were performance status 0-1 (71.6%) and male (58.1%). The comparisons showed CT/bevacizumab slightly prolonged OS (HR =0.84) but significantly improved PFS (HR =0.74). The ORRs of untreated and relapse patients were 71% and 19%, though no significant difference was observed than CT/placebo. The most grade 3-4 complication and bevacizumab-associated complications were neutropenia and hypertension, whose rates were 33% and 6%. Patients who received CT/bevacizumab had a higher hypertension rate than CT/placebo (6% 2%). No different complication rate was observed between high and lose dose groups.

Discussion: The present study suggests that bevacizumab in the combination of standard chemotherapy provides better PFS than chemotherapy alone. Although the combined regimen is well-tolerated, no superiority in OS or response rate is observed.
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http://dx.doi.org/10.21037/atm-21-963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422128PMC
August 2021

Fibrinogen Level Combined With Platelet Count for Predicting Hemorrhagic Transformation in Acute Ischemic Stroke Patients Treated With Mechanical Thrombectomy.

Front Neurol 2021 31;12:716020. Epub 2021 Aug 31.

Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

A serious complication of acute ischemic stroke (AIS) after mechanical thrombectomy (MT) is hemorrhagic transformation (HT), which is potentially associated with clinical deterioration. This study examined predictors of HT following MT in AIS patients. Patients with AIS due to large artery occlusion in the anterior circulation, treated with MT and successfully recanalized (modified Thrombolysis in Cerebral Infarction score 2b/3), were studied retrospectively. HT was evaluated by computed tomography (CT) 24 h after MT and was diagnosed and classified into parenchymal hematoma (PH) and hemorrhagic infarction (HI). Multivariate logistic regression models were used to determine the risk factors for HT. Receiver operating characteristic (ROC) curve analysis was performed to determine the predictive utility of risk factors for HT. We enrolled 135 patients: 49 in the HT group and 86 in the non-HT group. The two groups differed significantly in baseline fibrinogen levels ( = 0.003) and platelet counts ( = 0.006). Multivariate logistic regression analyses showed that lower fibrinogen levels [odds ratio (OR), 0.41; 95% CI, 0.23-0.72; = 0.002] and platelet counts (OR, 0.58; 95% CI, 0.33-0.99; = 0.048) were independently associated with a higher risk of HT. Together, the binary variates fibrinogen and platelets well-predicted HT (area under the curve, 0.703; specificity, 77.9%; sensitivity, 55.1%). The combination of fibrinogen <2.165 g/L and platelets <171.5 × 10/L was the strongest predictor of HT (OR, 23.17; 95% CI, 5.75-126.80; < 0.0001). Our study suggests that lower baseline fibrinogen levels and platelet counts may be risk factors for HT in AIS patients following MT and reperfusion. Specifically, the combination of fibrinogen level and platelet count may predict the risk of HT after MT in these patients.
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http://dx.doi.org/10.3389/fneur.2021.716020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439152PMC
August 2021

Multi-region exome sequencing reveals the intratumoral heterogeneity of surgically resected small cell lung cancer.

Nat Commun 2021 Sep 14;12(1):5431. Epub 2021 Sep 14.

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Small cell lung cancer (SCLC) is a highly malignant tumor which is eventually refractory to any treatment. Intratumoral heterogeneity (ITH) may contribute to treatment failure. However, the extent of ITH in SCLC is still largely unknown. Here, we subject 120 tumor samples from 40 stage I-III SCLC patients to multi-regional whole-exome sequencing. The most common mutant genes are TP53 (88%) and RB1 (72%). We observe a medium level of mutational heterogeneity (0.30, range 0.0~0.98) and tumor mutational burden (TMB, 10.2 mutations/Mb, range 1.1~51.7). Our SCLC samples also exhibit somatic copy number variation (CNV) across all patients, with an average CNV ITH of 0.49 (range 0.02~0.99). In terms of mutation distribution, ITH, TMB, mutation clusters, and gene signatures, patients with combined SCLC behave roughly the same way as patients with pure SCLC. This condition also exists in smoking patients and patients with EGFR mutations. A higher TMB per cluster is associated with better disease-free survival while single-nucleotide variant ITH is linked to worse overall survival, and therefore these features may be used as prognostic biomarkers for SCLC. Together, these findings demonstrate the intratumoral genetic heterogeneity of surgically resected SCLC and provide insights into resistance to treatment.
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http://dx.doi.org/10.1038/s41467-021-25787-xDOI Listing
September 2021

Signaling defects associated with insulin resistance in non-diabetic and diabetic individuals and modification by sex.

J Clin Invest 2021 Sep 10. Epub 2021 Sep 10.

Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, United States of America.

Insulin resistance is present in one-quarter of the general population, predisposing to a wide-range of diseases. Our aim was to identify cell-intrinsic determinants of insulin resistance in this population using IPS cell-derived myoblasts (iMyos). We found that these cells exhibited a large network of altered protein phosphorylation in vitro. Integrating these data with data from type-2-diabetic iMyos revealed critical sites of conserved altered phosphorylation in IRS-1, AKT, mTOR and TBC1D1, in addition to changes in protein phosphorylation involved in Rho/Rac signaling, chromatin organization and RNA processing. There were also striking differences in the phosphoproteome in cells from males versus females. These sex-specific and insulin resistance defects were linked to functional differences in downstream actions. Thus, there are cell-autonomous signaling alterations associated with insulin resistance within the general population and important differences in males and females, many of which are shared with diabetes, and contribute to differences in physiology and disease.
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http://dx.doi.org/10.1172/JCI151818DOI Listing
September 2021

Multiple-Factor Analyses of Futile Recanalization in Acute Ischemic Stroke Patients Treated With Mechanical Thrombectomy.

Front Neurol 2021 19;12:704088. Epub 2021 Aug 19.

Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Acute ischemic stroke (AIS) is a serious threat to the life and health of middle-aged and elderly people. Mechanical thrombectomy offers the advantages of rapid recanalization, but the response of patients to this treatment varies greatly. This study investigated the risk factors for futile recanalization in AIS patients after thrombectomy through multivariate analyses. A retrospective study was conducted in AIS patients with anterior circulation occlusion from a derivation cohort and a validation cohort who underwent thrombectomy and reperfusion defined as a modified Thrombolysis in Cerebral Infarction (mTICI) score of 2b/3. Using the modified Rankin Scale (mRS) at 90 days after the operation, the patients were divided into two groups, the meaningful recanalization group (mRS ≤ 2), and the futile recanalization group (mRS > 2). Multivariate logistic regression analyses were performed, and the receiver operating characteristic (ROC) curve was used to construct a risk prediction model for futile recanalization. The performance of prediction model was evaluated on the validation cohort. A total of 140 patients in the derivation cohort were enrolled, 46 patients in the meaningful recanalization group and 94 patients in the futile recanalization group. The two groups were significantly different in age, preoperative National Institute of Health Stroke Scale (NIHSS) score, and collateral circulation ASITN/SIR grade ( < 0.05). In multivariate regression analyses, patients' age ≥ 71, NIHSS ≥ 12, and ASITN/SIR ≤ 3 were risk factors for futile recanalization. Hence, an ANA (Age-NIHSS-ASITN/SIR) score scale consisting of age, NIHSS score, and ASITN/SIR grade factors can effectively predict the risk for futile recanalization (area under curve 0.75, 95% CI 0.67-0.83, specificity 67.4%, and sensitivity 73.4%). The proportion of patients with futile recanalization in ANA groups 0, 1, 2, and 3 were 21.05, 56.76, 79.03, and 90.91%, respectively. Furthermore, ANA score scale had also a good performance for predicting futile recanalization on the validation cohort. Old age, high baseline NIHSS, and poor collateral circulation are risk factors for futile recanalization in AIS patients treated with thrombectomy. An ANA score that considers age, NIHSS, and collateral ASITN/SIR can effectively predict the risk for futile recanalization. Further studies with a larger sample size are needed to validate the prognostic value of this combined score for futile recanalization.
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http://dx.doi.org/10.3389/fneur.2021.704088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416752PMC
August 2021

AgS monolayer: an ultrasoft inorganic Lieb lattice.

Nanoscale 2021 Sep 10;13(33):14008-14015. Epub 2021 Aug 10.

Department of Physics, National University of Singapore, Singapore 117542, Singapore.

Lieb lattice, a two-dimensional edge-centered square lattice, has attracted considerable interest due to its exotic electronic and topological properties. Although various optical and photonic Lieb lattices have been experimentally demonstrated, it remains challenging for an electronic Lieb lattice to be realized in real material systems. Here, based on first-principles calculations and tight-binding modeling, a silver sulfide (AgS) monolayer is reported as a long-sought-after inorganic electronic Lieb lattice. This Lieb-lattice AgS is further found to be ultrasoft, which enables its electronic properties and topological states near the Fermi level to be finely tuned, as evidenced by the strain-induced topologically non-trivial edge states near the valence band edge. These results not only provide an ideal platform to further explore and harvest interesting quantum properties but also pave a way to pursue other inorganic electronic Lieb lattices in a broader material domain.
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http://dx.doi.org/10.1039/d1nr02588kDOI Listing
September 2021

Case Report: Identification of Potential Prognosis-Related Mutation and Fusion in Primary Pituitary Lymphoma by Next Generation Sequencing: Two Cases.

Front Endocrinol (Lausanne) 2021 26;12:673908. Epub 2021 Jul 26.

Department of Neurosurgery, Peking Union Medical College Hospital, Beijing, China.

Background: Primary pituitary lymphoma (PPL) is an extremely rare disease with poor prognosis. Although PPL has been shown to be different from classical primary central nervous system lymphoma because of the embryological origin of structures, individual and precise treatment of PPL remains unknown.

Methods: A 61-year-old man and a 65-year-old woman both diagnosed with primary pituitary diffuse large B cell lymphoma underwent genetic analysis of cerebrospinal fluid and tumor tissue by next generation sequencing.

Results: In the first case, partial remission was achieved following R²-MTX chemotherapy. In the other case with mutation and - fusion, disease progressed although different chemotherapy regimens were given.

Conclusion: The gene mutation of and may be identified as a marker responsible for prognostic difference in patients with PPL. Genetic analysis may provide a novel approach for precise management and prognosis prediction.
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http://dx.doi.org/10.3389/fendo.2021.673908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350335PMC
July 2021

Using single-nucleus RNA-sequencing to interrogate transcriptomic profiles of archived human pancreatic islets.

Genome Med 2021 Aug 10;13(1):128. Epub 2021 Aug 10.

Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center and Harvard Medical School, Boston, MA, 02215, USA.

Background: Human pancreatic islets are a central focus of research in metabolic studies. Transcriptomics is frequently used to interrogate alterations in cultured human islet cells using single-cell RNA-sequencing (scRNA-seq). We introduce single-nucleus RNA-sequencing (snRNA-seq) as an alternative approach for investigating transplanted human islets.

Methods: The Nuclei EZ protocol was used to obtain nuclear preparations from fresh and frozen human islet cells. Such preparations were first used to generate snRNA-seq datasets and compared to scRNA-seq output obtained from cells from the same donor. Finally, we employed snRNA-seq to obtain the transcriptomic profile of archived human islets engrafted in immunodeficient animals.

Results: We observed virtually complete concordance in identifying cell types and gene proportions as well as a strong association of global and islet cell type gene signatures between scRNA-seq and snRNA-seq applied to fresh and frozen cultured or transplanted human islet samples.

Conclusions: We propose snRNA-seq as a reliable strategy to probe transcriptomic profiles of freshly harvested or frozen sources of transplanted human islet cells especially when scRNA-seq is not ideal.
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http://dx.doi.org/10.1186/s13073-021-00941-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356387PMC
August 2021

Patterns of mental health problems before and after easing COVID-19 restrictions: Evidence from a 105248-subject survey in general population in China.

PLoS One 2021 3;16(8):e0255251. Epub 2021 Aug 3.

Shantou Longhu People's Hospital, Shantou, Guangdong, China.

Background: The COVID-19 pandemic has alarming implications for individual and population level mental health. Although the future of COVID-19 is unknown at present, more countries or regions start to ease restrictions. The findings from this study have provided the empirical evidence of prevalence and patterns of mental disorders in Chinese general population before and after easing most COVID-19 restrictions, and information of the factors associated with these patterns.

Methods: A cross-sectional population-based online survey was carried out from February to March 2020 in the general population across all provinces in China. The 12-item General Health Questionnaire (GHQ-12) was incorporated in the survey. Latent class analyses were performed to investigate the patterns of mental disorders and multinomial logistic regressions were used to examine how individual and regional risk factors can predict mental disorder patterns.

Results: Four distinctive patterns of mental health were revealed in the general population. After the ease of most COVID-19 restrictions, the prevalence of high risk of mental disorders decreased from 25.8% to 20.9% and prevalence of being high risk of unhappiness and loss of confidence decreased from 10.1% to 8.1%. However, the prevalence of stressed, social dysfunction and unhappy were consistently high before and after easing restrictions. Several regional factors, such as case mortality rate and healthcare resources, were associated with mental health status. Of note, healthcare workers were less likely to have mental disorders, compared to other professionals and students.

Conclusions: The dynamic management of mental health and psychosocial well-being is as important as that of physical health both before and after the ease of COVID-19 restrictions. Our findings may help in mental health interventions in other countries and regions while easing COVID-19 restrictions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255251PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331222PMC
August 2021

DEPTOR inhibits lung tumorigenesis by inactivating the EGFR-mTOR signals.

Cancer Lett 2021 Oct 25;519:263-276. Epub 2021 Jul 25.

Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China. Electronic address:

DEPTOR plays vital roles in the regulation of cell proliferation and survival by directly modulating the activity of mTORC1/2. However, the physiological role of DEPTOR in lung tumorigenesis, as well as its clinical significance, remains elusive. In this study, we revealed that decreased DEPTOR expression correlated with increased tumor size, poor differentiation, and worse survival in patients with lung cancer. DEPTOR depletion promoted cell proliferation, survival, migration, and invasion in human lung cancer cells. Mechanistically, DEPTOR bound to the kinase domain of EGFR via its PDZ domain to inactivate EGFR signal. Thus, DEPTOR depletion not only directly activated mTORC1/2, but also relieved the inhibition of EGFR to subsequently activate mTOR signals, leading to the induction of cell proliferation and survival. Additionally, activated EGFR-mTOR signals upregulated the expression of ZEB1 and SLUG to induce epithelial-mesenchymal transition, resulting in enhanced migration and invasion. Importantly, Deptor deletion accelerated Kras;p53-induced lung tumorigenesis and shortened mouse life span via the activation of EGFR-mTOR signals. Collectively, our study demonstrated that DEPTOR acts as a tumor suppressor in lung tumorigenesis, and its reduction may advance the progression of human lung cancer.
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http://dx.doi.org/10.1016/j.canlet.2021.07.031DOI Listing
October 2021

Development of Perovskite Oxide-Based Electrocatalysts for Oxygen Evolution Reaction.

Small 2021 Jul 26:e2101605. Epub 2021 Jul 26.

Institute of Applied Physics and Materials Engineering, University of Macau, Taipa, Macao SAR, 999078, China.

Perovskite oxides are studied as electrocatalysts for oxygen evolution reactions (OER) because of their low cost, tunable structure, high stability, and good catalytic activity. However, there are two main challenges for most perovskite oxides to be efficient in OER, namely less active sites and low electrical conductivity, leading to limited catalytic performance. To overcome these intrinsic obstacles, various strategies are developed to enhance their catalytic activities in OER. In this review, the recent developments of these strategies is comprehensively summarized and systematically discussed, including composition engineering, crystal facet control, morphology modulation, defect engineering, and hybridization. Finally, perspectives on the design of perovskite oxide-based electrocatalysts for practical applications in OER are given.
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http://dx.doi.org/10.1002/smll.202101605DOI Listing
July 2021

Designing Intrinsic Topological Insulators in Two-Dimensional Metal-Organic Frameworks.

J Phys Chem Lett 2021 Jul 20;12(29):6934-6940. Epub 2021 Jul 20.

Institute of High Performance Computing, Agency for Science, Technology and Research, 1 Fusionopolis Way, #16-16 Connexis, Singapore 138632, Singapore.

The connection between electronic structures of metal-organic frameworks (MOFs) and their building subunits is a key cornerstone for rational MOF material design. Some two-dimensional conjugated MOFs were reported to be topological insulators. However, many of them are not intrinsic as the Fermi levels are far from the topological gaps. The subunit-to-MOF electronic orbital correspondence should be established to bridge their chemical structure and physical properties, thus understanding the design rules toward intrinsic topological insulators. Herein we reveal the fundamental role of the subunit-to-MOF symmetry relation in determining their orbital interaction and hybridization and, consequently, topological characteristics. In particular, such honeycomb-kagome MOFs possess delocalized symmetry-enforced nonbonding electronic states with the topological spin-orbit gap. The nonbonding nature of these states allows tailored band structure modulation through molecular structure and strain engineering, with the potential realization of an intrinsic metal-organic topological insulator.
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http://dx.doi.org/10.1021/acs.jpclett.1c01731DOI Listing
July 2021

Alginate oligosaccharide alleviates D-galactose-induced cardiac ageing via regulating myocardial mitochondria function and integrity in mice.

J Cell Mol Med 2021 Aug 6;25(15):7157-7168. Epub 2021 Jul 6.

Department of Geriatric Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China.

Ageing is a crucial risk factor for the development of age-related cardiovascular diseases. Therefore, the molecular mechanisms of ageing and novel anti-ageing interventions need to be deeply studied. Alginate oligosaccharide (AOS) possesses high pharmacological activities and beneficial effects. Our study was undertaken to investigate whether AOS could be used as an anti-ageing drug to alleviate cardiac ageing. D-galactose (D-gal)-induced C57BL/6J ageing mice were established by subcutaneous injection of D-gal (200 mg·kg ·d ) for 8 weeks. AOS (50, 100 and 150 mg·kg ·d ) were administrated intragastrically for the last 4 weeks. As a result, AOS prevented cardiac dysfunction in D-gal-induced ageing mice, including partially preserved ejection fraction (EF%) and fractional shortening (FS%). AOS inhibited D-gal-induced up-regulation of natriuretic peptides A (ANP), brain natriuretic peptide (BNP) and ageing markers p53 and p21 in a dose-dependent manner. To further explore the potential mechanisms contributing to the anti-ageing protective effect of AOS, the age-related mitochondrial compromise was analysed. Our data indicated that AOS alleviated D-gal-induced cardiac ageing by improving mitochondrial biogenesis, maintaining the mitochondrial integrity and enhancing the efficient removal of impaired mitochondria. AOS also decreased the ROS production and oxidative stress status, which, in turn, further inhibiting cardiac mitochondria from being destroyed. Together, these results demonstrate that AOS may be an effective therapeutic agent to alleviate cardiac ageing.
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http://dx.doi.org/10.1111/jcmm.16746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335675PMC
August 2021

Autophagic flux assessment by immunoblot.

Methods Cell Biol 2021 1;164:63-72. Epub 2021 Mar 1.

Centre de Recherche des Cordeliers, Équipe 11 Labellisée par la Ligue Contre le Cancer Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Université Paris Saclay, Villejuif, France; Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China; Pôle de Biologie, Hôpital Européen Georges-Pompidou, AP-HP, Paris, France; Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Electronic address:

Autophagy is one of the main adaptive mechanisms to maintain cellular homeostasis in response to multiple stresses. During autophagy diverse cellular components such as damaged organelles or superfluous proteins are targeted for lysosomal degradation. Importantly, during the initiation of autophagy MAP1LC3B (better known as LC3) lipidates into the membrane of the forming phagophore, which facilitates the formation and lengthening of autophagosomes. In addition, the autophagy receptor SQSTM1 (better known as p62) selectively recruits various cargos to autophagosomes for lysosomal degradation. Both, the conversion of LC3 as well as the degradation of p62 can be assessed as means of monitoring autophagy. Here we detail a protocol for assessing these key events of the autophagic flux via immunoblot.
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http://dx.doi.org/10.1016/bs.mcb.2020.10.005DOI Listing
March 2021

Magneto-Optical Transport Properties of Type-II Nodal Line Semimetals.

Materials (Basel) 2021 Jun 2;14(11). Epub 2021 Jun 2.

Department of Physics, Beihang University, Beijing 100191, China.

We investigate the magneto-optical transport properties and Landau levels of type-II nodal line semimetals. The tilted liner dispersion in type-II nodal line semimetals makes the conduction band and valence band asymmetric, and Landau levels are coupling in the presence of a magnetic field. We find the background of absorption peaks is curved. The oscillation peaks are tailless with the change of magnetic field. Through tuning tilt term, we find the absorption peaks of optical conductivity change from incomplete degenerate structure to splitting double peaks structure. We also find interband absorption peaks is no longer zero in the imaginary part of Hall conductivity. With the change of the tilt term, the contribution of the absorption peak has two forms, one is that the negative peak only appears at high frequencies, and the other is two adjacent peaks with opposite signs. In addition, the resistivity, circularly polarized light and magnetic oscillation of Hall conductivity are studied.
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http://dx.doi.org/10.3390/ma14113035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199786PMC
June 2021

Sugar-Sweetened Beverage Consumption Status and Its Association with Childhood Obesity among Chinese Children Aged 6-17 Years.

Nutrients 2021 Jun 27;13(7). Epub 2021 Jun 27.

National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing 100050, China.

Objective: There is a remarkable growth in sugar-sweetened (SSB) production and obesity prevalence among school-aged children in China. This paper describes SSB consumption and its association with obesity among Chinese children aged 6-17 years in 2012.

Methods: in total, 25,553 children aged 6~17 years enrolled in the China Nutrition and Health Surveillance 2010-2013 were included in this study. Data of SSB consumption frequency and quantity were obtained from a food frequency questionnaire, and the children's nutritional status was assessed. Multivariate logistic regression was used to evaluate the association between SSB consumption and obesity status.

Results: SSB intake was estimated as 181.0 g/day, occurring 2.2 times/week. Older children, males, children from urban areas, and children with higher socioeconomic status were more likely to consume SSBs. Children who consumed SSBs 1~<5 times/week (11.7%) and >5 times/week (12.9%) were more likely to be overweight/obesity than those who consumed SSBs less than once/week.

Conclusion: SSB consumption was common among Chinese school-aged children, especially among males, older children, and children from urban areas. High consumption of SSBs was associated with a higher prevalence of overweight/obesity. Actions and plans are required to reduce SSB consumption and control childhood obesity in China.
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http://dx.doi.org/10.3390/nu13072211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308281PMC
June 2021

Treatment of Short Stature with Aromatase Inhibitors: A Systematic Review and Meta-Analysis.

Horm Metab Res 2021 Jun 21;53(6):391-401. Epub 2021 Jun 21.

Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China.

The objective of the study is to determine the risks and benefits of treating idiopathic short stature (ISS) with aromatase inhibitors (AIs). We comprehensively searched PubMed, Embase, and the China National Knowledge Infrastructure between establishment year and January 31, 2020. Mean difference (MD)/Standardized mean differences (SMD) with 95% confidence intervals (CI) of individual studies were pooled using fixed or random effects models. Subgroup and sensitivity analyses were also performed. Publication bias was estimated using funnel plots and Egger tests. Fourteen studies including 388 participants were included. The meta-analysis results showed that AIs significantly increased final height (MD=2.46, 95% CI: 0.8-4.12) and predicted adult height (MD=0.34, 95% CI: 0.11-0.57). Changes in bone age (MD=-0.1, 95% CI: -0.86-0.66) and bone mineral density (MD=-0.05, 95% CI: -0.19-0.1) were not different between intervention and control group. AI significantly increased testosterone level (SMD=2.01, 95% CI: 0.8-3.23) and reduced estradiol level (SMD=-1.13, 95% CI: -1.87 to -0.40); The intervention and control group had no significant differences in the levels of high-density lipoprotein-cholesterol (SMD=-0.31, 95%CI: -0.68-0.06) and IGF-1 (SMD=0.7, 95% CI: -0.66-2.06) levels. Adverse events were more frequent in the intervention group than in the control group (odds ratio=3.12, 95% CI: 1.44-6.73). In conclusion, both AI monotherapy and AI combination therapy can increase predicted adult height and testosterone levels.
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http://dx.doi.org/10.1055/a-1492-2841DOI Listing
June 2021

CNSi/MXene/CNSi: Unique Structure with Specific Electronic Properties for Nanodevices.

Small 2021 Jun 20:e2101482. Epub 2021 Jun 20.

Institute of Applied Physics and Materials Engineering, University of Macau, Macao SAR, China.

2D materials have been interesting for applications into nanodevices due to their intriguing physical properties. In this work, four types of unique structures are designed that are composed of MXenes and C/N-Si layers (CNSi), where MXene is sandwiched by the CNSi layers with different thicknesses, for their practical applications into integrated devices. The systematic calculations on their elastic constants, phonon dispersions, and thermodynamic properties show that these structures are stable, depending on the composition of MXene. It is found: 1) different from MXene or N-functionalized MXene (M CN ), SiN /M X/SiN possess new electronic properties with free carriers only in the middle, leading to 2D free electron gas; 2) CNSi/MXene/CNSi shows an intrinsic Ohmic semiconductor-metal-semiconductor (S-M-S) contact, which is potential for applications into nanodevices; and 3) O/M C/SiN and N/M C/OSiN are also stable and show different electronic properties, which can be semiconductor or metal as a whole depending on the interface. A method is further proposed to fabricate the 2D structures based on the industrial availability. The findings may provide a novel strategy to design and fabricate the 2D structures for their application into nanodevices and integrated circuits.
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http://dx.doi.org/10.1002/smll.202101482DOI Listing
June 2021

Influence of wet flue gas desulfurization on the pollutants monitoring in FCC flue gas.

Environ Sci Pollut Res Int 2021 Jun 17. Epub 2021 Jun 17.

State Key Laboratory of Chemical Engineering, School of Chemical Engineering, East China University of Science and Technology, Shanghai, 200237, China.

Fluid catalytic cracking (FCC) unit emits a large amount of flue gas, which is a major concern of environmental protection supervision. Wet flue gas desulfurization (WFGD) technologies have been widely used to control the emissions of SO in refineries. In this study, stack tests for pollutants emission of a typical FCC unit were conducted. The emission characteristics of the FCC unit indicated that WFGD would cause a large amount of water vapor in the flue gas, which indirectly leads to large quantities of salt pollutants entrained in the flue gas including ammonium sulfite ((NH)SO) and ammonium sulfate ((NH)SO). A strong correlation among the concentrations of SO, NH, and HO was observed, and factor analysis shows that these concentrations are dominated by a common factor. It was also found that a mass quantity of NH and SO existed in the condensate water of the flue gas. The TG-MS analysis shows that (NH)SO could be decomposed at 94.1 °C, and NH, SO, and HO are released as reaction products in the form of gas. Therefore, a part of the NH and SO obtained by Fourier transform infrared spectroscopy (FTIR) monitoring may be derived from the decomposition of (NH)SO in the flue gas due to the high temperature during the sampling process, which was also confirmed in a lab experiment. The hot and wet sampling process will lead to overestimation of NH and SO emissions rather than FTIR method itself when monitoring the high-humidity FCC flue gas. Thus, the concentration of HO in the flue gas and the type of sampling process need to be taken into consideration during the monitoring process.
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http://dx.doi.org/10.1007/s11356-021-14767-9DOI Listing
June 2021

IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms.

J Immunother Cancer 2021 Jun;9(6)

Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France

Background: Pharmacological autophagy enhancement constitutes a preclinically validated strategy for preventing or treating most major age-associated diseases. Driven by this consideration, we performed a high-content/high-throughput screen on 65 000 distinct compounds on a robotized fluorescence microscopy platform to identify novel autophagy inducers.

Results: Here, we report the discovery of picropodophyllin (PPP) as a potent inducer of autophagic flux that acts on-target, as an inhibitor of the tyrosine kinase activity of the insulin-like growth factor-1 receptor (IGF1R). Thus, PPP lost its autophagy-stimulatory activity in cells engineered to lack IGF1R or to express a constitutively active AKT serine/threonine kinase 1 (AKT1) mutant. When administered to cancer-bearing mice, PPP improved the therapeutic efficacy of chemoimmunotherapy with a combination of immunogenic cytotoxicants and programmed cell death 1 (PDCD1, better known as PD-1) blockade. These PPP effects were lost when tumors were rendered PPP-insensitive or autophagy-incompetent. In combination with chemotherapy, PPP enhanced the infiltration of tumors by cytotoxic T lymphocytes, while reducing regulatory T cells. In human triple-negative breast cancer patients, the activating phosphorylation of IGF1R correlated with inhibited autophagy, an unfavorable local immune profile, and poor prognosis.

Conclusion: Altogether, these results suggest that IGF1R may constitute a novel and druggable therapeutic target for the treatment of cancer in conjunction with chemoimmunotherapies.
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http://dx.doi.org/10.1136/jitc-2021-002722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204183PMC
June 2021

Unravelling the Reaction Mechanisms of N Fixation on Molybdenum Nitride: A Full DFT Study from the Pristine Surface to Heteroatom Anchoring.

ChemSusChem 2021 Aug 28;14(16):3257-3266. Epub 2021 Jun 28.

Institute of Applied Physics and Materials Engineering, University of Macau, Macao SAR, 999078, P. R. China.

Transition metal nitrides (TMNs)-based materials have attracted increasing attention in electrochemical nitrogen reduction reaction (eNRR) because of their unique structures and inherent electronic properties. However, the eNRR mechanism on such nitrogen contained catalysts is still unclear, for example, which part of the catalyst act as the active sites, and how to achieve the optimal efficiency is also challenging. In this work, a comprehensive study was conducted to unravel the reaction mechanisms of N fixation on molybdenum nitride by using density functional theory (DFT) calculations. The activity and selectivity of eNRR on pristine (001) and (110) Mo N surfaces as well as few specific numbers of heteroatom-anchored N-terminated surfaces were all evaluated and compared. It was found that the Mo and N atoms on the pristine Mo N surface were both active for eNRR while following different pathways in mechanism. Moreover, the eNRR catalytic performance of Mo N could be further boosted by specific metal atoms anchoring, such as single atom, metal dimer, and heterodiatom pair. Finally, a full map of eNRR mechanism on pristine and metal atom-decorated Mo N surfaces was illustrated. This work not only provides a fundamental understanding of eNRR mechanism on TMNs based materials but also offers powerful strategies towards the rational design of efficient NRR electrocatalysts.
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http://dx.doi.org/10.1002/cssc.202101014DOI Listing
August 2021

Predictors for Surgeries With the Endoscope-Navigation System for Traumatic Optic Neuropathy and its Clinical Assessment.

J Craniofac Surg 2021 Jun 2. Epub 2021 Jun 2.

Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Department of Ophthalmology, Zhongda Hospital, Southeast University, Nanjing, China.

Background: To assess surgeries with the endoscope-navigation system (ENS) in patients who underwent traumatic optic neuropathy (TON) and find predictors for best corrected visual acuity (BCVA) outcomes.

Methods: The clinical data of 96 consecutive TON patients (96 eyes) who underwent decompression surgery with ENS in the Department of Ophthalmology, Shanghai Ninth People's Hospital, from January 2013 to December 2019 were retrospectively reviewed and analyzed. A binary logistic regression was performed to establish a predictive model for BCVA after treatment as TON outcome.

Results: By practicing ENS, 49/96 (51.0%) TON patients got improvement in BCVA, whereas the improvement rate of patients with BCVA of light perception or better was 72.5% (29/40). Hemorrhage within the postethmoid and/or sphenoid sinus, orbital fracture, time interval between trauma and treatment, and BCVA before treatment were predictors for BCVA improvement in TON patients by practicing ENS surgery. The area under raw current curves of the predictive model was 0.826.

Conclusions: Surgeries with the ENS showed positive outcomes for TON patients, especially for those with better BCVA before treatment, shorter time interval between trauma and treatment, without orbital fracture or hemorrhage within the postethmoid and/or sphenoid sinus.
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http://dx.doi.org/10.1097/SCS.0000000000007749DOI Listing
June 2021

ABE8e with Polycistronic tRNA-gRNA Expression Cassette Sig-Nificantly Improves Adenine Base Editing Efficiency in .

Int J Mol Sci 2021 May 26;22(11). Epub 2021 May 26.

Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture, Wuhan Botanical Garden, Chinese Academy of Sciences, Wuhan 430074, China.

Adenine base editor containing TadA8e (ABE8e) has been reported in rice. However, the application of ABE8e in other plant species has not been described, and the comparison between ABE8e and ABE7.10, which is widely used in plants, has also been poorly studied. Here, we developed the ABE8e with the polycistronic tRNA-gRNA expression cassette (PTG-ABE8e) and PTG-ABE7.10 and compared their A-to-G editing efficiencies using both transient and stable transformation in the allotetraploid . We found that the editing efficiency of PTG-ABE8e was significantly higher than that of PTG-ABE7.10, indicating that ABE8e was more efficient for A-to-G conversion in . We further optimized the ABE8e editing efficiency by changing the sgRNA expression cassette and demonstrated that both PTG and single transcript unit (STU) enhanced ABE8e efficiency for A-to-G conversion in . We also estimated the potential off-target effect of PTG-ABE8e at potential off-targeting sites predicted using an online tool in transgenic plants, and no off-target editing event was found for potential off-targeting sites selected, indicating that ABE8e could specifically facilitate A-to-G conversion. Our results showed that ABE8e with PTG structure was more suitable for A-to-G conversion in and provided valuable clues for optimizing ABE tools in other plants.
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http://dx.doi.org/10.3390/ijms22115663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198424PMC
May 2021

Exome sequencing reveals genetic architecture in patients with isolated or syndromic short stature.

J Genet Genomics 2021 05 22;48(5):396-402. Epub 2021 Mar 22.

Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China. Electronic address:

Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations. Although the diagnostic utility of clinical genetic testing in short stature has been implicated, the genetic architecture and the utility of genomic studies such as exome sequencing (ES) in a sizable cohort of patients with short stature have not been investigated systematically. In this study, we recruited 561 individuals with short stature from two centers in China during a 4-year period. We performed ES for all patients and available parents. All patients were retrospectively divided into two groups: an isolated short stature group (group I, n = 257) and an apparently syndromic short stature group (group II, n = 304). Causal variants were identified in 135 of 561 (24.1%) patients. In group I, 29 of 257 (11.3%) of the patients were solved by variants in 24 genes. In group II, 106 of 304 (34.9%) patients were solved by variants in 57 genes. Genes involved in fundamental cellular process played an important role in the genetic architecture of syndromic short stature. Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.
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http://dx.doi.org/10.1016/j.jgg.2021.02.008DOI Listing
May 2021

A Retrospective Analysis of Patients with Short Stature in Eastern China between 2013 and 2019.

Biomed Res Int 2021 20;2021:6640026. Epub 2021 Apr 20.

Department of Endocrinology, Affiliated Hospital of Jining Medical University, Jining Medical University, 89 Guhuai Road, Jining, Shandong 272029, China.

Objective: To identify the aetiology of growth and development diseases and assess the long-term effectiveness of recombinant human growth hormone (rhGH) therapy in a real-life clinical setting and provide better guidance in clinical strategy and decision making.

Methods: This retrospective study included 1145 children and adolescents with short stature admitted to the Department of Endocrinology, Affiliated Hospital of Jining Medical University, from January 2013 to December 2019, of whom 484 received rhGH treatment. The related anthropometrics and laboratory examinations were assessed in all participants.

Results: A total of 1145 children and adolescents with short stature aged 10.5 ± 3.3 years, including 740 boys and 405 girls, were analysed in this study. The number of children and adolescents with short stature gradually increased per year from 2013 to 2019. The mean pretreatment height standard deviation score (SDS) and insulin-like growth factor-1 SDS were -2.93 ± 1.05 and -1.01 (-1.83--0.16), respectively. The majority of the children (658, 57.47%) were prepubescent. In total, 484 subjects aged 10.6 ± 3.2 years received rhGH and were followed up, and among them, 292 children were treated for more than one year. As the treatment time increased, the children's height SDS gradually increased, and most of them attained a height SDS within the normal range. The mean height SDS in children who were treated for more than one year was -3.0 ± 1.0 at baseline and gradually increased to -0.8 ± 0.3 by year 6. The results were consistent across subgroups of different aetiologies of short stature.

Conclusions: Increasing attention has been given to the height of children during the period of 2013-2019 in eastern China. The present findings indicate that children with short stature need to be referred to a specialist centre to diagnose the cause of growth failure and that short children receiving rhGH therapy show a significant increase in height over time.
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http://dx.doi.org/10.1155/2021/6640026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081605PMC
May 2021

Roles of Anxiety and Depression in Predicting Cardiovascular Disease Among Patients With Type 2 Diabetes Mellitus: A Machine Learning Approach.

Front Psychol 2021 28;12:645418. Epub 2021 Apr 28.

Department of Medical Psychology, Harbin Medical University, Harbin, China.

Cardiovascular disease (CVD) is a major complication of type 2 diabetes mellitus (T2DM). In addition to traditional risk factors, psychological determinants play an important role in CVD risk. This study applied Deep Neural Network (DNN) to develop a CVD risk prediction model and explored the bio-psycho-social contributors to the CVD risk among patients with T2DM. From 2017 to 2020, 834 patients with T2DM were recruited from the Department of Endocrinology, Affiliated Hospital of Harbin Medical University, China. In this cross-sectional study, the patients' bio-psycho-social information was collected through clinical examinations and questionnaires. The dataset was randomly split into a 75% train set and a 25% test set. DNN was implemented at the best performance on the train set and applied on the test set. The receiver operating characteristic curve (ROC) analysis was used to evaluate the model performance. Of participants, 272 (32.6%) were diagnosed with CVD. The developed ensemble model for CVD risk achieved an area under curve score of 0.91, accuracy of 87.50%, sensitivity of 88.06%, and specificity of 87.23%. Among patients with T2DM, the top five predictors in the CVD risk model were body mass index, anxiety, depression, total cholesterol, and systolic blood pressure. In summary, machine learning models can provide an automated identification mechanism for patients at CVD risk. Integrated treatment measures should be taken in health management, including clinical care, mental health improvement, and health behavior promotion.
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http://dx.doi.org/10.3389/fpsyg.2021.645418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113686PMC
April 2021

Deep reinforcement learning approaches for global public health strategies for COVID-19 pandemic.

PLoS One 2021 13;16(5):e0251550. Epub 2021 May 13.

Department of Computer Science and Engineering, The Hong Kong University of Science and Technology, Hong Kong, China.

Background: Unprecedented public health measures have been used during this coronavirus 2019 (COVID-19) pandemic to control the spread of SARS-CoV-2 virus. It is a challenge to implement timely and appropriate public health interventions.

Methods And Findings: Population and COVID-19 epidemiological data between 21st January 2020 to 15th November 2020 from 216 countries and territories were included with the implemented public health interventions. We used deep reinforcement learning, and the algorithm was trained to enable agents to try to find optimal public health strategies that maximized total reward on controlling the spread of COVID-19. The results suggested by the algorithm were analyzed against the actual timing and intensity of lockdown and travel restrictions. Early implementations of the actual lockdown and travel restriction policies, usually at the time of local index case were associated with less burden of COVID-19. In contrast, our agent suggested to initiate at least minimal intensity of lockdown or travel restriction even before or on the day of the index case in each country and territory. In addition, the agent mostly recommended a combination of lockdown and travel restrictions and higher intensity policies than the policies implemented by governments, but did not always encourage rapid full lockdown and full border closures. The limitation of this study was that it was done with incomplete data due to the emerging COVID-19 epidemic, inconsistent testing and reporting. In addition, our research focuses only on population health benefits by controlling the spread of COVID-19 without balancing the negative impacts of economic and social consequences.

Interpretation: Compared to actual government implementation, our algorithm mostly recommended earlier intensity of lockdown and travel restrictions. Reinforcement learning may be used as a decision support tool for implementation of public health interventions during COVID-19 and future pandemics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251550PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118301PMC
May 2021

The characterization of metabolites alterations in white adipose tissue of diabetic GK Rats after ileal transposition surgery by an untargeted metabolomics approach.

Adipocyte 2021 12;10(1):275-284

Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.

Dysfunction of adipose tissue could lead to insulin resistance, obesity and type 2 diabetes. Thus, our present study aimed to investigate metabolites alterations in white adipose tissue (WAT) of diabetic GK rats after IT surgery. Ten-week-old male diabetic GK rats were randomly subjected to IT and Sham-IT surgery. Six weeks later, the untargeted metabolomics in WAT of diabetic GK rats was performed. Differential metabolites were selected according to the coefficient of variation (CV) of quality control (QC) sample <30%, variable importance in the projection (VIP) >1 and P < 0.05. Then, the hierarchical clustering of differential metabolites was conducted and the KEGG database was used for metabolic pathway analysis. A total of 50 (in positive ion mode) and 68 (in negative ion mode) metabolites were identified as differential metabolites in WAT of diabetic GK rats between IT group and Sham-IT group, respectively. These differential metabolites were well clustered, which in descending order of the number of involved differential metabolites is ubiquinone and other terpenoid-quinone biosynthesis, AMPK signalling pathway, pantothenate and CoA biosynthesis, ferroptosis, vitamin digestion and absorption, glycerophospholipid metabolism, phenylalanine metabolism, steroid hormone biosynthesis, neuroactive ligand-receptor interaction, porphyrin and chlorophyll metabolism and bile secretion, and correlated with the parameters of body weight, food intake, WAT mass and glucose metabolism, which were significantly improved after IT surgery. The differential metabolites in WAT of diabetic GK rats were mainly related to the pathway of energy metabolism, and correlated with the improved phenotypes of diabetic GK rats after IT surgery.
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http://dx.doi.org/10.1080/21623945.2021.1926139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118414PMC
December 2021

Identification and Functional Verification of Two Novel Mutations of Gene in the Chinese Children with Laron Syndrome.

Front Endocrinol (Lausanne) 2021 12;12:605736. Epub 2021 Apr 12.

Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.

Purpose: Laron syndrome (LS) is a severe growth disorder caused by gene mutation or post-receptor pathways defect. The clinical features of these patients collected in our present study were summarized, gene variants were investigated and further functional verification was carried out.

Methods: Four patients with LS were collected, their clinical characteristics were summarized, genomic DNA was extracted, and gene was amplified and sequenced. GHR wild type (GHR-WT) and mutant GHR expression plasmids were constructed, and transiently transfected into HepG2 cells and HEK293T cells to observe the subcellular distribution of the GHR protein by immunofluorescence and to determine the expression of GHR and its post-receptor signaling pathway changes by Western blotting.

Results: All of the four patients were male, and the median height was -4.72 SDS. Four gene variants including c.587A>C (p.Y196S), c.766C>T (p.Q256*), c.808A>G (p.I270V) and c.1707-1710del (p.E570Afs*30) were identified, and the latter two were novel mutations. The results of mutant GHR plasmids transfection experiments and immunofluorescence assay showed that the subcellular distribution of GHR-Q256* and GHR-E570Afs*30 mutant proteins in HepG2 and HEK293T cells presented with a unique ring-like pattern, gathering around the nucleus, while GHR-Y196S mutant protein was evenly distributed on HepG2 cell membrane similar to GHR-WT. The GHR protein levels of HepG2 cells transiently transfected with GHR-Y196S, GHR-Q256* and GHR-E570Afs*30 were all significantly lower when compared with cells transfected with GHR-WT (P<0.05). Further mutant GHR post-receptor signal transduction investigation demonstrated that GH induced phosphorylated STAT5 levels of HepG2 cells transfected with three mutant plasmids were all significantly decreased in comparison with that of GHR-WT (P<0.05).

Conclusions: Two novel gene mutations (I270V and E570Afs*30) were found in our patients with LS. GHR mutations influenced the subcellular distribution and GHR protein levels, then led to the impaired post-receptor signal transduction, suggesting that the mutations contributed to the pathological condition of LS patients.
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http://dx.doi.org/10.3389/fendo.2021.605736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072467PMC
April 2021
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