Publications by authors named "Teng Han"

26 Publications

  • Page 1 of 1

The E3/E4 ubiquitin conjugation factor UBE4B interacts with and ubiquitinates the HTLV-1 Tax oncoprotein to promote NF-κB activation.

PLoS Pathog 2020 12 23;16(12):e1008504. Epub 2020 Dec 23.

Department of Microbiology and Immunology, Penn State College School of Medicine, Hershey, Pennsylvania, United States of America.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), and the neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax protein persistently activates the NF-κB pathway to enhance the proliferation and survival of HTLV-1 infected T cells. Lysine 63 (K63)-linked polyubiquitination of Tax provides an important regulatory mechanism that promotes Tax-mediated interaction with the IKK complex and activation of NF-κB; however, the host proteins regulating Tax ubiquitination are largely unknown. To identify new Tax interacting proteins that may regulate its ubiquitination we conducted a yeast two-hybrid screen using Tax as bait. This screen yielded the E3/E4 ubiquitin conjugation factor UBE4B as a novel binding partner for Tax. Here, we confirmed the interaction between Tax and UBE4B in mammalian cells by co-immunoprecipitation assays and demonstrated colocalization by proximity ligation assay and confocal microscopy. Overexpression of UBE4B specifically enhanced Tax-induced NF-κB activation, whereas knockdown of UBE4B impaired Tax-induced NF-κB activation and the induction of NF-κB target genes in T cells and ATLL cell lines. Furthermore, depletion of UBE4B with shRNA resulted in apoptotic cell death and diminished the proliferation of ATLL cell lines. Finally, overexpression of UBE4B enhanced Tax polyubiquitination, and knockdown or CRISPR/Cas9-mediated knockout of UBE4B attenuated both K48- and K63-linked polyubiquitination of Tax. Collectively, these results implicate UBE4B in HTLV-1 Tax polyubiquitination and downstream NF-κB activation.
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http://dx.doi.org/10.1371/journal.ppat.1008504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790423PMC
December 2020

Acceptance of and six-month adherence to continuous positive airway pressure in patients with moderate to severe obstructive sleep apnea.

Clin Respir J 2021 Jan 22;15(1):56-64. Epub 2020 Sep 22.

Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.

Background: Continuous positive airway pressure (CPAP) is the most effective treatment for moderate to severe obstructive sleep apnea (OSA). Acceptance of and adherence to CPAP are crucial for optimal treatment outcomes. The aim of this study was to investigate the factors influencing patients' acceptance of and adherence to CPAP treatment.

Methods: One hundred eighty-eight patients with moderate to severe OSA who had received CPAP titration from October 2017 to September 2018 were recruited. They were interviewed at 2 weeks and at 6 months to assess CPAP use and barriers to acceptance and adherence.

Results: One hundred fourteen patients (60.6%) accepted CPAP treatment. Disease severity, assessed by apnea-hypopnea index (AHI) (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01-1.08), subjective satisfaction of titration (OR, 12.83; 95% CI, 3.83-42.99), initial intention of CPAP therapy (OR, 3.33; 95% CI, 1.05-10.51) and short-term home CPAP trial (OR, 9.40; 95% CI, 2.85-31.08) were associated with acceptance of CPAP treatment. Two-third of the 98 CPAP acceptors reported good CPAP adherence at 6 months follow-up. Average hours of CPAP use per day for the first 2 weeks (OR, 1.88; 95% CI, 1.28-3.04) and the global problems associated with CPAP use (OR, 0.82; 95% CI, 0.73-0.91) were independent predictors of the six-month CPAP adherence.

Conclusions: Nearly 40% of patients with moderate to severe OSA did not accept CPAP treatment, and one-third of those CPAP acceptors had poor adherence to CPAP treatment. Improvement in disease awareness, comfortable titration experience, short-term home CPAP trial may be of help to increase CPAP acceptance and early experience with CPAP is important for long-term adherence. The differences in predicting factors for CPAP acceptance and adherence highlight the importance of focusing on specific aspects during the whole process management of OSA.
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http://dx.doi.org/10.1111/crj.13269DOI Listing
January 2021

Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis.

Nature 2020 09 9;585(7825):426-432. Epub 2020 Sep 9.

Division of Regenerative Medicine, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.

Endothelial cells adopt tissue-specific characteristics to instruct organ development and regeneration. This adaptability is lost in cultured adult endothelial cells, which do not vascularize tissues in an organotypic manner. Here, we show that transient reactivation of the embryonic-restricted ETS variant transcription factor 2 (ETV2) in mature human endothelial cells cultured in a serum-free three-dimensional matrix composed of a mixture of laminin, entactin and type-IV collagen (LEC matrix) 'resets' these endothelial cells to adaptable, vasculogenic cells, which form perfusable and plastic vascular plexi. Through chromatin remodelling, ETV2 induces tubulogenic pathways, including the activation of RAP1, which promotes the formation of durable lumens. In three-dimensional matrices-which do not have the constraints of bioprinted scaffolds-the 'reset' vascular endothelial cells (R-VECs) self-assemble into stable, multilayered and branching vascular networks within scalable microfluidic chambers, which are capable of transporting human blood. In vivo, R-VECs implanted subcutaneously in mice self-organize into durable pericyte-coated vessels that functionally anastomose to the host circulation and exhibit long-lasting patterning, with no evidence of malformations or angiomas. R-VECs directly interact with cells within three-dimensional co-cultured organoids, removing the need for the restrictive synthetic semipermeable membranes that are required for organ-on-chip systems, therefore providing a physiological platform for vascularization, which we call 'Organ-On-VascularNet'. R-VECs enable perfusion of glucose-responsive insulin-secreting human pancreatic islets, vascularize decellularized rat intestines and arborize healthy or cancerous human colon organoids. Using single-cell RNA sequencing and epigenetic profiling, we demonstrate that R-VECs establish an adaptive vascular niche that differentially adjusts and conforms to organoids and tumoroids in a tissue-specific manner. Our Organ-On-VascularNet model will permit metabolic, immunological and physiochemical studies and screens to decipher the crosstalk between organotypic endothelial cells and parenchymal cells for identification of determinants of endothelial cell heterogeneity, and could lead to advances in therapeutic organ repair and tumour targeting.
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http://dx.doi.org/10.1038/s41586-020-2712-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480005PMC
September 2020

Ventilatory response to exercise is preserved in patients with obesity hypoventilation syndrome.

J Clin Sleep Med 2020 12;16(12):2089-2098

Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.

Study Objectives: Blunted ventilatory responses to hypoxia and hypercapnia during resting conditions are common findings in patients with obesity hypoventilation syndrome (OHS). Exercise increases the work and oxygen cost of breathing and produces excessive carbon dioxide (CO₂). The aim of this investigation was to study ventilatory responses to incremental exercise in patients with OHS.

Methods: Sixty-eight obese adults with OHS (n = 15), eucapnic obstructive sleep apnea (n = 26), or simple obesity (n = 27) participated in an incremental exercise test on a cycle ergometer and an in-laboratory sleep study.

Results: The peak oxygen uptake (peak VO₂) and peak pulse oxygen was decreased in patients with OHS compared with patients with either obstructive sleep apnea or simple obesity. The ventilatory response to exertional metabolic demand (nadir VE/VCO₂, ∆VE/∆VCO₂ slope, and VE/VCO₂ at peak exercise) did not significantly differ among the 3 groups. Minute ventilation, tidal volume, respiratory frequency, tidal volume/respiratory frequency, and inspiratory time/total time ratio at a given work rate were comparable among the 3 groups. Among the whole cohort, apnea-hypopnea index was not independently associated with peak VO₂, and no association was found between the ∆VE/∆VCO₂ slope and resting arterial partial pressure of CO₂.

Conclusions: The ventilatory response to incremental exercise is preserved in patients with OHS compared with patients with obstructive sleep apnea and simple obesity who were matched for age and body mass index. This result highlights the complexity of the respiratory control system during exercise for patients with OHS, which may be uncoupled with the ventilatory response during sleep and resting conditions.
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http://dx.doi.org/10.5664/jcsm.8766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848936PMC
December 2020

Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2.

Res Sq 2020 Aug 20. Epub 2020 Aug 20.

Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19) from mild to severe stages including fatality, with pro-inflammatory macrophages as one of the main mediators of lung hyper-inflammation. Therefore, there is an urgent need to better understand the interactions among SARS-CoV-2 permissive cells, macrophage, and the SARS-CoV-2 virus, thereby offering important insights into new therapeutic strategies. Here, we used directed differentiation of human pluripotent stem cells (hPSCs) to establish a lung and macrophage co-culture system and model the host-pathogen interaction and immune response caused by SARS-CoV-2 infection. Among the hPSC-derived lung cells, alveolar type II and ciliated cells are the major cell populations expressing the viral receptor ACE2 and co-effector TMPRSS2, and both were highly permissive to viral infection. We found that alternatively polarized macrophages (M2) and classically polarized macrophages (M1) had similar inhibitory effects on SARS-CoV-2 infection. However, only M1 macrophages significantly up-regulated inflammatory factors including IL-6 and IL-18, inhibiting growth and enhancing apoptosis of lung cells. Inhibiting viral entry into target cells using an ACE2 blocking antibody enhanced the activity of M2 macrophages, resulting in nearly complete clearance of virus and protection of lung cells. These results suggest a potential therapeutic strategy, in that by blocking viral entrance to target cells while boosting anti-inflammatory action of macrophages at an early stage of infection, M2 macrophages can eliminate SARS-CoV-2, while sparing lung cells and suppressing the dysfunctional hyper-inflammatory response mediated by M1 macrophages.
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http://dx.doi.org/10.21203/rs.3.rs-62758/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444287PMC
August 2020

Moderate-to-Severe Obstructive Sleep Apnea and Cognitive Function Impairment in Patients with COPD.

Int J Chron Obstruct Pulmon Dis 2020 27;15:1813-1822. Epub 2020 Jul 27.

Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People's Republic of China.

Purpose: Prior studies have indicated that patients with chronic obstructive pulmonary disease (COPD) exhibit significant cognitive defects on neuropsychological testing. Obstructive sleep apnea (OSA) is common in patients with COPD and is associated with reduced cognitive function; however, the combined impact of these two conditions on cognitive function is unknown. The aim of the study was to investigate the impact of OSA on cognitive impairment in patients with COPD.

Methods: Sixty-five stable COPD patients aged over 60 years underwent overnight polysomnography (PSG). Global cognitive functions were evaluated using the Mini-Mental State Examination (MMSE).

Results: Compared to patients with COPD alone, patients with both COPD and OSA performed worse on the MMSE (25.5±2.9 vs 23.5±3.2; p=0.01) and were more likely to be at risk for developing dementia based on the MMSE score (MMSE≤24) (31% vs 66%; p<0.01), independent of key demographic, educational and medical variables known to affect cognitive function in COPD. COPD patients with an apnea hypopnea index (AHI) of ≥30 events/h had lower MMSE scores than those with an AHI of <15 events/h. In addition to age and education level, the severity of nocturnal intermittent hypoxia is an independent predictor of the risk of dementia in patients with COPD (OR=1.24, 95% CI 1.04-1.48, p = 0.02).

Conclusion: The current findings indicate that patients with COPD with comorbid OSA may be at greater risk for global cognitive impairment relative to patients with COPD alone. The mechanisms underlying the exaggerated cognitive dysfunction seem to be related to intermittent hypoxia. Further work is needed to understand the impact of OSA on the specific domains of cognitive impairment and the therapeutic implications of OSA in COPD.
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http://dx.doi.org/10.2147/COPD.S257796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396955PMC
July 2020

An Allelic Series Reveals Distinct Phenotypes of Common Oncogenic Variants.

Cancer Discov 2020 Nov 12;10(11):1654-1671. Epub 2020 Aug 12.

Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York.

is the most frequently mutated oncogene in cancer, yet there is little understanding of how specific KRAS amino acid changes affect tumor initiation, progression, or therapy response. Using high-fidelity CRISPR-based engineering, we created an allelic series of new mutant mice, reflecting codon 12 and 13 mutations that are highly prevalent in lung (KRAS), pancreas (KRAS), and colon (KRAS) cancers. Induction of each allele in either the murine colon or pancreas revealed striking quantitative and qualitative differences between KRAS mutants in driving the early stages of transformation. Furthermore, using pancreatic organoid models, we show that KRAS mutants are sensitive to EGFR inhibition, whereas KRAS-mutant organoids are selectively responsive to covalent G12C inhibitors only when EGFR is suppressed. Together, these new mouse strains provide an ideal platform for investigating KRAS biology and for developing preclinical precision oncology models of KRAS-mutant pancreas, colon, and lung cancers. SIGNIFICANCE: KRAS is the most frequently mutated oncogene. Here, we describe new preclinical models that mimic tissue-selective KRAS mutations and show that each mutation has distinct cellular consequences and carries differential sensitivity to targeted therapeutic agents...
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http://dx.doi.org/10.1158/2159-8290.CD-20-0442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642097PMC
November 2020

Exploiting the Therapeutic Interaction of WNT Pathway Activation and Asparaginase for Colorectal Cancer Therapy.

Cancer Discov 2020 Nov 23;10(11):1690-1705. Epub 2020 Jul 23.

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Colorectal cancer is driven by mutations that activate canonical WNT/β-catenin signaling, but inhibiting WNT has significant on-target toxicity, and there are no approved therapies targeting dominant oncogenic drivers. We recently found that activating a β-catenin-independent branch of WNT signaling that inhibits GSK3-dependent protein degradation induces asparaginase sensitivity in drug-resistant leukemias. To test predictions from our model, we turned to colorectal cancer because these cancers can have WNT-activating mutations that function either upstream (i.e., R-spondin fusions) or downstream ( or β-catenin mutations) of GSK3, thus allowing WNT/β-catenin and WNT-induced asparaginase sensitivity to be unlinked genetically. We found that asparaginase had little efficacy in or β-catenin-mutant colorectal cancer, but was profoundly toxic in the setting of R-spondin fusions. Pharmacologic GSK3α inhibition was sufficient for asparaginase sensitization in or β-catenin-mutant colorectal cancer, but not in normal intestinal progenitors. Our findings demonstrate that WNT-induced therapeutic vulnerabilities can be exploited for colorectal cancer therapy. SIGNIFICANCE: Solid tumors are thought to be asparaginase-resistant via asparagine synthesis. In leukemia, GSK3α-dependent protein degradation, a catabolic amino acid source, mediates asparaginase resistance. We found that asparaginase is profoundly toxic to colorectal cancers with WNT-activating mutations that inhibit GSK3. Aberrant WNT activation can provide a therapeutic vulnerability in colorectal cancer...
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http://dx.doi.org/10.1158/2159-8290.CD-19-1472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642035PMC
November 2020

Lineage Reversion Drives WNT Independence in Intestinal Cancer.

Cancer Discov 2020 Oct 16;10(10):1590-1609. Epub 2020 Jun 16.

Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, New York.

The WNT pathway is a fundamental regulator of intestinal homeostasis, and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer. To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that although WNT suppression blocks tumor growth in most organoid and colorectal cancer models, the accumulation of colorectal cancer-associated genetic alterations enables drug resistance and WNT-independent growth. In intestinal epithelial cells harboring mutations in or , together with disruption of and , transient TGFβ exposure drives YAP/TAZ-dependent transcriptional reprogramming and lineage reversion. Acquisition of embryonic intestinal identity is accompanied by a permanent loss of adult intestinal lineages, and long-term WNT-independent growth. This work identifies genetic and microenvironmental factors that drive WNT inhibitor resistance, defines a new mechanism for WNT-independent colorectal cancer growth, and reveals how integration of associated genetic alterations and extracellular signals can overcome lineage-dependent oncogenic programs. SIGNIFICANCE: Colorectal and intestinal cancers are driven by mutations in the WNT pathway, and drugs aimed at suppressing WNT signaling are in active clinical development. Our study identifies a mechanism of acquired resistance to WNT inhibition and highlights a potential strategy to target those drug-resistant cells..
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http://dx.doi.org/10.1158/2159-8290.CD-19-1536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541594PMC
October 2020

Somatic Tissue Engineering in Mouse Models Reveals an Actionable Role for WNT Pathway Alterations in Prostate Cancer Metastasis.

Cancer Discov 2020 Jul 6;10(7):1038-1057. Epub 2020 May 6.

Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.

To study genetic factors influencing the progression and therapeutic responses of advanced prostate cancer, we developed a fast and flexible system that introduces genetic alterations relevant to human disease directly into the prostate glands of mice using tissue electroporation. These electroporation-based genetically engineered mouse models (EPO-GEMM) recapitulate features of traditional germline models and, by modeling genetic factors linked to late-stage human disease, can produce tumors that are metastatic and castration-resistant. A subset of tumors with alterations acquired spontaneous WNT pathway alterations, which are also associated with metastatic prostate cancer in humans. Using the EPO-GEMM approach and an orthogonal organoid-based model, we show that WNT pathway activation drives metastatic disease that is sensitive to pharmacologic WNT pathway inhibition. Thus, by leveraging EPO-GEMMs, we reveal a functional role for WNT signaling in driving prostate cancer metastasis and validate the WNT pathway as therapeutic target in metastatic prostate cancer. SIGNIFICANCE: Our understanding of the factors driving metastatic prostate cancer is limited by the paucity of models of late-stage disease. Here, we develop EPO-GEMMs of prostate cancer and use them to identify and validate the WNT pathway as an actionable driver of aggressive metastatic disease..
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http://dx.doi.org/10.1158/2159-8290.CD-19-1242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334089PMC
July 2020

Obstructive sleep apnea and liver injury in severely obese patients with nonalcoholic fatty liver disease.

Sleep Breath 2020 Dec 30;24(4):1515-1521. Epub 2020 Jan 30.

Department of Pulmonary and Critical Care Medicine, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, 100029, China.

Objectives: Obstructive sleep apnea (OSA) and nonalcoholic fatty liver disease (NAFLD) are common in subjects with severe obesity. It has been suggested that insulin resistance and systemic inflammation may play a role in the development of nonalcoholic steatohepatitis (NASH), but the mechanisms remain controversial. The aim of this study was to explore the influence of OSA on liver injury and its potential mechanisms in severely obese patients with NAFLD.

Methods: Severely obese patients requiring bariatric surgery were consecutively recruited between November 2017 and June 2018. Demographic, biochemical, liver ultrasound, and ambulatory polygraph data were collected.

Results: One hundred fifty-three subjects with liver ultrasound-verified NAFLD were classified into three groups according to the apnea-hypopnea index (AHI). The level of serum alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT) tended to increase with more severe OSA (P = 0.024 and P = 0.004, respectively). In the unadjusted analysis, both ALT and GGT were positively correlated with AHI, oxygen desaturation index, percentage of total sleep time spent with oxyhemoglobin saturation below 90%, male sex, homeostasis model assessment of insulin resistance (HOMA-IR), and total cholesterol, while liver enzymes were negatively related to lowest oxygen saturation. In multiple regression analysis, AHI (odds ratio (OR) = 1.052, P = 0.044) and HOMA-IR (OR = 1.135, P = 0.001) were independent risk factors for an elevated ALT level. High-sensitivity C-reactive protein (hs-CRP) was positively associated with BMI and GGT (r = 0.349 and r = 0.164 (P < 0.05), respectively), and no correlation was found between hs-CRP and AHI or other parameters of hypoxia. hs-CRP and GGT remained significantly correlated after adjusting for confounding parameters (OR = 2.509, P = 0.013).

Conclusions: OSA may play a role in liver injury among severely obese individuals with NAFLD. Insulin resistance and systemic inflammation were possible contributing factors in this process.
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http://dx.doi.org/10.1007/s11325-020-02018-zDOI Listing
December 2020

Obstructive Sleep Apnea in Patients With Fibrotic Interstitial Lung Disease and COPD.

J Clin Sleep Med 2019 12 26;15(12):1807-1815. Epub 2019 Oct 26.

Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.

Study Objectives: Despite the clinical and prognostic significance of obstructive sleep apnea (OSA) in chronic respiratory diseases (CRDs), there have been few studies about the possible predictors of OSA and the effect of OSA on quality of life in patients with CRDs. The objectives were to identify physiological and clinical parameters that predict the occurrence and severity of OSA and to investigate the effect of OSA on quality of life in patients with CRDs.

Methods: Seventy-three patients with chronic obstructive pulmonary disease (COPD) and 77 patients with fibrotic interstitial lung disease (ILD) underwent overnight polysomnography (PSG) and pulmonary function testing and completed clinical questionnaires. The oximetry tracing was interpreted blindly with respect to the PSG results.

Results: The prevalence of OSA was 44% and 62% in COPD and ILD, respectively. The COPD assessment test item scores related to sleep quality and daily vitality were worse among patients with OSA than among patients without OSA. The STOP-BANG questionnaire (cutoff point ≥ 3) and oxygen desaturation index from the oximetry recording (oxygen desaturation index (ODI) were associated with OSA in CRDs. The STOP-BANG questionnaire with a cutoff point ≥ 3 or 6 had the highest sensitivity and specificity, respectively, in detecting OSA in CRDs. ODI had the best accuracy in identifying OSA and was independently associated with the apnea-hypopnea index in CRDs.

Conclusions: We found OSA to be common and associated with worse sleep quality and less daily vitality in patients with advanced CRDs. The STOP-BANG questionnaire with different cutoff points may help rule in or rule out OSA. Overnight oximetry can be used as a screening tool for OSA and can assist the clinical evaluation of OSA in patients with CRDs.
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http://dx.doi.org/10.5664/jcsm.8090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099192PMC
December 2019

Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression.

Mol Cancer 2019 05 9;18(1):92. Epub 2019 May 9.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Box 69, New York, NY, 10065, USA.

The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers. We previously screened genes upregulated in human hepatocellular carcinomas for their metastatic function in a mouse model of pancreatic neuroendocrine tumor (PNET) and identified that human RHAMM promoted liver metastasis. It was unknown whether RHAMM is upregulated in pancreatic cancer or contributes to its progression. In this study, we found that RHAMM protein was frequently upregulated in human PNETs. We investigated alternative splicing isoforms, RHAMM and RHAMM, by RNA-Seq analysis of primary PNETs and liver metastases. RHAMM, but not RHAMM, was significantly upregulated in liver metastases. RHAMM was crucial for in vivo metastatic capacity of mouse and human PNETs. RHAMM, carrying an extra 15-amino acid-stretch, did not promote metastasis in spontaneous and experimental metastasis mouse models. Moreover, RHAMM was substantially higher than RHAMM in pancreatic ductal adenocarcinoma (PDAC). RHAMM, but not RHAMM, correlated with both higher EGFR expression and poorer survival of PDAC patients. Knockdown of EGFR abolished RHAMM-driven PNET metastasis. Altogether, our findings suggest a clinically relevant function of RHAMM, but not RHAMM, in promoting PNET metastasis in part through EGFR signaling. RHAMM can thus serve as a prognostic factor for pancreatic cancer.
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http://dx.doi.org/10.1186/s12943-019-1018-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506944PMC
May 2019

Applying a Pneumatic Interface to Intervene with Rapid Eating Behaviour.

Stud Health Technol Inform 2019 ;257:513-519

University of Manitoba.

Higher eating rates are positively correlate with obesity. In this paper, we propose the design of a new eating utensil that can reduce eating rate by interfering with eater's ability to eat quickly. This utensil can change its rigidity and shape by deflating itself to interfere with eating. In this study, a low fidelity proof-of-concept prototype device has been designed to provide physical resistance in order to help people reduce their eating rate. The proposed prototype could be used to demonstrate the feasibility of applying a pneumatically actuated shape-changing interface to embed physical resistance into an eating utensil.
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August 2019

Ursolic acid promotes the apoptosis of cervical cancer cells by regulating endoplasmic reticulum stress.

J Obstet Gynaecol Res 2019 Apr 10;45(4):877-881. Epub 2019 Jan 10.

Department of Gynecological Oncology, Harbin Medical University Cancer Hospital, Harbin, China.

Aim: Ursolic acid is a triterpenoid common in plants and exhibits anti-carcinogenic activity. This study aimed to reveal the role of endoplasmic reticulum stress in cervical cancer cell apoptosis promoted by ursolic acid.

Methods: HeLa cells were treated with ursolic acid or/and 4-phenylbutyric acid. The viability and apoptosis of HeLa cells were evaluated by MTT assay and flow cytometry, respectively.

Results: Ursolic acid decreased HeLa cell viability in a time- and dose- dependent manner, and induced HeLa cell apoptosis in a dose-dependent manner. Moreover, ursolic acid increased the expression of C/EBP homologous protein and glucose-regulated protein 78 at protein levels, while 4-phenylbutyric acid antagonized the apoptosis of HeLa cells induced by ursolic acid.

Conclusion: Ursolic acid inhibits the viability and promotes the apoptosis of HeLa cells. Endoplasmic reticulum stress may mediate the apoptosis of cervical cancer cells stimulated by ursolic acid.
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http://dx.doi.org/10.1111/jog.13919DOI Listing
April 2019

Thio-Michael addition of thioamides and allenes for the selective construction of polysubstituted 2-arylthiophenes via TBAI/HO promoted tandem oxidative annulation and 1,2-sulfur migration.

Org Biomol Chem 2018 09;16(37):8253-8257

School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. China.

A novel TBAI-catalyzed tandem thio-Michael addition/oxidative annulation of allenes and thioamides for the construction of polysubstituted 2-arylthiophenes under a sulfur migration transformation protocol has been developed. The transition-metal-free protocol achieves the oxidative cyclization reaction of thioamides containing electron-rich substituents with allenes to construct polysubstituted thiophenes selectively by controlling oxidation conditions.
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http://dx.doi.org/10.1039/c8ob01835aDOI Listing
September 2018

Optimized base editors enable efficient editing in cells, organoids and mice.

Nat Biotechnol 2018 10 3;36(9):888-893. Epub 2018 Jul 3.

Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.

CRISPR base editing enables the creation of targeted single-base conversions without generating double-stranded breaks. However, the efficiency of current base editors is very low in many cell types. We reengineered the sequences of BE3, BE4Gam, and xBE3 by codon optimization and incorporation of additional nuclear-localization sequences. Our collection of optimized constitutive and inducible base-editing vector systems dramatically improves the efficiency by which single-nucleotide variants can be created. The reengineered base editors enable target modification in a wide range of mouse and human cell lines, and intestinal organoids. We also show that the optimized base editors mediate efficient in vivo somatic editing in the liver in adult mice.
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http://dx.doi.org/10.1038/nbt.4194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130889PMC
October 2018

Synthesis of Polysubstituted 3-Aminothiophenes from Thioamides and Allenes via Tandem Thio-Michael Addition/Oxidative Annulation and 1,2-Sulfur Migration.

J Org Chem 2018 02 12;83(3):1538-1542. Epub 2018 Jan 12.

School of Pharmacy and Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology , 130 Meilong Road, Shanghai 200237, China.

A facile synthetic method for the construction of 3-aminothiophenes from readily available thioamides and alllenes in the presence of a TBAI/TBHP catalyst system was developed. This protocol represents an efficient and straightforward way to access highly functionalized thiophenes in moderate to excellent yields under mild conditions, via a tandem thio-Michael addition, oxidative annulation, and 1,2-sulfur migration pathway.
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http://dx.doi.org/10.1021/acs.joc.7b02616DOI Listing
February 2018

A Novel Case of Pulmonary Nocardiosis with Secondary Hemophagocytic Lymphohistiocytosis.

Chin Med J (Engl) 2017 Sep;130(17):2128-2129

Center for Respiratory Diseases, China-Japan Friendship Hospital; Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital; National Clinical Research Center for Respiratory Diseases, Beijing 100029, China.

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http://dx.doi.org/10.4103/0366-6999.213421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586188PMC
September 2017

R-Spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine.

Nat Commun 2017 07 11;8:15945. Epub 2017 Jul 11.

Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10021, USA.

Defining the genetic drivers of cancer progression is a key in understanding disease biology and developing effective targeted therapies. Chromosome rearrangements are a common feature of human malignancies, but whether they represent bona fide cancer drivers and therapeutically actionable targets, requires functional testing. Here, we describe the generation of transgenic, inducible CRISPR-based mouse systems to engineer and study recurrent colon cancer-associated EIF3E-RSPO2 and PTPRK-RSPO3 chromosome rearrangements in vivo. We show that both Rspo2 and Rspo3 fusion events are sufficient to initiate hyperplasia and tumour development in vivo, without additional cooperating genetic events. Rspo-fusion tumours are entirely Wnt-dependent, as treatment with an inhibitor of Wnt secretion, LGK974, drives rapid tumour clearance from the intestinal mucosa without effects on normal intestinal crypts. Altogether, our study provides direct evidence that endogenous Rspo2 and Rspo3 chromosome rearrangements can initiate and maintain tumour development, and indicate a viable therapeutic window for LGK974 treatment of RSPO-fusion cancers.
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http://dx.doi.org/10.1038/ncomms15945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508203PMC
July 2017

Transplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer.

Nat Biotechnol 2017 06 1;35(6):577-582. Epub 2017 May 1.

Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Colorectal cancer (CRC) is a leading cause of death in the developed world, yet facile preclinical models that mimic the natural stages of CRC progression are lacking. Through the orthotopic engraftment of colon organoids we describe a broadly usable immunocompetent CRC model that recapitulates the entire adenoma-adenocarcinoma-metastasis axis in vivo. The engraftment procedure takes less than 5 minutes, shows efficient tumor engraftment in two-thirds of mice, and can be achieved using organoids derived from genetically engineered mouse models (GEMMs), wild-type organoids engineered ex vivo, or from patient-derived human CRC organoids. In this model, we describe the genotype and time-dependent progression of CRCs from adenocarcinoma (6 weeks), to local disseminated disease (11-12 weeks), and spontaneous metastasis (>20 weeks). Further, we use the system to show that loss of dysregulated Wnt signaling is critical for the progression of disseminated CRCs. Thus, our approach provides a fast and flexible means to produce tailored CRC mouse models for genetic studies and pre-clinical investigation.
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http://dx.doi.org/10.1038/nbt.3837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462850PMC
June 2017

[Correlation between root irrigation of Bacillus subtilis Tpb55 and variation of bacterial diversity in tobacco rhizosphere].

Wei Sheng Wu Xue Bao 2016 May;56(5):835-45

Objective: The impact of inoculation with the biocontrol agent Bacillus subtilis on bacterial communities in rhizospheric soil of Nicotiana tabacum was assessed by using 454 pyrosequencing technology. The control effect of Tpb55 on tobacco black shank was also studied.

Methods: Two treatments were done as follows: irrigating root with Bacillus subtilis strain Tpb55 inoculants (108 CFU/mL) and the control. Soil samples from tobacco rhizosphere were collected at 0d, 10d and 22 d after the treatment. Genomic DNA of soil samples was extracted and amplified for the 16S rDNA V1-V3 tags, and then the tags were sequenced by 454 sequencing. Qiime was used to analyze soil bacterial diversities.

Results: A total of 41207 high quality sequences were obtained from all samples, which were classified into 25 phyla. The dominant bacteriophyta were Actinobacteria, Proteobacteria and Acidobacteria in all samples. The content of Actinobacteria was decreased gradually in the development of disease, whereas Proteobacteria showed an opposite tendency. Acidobacteria revealed a marked increase andexceeded control in content after inoculation with Tpb55. The control showed a significant decline in Bacillaceae, as well as Oxalobacteraceae which was known as an indicator for bacterial diversity. However, Bacillaceae showed an increasing tendency and Oxalobacteraceae was relatively constant in Tpb55 treatment. The Chao 1, ACE and Shannon index of treatment showed a constant improvement of variety and richness. In 10 d and 22 d after Tpb55 inoculation, the number of sequences with high homology of V1-V3 regions of Tpb55 16S rDNA was 31 and 45, respectively. The disease index of tobacco black shank in inoculated tobacco (5.29) was significantly lower than the control (38.52).

Conclusion: Tpb55 could improve the diversity of soil bacterial community and ecosystem stability, which presented a possible reason for its biocontrol efficacy on tobacco black shank.
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May 2016

Wnt3a signal pathways activate MyoD expression by targeting cis-elements inside and outside its distal enhancer.

Biosci Rep 2015 Mar 18;35(2). Epub 2015 Mar 18.

*Department of Life Sciences, National Central University, 300 Jhongda Road, Jhongli 32001, Taiwan.

Wnt proteins are secreted cytokines and several Wnts are expressed in the developing somites and surrounding tissues. Without proper Wnt stimulation, the organization of the dermomyotome and myotome can become defective. These Wnt signals received by somitic cells can lead to activation of Pax3/Pax7 and myogenic regulatory factors (MRFs), especially Myf5 and MyoD. However, it is currently unknown whether Wnts activate Myf5 and MyoD through direct targeting of their cis-regulatory elements or via indirect pathways. To clarify this issue, in the present study, we tested the regulation of MyoD cis-regulatory elements by Wnt3a secreted from human embryonic kidney (HEK)-293T cells. We found that Wnt3a activated the MyoD proximal 6.0k promoter (P6P) only marginally, but highly enhanced the activity of the composite P6P plus distal enhancer (DE) reporter through canonical and non-canonical pathways. Further screening of the intervening fragments between the DE and the P6P identified a strong Wnt-response element (WRE) in the upstream -8 to -9k region (L fragment) that acted independently of the DE, but was dependent on the P6P. Deletion of a Pax3/Pax7-targeted site in the L fragment significantly reduced its response to Wnt3a, implying that Wnt3a activates the L fragment partially through Pax3/Pax7 action. Binding of β-catenin and Pax7 to their target sites in the DE and the L fragment respectively was also demonstrated by ChIP. These observations demonstrated the first time that Wnt3a can directly activate MyoD expression through targeting cis-elements in the DE and the L fragment.
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http://dx.doi.org/10.1042/BSR20140177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370097PMC
March 2015

Valproic acid enhances Oct4 promoter activity through PI3K/Akt/mTOR pathway activated nuclear receptors.

Mol Cell Endocrinol 2014 Mar 19;383(1-2):147-58. Epub 2013 Dec 19.

Department of Life Sciences, National Central University, Jhongli 32001, Taiwan. Electronic address:

Valproic acid (VPA) has been shown to increase the reprogramming efficiency of induced pluripotent stem cells (iPSC) from somatic cells, but the mechanism by which VPA enhances iPSC induction has not been defined. Here we demonstrated that VPA directly activated Oct4 promoter activity through activation of the PI3K/Akt/mTOR signaling pathway that targeted the proximal hormone response element (HRE, -41∼-22) in this promoter. The activating effect of VPA is highly specific as similar compounds or constitutional isomers failed to instigate Oct4 promoter activity. We further demonstrated that the upstream 2 half-sites in this HRE were essential to the activating effect of VPA and they were targeted by a subset of nuclear receptors, such as COUP-TFII and TR2. These findings show the first time that NRs are implicated in the VPA stimulated expression of stem cell-specific factors and should invite more investigation on the cooperation between VPA and NRs on iPSC induction.
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http://dx.doi.org/10.1016/j.mce.2013.12.008DOI Listing
March 2014

Valproic acid enhances Oct4 promoter activity in myogenic cells.

J Cell Biochem 2010 Jul;110(4):995-1004

Department of Life Sciences, National Central University, Jhongli 32054, Taiwan, ROC.

Induced pluripotent stem (iPS) cells are reprogrammed from somatic cells through ectopic expression of stem cell-specific transcription factors, including Oct4, Nanog, Sox2, Lin28, Klf4, and c-Myc. Although iPS cells are similar to embryonic stem (ES) cells in their pluripotency, their inherited defects, such as insertion mutagenesis, employment of oncogenes, and low efficiency, associated with the reprogramming procedure have hindered their clinical application. A study has shown that valproic acid (VPA) treatment can significantly enhance the reprogramming efficiency and avoid the usage of oncogenes. To understand how VPA can enhance pluripotency, we stably transfected an Oct4 promoter driven luciferase reporter (Oct4-1.9k-Luc) into P19 embryonic carcinoma (EC) cells and C2C12 myoblasts and examined their response to VPA. We found that VPA could both activate Oct4 promoter and rescue its inhibition by retinoic acid (RA). In C2C12 myoblasts, VPA treatment also enhanced endogenous Oct4 expression but repressed that of MyoD. Furthermore, both RARalpha over-expression and mutation of a proximal hormone response element (HRE) blocked the activation effect of VPA on Oct4 promoter, implying that VPA may exert its activation effect through factors targeting this HRE. Taken together, these observations identify a molecular mechanism by which VPA directly regulate Oct4 expression to ensure the acquirement and maintenance of pluripotency.
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http://dx.doi.org/10.1002/jcb.22613DOI Listing
July 2010

Simultaneous overexpression of Oct4 and Nanog abrogates terminal myogenesis.

Am J Physiol Cell Physiol 2009 Jul 29;297(1):C43-54. Epub 2009 Apr 29.

Dept. of Life Sciences, National Central University, 300 Jhongda Rd., Jhongli 32054, Taiwan, ROC.

Oct4 and Nanog are two embryonic stem (ES) cell-specific transcription factors that play critical roles in the maintenance of ES cell pluripotency. In this study, we investigated the effects of Oct4 and Nanog expression on the differentiation state of myogenic cells, which is sustained by a strong positive feedback loop. Oct4 and Nanog, either independently or simultaneously, were overexpressed in C2C12 myoblasts, and the expression of myogenic lineage-specific genes and terminal differentiation was observed by RT-PCR. Overexpression of Oct4 in C2C12 cultures repressed, while exogenous Nanog did not significantly alter C2C12 terminal differentiation. The expression of Pax7 was reduced in all Oct4-overexpressing myoblasts, and we identified a major Oct4-binding site in the Pax7 promoter. Simultaneous expression of Oct4 and Nanog in myoblasts inhibited the formation of myotubes, concomitant with a reduction in the endogenous levels of hallmark myogenic markers. Furthermore, overexpression of Oct4 and Nanog induced the expression of their endogenous counterparts along with the expression of Sox2. Using mammalian two-hybrid assays, we confirmed that Oct4 functions as a transcriptional repressor whereas Nanog functions as a transcriptional activator during muscle terminal differentiation. Importantly, in nonobese diabetic (NOD) severe combined immunodeficiency (SCID) mice, the pluripotency of C2C12 cells was conferred by overexpression of Oct4 and Nanog. These results suggest that Oct4 in cooperation with Nanog strongly suppresses the myogenic differentiation program and promotes pluripotency in myoblasts.
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http://dx.doi.org/10.1152/ajpcell.00468.2008DOI Listing
July 2009