Publications by authors named "Ke Peng"

192 Publications

Author Correction: Calcium channel blocker amlodipine besylate therapy is associated with reduced case fatality rate of COVID-19 patients with hypertension.

Cell Discov 2021 May 3;7(1):29. Epub 2021 May 3.

State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China.

A Correction to this paper has been published: https://doi.org/10.1038/s41421-021-00267-0.
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http://dx.doi.org/10.1038/s41421-021-00267-0DOI Listing
May 2021

The time-dependent effects of early-onset Epstein-Barr viremia on adult acute leukemia patients following allo-HSCT with ATG-containing MAC regimen.

Ann Hematol 2021 Apr 22. Epub 2021 Apr 22.

National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China.

Epstein-Barr virus (EBV) viremia is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The purpose of this study was to evaluate the impacts of early-onset EBV viremia in acute leukemia (AL) patients who underwent allo-HSCT with anti-thymocyte globulin (ATG)-containing myeloablative conditioning (MAC) regimen. Two hundred and ninety-six patients were included between January 2013 and December 2015. In 126 patients (42.6%) who developed early-onset EBV viremia, with a median time of 48 (range 18~99) days after allo-HSCT. The cumulative incidence of EBV viremia at 30 and 90 days after allo-HSCT were 4.1 and 39.9%, respectively. Prognostic analysis showed that the adjusted overall survival in early-EBV group was significantly lower than early-EBV group within the first 26.7 months after allo-HSCT [hazard ratio (HR), 1.63, P = 0.012], but significantly higher than those afterward (after 26.7 months: HR 0.11, P = 0.035); for the adjusted event-free survival, early-EBV group was significantly inferior in early-EBV group within the first 10.8 months after transplantation (HR: 1.55, P = 0.042), and this adverse effect was not detected any more after 10.8 months (HR: 0.58, P = 0.107). Compared with early-EBV group after adjusting by aGVHD and CMV viremia, HR for death from transplant-related mortality was 2.78-fold higher in patients with early-EBV viremia in piecewise constant Cox analysis (P = 0.006), and this adverse effect was not detected any more after the cut-point time (HR: 0.67, P = 0.361). No differences in terms of relapse and relapse mortality were observed between early-EBV and early-EBV group (P > 0.05). In conclusion, the impacts on transplant outcomes of early-EBV viremia were time-dependent, which may help to optimize management strategies for early-EBV viremia after allo-HSCT, especially in AL patients with ATG-containing MAC regimen.
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http://dx.doi.org/10.1007/s00277-021-04528-6DOI Listing
April 2021

LncRNA GAS5 activates the HIF1A/VEGF pathway by binding to TAF15 to promote wound healing in diabetic foot ulcers.

Lab Invest 2021 Apr 19. Epub 2021 Apr 19.

The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, PR China.

A diabetic foot ulcer (DFU) is one of the most devastating complications of diabetes. It has been reported that lncRNA GAS5 plays a vital role in wound healing in DFUs. However, the specific mechanism remains unclear. In this research, we aimed to investigate the role of GAS5 in wound healing in DFUs as well as the underlying mechanism. qPCR or western blotting was performed to measure the expression levels of GAS5, HIF1A, VEGF and TAF15. CCK-8 or EdU assays, flow cytometry, wound healing assays and tube formation assays were carried out to assess the proliferation, apoptosis, wound healing and in vitro angiogenesis of HUVECs, respectively. RNA pull-down and RIP assays were performed to verify the interaction between GAS5 and TAF15. ChIP and luciferase assays were conducted to verify the binding of TAF15 to the HIF1A promoter. In the DFU mouse model, H&E and Masson staining were used to determine epidermal and dermal thickness and collagen formation. GAS5 and HIF1A were downregulated in the skin tissues of DFU patients, and GAS5 overexpression promoted cell proliferation, wound healing and tubule formation in HG-treated HUVECs. In addition, GAS5 facilitated HIF1A expression by interacting with TAF15. Rescue assays demonstrated that the suppression of HIF1A/VEGF pathway activation partially reversed the functional roles of GAS5 in HUVECs. Furthermore, GAS5 accelerated wound healing by activating the HIF1A/VEGF pathway in mice with DFUs. GAS5 activates the HIF1A/VEGF pathway by binding to TAF15, resulting in accelerated wound healing in DFUs. Our findings may provide a theoretical basis for the clinical treatment of DFUs.
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http://dx.doi.org/10.1038/s41374-021-00598-2DOI Listing
April 2021

Inhibiting BDNF/TrkB.T1 receptor improves resiniferatoxin-induced postherpetic neuralgia through decreasing ASIC3 signaling in dorsal root ganglia.

J Neuroinflammation 2021 Apr 19;18(1):96. Epub 2021 Apr 19.

Department of Anesthesiology and Pain Management, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, China.

Background: Postherpetic neuralgia (PHN) is a devastating complication after varicella-zoster virus infection. Brain-derived neurotrophic factor (BDNF) has been shown to participate in the pathogenesis of PHN. A truncated isoform of the tropomyosin receptor kinase B (TrkB) receptor TrkB.T1, as a high-affinity receptor of BDNF, is upregulated in multiple nervous system injuries, and such upregulation is associated with pain. Acid-sensitive ion channel 3 (ASIC3) is involved in chronic neuropathic pain, but its relation with BDNF/TrkB.T1 in the peripheral nervous system (PNS) during PHN is unclear. This study aimed to investigate whether BDNF/TrkB.T1 contributes to PHN through regulating ASIC3 signaling in dorsal root ganglia (DRGs).

Methods: Resiniferatoxin (RTX) was used to induce rat PHN models. Mechanical allodynia was assessed by measuring the paw withdrawal thresholds (PWTs). Thermal hyperalgesia was determined by detecting the paw withdrawal latencies (PWLs). We evaluated the effects of TrkB.T1-ASIC3 signaling inhibition on the behavior, neuronal excitability, and inflammatory response during RTX-induced PHN. ASIC3 short hairpin RNA (shRNA) transfection was used to investigate the effect of exogenous BDNF on inflammatory response in cultured PC-12 cells.

Results: RTX injection induced mechanical allodynia and upregulated the protein expression of BDNF, TrkB.T1, ASIC3, TRAF6, nNOS, and c-Fos, as well as increased neuronal excitability in DRGs. Inhibition of ASIC3 reversed the abovementioned effects of RTX, except for BDNF and TrkB.T1 protein expression. In addition, inhibition of TrkB.T1 blocked RTX-induced mechanical allodynia, activation of ASIC3 signaling, and hyperexcitability of neurons. RTX-induced BDNF upregulation was found in both neurons and satellite glia cells in DRGs. Furthermore, exogenous BDNF activated ASIC3 signaling, increased NO level, and enhanced IL-6, IL-1β, and TNF-α levels in PC-12 cells, which was blocked by shRNA-ASIC3 transfection.

Conclusion: These findings demonstrate that inhibiting BDNF/TrkB.T1 reduced inflammation, decreased neuronal hyperexcitability, and improved mechanical allodynia through regulating the ASIC3 signaling pathway in DRGs, which may provide a novel therapeutic target for patients with PHN.
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http://dx.doi.org/10.1186/s12974-021-02148-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054387PMC
April 2021

Withholding vs. Continuing Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers Before Non-cardiac Surgery in Older Patients: Study Protocol for a Multicenter Randomized Controlled Trial.

Front Med (Lausanne) 2021 30;8:654700. Epub 2021 Mar 30.

Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China.

Older hypertensive adults are at increased risk for postoperative morbidity and mortality. As first line antihypertensive drug therapy, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) have many beneficial effects. However, the use of ACEIs/ARBs in the perioperative period remains controversial. This study aims to determine the effects of withholding vs. continuing ACEIs/ARBs before non-cardiac surgery on perioperative hypotension and postoperative outcomes in older patients. In this multicenter, randomized, double-blind, placebo-controlled trial, a total of 2036 patients aged 60-80 years undergoing non-cardiac surgical procedures will be randomly assigned, in a 1:1 ratio, to receive oral ACEIs/ARBs (the ACEIs/ARBs continued group) or inactive placebos (the ACEIs/ARBs withheld group) on the morning of surgery. For both groups, the ACEIs/ARBs will be continued from the first postoperative day. The primary outcome measure is the incidence of perioperative hypotensive events, defined as mean blood pressure (MBP) < 65 mmHg or ≥30% reduction in MBP from baseline during surgery and in a post-anesthesia care unit. The secondary outcomes include duration of perioperative hypotension, intraoperative use of fluids and vasopressors, hypotensive events within postoperative 3 days, and perioperative neurocognitive disorders, major adverse cardiocerebral events (a composite outcome of stroke, coma, myocardial infarction, heart block, and cardiac arrest), and mortality within 30 days after surgery. The results of this trial will offer an evidence-based perioperative ACEIs/ARBs therapy for older hypertensive adults undergoing non-cardiac surgery. This study is approved by the Medical Ethics Committee of The First Affiliated Hospital of Soochow University (Approval No. 2020-077-1) and by the institutional ethics review board of each participating center. This protocol is registered at the Chinese Clinical Trials Registry (ChiCTR2000039376).
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http://dx.doi.org/10.3389/fmed.2021.654700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042130PMC
March 2021

Clinical effect and antiviral mechanism of T-705 in treating severe fever with thrombocytopenia syndrome.

Signal Transduct Target Ther 2021 Apr 16;6(1):145. Epub 2021 Apr 16.

Department of Cancer, People's Liberation Army General Hospital, Beijing, P. R. China.

Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) is an emerging tick-borne virus with high fatality and an expanding endemic. Currently, effective anti-SFTSV intervention remains unavailable. Favipiravir (T-705) was recently reported to show in vitro and in animal model antiviral efficacy against SFTSV. Here, we conducted a single-blind, randomized controlled trial to assess the efficacy and safety of T-705 in treating SFTS (Chinese Clinical Trial Registry website, number ChiCTR1900023350). From May to August 2018, laboratory-confirmed SFTS patients were recruited from a designated hospital and randomly assigned to receive oral T-705 in combination with supportive care or supportive care only. Fatal outcome occurred in 9.5% (7/74) of T-705 treated patients and 18.3% (13/71) of controls (odds ratio, 0.466, 95% CI, 0.174-1.247). Cox regression showed a significant reduction in case fatality rate (CFR) with an adjusted hazard ratio of 0.366 (95% CI, 0.142-0.944). Among the low-viral load subgroup (RT-PCR cycle threshold ≥26), T-705 treatment significantly reduced CFR from 11.5 to 1.6% (P = 0.029), while no between-arm difference was observed in the high-viral load subgroup (RT-PCR cycle threshold <26). The T-705-treated group showed shorter viral clearance, lower incidence of hemorrhagic signs, and faster recovery of laboratory abnormities compared with the controls. The in vitro and animal experiments demonstrated that the antiviral efficacies of T-705 were proportionally induced by SFTSV mutation rates, particularly from two transition mutation types. The mutation analyses on T-705-treated serum samples disclosed a partially consistent mutagenesis pattern as those of the in vitro or animal experiments in reducing the SFTSV viral loads, further supporting the anti-SFTSV effect of T-705, especially for the low-viral loads.
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http://dx.doi.org/10.1038/s41392-021-00541-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050330PMC
April 2021

Occupational Burnout Among Frontline Health Professionals in a High-Risk Area During the COVID-19 Outbreak: A Structural Equation Model.

Front Psychiatry 2021 26;12:575005. Epub 2021 Mar 26.

Department of Psychiatry, Hunan Medical Center for Mental Health, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China.

The outbreak of coronavirus disease 2019 (COVID-19) resulted in a substantial workload and stress for frontline health professionals in high-risk areas. Little research has investigated the mechanism of occupational burnout among the frontline health professionals located in the center of the epidemic in Wuhan, China. A total of 199 frontline health professionals from Wuhan Jinyintan Hospital completed the cross-sectional survey. Mechanisms of occupational burnout (according to the Maslach Burnout Inventory-General Survey, MBI-GS) among the health professionals in Jinyintan Hospital during the COVID-19 outbreak were examined using a structural equation model (SEM). The levels of the three burnout dimensions (emotional exhaustion, cynicism, and professional efficacy) were high at 34.2, 50.8, and 35.2%, respectively. Frontline health professionals in this stressful period reported significantly greater emotional exhaustion ( < 0.001) and job-related cynicism ( < 0.001), but no significant difference in professional efficacy ( = 0.449), when compared to employees in a large multinational company. The SEM results revealed that both acute stress symptoms and psychosomatic symptoms significantly predicted the emotional exhaustion and occupation cynicism dimensions of burnout. The study reveals the occupational burnout mechanism of frontline health professionals during the COVID-19 peak at the time of the outbreak. This study provides an important contribution to understanding the future psychological interventions necessary for frontline health professionals during an epidemic crisis.
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http://dx.doi.org/10.3389/fpsyt.2021.575005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032859PMC
March 2021

Dexmedetomidine Attenuates Ischemia/Reperfusion-Induced Myocardial Inflammation and Apoptosis Through Inhibiting Endoplasmic Reticulum Stress Signaling.

J Inflamm Res 2021 31;14:1217-1233. Epub 2021 Mar 31.

Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People's Republic of China.

Background: Endoplasmic reticulum stress (ERS)-mediated myocardial inflammation and apoptosis plays an important role in myocardial ischemia/reperfusion (I/R) injury. Dexmedetomidine has been used clinically with sedative, analgesic, and anti-inflammatory properties. This study aimed to determine the effects of dexmedetomidine pretreatment on inflammation, apoptosis, and the expression of ERS signaling during myocardial I/R injury.

Methods: Rats underwent myocardial ischemia for 30 min and reperfusion for 6 h, and H9c2 cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury (OGD for 12 h and reoxygenation for 3 h). Dexmedetomidine was administered prior to myocardial ischemia in rats or ODG in cardiomyocytes. In addition, the α2-adrenergic receptor antagonist (yohimbine) or the PERK activator (CCT020312) was given prior to dexmedetomidine treatment.

Results: Dexmedetomidine pretreatment decreased serum levels of cardiac troponin I, reduced myocardial infarct size, alleviated histological structure damage, and improved left ventricular function following myocardial I/R injury in rats. In addition, dexmedetomidine pretreatment increased cell viability and reduced cytotoxicity following OGD/R injury in cardiomyocytes. Mechanistically, the cardioprotection offered by dexmedetomidine was mediated via the inhibition of inflammation and apoptosis through downregulating the expression of the ERS signaling pathway, including glucose-regulated protein 78 (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), C/EBP homologous protein (CHOP), inositol-requiring protein 1 (IRE1), and activating transcription factor 6 (ATF6). Conversely, the protective effects of dexmedetomidine were diminished by blocking the α2 adrenergic receptors with yohimbine or promoting PERK phosphorylation with CCT020312.

Conclusion: Dexmedetomidine pretreatment protects the hearts against I/R injury via inhibiting inflammation and apoptosis through downregulation of the ERS signaling pathway. Future clinical studies are needed to confirm the cardioprotective effects of dexmedetomidine in patients at risk of myocardial I/R injury.
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http://dx.doi.org/10.2147/JIR.S292263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020464PMC
March 2021

Pan-ERBB kinase inhibition augments CDK4/6 inhibitor efficacy in oesophageal squamous cell carcinoma.

Gut 2021 Mar 31. Epub 2021 Mar 31.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Objective: Oesophageal squamous cell carcinoma (OSCC), like other squamous carcinomas, harbour highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of existing CDK4/6 inhibitors in these cancers. Although CDK4/6 inhibition has shown striking success when combined with endocrine therapy in oestrogen receptor positive breast cancer, CDK4/6 inhibitor palbociclib monotherapy has not revealed evidence of efficacy to date in OSCC clinical studies. Herein, we sought to elucidate the identification of key dependencies in OSCC as a foundation for the selection of targets whose blockade could be combined with CDK4/6 inhibition.

Design: We combined large-scale genomic dependency and pharmaceutical screening datasets with preclinical cell line models, to identified potential combination therapies in squamous cell cancer.

Results: We identified sensitivity to inhibitors to the ERBB family of receptor kinases, results clearly extending beyond the previously described minority of tumours with EGFR amplification/dependence, specifically finding a subset of OSCCs with dual dependence on ERBB3 and ERBB2. Subsequently. we demonstrated marked efficacy of combined pan-ERBB and CDK4/6 inhibition in vitro and in vivo. Furthermore, we demonstrated that squamous lineage transcription factor KLF5 facilitated activation of ERBBs in OSCC.

Conclusion: These results provide clear rationale for development of combined ERBB and CDK4/6 inhibition in these cancers and raises the potential for KLF5 expression as a candidate biomarker to guide the use of these agents. These data suggested that by combining existing Food and Drug Administration (FDA)-approved agents, we have the capacity to improve therapy for OSCC and other squamous cancer.
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http://dx.doi.org/10.1136/gutjnl-2020-323276DOI Listing
March 2021

A method for estimating neighborhood characterization in studies of the association with availability of sit-down restaurants and supermarkets.

Int J Health Geogr 2021 Mar 25;20(1):15. Epub 2021 Mar 25.

Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Although neighborhood-level access to food differs by sociodemographic factors, a majority of research on neighborhoods and food access has used a single construct of neighborhood context, such as income or race. Therefore, the many interrelated built environment and sociodemographic characteristics of neighborhoods obscure relationships between neighborhood factors and food access.

Methods: The objective of this study was to account for the many interrelated characteristics of food-related neighborhood environments and examine the association between neighborhood type and relative availability of sit-down restaurants and supermarkets. Using cluster analyses with multiple measures of neighborhood characteristics (e.g., population density, mix of land use, and sociodemographic factors) we identified six neighborhood types in 1993 in the Twin Cities Region, Minnesota. We then used mixed effects regression models to estimate differences in the relative availability of sit-down restaurants and supermarkets in 1993, 2001, and 2011 across the six neighborhood types.

Results: We defined six types of neighborhoods that existed in 1993, namely, urban core, inner city, urban, aging suburb, high-income suburb, and suburban edge. Between 1993 and 2011, inner city neighborhoods experienced a greater increase in the percent of sit-down restaurants compared with urban core, urban, and aging suburbs. Differences in the percent of sit-down restaurants between inner city and aging suburbs, high-income suburbs and suburban edge neighborhoods increased between 1993 and 2011. Similarly, aging suburb neighborhoods had a greater percent of supermarkets compared with urban and high-income suburb neighborhoods in 2001 and 2011, but not in 1993, suggesting a more varied distribution of food stores across neighborhoods over time. Thus, the classification of neighborhood type based on sociodemographic and built environment characteristics resulted in a complex and increasingly varied distribution of restaurants and food stores.

Conclusions: The temporal increase in the relative availability of sit-down restaurants in inner cities after accounting for all restaurants might be partly related to a higher proportion of residents who eat-away-from-home, which is associated with higher calorie and fat intake.
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http://dx.doi.org/10.1186/s12942-020-00257-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995746PMC
March 2021

Corrigendum to "Trend of HIV-1 drug resistance in China: A systematic review and meta-analysis of data accumulated over 17 years (2001-2017)" [EClinicalMedicine 18 (2020) 100238].

EClinicalMedicine 2021 Mar 12;33:100696. Epub 2021 Mar 12.

CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.

[This corrects the article DOI: 10.1016/j.eclinm.2019.100238.].
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http://dx.doi.org/10.1016/j.eclinm.2020.100696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957092PMC
March 2021

Pain stickiness in pediatric complex regional pain syndrome: A role for the nucleus accumbens.

Neurobiol Pain 2021 Jan-Jul;9:100062. Epub 2021 Feb 19.

Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305, United States.

Some individuals with chronic pain experience improvement in their pain with treatment, whereas others do not. The neurobiological reason is unclear, but an understanding of brain structure and functional patterns may provide insights into pain's responsivity to treatment. In this investigation, we used magnetic resonance imaging (MRI) techniques to determine grey matter density alterations on resting functional connectivity (RFC) strengths between pain responders and nonresponders in patients with complex regional pain syndrome. Brain metrics of pediatric patients at admission to an intensive pain rehabilitative treatment program were evaluated. Pain responders reported significant pain improvement at discharge and/or follow-up whereas nonresponders reported no improvements in pain, increases in pain, or emergence of new pain symptoms. The pain (responder/nonresponder) groups were compared with pain-free healthy controls to examine predictors of pain responder status via brain metrics. Our results show: (1) on admission, pain nonresponders had decreased grey matter density (GMD) within the nucleus accumbens (NAc) and reduced RFC strength between the NAc and the dorsolateral prefrontal cortex vs. responders; (2) Connectivity strength was positively correlated with change in pain intensity from admission to discharge; (3) Compared with pain-free controls, grey matter and RFC differences emerged only among pain nonresponders; and (4) Using a discriminative model, combining GMD and RFC strengths assessed at admission showed the highest prediction estimate (87%) on potential for pain improvement, warranting testing in a de novo sample. Taken together, these results support the idea that treatment responsiveness on pain is underpinned by concurrent brain structure and resting brain activity.
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http://dx.doi.org/10.1016/j.ynpai.2021.100062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941018PMC
February 2021

Identification of key genes involved in tumor immune cell infiltration and cetuximab resistance in colorectal cancer.

Cancer Cell Int 2021 Feb 25;21(1):135. Epub 2021 Feb 25.

Department of Medical Oncology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, 200032, People's Republic of China.

Background: The anti-epidermal growth factor receptor (EGFR) antibody introduces adaptable variations to the transcriptome and triggers tumor immune infiltration, resulting in colorectal cancer (CRC) treatment resistance. We intended to identify genes that play essential roles in cetuximab resistance and tumor immune cell infiltration.

Methods: A cetuximab-resistant CACO2 cellular model was established, and its transcriptome variations were detected by microarray. Meanwhile, public data from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) database were downloaded. Integrated bioinformatics analysis was applied to detect differentially expressed genes (DEGs) between the cetuximab-resistant and the cetuximab-sensitive groups. Then, we investigated correlations between DEGs and immune cell infiltration. The DEGs from bioinformatics analysis were further validated in vitro and in clinical samples.

Results: We identified 732 upregulated and 1259 downregulated DEGs in the induced cellular model. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, along with Gene Set Enrichment Analysis and Gene Set Variation Analysis, indicated the functions of the DEGs. Together with GSE59857 and GSE5841, 12 common DEGs (SATB-2, AKR1B10, ADH1A, ADH1C, MYB, ATP10B, CDX-2, FAR2, EPHB2, SLC26A3, ORP-1, VAV3) were identified and their predictive values of cetuximab treatment were validated in GSE56386. In online Genomics of Drug Sensitivity in Cancer (GDSC) database, nine of twelve DEGs were recognized in the protein-protein (PPI) network. Based on the transcriptome profiles of CRC samples in TCGA and using Tumor Immune Estimation Resource Version 2.0, we bioinformatically determined that SATB-2, ORP-1, MYB, and CDX-2 expressions were associated with intensive infiltration of B cell, CD4 T cell, CD8 T cell and macrophage, which was then validated the correlation in clinical samples by immunohistochemistry. We found that SATB-2, ORP-1, MYB, and CDX-2 were downregulated in vitro with cetuximab treatment. Clinically, patients with advanced CRC and high ORP-1 expression exhibited a longer progression-free survival time when they were treated with anti-EGFR therapy than those with low ORP-1 expression.

Conclusions: SATB-2, ORP-1, MYB, and CDX-2 were related to cetuximab sensitivity as well as enhanced tumor immune cell infiltration in patients with CRC.
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http://dx.doi.org/10.1186/s12935-021-01829-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905896PMC
February 2021

Safety and efficacy of different doses of anthracyclines combined with arsenic trioxide and all-trans retinoic acid in the treatment of de novo acute promyelocytic leukemia.

Hematology 2021 Dec;26(1):271-276

Soochow Hopes Hematology Hospital, Suzhou, People's Republic of China.

Objectives: The purpose of this study was to evaluate the efficacy and safety of different doses of anthracyclines combined with arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) for induction in newly diagnosed acute promyelocytic leukemia (APL).

Methods: One hundred and forty patients were included between January 2011 and December 2017. Seventy patients received low dose anthracycline, ATO and ATRA for induction chemotherapy; and other seventy patients received standard dose anthracycline, ATO and ATRA for induction chemotherapy.

Results: The outcomes of both groups were similar: low dose group versus standard dose group: early mortality 5.7% vs. 10.0% ( = 0.532), disease-free survival (DFS), probabilities of overall-survival (OS) at 2 years 94.6% vs. 95.1% ( = 0.657), 92.8% vs. 88.2% ( = 0.951), respectively. However, the standard-dose group was associated with a longer duration of neutropenia ( < 0.001) and thrombocytopenia ( < 0.001), more volumes of platelets ( = 0.037) and red blood cell transfusions ( < 0.001), and a higher rate of infections ( = 0.042).

Conclusion: Low-dose group achieves outcomes similar to those of standard dose group for APL patients, but the low-dose group may be even safer than standard-dose group. So the low-dose anthracycline may be a better choice for newly diagnosed APL patients.
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http://dx.doi.org/10.1080/16078454.2021.1889159DOI Listing
December 2021

The complete mitochondrial genome of (Diptera: Syrphoidea: Syrphidae).

Mitochondrial DNA B Resour 2021 Feb 11;6(2):519-521. Epub 2021 Feb 11.

Laboratory of Molecular Evolution and Biodiversity, College of Life Sciences, Anhui Normal University, Anhui, Wuhu, P. R. China.

The complete mitochondrial genome of was determined in this study. The double-stranded circular DNA molecule was 16,530 bp in length, containing 37 typical genes: 13 protein-coding genes (PCGs), 2 rRNA genes, 22 tRNA genes, and an A + T-rich region. Thirteen PCGs were 11,196 bp in size, encoding 3720 amino acids in total. All the PCGs started with ATN, except the used TTG as its initiation codon. Most PCGs terminated with standard codon TAA, while the ended with T and the ended with TA. The and genes were 1341 bp and 793 bp in length, respectively. The A + T-rich region harbored some typical structures characteristic of the dipterans. The phylogenetic tree showed that was closely related to , and the Syrphidae and Pipunculidae constituted a monophyletic group within the Syrphoidea.
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http://dx.doi.org/10.1080/23802359.2021.1872446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889120PMC
February 2021

Point-of-care test system for detection of immunoglobulin-G and -M against nucleocapsid protein and spike glycoprotein of SARS-CoV-2.

Sens Actuators B Chem 2021 Mar 4;331:129415. Epub 2021 Jan 4.

Center for Advanced Measurement Science, National Institute of Metrology, Beijing, 100029, PR China.

The coronavirus disease 2019 (COVID-19) epidemic continues to ravage the world. In epidemic control, dealing with a large number of samples is a huge challenge. In this study, a point-of-care test (POCT) system was successfully developed and applied for rapid and accurate detection of immunoglobulin-G and -M against nucleocapsid protein (anti-N IgG/IgM) and receptor-binding domain in spike glycoprotein (anti-S-RBD IgG/IgM) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Any one of the IgG/IgM found in a sample was identified as positive. The POCT system contains colloidal gold-based lateral flow immunoassay test strips, homemade portable reader, and certified reference materials, which detected anti-N and anti-S-RBD IgG/IgM objectively in serum within 15 min. Receiver operating characteristic curve analysis was used to determine the optimal cutoff values, sensitivity, and specificity. It exhibited equal to or better performances than four approved commercial kits. Results of the system and chemiluminescence immunoassay kit detecting 108 suspicious samples had high consistency with kappa coefficient at 0.804 (P < 0.001). Besides, the levels and alterations of the IgG/IgM in an inpatient were primarily investigated by the POCT system. Those results suggested the POCT system possess the potential to contribute to rapid and accurate serological diagnosis and epidemiological survey of COVID-19.
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http://dx.doi.org/10.1016/j.snb.2020.129415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833039PMC
March 2021

Suppressed prefrontal cortex oscillations associate with clinical pain in fibrodysplasia ossificans progressiva.

Orphanet J Rare Dis 2021 01 30;16(1):54. Epub 2021 Jan 30.

Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Background: Pain is a highly prevalent symptom experienced by patients across numerous rare musculoskeletal conditions. Much remains unknown regarding the central, neurobiological processes associated with clinical pain in musculoskeletal disease states. Fibrodysplasia ossificans progressiva (FOP) is an inherited condition characterized by substantial physical disability and pain. FOP arises from mutations of the bone morphogenetic protein (BMP) receptor Activin A receptor type 1 (ACVR1) causing patients to undergo painful flare-ups as well as heterotopic ossification (HO) of skeletal muscles, tendons, ligaments, and fascia. To date, the neurobiological processes that underlie pain in FOP have rarely been investigated. We examined pain and central pain mechanism in FOP as a model primary musculoskeletal condition. Central nervous system (CNS) functional properties were investigated in FOP patients (N = 17) stratified into low (0-3; 0-10 Scale) and high (≥ 4) pain cohorts using functional near-infrared spectroscopy (fNIRS). Associations among clinical pain, mental health, and physical health were also quantified using responses derived from a battery of clinical questionnaires.

Results: Resting-state fNIRS revealed suppressed power of hemodynamic activity within the slow-5 frequency sub-band (0.01-0.027 Hz) in the prefrontal cortex in high pain FOP patients, where reduced power of slow-5, prefrontal cortex oscillations exhibited robust negative correlations with pain levels. Higher clinical pain intensities were also associated with higher magnitudes of depressive symptoms.

Conclusions: Our findings not only demonstrate a robust coupling among prefrontal cortex functionality and clinical pain in FOP but lays the groundwork for utilizing fNIRS to objectively monitor and central pain mechanisms in FOP and other musculoskeletal disorders.
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http://dx.doi.org/10.1186/s13023-021-01709-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847608PMC
January 2021

Discovery of a Pyrimidothiazolodiazepinone as a Potent and Selective Focal Adhesion Kinase (FAK) Inhibitor.

ACS Med Chem Lett 2021 Jan 14;12(1):30-38. Epub 2020 Dec 14.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States.

Focal adhesion kinase (FAK) is a tyrosine kinase with prominent roles in protein scaffolding, migration, angiogenesis, and anchorage-independent cell survival and is an attractive target for the development of cancer therapeutics. However, current FAK inhibitors display dual kinase inhibition and/or significant activity on several kinases. Although multitargeted activity is at times therapeutically advantageous, such behavior can also lead to toxicity and confound chemical-biology studies. We report a novel series of small molecules based on a tricyclic pyrimidothiazolodiazepinone core that displays both high potency and selectivity for FAK. Structure-activity relationship (SAR) studies explored modifications to the thiazole, diazepinone, and aniline "tail," which identified lead compound BJG-03-025. BJG-03-025 displays potent biochemical FAK inhibition (IC = 20 nM), excellent kinome selectivity, activity in 3D-culture breast and gastric cancer models, and favorable pharmacokinetic properties in mice. BJG-03-025 is a valuable chemical probe for evaluation of FAK-dependent biology.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812608PMC
January 2021

Effective virus-neutralizing activities in antisera from the first wave of survivors of severe COVID-19.

JCI Insight 2021 02 22;6(4). Epub 2021 Feb 22.

State Key Laboratory of Virology, Institute of Medical Virology and School of Basic Medical Sciences, Wuhan University, Wuhan, China.

The coronavirus disease 19 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become the worst public health crisis in a century. However, knowledge about the dynamics of antibody responses in patients with COVID-19 is still poorly understood. In this study, we performed a serological study with serum specimens collected at the acute and the convalescent phases from 104 patients with severe COVID-19 who were part of the first wave of COVID-19 cases in Wuhan, China. Our findings revealed that neutralizing antibodies to SARS-CoV-2 are persistent for at least 6 months in patients with severe COVID-19, despite that IgG levels against the receptor binding domain (RBD) and nucleocapsid protein (N) IgG declined from the acute to the convalescent phase. Moreover, we demonstrate that the level of RBD-IgG is capable of correlating with SARS-CoV-2-neutralizing activities in COVID-19 serum. In summary, our findings identify the magnitude, functionality, and longevity of antibody responses in patients with COVID-19, which sheds light on the humoral immune response to COVID-19 and would be beneficial for developing vaccines.
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http://dx.doi.org/10.1172/jci.insight.146267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934937PMC
February 2021

Counselling and psychotherapy service use in Chinese sexual minority populations: a nationwide survey.

BMC Psychiatry 2021 01 7;21(1):11. Epub 2021 Jan 7.

National Clinical Research Center for Mental Disorders, Department of Psychiatry, and China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.

Background: This study investigated the prevalence and factors associated with counselling and psychotherapy service use among Chinese sexual minority populations.

Methods: A nationwide cross-sectional study was performed using snowball sampling method, which led to the inclusion of 18,193 participants. Participants' sociodemographic background, clinical, and psychological data were gathered. Multivariate logistic regression analysis was performed to explore any associated factors.

Results: There were 2007 participants who had used counselling and psychotherapy service out of the total population. Among those who had used psychotherapy services, 80.2% participants perceived discrimination, 1.1% reported that they had been refused treatment by a counsellor and/or psychotherapist, 1.6% had experienced verbal harassment, and 8.4% reported that their counsellor and/or psychotherapist lacked knowledge and experience in treating sexual minorities. In addition, regression analyses indicated that those who were divorced/widowed, had religious beliefs, and those who had experienced discrimination, verbal harassment, and rejection for treatment by health professionals all had an increased likelihood of utilising counselling and psychotherapy service.

Conclusions: Service providers and policy makers in China should improve the quality and availability of counselling and psychotherapy services to address the mental health needs of sexual minority populations.
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http://dx.doi.org/10.1186/s12888-020-03010-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791743PMC
January 2021

Microneedle array systems for long-acting drug delivery.

Eur J Pharm Biopharm 2021 Feb 24;159:44-76. Epub 2020 Dec 24.

School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK. Electronic address:

The development of microneedles (MNs) assisted drug delivery technologies have been highly active for more than two decades. The minimally invasive and self-administered MN technology bypasses many challenges associated with injectable drug delivery systems, by delivering the therapeutic materials directly into the dermal and ocular space and allowing the release of the active ingredient in a sustained or controlled manner. Different types of MNs (biodegradable solid/dissolving MNs and nanoparticle loaded/coated polymeric MNs or delivery by hollow MNs) have been envisioned for long-acting sustained delivery of therapeutic payloads, with the aim of reducing the side effects and administration frequency to improve the patient compliance. In this review, we covered the different types of MNs loaded with different nano/biotherapeutics for long-acting delivery for a wide range of potential clinical applications. We also outlined the future development scenario of such long-acting MN delivery systems for different disease conditions to achieve improved clinical benefit. Finally, we discussed the challenges lie ahead to realize the full potential of sustained-release long-acting MNs in the clinic.
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http://dx.doi.org/10.1016/j.ejpb.2020.12.006DOI Listing
February 2021

Calcium channel blocker amlodipine besylate therapy is associated with reduced case fatality rate of COVID-19 patients with hypertension.

Cell Discov 2020 Dec 22;6(1):96. Epub 2020 Dec 22.

State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.

The coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread to >200 countries posing a global public health concern. Patients with comorbidity, such as hypertension suffer more severe infection with elevated mortality. The development of effective antiviral drugs is in urgent need to treat COVID-19 patients. Here, we report that calcium channel blockers (CCBs), a type of antihypertensive drug that is widely used in clinics, inhibited the post-entry replication events of SARS-CoV-2 in vitro, while no in vitro anti-SARS-CoV-2 effect was observed for the two other major types of antihypertensive drugs, namely, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. CCB combined with chloroquine showed a significantly enhanced anti-SARS-CoV-2 efficacy. A retrospective clinical investigation on hospitalized COVID-19 patients with hypertension as the only comorbidity revealed that the CCB amlodipine besylate therapy was associated with a decreased case fatality rate. The results from this study suggest that CCB administration to COVID-19 patients with hypertension as the comorbidity might improve the disease outcome.
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http://dx.doi.org/10.1038/s41421-020-00235-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752915PMC
December 2020

Virus-induced p38 MAPK activation facilitates viral infection.

Theranostics 2020 30;10(26):12223-12240. Epub 2020 Oct 30.

State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan 430072, Hubei, China.

Many viral infections are known to activate the p38 mitogen-activated protein kinase (MAPK) signaling pathway. However, the role of p38 activation in viral infection and the underlying mechanism remain unclear. The role of virus-hijacked p38 MAPK activation in viral infection was investigated in this study. The correlation of hepatitis C virus (HCV) infection and p38 activation was studied in patient tissues and primary human hepatocytes (PHHs) by immunohistochemistry and western blotting. Coimmunoprecipitation, GST pulldown and confocal microscopy were used to investigate the interaction of p38α and the HCV core protein. kinase assays and mass spectrometry were used to analyze the phosphorylation of the HCV core protein. Plaque assays, quantitative real time PCR (qRT-PCR), western blotting, siRNA and CRISPR/Cas9 were used to determine the effect of p38 activation on viral replication. HCV infection was associated with p38 activation in clinical samples. HCV infection increased p38 phosphorylation by triggering the interaction of p38α and TGF-β activated kinase 1 (MAP3K7) binding protein 1 (TAB1). TAB1-mediated p38α activation facilitated HCV replication, and pharmaceutical inhibition of p38α activation by SB203580 suppressed HCV infection at the viral assembly step. Activated p38α interacted with the N-terminal region of the HCV core protein and subsequently phosphorylated the HCV core protein, which promoted HCV core protein oligomerization, an essential step for viral assembly. As expected, SB203580 or the HCV core protein N-terminal peptide (CN-peptide) disrupted the p38α-HCV core protein interaction, efficiently impaired HCV assembly and impeded normal HCV replication in both cultured cells and primary human hepatocytes. Similarly, severe fever with thrombocytopenia syndrome virus (SFTSV), herpes simplex virus type 1 (HSV-1) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection also activated p38 MAPK. Most importantly, pharmacological blockage of p38 activation by SB203580 effectively inhibited SFTSV, HSV-1 and SARS-CoV-2. Our study shows that virus-hijacked p38 activation is a key event for viral replication and that pharmacological blockage of p38 activation is an antiviral strategy.
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http://dx.doi.org/10.7150/thno.50992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667676PMC
December 2020

High-Throughput Screening of an FDA-Approved Drug Library Identifies Inhibitors against Arenaviruses and SARS-CoV-2.

ACS Infect Dis 2020 Nov 12. Epub 2020 Nov 12.

State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, PR China.

Arenaviruses are a large family of enveloped negative-strand RNA viruses that include several causative agents of severe hemorrhagic fevers. Currently, there are no FDA-licensed drugs to treat arenavirus infection except for the off-labeled use of ribavirin. Here, we performed antiviral drug screening against the Old World arenavirus lymphocytic choriomeningitis virus (LCMV) using an FDA-approved drug library. Five drug candidates were identified, including mycophenolic acid, benidipine hydrochloride, clofazimine, dabrafenib, and apatinib, for having strong anti-LCMV effects. Further analysis indicated that benidipine hydrochloride inhibited LCMV membrane fusion, and an adaptive mutation on the LCMV glycoprotein D414 site was found to antagonize the anti-LCMV activity of benidipine hydrochloride. Mycophenolic acid inhibited LCMV replication by depleting GTP production. We also found mycophenolic acid, clofazimine, dabrafenib, and apatinib can inhibit the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Owing to their FDA-approved status, these drug candidates can potentially be used rapidly in the clinical treatment of arenavirus and SARS-CoV-2 infection.
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http://dx.doi.org/10.1021/acsinfecdis.0c00486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671101PMC
November 2020

MicroRNA‑145‑5p suppresses fascin to inhibit the invasion and migration of cervical carcinoma cells.

Mol Med Rep 2020 Dec 14;22(6):5282-5292. Epub 2020 Oct 14.

Department of Gynecology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.

MicroRNAs (miRs) can affect the progression of cervical cancer (CC). The present study investigated the function of miR‑145‑5p in CC and demonstrated its association with fascin (FSCN1). The expression levels of miR‑145‑5p in CC tissues and cell lines were analyzed using reverse transcription‑quantitative PCR, and its direct targets were explored using a luciferase reporter assay. The viability, migration and invasion of HeLa cells transfected with small interfering FSCN1 or with miR‑145‑5p mimics and inhibitors were analyzed using Cell Counting Kit‑8 and Transwell assays. The expression levels of FSCN1 mRNA and protein were investigated using reverse transcription PCR and western blotting. miR‑145‑5p was downregulated in CC tissues and cell lines. Moreover, overexpression of miR‑145‑5p inhibited the migration, invasion and viability of HeLa cells. miR‑145‑5p directly targeted FSCN1, which regulated the suppressive functions of miR‑145‑5p in CC cells. Overall, miR‑145‑5p is a tumor suppressor gene and a promising target for CC treatment.
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http://dx.doi.org/10.3892/mmr.2020.11592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646994PMC
December 2020

NIRS measures in pain and analgesia: Fundamentals, features, and function.

Neurosci Biobehav Rev 2021 01 4;120:335-353. Epub 2020 Nov 4.

Center for Pain and the Brain, Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, United States. Electronic address:

Current pain assessment techniques based only on clinical evaluation and self-reports are not objective and may lead to inadequate treatment. Having a functional biomarker will add to the clinical fidelity, diagnosis, and perhaps improve treatment efficacy in patients. While many approaches have been deployed in pain biomarker discovery, functional near-infrared spectroscopy (fNIRS) is a technology that allows for non-invasive measurement of cortical hemodynamics. The utility of fNIRS is especially attractive given its ability to detect specific changes in the somatosensory and high-order cortices as well as its ability to measure (1) brain function similar to functional magnetic resonance imaging, (2) graded responses to noxious and innocuous stimuli, (3) analgesia, and (4) nociception under anesthesia. In this review, we evaluate the utility of fNIRS in nociception/pain with particular focus on its sensitivity and specificity, methodological advantages and limitations, and the current and potential applications in various pain conditions. Everything considered, fNIRS technology could enhance our ability to evaluate evoked and persistent pain across different age groups and clinical populations.
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http://dx.doi.org/10.1016/j.neubiorev.2020.10.023DOI Listing
January 2021

Association between Neighborhood Food Access, Household Income, and Purchase of Snacks and Beverages in the United States.

Authors:
Ke Peng Nikhil Kaza

Int J Environ Res Public Health 2020 10 15;17(20). Epub 2020 Oct 15.

Department of City and Regional Planning, University of North Carolina at Chapel Hill, Campus Box 3140, Chapel Hill, NC 27599, USA.

Considerable research on the risk factors of obesity and chronic diseases has focused on relationships between where people live, where they shop, and the types of food they purchase. Rarely have investigators used a national sample and explicitly addressed the amount of energy-dense and nutrient-poor foods purchased in different types of neighborhood food stores. Even more rarely have studies accounted for the characteristics of the broader built environment in which food stores are located and which affect the convenience of using neighborhood food stores. We used a large population-based cohort of predominantly white U.S. households from the Nielsen Homescan Consumer Panel 2010 dataset to examine whether there were positive cross-sectional associations between availability of neighborhood convenience stores and supermarkets and self-reported household annual expenditures for snacks and beverages. We examined this relationship separately for poor and non-poor households as defined by the 2010 U.S. federal poverty threshold. We used mixed error-component regression models to examine associations between availability of neighborhood food stores and the expenditures on snacks and beverages, controlling for regional destination accessibility, availability and diversity of neighborhood destinations, and neighborhood street connectivity. In multivariate analyses, we observed that poor households in neighborhoods with few convenience stores purchased more snacks than poor households in neighborhoods with many convenience stores (b = -0.008, < 0.05). Non-poor households in neighborhoods with many convenience stores and fewer supermarkets purchased more snacks than non-poor households in neighborhoods with few convenience stores and many supermarkets (b = 0.002, < 0.05 for convenience stores; b = -0.027, < 0.05 for supermarkets). Increase in number of convenience stores decreased the purchase of snacks by poor households, but increased in non-poor households. On other hand, increase in number of supermarkets discouraged purchase of snacks by non-poor households but had no effect on the purchasing behavior of the poor-households.Therefore, evaluation of access to energy-dense and nutrient-poor foods should include a consideration of geographic proximity. Local governments should consider strategies to expand the availability and access to nutrient-rich food and beverage products in convenience stores for consumers.
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http://dx.doi.org/10.3390/ijerph17207517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602560PMC
October 2020

Formulation of Gelled Non-toxic Bicontinuous Microemulsions Stabilized by Highly Efficient Alkanoyl Methylglucamides.

Langmuir 2020 10 16;36(42):12692-12701. Epub 2020 Oct 16.

Institute of Physical Chemistry, University of Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany.

Gelled non-toxic bicontinuous microemulsions have a great potential for transdermal drug delivery as the microemulsion facilitates the solubilization of both hydrophilic and hydrophobic drugs, while the gel network provides mechanical stability and thus an easy application on the skin. In our previous study, we formulated a gelled non-toxic bicontinuous microemulsion: we gelled the system HO-isopropyl myristate (IPM)-Plantacare 1200 UP (CG)-1,2-octanediol with the low molecular weight organogelator 1,3:2,4-dibenzylidene-d-sorbitol (DBS). However, a large amount of Plantacare 1200 UP (12 wt %) is needed to form a bicontinuous microemulsion. To solve this problem, we studied a new class of surfactants, namely, alkanoyl methylglucamides (MEGA), which have been rarely used for the formulation of microemulsions. The phase behavior of microemulsions stabilized by MEGA-8/10, MEGA-12/14-PC, and MEGA-12/14-HC was compared with that of systems stabilized by alkyl polyglucosides. We found that even with 2 wt % MEGA-12/14-HC, a bicontinuous microemulsion can be formed, which is 1/6 of the amount of Plantacare 1200 UP. The bicontinuous microstructure of the non-toxic microemulsion HO-IPM-MEGA-12/14-HC-1,2-octanediol was confirmed by small-angle neutron scattering. Furthermore, the phase boundaries remained unchanged when gelled by DBS. The rheological properties of the gel were studied by oscillatory shear rheometry. Finally, freeze-fracture electron microscopy images show the coexistence of gel fibers and bicontinuous oil and water domains. These results suggest that the new gelled non-toxic bicontinuous microemulsion is an orthogonal self-assembled system.
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http://dx.doi.org/10.1021/acs.langmuir.0c02314DOI Listing
October 2020

ASK1 inhibits proliferation and migration of lung cancer cells via inactivating TAZ.

Am J Cancer Res 2020 1;10(9):2785-2799. Epub 2020 Sep 1.

School of Medicine, Jiangsu University 301 Xuefu Road, Zhenjiang, Jiangsu, China.

ASK1 (Apoptosis Signal-regulating Kinase 1, also MEKK5) is known to mediate cellular stress signaling pathways through activating p38 kinase. We here observed that ectopically expression of ASK1, but not its kinase-dead mutant, impaired cell proliferation and migration in lung cancer A549 and NCI-H1975 cells. To our surprise, this inhibitory effect of ASK1 is independent on activation of p38 kinase. We further discovered that ASK1 interacts with the WW domain of YAP and TAZ (also WWTR1) that are transcriptional co-activators and the Hippo signaling effectors. Overexpression of wild type ASK1, but not the kinase-dead mutant, in the lung cancer cells down-regulated the expression of the YAP/TAZ target genes and . It seems that ASK1 specifically inactivates TAZ, not YAP, as ASK1 blocked nuclear translocation of TAZ only, while had no effect on YAP. Furthermore, knockdown of TAZ in the lung cancer cells caused the same inhibitory effect on cell proliferation and migration as that of overexpression of ASK1. Thus, our studies have defined a new signaling pathway of ASK1 for regulation of lung cancer cell proliferation and migration via interacting with and inactivating TAZ.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539782PMC
September 2020