Publications by authors named "Jianhua Li"

676 Publications

Development of a predictive nomogram for early recurrence of hepatocellular carcinoma in patients undergoing liver transplantation.

Ann Transl Med 2021 Mar;9(6):468

Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.

Background: An individual prognostic model that includes inflammation caused by the delayed recovery of liver function after surgery for the early recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) has not been well determined. Our aim was to develop a nomogram model for predicting individual survival and early recurrence following LT for patients.

Methods: Retrospective data, including clinical pathology and follow-up data, on HCC patients were collected between October 2016 and October 2019 at Huashan Hospital Affiliated to Fudan University. A nomogram estimating recurrence post-transplantation was constructed using multivariate Cox regression analysis.

Results: A total of 210 patients were included in the present study. The multivariate estimators of recurrence consisted of age, maximum tumor diameter, tumor thrombus, microvascular invasion (MVI), alanine aminotransferase and alpha-fetoprotein on postoperative day 7. Nomogram of recurrence-free survival was developed. The calibration and discrimination of the novel model were assessed with the calibration curves and concordance index (C-index). Its reliability and advantages were evaluated by comparing it with the conventional American Joint Committee on Cancer (AJCC) 8th edition staging system using integrated discrimination improvement (IDI) and net reclassification improvement (NRI). In comparison to the AJCC 8th edition staging system, the C-index (development set: 0.796 0.643, validation set: 0.741 0.563), the area under the receiver operating characteristic curve (AUC) of the validation set (1-year AUC: 0.732 0.586, 2-year AUC: 0.705 0.504), the development set (1-year AUC: 0.799 0.551, 2-year AUC: 0.801 0.512), and this model's calibration plots all showed improved performance. In addition, NRI and IDI verified that the nomogram is an accurate prognostic tool. Subsequently, a web calculator was generated to assess the risk of tumor recurrence post-LT.

Conclusions: The nomogram, based on clinical and pathological factors, showed good accuracy in estimating prognostic recurrence and can be used to guide individual patient follow-up and treatment.
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http://dx.doi.org/10.21037/atm-21-334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039665PMC
March 2021

Influence of anesthetic induction of propofol combined with esketamine on perioperative stress and inflammatory responses and postoperative cognition of elderly surgical patients.

Am J Transl Res 2021 15;13(3):1701-1709. Epub 2021 Mar 15.

Department of Anesthesiology, Yichun People's Hospital Yichun 336000, Jiangxi Province, China.

Objective: To analyze the influence of anesthetic induction of propofol combined with esketamine on perioperative stress and inflammatory responses and postoperative cognition in elderly surgical patients.

Methods: A total of 80 elderly surgical patients were randomly divided into a control group (n=40) and a study group (n=40). The control group received anesthetic induction with propofol combined with sufentanil, while the study group received anesthetic induction with propofol combined with esketamine. Hemodynamics, stress and inflammatory responses and changes in cognitive function, perioperative related indexes and adverse responses were compared between the two groups.

Results: At T, the levels of adrenaline, norepinephrine, endothelin, C-reactive protein, white blood cell and procalcitonin in the two groups were not markedly changed compared with those at T. The levels of the indices at T and T were elevated compared with those at T. However, the levels of the indices at T were almost close to those at T, and the levels in the study group were higher than those in the control group. There were statistically significant differences in the comparison of the interaction of the levels of the aforementioned indices between groups, between time points, and between groups and time points ( < 0.05). At 24 h after surgery, the Montreal Cognitive Assessment (MoCA) scores were decreased in both groups, and the MoCA scores in the study group were higher than those in the control group ( < 0.05). The anesthesia time and consciousness recovery time in the study group were shorter than those in the control group ( < 0.05).

Conclusion: The anesthetic induction of propofol combined with esketamine, exhibits a good safety profile and reliability, it can improve hemodynamics and surgical stress and inflammatory responses, shorten anesthesia time, promote the recovery of postoperative cognitive function, and cause relatively mild adverse responses.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014402PMC
March 2021

Factors associated with delayed enteral nutrition in the intensive care unit: a propensity score-matched retrospective cohort study.

Am J Clin Nutr 2021 Apr 7. Epub 2021 Apr 7.

Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.

Background: Guidelines recommend enteral nutrition (EN) within 48 h of admission to the medical intensive care unit (ICU) in appropriate patients. However, delayed EN is still common.

Objectives: This study sought to identify risk factors for delayed EN ordering in the ICU and to examine its association with patient outcomes.

Methods: This was a retrospective study from 2010-2018. Adult patients were included if they were admitted to the medical ICU for >48 h, were appropriate for EN, and had an order for EN placed within 30 d of admission. The primary outcome was ordering of EN, classified as early if ordered within 48 h of ICU admission and otherwise as delayed. Propensity score matching was used to examine the relation between delayed EN and ICU-free days, and outcomes such as length of ICU admission, length of hospitalization during 30 d of follow-up, and mortality.

Results: A total of 738 (79%) patients received early EN and 196 (21%) received delayed EN. The exposures most strongly associated with delayed EN were order placement by a Doctor of Medicine compared with a dietitian [adjusted OR (aOR): 2.58; 95% CI: 1.57, 4.24] and use of vasopressors within 48 h of ICU admission (aOR: 1.78; 95% CI: 1.22, 2.59). After propensity score matching to balance baseline characteristics, delayed EN ordering was significantly associated with fewer ICU-free days, longer ICU admissions, and longer hospitalizations, but not mortality, compared with early EN.

Conclusions: Provider-level factors were associated with delayed ordering of EN which itself was associated with worse outcomes. Interventions directed at providers may increase timely EN in the ICU and improve outcomes.
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http://dx.doi.org/10.1093/ajcn/nqab023DOI Listing
April 2021

Extracellular vesicles secreted by Giardia duodenalis regulate host cell innate immunity via TLR2 and NLRP3 inflammasome signaling pathways.

PLoS Negl Trop Dis 2021 Apr 2;15(4):e0009304. Epub 2021 Apr 2.

Key Laboratory of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.

Giardia duodenalis, also known as G. intestinalis or G. lamblia, is the major cause of giardiasis leading to diarrheal disease with 280 million people infections annually worldwide. Extracellular vesicles (EVs) have emerged as a ubiquitous mechanism participating in cells communications. The aim of this study is to explore the roles of G. duodenalis EVs (GEVs) in host-pathogen interactions using primary mouse peritoneal macrophages as a model. Multiple methods of electron microscopy, nanoparticle tracking analysis, proteomic assays, flow cytometry, immunofluorescence, qPCR, western blot, ELISA, inhibition assays, were used to characterize GEVs, and explore its effects on the host cell innate immunity as well as the underlying mechanism using primary mouse peritoneal macrophages. Results showed that GEVs displayed typical cup-shaped structure with 150 nm in diameter. GEVs could be captured by macrophages and triggered immune response by increasing the production of inflammatory cytokines Il1β, Il6, Il10, Il12, Il17, Ifng, Tnf, Il18, Ccl20 and Cxcl2. Furthermore, activation of TLR2 and NLRP3 inflammasome signaling pathways involved in this process. In addition, CA-074 methyl ester (an inhibitor of cathepsin B) or zVAD-fmk (an inhibitor of pan-caspase) pretreatment entirely diminished these effects triggered by GEVs exposure. Taken together, these findings demonstrated that GEVs could be internalized into mouse peritoneal macrophages and regulate host cell innate immunity via TLR2 and NLRP3 inflammasome signaling pathways.
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http://dx.doi.org/10.1371/journal.pntd.0009304DOI Listing
April 2021

Monoclonal antibodies capable of binding SARS-CoV-2 spike protein receptor-binding motif specifically prevent GM-CSF induction.

J Leukoc Biol 2021 Mar 24. Epub 2021 Mar 24.

The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.

A severe acute respiratory syndrome (SARS)-like coronavirus 2 (SARS-CoV-2) has recently caused a pandemic COVID-19 disease that infected approximately 94 million and killed more than 2,000,000 people worldwide. Like the SARS-CoV, SARS-CoV-2 also employs a receptor-binding motif (RBM) of its envelope spike protein for binding the host angiotensin-converting enzyme 2 (ACE2) to gain viral entry. Currently, extensive efforts are being made to produce vaccines against a surface fragment of a SARS-CoV-2, such as the spike protein, in order to boost protective antibodies that can inhibit virus-ACE2 interaction to prevent viral entry. It was previously unknown how spike protein-targeting antibodies would affect innate inflammatory responses to SARS-CoV-2 infections. Here we generated a highly purified recombinant protein corresponding to the RBM of SARS-CoV-2, and used it to screen for cross-reactive monoclonal antibodies (mAbs). We found two RBM-binding mAbs that competitively inhibited its interaction with human ACE2, and specifically blocked the RBM-induced GM-CSF secretion in both human peripheral blood mononuclear cells and murine macrophage cultures. Our findings have suggested a possible strategy to prevent SARS-CoV-2-elicited "cytokine storm," and revealed a potentially anti-inflammatory and protective mechanism for SARS-CoV-2 spike-based vaccines.
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http://dx.doi.org/10.1002/JLB.3COVCRA0920-628RRDOI Listing
March 2021

Occurrence of macroprolactinemia in schizophrenia patients treated with risperidone or amisulpride.

Asia Pac Psychiatry 2021 Mar 22:e12469. Epub 2021 Mar 22.

Huzhou Third Municipal Hospital, the Affiliated Hospital of Huzhou University, Zhejiang, China.

Objective: To investigate macroprolactinemia caused by antipsychotics and its clinical significance.

Methods: A total of 133 patients with schizophrenia were selected, all of whom were treated with either risperidone or amisulpride alone. The levels of total prolactin (T-PRL) and macroprolactin (MPRL) were measured before treatment as well as the second, fourth, and sixth weeks of treatment.

Results: After 2 weeks of treatment, 75.09% (100/133) of the patients met the diagnostic criteria for hyperprolactinemia, the incidence of macroprolactinemia was 43% (43/100), and MPRL levels were positively correlated T-PRL levels.

Conclusion: Risperidone and amisulpride caused hyperprolactinemia and macroprolactinemia; thus, detection of MPRL in the clinical setting should be performed as this phenomenon appears early in treatment (the second week) and continues, that can avoid unnecessary examination and treatment for asymptomatic patients with macroprolactinemia.
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http://dx.doi.org/10.1111/appy.12469DOI Listing
March 2021

Protective Immunity Against Infection Induced by 14-3-3 Protein in Mice.

Front Vet Sci 2021 3;8:638173. Epub 2021 Mar 3.

Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.

is an apicomplexan parasite that infects many mammals and remains a threatening disease worldwide because of the lack of effective drugs and vaccines. Our previous studies demonstrated that 14-3-3 protein (Nc14-3-3), which is included in extracellular vesicles (NEVs), can induce effective immune responses and stimulate cytokine expression in mouse peritoneal macrophages. However, whether Nc14-3-3 has a protective effect and its mechanisms are poorly understood. Here, we evaluated the immune responses and protective effects of Nc14-3-3 against exposure to 2 × 10 Nc-1 tachyzoites. Antibody (IgG, IgGl, and IgG2a) levels and Th1-type (IFN-γ and IL-12) and Th2-type (IL-4 and IL-10) cytokines in mouse serum, survival rates, survival times, and parasite burdens were detected. In the present study, the immunostimulatory effect of Nc14-3-3 was confirmed, as it triggered Th1-type cytokine (IFN-γ and IL-12) production in mouse serum 2 weeks after the final immunization. Moreover, the immunization of C57BL/6 mice with Nc14-3-3 induced high IgG antibody levels and significant increases in CD8 T lymphocytes in the spleens of mice, indicating that the cellular immune response was significantly stimulated. Mouse survival rates and times were significantly prolonged after immunization; the survival rates were 40% for Nc14-3-3 immunization and 60% for NEV immunization, while mice that received GST, PBS, or blank control all died at 13, 9, or 8 days, respectively, after intraperitoneal challenge. In addition, qPCR analysis indicated that there was a reduced parasite burden and diminished pathological changes in the mice immunized with Nc14-3-3. Our data demonstrate that vaccination of mice with Nc14-3-3 elicits both cellular and humoral immune responses and provides partial protection against acute neosporosis. Thus, Nc14-3-3 could be an effective antigen candidate for vaccine development for neosporosis.
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http://dx.doi.org/10.3389/fvets.2021.638173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965954PMC
March 2021

Inappropriateness of Proton Pump Inhibitors After Hospital Discharge Is Associated with Thirty-Day Hospital Readmission.

Dig Dis Sci 2021 Mar 16. Epub 2021 Mar 16.

Division of Digestive and Liver Diseases, Department of Medicine, New York Presbyterian Columbia University Medical Center, 622 West 168th Street, New York, NY, USA.

Background And Aims: Concerns have been raised about the adverse effects of proton pump inhibitors (PPIs). Rather than PPIs themselves causing harm, we hypothesized that PPIs prescribed without appropriate indications would be associated with adverse outcomes compared to appropriately indicated PPIs.

Methods: Adult patients initiated on a new PPI during a hospitalization at our institution from 2014 to 2018 were analyzed. The primary outcome was all-cause 30-day readmission rate. The primary exposure was long-term appropriateness of PPI determined by the presence of prespecified diagnostic codes and discharge medications. Logistic regression modeling was used to estimate the odds of 30-day readmission in patients discharged on inappropriate compared to appropriate new PPIs.

Results: Of 84,236 patients admitted to our institution, 7745 (9.2%) were discharged on a new PPI, of which 5136 (66.3%) lacked an appropriately documented indication. Inappropriate PPIs were associated with 30-day hospital readmission after adjusting for other factors (adjusted odds ratio 1.30, 95% confidence interval 1.10-1.53). The excess risk associated with lack of appropriate documentation for PPIs in these patients was 44 readmissions per 1000 hospitalizations (95% confidence interval 21-67).

Conclusions: Discharge on inappropriate PPIs was associated with 30-day hospital readmission compared to appropriate PPIs. The harm associated with inappropriate PPIs is not likely due to direct effects of PPIs because all patients in the study received PPIs. Rather, patients who receive inappropriate PPIs may have additional patient-specific factors that place them at increased risk for hospital readmission.
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http://dx.doi.org/10.1007/s10620-021-06909-3DOI Listing
March 2021

The Deubiquitinating Enzyme UCHL1 Induces Resistance to Doxorubicin in HER2+ Breast Cancer by Promoting Free Fatty Acid Synthesis.

Front Oncol 2021 24;11:629640. Epub 2021 Feb 24.

Department of Pharmacy, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.

Ubiquitin C-terminal hydrolase L1 (UCHL1), which is a deubiquitinating enzyme, is known to play a role in chemoresistance in cancers. However, its potential roles and mechanisms in the chemoresistance of breast cancer (BC) remain unclear. In this study, we examined its expression in patients with BC and employed Kaplan-Meier analysis and the log-rank test for survival analyses. It was found that up-regulated UCHL1 expression was positively associated with both chemoresistance and poor prognosis, especially in patients with HER2+ BC. Moreover, UCHL1 expression was elevated in HER2+ BC cells (SK-BR-3 and BT474). Similarly, doxorubicin (DOX)-resistant BC cells (MCF-7/DOX) had higher UCHL1 levels than MCF-7 cells. CCK-8 assay showed that BC cells with higher UCHL1 levels were more resistant to DOX. Furthermore, by inhibiting UCHL1 in BC cells with elevated UCHL1 expression, we demonstrated that UCHL1 promoted DOX-resistance in BC. Mechanistically, UCHL1 probably promoted DOX-resistance of BC by up-regulating free fatty acid (FFA) synthesis, as exhibited by reduced FFA synthase expression and resurrected DOX-sensitivity upon UCHL1 inhibition. Overall, UCHL1 up-regulation is associated with DOX-resistance and poor prognosis in patients with HER2+ BC. UCHL1 induces DOX-resistance by up-regulating FFA synthesis in HER2+ BC cells. Thus, UCHL1 might be a potential clinical target for overcoming DOX resistance in patients with HER2+ BC.
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http://dx.doi.org/10.3389/fonc.2021.629640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943833PMC
February 2021

A study on eccentric occluder via ultra minimal incision of doubly committed subarterial ventricular septal defects.

J Card Surg 2021 Mar 11. Epub 2021 Mar 11.

Department of Cardiac Surgery and Heart Center, The Childern's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, China.

Object: To compare the clinical data of sternotomy and left intercostals incision, combined with the literature, to provide the best surgical incision for committed subarterial ventricular septal defect (DCS-VSD).

Methods: From July 2016 to July 2020, a total of 117 cases of occlusion surgeries for DCSVSD, which guided by transoesophagel echocardiography (TEE) were completed, including 34 cases with sternotomy incision and 83 cases with left intercostal incision. Statistics and analysis of the operation and follow-up.

Results: A total of 115 cases successfully occluded, the successful rate was 98.29%, and 1 case failed in each group. Pericardial effusion occurred in five children after the drainage device was removed, and the pericardial effusion disappeared after diuretic treatment. There was no statistical difference between the two groups in operation time, occlusion time, thoracotomy time and postoperative hospital stay. All the children recovered and were discharged from the hospital, and were followed-up for 2-30 months after operation.

Conclusion: TEE-guided intercostal DCS-VSD occlusion is safe and effective. There is no statistical difference between two approach with the operation time, chest opening and closing time, occluder placing time, and postoperative hospital staying. At the same time, the surgical incision by intercostal incisionis smaller and the operation invasion is less, it is a surgical approach which worth to develop.
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http://dx.doi.org/10.1111/jocs.15484DOI Listing
March 2021

Disruption of Dense Granular Protein 2 (GRA2) Decreases the Virulence of .

Front Vet Sci 2021 19;8:634612. Epub 2021 Feb 19.

Key Laboratory of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.

causes abortions in cattle and nervous system dysfunction in dogs. Dense granular proteins (GRAs) play important roles in virulence; however, studies on NcGRA functions are limited. In the present study, multiple methods, including site-directed mutagenesis; CRISPR/Cas9 gene editing; Western blotting; quantitative polymerase chain reaction; confocal microscopy; plaque, invasion, egress, and replication assays; animal assays of survival rate and parasite burden; and hematoxylin-eosin staining, were used to characterize the NcGRA2 protein, construct an NcGRA2 gene disruption (ΔNcGRA2) strain, and explore its virulence and . The results showed that NcGRA2 shared 31.31% homology with TgGRA2 and was colocalized with NcGRA6 at the posterior end of tachyzoites and the intravacuolar network of parasitophorous vacuoles (PVs). Cell fractionation analysis showed that NcGRA2 behaved as a transmembrane and membrane-coupled protein. The ΔNcGRA2 strain was constructed by coelectroporation of the NcGRA2-targeting CRISPR plasmid (pNc-SAG1-Cas9:U6-SgGRA2) and DHFR-TS DNA donor and verified at the protein, genome, and transcriptional levels and by immunofluorescence localization analysis. The virulence results showed that the ΔNcGRA2 strain displayed smaller plaques, similar invasion and egress abilities, and slower intracellular growth. The virulence results showed a prolonged survival time, lower parasite burden, and mild histopathological changes. Overall, the present study indicates that NcGRA2, as a dense granular protein, forms the intravacuolar network structure of PVs and weakens virulence by slowing proliferation. These data highlight the roles of NcGRA2 and provide a foundation for research on other protein functions in .
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http://dx.doi.org/10.3389/fvets.2021.634612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933011PMC
February 2021

Inhibitory role of circRNA_100395 in the proliferation and metastasis of prostate cancer cells.

J Int Med Res 2021 Feb;49(2):300060521992215

Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Objective: Circular RNAs (circRNAs) are non-coding RNAs with high cancer-specific expression and the potential for regulating tumorigenesis. CircRNA_100395 is expressed at low levels in many cancers and is involved in the regulation of tumor cell proliferation and metastasis. However, its expression and function in prostate cancer remain unclear.

Methods: Endogenous expression levels of circRNA_100395 and microRNA-1228 (miR-1228) in prostate cancer tissue samples and cell lines were detected by quantitative reverse transcription-polymerase chain reaction. Cell proliferation, invasion, and migration, cell cycle distribution, and epithelial-mesenchymal transition (EMT) were analyzed in circRNA_100395-overexpressing prostate cancer cells by Cell Counting Kit-8, flow cytometry, Transwell assay, and western blotting, respectively.

Results: CircRNA_100395 expression was downregulated in cancerous prostate tissues relative to adjacent normal tissues. CircRNA_100395 expression was negatively correlated with tumor size, Gleason score, tumor stage, and lymph node metastasis. Moreover, circRNA_100395 overexpression inhibited cell proliferation, altered cell cycle distribution, reduced cell migration and invasion abilities, and suppressed EMT in prostate cancer cells. Moreover, miR-1228 was a direct downstream target of circRNA_100395, and the anti-tumor ability of circRNA_100395 was significantly reversed by miR-1228.

Conclusion: This study identified circRNA_100395 as an anti-tumor circRNA and a potential therapeutic target for prostate cancer.
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http://dx.doi.org/10.1177/0300060521992215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917968PMC
February 2021

Association between antecedent statin use and decreased mortality in hospitalized patients with COVID-19.

Nat Commun 2021 02 26;12(1):1325. Epub 2021 Feb 26.

NewYork-Presbyterian Hospital and the Columbia University Irving Medical Center, New York, NY, USA.

The coronavirus disease 2019 (COVID-19) can result in a hyperinflammatory state, leading to acute respiratory distress syndrome (ARDS), myocardial injury, and thrombotic complications, among other sequelae. Statins, which are known to have anti-inflammatory and antithrombotic properties, have been studied in the setting of other viral infections, but their benefit has not been assessed in COVID-19. This is a retrospective analysis of patients admitted with COVID-19 from February 1 through May 12, 2020 with study period ending on June 11, 2020. Antecedent statin use was assessed using medication information available in the electronic medical record. We constructed a multivariable logistic regression model to predict the propensity of receiving statins, adjusting for baseline sociodemographic and clinical characteristics, and outpatient medications. The primary endpoint includes in-hospital mortality within 30 days. A total of 2626 patients were admitted during the study period, of whom 951 (36.2%) were antecedent statin users. Among 1296 patients (648 statin users, 648 non-statin users) identified with 1:1 propensity-score matching, statin use is significantly associated with lower odds of the primary endpoint in the propensity-matched cohort (OR 0.47, 95% CI 0.36-0.62, p < 0.001). We conclude that antecedent statin use in patients hospitalized with COVID-19 is associated with lower inpatient mortality.
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http://dx.doi.org/10.1038/s41467-021-21553-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910606PMC
February 2021

Targeting xenobiotic nuclear receptors PXR and CAR to prevent cobicistat hepatotoxicity.

Toxicol Sci 2021 Feb 25. Epub 2021 Feb 25.

Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Liver-related diseases including drug-induced liver injury are becoming increasingly prominent in AIDS patients. Cobicistat (COBI) is the backbone of multiple regimens for antiretroviral therapy. The current work investigated the mechanisms of adverse drug-drug interactions associated with COBI that lead to liver damage. For individuals co-infected with HIV and tuberculosis (TB), the World Health Organization recommends the initiation of TB treatment followed by antiretroviral therapy. Rifampicin (RIF), a first line anti-TB drug, is a human specific activator of pregnane X receptor (PXR). Using PXR-humanized mice, we found that RIF-mediated PXR activation potentiates COBI hepatotoxicity. In contrast, rifabutin, a PXR-neutral analog of RIF, has no impact on COBI hepatotoxicity. Because of the crosstalk between PXR and the constitutive androstane receptor (CAR), the role of CAR in COBI hepatotoxicity was also investigated. Similar to PXR, ligand-dependent activation of CAR also potentiates COBI hepatotoxicity. Our further studies illustrated that PXR and CAR modulate COBI hepatotoxicity through the CYP3A4-dependent pathways. In summary, the current work determined PXR and CAR as key modulators of COBI hepatotoxicity. Given the fact that many prescription drugs and herbal supplements can activate PXR and CAR, these two receptors should be considered as targets to prevent COBI hepatotoxicity in the clinic.
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http://dx.doi.org/10.1093/toxsci/kfab023DOI Listing
February 2021

Recent Advances in Metabolic Engineering, Protein Engineering, and Transcriptome-Guided Insights Toward Synthetic Production of Taxol.

Front Bioeng Biotechnol 2021 5;9:632269. Epub 2021 Feb 5.

Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, China.

The diterpenoid paclitaxel (Taxol) is a blockbuster anticancer agent that was originally isolated from the Pacific yew () five decades ago. Despite the wealth of information gained over the years on Taxol research, there still remains supply issues to meet increasing clinical demand. Although alternative Taxol production methods have been developed, they still face several drawbacks that cause supply shortages and high production costs. It is highly desired to develop biotechnological production platforms for Taxol, however, there are still gaps in our understanding of the biosynthetic pathway, catalytic enzymes, regulatory and control mechanisms that hamper production of this critical drug by synthetic biology approaches. Over the past 5 years, significant advances were made in metabolic engineering and optimization of the Taxol pathway in different hosts, leading to accumulation of taxane intermediates. Computational and experimental approaches were leveraged to gain mechanistic insights into the catalytic cycle of pathway enzymes and guide rational protein engineering efforts to improve catalytic fitness and substrate/product specificity, especially of the cytochrome P450s (CYP450s). Notable breakthroughs were also realized in engineering the pathway in plant hosts that are more promising in addressing the challenging CYP450 chemistry. Here, we review these recent advances and in addition, we summarize recent transcriptomic data sets of species and elicited culture cells, and give a bird's-eye view of the information that can be gleaned from these publicly available resources. Recent mining of transcriptome data sets led to discovery of two putative pathway enzymes, provided many lead candidates for the missing steps and provided new insights on the regulatory mechanisms governing Taxol biosynthesis. All these inferences are relevant to future biotechnological production of Taxol.
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http://dx.doi.org/10.3389/fbioe.2021.632269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892896PMC
February 2021

Relationship Between the ApoE Gene Polymorphism and Type 2 Diabetes Mellitus Complications.

Genet Test Mol Biomarkers 2021 Feb;25(2):111-115

Cadre Ward-2, Fourth Medical Center of General Hospital of PLA, Beijing, China.

Apolipoprotein E (ApoE) polymorphisms are associated with type 2 diabetes mellitus (T2DM) and its complications, but studies have shown conflicting results. To examine the relationship of ApoE gene polymorphisms with T2DM and its complications. This case-control study of patients with T2DM was conducted between June 2016 and July 2019. Healthy individuals were recruited as controls. The patients were grouped according to coronary heart disease (CHD), cerebral infarction (CI), diabetic nephropathy (DN), and neurological complications. The ApoE genotype was determined using a commercial gene chip. Compared with controls, the frequencies of genotype (20.8% vs. 11.7%,  = 0.04) and allele (14.3% vs. 8.3%,  = 0.03) of patients with T2DM were higher. The frequency of genotype was higher in the T2DM with CHD group (30.4% vs. 17.4%,  = 0.01 vs. non-CHD) and in T2DM with CI (29.2% vs. 18.1%,  = 0.045 vs. non-CI). The frequency of genotype was higher in the T2DM with DN group (19.3% vs. 9.1%,  = 0.01 vs. non-DN). There were no significant differences between T2DM with and without neuropathy ( > 0.05). The ApoE allele may be a risk factor for T2DM, CHD in T2DM, and CI in T2DM, while the ApoE allele may be a risk factor for DN.
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http://dx.doi.org/10.1089/gtmb.2020.0130DOI Listing
February 2021

Learning to Detect Salient Object with Multi-source Weak Supervision.

IEEE Trans Pattern Anal Mach Intell 2021 Feb 16;PP. Epub 2021 Feb 16.

High-cost pixel-level annotations makes it appealing to train saliency detection models with weak supervision. However, a single weak supervision source hardly contain enough information to train a well-performing model. To this end, we introduce a unified two-stage framework to learn from category labels, captions, web images and unlabeled images. In the first stage, we design a classification network (CNet) and a caption generation network (PNet), which learn to predict object categories and generate captions, respectively, meanwhile highlights the potential foreground regions. We present an attention transfer loss to transmit supervisions between two tasks and an attention coherence loss to encourage the networks to detect generally salient regions instead of task-specific regions. In the second stage, we create two complementary training datasets using CNet and PNet, i.e., natural image dataset with noisy labels for adapting saliency prediction network (SNet) to natural image input, and synthesized image dataset by pasting objects on background images for providing SNet with accurate ground-truth. During the testing phases, we only need SNet to predict saliency maps. Experiments indicate the performance of our method compares favorably against unsupervised, weakly supervised methods and even some supervised methods.
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http://dx.doi.org/10.1109/TPAMI.2021.3059783DOI Listing
February 2021

In vitro assays on the susceptibility of four species of nematophagous fungi to anthelmintics and chemical fungicides/antifungal drug.

Lett Appl Microbiol 2021 Feb 15. Epub 2021 Feb 15.

Key Laboratory of Zoonosis Research by Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, China.

Using nematophagous fungi for the biological control of animal parasitic nematodes will become one of the most promising strategies in the search for alternative chemical drugs. The purpose of this study was to check the in vitro activity of four anthelmintics, four chemical fungicides, and two antifungal drugs on the spore germination of nematophagous fungi: Duddingtonia flagrans (SF170), Arthrobotrys oligospora (447), Arthrobotrys superba (435), and Arthrobotrys sp. (PS011). A modified 24-well cell culture plate assay was conducted to evaluate the susceptibility of nematophagous fungi against drugs tested by calculating the effective middle concentrations (EC ) of each tested drug to inhibit the germination of fungal spores. EC ranged between 0.7 and 47.2 μg/mL for fenbendazole, thiabendazole, and ivermectin, except levamisole (546.5-4057.8 μg/mL). EC of tested fungicides was 0.6-2.3 μg/mL for carbendazim, 55.9-247.4 μg/mL for metalaxyl, 24.4-45.2 μg/mL for difenoconazole, and 555.9-1438.3 μg/mL for pentachloronitrobenzene. EC of two antifungal drugs was 0.03-3.4μg/mL for amphotericin B and 0.3-10.9 μg/mL for ketoconazole. The results showed that ten tested drugs, except for levamisole and pentachloronitrobenzene, had in vitro inhibitory effects on nematophagous fungi. The chlamydospores of D. flagrans had the highest sensitivity to nine tested drugs, except for ketoconazole.
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http://dx.doi.org/10.1111/lam.13462DOI Listing
February 2021

Serum concentrations of neonicotinoids, and their associations with lipid molecules of the general residents in Wuxi City, Eastern China.

J Hazard Mater 2021 Jan 29;413:125235. Epub 2021 Jan 29.

Jiangsu Provincial Center for Disease Control and Prevention, 210009 Nanjing, People's Republic of China. Electronic address:

Exposure to neonicotinoid insecticides (NNIs) was proven to be harmful to organisms, however, there is a dearth of information regarding their occurrence and adverse effects on the general residents. Here, n = 120 human serum samples were collected from the same area of Wuxi city, Eastern China, and these serum samples were further analyzed for nine NNIs and nine target lipid molecules by use of ultrahigh performance liquid chromatography-quadrupole orbitrap high-resolution mass spectrometer. We observed that four out of nine NNIs exhibited relatively high detection frequencies (DF), and these NNIs were imidacloprid (IMI; DF = 28.3%), clothianidin (CLO; 16.7%), thiacloprid (THI; 14.2%), and acetamiprid (ACE; 12.5%), respectively, with 95th concentrations ranging from 32.0 to 427 pg/mL. Median concentrations of imidacloprid-equivalent total neonicotinoids (IMI) and ∑NNI were 46.6 pg/mL and 26 pg/mL, respectively. Five out of nine lipid molecules exhibited higher levels, that were docosahexaenoic acid [FA(22:6)], 18:0 phosphocholine [LysoPC(18:0)], 18:0 phosphoethanolamine [LysoPE(18:0)], D18:1-18:0 sphingomyelin [SM(d18:1/18:0)], and 18:1-18:1 diglycerol [DG(18:1/18:1)], respectively. More interestingly, we observed statistically significant correlations (student's t-test, one-way ANOVA, or Mann-Whitney test; p < 0.05) between NNI levels and population characteristics (i.e. age, smoking, and health status). Beyond that, we also observed statistically significant correlations between levels of selected NNIs (CLO, ACE, or THI) and lipid molecules [LysoPE(18:0), SM(d18:1/18:0), and DG(18:1/18:1)]. Collectively, for the first time, we provided the information on contamination levels of NNIs in serum samples of general residents in China and demonstrated the associations between concentrations of NNIs and levels of lipid molecular species.
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http://dx.doi.org/10.1016/j.jhazmat.2021.125235DOI Listing
January 2021

GYY4137 alleviates sepsis-induced acute lung injury in mice by inhibiting the PDGFRβ/Akt/NF-κB/NLRP3 pathway.

Life Sci 2021 Apr 10;271:119192. Epub 2021 Feb 10.

Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address:

Aims: GYY4137 [GYY, morpholin-4-ium-4-methoxyphenyl (morpholino) phosphinodithioate] is a novel and perfect hydrogen sulfide (HS) donor that is stable in vivo and in vitro. HS, along with CO and NO, has been recognized as the third physiological gas signaling molecule that plays an active role in fighting various lung infections. However, the mechanism by which GYY4137 affects cecal ligation and puncture (CLP)-induced acute lung injury (ALI) is not understood. This study aimed to investigate whether GYY4137 inhibits the activation of the pyrin domain-containing protein 3 (NLRP3) inflammasome by inhibiting the PDGFRβ/Akt/NF-κB pathway.

Main Methods: The model of CLP-induced ALI was established in vivo. The mice were subsequently treated with GYY4137 (25 μg/g and 50 μg/g) to simulate the realistic conditions of pathogenesis. Western blotting and immunohistochemical staining were used to examine protein expression, hematoxylin and eosin staining was used for the histopathological analysis, and the levels of inflammatory factors were determined using enzyme-linked immunosorbent assays (ELISAs).

Key Findings: GYY4137 significantly increased the 7-day survival of mice with septic peritonitis and protected against CLP-induced ALI, including decreasing neutrophil infiltration, improving sepsis-induced lung histopathological changes, diminishing lung tissue damage, and attenuating the severity of lung injury in mice. The protective effect of GYY4137 was undoubtedly dose-dependent. We discovered that GYY4137 reduced the levels of the p-PDGFRβ, p-NF-κB, ASC, NLRP3, caspase-1, and p-Akt proteins in septic mouse lung tissue. Akt regulates the generation of proinflammatory cytokines in endotoxemia-associated ALI by enhancing the nuclear translocation of NF-κB.

Significance: These results indicate a new molecular mechanism explaining the effect of GYY4137 on the treatment of CLP-induced ALI in mice.
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http://dx.doi.org/10.1016/j.lfs.2021.119192DOI Listing
April 2021

The utility of diffusion-weighted imaging and ADC values in the characterization of mumps orchitis and seminoma.

Acta Radiol 2021 Feb 8:284185121991980. Epub 2021 Feb 8.

Department of Radiology, People's Hospital of Longhua District, The Affiliated Hospital of Southern Medical University, Shenzhen, China.

Background: Diffusion-weighted imaging (DWI) can quantitatively reflect the diffusion characteristics of tissues, providing a theoretical basis for qualitative diagnosis and quantitative analysis of a disease.

Purpose: To characterize testicular lesions that present as a hypointense signal on magnetic resonance imaging (MRI) T2-weighted images using DWI.

Material And Methods: Study participants were divided into three groups. Group A were healthy controls (n = 35), group B included patients with mumps orchitis (n = 20), and group C included patients with seminoma (n = 15). DWI sequences used b-values of 0, 1000, and 2000 s/mm. Apparent diffusion coefficient (ADC) values between 1000 and 2000 s/mm were calculated by MRI postprocessing software. The Kruskal-Wallis test and receiver operating characteristic analysis were performed to evaluate how well ADC values distinguished between mumps orchitis and seminoma.

Results: Normal testicular tissue showed a hyperintense signal on DWI and hypointensity on the ADC map: mean ADC value was 0.77 (0.69-0.85) ± 0.08 ×10 mm/s. Mumps orchitis and seminoma showed slight hyperintensity on DWI: mean ADC values were 0.85 (0.71-0.99) ± 0.15 ×10 mm/s and 0.43 (0.39-0.47) ± 0.04 × 10 mm/s, respectively. There were statistically significant differences in mean ADC values between normal testicular tissue and seminoma and between mumps orchitis and seminoma. The cutoff ADC value for differentiating seminoma from mumps orchitis was 0.54 × 10 mm/s. The sensitivity, specificity, and Youden Index for diagnosing seminoma were 99%, 31%, and 30%, respectively.

Conclusion: High b-value DWI has potential utility for differentiating mumps orchitis from seminoma in the clinical setting.
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http://dx.doi.org/10.1177/0284185121991980DOI Listing
February 2021

Liquid Crystal Monomers (LCMs) in Sediments: Method Validation and Detection in Sediment Samples from Three Typical Areas.

Environ Sci Technol 2021 Feb 2;55(4):2336-2345. Epub 2021 Feb 2.

School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing 210094, Jiangsu, China.

Liquid crystal monomers (LCMs) have been proposed to be persistent, bioaccumulative, and toxic (PBT) substances; however, there is a dearth of information regarding their occurrence in sediment samples. Here, an analytical method was developed for the quantitative determination of LCMs in sediment samples, and = 76 sediment samples were collected and analyzed to determine accurate concentrations of LCMs. Our results indicated that the developed pretreatment procedure was applicable for the determination of LCM concentrations in sediments. We observed that LCMs were detected in 75 out of the 76 sediment samples, and 23, 18, and 14 out of the 39 target LCMs were quantified in at least one of the analyzed sediments from rivers around LCM or liquid crystal device (LCD) manufacturers, Taihu Lake, and rivers around e-waste recycling sites, respectively. The LCMs in the samples from rivers around LCM/LCD manufacturers exhibited the greatest mean concentrations of 26.1 ng/g dry weight (dw), followed by those from e-waste recycling site areas (1.15 ng/g dw) and Taihu Lake (0.076 ng/g dw). Collectively, this study provided the first analytical method that was able to quantify the concentrations of LCMs in sediment samples and provided the first evidence for the occurrence of LCMs in sediment samples.
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http://dx.doi.org/10.1021/acs.est.0c06427DOI Listing
February 2021

Shengxian decoction decreases doxorubicin‑induced cardiac apoptosis by regulating the TREM1/NF‑κB signaling pathway.

Mol Med Rep 2021 Mar 26;23(3). Epub 2021 Jan 26.

Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P.R. China.

Shengxian decoction (SXT) is a traditional Chinese medicine that is clinically used for treating cardiovascular diseases. It is known for its beneficial effect on cardiomyocyte injuries, some of which can be induced by anticancer agents including doxorubicin (DOX). To determine the molecular mechanisms involved in the cardioprotective effects of SXT, DOX‑induced H9c2 cells were analyzed for apoptosis and expression levels of apoptosis biomarkers. Cell viability and apoptosis were measured by CCK‑8 and flow cytometry. Triggering receptors expressed on myeloid cells 1 (TREM1), cleaved caspase‑3, survivin and NF‑κBp65 expression levels were measured by reverse transcription‑quantitative PCR and/or western blotting. A total of 30 adult male Sprague‑Dawley rats were randomly allocated into five groups (n=6 each); control group receiving 0.9% saline, 1 DOX group receiving 2.5 mg/kg of DOX and 3 DOX + SXT groups, receiving a DOX dose equivalent to the DOX‑only group and either 0.4, 0.8 or 1.6 g/kg of SXT. It was found that DOX increased apoptosis and NF‑κB activation of H9c2 cells by increasing TREM1 expression and that SXT inhibited apoptosis and NF‑κB activation of H9c2 cells induced by DOX or overexpression. SXT also significantly reversed DOX‑induced cardiotoxicity in rats. The results suggested that the protective effects of SXT against DOX‑induced apoptosis may be attributed to its downregulation of TREM1.
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http://dx.doi.org/10.3892/mmr.2021.11858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845587PMC
March 2021

Advancing Versatile Ferroelectric Materials Toward Biomedical Applications.

Adv Sci (Weinh) 2020 Jan 3;8(1):2003074. Epub 2020 Dec 3.

Department of Biomaterials, School and Hospital of Stomatology, Cheeloo College of Medicine Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration Jinan 250012 China.

Ferroelectric materials (FEMs), possessing piezoelectric, pyroelectric, inverse piezoelectric, nonlinear optic, ferroelectric-photovoltaic, and many other properties, are attracting increasing attention in the field of biomedicine in recent years. Because of their versatile ability of interacting with force, heat, electricity, and light to generate electrical, mechanical, and optical signals, FEMs are demonstrating their unique advantages for biosensing, acoustics tweezer, bioimaging, therapeutics, tissue engineering, as well as stimulating biological functions. This review summarizes the current-available FEMs and their state-of-the-art fabrication techniques, as well as provides an overview of FEMs-based applications in the field of biomedicine. Challenges and prospects for future development of FEMs for biomedical applications are also outlined.
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http://dx.doi.org/10.1002/advs.202003074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788502PMC
January 2020

Apparent diffusion coefficient values of cryptorchid testes and malignant transformation of cryptorchidism (MTC) (seminoma) in postpubertal patients.

Br J Radiol 2021 Mar 7;94(1119):20200624. Epub 2021 Jan 7.

Department of Radiology, The People's Hospital of Longhua, The Affiliated Hospital of Southern Medical University, Shenzhen 518109, China.

Objectives: Diffusion-weighted imaging signal contrast can be quantified by apparent diffusion coefficient (ADC) maps, which reflect the diffusion properties of the examined tissue and are helpful for identifying pathology. To determine ADC values of cryptorchid testes in post-pubertal patients and assess performance for characterizing cryptorchid testes.

Methods: The medical records from 35 patients with unilateral scrotal vacuity were retrospectively reviewed. Data were analyzed in three groups: Group A, normal testes ( the contralateral testes of the patients with cryptorchidism or MTC); Group B, cryptorchid testes; and Group C, malignant transformation of cryptorchidism (MTC) (seminoma). DWI used b-values of 0 and 800 s/mm. Mean ADC values were compared using the independent samples -test. The ability of ADC values was assessed using receiver operating characteristic curve analysis. The sensitivity, specificity, and accuracy were calculated.

Results: Mean ADC values for normal testes, cryptorchid testes, and MTC were 1.18 ± 0.18×10 mm/s, 1.82 ± 0.40×10 mm/s, and 0.80 ± 0.06×10 mm/s, respectively. There were statistically significant differences in mean ADC values between normal testes and cryptorchid testes or MTC ( < 0.001). The cut-off ADC value for differentiating normal testes from cryptorchid testes was 1.47 × 10 mm/s. The sensitivity, specificity, and accuracy were 88%, 91%, and 90%, respectively. The cut-off ADC value for differentiating normal testes from MTC was 1.22 × 10 mm/s. The sensitivity, specificity, and accuracy were 100%, 31%, and 43%, respectively.

Conclusion: ADC values of cryptorchid testes may be used to inform clinical decision-making and also monitor testicular function in patients who retain undescended testicles or post-operatively.

Advances In Knowledge: Mean ADC values of cryptorchidism and MTC (seminoma) were used to reflect their pathological features.
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http://dx.doi.org/10.1259/bjr.20200624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011245PMC
March 2021

Multimodal imaging of a rare interventricular septum dissecting aneurysm: A case report.

J Clin Ultrasound 2021 Jan 5. Epub 2021 Jan 5.

Department of Ultrasound, Yanan Hospital of Kunming City, The Affiliated Hospital of Kunming Medical University, Kunming, China.

We report the case of a patient who presented with chest pain and palpitation, and in whom multimodality imaging, including transthoracic echocardiography, computer tomography angiogram, and coronary angiogram led to the diagnosis of interventricular septum dissecting aneurysm resulting from the rupture of a sinus of Valsalva aneurysm and paravalvular aortic root pseudoaneurysm. The patient underwent the modified Cabrol procedure in the cardiac surgery department. His ruptured sinus of Valsalva aneurysm was repaired and its communication with the pseudoaneurysm was closed. This case report highlights the role of multimodality cardiac imaging.
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http://dx.doi.org/10.1002/jcu.22972DOI Listing
January 2021

Defect-Assisted Loading and Docking Conformations of Pharmaceuticals in Metal-Organic Frameworks.

Angew Chem Int Ed Engl 2021 03 25;60(14):7719-7727. Epub 2021 Feb 25.

Center for Chemistry of High-Performance and Novel Materials, Department of Chemistry, Zhejiang University, Hangzhou, 310027, P. R. China.

Understanding of drug-carrier interactions is essential for the design and application of metal-organic framework (MOF)-based drug-delivery systems, and such drug-carrier interactions can be fundamentally different for MOFs with or without defects. Herein, we reveal that the defects in MOFs play a key role in the loading of many pharmaceuticals with phosphate or phosphonate groups. The host-guest interaction is dominated by the Coulombic attraction between phosphate/phosphonate groups and defect sites, and it strongly enhances the loading capacity. For similar molecules without a phosphate/phosphonate group or for MOFs without defects, the loading capacity is greatly reduced. We employed solid-state NMR spectroscopy and molecular simulations to elucidate the drug-carrier interaction mechanisms. Through a synergistic combination of experimental and theoretical analyses, the docking conformations of pharmaceuticals at the defects were revealed.
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http://dx.doi.org/10.1002/anie.202010231DOI Listing
March 2021

Sympathetic Nerve Control of Blood Pressure Response during Exercise in Peripheral Artery Disease and Current Application of Experimental Disease Models.

Authors:
Lu Qin Jianhua Li

Am J Biomed Sci Res 2020 25;9(3):204-209. Epub 2020 Jun 25.

Heart & Vascular Institute, The Penn State University College of Medicine, US.

In patients with peripheral artery disease (PAD), the blood supply directed to the lower limbs is reduced. This results in severe limb ischemia and thereby intermittent claudicating which is characterized by pain in lower limbs that occurs with walking and is relieved by rest. Of note, PAD can extremely affect the quality of living of patients and increase high risk of coronary and cerebral vascular accidents. However, effective treatments of PAD are still challenging in clinics. A number of reports have demonstrated the beneficial effects of supervised exercise on symptoms of PAD patients. This review will summarize results obtained from recent human and animal studies, which include the abnormalities in sympathetic control of blood pressure response during exercise in PAD, and rationality of animal models used for study human PAD. Nonetheless, additional in-depth studies are necessary to better explore the underlying mechanisms of the exaggerated responses of sympathetic nerve and blood pressure in PAD at molecular and cellular levels.
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http://dx.doi.org/10.34297/AJBSR.2020.09.001387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774331PMC
June 2020

Hypoxic exposure activates the B cell-specific Moloney murine leukaemia virus integration site 1/PI3K/Akt axis and promotes EMT in leukaemia stem cells.

Oncol Lett 2021 Feb 8;21(2):98. Epub 2020 Dec 8.

Department of Pediatric Hematology and Oncology, West China Second University Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China.

Acute myeloid leukemia (AML) is a malignant tumor of the immature myeloid hematopoietic cells in the bone marrow. Disease recurrence driven by leukaemia stem cells (LSCs), a sub-population of leukaemia cells presenting self-renewal capacity and differentiation potential, is a major problem in the treatment of AML. Although a hypoxic microenvironment is considered to promote AML malignant behaviours and is considered a potential therapeutic target, the effect of hypoxic stimulation of LSCs is still largely unknown. Therefore, the present study analysed the effects of hypoxia on the malignant behaviours of LSCs. Hypoxia exposure upregulated hypoxia-inducible factor (HIF)-1α, which upregulated the transcription of B cell-specific Moloney murine leukaemia virus integration site 1 (BMI-1). Hypoxia exposure also activated the PI3K/Akt pathway and promoted the epithelial mesenchymal transition (EMT) in LSCs via hypoxia-mediated activation of HIF-1α. BMI-1 served an important role in the hypoxia-induced activation of the PI3K/Akt pathway and the promotion of EMT. Hypoxia exposure promoted chemoresistance against cytarabine arabinoside by inducing HIF-1α, thus activating the transcriptional activity of HIF-1α. Knockdown of BMI-1 disrupted hypoxia-induced chemoresistance in LSCs, indicating that HIF-1α-induced BMI-1 has a role in hypoxia-promoted malignant behaviours. Furthermore, it was demonstrated that induced BMI-1 inhibits the self-renewal capacity in LSCs under hypoxic conditions. The present study provides evidence demonstrating that hypoxia exposure regulates LSCs by activating HIF-1α/BMI-1 signalling, in turn modulating PI3K/Akt signalling and EMT. These results highlight potentially novel therapeutic targets of LSCs to improve the treatment of AML.
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http://dx.doi.org/10.3892/ol.2020.12359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751341PMC
February 2021

Burden and risk factors for inappropriate Clostridioides Difficile infection testing among hospitalized patients.

Diagn Microbiol Infect Dis 2021 Apr 5;99(4):115283. Epub 2020 Dec 5.

Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY, USA.

Background: The purpose of this study was to identify the burden and risk factors for inappropriate Clostridioides difficile infection (CDI) testing.

Methods: This was a retrospective cohort study among adults hospitalized between 2010 and 2019. Inappropriate CDI testing was defined as a formed stool specimen, an order within 7 days of a previously negative test, or an order within 24 hours of laxative administration.

Results: A total of 51,302 CDI orders were placed for 29,840 unique patients. 59% were appropriate and 41% were inappropriate. An additional 24% of the appropriate orders never resulted. Risk factors for inappropriate testing included orders placed by a nurse practitioner, orders placed by high-ordering providers, specific hospital units, fever, and leukocytosis.

Conclusions: Nearly half of all CDI orders were inappropriate among hospitalized patients, and an additional 24% of test results never returned. Provider- and patient-level risk factors included type of provider, specific hospital units, and signs of sepsis.
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http://dx.doi.org/10.1016/j.diagmicrobio.2020.115283DOI Listing
April 2021