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1.
Artigo em Inglês | MEDLINE | ID: mdl-33010011

RESUMO

The MIL-53(Al)-NH2 was designed to remove fluoride with hierarchical hollow morphology. It was used as an adsorbent for fluoride removal at a wide pH range (1-12) due to the positive zeta potential of MIL-53(Al)-NH2. The pH did not significantly influence the fluoride adsorption into MIL-53(Al)-NH2. However, the adsorbent indicated good adsorption capacity with maximum adsorption of 1070.6 mg g-1. Different adsorption kinetic and thermodynamic models were investigated for MIL-53(Al)-NH2. The adsorption of fluoride into MIL-53(Al)-NH2 followed the pseudo-second-order model and a well-fitted Langmuir model indicating chemical and monolayer adsorption process. When mass transfer model was used at initial concentrations of 100 ppm and 1000 ppm, the rates of conversion were 8.4 × 10-8 and 4.7 × 10-8 m s-1. Moreover, anions such as [Formula: see text], [Formula: see text], [Formula: see text], Cl-, and Br- also had less effect on the adsorption of fluoride. Also, experimental and theoretical calculations on adsorption mechanism of MIL-53(Al)-NH2 revealed that the material had good stability and regenerative capacity using alum as regenerant. In a nutshell, the dominant crystal face (1 0 1) and adsorption sites Al, O, and N combined well with F-, HF, and HF2- through density functional theory. It opens a good way of designing hollow MOFs for adsorbing contaminants in wastewater.

2.
J Clin Nurs ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33031590

RESUMO

AIM: To identify determinants of family cohesion and adaptability among Chinese registered nurses. BACKGROUND: In China, the shortage of registered nurses imposes a higher physical and emotional workload, which will aggravate their work-family conflicts. Therefore, it is easy for nurses to ignore the importance of family, which is undeniably detrimental to healthy self-development and providing better care to patients. DESIGN: ith a cross-sectional and observational study design (See the STROBE checklist and Supplementary File 1). METHODS: The Family Cohesion and Adaptability Scale was administered to registered nurses (N = 825) from 10 hospitals throughout China. Multiple linear regression was used to analyze the related factors for family cohesion and adaptability. RESULTS: The multiple regression analysis revealed that inharmonious relationship with spouse's parents, discordant nurse-patient relationship, parents live in countryside, poor leadership were found to be important risk predictors of family cohesion, and inharmonious relationship with spouse's parents, discordant nurse-patient relationship, high education, feel overworked, poor leadership were found to be important risk predictors of family adaptability. CONCLUSION: Hospital managers need to pay attention to the risk factors that affect nurses' family cohesion and adaptability. To achieve this, they should employ targeted measures to enhance these aspects in time, which will help improve nurses' family life and promote their participation and role in family decision-making. This will not only help them create a better external environment for their healthy self-development but also allow them to maintain a better mood and energy to take care of patients. RELEVANCE TO CLINICAL PRACTICE: Family cohesion and adaptability are important for nurses, as they may affect nurses' healthy self-development and quality of service provided to patients. Hospital managers should pay attention to the risk factors of nurses' family cohesion and adaptability, such as poor nurse-patient relationship, and consider employing corresponding measures to help them.

3.
BMC Gastroenterol ; 20(1): 343, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33059614

RESUMO

BACKGROUND: The significance of human epidermal growth factor receptor 2 (Her2) and nucleus-associated antigen Ki-67 expression remains controversial in gastric adenocarcinoma (GaC). The aim of this study was to investigate the expression and clinicopathologic and prognostic significance of Her2 and Ki-67 in resected GaC without distant metastasis. METHODS: Malignant tissues and clinicopathologic data were obtained from 195 patients with resected non-metastatic GaC. Immunohistochemistry staining was performed to examine the expression of Her2 and Ki-67; their association with clinicopathologic factors were investigated using logistic regression, and their association with survival was explored using Kaplan-Meier analysis and Cox proportional hazards regression. RESULTS: Her2 was majorly expressed in cell membrane and Ki-67 in cell nucleus in non-metastatic GaC. Stronger Her2 expression was significantly associated with better tumor differentiation, neurovascular invasion, less advanced pathological tumor (pT) stage, and more advanced pathological node (pN) stage; while Ki-67 expression was not significantly associated with any investigated clinicopathologic factors. Patients with both negative Her2 and negative Ki-67 expression had poorer tumor differentiation, and more advanced pT and pathological tumor-node-metastasis (pTNM) stages; the association with pT and pTNM stages were further confirmed by multivariable analyses, especially in node-negative disease. Her2 or Ki-67 alone was not significantly associated with pTNM stage. A strongly positive (+++) Her2 expression was associated with poorer survival in multivariable analysis only (P = 0.047); while Ki-67 or combined expression was not significantly associated with prognosis. CONCLUSIONS: In non-metastatic GaC, Her2 expression and combined expression of Her2 and Ki-67 were associated with several clinicopathologic factors including tumor differentiation and stage, and only a +++ Her2 expression was associated with poorer prognosis in multivariable analysis with marginal significance in this study; while Ki-67 alone had both limited clinicopathologic and prognostic values.

4.
Biomed Res Int ; 2020: 2918517, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33062675

RESUMO

The interleukin- (IL-) 33/ST2 axis plays a pivotal role in tumorigenesis through influencing cancer stemness and other mechanisms. CD44 is one of the critical markers of hepatocellular carcinoma (HCC) among the cancer stem cells (CSCs). There is still a lack of CD44 gene single-nucleotide polymorphisms (SNPs) combined with IL-33/ST2 pathway single-nucleotide polymorphisms in HCC susceptibility analysis literature, although CD44 and IL-33/ST2 have been reported separately in human cancers. This study is aimed at investigating the relationship between CD44, IL-33, and ST2 SNPs and HCC susceptibility and clinicopathological features. We analyzed 565 HCC patients and 561 healthy controls in the Chinese population. The genes for CD44rs187115A>G, IL-33 rs1929992A>G, and ST2 rs3821204G>C were typed using the SNaPshot method. We found that the distribution frequencies of CD44 and ST2 alleles and genotypes in both the HCC case group and the control group were statistically significant (p < 0.05). The results showed that individuals carrying at least one G allele of the CD44 rs187115 gene were at a higher risk than the AA genotype carriers (p = 0.007, odds ratio (OR) = 1.429, 95% confidence interval (CI): 1.102-1.854). Similarly, individuals with at least one C allele of ST2 rs3821204 had a higher risk of HCC than those with GG genes (p ≤ 0.001, OR = 1.647, 95% CI: 1.296-2.093). Combining the haplotype analysis of the 3 loci suggested that CD44 rs187115, IL-33 rs1929992, and ST2 rs3821204 are associated with the risk of HCC and could potentially serve as useful genetic markers for HCC in some populations of China.

6.
Psychol Health Med ; : 1-6, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33080151

RESUMO

Medical staff in radiology departments faces a higher risk of infection and a heavier workload during the new coronavirus disease (COVID-19) outbreak. High perceived stress levels endanger physical and mental health and affect work efficiency and patient safety. Therefore, it is urgent to understand the perceived stress levels of medical staff and explore its risk factors. We recruited 600 medical staff from the radiology departments of 32 public hospitals in Sichuan Province, China, to evaluate perceived stress scores via a mobile app-based questionnaire. The results showed that the perceived stress level among medical staff in the radiology departments during the COVID-19 outbreak was high and a sense of tension was strongly present. A positive correlation was found between anxiety score and perceived stress. Multivariate analysis showed that risk factors for perceived stress were female, existing anxiety, and fears of being infected at work, an uncontrollable outbreak, and not being able to pay rent or mortgage. Conversely, good knowledge about COVID-19, being unmarried, and working in a higher-grade hospital were protective factors for perceived stress. Therefore, more attention should be given to medical staff in the radiology departments that present the risk factors outlined above. Timely risk assessment of psychological stress and effective intervention measures should be taken for these high-risk groups to keep their perceived stress within normal limits.

7.
World J Clin Cases ; 8(19): 4572-4578, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33083420

RESUMO

BACKGROUND: Squamous cell carcinoma antigen (SCCA) is regarded as a specific indicator of epithelial malignancies and is widely used in the diagnosis of squamous cell carcinoma (SCC). However, the expression of SCCA in gastric adenocarcinoma has not been studied in detail. CASE SUMMARY: A 52-year-old man was admitted to our hospital for a 2.5 cm × 2.5 cm ulcer at the antrum-body junction with dull pain and fullness in the upper abdomen for 2 mo. His pre-surgery serological testing results showed 0.51 ng/mL SCCA (reference interval, < 1.5 ng/mL) and 9.9 ng/mL carcinoembryonic antigen (reference range, < 4.7 ng/mL). He underwent radical distal gastrectomy and Roux-en Y anastomosis and was diagnosed with poorly differentiated mucinous adenocarcinoma (Lauren classification: Diffuse) by pathological examination of the resected lesion. Immunohistochemistry showed that SCCA was highly expressed in the cytoplasm of cancer cells. After surgery, the patient received an S-1 adjuvant chemotherapy regimen for six cycles containing tegafur, gimeracil, and oteracil potassium. He showed no sign of recurrence or metastasis within 24-mo follow-up. CONCLUSION: This is a frontal report of SCCA overexpression in poorly differentiated adenocarcinoma of the stomach.

8.
BMC Health Serv Res ; 20(1): 965, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087121

RESUMO

BACKGROUND: High burnout has been reported in physician populations. Although the standardized residency training (SRT) in China includes components that might put residents at a higher risk for burnout, the burnout of Chinese medical residents is unknown. This study aimed to evaluate the prevalence of burnout and the associated risk and protective factors for medical residents in the SRT program in Shanghai, China. METHODS: This study was a prospective cross-sectional design. A random sampling strategy was used to recruit 330 resident physicians from four SRT sites in Shanghai, and 318 completed questionnaires were returned. Respondents completed a self-made questionnaire including demographic and work characteristics, four burnout and wellness-specific surveys. Bivariate analyses and hierarchical multiple regression models were used to analyze factors associated with three sub-scales of burn out separately. RESULTS: The overall burnout rate was 71.4%. Low level rate of personal accomplishment (PA) was extremely high at 69.5%. Night shift experience, high occupational stress, and low social support were significant predictors, which explained 49.1% variance of emotional exhaustion (EE) (F = 26.528, P < 0.01). Factors that significantly predicted depersonalization (DP) included male gender, senior residents, night shift experience, high occupational stress, and low psychological empathy, which explained 51.5% variance totally (F = 29.004, P < 0.01). Senior residents, high income, low occupational stress, and high empathy were also significant predictors of decreased personal achievement (PA), which explained 18.4% variance totally (F = 12.897, P < 0.01). CONCLUSIONS: There was a high burnout rate among SRT residents in Shanghai. Occupational stress and several work-related factors were significant and strong risk factors for burnout, while empathy and social support were mild protective factors. Decreased work-related demands and increased access to resources could assist residents in reducing their work stress and improving their well-being.

9.
Sci Rep ; 10(1): 17617, 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33077783

RESUMO

Heterologous expression is the main approach for recombinant protein production ingenetic synthesis, for which codon optimization is necessary. The existing optimization methods are based on biological indexes. In this paper, we propose a novel codon optimization method based on deep learning. First, we introduce the concept of codon boxes, via which DNA sequences can be recoded into codon box sequences while ignoring the order of bases. Then, the problem of codon optimization can be converted to sequence annotation of corresponding amino acids with codon boxes. The codon optimization models for Escherichia Coli were trained by the Bidirectional Long-Short-Term Memory Conditional Random Field. Theoretically, deep learning is a good method to obtain the distribution characteristics of DNA. In addition to the comparison of the codon adaptation index, protein expression experiments for plasmodium falciparum candidate vaccine and polymerase acidic protein were implemented for comparison with the original sequences and the optimized sequences from Genewiz and ThermoFisher. The results show that our method for enhancing protein expression is efficient and competitive.

10.
Ann Clin Microbiol Antimicrob ; 19(1): 46, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33032608

RESUMO

BACKGROUND: Infections were the primary cause of death (34.3-55.5%) in patients with pemphigus. Skin was usually the origin of infections. The study aimed to explore features and associated factors of bacterial skin infections (BSIs) in inpatients with pemphigus. METHODS: One hundred and seventy-seven inpatients with pemphigus hospitalizing from November 2014 to April 2019 were continuously recruited through Peking University First Hospital's inpatient records inpatients with pemphigus hospitalizing from November 2014 to April 2019 were continuously recruited through Peking University First Hospital's inpatient records. Then, we retrieved the clinical and laboratory data to explore the characteristics and associated factors of BSIs. RESULTS: Of patients enrolled, pemphigus vulgaris (PV, n = 142) and pemphigus foliaceus (PF, n = 9) were most common, followed by pemphigus erythematosus (PE, n = 25) and pemphigus vegetans (Pveg, n = 1). Eighty-seven of 177 (49.2%) inpatients developed BSIs, and they had a longer length of stay compared with inpatients without BSIs (median: 18.9 vs. 14.1 days, p = 0.008). Staphylococcus aureus was the most common bacteria (71.3%, 62/87) and highly resistant to penicillin (91.9%, 57/62). Higher levels of anti-Dsg1 autoantibodies (> 124.2 U/mL) (p < 0.001, odds ratio [OR] = 3.564, 95% confidence interval [CI]: 1.784-7.123) and anti-Dsg3 autoantibodies (> 169.5 U/mL) (p = 0.03, OR = 2.074, 95% CI: 1.084-3.969) were underlying risk factors of BSIs when analyzed by binary regression analysis. As for Gram's stain of bacteria, females had a lower rate of Gram-positive infections (p = 0.03). Patients using oral antibiotics (p = 0.05) had a higher rate of Gram-negative infections. Inpatients who were hospitalized in other hospitals within 2 weeks before the current admission had a higher rate of Gram-negative and co-infections (p = 0.03). CONCLUSIONS: Inpatients with pemphigus had a high incidence of BSIs. Some factors were associated with the susceptibility of BSIs and bacterial species.

11.
Viruses ; 12(10)2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33050303

RESUMO

The integrins function as the primary receptor molecules for the pathogenic infection of foot-and-mouth disease virus (FMDV) in vivo, while the acquisition of a high affinity for heparan sulfate (HS) of some FMDV variants could be privileged to facilitate viral infection and expanded cell tropism in vitro. Here, we noted that a BHK-adapted Cathay topotype derivative (O/HN/CHA/93tc) but not its genetically engineered virus (rHN), was able to infect HS-positive CHO-K1 cells and mutant pgsD-677 cells. There were one or three residue changes in the capsid proteins of O/HN/CHA/93tc and rHN, as compared with that of their tissue-originated isolate (O/HN/CHA/93wt). The phenotypic properties of a set of site-directed mutants of rHN revealed that E83K of VP1 surrounding the fivefold symmetry axis was necessary for the integrin-independent infection of O/HN/CHA/93tc. L80 in VP2 was essential for the occurrence of E83K in VP1 during the adaptation of O/HN/CHA/93wt to BHK-21 cells. L80M in VP2 and D138G in VP1 of rHN was deleterious, which could be compensated by K83R of VP1 for restoring an efficient infection of integrin-negative CHO cell lines. These might have important implications for understanding the molecular and evolutionary mechanisms of the recognition and binding of FMDV with alternative cellular receptors.

12.
Nat Commun ; 11(1): 5033, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024092

RESUMO

Soaring cases of coronavirus disease (COVID-19) are pummeling the global health system. Overwhelmed health facilities have endeavored to mitigate the pandemic, but mortality of COVID-19 continues to increase. Here, we present a mortality risk prediction model for COVID-19 (MRPMC) that uses patients' clinical data on admission to stratify patients by mortality risk, which enables prediction of physiological deterioration and death up to 20 days in advance. This ensemble model is built using four machine learning methods including Logistic Regression, Support Vector Machine, Gradient Boosted Decision Tree, and Neural Network. We validate MRPMC in an internal validation cohort and two external validation cohorts, where it achieves an AUC of 0.9621 (95% CI: 0.9464-0.9778), 0.9760 (0.9613-0.9906), and 0.9246 (0.8763-0.9729), respectively. This model enables expeditious and accurate mortality risk stratification of patients with COVID-19, and potentially facilitates more responsive health systems that are conducive to high risk COVID-19 patients.


Assuntos
Infecções por Coronavirus/mortalidade , Aprendizado de Máquina , Pandemias , Pneumonia Viral/mortalidade , Idoso , Betacoronavirus , China/epidemiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Redes Neurais de Computação , Medição de Risco , Máquina de Vetores de Suporte
13.
Risk Anal ; 2020 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-33073419

RESUMO

The ubiquitous presence of more than 80,000 chemicals in thousands of consumer products used on a daily basis stresses the need for screening a broader set of chemicals than the traditional well-studied suspect chemicals. This high-throughput screening combines stochastic chemical-product usage with mass balance-based exposure models and toxicity data to prioritize risks associated with household products. We first characterize product usage using the stochastic SHEDS-HT model and chemical content in common household products from the CPDat database, the chemical amounts applied daily varying over more than six orders of magnitude, from mg to kg. We then estimate multi-pathways near- and far-field exposures for 5,500 chemical-product combinations, applying an extended USEtox model to calculate product intake fractions ranging from 0.001 to ∼1, and exposure doses varying over more than nine orders of magnitude. Combining exposure doses with chemical-specific dose-responses and reference doses shows that risks can be substantial for multiple home maintenance products, such as paints or paint strippers, for some home-applied pesticides, leave-on personal care products, and cleaning products. Sixty percent of the chemical-product combinations have hazard quotients exceeding 1, and 9% of the combinations have lifetime cancer risks exceeding 10-4 . Population-level impacts of household products ingredients can be substantial, representing 5 to 100 minutes of healthy life lost per day, with users' exposures up to 103 minutes per day. To address this issue, present mass balance-based models are already able to provide exposure estimates for both users and populations. This screening study shows large variations of up to 10 orders of magnitude in impact across both chemicals and product combinations, demonstrating that prioritization based on hazard only is not acceptable, since it would neglect orders of magnitude variations in both product usage and exposure that need to be quantified. To address this, the USEtox suite of mass balance-based models is already able to provide exposure estimates for thousands of product-chemical combinations for both users and populations. The present study calls for more scrutiny of most impacting chemical-product combinations, fully ensuring from a regulatory perspective consumer product safety for high-end users and using protective measures for users.

14.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(8): 941-947, 2020 Aug 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33053536

RESUMO

OBJECTIVES: To compare the clinical effect of low molecular weight heparin (LMWH) and regional citrate anticoagulation (RCA) in continuous renal replacement therapy (CRRT) after heart valve replacement. METHODS: Retrospective analysis of clinical data from 60 patients undergoing continuous renal replacement therapy after heart valve replacement in Peking University Shenzhen Hospital from January 2015 to July 2019, including 35 males and 25 females, aged (58.83 ±16.36) years. The patients were divided into a LMWH group and a RCA group according to the anticoagulation regimen, with 30 patients in each group. The 24 h postoperative drainage volume (pericardium, mediastinum), postoperative ventilator use time and ICU stay time, incidence of postoperative respiratory tract bleeding and gastrointestinal bleeding, postoperative skin ecchymosis incidence and mortality between the 2 groups were compared; the thromboplastin time (APTT), fibrinogen (FIB), thrombin time (TT), prothrombin time (PT), international normalized ratio (INR), and PLT between the 2 groups after anticoagulation treatment were compared; the service life of dialysis filters and CRRT time between the 2 groups were compared; and the levels of urea nitrogen and serum creatinine between the 2 groups before and after treatment were also compared. RESULTS: After anticoagulant treatment, the RCA group had less 24 h postoperative drainage volume than the LMWH group, shorter ventilator use time, ICU stay time, and hospitalization days than the LMWH group, and lower respiratory tract bleeding and gastrointestinal bleeding incidence than the LMWH group, with significant differences (all P<0.05); there was no significant difference in the incidence of skin ecchymosis and mortality after treatment between the 2 groups (all P>0.05); there was no significant difference in APTT, FIB, and TT between the 2 groups (all P>0.05); the PT and INR of the RCA group were higher than those in the LMWH group, while the PLT of RCA group was lower than that in the LMWH group, with significant differences (all P<0.05); there was no significant difference in CRRT time between the two groups (P=0.073). After the treatment, there were no significant differences in urea nitrogen and serum creatinine levels between the 2 groups (all P>0.05). CONCLUSIONS: CRRT after cardiac valve replacement with RCA can effectively reduce pericardial and mediastinal drainage, reduce the risk of bleeding, shorten the time of ventilator use and ICU stay, and promote postoperative recovery of patients, which have positive significance for reducing the burden on patients and their families.


Assuntos
Terapia de Substituição Renal Contínua , Heparina de Baixo Peso Molecular , Adulto , Idoso , Anticoagulantes/uso terapêutico , Feminino , Valvas Cardíacas , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Substituição Renal , Estudos Retrospectivos
15.
Clin Cancer Res ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028595

RESUMO

PURPOSE: Multi-site stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) has demonstrated safety in advanced solid tumors (AST). However, no studies have examined the relationships between irradiated tumor response, SBRT-induced tumor gene expression, and overall survival (OS). EXPERIMENTAL DESIGN: Patients with AST received SBRT (30-50 Gy in 3-5 fractions) to 2-4 metastases followed by pembrolizumab (200mg IV every 3 weeks). SBRT was prescribed to a maximum tumor volume of 65cc. Small metastases received the complete prescribed coverage (complete-Rx), while larger metastases received partial-coverage (partial-Rx). Treated metastasis control (TMC) was defined as a lack of progression for an irradiated metastasis. Landmark analysis was used to assess the relationship between TMC and OS. Thirty-five biopsies were obtained from 24 patients: 19 pre-SBRT and 16 post-SBRT (11-matched) prior to pembrolizumab and were analyzed via RNA microarray. RESULTS: 68 patients (139 metastases) were enrolled with a median follow-up of 10.4 months. One-year TMC was 89.5% with no difference between complete-Rx or partial-Rx. On MVA, TMC was independently associated with a reduced risk for death (hazard ratio, 0.36; 95% CI, 0.17-0.75; P=0.006). SBRT increased expression of innate and adaptive immune genes and concomitantly decreased expression of cell cycle and DNA repair genes in the irradiated tumors. Elevated post-SBRT expression of DNASE1 correlated with increased expression of cytolytic T cell genes and irradiated tumor response. CONCLUSIONS: In the context of SBRT+P, TMC independently correlates with OS. SBRT impacts intratumoral immune gene expression associated with TMC. Randomized trials are needed to validate these findings.

16.
Neurotherapeutics ; 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32918234

RESUMO

Brain edema is a vital contributor to early brain injury after subarachnoid hemorrhage (SAH), which is responsible for prolonged hospitalization and poor outcomes. Pharmacological therapeutic targets on edema formation have been the focus of research for decades. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to participate in neural development and brain injury. Here, we used PACAP knockout CRISPR to demonstrate that endogenous PACAP plays an endogenous neuroprotective role against brain edema formation after SAH in rats. The exogenous PACAP treatment provided both short- and long-term neurological benefits by preserving the function of the blood-brain barrier and glymphatic system after SAH. Pretreatment of inhibitors of PACAP receptors showed that the PACAP-involved anti-edema effect and neuroprotection after SAH was facilitated by the selective PACAP receptor (PAC1). Further administration of adenylyl cyclase (AC) inhibitor and sulfonylurea receptor 1 (SUR1) CRISPR activator suggested that the AC-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) axis participated in PACAP signaling after SAH, which inhibited the expression of edema-related proteins, SUR1 and aquaporin-4 (AQP4), through SUR1 phosphorylation. Thus, PACAP may serve as a potential clinical treatment to alleviate brain edema in patients with SAH.

17.
J Infect Dev Ctries ; 14(8): 908-917, 2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32903236

RESUMO

INTRODUCTION: Hypocalcemia has been widely recognized in sepsis patients. However, the cause of hypocalcemia in sepsis is still not clear, and little is known about the subcellular distribution of Ca2+ in tissues during sepsis. METHODOLOGY: We measured the dynamic change in Ca2+ levels in body fluid and subcellular compartments, including the cytosol, endoplasmic reticulum and mitochondria, in major organs of cecal ligation and puncture (CLP)-operated rats, as well as the subcellular Ca2+ flux in HUVECs which treated by endotoxin and cytokines. RESULTS: In the model of CLP-induced sepsis, the blood and urinary Ca2+ concentrations decreased rapidly, while the Ca2+ concentration in ascites fluid increased. The Ca2+ concentrations in the cytosol, ER, and mitochondria were elevated nearly synchronously in major organs in our sepsis model. Moreover, the calcium overload in CLP-operated rats treated with calcium supplementation was more severe than that in the non-calcium-supplemented rats but was alleviated by treatment with the calcium channel blocker verapamil. Similar subcellular Ca2+ flux was found in vitro in HUVECs and was triggered by lipopolysaccharide (LPS)/TNF-α. CONCLUSIONS: Ca2+ influx from the blood into the intercellular space and Ca2+ release into ascites fluid may cause hypocalcemia in sepsis and that this process may be due to the synergistic effect of endotoxin and cytokines.

18.
Cell Death Differ ; 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929219

RESUMO

Clinical response to immunotherapy is closely associated with the immunosuppressive tumour microenvironment (TME), and influenced by the dynamic interaction between tumour cells and lymphatic endothelial cells (LECs). Here, we show that high levels of miR-142-5p positively correlate with indoleamine 2,3-dioxygenase (IDO) expression in tumour-associated lymphatic vessels in advanced cervical squamous cell carcinoma (CSCC). The miR-142-5p is transferred by CSCC-secreted exosomes into LECs to exhaust CD8+ T cells via the up-regulation of lymphatic IDO expression, which was abrogated by an IDO inhibitor. Mechanistically, miR-142-5p directly down-regulates lymphatic AT-rich interactive domain-containing protein 2 (ARID2) expression, inhibits DNA methyltransferase 1 (DNMT1) recruitment to interferon (IFN)-γ promoter, and enhances IFN-γ transcription by suppressing promoter methylation, thereby leading to elevated IDO activity. Furthermore, increased serum exosomal miR-142-5p levels and the consequent IDO activity positively correlate with CSCC progression. In conclusion, exosomes secreted by CSCC cells deliver miR-142-5p to LECs and induce IDO expression via ARID2-DNMT1-IFN-γ signalling to suppress and exhaust CD8+ T cells. Our study suggests that LECs act as an integral component of the immune checkpoint(s) in the TME and may serve as a potential new target for CSCC diagnosis and treatment.

19.
Drug Des Devel Ther ; 14: 3201-3214, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32982167

RESUMO

Introduction: Overexpression of c-Met, or hepatocyte growth factor (HGF) receptor, is commonly observed in tumor biopsies and often associated with poor patient survival, which makes HGF/c-Met pathway an attractive molecular target for cancer therapy. A number of antibody-based therapeutic strategies have been explored to block c-Met or HGF in cancers; however, clinical efficacy has been very limited, indicating that blockade of c-Met signal alone is not sufficient. Thus, an alternative approach is to develop an immunotherapy strategy for c-Met-overexpressing cancers. c-Met/CD3 bispecific antibody (BsAb) could bridge CD3-positive T lymphocytes and tumor cells to result in potent tumor cell killing. Materials and Methods: A bispecific antibody, BS001, which binds both c-Met and CD3, was generated using a novel BsAb platform. Western blotting and T cells-mediated killing assays were utilized to evaluate the BsAb's effects on cell proliferation, survival and signal transduction in tumor cells. Subcutaneous tumor mouse models were used to analyze the in vivo anti-tumor effects of the bispecific antibody and its combination therapy with PD-L1 antibody. Results: BS001 showed potent T-cell mediated tumor cells killing in vitro. Furthermore, BS001 inhibited phosphorylation of c-Met and downstream signal transduction in tumor cells. In A549 lung cancer xenograft model, BS001 inhibited tumor growth and increased the proportion of activated CD56+ tumor infiltrating lymphocytes. In vivo combination therapy of BS001 with Atezolizumab (an anti-programmed cell death protein1-ligand (PD-L1) antibody) showed more potent tumor inhibition than monotherapies. Similarly, in SKOV3 xenograft model, BS001 showed a significant efficacy in tumor growth inhibition and tumor recurrence was not observed in more than half of mice treated with a combination of BS001 and Pembrolizumab. Conclusion: c-Met/CD3 bispecific antibody BS001 exhibited potent anti-tumor activities in vitro and in vivo, which was achieved through two distinguished mechanisms: through antibody-mediated tumor cell killing by T cells and through inhibition of c-Met signal transduction.

20.
Methods Cell Biol ; 160: 3-20, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32896324

RESUMO

The exocytosis process delivers proteins, lipids, and carbohydrates to the plasma membrane or the extracellular space to sustain plant cell growth, development, and response to environmental stimuli. Plant exocytosis is highly dynamic and requires the coordinated functions of multiple cellular components such as tethering complexes, GTPase signaling, and vesicle fusion machinery. Accurate spatio-temporal control of plant exocytosis is critical for the proper functions of plant cells. Live-cell imaging of fluorescence-tagged cargo proteins allows for quantitative analysis of exocytosis dynamics in plant cells. Small molecule inhibitors that target important components in the exocytosis machinery allow for transient manipulation of the exocytosis process. In this chapter, we describe procedures that use Endosidin2 (ES2) and Brefeldin A (BFA) as small molecule inhibitors to disrupt plant exocytic processes and use fluorescent protein-tagged PIN-formed 2 (PIN2) and Cellulose Synthase (CESA) as cargo proteins to quantify exocytosis dynamics in plant cells.

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