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1.
Artigo em Inglês | MEDLINE | ID: mdl-33401486

RESUMO

BACKGROUND: Research suggests that drivers tend to engage in risk-taking behaviours on public holidays. Studies that examined the association between holidays (or other special days) and fatal injuries are inconsistent. This study used UK STATS19 data to investigate the associations of nine public holidays on road crash casualties. METHODS: This retrospective study assessed UK STATS19 crash data for 1990-2017. All casualties from two vehicle crashes were initially considered; subsequently, casualties with missing data were excluded. Multiple logistic regression was estimated to explore the associations of potential risk factors with the likelihood of killed or seriously injured (KSI) casualties and to calculate adjusted odds ratios (AORs). RESULTS: In total, 3,751,998 casualties from traffic accidents in the United Kingdom during 1990-2017 were included in the final data set; among these, 410,299 (10.9%) were KSI casualties, and 3,341,699 (89.1%) were slight injuries. Crashes on public holidays were 16% (AOR = 1.16; 95% confidence interval [CI] = 1.13-1.19) more likely to involve KSI casualties than were crashes on non-holidays. With other factors controlled for, crashes during the Queen's 2002 Golden Jubilee and on New Year's Day were 48% (AOR = 1.48; 95% CI = 1.06-2.07) and 36% (AOR = 1.36; 1.26-1.48) more likely to lead to KSIs, respectively. CONCLUSIONS: The proportion of crashes resulting in KSI casualties on public holidays was higher than that on non-holidays. Furthermore, crashes during the Queen's 2002 Golden Jubilee had the highest risk of KSI casualties followed by New Year's Day.

2.
J Chin Med Assoc ; Publish Ahead of Print2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33433133

RESUMO

BACKGROUND: Patients with hepatocellular carcinoma (HCC) and with a single tumor <2 cm in size are classified as having Barcelona Clinic Liver Cancer (BCLC) stage 0 HCC. We aimed to investigate the role of the albumin-bilirubin (ALBI) grade in predicting outcomes in patients with BCLC stage 0 HCC. METHODS: We retrospectively enrolled patients with BCLC stage 0 HCC in Taipei Veterans General Hospital from 2007 to 2015. Prognostic factors were analyzed using a Cox proportional hazards model and propensity score matching (PSM) analysis. RESULTS: There were 420 patients enrolled, including 207 with ALBI grade 1, and 213 with ALBI grade 2 or 3. After a median follow-up of 60.0 months (interquartile range, 37.2-84.6 months), 179 patients died. The cumulative 5-year overall survival (OS) rates were 80.6% in patients with ALBI grade 1 and 53.7% in those with ALBI grade 2 or 3, respectively (p <0.001). Multivariate analysis showed that age >65 years, negative hepatitis B surface in serum, creatinine >1.0 mg/dL, platelet count ≤105/mm3, tumor size >1.5 cm, non-surgical resection (SR) therapy, and higher ALBI grade were independent risk factors related to poor OS. Patients who underwent SR had a better OS and recurrence-free survival than those who received radiofrequency ablation, which was confirmed by a multivariate analysis and PSM analysis. CONCLUSION: The ALBI grade can determine OS for patients with BCLC stage 0 HCC. SR can also provide a better outcome than non-surgical treatment.

3.
BMC Cancer ; 21(1): 56, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33435909

RESUMO

BACKGROUND: Surgery is the only treatment option for operable gastric cancer. The CLASSIC and ACTS-GC studies showed that the 5-year overall survival (OS) of patients with stage III gastric cancer undergoing D2 gastrectomy is still very low. Whether adjuvant nanoparticle albumin-bound paclitaxel (nab-paclitaxel) combined chemotherapy is more effective than the XELOX standard adjuvant chemotherapy in patients with stage III gastric cancer has not been confirmed. METHODS: This is a multicenter, open-label, phase III clinical study. In this trial, 616 patients with locally advanced stage III gastric cancer that underwent curative D2 radical surgery and achieved R0 are planned to be included. Patients will be randomized 1:1 to nab-paclitaxel combined with S-1 (AS) vs. oxaliplatin combined with capecitabine (XELOX). XELOX group: Patients assigned to the XELOX group received eight 3-week cycles of oral capecitabine (1000 mg/m2) twice daily on days 1-14 of each cycle plus intravenous oxaliplatin 130 mg/m2 on day 1 of each cycle. AS group: AS group received eight 3-week cycles of oral S-1 (80-120 mg) (< 1.25 m2, 40 mg; 1.25 to < 1.5 m2, 50 mg; and > 1.5 m2, 60 mg) twice daily on days 1-14 plus intravenous nab-paclitaxel 120 mg/m2 on days 1 and 8 of each cycle. The primary endpoint was the 3-year disease-free survival (3-year-DFS) defined as the time from randomisation to the time of recurrence of the original gastric cancer, development of a new gastric cancer, or death from any cause. The secondary endpoints were the overall survival, (defined as the time from the date of randomisation to date of death from any cause) and safety (any adverse event). DISCUSSION: Compared with previous studies, this study includes nab-paclitaxel based on S-1 adjuvant chemotherapy, which is expected to achieve better efficacy and lower toxicity than the standard treatment. This study is the first clinical study to evaluate the safety and efficacy of nab-paclitaxel combined with S-1 in patients with stage III gastric cancer after D2 radical resection. TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov, registration number: NCT04135781 , on October 20th, 2019.

4.
BMC Palliat Care ; 20(1): 13, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33435925

RESUMO

BACKGROUND: Artificial nutrition and hydration do not prolong survival or improve clinical symptoms of terminally ill cancer patients. Nonetheless, little is known about the effect of artificial hydration (AH) alone on patients' survival, symptoms or quality of dying. This study explored the relationship between AH and survival, symptoms and quality of dying among terminally ill cancer patients. METHODS: A pilot prospective, observational study was conducted in the palliative care units of three tertiary hospitals in Taiwan between October 2016 and December 2017. A total of 100 patients were included and classified into the hydration and non-hydration group using 400 mL of fluid per day as the cut-off point. The quality of dying was measured by the Good Death Scale (GDS). Multivariate analyses using Cox's proportional hazards model were used to assess the survival status of patients, the Wilcoxon rank-sum test for within-group analyses and the Mann-Whitney U test for between-groups analyses to evaluate changes in symptoms between day 0 and 7 in both groups. Logistic regression analysis was used to assess the predictors of a good death. RESULTS: There were no differences in survival (p = 0.337) or symptom improvement between the hydration and non-hydration group, however, patients with AH had higher GDS scores. CONCLUSIONS: AH did not prolong survival nor significantly improve dehydration symptoms of terminally ill cancer patients but it may influence the quality of dying. Communication with patients and their families on the effect of AH may help them better prepared for the end-of-life experience.

5.
Mol Immunol ; 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33451863

RESUMO

T regulatory type 1 (Tr1) cells act as a key regulator in maintaining peripheral immune tolerance. Several costimulatory molecules for T cells have been identified in Tr1 cells, but their intrinsic functions are still unclear. Here we showed CD226 was highly expressed in Tr1 cells. CD226-deficient Tr1 cells were defective in proliferation and sensitive to apoptosis. In addition, CD226-deficient Tr1 cells showed lower inhibitory capacity of T cell proliferation and reduced IL-10 production. CD226 deficiency also inhibited Tr1 cell differentiation in vitro. When stimulated with IL-2, CD226-deficient Tr1 cells showed impaired STAT5 signaling. Therefore, our data suggest CD226 might play an important role in Tr1 cell homeostasis, function and differentiation. This study facilitates further biological characterization of this regulatory T cell subset.

6.
Medicine (Baltimore) ; 100(1): e23702, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429738

RESUMO

BACKGROUND: Diabetic peripheral neuropathy is a common complication of diabetes and the main cause of disability. At present, there is no specific therapeutic regimen. Mecobalamin is often used as a neurotrophic drug, and its long-term effects are not satisfactory when used alone. Clinical practice indicates that traditional Chinese medicine injection with mecobalamin has a therapeutic advantage in treating diabetic peripheral neuropathy while it lacks evidence-based medicine. In this scheme, the efficacy and safety of traditional Chinese medicine injection with mecobalamin in treating diabetic peripheral neuropathy has been studied. METHODS: Computers were used to search the English database (PubMed, the Cochrane Library, Embase, Web of Science), and Chinese database (CNKI, Wanfang, CBMDISC, VIP). Besides, manual searching was conducted to search for Baidu Scholar, CHICTR, Google Scholar. During the establishment of the database to November 2020, a randomized controlled trial on traditional Chinese medicine injection with mecobalamin in treating diabetic peripheral neuropathy was conducted. There were 2 researchers independently conducting data extraction and quality evaluation of literature on the included studies, RevMan5.3 was performed for meta-analysis on the included literature. RESULTS: In this study, the efficacy and safety of traditional Chinese medicine injection with mecobalamin in treating diabetic peripheral neuropathy was evaluated by the total effective rate, motor nerve conduction velocity, sensory nerve conduction velocity, adverse reactions, and glucose metabolism level. CONCLUSION: This study can provide an evidence-based basis on the clinical applications of traditional Chinese medicine injection with mecobalamin in the treatment of diabetic peripheral neuropathy. ETHICS AND DISSEMINATION: The study does not involve patient privacy or rights and does not require approval from an ethics committee. The results may be published in peer-reviewed journals or disseminated at relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/KPW5E.

7.
Anal Chem ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33410328

RESUMO

Photoionization mass spectrometry (PI-MS) is a powerful and highly sensitive analytical technique for online monitoring of volatile organic compounds (VOCs). However, due to the large difference of PI cross sections for different compounds and the limitation of photon energy, the ability of lamp-based PI-MS for detection of compounds with low PI cross sections and high ionization energies (IEs) is insufficient. Although the ion production rate can be improved by elevating the ion source pressure, the problem of generating plenty of cluster ions, such as [MH]+·(H2O)n (n = 1 and 2) and [M2]+, needs be solved. In this work, we developed a new nonuniform electric field high-pressure photoionization/photoionization-induced chemical ionization (NEF-HPPI/PICI) source with the abilities of both HPPI and PICI, which was accomplished through ion-molecule reactions with high-intensity H3O+ reactant ions generated by photoelectron ionization (PEI) of water molecules. By establishing a nonuniform electric field in a three-zone ionization region to enhance in-source declustering and using 99.999% helium as the carrier gas, not only the formation of cluster ions was significantly diminished, but the ion transmission efficiency was also improved. Consequently, the main characteristic ion for each analyte both in HPPI and PICI occupied more than 80%, especially [HCOOH·H]+ with a yield ratio of 99.2% for formic acid. The analytical capacity of this system was demonstrated by operando monitoring the hydrocarbons and oxygenated VOC products during the methanol-to-olefins and methane conversion catalytic reaction processes, exhibiting wide potential applications in process monitoring, reaction mechanism research, and online quality control.

8.
Life Sci ; : 119004, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33417960

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) are widely applied in various clinical disorders, including acute lung injury (ALI). We aimed to investigate the effects of human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs)-derived exosomal microRNA-22-3p (miR-22-3p) on lipopolysaccharid (LPS)-induced ALI via regulating frizzled class receptor 6 (FZD6). METHODS: Rat lung cells were selected to construct the LPS-induced ALI cell model. The LPS-treated cells were transfected with restored miR-22-3p and depleted FZD6 for investigating their roles in ALI. Human UCB-MSCs were cultured and exosomes were extracted. Rat lung cells were co-cultured with exosomes that had been transfected with restored miR-22-3p and upregulated FZD6 to detect their roles in inflammatory reaction, oxidative stress, cell proliferation activity and apoptosis. The ALI rat model was established through LPS inhalation and the rats were respectively treated. Then, the pathology, apoptosis and expression of the NF-κB signaling pathway-related factors in rat lung tissues were determined. RESULTS: miR-22-3p expression was reduced and FZD6 expression was enhanced in LPS-treated rat lung cells while exosomes raised miR-22-3p expression and decreased FZD6 expression. In LPS-treated cells, up-regulating miR-22-3p or depleting FZD6 reduced inflammatory reaction and oxidative stress response, raised rat lung cell proliferation activity and inhibited cell apoptosis rate. In the in vivo ALI model, exosomes suppressed pathological changes, apoptosis and NF-κB expression in LPS-treated rats. Upregulated miR-22-3p further attenuated ALI. CONCLUSION: Our study highlights the potential of UCB-MSC-exosomal miR-22-3p in preventing ALI. This study may provide further insights into ALI therapy.

10.
Clin Sci (Lond) ; 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33393635

RESUMO

Benign prostatic hyperplasia (BPH) is a common disease among aging males with the etiology remaining unclear. We recently found myosin II was abundantly expressed in rat and cultured human prostate cells with permissive roles in the dynamic and static components. This study aimed to explore the expression and functional activities of myosin II isoforms including smooth muscle myosin II (SMM II) and non-muscle myosin (NMM II) in the hyperplastic prostate. Human prostate cell lines and tissues from normal human and BPH patients were used. H&E, Masson's trichrome, immunohistochemical staining, in vitro organ bath, RT-PCR and Western-blotting were performed. We further created cell models with NMM II isoforms silenced and proliferation, cycle, and apoptosis of prostate cells were determined by CCK-8 assay and flow cytometry. Hyperplastic prostate SM expressed more SM1 and LC17b isoforms compared to their alternatively spliced counterparts, favoring a slower more tonic-type contraction and greater force generation. For BPH group, blebbistatin (BLEB, a selective myosin II inhibitor), exhibited a stronger effect on relaxing phenylephrine (PE) pre-contracted prostate strips and inhibiting PE induced contraction. Additionally, NMMHC-A and NMMHC-B were upregulated in hyperplastic prostate with no change in NMMHC-C. Knockdown of NMMHC-A or NMMHC-B inhibited prostate cell proliferation and induced apoptosis, with no changes in cell cycle. Our novel data demonstrates that expression and functional activities of myosin II isoforms are altered in human hyperplastic prostate, suggesting a new pathological mechanism for BPH. Thus, the myosin II system may provide potential new therapeutic targets for BPH/lower urinary tract symptoms (LUTS).

11.
Cell Prolif ; 54(1): e12919, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33129231

RESUMO

OBJECTIVES: Targeting the deubiquitinases (DUBs) has become a promising avenue for anti-cancer drug development. However, the effect and mechanism of pan-DUB inhibitor, PR-619, on oesophageal squamous cell carcinoma (ESCC) cells remain to be investigated. MATERIALS AND METHODS: The effect of PR-619 on ESCC cell growth and cell cycle was evaluated by CCK-8 and PI staining. Annexin V-FITC/PI double staining was performed to detect apoptosis. LC3 immunofluorescence and acridine orange staining were applied to examine autophagy. Intercellular Ca2+ concentration was monitored by Fluo-3AM fluorescence. The accumulation of ubi-proteins and the expression of the endoplasmic reticulum (ER) stress-related protein and CaMKKß-AMPK signalling were determined by immunoblotting. RESULTS: PR-619 could inhibit ESCC cell growth and induce G2/M cell cycle arrest by downregulating cyclin B1 and upregulating p21. Meanwhile, PR-619 led to the accumulation of ubiquitylated proteins, induced ER stress and triggered apoptosis by the ATF4-Noxa axis. Moreover, the ER stress increased cytoplasmic Ca2+ and then stimulated autophagy through Ca2+ -CaMKKß-AMPK signalling pathway. Ubiquitin E1 inhibitor, PYR-41, could reduce the accumulation of ubi-proteins and alleviate ER stress, G2/M cell cycle arrest, apoptosis and autophagy in PR-619-treated ESCC cells. Furthermore, blocking autophagy by chloroquine or bafilomycin A1 enhanced the cell growth inhibition effect and apoptosis induced by PR-619. CONCLUSIONS: Our findings reveal an unrecognized mechanism for the cytotoxic effects of general DUBs inhibitor (PR-619) and imply that targeting DUBs may be a potential anti-ESCC strategy.

12.
J Pain Symptom Manage ; 61(2): 315-322.e1, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32777459

RESUMO

BACKGROUND: The characteristics of physician communication with patients at the end of life (EOL) in East Asia have not been well studied. We investigated physicians' communications with imminently dying patients with cancer and their families in palliative care units (PCUs) in Japan, South Korea, and Taiwan. METHODS: This observational study included patients with cancer newly admitted and deceased during their first admission to 39 PCUs in three countries. We evaluated 1) the prevalence and timing of informing patients and families of patients' impending death and 2) the prevalence of communication to assure the families of the patient's comfort. RESULTS: We analyzed 2138 patients (Japan: 1633, South Korea: 256, Taiwan: 249). Fewer Japanese (4.8%: 95% confidence interval [95% CI], 3.8%-5.9%) and South Korean (19.6%: 95% CI, 15.2%-25.0%) patients were informed of their impending death, whereas 66.4% (95% CI, 60.2%-72.1%) of Taiwanese were informed; among all three countries, ≥90% of families were informed. Although most patients in all three countries and the families in South Korea and Taiwan were informed of the impending death greater than or equal to four days before death, 62.1% (95% CI, 59.6%-64.6%) of Japanese families were informed less than or equal to three days prior. Most families in all three countries received assurance that the patient would remain comfortable (could hear until death, no distress with death rattle or respiration with mandibular movement). CONCLUSIONS: Physicians in Taiwan communicated about patient's impending death most frequently, and physicians in all three countries generally provided assurance to families that the patients would remain comfortable. Further studies should explore the reasons for these differences and the effects of such communications in East Asia.

13.
J Cell Mol Med ; 25(1): 397-410, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33191617

RESUMO

Recent reports showed that haematological and neurological expressed 1-like (HN1L) gene participated in tumorigenesis and tumour invasion. However, the expression and role of HN1L in breast cancer remain to be investigated. Here, bioinformatics, western blot and immunohistochemistry were used to detect the expression of HN1L in breast cancer. Wound healing, transwell assay, immunofluorescence assay and mass spectrum were used to explore the role and mechanism of HN1L on the migration and invasion of breast cancer, which was confirmed in vivo using a nude mice model. Results showed that HN1L was significantly over-expressed in breast cancer tissues, which was positively correlated with M metastasis of breast cancer patients. Silencing HN1L significantly inhibited the invasion and metastasis of breast cancer cells in vitro and lung metastasis in nude mice metastasis model of breast cancer. Mechanistically, HN1L interacted with HSPA9 and affected the expression of HMGB1, playing a key role in promoting the invasion and metastasis of breast cancer cell. These results suggested that HN1L was an appealing drug target for breast cancer.

14.
JAMA Intern Med ; 181(1): 71-78, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32910179

RESUMO

Importance: Lymphopenia is common and correlates with poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19). Objective: To determine whether a therapy that increases peripheral blood leukocyte and lymphocyte cell counts leads to clinical improvement in patients with COVID-19. Design, Setting and Participants: Between February 18 and April 10, 2020, we conducted an open-label, multicenter, randomized clinical trial at 3 participating centers in China. The main eligibility criteria were pneumonia, a blood lymphocyte cell count of 800 per µL (to convert to ×109/L, multiply by 0.001) or lower, and no comorbidities. Severe acute respiratory syndrome coronavirus 2 infection was confirmed with reverse-transcription polymerase chain reaction testing. Exposures: Usual care alone, or usual care plus 3 doses of recombinant human granulocyte colony-stimulating factor (rhG-CSF, 5 µg/kg, subcutaneously at days 0-2). Main Outcomes and Measures: The primary end point was the time from randomization to improvement of at least 1 point on a 7-category disease severity score. Results: Of 200 participants, 112 (56%) were men and the median (interquartile range [IQR]) age was 45 (40-55) years. There was random assignment of 100 patients (50%) to the rhG-CSF group and 100 (50%) to the usual care group. Time to clinical improvement was similar between groups (rhG-CSF group median of 12 days (IQR, 10-16 days) vs usual care group median of 13 days (IQR, 11-17 days); hazard ratio, 1.28; 95% CI, 0.95-1.71; P = .06). For secondary end points, the proportion of patients progressing to acute respiratory distress syndrome, sepsis, or septic shock was lower in the rhG-CSF group (rhG-CSF group, 2% vs usual care group, 15%; difference, -13%; 95%CI, -21.4% to -5.4%). At 21 days, 2 patients (2%) had died in the rhG-CSF group compared with 10 patients (10%) in the usual care group (hazard ratio, 0.19; 95%CI, 0.04-0.88). At day 5, the lymphocyte cell count was higher in the rhG-CSF group (rhG-CSF group median of 1050/µL vs usual care group median of 620/µL; Hodges-Lehmann estimate of the difference in medians, 440; 95% CI, 380-490). Serious adverse events, such as sepsis or septic shock, respiratory failure, and acute respiratory distress syndrome, occurred in 29 patients (14.5%) in the rhG-CSF group and 42 patients (21%) in the usual care group. Conclusion and Relevance: In preliminary findings from a randomized clinical trial, rhG-CSF treatment for patients with COVID-19 with lymphopenia but no comorbidities did not accelerate clinical improvement, but the number of patients developing critical illness or dying may have been reduced. Larger studies that include a broader range of patients with COVID-19 should be conducted. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2000030007.


Assuntos
/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Fármacos Hematológicos/uso terapêutico , Mortalidade Hospitalar , Linfopenia/tratamento farmacológico , Corticosteroides/uso terapêutico , Adulto , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Linfócitos B , Contagem de Linfócito CD4 , /complicações , China , Progressão da Doença , Feminino , Humanos , Células Matadoras Naturais , Contagem de Leucócitos , Contagem de Linfócitos , Linfopenia/sangue , Linfopenia/complicações , Masculino , Pessoa de Meia-Idade , Mortalidade , Ventilação não Invasiva , Oxigenoterapia , Proteínas Recombinantes , Insuficiência Respiratória/fisiopatologia , Sepse/fisiopatologia , Choque Séptico/fisiopatologia , Fatores de Tempo
15.
Pain ; 162(1): 263-274, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32701650

RESUMO

Plastic changes in the anterior cingulate cortex (ACC) are critical in pain hypersensitivity caused by peripheral nerves injury. The Notch signaling pathway has been shown to regulate synaptic differentiation and transmission. Therefore, this study was to investigate the function of the Notch signaling pathway in the ACC during nociceptive transmission induced by neuropathic pain. We adopted Western blotting, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) microinjections, RNA interference targeting Notch1, Hairy and enhancer of split (Hes) 1 or Hes5, electrophysiological recordings, and behavioral tests to verify the link between Notch signaling in ACC and neuropathic pain with adult male Sprague-Dawley rats. Levels of the Notch intracellular domain were increased in ACC on day 7 after chronic constriction injury surgery or spared nerve injury. Meanwhile, the mRNA level of the downstream effector of Notch signaling Hes1 was increased, whereas the level of Hes5 mRNA did not change. Microinjection of DAPT, a γ-secretase (a key enzyme involved in Notch pathway) inhibitor, into ACC significantly reversed neuropathic pain behaviors. Intra-ACC injection of short hairpin RNA-Notch reduced Notch intracellular domain expression and decreased the potentiation of synaptic transmission in the ACC. Moreover, pain perceptions were also alleviated in rats subjected to chronic constriction injury or spared nerve injury. This process was mainly mediated by the downstream effector Hes1, but not Hes5. Based on these results, the activation of the Notch/Hes1 signaling pathway in the ACC participates in the development of neuropathic pain, indicating that the Notch pathway may be a new therapeutic target for treating chronic pain.

16.
Gene ; 766: 145150, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32949695

RESUMO

There are a few studies indicating that small molecular compounds affect the proliferation, differentiation, apoptosis, and autophagy of female germline stem cells (FGSCs). However, whether small molecular compound 28 (C28) affect development of FGSCs remains unknown. In this study, we found that C28 reduced the viability and proliferation of FGSCs, respectively. Additionally, western blotting showed that the expression of autophagy marker light chain 3 beta II (LC3B-II) was significantly increased and expression of sequestosome-1 (SQSTM1) was significantly reduced in C28-treated groups. Immunofluorescence showed that, in C28-treated groups, the number of LC3B-II-positive puncta was increased significantly. These results indicated that C28 induced autophagy of FGSCs in vitro. Furthermore, data from Chromatin Immunoprecipitation Sequencing for H3K27ac showed that autophagy-related biological processes such as regulation of mitochondrial membrane potential, Golgi vesicle transport, and cellular response to reactive oxygen species were different after C28-treated. In addition, RNA-Seq showed that the expression of genes (Trib3, DDIT3, and ATF4) related to endoplasmic reticulum (ER) stress was enhanced by C28. These results suggest that the changes of H3K27ac and ER stress might be associated with C28-induced FGSC autophagy.


Assuntos
Acetilação/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Histonas/genética , Células-Tronco de Oogônios/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Transcriptoma/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Complexo de Golgi/efeitos dos fármacos , Complexo de Golgi/genética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco de Oogônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
J Hazard Mater ; 403: 123582, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32781276

RESUMO

Photocatalytic degradation of typical pharmaceuticals in natural sunlight and in actual water is of great significance. In this study, the oxygen or nitrogen linked heptazine-base polymer (ONLH) was successfully incorporated with TiO2 nanoparticles and formed a TiO2/ONLH nanocomposite which was responded to the natural sunlight. Under natural sunlight, the TiO2/ONLH can effectively degrade ten types of pharmaceuticals. In particular, fluoroquinolone containing N-piperazinyl, and cardiovascular drugs containing long aromatic side chains were easily degraded. The half-life of the best degradation performance of propranolol was less than 5 min. The rate constants of propranolol using the TiO2/ONLH were approximately six- and eight-fold higher than those of pristine TiO2 and ONLH, respectively. Two reactive species (OH and O2-) facilitated the rapid degradation of propranolol, which occurred primarily through the hydroxyl radical addition, ring-opening, and ipso substitution reactions. An acute toxicity test using luminescent bacteria indicated that the toxicity of the propranolol reaction solution gradually decreased with lower total organic carbon (TOC). According to the toxicity evaluation of monomer products, the TiO2/ONLH also reduced the generation of toxic transformation products. The effects of actual water/wastewater have further shown the TiO2/ONLH might be applied for the removal of pharmaceuticals in wastewater.

18.
J Med Chem ; 64(1): 644-661, 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33356246

RESUMO

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3S)-3-{[2'-amino-5-fluoro-2-(morpholin-4-yl)-4,5'-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1) (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1.

19.
J Hazard Mater ; 401: 123257, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32659572

RESUMO

As an emerging carbon nanomaterial, carbon dots (CDs) have superior prospects for applications in the area of photocatalysis due to their unique optical and electronic properties. In this study, a novel CDs modified g-C3N4/SnO2 photocatalyst (CDs/g-C3N4/ SnO2) was successfully synthesized by the thermal polymerization. Under visible light irradiation, the resulting CDs/g-C3N4/SnO2 photocatalyst exhibited excellent photocatalytic activity for the degradation of indomethacin (IDM). It was demonstrated that a 0.5 % loading content of CDs led to the highest IDM degradation rate, which was 5.62 times higher than that of pristine g-C3N4. This improved photocatalytic activity might have been attributed to the unique up-conversion photoluminescence (PL) properties and efficient charge separation capacities of the CDs. Moreover, the combination of g-C3N4 with SnO2 improved the separation of photoinduced carriers and augmented the specific surface area. Reactive species (RSs) scavenging experiments and electron spin resonance (ESR) revealed that superoxide radical anions (O2·-) and photogenerated holes (h+) played critical roles during the photocatalytic process. The results of the detection of H2O2 and ESR confirmed that CDs/g-C3N4/ SnO2 was a Z-scheme heterojunction photocatalyst. Further, HRAM LC-MS/MS was employed to identify the byproducts of IDM, and the major IDM degradation pathways of the CDs/g-C3N4/SnO2 photocatalyst were proposed. This study provides new ideas for the design of novel CDs modified photocatalysts for environmental remediation.

20.
Clin Imaging ; 69: 27-32, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32652454

RESUMO

OBJECTIVE: The purpose of this study was to investigate the chest CT imaging features and clinical outcome of coronavirus disease 2019 (COVID-19) in Ningbo, China. METHODS: In this retrospective study, twenty-eight confirmed and seven highly suspected cases of COVID-19 were enrolled in Ningbo first hospital from January 26, 2020 to March 5, 2020. Cases were confirmed by real-time polymerase chain reaction (RT-PCR). The initial and follow-up chest CT imaging features, epidemiological history, and outcome were analyzed. RESULTS: The average age of the patients was 57.3 ± 15.3 years (range: 27-96 years), including 25 females and 10 males. On CT images, 89.3% (25/28) confirmed and 100% (7/7) suspected patients had ground-glass opacities (GGOs), and GGOs with mixed consolidations were observed in 35.7% (10/28) confirmed and 42.9% (3/7) suspected cases, most of these lesions were distributed under the peripheral of both lungs. 17 confirmed and 4 suspected cases had a history of participating in Ningbo Tian-tong Temple rituals and all had GGOs in their lungs during the initial CT scan. As of March 25, 2020, the lung lesions of our cases were significantly resolved and all patients have been discharged from the hospital. CONCLUSION: The most common chest CT features are multiple bilateral and peripheral GGOs with mixed consolidations or not in the lungs of patients with COVID-19. Chest CT plays an important role in the diagnosis and monitoring treatment response of this disease. There was no reported death in our cases.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Pneumonia Viral , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Estudos Retrospectivos , Tórax , Tomografia Computadorizada por Raios X
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