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1.
Clin Cancer Res ; 2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34844979

RESUMO

BACKGROUND: Phase I results of this phase I/II study showed that pamiparib 60 mg BID had antitumor activity and an acceptable safety profile in Chinese patients with advanced cancer, including epithelial ovarian cancer (OC). METHODS: This open-label phase II study was conducted in China and enrolled adult ({greater than or equal to}18 years) patients with platinum-sensitive OC (PSOC, disease progression occurring {greater than or equal to}6 months after last platinum treatment) or platinum-resistant OC (PROC, disease progression occurring <6 months after last platinum treatment). Eligible patients had known or suspected deleterious germline BRCA mutation (gBRCA mut) and had previously received {greater than or equal to}2 lines of therapy. Pamiparib 60 mg PO BID was administered until disease progression, toxicity, or patient withdrawal. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per RECIST version 1.1. RESULTS: In the total patient population (N=113; PSOC, n=90; PROC, n=23), median age was 54 years (range, 34-79) and 25.6% of patients received {greater than or equal to}4 prior systemic chemotherapy lines. Median study follow-up was 12.2 months (range, 0.2-21.5). Eighty-two PSOC patients and 19 PROC patients were evaluable for efficacy. In PSOC patients, 8 achieved a complete response (CR) and 45 achieved a partial response (PR); ORR was 64.6% (95% CI, 53.3-74.9). In PROC patients, 6 achieved a PR; ORR was 31.6% (95% CI, 12.6-56.6). Frequently reported grade {greater than or equal to}3 adverse events (AEs) were hematologic toxicities, including anemia and decreased neutrophil count. CONCLUSIONS: Pamiparib 60 mg BID showed antitumor activity with durable responses in patients with PSOC or PROC with gBRCA mut, and had a manageable safety profile.

2.
Microb Pathog ; 161(Pt B): 105284, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34767930

RESUMO

Chlamydia pneumoniae (Cpn) has been reported to be involved in the pathogenesis of early atherosclerosis by inducing macrophage-derived foam cell formation in the presence of low-density lipoprotein (LDL). However, the biochemical mechanisms underlying Cpn-induced foam cell formation are still not fully elucidated. The present study showed that in LDL-treated THP-1-derived macrophages, Cpn not only upregulated the expression of scavenger receptor A1 (SR-A1) and acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1), but it also downregulated the expression of ATP binding cassette transporters (ABCA1 and ABCG1) at both the mRNA and protein levels. These processes facilitated cholesterol accumulation and promoted macrophage-derived foam cell formation. Treatment with the peroxisome proliferator-activated receptor (PPAR)-γ agonist rosiglitazone or the PPARα agonist fenofibrate decreased the number of foam cells induced by Cpn, while the PPARγ antagonist GW9662, the PPARα antagonist MK886, or PPARα/γ siRNAs enhanced the effect of Cpn on foam cell formation and gene expression of SR-A1, ACAT1, and ABCA1/G1. Moreover, the PPARγ agonist rosiglitazone reversed the downregulation of CD36 by Cpn, while PPARγ siRNA and the PPARγ inhibitor GW9662 further suppressed CD36 expression. However, the PPARα agonist, inhibitor, and siRNA all showed no effect on CD36 expression. In conclusion, the PPARα and PPARγ pathways are both involved in Cpn-induced macrophage-derived foam cell formation by upregulating SR-A1 and ACAT1 and downregulating ABCA1/G1 expression.

3.
World J Surg Oncol ; 19(1): 323, 2021 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-34743715

RESUMO

BACKGROUND: Removing more inframesenteric nodes is not only significantly increases the likelihood of finding metastasis for endometrial cancer, but also can add survival advantage. As most patients diagnosed with endometrial cancer are overweight or obesity, a high efficiency approach is important. Aim of this study was to compare the surgical outcomes of extraperitoneal laparoscopic, transperitoneal laparoscopic, and laparotomic para-aortic lymphadenectomy in endometrial carcinoma staging. METHODS: We retrospectively reviewed data of all patients diagnosed with primary endometrial carcinoma who were treated at the Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center from 1 January 2017 to 31 December 2019. The numbers of para-aortic lymph nodes, surgical time, complications, blood loss and hospital stay were compared. The patients' medical records and pathological reports were carefully reviewed. Statistical significance was defined as p < 0.05. RESULTS: We retrospectively compared patients who underwent extraperitoneal laparoscopy (Group E, n = 20), transperitoneal laparoscopy (group T, n = 21), and laparotomy (group L, n = 135). The median number of para-aortic lymph nodes was significantly higher in group E than in groups T and L (9.5, 5, and 6, respectively; p = 0.004 and 0.0004, respectively). All patients in group E underwent successfully dissection to the renal vessel level. The median operation time was significantly shorter in group L than in groups T and E (94, 174, and 233 min, respectively; p < 0.0001). The median estimated blood loss volume was higher in group L than in groups T and E (200, 100, and 142.5 ml, respectively; all comparisons p < 0.001), and the length of hospital stay was significantly longer in group L than in Groups T and E (6, 5, and 6 days, respectively; all comparisons p < 0.001). CONCLUSION: The extraperitoneal laparoscopic approach for staging endometrial carcinoma harvested higher numbers of para-aortic lymph nodes which could be considered for endometrial carcinoma staging, especially for para-aortic lymph node harvest.


Assuntos
Neoplasias do Endométrio , Laparoscopia , China , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Excisão de Linfonodo , Linfonodos/patologia , Linfonodos/cirurgia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
4.
Front Genet ; 12: 743758, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34777471

RESUMO

Drought is one of the most devasting and frequent abiotic stresses in agriculture. While many morphological, biochemical and physiological indicators are being used to quantify plant drought responses, stomatal control, and hence the transpiration and photosynthesis regulation through it, is of particular importance in marking the plant capacity of balancing stress response and yield. Due to the difficulties in simultaneous, large-scale measurement of stomatal traits such as sensitivity and speed of stomatal closure under progressive soil drought, forward genetic mapping of these important behaviors has long been unavailable. The recent emerging phenomic technologies offer solutions to identify the water relations of whole plant and assay the stomatal regulation in a dynamic process at the population level. Here, we report high-throughput physiological phenotyping of water relations of 106 cowpea accessions under progressive drought stress, which, in combination of genome-wide association study (GWAS), enables genetic mapping of the complex, stomata-related drought responsive traits "critical soil water content" (θcri) and "slope of transpiration rate declining" (KTr). The 106 accessions showed large variations in θcri and KTr, indicating that they had broad spectrum of stomatal control in response to soil water deficit, which may confer them different levels of drought tolerance. Univariate GWAS identified six and fourteen significant SNPs associated with θcri and KTr, respectively. The detected SNPs distributed in nine chromosomes and accounted for 8.7-21% of the phenotypic variation, suggesting that both stomatal sensitivity to soil drought and the speed of stomatal closure to completion were controlled by multiple genes with moderate effects. Multivariate GWAS detected ten more significant SNPs in addition to confirming eight of the twenty SNPs as detected by univariate GWAS. Integrated, a final set of 30 significant SNPs associated with stomatal closure were reported. Taken together, our work, by combining phenomics and genetics, enables forward genetic mapping of the genetic architecture of stomatal traits related to drought tolerance, which not only provides a basis for molecular breeding of drought resistant cultivars of cowpea, but offers a new methodology to explore the genetic determinants of water budgeting in crops under stressful conditions in the phenomics era.

5.
Front Oncol ; 11: 720343, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34796105

RESUMO

Objective: This phase II, single-arm, prospective study aimed to evaluate the efficacy and safety of anlotinib in Chinese patients with recurrent or metastatic cervical cancer (CC). Methods: Patients with histologically proven recurrent or metastatic advanced CC were enrolled at Fudan University Shanghai Cancer Center. Patients received 12 mg of oral anlotinib daily before breakfast for 2 weeks of each 3-week (21 days) cycle separated by a 1-week interval. Anlotinib was administered orally until disease progression, patient withdrawal, intolerant toxicity, or death. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors, and the secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between September 2018 and November 2019, 41 patients were recruited. The median age was 53 years old. The histological results revealed that 82.9% of the recruited patients had squamous cell carcinoma, 14.6% had adenocarcinoma, and 2.4% had other types. At the data cutoff date, six patients were still being treated, and 35 patients had discontinued treatment. Forty (40/41, 97.5%) patients were evaluated for treatment response. The median PFS and OS was 3.2 and 9.9 months, respectively, in patients who received anlotinib treatment. The ORR was 24.4%. In addition, 34.2% (14/41) of patients were confirmed to have stable disease, and 39.0% (16/41) of patients were confirmed to have progressive disease. The DCR was 58.5%. Ten patients (10/41) had a confirmed response during the follow-up period. Most adverse events (AEs) were grade 1 or 2. High-grade AEs (grade 3) included urinary leukocyte positivity (9.8%), hematuria (4.9%), and hypertension (2.4%). Conclusion: This is the first study to evaluate the efficacy and safety of anlotinib in Chinese patients with recurrent or metastatic CC. Anlotinib produced durable clinical responses with manageable safety in these patients.

6.
Int J Gynecol Cancer ; 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34799418

RESUMO

BACKGROUND: Pembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer (KEYNOTE-146/Study 111) after ≤2 previous lines of therapy. In a randomized phase 3 trial of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer (KEYNOTE-775/Study 309), after 1‒2 previous lines of therapy (including neoadjuvant/adjuvant), this combination improved objective response rates, progression-free survival, and overall survival compared with chemotherapy. PRIMARY OBJECTIVE: To compare the efficacy and safety of first-line pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease. STUDY HYPOTHESIS: Pembrolizumab plus lenvatinib is superior to chemotherapy with respect to progression-free survival and overall survival in patients with mismatch repair-proficient tumors and all patients (all-comers). TRIAL DESIGN: Phase 3, randomized (1:1), open-label, active-controlled trial. Patients will receive pembrolizumab intravenously every 3 weeks plus lenvatinib orally daily or paclitaxel plus carboplatin intravenously every 3 weeks, stratified by mismatch repair status (proficient vs deficient). Patients with mismatch repair-proficient tumors will be further stratified by Eastern Cooperative Oncology Group performance status (0/1), measurable disease (yes/no), and prior chemotherapy and/or chemoradiation (yes/no). MAJOR INCLUSION/EXCLUSION CRITERIA: Adults with stage III/IV/recurrent histologically confirmed endometrial cancer that is measurable or radiographically apparent per blinded independent central review. Patients may have received previous chemotherapy only as neoadjuvant/adjuvant therapy and/or concurrently with radiation. Patients with carcinosarcoma (malignant mixed Müllerian tumor), endometrial leiomyosarcoma, or other high grade sarcomas, or endometrial stromal sarcomas were excluded. PRIMARY ENDPOINTS: Progression-free and overall survival (dual primary endpoints). SAMPLE SIZE: About 875 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Enrollment is expected to take approximately 24 months, with presentation of results in 2022. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03884101.

7.
Mol Cell ; 81(21): 4440-4456.e7, 2021 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-34597596

RESUMO

Protection of stalled replication forks is critical to genomic stability. Using genetic and proteomic analyses, we discovered the Protexin complex containing the ssDNA binding protein SCAI and the DNA polymerase REV3. Protexin is required specifically for protecting forks stalled by nucleotide depletion, fork barriers, fragile sites, and DNA inter-strand crosslinks (ICLs), where it promotes homologous recombination and repair. Protexin loss leads to ssDNA accumulation and profound genomic instability in response to ICLs. Protexin interacts with RNA POL2, and both oppose EXO1's resection of DNA on forks remodeled by the FANCM translocase activity. This pathway acts independently of BRCA/RAD51-mediated fork stabilization, and cells with BRCA2 mutations were dependent on SCAI for survival. These data suggest that Protexin and its associated factors establish a new fork protection pathway that counteracts fork resection in part through a REV3 polymerase-dependent resynthesis mechanism of excised DNA, particularly at ICL stalled forks.

8.
Front Cell Dev Biol ; 9: 730538, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621748

RESUMO

The RNA component of mitochondrial RNA-processing endoribonuclease (RMRP) was recently shown to play a role in cancer development. However, the function and mechanism of RMRP during cancer progression remain incompletely understood. Here, we report that RMRP is amplified and highly expressed in various malignant cancers, and the high level of RMRP is significantly associated with their poor prognosis, including breast cancer. Consistent with this, ectopic RMRP promotes proliferation and migration of TP53-mutated breast cancer cells, whereas depletion of RMRP leads to inhibition of their proliferation and migration. RNA-seq analysis reveals AKT as a downstream target of RMRP. Interestingly, RMRP indirectly elevates AKT expression by preventing AKT mRNA from miR-206-mediated targeting via a competitive sequestering mechanism. Remarkably, RMRP endorses breast cancer progression in an AKT-dependent fashion, as knockdown of AKT completely abolishes RMRP-induced cancer cell growth and migration. Altogether, our results unveil a novel role of the RMRP-miR-206-AKT axis in breast cancer development, providing a potential new target for developing an anti-breast cancer therapy.

9.
Environ Res ; : 112161, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34626591

RESUMO

BACKGROUND: Congenital anomalies (CAs) are the leading causes for children's disabilities and mortalities worldwide. The associations between air pollution and CAs are not fully characterized in fetuses born by in vitro fertilization (IVF) who are at high risk of congenital anomalies. METHODS: We conducted a cross-sectional study including 16,971 IVF cycles from three hospitals in Hebei Province, China, 2014-2019. Air quality data was obtained from 149 air monitoring stations. Individual average daily concentrations of PM2.5, PM10, NO2, SO2, CO, and O3 were estimated by spatiotemporal kriging method. Exposure windows were divided into 5: preantral follicle period, antral follicle period, germinal period, embryonic period and early fetal period. Logistic generalized estimating equations were used to estimate the associations between air pollutants and overall or organ-system specific congenital anomalies. Negative control exposure method was used to detect and reduce bias of estimation. RESULTS: We found increasing levels of PM2.5 and PM10 were associated with higher risk of overall congenital anomalies during early fetal period, equating gestation 10-12 weeks (OR: 1.05, 95% CI: 1.02-1.09, p = 0.013 for a 10 µg/m3 increase of PM2.5; OR: 1.03, 95% CI: 1.01-1.06, p = 0.021 for a 10 µg/m3 increase of PM10). Cleft lip and cleft palate were associated with PM10 in germinal period and early fetal period. The CAs of eye, ear, face and neck were related to CO in preantral follicle stage. We did not find an association between chromosome abnormalities and air pollution exposure. CONCLUSIONS: We concluded that ambient air pollution was a risk factor for congenital anomalies in the fetuses conceived through IVF, especially exposure in early fetal period.

10.
Mol Ther Nucleic Acids ; 26: 557-574, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34631285

RESUMO

Expansion in vitro prior to mesenchymal stem cells (MSCs) application is a necessary process. Functional and genomic stability has a crucial role in stem-cell-based therapies. However, the exact expression and co-expressed profiles of coding and non-coding RNAs in human bone marrow (BM)-MSCs in vitro aging are still lacking. In the present studies, the change of morphology, immunophenotype, and capacity of proliferation, differentiation, and immunoregulation of MSCs at passage (P) 4, P6, P8, P10, and P12 were investigated. RNA sequencing identified that 439 mRNAs, 65 long noncoding RNAs (lncRNAs), 59 microRNAs (miRNAs), and 229 circular RNAs (circRNAs) were differentially expressed (DE) in P12 compared with P4, with a similar trend in P6. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) identified several significant biological processes and pathways, including binding, ossification, and Wnt and PPAR signaling pathways. Interaction and co-expression/localization analyses were performed for DE mRNAs and lncRNAs, and several key lncRNAs, circRNAs, and important pathways like autophagy and mitophagy were identified in the competing endogenous RNA (ceRNA) network. Some key RNAs found in the bioinformatics analysis were validated. Our studies indicate that replicative senescence of MSCs is a continuous process, including widespread alterations in biological characteristics and global gene expression patterns that need to be considered before therapeutic applications of MSCs.

11.
Curr Opin Genet Dev ; 71: 163-170, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34481360

RESUMO

Break-induced replication (BIR) is a pathway specialized in repair of double-strand DNA breaks with only one end capable of invading homologous template that can arise following replication collapse, telomere erosion or DNA cutting by site-specific endonucleases. For a long time, yeast remained the only model system to study BIR. Studies in yeast demonstrated that BIR represents an unusual mode of DNA synthesis that is driven by a migrating bubble and leads to conservative inheritance of newly synthesized DNA. This unusual type of DNA synthesis leads to high levels of mutations and chromosome rearrangements. Recently, multiple examples of BIR were uncovered in mammalian cells that allowed the comparison of BIR between organisms. It appeared initially that BIR in mammalian cells is predominantly independent of RAD51, and therefore different from BIR that is predominantly Rad51-dependent in yeast. However, a series of systematic studies utilizing site-specific DNA breaks for BIR initiation in mammalian reporters led to the discovery of highly efficient RAD51-dependent BIR, allowing side-by side comparison with BIR in yeast which is the focus of this review.

12.
Bioengineered ; 12(1): 5552-5565, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34517782

RESUMO

Ischemic heart disease in children may be induced by varied factors, and there is no corresponding systematic treatment up to now. This study aims to investigate the effects of microRNA (miR)-148 on myocardial injury in immature rats with myocardial ischemia-reperfusion (MI/R) injury. In this study, MI/R model was established by ligating the coronary artery of heart. The results showed that miR-148 alleviated myocardial injury and rescued relevant parameters (mean ventricular systolic blood pressure (MAP), left ventricular systolic blood pressure (LVSP), heart rate (HR), creatine kinase-MB (CK-MB), cTn1 and Mb in immature rats with MI/R injury. Besides, miR-148 improved the immune dysfunction induced by MI/R through increasing the number of interleukin (IL)-10+ cells and reducing the number of inducible nitric oxide synthase (iNOS)+ cells. In addition, miR-148 relieved the apoptosis of cardiomyocytes induced by MI/R through inhibiting the expression of Bax and elevating the expression of Bcl-2. Further molecular mechanism indicated that pyruvate dehydrogenase kinase 4 (PDK4) was the downstream target of miR-148, which was further confirmed by dual luciferase reporter assay and related expression detection. Accordingly, silenced PDK4 attenuated cardiac dysfunction, immune disorder and myocardial apoptosis in immature rats and enhanced the ability of antioxidant enzymes. What is more, activated SMAD pathway induced by MI/R injury was then blocked by silenced PDK4. Taken together, our study demonstrated that overexpressed miR-148 relieved cardiac dysfunction, immune disorder and cardiomyocyte apoptosis in immature MI/R rats by PDK4 inhibition, which provided novel targets for MI/R injury treatment.

13.
Am J Obstet Gynecol ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34461074

RESUMO

BACKGROUND: Minimally invasive radical trachelectomy has emerged as an alternative to open radical hysterectomy for patients with early-stage cervical cancer desiring future fertility. Recent data suggest worse oncologic outcomes after minimally invasive radical hysterectomy than after open radical hysterectomy in stage I cervical cancer. OBJECTIVE: We aimed to compare 4.5-year disease-free survival after open vs minimally invasive radical trachelectomy. STUDY DESIGN: This was a collaborative, international retrospective study (International Radical Trachelectomy Assessment Study) of patients treated during 2005-2017 at 18 centers in 12 countries. Eligible patients had squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma; had a preoperative tumor size of ≤2 cm; and underwent open or minimally invasive (robotic or laparoscopic) radical trachelectomy with nodal assessment (pelvic lymphadenectomy and/or sentinel lymph node biopsy). The exclusion criteria included neoadjuvant chemotherapy or preoperative pelvic radiotherapy, previous lymphadenectomy or pelvic retroperitoneal surgery, pregnancy, stage IA1 disease with lymphovascular space invasion, aborted trachelectomy (conversion to radical hysterectomy), or vaginal approach. Surgical approach, indication, and adjuvant therapy regimen were at the discretion of the treating institution. A total of 715 patients were entered into the study database. However, 69 patients were excluded, leaving 646 in the analysis. Endpoints were the 4.5-year disease-free survival rate (primary), 4.5-year overall survival rate (secondary), and recurrence rate (secondary). Kaplan-Meier methods were used to estimate disease-free survival and overall survival. A post hoc weighted analysis was performed, comparing the recurrence rates between surgical approaches, with open surgery being considered as standard and minimally invasive surgery as experimental. RESULTS: Of 646 patients, 358 underwent open surgery, and 288 underwent minimally invasive surgery. The median (range) patient age was 32 (20-42) years for open surgery vs 31 (18-45) years for minimally invasive surgery (P=.11). Median (range) pathologic tumor size was 15 (0-31) mm for open surgery and 12 (0.8-40) mm for minimally invasive surgery (P=.33). The rates of pelvic nodal involvement were 5.3% (19 of 358 patients) for open surgery and 4.9% (14 of 288 patients) for minimally invasive surgery (P=.81). Median (range) follow-up time was 5.5 (0.20-16.70) years for open surgery and 3.1 years (0.02-11.10) years for minimally invasive surgery (P<.001). At 4.5 years, 17 of 358 patients (4.7%) with open surgery and 18 of 288 patients (6.2%) with minimally invasive surgery had recurrence (P=.40). The 4.5-year disease-free survival rates were 94.3% (95% confidence interval, 91.6-97.0) for open surgery and 91.5% (95% confidence interval, 87.6-95.6) for minimally invasive surgery (log-rank P=.37). Post hoc propensity score analysis of recurrence risk showed no difference between surgical approaches (P=.42). At 4.5 years, there were 6 disease-related deaths (open surgery, 3; minimally invasive surgery, 3) (log-rank P=.49). The 4.5-year overall survival rates were 99.2% (95% confidence interval, 97.6-99.7) for open surgery and 99.0% (95% confidence interval, 79.0-99.8) for minimally invasive surgery. CONCLUSION: The 4.5-year disease-free survival rates did not differ between open radical trachelectomy and minimally invasive radical trachelectomy. However, recurrence rates in each group were low. Ongoing prospective studies of conservative management of early-stage cervical cancer may help guide future management.

14.
3 Biotech ; 11(8): 391, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34458061

RESUMO

Bioassay-guided experimental design and chromatographic analysis led to the isolation and identification of ten compounds (1-10) including two unusual sulfur-containing curvularin macrolides (1 and 2) from a Hawaiian fungal strain Aspergillus polyporicola FS910. Compounds 1 and 2 are rare curvularin macrolides each with a five-membered cyclic sulfur-containing moiety. The structures of the compounds were identified by HRESIMS, NMR spectroscopy, X-ray crystallography, ECD and DFT energy calculation, as well as comparing with previous literatures. Compounds 4, 6 and 8 were active against TNF-α-induced NF-κB inhibitory activity with IC50 values of 26.45, 5.41 and 15.8 µM, respectively. Compounds 3 and 5-8 exhibited anti-proliferative activity against HT1080, T46D, and A2780S cell lines, with IC50 values ranging from 2.48 to 29.17 µM. Additionally, Compound 3 showed promising antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), Bacillus subtilis, Escherichia coli and Candida albicans. Moreover, when tested in combination with antibiotic adjuvant disulfiram [4 µg/mL], compounds 4, 5 and 10 also displayed significant antibacterial activity against S. aureus. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-021-02877-7.

15.
Front Chem ; 9: 724617, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34434921

RESUMO

Two new alkaloids tryptoquivaline Y (1) and pseurotin I (2), together with eight known compounds (3-10), were purified from a fungal strain Aspergillus felis FM324, which was isolated from a Hawaiian beach soil sample. The absolute configuration and physicochemical data of tryptoquivaline Z (3) were reported for the first time here in this paper. Compound 1 is an uncommon tryptoquivaline analog containing a 3-O-isobutanoyl group. The structures of the new compounds 1-2 and known compound 3 were elucidated through HRESIMS, NMR spectroscopy and ECD analysis. All the compounds were evaluated for their antiproliferative, antibacterial and NF-κB inhibitory activities. Compound 4 showed weak antibacterial activity against Staphylococcus aureus, methicillin resistant Staphylococcus aureus and Bacillus subtilis with the same MIC value of 59.2 µM. Compounds 3 and 2 inhibited NF-κB with IC50 values of 26.7 and 30.9 µM, respectively.

16.
Cell Rep ; 36(6): 109502, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34380037

RESUMO

Enhanced appetite occurs as a means of behavioral thermoregulation at low temperature. Neural circuitry mediating this crosstalk between behavioral thermoregulation and energy homeostasis remains to be elucidated. We find that the hypothalamic orexigenic agouti-related neuropeptide (AgRP) neurons in the arcuate nucleus (ARC) are profoundly activated by cold exposure. The calcium signals in ARCAgRP neurons display an immediate-response pattern in response to cold stimulation. Cold-responsive neurons in the medial preoptic area (mPOA) make excitatory synapses onto ARCAgRP neurons. Inhibition of either ARCAgRP neurons or ARC-projecting mPOA neurons attenuates cold-evoked feeding, while activation of the mPOA-to-ARC projection increases food intake. These findings reveal an mPOA-ARCAgRP neural pathway that modulates cold-evoked feeding behavior.

17.
Quant Imaging Med Surg ; 11(8): 3392-3398, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34341717

RESUMO

Background: To assess the diagnostic accuracy of 18F-FDG PET/CT to determine the Eisenkop score and peritoneal cancer index (PCI) in correlation with surgical findings. Methods: Forty-three patients underwent preoperative 18F-FDG PET/CT scan, followed by primary cytoreductive surgery for advanced ovarian cancer between September 2015 and February 2018. Clinical data were prospectively collected, including intraoperative assessment (with Eisenkop and PCI scores) and surgical results. The sensitivity, specificity, and accuracy were calculated at each anatomical site. The Eisenkop score, PCI score, and tumor volume of PET/CT scans were compared with surgical findings. Results: A total of 32 (74.4%) patients were diagnosed with stage III, and 11 (25.6%) patients were stage IV. Among these individuals, 19 (44.2%) patients had no residual disease after primary surgery. The median [range] Eisenkop score on PET/CT scans and surgical findings were 5 [1-13] and 6 [2-13], respectively. PET/CT scans correctly predicted the Eisenkop score with high sensitivity (84.2%), specificity (87.0%), and accuracy (85.1%). The diagnostic accuracy of PET/CT scans for PCI scores was lower (78.5%), with 72.7% sensitivity and 84.9% specificity. Preoperative PET/CT scans might underestimate tumor volume compared with surgical findings. Conclusions: 18F-FDG PET/CT scans accurately predicted peritoneal metastases in advanced ovarian cancer before surgery using Eisenkop score.

18.
Clin Transl Med ; 11(8): e500, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34459128

RESUMO

BACKGROUND: High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive histotype of epithelial ovarian cancer. The heterogeneity and molecular basis of this disease remain incompletely understood. METHODS: To address this question, we have performed a single-cell transcriptomics analysis of matched primary and metastatic HGSOC samples. RESULTS: A total of 13 571 cells are categorized into six distinct cell types, including epithelial cells, fibroblast cells, T cells, B cells, macrophages, and endothelial cells. A subset of aggressive epithelial cells with hyperproliferative and drug-resistant potentials is identified. Several new markers that are highly expressed in epithelial cells are characterized, and their roles in ovarian cancer cell growth and migration are further confirmed. Dysregulation of multiple signaling pathways, including the translational machinery, is associated with ovarian cancer metastasis through the trajectory analysis. Moreover, single-cell regulatory network inference and clustering (SCENIC) analysis reveals the gene regulatory networks and suggests the JUN signaling pathway as a potential therapeutic target for treatment of ovarian cancer, which is validated using the JUN/AP-1 inhibitor T-5224. Finally, our study depicts the epithelial-fibroblast cell communication atlas and identifies several important receptor-ligand complexes in ovarian cancer development. CONCLUSIONS: This study uncovers new molecular features and the potential therapeutic target of HGSOC, which would advance the understanding and treatment of the disease.

19.
Nurs Crit Care ; 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34261191

RESUMO

BACKGROUND: Nurse turnover is considered a major cause of nurse shortage, representing problems for health care systems in terms of both quality and cost of care for patients, and intention to leave is the strongest practical predictor variable of actual turnover. AIMS AND OBJECTIVES: This systematic review and meta-analysis aims at exploring the global prevalence of turnover intention in intensive care nurses. DESIGN: This was a systematic literature review. METHODS: A systematic review of empirical quantitative studies on turnover intention in nurses of intensive care units (ICUs), published in English till March 2021, was conducted. The databases PubMed, Embase, ISI Web of Knowledge, and CINAHL were searched. Eligible studies were observational or descriptive studies that reported the prevalence of turnover intention among nurses in all types of ICUs. The quality of studies was assessed using a modified Newcastle-Ottawa Scale. A random effect meta-analysis was conducted to estimate the pooled prevalence of turnover intention among ICU nurses. RESULTS: We identified 18 cross-sectional studies investigating a total of 23 140 intensive care nurses from 23 countries. The intention to leave rate was ranged from 3.0% to 75.0%. The pooled prevalence of turnover intention was 27.7% (95% confidence interval: 21.6%-34.3%). CONCLUSIONS: This meta-analysis showed that more than 27% of the intensive care nurses had the intention to leave worldwide. In the current context of nursing shortage, efforts should be made to improve conditions for this important group of care providers. RELEVANCE TO CLINICAL PRACTICE: The prevalence of turnover intention is relatively high among intensive care nurses. Nurse managers should take this intention seriously, as the intention to leave may lead to an actual decision to leave the profession.

20.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202670

RESUMO

Astragalus membranaceus is a famous herb found among medicinal and food plants in East and Southeastern Asia. The Nrf2-ARE assay-guided separation of an extract from Jing liqueur led to the identification of a nontoxic Nrf2 activator, methylnissolin-3-O-ß-d-glucopyranoside (MNG, a component of A. membranaceus). Nrf2 activation by MNG has not been reported before. Using Western Blot, RT-qPCR and imaging, we investigated the cytoprotective effect of MNG against hydrogen peroxide-induced oxidative stress. MNG induced the expression of Nrf2, HO-1 and NQO1, accelerated the translocation of Nrf2 into nuclei, and enhanced the phosphorylation of AKT. The MNG-induced expression of Nrf2, HO-1, and NQO1 were abolished by Nrf2 siRNA, while the MNG-induced expression of Nrf2 and HO-1 was abated and the AKT phosphorylation was blocked by LY294002 (a PI3K inhibitor). MNG reduced intracellular ROS generation. However, the protection of MNG against the H2O2 insult was reversed by Nrf2 siRNA with decreased cell viability. The enhancement of Nrf2 and HO-1 by MNG upon H2O2 injury was reduced by LY294002. These data showed that MNG protected EA.hy926 cells against oxidative damage through the Nrf2/HO-1 and at least partially the PI3K/Akt pathways.


Assuntos
Astragalus propinquus/química , Citoproteção/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Cromonas , Células Hep G2 , Humanos , Morfolinas , Compostos Fitoquímicos/química
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