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1.
J Immunother Cancer ; 9(4)2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33820822

RESUMO

BACKGROUND: Programmed death-1 (PD-1) blockade monotherapy induced durable remission in a subset of patients with relapsed/refractory classical Hodgkin lymphoma (cHL). We asked whether the anti-PD-1 agent, camrelizumab, combined with the DNA demethylating agent, decitabine, improves progression-free survival (PFS) in patients with relapsed/refractory cHL over camrelizumab alone. METHODS: This extended follow-up of an ongoing randomized phase II trial analyzed PFS among patients enrolled from January 2017 through July 2018. Sixty-one patients with relapsed/refractory cHL who were clinically naïve to PD-1 blockade and had received ≥2 previous therapies were randomized 1:2 to receive either camrelizumab (200 mg) monotherapy or camrelizumab (200 mg, day 8) combined with decitabine (10 mg/day, days 1-5) every 3 weeks. RESULTS: With a median follow-up of 34.5 months, complete remission was 79% (95% CI 63% to 90%) in the decitabine-plus-camrelizumab group versus 32% (95% CI 13% to 57%) in the camrelizumab group (p=0.001). Median duration of response was not reached in the decitabine-plus-camrelizumab group, with an estimated 63% (95% CI 46% to 75%) of patients maintaining a response at 24 months. Median PFS with decitabine-plus-camrelizumab therapy was 35.0 months (95% CI not reached) and 15.5 months (95% CI 8.4 to 22.7 months) with camrelizumab monotherapy (HR, 0.46; 95% CI 0.21 to 1.01; p=0.02). Female gender, lower tumor burden, and fewer previous therapies were favorable prognostic factors for durable remission with camrelizumab monotherapy. The PFS benefits of decitabine-plus-camrelizumab versus camrelizumab were observed in most subgroups, especially in patients with relative larger tumor burdens and those treated with ≥3 prior therapies. After decitabine-plus-camrelizumab treatment, the percentage increase of circulating peripheral central memory T-cells correlated with both improved clinical response and PFS, suggesting a putative biomarker of decitabine-plus-camrelizumab therapy for cHL. CONCLUSIONS: Decitabine-plus-camrelizumab results in longer PFS compared with camrelizumab alone in patients with relapsed/refractory cHL. TRIAL REGISTRATION NUMBERS: NCT02961101 and NCT03250962.

2.
J Trace Elem Med Biol ; 66: 126755, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33838565

RESUMO

OBJECTIVE: We aimed to evaluate the association between baseline plasma zinc and the development of proteinuria as well as possible effect modifiers in hypertensive patients. METHODS: This is a subset of the China Stroke Primary Prevention Trial (CSPPT) Renal Sub-Study. In the CSPPT, participants were randomized to receive a daily oral dose of 1 tablet containing 10 mg enalapril and 0.8 mg folic acid or 1 tablet containing 10 mg enalapril only. A total of 783 participants with plasma zinc measurements and without proteinuria at baseline were included in the current study. The study outcome was the development of proteinuria during the follow-up, defined as a urine dipstick reading of trace or ≥1+ at the exit visit. RESULTS: During a median follow-up duration of 4.4 years, the development of proteinuria occurred in 93 (11.9 %) participants. There was an inverse relation of baseline plasma zinc with the development of proteinuria (per SD increment; OR, 0.74, 95 % CI: 0.55-0.99), p for trend of quartiles = 0.005. CONCLUSIONS: In Chinese hypertensive patients, there was a significant inverse association between baseline plasma zinc and the development of proteinuria, although plasma zinc remained in the reference range.

3.
Gene ; 785: 145620, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33794327

RESUMO

Fritillariae cirrhosae bulbus, a well-known and precious medicinal and edible herb in China, causes remarkable effects on swelling and relieving cough, with fewer side effects than other congeneric medicine. It has been subject to various cheaper congeneric adulteration because of its high price and limited production. In this paper, a rapid, high throughput, sensitive and efficient technique was described for simultaneous identification of F. cirrhosae bulbus and its common adulterants by employing multiplex ligation-dependent probe amplification coupled with high-resolution melting (MLPA-HRM) curve assay in their internal transcribed spacer 1 (ITS1) regions. This assay was highly sensitive with a detection limit of 0.19 ng genomic DNA, and highly specific with no cross-reaction with common adulterants. Mixed sample analysis showed as low as 10% adulteration can be detected from F. cirrhosae bulbus in one MLPA-HRM reaction. Overall, the method described in this paper is well suited for detecting adulteration in F. cirrhosae bulbus.

4.
Eat Weight Disord ; 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33844178

RESUMO

PURPOSE: Visceral adiposity index (VAI) is a reliable indicator for the distribution and function of adipose tissue in the body. The relation of VAI with new-onset type 2 diabetes and new-onset impaired fasting glucose (IFG) remains uncertain. We aimed to investigate the prospective relation of VAI with new-onset type 2 diabetes and new-onset IFG in Chinese hypertensive adults. METHODS: A total of 14,838 hypertensive adults free of type 2 diabetes at baseline were included from the China Stroke Primary Prevention Trial. The primary outcome was new-onset type 2 diabetes, defined as physician-diagnosed diabetes or use of glucose-lowering drugs during follow-up, or fasting glucose ≥ 7.0 mmol/L at the exit visit. The secondary outcome was new-onset IFG, defined as fasting glucose < 6.1 mmol/L at baseline, while fasting glucose ≥ 6.1 mmol/L and < 7.0 mmol/L at the exit visit. RESULTS: Over a median of 4.5 years' follow-up, 1612 (10.9%) participants developed type 2 diabetes. When VAI was categorized into quartiles, compared with participants in quartile 1-3 (< 2.80), significantly higher risk of new-onset type 2 diabetes (OR 1.30; 95% CI 1.08-1.56) and new-onset IFG (OR 1.28; 95% CI 1.08-1.52) was found in those in quartile 4 (≥ 2.80). Moreover, the positive associations were consistent in participants with or without single abnormal VAI components, including general obesity, abdominal obesity, elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C) levels; or with different numbers of abnormal VAI components (all P interactions > 0.05). CONCLUSION: Our study suggested a positive relation of VAI with the risk of new-onset type 2 diabetes and new-onset IFG in Chinese hypertensive patients, independent of its components. LEVEL OF EVIDENCE: Level III, a well-designed cohort.

5.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33809929

RESUMO

The occurrence of distant tumor metastases is a major barrier in non-small cell lung cancer (NSCLC) therapy, and seriously affects clinical treatment and patient prognosis. Recently, long non-coding RNAs (lncRNAs) have been demonstrated to be crucial regulators of metastasis in lung cancer. The aim of this study was to reveal the underlying mechanisms of a novel lncRNA LNC CRYBG3 in regulating NSCLC metastasis. Experimental results showed that LNC CRYBG3 was upregulated in NSCLC cells compared with normal tissue cells, and its level was involved in these cells' metastatic ability. Exogenously overexpressed LNC CRYBG3 increased the metastatic ability and the protein expression level of the metastasis-associated proteins Snail and Vimentin in low metastatic lung cancer HCC827 cell line. In addition, LNC CRYBG3 contributed to HCC827 cell metastasis in vivo. Mechanistically, LNC CRYBG3 could directly combine with eEF1A1 and promote it to move into the nucleus to enhance the transcription of MDM2. Overexpressed MDM2 combined with MDM2 binding protein (MTBP) to reduce the binding of MTBP with ACTN4 and consequently increased cell migration mediated by ACTN4. In conclusion, the LNC CRYBG3/eEF1A1/MDM2/MTBP axis is a novel signaling pathway regulating tumor metastasis and may be a potential therapeutic target for NSCLC treatment.

6.
Plant J ; 2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33713355

RESUMO

Cucurbit phloem is complex, with large sieve tubes on both sides of the xylem (bicollateral phloem), and extrafascicular elements that form an intricate web linking the rest of the vasculature. Little is known of the physical interconnections between these networks or their functional specialization, largely because the extrafascicular phloem strands branch and turn at irregular angles. Here, export in the phloem from specific regions of the lamina of cucumber (Cucumis sativus L.) was mapped using carboxyfluorescein and 14 C as mobile tracers. We also mapped vascular architecture by conventional microscopy and X-ray computed tomography using optimized whole-tissue staining procedures. Differential gene expression in the internal (IP) and external phloem (EP) was analyzed by laser-capture microdissection followed by RNA-seq. The vascular bundles of the lamina form a nexus at the petiole junction, emerging in a predictable pattern, each bundle conducting photoassimilate from a specific region of the blade. The vascular bundles of the stem interconnect at the node, facilitating lateral transport around the stem. Elements of the extrafascicular phloem traverse the stem and petiole obliquely, joining the IP and EP of adjacent bundles. Using pairwise comparisons and weighted gene coexpression network analysis (WGCNA), we found differences in gene expression patterns between the petiole and stem and between IP and EP, and we identified hub genes of tissue-specific modules. Genes related to transport were expressed primarily in the EP while those involved in cell differentiation and development as well as amino acid transport and metabolism were expressed mainly in the IP.

7.
J Environ Manage ; 288: 112382, 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33756386

RESUMO

With rapid economic growth and urbanisation, the reuse and recycling of solid wastes has become a high priority for the sustainable development of modern cities. In this study, two typical solid wastes, incinerated sewage sludge ash (ISSA) and waste bentonite, were co-valorised to produce granular adsorbents through a simple and energy-saving pelletisation/sintering process. A mixture of ISSA and bentonite at a weight ratio of 3:1 was pelletised and sintered at 700 °C. The resultant ceramsite, with good mechanical strength, could effectively remove Pb(Ⅱ) from aqueous solutions. The adsorption kinetics can be described by the pseudo-first-order (PFO) model. The results indicated that the Pb(Ⅱ) adsorption process was dominated by electrostatic attraction, precipitation, and complexation. The isothermal data exhibited a good correlation with the Freundlich model, indicating that the adsorption process was non-ideal and spontaneous. The maximum adsorption capacity was approximately 21.6 ± 0.35 mg/g at 318 K. After 5 cycles of regeneration, the adsorbent maintained good adsorption performance. Moreover, the removal rate was not greatly affected by ionic strength. These findings demonstrate that the granular adsorbent prepared with ISSA and waste bentonite can be recognised as a promising adsorbent for Pb-containing wastewater treatment.

8.
J Control Release ; 333: 362-373, 2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33785418

RESUMO

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. There are still challenges for HCC treatments, especially high resistance of the cancer cells to chemotherapy and/or target therapy. In this study, a responsive charge-reversal vehicle consists of negatively charged heparin core and positively charged ethanolamine (EA)-modified poly(glycidyl methacrylate) (PGEA) shell (named Hep@PGEA) with self-accelerating release for condensed nucleic acids was proposed to deliver the pCas9 plasmid encoding clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) and the sgRNA targeting oncogene survivin to treat HCC. The Hep@PGEA/pCas9 system showed high anti-tumor efficiency via inducing apoptosis and inhibiting proliferation, migration and invasion capability of HCC cells. The Hep@PGEA/pCas9 system was further utilized to treat orthotopic HCC in mice via tail vein injection. The system exhibited an evident accumulation in the liver of mice and achieved obvious anti-tumor effects. The Hep@PGEA/pCas9 system also showed marked improvement of HCC therapy with sorafenib and provided promising combination HCC treatment potentials. Moreover, enrichment of the Hep@PGEA-based delivery system in liver highlights its possibilities for treatments of other liver diseases.

9.
BMC Health Serv Res ; 21(1): 258, 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33743706

RESUMO

BACKGROUND: To investigate the impact of the US Medicaid expansion on care utilization and health outcomes of patients treated in the inpatient rehabilitation facilities (IRF). METHODS: A retrospective observational study with a difference-in-difference design. The data was obtained from Inpatient Rehabilitation Facility - Patient Assessment Instrument (IRF-PAI). Sample included all Medicaid beneficiaries (aged 18-64 years) who received initial inpatient rehabilitation for stroke, hip fracture (acute conditions), or joint replacement (elective condition) (N = 14,917) before (2013) and after (2016) the expansion. The study estimated the differences in length of stay, functional improvement, and possibility of returning to community before and after ACA Medicaid expansion in the expansion regions relative to the non-expansion regions. The analysis was fully adjusted for patient demographics, health conditions, facility characteristics and time trends. RESULTS: Compared with non-expansion states, service volume in the expansion regions increased more for the two acute conditions (49 and 27% vs. 1% and - 4%) and decreased less for the selective condition (- 12% vs. -34%) after ACA Medicaid expansion. Medicaid expansion was associated with significant decreases in patient functional improvements (- 1.63 points for stroke, - 3.61 points for fracture and - 2.73 points for joint; P < 0.05). Length of stay and the possibility of returning to community after discharge were not significantly different. CONCLUSIONS: Medicaid expansion was associated with increases in the utilization of inpatient rehabilitation services and decreases in the patient functional improvements. Cautions should be taken with the decreases in functional improvements among some subpopulation in the short-term; longer follow up periods are needed to account for gradual changes in patient needs.

10.
ACS Sens ; 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33761245

RESUMO

X-ray dosimeters are of significance for detecting the levels of ionizing radiation exposure in cells and phantoms; thus, they can further optimize X-ray radiotherapy in the clinic. In this paper, we designed a polyacrylamide-based nanogel sensor that is capable of measuring X-ray doses. The dosimeters were prepared by anchoring an X-ray-responsive probe (aminophenyl fluorescein, APF) to poly(acrylamide-co-N-(3-aminopropyl) methyl acrylamide) nanogels. The premise behind the dose measurement is the transition of APF to fluorescence in the presence of hydroxyl radicals that are caused by the radiolysis of water molecules under X-rays. Therefore, the dose of X-rays can be readily detected by measuring the fluorescence intensity of the resultant nanogel immediately after irradiation using fluorescence spectroscopy principles. Using an RS2000 X-ray biological irradiator, our dosimeters showed good linearity responsivity at X-ray doses ranging from 0 to 15 Gy, with a limit of detection (LOD) of 0.5 Gy. Additionally, the signals showed temperature stability (25-65 °C), durability (5 weeks), and dose-rate (1.177 and 6 Gy/min) and energy independence (160 kVp and 6 MV). As a proof-of-concept, we used our sensors to fluorescently detect X-ray doses in A549 tumor cells and 3D-printed eye phantoms. The results showed that our dosimeters were able to accurately predict doses similar to those used by treatment plan systems.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33653812

RESUMO

BACKGROUND: There is growing evidence of an association between sugar-sweetened beverages (SSB) and increased risk of mortality in various populations. However, SSB influence on mortality among breast cancer patients is unknown. METHODS: We assessed the relationship between sugar-sweetened soda and both all-cause and breast cancer mortality among women with incident, invasive breast cancer from the Western New York Exposures and Breast Cancer (WEB) Study. Breast cancer cases were followed for a median of 18.7 years, with ascertainment of vital status via the National Death Index (NDI). Frequency of sugar-sweetened soda consumption was determined via a food frequency questionnaire (FFQ). Cox proportional hazards, adjusting for relevant variables, were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Of the 927 breast cancer cases, 386 (54.7%) had died by the end of follow-up. Compared to never/rarely sugar-sweetened soda drinkers, consumption at {greater than or equal to} 5 times per week was associated with increased risk of both total (HR=1.62, 95% CI: 1.16, 2.26, p-trend<0.01) and breast cancer mortality (HR=1.85, 95% CI: 1.16, 2.94; p-trend<0.01). Risk of mortality was similarly increased among ER-positive, but not ER-negative patients, among women with BMI above the median, but not below the median; and among pre-, but not post-menopausal women for total mortality only. CONCLUSIONS: Reported higher frequency of sugar-sweetened soda intake was associated with increased risks of total and breast cancer mortality among breast cancer patients. IMPACT: These results support existing guidelines on reducing consumption of SSB, including for women with a diagnosis of breast cancer.

12.
J Neurosurg ; : 1-12, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33668037

RESUMO

OBJECTIVE: An assessment of the transcranial approach (TCA) and the endoscopic endonasal approach (EEA) for craniopharyngiomas (CPs) according to tumor types has not been reported. The aim of this study was to evaluate both surgical approaches for different types of CPs. METHODS: A retrospective review of primary resected CPs was performed. A QST classification system based on tumor origin was used to classify tumors into 3 types as follows: infrasellar/subdiaphragmatic CPs (Q-CPs), subarachnoidal CPs (S-CPs), and pars tuberalis CPs (T-CPs). Within each tumor type, patients were further arranged into two groups: those treated via the TCA and those treated via the EEA. Patient and tumor characteristics, surgical outcomes, and postoperative complications were obtained. All variables were statistically analyzed between surgical groups for each tumor type. RESULTS: A total of 315 patients were included in this series, of whom 87 were identified with Q-CPs (49 treated via TCA and 38 via EEA); 56 with S-CPs (36 treated via TCA and 20 via EEA); and 172 with T-CPs (105 treated via TCA and 67 via EEA). Patient and tumor characteristics were equivalent between both surgical groups in each tumor type. The overall gross-total resection rate (90.5% TCA vs 91.2% EEA, p = 0.85) and recurrence rate (8.9% TCA vs 6.4% EEA, p = 0.35) were similar between surgical groups. The EEA group had a greater chance of visual improvement (61.6% vs 35.8%, p = 0.01) and a decreased risk of visual deterioration (1.6% vs 11.0%, p < 0.001). Of the patients with T-CPs, postoperative hypothalamic status was better in the TCA group than in the EEA group (p = 0.016). Postoperative CSF leaks and nasal complication rates occurred more frequently in the EEA group (12.0% vs 0.5%, and 9.6% vs 0.5%; both p < 0.001). For Q-CPs, EEA was associated with an increased gross-total resection rate (97.4% vs 85.7%, p = 0.017), decreased recurrence rate (2.6% vs 12.2%, p = 0.001), and lower new hypopituitarism rate (28.9% vs 57.1%, p = 0.008). The recurrence-free survival in patients with Q-CPs was also significantly different between surgical groups (log-rank test, p = 0.037). The EEA required longer surgical time for T-CPs (p = 0.01). CONCLUSIONS: CPs could be effectively treated by radical surgery with favorable results. Both TCA and EEA have their advantages and limitations when used to manage different types of tumors. Individualized surgical strategies based on tumor growth patterns are mandatory to achieve optimal outcomes.

13.
Clin Cancer Res ; 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674274

RESUMO

PURPOSE: Programmed death-1 (PD-1) blockade monotherapy is effective in relapsed/refractory classical Hodgkin lymphoma (cHL), but a subset of patients is recalcitrant to PD-1 inhibitors and only a minority of patients achieves durable remission. Effective treatment regimens for those with relapsed/progressive cHL after single-agent anti-PD-1 are urgently needed. Anti-PD-1 combination with the DNA-demethylating agent decitabine showed positive preliminary results in our test cohort patients who were resistant to anti-PD-1. Here, we assess the efficacy of decitabine plus anti-PD-1 therapy in an expansion cohort and after longer follow-up. PATIENTS AND METHODS: We present the response and progression-free survival rates from patients with relapsed/refractory cHL who relapsed/progressed after prior anti-PD-1 monotherapy, and who received decitabine (10 mg/day, days 1-5) plus the anti-PD-1 camrelizumab (200 mg, day 8), every 3 weeks in a phase II trial (ClinicalTrials.gov: NCT02961101 and NCT03250962). RESULTS: Overall, 51 patients (test cohort: 25, expansion cohort: 26) were treated and 50 evaluated for efficacy. The objective response rate was 52% [nine complete responses (CR); 36%] in the test cohort, and 68% (six CRs; 24%) in the expansion cohort. Median progression-free survival with decitabine plus camrelizumab was 20.0 and 21.6 months, respectively, which was significantly longer than that achieved with prior anti-PD-1 monotherapy. Durable response was observed in an estimated 78% of patients who achieved CR at 24 months. After decitabine plus camrelizumab, the ratio increase of circulating peripheral central memory T cells directly correlated with both clinical response and progression-free survival. CONCLUSIONS: Decitabine plus camrelizumab is associated with high response rates and long-term benefits in patients with relapsed/refractory cHL who failed PD-1 inhibitors.

14.
Proc Natl Acad Sci U S A ; 118(8)2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33602821

RESUMO

Plant cystatins are cysteine proteinase inhibitors that play key roles in defense responses. In this work, we describe an unexpected role for the cystatin-like protein DEFORMED FLORAL BUD1 (CsDFB1) as a transcriptional regulator of local auxin distribution in cucumber (Cucumis sativus L.). CsDFB1 was strongly expressed in the floral meristems, floral primordia, and vasculature. RNA interference (RNAi)-mediated silencing of CsDFB1 led to a significantly increased number of floral organs and vascular bundles, together with a pronounced accumulation of auxin. Conversely, accompanied by a decrease of auxin, overexpression of CsDFB1 resulted in a dramatic reduction in floral organ number and an obvious defect in vascular patterning, as well as organ fusion. CsDFB1 physically interacted with the cucumber ortholog of PHABULOSA (CsPHB), an HD-ZIP III transcription factor whose transcripts exhibit the same pattern as CsDFB1 Overexpression of CsPHB increased auxin accumulation in shoot tips and induced a floral phenotype similar to that of CsDFB1-RNAi lines. Furthermore, genetic and biochemical analyses revealed that CsDFB1 impairs CsPHB-mediated transcriptional regulation of the auxin biosynthetic gene YUCCA2 and the auxin efflux carrier PIN-FORMED1, and thus plays a pivotal role in auxin distribution. In summary, we propose that the CsDFB1-CsPHB module represents a regulatory pathway for local auxin distribution that governs floral organogenesis and vascular differentiation in cucumber.

15.
Nanotechnology ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33561843

RESUMO

Lead halide quantum dots have unique optical properties such as a tunable wavelength, narrow band, and high quantum efficiency, and have been used in optoelectronics such as light-emitting diode (LED) device, and photodetector. Recently, solution-processed perovskite has also attracted great attention for high sensitivity X-ray detector. Here, we have investigated the scintillation performances of Pb halide perovskite quantum dots solution. Both CH3NH3PbBr3 and CsPbBr3 quantum dots liquid scintillator exhibits the scintillation performances such as the linear relationship with the irradiation dose rate in a wide range, high radiation hardness, thermal stability, and fast counting speed. The scintillation performances of these liquid perovskite quantum dots solution provide a promising potential application for indirect radiation applications including fast gamma-ray counter and wide range dosimeter.

16.
Hypertens Res ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33564178

RESUMO

We aimed to investigate the association between neutrophil counts and first stroke and examine possible effect modifiers among treated hypertensive adults. This is a post hoc analysis of the China Stroke Primary Prevention Trial (CSPPT). A total of 11,878 hypertensive adults with data on neutrophil counts at baseline were included in the current study. The primary outcome was first stroke. During a median follow-up of 4.5 years, 414 (3.5%) participants experienced a first stroke, including 358 with ischemic stroke, 55 with hemorrhagic stroke and one with uncertain type of stroke. Compared with participants in quartile 1 (<2.9 × 109/L) of neutrophil counts, those in the upper quartiles (quartile 2-4 [≥2.9 × 109/L]) had a significantly higher risk of first stroke (HR, 1.35; 95% CI: 1.02, 1.78) or first ischemic stroke (HR, 1.38; 95% CI: 1.02, 1.86). Moreover, a strong positive association between neutrophil counts and first ischemic stroke was found in participants with total homocysteine (tHcy) levels <15 µmol/L (HR, 1.74; 95% CI: 1.17, 2.58; vs. ≥15 µmol/L; HR, 0.91; 95% CI: 0.57, 1.46, P interaction = 0.042) at baseline or time-averaged mean arterial pressure (MAP) ≥102 mmHg (median) (HR, 1.92; 95% CI: 1.27, 2.89; vs. <102 mmHg; HR, 0.89; 95% CI: 0.57, 1.41, P interaction = 0.015) during the treatment period. However, no such association between neutrophil counts and first hemorrhagic stroke was found. In summary, high baseline neutrophil counts were associated with an increased risk of first ischemic stroke among hypertensive patients, especially in those with low tHcy at baseline or high time-averaged MAP during the treatment period.

17.
Oncogene ; 40(10): 1821-1835, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33564066

RESUMO

Aneuploidy is a hallmark of genomic instability that leads to tumor initiation, progression, and metastasis. CDC20, Bub1, and Bub3 form the mitosis checkpoint complex (MCC) that binds the anaphase-promoting complex or cyclosome (APC/C), a crucial factor of the spindle assembly checkpoint (SAC), to ensure the bi-directional attachment and proper segregation of all sister chromosomes. However, just how MCC is regulated to ensure normal mitosis during cellular division remains unclear. In the present study, we demonstrated that LNC CRYBG3, an ionizing radiation-inducible long noncoding RNA, directly binds with Bub3 and interrupts its interaction with CDC20 to result in aneuploidy. The 261-317 (S3) residual of the LNC CRYBG3 sequence is critical for its interaction with Bub3 protein. Overexpression of LNC CRYBG3 leads to aneuploidy and promotes tumorigenesis and metastasis of lung cancer cells, implying that LNC CRYBG3 is a novel oncogene. These findings provide a novel mechanistic basis for the pathogenesis of NSCLC after exposure to ionizing radiation as well as a potential target for the diagnosis, treatment, and prognosis of an often fatal disease.

18.
Nat Commun ; 12(1): 409, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462245

RESUMO

Insufficient eradication capacity and dysfunction are common occurrences in T cells that characterize cancer immunotherapy failure. De novo DNA methylation promotes T cell exhaustion, whereas methylation inhibition enhances T cell rejuvenation in vivo. Decitabine, a DNA methyltransferase inhibitor approved for clinical use, may provide a means of modifying exhaustion-associated DNA methylation programmes. Herein, anti-tumour activities, cytokine production, and proliferation are enhanced in decitabine-treated chimeric antigen receptor T (dCAR T) cells both in vitro and in vivo. Additionally, dCAR T cells can eradicate bulky tumours at a low-dose and establish effective recall responses upon tumour rechallenge. Antigen-expressing tumour cells trigger higher expression levels of memory-, proliferation- and cytokine production-associated genes in dCAR T cells. Tumour-infiltrating dCAR T cells retain a relatively high expression of memory-related genes and low expression of exhaustion-related genes in vivo. In vitro administration of decitabine may represent an option for the generation of CAR T cells with improved anti-tumour properties.


Assuntos
Decitabina/farmacologia , Imunoterapia Adotiva/métodos , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/terapia , Linfócitos T/transplante , Animais , Técnicas de Cultura de Células/métodos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Citocinas/genética , Citocinas/imunologia , Metilação de DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Camundongos , Neoplasias/sangue , Neoplasias/imunologia , Neoplasias/patologia , RNA-Seq , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Affect Disord ; 282: 707-711, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33445097

RESUMO

BACKGROUND: The estimated global burden of suicide is almost 1 million deaths per year, representing 57% of all violent deaths worldwide. In order to better identify at risk individuals and develop effective prevention strategies at the population level, a comprehensive understanding of the biological, psychological and social risk factors is required. METHOD: Data from the National Health Interview Survey (1997- 2004) were analyzed. Multivariable Cox proportional hazards regression models were used to compute hazard ratios (HRs) and accompanying 95% confidence intervals (CI). RESULTS: During a mean 6.3 years of follow-up of 242, 952 people (1.56 million person-years), 180 deaths due to suicide occurred. Of 18 risk factors, eight revealed associations with suicide. Participants who had never been married (HR, 2.58; 95% CI, 1.44-4.62), current smokers (HR, 2.26; 1.49-3.43), current drinkers (HR, 1.93; 1.14-3.27]), participants with serious psychological distress (HR, 3.34; 1.81-6.18), and a history of emphysema (HR, 2.79; 1.18-6.59), liver disease (HR, 4.63; 2.10-10.20), kidney disease (HR, 2.26; 1.00-5.06) and cancer (HR, 2.18; 1.32-3.59) were at increased risk of completed suicide. LIMITATIONS: Due to the observational nature of this study, we cannot exclude the possibility of reverse or bi-directional causality. CONCLUSIONS: This large, prospective cohort study identified a series of biopsychosocial risk factors that may have utility in suicide prevention.

20.
Xenobiotica ; 51(5): 513-521, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33512253

RESUMO

6-Hydroxykynurenic acid (6-HKA) is a nitrogen-containing phenolic acid compound in Ginkgo biloba leaves. The pharmacological activities of 6-HKA have been reported and shown that 6-HKA has the potential to become a therapeutic drug and may play an important role in the treatment of nervous system diseases. However, there are few studies on the drug metabolism and transport of 6-HKA. The aim of this study is to investigate the in vitro metabolism of 6-HKA and its interaction with multiple important drug transporters.The in vitro metabolism experiments in the present study demonstrate that 6-HKA might not undergo phase-I or phase-II metabolism in hepatic microsomes/S9 of rats. In addition, some drug transporters, including OAT1/3, OCT2, MDR1, OATP1B1, MATE1/2K and OCTN2, were investigated. The cellular uptake assays indicate that 6-HKA exhibits inhibition to the transport of classical substrates mediated by OAT3, OCT2, MATE2K and OCTN2 but has no significant effect on the transport of substrates mediated by MDR1, OAT1, OATP1B1 or MATE1. Further investigation of cellular accumulation assays shows that 6-HKA might be the substrate of OAT3, but not OCT2 or OCTN2. The bidirectional transport study suggests that 6-HKA is not a substrate of MDR1.The information about the in vitro metabolism of 6-HKA and the interaction between 6-HKA and some transporters will help us to better understand the pharmacokinetic properties of 6-HKA and provide reference for its pharmacodynamics, DDIs and drug-food interactions studies.

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