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1.
J Natl Cancer Inst ; 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-33225344

RESUMO

BACKGROUND: The influence of type 2 diabetes mellitus (T2D) duration on cancer incidence remains poorly understood. METHODS: We prospectively followed for cancer incidence 113 429 women in the Nurses' Health Study (1978-2014) and 45 604 men in the Health Professionals Follow-up Study (1988-2014) who were free of diabetes and cancer at baseline. Cancer incidences were ascertained by review of medical records. RESULTS: In the multivariable-adjusted model incident, T2D was associated with higher risk of cancers in the colorectum, lung, pancreas, esophagus, liver, thyroid, breast, and endometrium. The pooled hazard ratios (HRs) ranged from 1.21 (95% confidence interval [CI] = 1.06 to 1.38) for colorectal cancer to 3.39 (95% CI = 2.24 to 5.12) for liver cancer. For both composite cancer outcomes and individual cancers, the elevated risks did not further increase after 8 years of T2D duration. The hazard ratio for total cancer was 1.28 (95% CI = 1.17 to 1.40) for T2D duration of 4.1-6.0 years, 1.37 (95% CI = 1.25 to 1.50) for 6.1-8.0 years, 1.21 (95% CI = 1.09 to 1.35) for 8.1-10.0 years, and 1.04 (95% CI = 0.95 to 1.14) after 15.0 years. In a cross-sectional analysis, a higher level of plasma C-peptide was found among participants with prevalent T2D of up to 8 years than those without T2D, whereas a higher level of HbA1c was found for those with prevalent T2D of up to 15 years. CONCLUSIONS: Incident T2D was associated with higher cancer risk, which peaked at approximately 8 years after diabetes diagnosis. Similar duration-dependent pattern was observed for plasma C-peptide. Our findings support a role of hyperinsulinemia in cancer development.

2.
Arch Gynecol Obstet ; 2020 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-33221958

RESUMO

PURPOSE: N6-methyladenosine (m6A) and demethylase fat mass and obesity-associated protein (FTO) were reported to be associated with oocyte development and maturation. But the relationship between FTO and ovarian aging was still unclear. This study was aimed at investigating the FTO expression level and the m6A content during ovarian aging. METHODS: The expression level of FTO and the content of m6A RNA methylation in human follicular fluid (FF), granulosa cells (GCs) and mouse ovary from different age groups were studied by ELISA, WB, qRT-PCR, IHC and m6A Colorimetric. RESULTS: Human FF ELISA quantified that the level of FTO protein decreased with age (P = 0.025). QRT-PCR results showed that the relative expression of FTO in human GCs was lower in the elderly group than in the young group (P = 0.012). FTO mRNA and protein expression levels were lower in the ovary of 32-week-old mice than in 3- and 8-week-old mice (P < 0.05). Immunohistochemistry showed FTO was relatively decreased in 32-week-old mice (P < 0.05). The m6A content in total RNA from old human GCs and ovary from 32-week-old mice was significantly higher compared with the younger ones. CONCLUSIONS: In human FF, GCs and mouse ovary, the expression of FTO decreased while the content of m6A increased with aging. However, the inner mechanism still needs further investigation.

3.
Medicine (Baltimore) ; 99(45): e22017, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157910

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 viral infection resulting in corona virus disease 2019 (COVID-19) disease has recently been designated by the World Health Organization as a global pandemic. Some doctors are using convalescent plasma (CP) therapies to treat COVID-19 patients. However, whether CP therapy is effective for children with COVID-19 remains controversial. Therefore, this study further explores the effectiveness and safety of human coronavirus immune CP in the treatment of COVID-19 in children. METHODS: Comprehensively search the electronic databases such as the Cochrane Library, PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure, and WanFang, and collect relevant documents. We will also look for other sources. All document sources will not be restricted by language and publication status. Two researchers will independently conduct research selection, data extraction and research quality assessment. RevMan 5.3 was used for statistical analysis. RESULTS: This study will provide high-quality comprehensive evidence for the effectiveness and safety of human coronavirus immuno CP in the treatment of COVID-19 in children CONCLUSIONS:: The results of this study will provide the basis for the effectiveness and safety of human coronavirus immuno CP treatment of COVID-19 in children. PROSPERO REGISTRATION NUMBER: CRD42020199410.


Assuntos
Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Betacoronavirus , Criança , Criança Hospitalizada , Humanos , Imunização Passiva , Metanálise como Assunto , Pandemias , Projetos de Pesquisa , Revisões Sistemáticas como Assunto
4.
Am J Clin Nutr ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33022694

RESUMO

BACKGROUND: Yogurt is a commonly consumed fermented food. Regular yogurt consumption may contribute to a favorable gut microbiome and gut health, but few epidemiologic studies have considered the relation between regular yogurt consumption and the incidence of and mortality from colorectal cancer. OBJECTIVES: We used data from 2 large, prospective cohort studies, the Nurses' Health Study and the Health Professionals Follow-Up Study, to examine the role of yogurt consumption on colorectal cancer incidence and mortality. METHODS: During 32 years of follow-up in 83,054 women (mean age at baseline, 45.7 years) and 26 years of follow-up in 43,269 men (mean age at baseline, 52.3 years), we documented a total of 2666 newly diagnosed cases of colorectal cancer in these cohorts. We modeled yogurt consumption at baseline and cumulatively updated it throughout follow-up. Results: Baseline yogurt consumption was associated with a reduced risk of colon cancer in age-adjusted analyses (P for trend < 0.001). Associations remained statistically significant after adjusting for potential confounders, including calcium and fiber intake (P for trend = 0.03), and were restricted to proximal colon cancer. The consumption of 1 + servings per week of yogurt at baseline, compared to no yogurt consumption, was associated with a multivariable HR of 0.84 (95% CI, 0.70-0.99; P trend = 0.04) for the proximal colon cancer incidence. Latency analyses suggested that the most important window of opportunity for regular yogurt consumption to prevent colorectal cancer was 16-20 years in the past. When yogurt consumption was cumulatively updated, associations attenuated and were no longer significant. No statistically significant inverse trend was observed between yogurt consumption and the colorectal cancer mortality. CONCLUSIONS: In these large cohorts, the frequency of yogurt consumption was associated with a reduced risk of proximal colon cancer with a long latency period. No significant inverse trend was observed for colorectal cancer mortality.

5.
Biotechnol Lett ; 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33108571

RESUMO

OBJECTIVE: Jatropha curcashas been used in traditional medicine in Africa to treat cancer for thousands of years. This study aimed to examine the anti-endometrial cancer effect of Curcusone C, a naturally occurring rhamnofolane diterpene, isolated from J. curcas and reveal its molecular mechanism of action. RESULTS: Curcusone C treatment caused significant anti-proliferative and apoptotic effects in human endometrial cancer (EC) Ishikawa and HEC-1A cells in a dose-dependent manner. Exposure of EC cells to Curcusone C resulted in apoptosis, which was associated with cytochrome c release, caspase-3 and caspase-9 activation, Bcl-xL/Bax dysregulation, and decreased expression of inhibitors of apoptosis proteins, such as XIAP and survivin. The inhibitory effect induced by Curcusone C was greatly impaired by the overexpression of survivin or Bax-/- MEFs or the knockdown of Bim expression. Moreover, Curcusone C activated mitogen-activated protein kinases, and the ERK inhibitor U0126 significantly attenuated the growth-inhibitory and apoptotic effects of Curcusone C in Ishikawa cells. CONCLUSION: Taken together, the results demonstrate the anti-endometrial cancer potential of Curcusone C for the treatment of endometrial cancer.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33055203

RESUMO

BACKGROUND: Studies have shown an inverse association between use of glucosamine and chondroitin supplements and colorectal cancer risk. However, the association with the precursor lesion, colorectal adenoma and serrated polyp, has not been examined. METHODS: Analyses include 43,163 persons from the Nurses' Health Study (NHS), Health Professionals Follow-up Study (HPFS), and NHS2 who reported on glucosamine/chondroitin use in 2002 and who subsequently underwent ≥1 lower gastrointestinal endoscopy. By 2012, 5,715 conventional (2,016 high-risk) adenomas were detected, as were 4,954 serrated polyps. Multivariable logistic regression for clustered data was used to calculate OR and 95% confidence intervals (CI). RESULTS: Glucosamine/chondroitin use was inversely associated with high risk and any conventional adenoma in NHS and HPFS: in the pooled multivariable-adjusted model, glucosamine + chondroitin use at baseline was associated with a 26% (OR = 0.74; 95% CI, 0.60-0.90; P heterogeneity = 0.23) and a 10% (OR = 0.90; 95% CI, 0.81-0.99; P heterogeneity = 0.36) lower risk of high-risk adenoma and overall conventional adenoma, respectively. However, no association was observed in NHS2, a study of younger women (high-risk adenoma: OR = 1.09; 95% CI, 0.82-1.45; overall conventional adenoma: OR = 1.00; 95% CI, 0.86-1.17), and effect estimates pooled across all three studies were not significant (high-risk: OR = 0.83; 95% CI, 0.63-1.10; P heterogeneity = 0.03; overall conventional adenoma: OR = 0.93; 95% CI, 0.85-1.02; P heterogeneity = 0.31). No associations were observed for serrated polyps. CONCLUSIONS: Glucosamine/chondroitin use was associated with lower risks of high-risk and overall conventional adenoma in older adults; however, this association did not hold in younger women, or for serrated polyps. IMPACT: Our study suggests that glucosamine and chondroitin may act on early colorectal carcinogenesis in older adults.

7.
J Clin Med ; 9(10)2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33007946

RESUMO

Given the unalterable nature of most risk factors for colorectal cancer (CRC) survival (e.g., disease stage), identifying modifiable determinants is critical. We investigated whether anxiety and depression were related to CRC survival using data from the Nurses' Health Study (NHS) and Health Professional Follow-up Study (HPFS). Participants who received a CRC diagnosis and provided information about anxiety (nNHS = 335; nHPFS = 232) and depression (nNHS = 893; nHPFS = 272) within 4 years of diagnosis were included. Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) of overall mortality, while controlling for covariates (sociodemographics, cancer characteristics, and lifestyle factors). Pooled risk estimates were derived from fixed effects meta-analyses of the cohorts. Among 1732 CRC patients, 814 deaths occurred during the 28-year follow-up. Each 1 standard deviation increase in anxiety or depression symptoms was associated with a similar 16% higher mortality risk (anxiety: 95% CI = 1.05-1.29; depression: 95% CI = 1.07-1.26). Comparable results were observed across all sensitivity analyses (introducing a 1-year lag, restricting to CRC-related mortality, considering potential behavioral pathways) and stratified models (cancer stage, sex). Our findings suggest greater anxiety and depression symptoms can not only impede adherence to healthy habits and reduce quality of life in cancer patients but could also be a marker for accelerated CRC progression.

8.
Metabolism ; 113: 154398, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33058854

RESUMO

BACKGROUND & AIMS: Obesity is established as a major risk factor for the development of nonalcoholic fatty liver disease (NAFLD). However, the influence of dynamic changes in adiposity over the life course on NAFLD risk remains poorly understood. METHODS: We collected data from 110,054 women enrolled in the Nurses' Health Study II cohort. Early adulthood weight was ascertained at age 18 years, and weight gain since early adulthood was defined prospectively every 2 years. We used a group-based modeling approach to identify five trajectories of body shape from age 5 years up to age 50 years. NAFLD was defined by physician-confirmed diagnoses of fatty liver, after excluding excess alcohol intake and viral hepatitis, using validated approaches. RESULTS: We documented 3798 NAFLD cases over a total of 20 years of follow-up. Compared to women who maintained stable weight (±2 kg), women with ≥20 kg of adulthood weight gain had the multivariable aHR of 6.96 (95% CI, 5.27-9.18), and this remained significant after further adjusting for early adulthood BMI and updated BMI (both P trend <0.0001). Compared to women with a medium-stable body shape trajectory, the multivariable aHRs for NAFLD were, 2.84 (95% CI, 2.50-3.22) for lean-marked increase, 2.60 (95% CI, 2.27-2.98) for medium-moderate increase, and 3.39 (95% CI, 2.95-3.89) for medium-marked increase. CONCLUSIONS: Both early adulthood weight gain and lifetime body shape trajectory were significantly and independently associated with excess risk of developing NAFLD in mid-life. Maintaining both lean and stable weight throughout life may offer the greatest benefit for the prevention of NAFLD.

9.
Asia Pac J Public Health ; : 1010539520960987, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32975428

RESUMO

This study evaluated the relationships between parity and the age at menopause and menopausal syndrome among Chinese women in Gansu. A total of 7236 women aged 40 to 55 years met study eligibility criteria. The modified Kupperman Menopausal Index scale was used to assess the severity of menopausal syndrome. Cox regression was applied to estimate hazard ratio and 95% confidence interval, and logistic regression was performed to calculate odds ratio and confidence interval. The mean age at menopause was 47.91 ± 3.31 years. There is no relationship between parity and age at menopause. Women with nulliparity or multiparity seemed to have higher risks of moderate and severe menopausal syndrome. The potential beneficial effects of 1 or 2 births on menopausal syndrome were also observed by applying the multivariable logistic regression analysis, particularly in urogenital symptoms. Women with nulliparity and multiparity appeared to be at the higher risks of menopause syndrome.

10.
Crit Rev Biotechnol ; 40(8): 1232-1249, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32907412

RESUMO

In recent years, there has been increasing interest in microbial biotechnology for the production of value-added compounds from renewable resources. Pseudomonas species have been proposed as a suitable workhorse for high-value secondary metabolite production because of their unique characteristics for fast growth on sustainable carbon sources, a clear inherited background, versatile intrinsic metabolism with diverse enzymatic capacities, and their robustness in an extreme environment. It has also been demonstrated that metabolically engineered Pseudomonas strains can produce several industrially valuable aromatic chemicals and natural products such as phenazines, polyhydroxyalkanoates, rhamnolipids, and insecticidal proteins from renewable feedstocks with remarkably high yields suitable for commercial application. In this review, we summarize cell factory construction in Pseudomonas for the biosynthesis of native and non-native bioactive compounds in P. putida, P. chlororaphis, P. aeruginosa, as well as pharmaceutical proteins production by P. fluorescens. Additionally, some novel strategies together with metabolic engineering strategies in order to improve the biosynthetic abilities of Pseudomonas as an ideal chassis are discussed. Finally, we proposed emerging opportunities, challenges, and essential strategies to enable the successful development of Pseudomonas as versatile microbial cell factories for the bioproduction of diverse bioactive compounds.

11.
Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi ; 34(4): 343-345;350, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32842230

RESUMO

Objective:To compare the consistency of RSI and RFS, pepsin detection and 24 h Dx-pH monitoring in the diagnosis of laryngopharyngeal reflux (LPR) in children. Method:A retrospective analysis was made of 76 children with suspicious LPR. A total of 65 children with suspicious LPR were finally diagnosed. RSI and RFS scales, pepsin detection and Dx-pH monitoring were performed simultaneously. The diagnostic consistency of the three methods was tested, and the sensitivity and specificity were calculated. Result:The sensitivity of pepsin detection, 24 h Dx-pH monitoring, RSI and RFS in the diagnosis of LPR in 76 suspected LPR patients were 95.31%, 66.15% and 84.62%, and the specificity were 100%, 81.82% and 72.73%. The pepsin detection was well consistent with the scale(Kappa>0.75), pepsin detection and 24 h Dx-pH monitoring were in medium consistency(Kappa=0.467), and 24 h Dx-pH monitoring and scale were in medium consistency(Kappa=0.446). Conclusion:Pepsin detection can be used as a reliable index for the diagnosis of LPR in children. It is objective, economical, non-invasive, comfortable and easy to spread.


Assuntos
Refluxo Laringofaríngeo , Criança , Monitoramento do pH Esofágico , Humanos , Pepsina A , Estudos Retrospectivos , Sensibilidade e Especificidade
12.
Protein Expr Purif ; 175: 105721, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32763465

RESUMO

Lipomax is a commercialized foldase-dependent Pseudomonas lipase that was previously expressed only in Pseudomonas strains. Here, using Pichia pastoris as the host, we report a new co-expression method that leads to the successful production of Lipomax. The active Lipomax is extracellularly co-expressed with its cognate foldase (LIM); and the purified enzyme mix has the optimum pH at pH 8.0 and an optimal temperature around 40 °C. N-glycosylation was observed for Pichia produced Lipomax, and its reduction was shown to increase the lipolytic activity. With different p-nitrophenyl esters as the substrates, the substrate profiling analyses further indicate that Lipomax prefers esters with middle-long chain fatty acids, showing the highest specific activity to p-nitrophenyl caprylate (C8). The extracellular co-expression of Lipomax and LIM in Pichia will not only increase our ability to investigate additional eukaryotic hosts for lipase expression, but also be of considerable value in analyzing other foldase-dependent lipases.

13.
Environ Res ; 190: 109781, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32791343

RESUMO

INTRODUCTION: Reasons why pancreatic ductal adenocarcinoma (PDAC) continues to have poor survival are only partly known. No previous studies have analyzed the combined influence of KRAS mutations, persistent organic pollutants (POPs), and trace elements upon survival in PDAC or in any other human cancer. OBJECTIVE: To analyze the individual and combined influence of KRAS mutations, POPs, and trace elements upon survival from PDAC. METHODS: Incident cases of PDAC (n = 185) were prospectively identified in five hospitals in Eastern Spain in 1992-1995 and interviewed face-to-face during hospital admission. KRAS mutational status was determined from tumour tissue through polymerase chain reaction and artificial restriction fragment length polymorphism. Blood and toenail samples were obtained before treatment. Serum concentrations of POPs were analyzed by high-resolution gas chromatography with electron-capture detection. Concentrations of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. Multivariable Cox proportional hazards regression was used to assess prognostic associations. RESULTS: Patients with a KRAS mutated tumor had a 70% higher risk of early death than patients with a KRAS wild-type PDAC (hazard ratio [HR] = 1.7, p = 0.026), adjusting for age, sex, and tumor stage. KRAS mutational status was only modestly and not statistically significantly associated with survival when further adjusting by treatment or by treatment intention. The beneficial effects of treatment remained unaltered when KRAS mutational status was taken into account, and treatment did not appear to be less effective in the subgroup of patients with a KRAS mutated tumor. POPs did not materially influence survival: the adjusted HR of the highest POP tertiles was near unity for all POPs. When considering the joint effect on survival of POPs and KRAS, patients with KRAS mutated tumors had modest and nonsignificant HRs (most HRs around 1.3 to 1.4). Higher concentrations of lead, cadmium, arsenic, vanadium, and aluminium were associated with better survival. When KRAS status, POPs, and trace elements were simultaneously considered along with treatment, only the latter was statistically significantly related to survival. CONCLUSIONS: In this study based on molecular, clinical, and environmental epidemiology, KRAS mutational status, POPs, and trace elements were not adversely related to PDAC survival when treatment was simultaneously considered; only treatment was independently related to survival. The lack of adverse prognostic effects of POPs and metals measured at the time of diagnosis provide scientific and clinical reassurance on the effects of such exposures upon survival of patients with PDAC. The weak association with KRAS mutations contributes to the scant knowledge on the clinical implications of a genetic alteration highly frequent in PDAC.

14.
Exp Ther Med ; 20(3): 2191-2199, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32765695

RESUMO

The optimal protocol for endometrial preparation in patients with infertility remains unclear. Due to this, the current study retrospectively analyzed 1,589 patients with infertility and regular menstrual cycles to assess reproductive outcomes per embryo transferred and per embryo transfer (ET) cycle following the transfer of frozen-thawed embryos (FET) in a modified natural cycle (mNC) or hormone therapy cycle (HT) with or without gonadotropin-releasing hormone agonist (GnRHa)-induced pituitary suppression. The molecular mechanisms involved were also studied using tissues from endometrial biopsies. Patients who underwent FET were assigned to 5 groups as follows: Group A underwent a mNC (n=276); group B (n=338) received estradiol (E2) and progesterone (P4); group C received 1 cycle of GnRHa, E2 and P4 (n=323); group D received 2 cycles of GnRHa, E2 and P4 (n=329); and group E received 3 cycles of GnRHa, E2 and P4 (n=323). Tissues from endometrial biopsies of 91 patients performed on the day of ET were tested for endometrial receptivity marker mRNA expression and microRNA (miR)-223-3p mRNA. Furthermore, endometrial stromal cells (ESCs) were used for an in-depth study of the molecular mechanisms involved. Among the 5 groups of patients, implantation rates, clinical pregnancy rates and live birth rates were not significantly different. However, endometrial receptivity was enhanced in group E when compared with groups A-D, which was associated with endometrial leukemia inhibitory factor (LIF), osteopontin, vascular endothelial growth factor, integrin ß3 and homeobox gene 10 and 11 mRNA upregulation, and miR-223-3p miRNA downregulation. Transfection of ESCs with an miR-223-3p mimic significantly reduced levels of LIF mRNA and protein. In addition, pre-treating ESCs with GnRHa upregulated mRNA and protein expression of the decidualization markers prolactin and insulin-like growth factor binding protein-1 in a time-dependent manner. In conclusion, these results indicated that HT with GnRHa may be a potential endometrial preparation protocol for FET.

15.
Water Res ; 184: 116177, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32693267

RESUMO

The H2-based membrane biofilm reactor (H2-MBfR) is an emerging technology for removal of nitrate (NO3-) in water supplies. In this research, a lab-scale H2-MBfR equipped with a separated CO2 providing system and a microsensor measuring unit was developed for NO3- removal from synthetic groundwater. Experimental results show that efficient NO3- reduction with a flux of 1.46 g/(m2⋅d) was achieved at the optimal operating conditions of hydraulic retention time (HRT) 80 min, influent NO3- concentration 20 mg N/L, H2 pressure 5 psig and CO2 addition 50 mg/L. Given the complex counter-diffusion of substrates in the H2-MBfR, mathematical modeling is a key tool to both understand its behavior and optimize its performance. A sophisticated model was successfully established, calibrated and validated via comparing the measured and simulated system performance and/or substrate gradients within biofilm. Model results indicate that i) even under the optimal operating conditions, denitrifying bacteria (DNB) in the interior and exterior of biofilm suffered low growth rate, attributed to CO2 and H2 limitation, respectively; ii) appropriate operating parameters are essential to maintaining high activity of DNB in the biofilm; iii) CO2 concentration was the decisive factor which matters its dominant role in mediating hydrogenotrophic denitrification process; iv) the predicted optimum biofilm thickness was 650 µm that can maximize the denitrification flux and prevent loss of H2.


Assuntos
Reatores Biológicos , Desnitrificação , Biofilmes , Dióxido de Carbono , Nitratos
17.
EBioMedicine ; 57: 102860, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32652320

RESUMO

BACKGROUND: Tumour budding and poorly differentiated clusters (PDC) represent forms of tumour invasion. We hypothesised that T-cell densities (reflecting adaptive anti-tumour immunity) might be inversely associated with tumour budding and PDC in colorectal carcinoma. METHODS: Utilising 915 colon and rectal carcinomas in two U.S.-wide prospective cohort studies, and multiplex immunofluorescence combined with machine learning algorithms, we assessed CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 co-expression patterns in lymphocytes. Tumour budding and PDC at invasive fronts were quantified by digital pathology and image analysis using the International tumour Budding Consensus Conference criteria. Using covariate data of 4,420 incident colorectal cancer cases, inverse probability weighting (IPW) was integrated with multivariable logistic regression analysis that assessed the association of T-cell subset densities with tumour budding and PDC while adjusting for selection bias due to tissue availability and potential confounders, including microsatellite instability status. FINDINGS: Tumour budding counts were inversely associated with density of CD3+CD8+ [lowest vs. highest: multivariable odds ratio (OR), 0.50; 95% confidence interval (CI), 0.35-0.70; Ptrend < 0.001] and CD3+CD8+CD45RO+ cells (lowest vs. highest: multivariable OR, 0.44; 95% CI, 0.31-0.63; Ptrend < 0.001) in tumour epithelial region. Tumour budding levels were associated with higher colorectal cancer-specific mortality (multivariable hazard ratio, 2.13; 95% CI, 1.57-2.89; Ptrend < 0.001) in Cox regression analysis. There were no significant associations of PDC with T-cell subsets. INTERPRETATION: Tumour epithelial naïve and memory cytotoxic T cell densities are inversely associated with tumour budding at invasive fronts, suggesting that cytotoxic anti-tumour immunity suppresses tumour microinvasion.

18.
J Steroid Biochem Mol Biol ; 202: 105709, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32535031

RESUMO

The current study aims to evaluate the antiproliferative activity of B-norcholesteryl benzimidazole compounds in human ovarian cancer cells (SKOV3). Our experimental data indicates that the tested compounds can induce apoptosis in SKOV3 cells, block S-phase growth, and decrease mitochondrial membrane potential. Western blot results showed that B-norcholesteryl benzimidazole compounds (1 and 2) induced apoptosis in SKOV3 cells via activation of the mitochondrial signaling pathway. Following SKOV3 cells treatment with compounds 1 and 2, the cell metabolism was assessed using the UHPLC-QE-MS (Ultra High Performance Liquid Chromatography-Q Exactive Orbitrap- Mass Spectrometry) non-target metabolomics analysis method. The results showed 10 metabolic pathways that mediated the effects of compound 1, including arginine and proline metabolism; alanine, aspartate, and glutamate metabolism; histidine metabolism; D-glutamine and D-glutamine and D-glutamate metabolism; cysteine and methionine metabolism; aminoacyl-tRNA biosynthesis; purine metabolism; Glutathione metabolism; D-Arginine and D-ornithine metabolism; and Nitrogen metabolism. From the perspective of metabolomics, compound 1 inhibits intracellular metabolism, protein synthesis, and slows down energy metabolism in SKOV3 cells. These changes result in the inhibition of proliferation and signal transduction, abrogate invasive and metastatic properties, and induce apoptosis, thus, exerting anti-tumor effects. Application of compound 2 altered activation of metabolic pathways in SKOV3 cells. The main metabolic pathways involved were glycerophospholipid metabolism; arginine and proline metabolism; purine metabolism; glycine, serine, and threonine metabolism; and ether lipid metabolism. The metabolic pathway with the greatest impact and the deepest enrichment was the glycerophospholipid metabolism. In conclusion, compound 2 inhibits proliferation of SKOV3 cells by interfering with glycerate metabolism, which plays a major role in regulation of cell membrane structure and function. Additionally, compound 2 can inhibit the invasion and metastasis of SKOV3 cells and induce apoptosis via interfering with the metabolism of arginine and proline.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Neoplasias Ovarianas/metabolismo , Apoptose/efeitos dos fármacos , Arginina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Metabolômica , Neoplasias Ovarianas/tratamento farmacológico , Prolina/metabolismo
19.
Br J Cancer ; 123(5): 844-851, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32541871

RESUMO

BACKGROUND: Despite several plausible biological mechanisms linking proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs) with colorectal tumorigenesis, their association with risk of colorectal cancer (CRC) has not been adequately assessed in prospective epidemiological studies. METHODS: We evaluated the association of acid-suppressive medication use with CRC risk among 175,871 (PPI) and 208,831 (H2RA) participants from three large prospective cohort studies. Medication use was assessed at baseline and updated biennially. The association was evaluated using multivariate Cox proportional hazards regression models. RESULTS: There was no significant association between baseline PPI use (hazard ratio (HR) = 0.89, 95% confidence interval (CI), 0.71-1.12) or PPI use after a lag of 8-10 years (HR = 1.12, 95% CI, 0.78-1.59) with CRC risk. We observed no significant association between H2RA use after a lag of 8-10 years and CRC risk (HR = 1.02, 95% CI, 0.81-1.28), while risk was lower for participants with baseline H2RA use (HR = 0.76, 95% CI, 0.60-0.95). Duration of PPI use or H2RA use was not associated with CRC risk (P-trend = 0.21 and 0.95, respectively). CONCLUSIONS: Among participants from three large prospective cohorts, use of PPI or H2RA was not associated with higher risk of colorectal cancer.

20.
Eur J Nutr ; 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32548645

RESUMO

PURPOSE: Although evidence suggests an inverse association between yogurt consumption and the risk of disorders, such as type 2 diabetes and certain cancers, the mechanisms remain poorly understood. We aimed to examine the association between yogurt consumption and concentrations of plasma soluble CD14, a marker of gut barrier dysfunction. METHODS: We analyzed cross-sectional data from 632 women in the Nurses' Health Study (1989-1990) and 444 men in the Health Professionals Follow-up Study (1993-1994) with soluble CD14 concentrations. We estimated yogurt consumption from food frequency questionnaires. We used multivariable-adjusted linear regression models to estimate the percentage difference (95% CI) of soluble CD14 concentrations by yogurt consumption. RESULTS: Among men, higher consumption was associated with a lower soluble CD14 concentration (at least 2 cups/week vs. non-consumers; unadjusted % difference: - 7.6%; 95% CI - 13.0%, - 2.1%; Ptrend = 0.003). The inverse association was slightly attenuated following multivariable adjustment (% difference: - 5.8%; 95% CI - 11.0%, - 0.1%; Ptrend = 0.01). For the same comparison, yogurt consumption was inverse, but not statistically significant associated with soluble CD14 concentration in women (% difference: - 1.2%; 95% CI - 5.6%, 3.5%; Ptrend = 0.64). In stratified analyses, the inverse association between yogurt consumption and the concentrations of soluble CD14 was slightly stronger in men who consumed alcohol at least 20 g/day. CONCLUSIONS: Higher yogurt consumption was associated with lower soluble CD14 concentrations, especially in men. Our findings suggest the strengthening of gut barrier function as a plausible mechanism for the observed inverse associations of yogurt consumption with gastrointestinal diseases and disorders involving other systems.

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