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1.
Artigo em Inglês | MEDLINE | ID: mdl-31728618

RESUMO

PURPOSE: Concurrent chemoradiotherapy (CCRT) is one of the standard treatments for patients with advanced head and neck squamous cell carcinoma (HNSCC). However, CCRT may lead to decreased quality of life (QoL) and treatment compliance. This study aimed to determine the effects of PG2 (Astragalus polysaccharides) injection on CCRT-associated adverse events (AEs) and patients' compliance with the CCRT course. METHODS: In this phase II double-blind randomized placebo-controlled trial, PG2 injection (sterile powder form) or placebo was administrated three times per week in parallel with CCRT to patients with HNSCC. The chemotherapy regimen included 50 mg/m2 cisplatin every 2 weeks with daily tegafur-uracil (300 mg/m2) and leucovorin (60 mg/day). RESULTS: The study was terminated prematurely due to the successful launch of a newly formulated PG2 injection (lyophilized form). A total of 17 patients were enrolled. The baseline demographics and therapeutic compliance were comparable between the CCRT/PG2 and CCRT/placebo groups. During CCRT, severe treatment-associated AEs were less frequent in the CCRT/PG2 group than in the CCRT/placebo group. Furthermore, less QoL fluctuations from the baseline during CCRT were noted in the CCRT/PG2 group than in the CCRT/placebo group, with a significant difference in the pain, appetite loss, and social eating behavior. The tumor response, disease-specific survival and overall survival did not differ between the two groups. CONCLUSION: This preliminary study demonstrated PG2 injection exhibited an excellent safety profile, and has potential in ameliorating the deterioration in QoL and the AEs associated with active anticancer treatment among patients with advanced pharyngeal or laryngeal HNSCC under CCRT. Further research in patients with other cancer types or treatment modalities may widen PG2's application in clinical settings.

2.
J Neuroinflammation ; 16(1): 187, 2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31606043

RESUMO

BACKGROUND: The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor activated by environmental agonists and dietary tryptophan metabolites for the immune response and cell cycle regulation. Emerging evidence suggests that AHR activation after acute stroke may play a role in brain ischemic injury. However, whether AHR activation alters poststroke astrogliosis and neurogenesis remains unknown. METHODS: We adopted conditional knockout of AHR from nestin-expressing neural stem/progenitor cells (AHRcKO) and wild-type (WT) mice in the permanent middle cerebral artery occlusion (MCAO) model. WT mice were treated with either vehicle or the AHR antagonist 6,2',4'-trimethoxyflavone (TMF, 5 mg/kg/day) intraperitoneally. The animals were examined at 2 and 7 days after MCAO. RESULTS: The AHR signaling pathway was significantly upregulated after stroke. Both TMF-treated WT and AHRcKO mice showed significantly decreased infarct volume, improved sensorimotor, and nonspatial working memory functions compared with their respective controls. AHR immunoreactivities were increased predominantly in activated microglia and astrocytes after MCAO compared with the normal WT controls. The TMF-treated WT and AHRcKO mice demonstrated significant amelioration of astrogliosis and microgliosis. Interestingly, these mice also showed augmentation of neural progenitor cell proliferation at the ipsilesional neurogenic subventricular zone (SVZ) and the hippocampal subgranular zone. At the peri-infarct cortex, the ipsilesional SVZ/striatum, and the hippocampus, both the TMF-treated and AHRcKO mice demonstrated downregulated IL-1ß, IL-6, IFN-γ, CXCL1, and S100ß, and concomitantly upregulated Neurogenin 2 and Neurogenin 1. CONCLUSION: Neural cell-specific AHR activation following acute ischemic stroke increased astrogliosis and suppressed neurogenesis in adult mice. AHR inhibition in acute stroke may potentially benefit functional outcomes likely through reducing proinflammatory gliosis and preserving neurogenesis.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31499138

RESUMO

PURPOSE: The evidence for adjuvant therapy of oral cavity squamous cell carcinoma (OCSCC) in NCCN guidelines derives from patients with head and neck cancer. Here, we examined whether adjuvant therapy should be guided by a detailed analysis of pathological risk factors in pure OCSCC patients. METHODS: Between 2004 and 2016, we retrospectively reviewed 1200 consecutive OCSCC patients who underwent radical surgery and neck dissection in the XXX Hospital (XXXH). Patients were divided into three prognostic groups. High-risk patients were those with extra-nodal extension and/or positive margins (ENE/margins+, n=267). Intermediate-risk patients were further divided into three subgroups: 1) patients in whom adjuvant therapy was indicated according to the XXXX but not the NCCN guidelines (NCCN[-]/XXXX[+], n=14); 2) patients in whom adjuvant therapy was indicated by the NCCN but not the XXXX guidelines (NCCN[+]/XXXX[-], n=160); and 3) patients in whom adjuvant therapy was indicated according to both guidelines (NCCN[+]/XXXX [+], n=411). Low-risk patients were those for whom adjuvant therapy was not suggested in light of both guidelines (NCCN[-]/XXXX[-], n=348). RESULTS: According to NCCN guidelines, postoperative adjuvant therapy was indicated in 69.8% of the participants. However, only 57.7% of the patients were in need of adjuvant therapy by XXXX guidelines. The following 5-year outcomes were observed in the NCCN(-)/XXXX(-), NCCN(-)/XXXX(+), NCCN(+)/XXXX(-), NCCN(+)/XXXX(+), and ENE/margins+ subgroups: loco-regional control, 88%/70%/83%/79%/68%, P<0.001 (NCCN[+]/XXXX[-] vs. NCCN[+]/XXXX[+], P=0.576), distant metastases, 2%/7%/2%/9%/36%, P<0.001 (NCCN[+]/XXXX[-] vs. NCCN[+]/XXXX[+], P=0.003), disease-specific survival, 97%/86%/94%/84%/56%, P<0.001 (NCCN[+]/XXXX[-] vs. NCCN[+]/XXXX[+], P<0.001), and overall survival, 92%/86%/87%/68%/42%, P<0.001 (NCCN[+]/XXXX[-] vs. NCCN[+]/XXXX[+], P<0.001), respectively. CONCLUSIONS: Patients in the NCCN(+)/XXXX(-) subgroup, 28% (160/571[160+411]) of NCCN intermediate-risk patients, had more favorable 5-year disease-specific/overall survivals (94%/87%) than NCCN(+)/XXXX(+) subgroup. The former are unlikely to derive clinical benefits from NCCN guidelines. The 70% adjuvant therapy rate required by NCCN guidelines after radical surgery might be too high, ultimately leaving room for improvement.

4.
Sci Rep ; 9(1): 12900, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501504

RESUMO

Sleep apnea has been associated with a variety of diseases, but its impact on sepsis outcome remains unclear. This study investigated the effect of intermittent hypoxia [IH]-the principal feature of sleep apnea-on murine sepsis. 5-week-old male C57BL6 mice were assigned to groups receiving severe IH (O2 fluctuating from room air to an O2 nadir of 5.7% with a cycle length of 90 seconds), mild IH (room air to 12%, 4 minutes/cycle), or room air for 3 weeks. Sepsis was induced by cecal ligation and puncture and survival was monitored. Sepsis severity was evaluated by murine sepsis scores, blood bacterial load, plasma tumor necrosis factor-α [TNF-α]/interleukin-6 [IL-6] levels and histopathology of vital organs. Compared with normoxic controls, mice subjected to severe IH had earlier mortality, a lower leukocyte count, higher blood bacterial load, higher plasma TNF-α and IL-6 levels, more severe inflammatory changes in the lung, spleen and small intestine. Mice subjected to mild IH did not differ from normoxic controls, except a higher IL-6 level after sepsis induced. The adverse impact of severe IH was reversed following a 10-day normoxic recovery. In conclusion, severe IH, not mild IH, contributed to poorer outcomes in a murine sepsis model.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31388722

RESUMO

OBJECTIVE: Clinical outcomes of patients with resected oral cavity squamous cell carcinoma (OCSCC) chiefly depend on the presence of specific clinicopathological risk factors (RFs). Here, we performed a combined analysis of FDG-PET, genetic markers, and clinicopathological RFs in an effort to improve prognostic stratification. METHODS: We retrospectively reviewed the clinical records of 2036 consecutive patients with first primary OCSCC who underwent surgery between 1996 and 2016. Of them, 345 underwent ultra-deep targeted sequencing (UDTS, between 1996 and 2011) and 168 whole exome sequencing (WES, between 2007 and 2016). Preoperative FDG-PET imaging was performed in 1135 patients from 2001 to 2016. Complete data on FDG-PET, genetic markers, and clinicopathological RFs were available for 327 patients. RESULTS: Using log-ranked tests based on 5-year disease-free survival (DFS), the optimal cutoff points for maximum standardized uptake values (SUV-max) of the primary tumor and neck metastatic nodes were 22.8 and 9.7, respectively. The 5-year DFS rates were as follows: SUVtumor-max ≥ 22.8 or SUVnodal-max ≥ 9.7 (n = 77) versus SUVtumor-max < 22.8 and SUVnodal-max < 9.7 (n = 250), 32%/62%, P < 0.001; positive UDTS or WES gene panel (n = 64) versus negative (n = 263), 25%/62%, P < 0.001; pN3b (n = 165) versus pN1-2 (n = 162), 42%/68%, P < 0.001. On multivariate analyses, SUVtumor-max ≥ 22.8 or SUVnodal-max ≥ 9.7, a positive UDTS/WES gene panel, and pN3b disease were identified as independent prognosticators for 5-year outcomes. Based on these variables, we devised a scoring system that identified four distinct prognostic groups. The 5-year rates for patients with a score from 0 to 3 were as follows: loco-regional control, 80%/67%/47%/24% (P < 0.001); distant metastases, 13%/23%/55%/92% (P < 0.001); DFS, 74%/58%/28%/7% (P < 0.001); and disease-specific survival, 80%/64%/35%/7% (P < 0.001) respectively. CONCLUSIONS: The combined assessment of tumor and nodal SUV-max, genetic markers, and pathological node status may refine the prognostic stratification of OCSCC patients.

6.
Oral Oncol ; 96: 15-20, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31422207

RESUMO

OBJECTIVES: The marsupialization of Stensen's duct after buccal cancer excision and free flap reconstruction has seldom been reported. In this study, we evaluated the alteration in Stensen's duct and parotid gland, without marsupialization or relocation, between the time of surgery and 24 months postoperatively to determine whether ductal management is needed in patients with buccal squamous cell carcinoma (BSCC). METHODS: Eighty-five patients with BSCC receiving primary radical surgery and free flap reconstruction were recruited. Alterations in Stensen's duct and parotid gland were assessed by computed tomography during the postoperative period. RESULTS: The 81 males and 4 females enrolled in study had a tumor status of cT2 (n = 52, 61%) or cT3 (n = 33, 39%). In total, 52 (61%) patients received surgery alone, and 33 (39%) received adjuvant concurrent chemoradiotherapy (CCRT) postoperatively. Stensen's duct on the affected side was significantly dilated compared to the non-affected side (p < 0.001). The difference in diameter of Stensen's duct between the surgery plus CCRT group and the surgery alone group was not significant (p > 0.05), indicating that changes in parotid gland occurred mainly due to surgery. In both the surgery and surgery plus CCRT groups, inflammation of parotid gland had regressed by 24 months. CONCLUSIONS: Stensen's duct in BSCC dilatation peaked in the 3rd month after surgery. Changes in parotid gland on the surgically treated side regressed into fatty change by 24 months after surgery.

7.
Ann Surg Oncol ; 26(11): 3663-3672, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31264118

RESUMO

BACKGROUND: According to the AJCC third to seventh edition staging manuals (1988-2010), the presence of through cortex and/or skin invasion in oral cavity squamous cell carcinoma (OCSCC) identifies T4a tumors. The AJCC eighth edition (2018) introduced a depth of invasion (DOI) > 20 mm as a criterion for pT4a. Subsequently, a revision maintained that tumors > 4 cm with a DOI > 10 mm should be classified as pT4a. We sought to analyze the prognostic impact of the three distinct criteria identifying pT4a disease. METHODS: We examined 667 consecutive patients with pT3-4 buccal/gum/hard palate/retromolar SCC who underwent surgery between 1996 and 2016. pT1/pT2 (n = 108/359) disease were included for comparison purposes. RESULTS: The 5-year outcomes of patients with pT1/pT2/without (n = 406)/with tumor > 4 cm/DOI > 10 mm (n = 261), pT1/pT2/DOI ≤ 20 mm (n = 510)/> 20 mm (n = 157), and pT1/pT2/without (n = 305)/with through cortex/skin invasion (n = 362) were as follows: disease-specific survival (DSS), 98%/89%/79%/65%, p < 0.001, 98%/89%/78%/59%, p < 0.001, and 98%/89%79%/69%, p < 0.001; overall survival (OS), 90%/79%/63%/51%, p < 0.001, 90%/79%/63%/42%, p < 0.001, and 90%/79%/65%/52%, p < 0.001. In pT3-4 disease, a tumor > 4 cm/DOI > 10 mm was an independent adverse prognosticator for 5-year DSS rate, DOI > 20 mm was an independent adverse prognosticator for 5-year DSS and OS rates, whereas through cortex/skin invasion independently predicted 5-year OS rates. CONCLUSIONS: All of the three criteria (tumor > 4 cm/DOI > 10 mm, DOI > 20 mm, and through cortex/skin invasion) identify high-risk patients, which should be reflected in further revisions of pT4a classification in OCSCC.

9.
Biomed Res Int ; 2019: 6740616, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31321239

RESUMO

Identification of new pharmacological approaches to inhibit the excessive fat intake-induced steatohepatitis and chronic kidney disease (CKD) is important. High-fat diet (HFD)-induced steatohepatitis and CKD share common pathogenesis involving peroxisome proliferator-activated receptor (PPAR)-α and -δ. Elafibranor, a dual PPARα/δ agonist, can ameliorate the HFD-induced steatohepatitis. Nonetheless, the effects of HFD-induced CKD had not yet explored. This study investigated the effects of elafibranor (elaf) on the progression of HFD-induced CKD in mice. In vivo and in vitro renal effects were evaluated in HFD-elaf mice receiving 12 weeks of elafibranor (from 13th to 24th week of HFD feeding) treatment. In elafibranor-treated HFD mice, increased insulin sensitivity, reduced obesity and body fat mass, decreased severity of steatohepatitis, increased renal expression of PPARα, PPARδ, SIRT1, and autophagy (Beclin-1 and LC3-II) as well as glomerular/renal tubular barrier markers [synaptopodin (podocyte marker), zona occludin-1, and cubulin], reduced renal oxidative stress and caspase-3, and less urinary 8-isoprostanes excretion were observed. Aforementioned benefits of elafibranor were associated with low renal tubular injury and tubulointerstitial fibrosis scores, less albuminuria, low urinary albumin-to-creatinine ratio, and preserved glomerular filtration rate. Acute incubation of podocytes and HK-2 cells with elafibranor or recombinant SIRT1 reversed the HFD-sera-induced oxidative stress, autophagy dysfunction, cell apoptosis, barrier marker loss, albumin endocytosis, and reuptake reduction. Besides hepatoprotective and metabolic beneficial effects, current study showed that elafibranor inhibited the progression of HFD-induced CKD through activation of renal PPARα, PPARδ, SIRT1, autophagy, reduction of oxidative stress, and apoptosis in mice with steatohepatitis.

10.
J Transl Med ; 17(1): 191, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171000

RESUMO

BACKGROUND: Elevated protein expressions of CD markers such as IL2RA/CD25, CXCR4/CD184, CD34 and CD56 are associated with adverse prognosis in acute myeloid leukemia (AML). However, the prognostic value of mRNA expressions of these CD markers in AML remains unclear. Through our pilot evaluation, IL2RA mRNA expression appeared to be the best candidate as a prognostic biomarker. Therefore, the aim of this study is to characterize the prognostic value of IL2RA mRNA expression and evaluate its potential to refine prognostification in AML. METHODS: In a cohort of 239 newly diagnosed AML patients, IL2RA mRNA expression were measured by TaqMan realtime quantitative PCR. Morphological, cytogenetics and mutational analyses were also performed. In an intermediate-risk AML cohort with 66 patients, the mRNA expression of prognostic biomarkers (BAALC, CDKN1B, ERG, MECOM/EVI1, FLT3, ID1, IL2RA, MN1 and WT1) were quantified by NanoString technology. A TCGA cohort was analyzed to validate the prognostic value of IL2RA. For statistical analysis, Mann-Whitney U test, Fisher exact test, logistic regression, Kaplan-Meier and Cox regression analyses were used. RESULTS: In AML cohort of 239 patients, high IL2RA mRNA expression independently predicted shorter relapse free survival (RFS, p < 0.001) and overall survival (OS, p < 0.001) irrespective of age, cytogenetics, FLT3-ITD or c-KIT D816V mutational status. In core binding factor (CBF) AML, high IL2RA mRNA expression correlated with FLT3-ITD status (p = 0.023). Multivariable analyses revealed that high IL2RA expression (p = 0.002), along with c-KIT D816V status (p = 0.013) significantly predicted shorter RFS, whereas only high IL2RA mRNA expression (p = 0.014) significantly predicted shorter OS in CBF AML. In intermediate-risk AML in which multiple gene expression markers were tested by NanoString, IL2RA significantly correlated with ID1 (p = 0.006), FLT3 (p = 0.007), CDKN1B (p = 0.033) and ERG (p = 0.030) expressions. IL2RA (p < 0.001) and FLT3 (p = 0.008) expressions remained significant in predicting shorter RFS, whereas ERG (p = 0.008) and IL2RA (p = 0.044) remained significant in predicting shorter OS. Similar analyses in TCGA intermediate-risk AML showed the independent prognostic role of IL2RA in predicting event free survival (p < 0.001) and OS (p < 0.001). CONCLUSIONS: High IL2RA mRNA expression is an independent and adverse prognostic factor in AML and specifically stratifies patients to worse prognosis in both CBF and intermediate-risk AML.

11.
Anticancer Res ; 39(4): 2025-2033, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952746

RESUMO

BACKGROUND/AIM: Tumor-related and inflammation-related markers were reported to be prognostic in cancer patients. In this study, we evaluated squamous cell carcinoma antigen (SCC-Ag), cytokeratin 19 fragment (CYFRA 21-1) and C-reactive protein (CRP) simultaneously in oral cavity squamous cell carcinoma (OSCC) patients. PATIENTS AND METHODS: Two hundred and forty-six newly diagnosed OSCC patients were retrospectively recruited between December 2010 and December 2016. RESULTS: The elevation of CRP levels (≥5.0 mg/l) and SCC-Ag levels (≥2.0 ng/ml) were significantly related with tumor invasion parameters and metastatic factors. In contrast, the elevation of CYFRA 21-1 levels (≥3.3 ng/ml) was related with extranodal extension alone. For patients with all three markers being elevated before surgery, their overall survival and disease-free survival were significantly worse than others. CONCLUSION: Concurrent elevation of preoperative SCC-Ag, CYFRA 21-1 and CRP serum levels can be correlated with worse survival rates in OSCC.


Assuntos
Antígenos de Neoplasias/sangue , Proteína C-Reativa/análise , Carcinoma de Células Escamosas/sangue , Queratina-19/sangue , Neoplasias Bucais/sangue , Serpinas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Neoplasias Bucais/cirurgia , Prognóstico
12.
Sci Adv ; 5(4): eaar5478, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31032398

RESUMO

Phylogenetic analysis has shown that males' propensity to engage in aggressive encounters is associated with females having greater longevity. Here, we confirm the causal link between aggression and reduced longevity by looking at an egg-eating snake (Oligodon formosanus) in which females defend territories in the presence of sea turtle eggs. We monitored aggressiveness and survival at two sites: a control site with a stable supply of turtle eggs, and a second site where we collected data before and after a storm that eroded the beach on which turtles nested, thus leading to a loss of territoriality. We show that territoriality was the driver behind higher injury rates in females. Territorial females also had lower survival and decreased longevity compared with the nonterritorial males, but these differences disappeared when females were not territorial. Our study demonstrates how resource availability can influence the evolution of sex-specific patterns of survival across vertebrates.

13.
Oncologist ; 24(9): e891-e897, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30898891

RESUMO

BACKGROUND: Research on cancer survivorship associated with nasopharyngeal carcinoma (NPC) is rare. We aimed to elucidate the risk of ischemic stroke in 5-year survivors of NPC following radiotherapy (RT) or concurrent chemoradiation therapy (CCRT). SUBJECTS, MATERIALS, AND METHODS: NPC survivors, defined as those who survived longer than 5 years after diagnosis, were identified and matched at a 1:5 ratio with normal controls from the Longitudinal Health Insurance Database 2005 of Taiwan. The stratified Cox regression models were used to access the risk of ischemic stroke, with adjustment for age, treatment modality, comorbidities, and socioeconomic characteristics. RESULTS: From 2000 to 2005, a total of 3,016 NPC survivors who had received RT (n = 959) or CCRT (n = 2,057) and 15,080 controls were matched for age, sex, income, and urbanization level. The risk of ischemic stroke was significantly higher in the NPC survivor cohort than in the control cohort. Stroke was positively related to death. Moreover, the age onset of stroke for NPC survivors was 10 years earlier than that for the general population. CONCLUSION: Not only was the stroke risk in NPC survivors higher than that in the general population, but the onset age was also 10 years earlier. Future survivorship care should include ischemic stroke as a late complication, for its proper prevention and management. IMPLICATIONS FOR PRACTICE: Nasopharyngeal carcinoma (NPC) is endemic in Taiwan, and its 5-year survival is 65.2%. With the increased 5-year cancer survivors, survivorship has become an important issue. However, research on NPC survivorship is very rare. To the authors' knowledge, this is the first population-based study on long-term NPC survivors. This study's results indicated that not only was the risk of ischemic stroke in NPC survivors at least triple that of the general population, but the onset age was also 10 years earlier. These results may provide solid evidence that survivorship care guidelines should include stroke as a late complication in 5-year NPC survivors, for its proper prevention and management.

14.
Basic Res Cardiol ; 114(3): 20, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30900023

RESUMO

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor beta 1 (TGF-ß1) superfamily that reverses age-related cardiac hypertrophy, improves muscle regeneration and angiogenesis, and maintains progenitor cells in injured tissue. Recently, targeted myocardial delivery of the GDF11 gene in aged mice was found to reduce heart failure and enhance the proliferation of cardiac progenitor cells after myocardial ischemia-reperfusion (I-R). No investigations have as yet explored the cardioprotective effect of exogenous recombinant GDF11 in acute I-R injury, despite the convenience of its clinical application. We sought to determine whether exogenous recombinant GDF11 protects against acute myocardial I-R injury and investigate the underlying mechanism in Sprague-Dawley rats. We found that GDF11 reduced arrhythmia severity and successfully attenuated myocardial infarction; GDF11 also increased cardiac function after I-R, enhanced HO-1 expression and decreased oxidative damage. GDF11 activated the canonical TGF-ß signaling pathway and inactivated the non-canonical pathways, ERK and JNK signaling pathways. Moreover, administration of GDF11 prior to reperfusion protected the heart from reperfusion damage. Notably, pretreatment with the activin-binding protein, follistatin (FST), inhibited the cardioprotective effects of GDF11 by blocking its activation of Smad2/3 signaling and its inactivation of detrimental TGF-ß signaling. Our data suggest that exogenous GDF11 has cardioprotective effects and may have morphologic and functional recovery in the early stage of myocardial I-R injury. GDF11 may be an innovative therapeutic approach for reducing myocardial I-R injury.


Assuntos
Fatores de Diferenciação de Crescimento/uso terapêutico , Coração/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fator de Crescimento Transformador beta/metabolismo , Animais , Apoptose/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Proteína Forkhead Box O3/metabolismo , Fatores de Diferenciação de Crescimento/farmacologia , Heme Oxigenase (Desciclizante)/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Proteínas Smad Reguladas por Receptor/metabolismo
15.
Cancer Prev Res (Phila) ; 12(4): 247-254, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30842089

RESUMO

Multiple primary tumors (MPT), especially in the hypopharynx and esophagus, are challenging in patients with head and neck cancer (HNC). Alcohol and alcohol-metabolizing genes were reported to be related to upper digestive tract cancers. Here, we investigated whether the genotypes of alcohol-metabolizing enzymes (ADH1B, ADH1C, and ALDH2) affected patients' susceptibility to developing MPTs. We recruited 659 male patients with HNC between March 1996 and February 2017. Age- and gender-matched controls were also recruited. A total of 164 patients with HNC were identified to have second or third malignancies. The single-nucleotide polymorphisms in ADH1B (rs1229984), ADH1C (rs698), and ALDH2 (rs671) were analyzed by TaqMan assays. The prevalence of ALDH2 *2 allele carriers is significantly higher than that of *1*1 homozygotes for oral cavity (P = 0.013) and oropharyngeal cancers (P = 0.012). For ADH1B, the number of *1 allele carriers is significantly higher than that of *2*2 homozygotes for oropharyngeal (P = 0.017) and hypopharyngeal cancers (P < 0.001). ADH1C (rs698) SNPs are not significantly associated with tumor subsites (all P > 0.05). Polymorphisms in ALDH2 (*2 allele carriers) and ADH1B (*1 allele carriers) significantly increase the risk of developing MPTs in the upper digestive tract [P < 0.001, OR (95% confidence interval (CI): 5.186 (2.444-11.004) and P < 0.05, OR (95% CI): 2.093 (1.149-3.812), respectively]. ALDH2 (rs671) *2 and ADH1B (rs1229984) *1 allele carriers were shown to develop MPTs in the upper digestive tract. Genetic information may be used to identify high-risk patients for the development of MPTs.

16.
Clin Sci (Lond) ; 133(3): 531-544, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30602573

RESUMO

Background: Reversal of alcohol-induced peroxisome proliferator-activated receptor (PPAR) α (PPARα) and PPARδ dysfunction has been reported to decrease the severity of alcoholic steatohepatitis (ASH). Autophagy is essential for cell survival and tissue energy homeostasis. Emerging evidence indicates that alcohol-induced adipose tissue (AT) autophagy dysfunction contributes to injury in the intestine, liver, and AT of ASH. Methods: The effects and mechanisms of dual PPARα/δ agonist elafibranor on autophagy stimulation were investigated using mice with ASH. Results: C57BL/6 mice on ethanol diet showed AT dysfunction, disrupted intestinal barrier, and ASH, which was accompanied by alcohol-mediated decrease in PPARα, PPARδ, and autophagy levels in intestine, liver, and AT. Chronic treatment with elafibranor attenuated AT apoptosis and inflammation by restoration of tissue PPARα, PPARδ, and autophagy levels. In ASH mice, alcohol-induced AT dysfunction along with increased fatty acid (FA) uptake and decreased free FA (FFA) release from AT was inhibited by elafibranor. The improvement of AT autophagy dysfunction by elafibranor alleviated inflammation and apoptosis-mediated intestinal epithelial disruption in ASH mice. Acute elafibranor incubation inhibited ethanol-induced ASH-mice-sera-enhanced autophagy dysfunction, apoptosis, barrier disruption, and intracellular steatosis in Caco-2 cells and primary hepatocytes (PHs). Conclusion: Altogether, these findings demonstrated that the PPARα/δ agonist, elafibranor, decreased the severity of liver injury by restoration of alcohol-suppressed AT autophagy function and by decreasing the release of apoptotic markers, inflammatory cytokines, and FFA, thereby reducing intestinal epithelium disruption and liver inflammation/apoptosis/steatosis in ASH mice. These data suggest that dual PPAR agonists can serve as potential therapeutic agents for the management of ASH.

17.
Environ Sci Pollut Res Int ; 26(7): 6957-6970, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30644049

RESUMO

The northern Beibu Gulf is one of the major habitats for the Indo-Pacific humpback dolphin (Sousa chinensis) in China. In this habitat, the core distribution zone of humpback dolphins was confined to the Sanniang Bay (SNB) and Dafengjiang River Estuary (DRE) areas. In our present research, the sediments of 14 sampling sites across the SNB and DRE waters were collected and further conducted for microbiomic and environmental analysis to explore the ecosystem characteristics of major humpback dolphin habitats in Northern Beibu Gulf. The environmental condition includes ammonia nitrogen (NH4+-N), nitrate nitrogen (NO3--N), dissolved reactive phosphorus (DRP), sulfur content in the form of sulfuric acid (SO42--S), Fe, and heavy metals (including Cu, Zn, Cd, Pb, and As). The composition of the bacterial community was characterized by 16S ribosomal DNA analysis of the V3-V4 regions using the Illumina-based sequencing platform. The environmental characteristic of the nutrient elements and heavy metals indicated that SNB suffered more anthropogenic impact than DRE. The comparably higher concentration of NH4+-N, NO3--N, DRP, Pb, and Cd in the SNB region was detected. The comparably higher nutrients in the SNB may have resulted in higher biomass and lower dissolved oxygen (DO) profile, which was further proved by Landsat thermal image data. The microbiome analysis showed that the DRE region was oligotrophic and SNB reflected an anaerobic environment in the sediments. Environmental factors rather than the spatial distance determined the similarity of bacterial community among different sites. Ecological associations between environmental, oceanographic, and bacterial characteristics were illustrated, which exhibited strong mutual associations. Our findings presented a feasibility that integrates empirical and remote sensing data to distinguish ecological features and evaluate ecosystem healthiness for the humpback dolphin habitats.


Assuntos
Golfinhos/microbiologia , Ecossistema , Monitoramento Ambiental , Sedimentos Geológicos/microbiologia , Microbiota/fisiologia , Poluentes Químicos da Água/análise , Animais , Biomassa , China , Golfinhos/metabolismo , Estuários , Sedimentos Geológicos/química , Metais Pesados/análise , Metais Pesados/metabolismo , Rios , Poluentes Químicos da Água/metabolismo
18.
Eur J Clin Invest ; 49(5): e13068, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30620398

RESUMO

BACKGROUND: The dysbiosis of gut microbiome and interaction with host immunity after Mycobacterium tuberculosis (MTB) infection are under investigation. We had found fatigue symptom concurrent with dysbiosis by decreasing the ratio of Firmicutes to Bacteroidetes (F/B ratio) in active tuberculosis (TB). The study aims to assess the inflammatory biomarkers and their interaction with gut microbiome in active TB and latent TB infection before starting anti-TB regimens. MATERIALS AND METHOD: Interleukin-1 beta (IL-1B), IL-4, IL-6, IL-10, CD3+, CD4+, CD8+ T cells and interferon-gamma (IFN-γ) releasing assay (IGRA) were measured in 25 active TB patients, 32 LTBI subjects and 23 healthy controls (HC). Gut microbiome profiles were obtained using 16S rRNA MiSeq sequencing method. RESULTS: The leucocytosis (7032 ± 387 cell/cum, P < 0.05), increase in IL-6 (229.7 ± 104 µg/dL, P < 0.05), and decrease in IL-4 (0.27 µg/dL ± 0.1, P < 0.05) were presented in active TB. The proportion of polymorphic neutrophil (PMN) in peripheral blood was positively related to the relative abundance of Bacteroidetes in LTBI and active TB (R2  = 0.23, P < 0.05). The F/B ratio was positively related to the detectable IL-1B in TB (R2  = 0.97, P < 0.01) and to the IL-4 in LTBI (R2  = 0.27, P < 0.05). In LTBI, the relative abundances of Coriobacteriaceae were positively related to the secretion of IFN-gamma against MTB-antigens more likely associated with of CD4+ T cell (R2  = 0.42, P < 0.05). CONCLUSION: In active TB, dysbiosis with higher relative abundances of Bacteroidetes in stool and low F/B ratio was related to systemic proinflammation. In LTBI, dose-response relationship between peripheral PMN and relative abundances of Bacteroidetes was remained but not leads to systemic inflammation.

19.
Oral Oncol ; 86: 188-194, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30409299

RESUMO

OBJECTIVE: According to the AJCC 2017 Staging Manual, oral cavity squamous cell carcinoma (OCSCC) with pN2 disease (based on the AJCC 2010 criteria) and extra-nodal extension (ENE) should be classified as pN3b. We performed a detailed outcome analyses in this patient subgroup. MATERIAL AND METHODS: We retrospectively reviewed the clinical records of consecutive OCSCC patients who underwent radical surgery between 1996 and 2017. Patients with pN3b disease (n = 365) were divided into a pN+ ≥8/ENE ≥5 subgroup (defined by the presence of pN+ ≥8 nodes or ENE ≥5 nodes, n = 77) and a pN+ ≤7/ENE ≤4 subgroup (defined by the presence of pN+ ≤7 nodes and ENE ≤4 nodes, n = 288). Patients with pN0/pN1/pN2 (n = 1192/179/197) disease were included for comparison purposes. RESULTS: Patients in the pN+ ≥8/ENE ≥5 subgroup had less favorable 5-year outcomes than those in the pN+ ≤7/ENE ≤4/pN2/pN1/pN0 groups (local control, 64%/79%/86%/83%/88%, p < 0.001; neck control, 55%/75%/80%/86%/93%, p < 0.001; distant metastases, 67%/28%/20%/12%/3%, p < 0.001; disease-free survival, 21%/51%/64%/72%/82%, p < 0.001; disease-specific survival, 25%/55%/71%/82%/92%, p < 0.001; overall survival, 19%/40%/54%/64%/82%, p < 0.001; respectively). Among patients with pN3b disease, multivariable analysis identified the pN+ ≥8/ENE ≥5 subgroup, lower neck (level IV/V) metastases, and depth of invasion ≥25 mm as independent adverse prognostic factors for 5-year distant metastases and survival rates. CONCLUSIONS: Patients in the pN+ ≥8/ENE ≥5 subgroup have an unfavorable prognosis and their classification as pN3b is advisable. In contrast, patients in the pN+ ≤7/ENE ≤4 subgroup should be classified as pN3a.

20.
Proteomics Clin Appl ; : e1700179, 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30365225

RESUMO

PURPOSE: To rapidly identify protein abundance changes in biopsy-level fresh-frozen hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: The pressure-cycling technology (PCT) is applied and sequential window acquisition of all theoretical mass spectra (SWATH-MS) workflow is optimized to analyze 38 biopsy-level tissue samples from 19 HCC patients. Each proteome is analyzed with 45 min LC gradient. MCM7 is validated using immunohistochemistry (IHC). RESULTS: A total of 11 787 proteotypic peptides from 2579 SwissProt proteins are quantified with high confidence. The coefficient of variation (CV) of peptide yield using PCT is 32.9%, and the R2 of peptide quantification is 0.9729. Five hundred forty-one proteins showed significant abundance change between the tumor area and its adjacent benign area. From 24 upregulated pathways and 13 suppressed ones, enhanced biomolecule synthesis and suppressed small molecular metabolism in liver tumor tissues are observed. Protein changes based on α-fetoprotein expression and hepatitis B virus infection are further analyzed. The data altogether highlight 16 promising tumor marker candidates. The upregulation of minichromosome maintenance complex component 7 (MCM7) is further observed in multiple HCC tumor tissues by IHC. CONCLUSIONS AND CLINICAL RELEVANCE: The practicality of rapid proteomic analysis of biopsy-level fresh-frozen HCC tissue samples with PCT-SWATH has been demonstrated and promising tumor marker candidates including MCM7 are identified.

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