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1.
Int Immunopharmacol ; 137: 112417, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-38897122

RESUMO

Drug local delivery system that directly supply anti-cancer drugs to the tumor microenvironment (TME) results in excellent tumor control and minimizes side effects associated with the anti-cancer drugs. Immune checkpoint inhibitors (ICIs) have been the mainstay of cancer immunotherapy. However, the systemic administration of ICIs is accompanied by considerable immunotherapy-related toxicity. To explore whether an anti-PD-L1 antibody administered locally via a sustained-release gel-forming carrier retains its effective anticancer function while causing fewer colitis-like side effects, CT, a previously reported depot system, was used to locally deliver an anti-PD-L1 antibody together with curcumin to the TME in bladder cancer-bearing ulcerative colitis model mice. We showed that CT-mediated intratumoral coinjection of an anti-PD-L1 antibody and curcumin enabled sustained release of both the loaded anti-PD-L1 antibody and curcumin, which contributed to substantial anticancer effects with negligible side effects on the colons of the UC model mice. However, although the anti-PD-L1 antibody administered systemically synergized with the CT-mediated intratumoral delivery of curcumin in inhibiting tumour growth, colitis was significantly worsened by intraperitoneal administration of anti-PD-L1 antibody. These findings suggested that CT is a promising agent for the local delivery of anticancer drugs, as it can allow effective anticancer functions to be retained while sharply reducing the adverse side effects associated with the systemic administration of these drugs.


Assuntos
Antígeno B7-H1 , Curcumina , Inibidores de Checkpoint Imunológico , Imunoterapia , Neoplasias da Bexiga Urinária , Animais , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/terapia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Curcumina/uso terapêutico , Curcumina/administração & dosagem , Camundongos , Imunoterapia/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Humanos , Linhagem Celular Tumoral , Feminino , Colite/induzido quimicamente , Colite/imunologia , Colite/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Sistemas de Liberação de Medicamentos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/imunologia
2.
Medicine (Baltimore) ; 102(41): e35243, 2023 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-37832095

RESUMO

The ongoing ENPOWER study exploring the efficacy and safety of the recombinant human endostatin (endostar) combined with programmed cell death 1 antibody sintilimab and chemotherapy showed encouraging efficacy and safety in advanced non-squamous non-small cell lung cancer. To evaluate the real-world efficacy and safety of endostar combined with immune checkpoint inhibitor and chemotherapy (EIC) for advanced non-squamous non-small cell lung cancer patients negative for actionable molecular biomarkers (NSCLCnm), patients with advanced NSCLCnm hospitalized to Zhejiang Provincial People's Hospital from January 2020 to December 2022 were screened for eligibility. The included patients were analyzed for the objective response rate (ORR) and disease control rate (DCR). The pre- and posttreatment expression levels of serum tumor associated biomarkers, chemokines and subpopulations of immune cells in peripheral blood were compared. For the 31 patients with advanced NSCLCnm treated with EIC, the median follow-up and treatment cycles were 18.0 months and 4, respectively. The ORR and DCR were 38.7% and 90.3%, respectively. For those who received EIC as first-line treatment, the ORR and DCR were 63.2% and 94.7%, respectively. EIC significantly decreased expression levels of carcinoma antigen 125, carcinoma embryonic antigen and cytokeratin 19 (P<0.05) in patients who were partial remission or stable disease. Among the 31 patients, 27 (87.1%) experienced at least 1 treatment-related adverse events, and 13 (41.9%) had the treatment-related adverse events of grade 3 or higher. No antiangiogenesis-related adverse events were observed. The current study showed that EIC was potentially effective for patients with NSCLCnm, especially when used as first-line therapy, and well tolerated.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/uso terapêutico , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/patologia , Endostatinas , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/patologia , Receptor de Morte Celular Programada 1/uso terapêutico
3.
Front Immunol ; 14: 1148425, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37559729

RESUMO

Immune checkpoint inhibitors (ICIs) are an integral antitumor therapy for many malignancies. Most patients show very good tolerability to ICIs; however, serious immune-related adverse events (irAEs) with ICIs have been well documented and prevent some patients from continuing ICIs or even become the direct cause of patient death. Cytopenia is a rare irAE but can be life-threatening. Here, we present the case of a 66-year-old male patient with metastatic lung adenocarcinoma who received two doses of chemotherapy + PD-1 antibody tislelizumab and developed pancytopenia after each dose. Although the first episode of pancytopenia resolved with a treatment regimen of granulocyte colony-stimulating factor (G-CSF), thrombopoietin (TPO), and red blood cell and platelet transfusion, the second episode showed extreme resistance to these treatments and improved only after the administration of steroids. His second pancytopenia episode resolved after a long course of treatment with methylprednisolone, G-CSF, TPO, hetrombopag and multiple red blood cell and platelet transfusions. However, he suffered a cerebral infarction when his platelet count was in the normal range and gradually recovered 1 week later. This case highlights the importance of the early recognition and management of hematological irAEs.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Pancitopenia , Masculino , Humanos , Idoso , Pancitopenia/induzido quimicamente , Pancitopenia/diagnóstico , Adenocarcinoma de Pulmão/complicações , Adenocarcinoma de Pulmão/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Infarto Cerebral
4.
Ophthalmol Sci ; 2(1): 100093, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36246175

RESUMO

Purpose: Crystallin protein mutations are associated with congenital cataract (CC), and several disease-causing mutations in the CRYGC gene have been identified. We present the location of a new mutation in CRYGC in members of a Chinese family who presented with CCs with or without microcornea. Design: Observational study. Participants: A Chinese family diagnosed with autosomal dominant (AD) CCs with or without microphthalmia. Methods: Because this was an observational study, it was not registered as a clinical trial. The proband and her 2 children were diagnosed with AD CCs and microcornea and were recruited for the study. Participants underwent complete ophthalmological examinations, and blood samples were used for genomic extraction. Main Outcome Measures: We detected 1 disease-associated variant using Exomiser analysis by matching the proband's phenotype and the inheritance pattern. The variant was determined to be pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines. Results: We detected 1 disease-associated variant using Exomiser analysis by matching the proband's phenotype and the inheritance pattern. The variant was determined to be pathogenic according to the American College of Medical Genetics and Genomics guidelines. Next-generation sequencing was verified using Sanger sequencing, and we confirmed that the proband and her children carried the same mutation. We identified the heterozygous variant c.389_390insGCTG (p.C130fs), which includes a frameshift mutation. The residues in p.C130fs are all highly conserved across species. This disease-causing frameshift mutation in the CRYGC gene is not currently present in the ClinVar database. Conclusions: Our findings expand the repertoire of known mutations in the CRYGC gene that cause CCs and provide new insights into the etiology and molecular diagnosis of CCs; however, the molecular mechanism of this mutation warrants further investigation.

5.
Ying Yong Sheng Tai Xue Bao ; 33(7): 1993-2000, 2022 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-36052804

RESUMO

The Pearl River Delta Urban Agglomeration (PRDUA) is a highly urbanized region in China. The urbanized climate, especially the heat island effect, has a significant impact on urban ecosystems and habitats. Based on MODIS land surface temperature (LST) data and land cover data in 2000, 2005, 2010, 2015, and 2019, we quantified the land surface thermal environment and ecosystem service value (ESV), analyzed the decoupling between LST and ESV in the PRDUA from 2000 to 2019 using the decoupling analysis model, revealed the trade-off between them, and analyzed the spatiotemporal variation of the synergistic state between LST and ESV in PRDUA. The results showed that, from 2000 to 2019, the spatial pattern of land surface thermal environment in the PRDUA was relatively stable in time series but showed spatial variation with high fluctuation in the core area and low fluctuation in the peripheral area. The ESV of the PRDUA showed a trend of stable spatial distribution and decreasing in time series. The ESV of all the nine cities in PRDUA decreased by more than 9%. The decoupling between land surface thermal environment and the overall ESV of the PRDUA, as well as with the values of provisioning, regulating and support services, was dominated by weak negative decoupling and strong negative decoupling, showing a more significant trade-off, which indicated that the ecosystems of the PRDUA were still significantly influenced by the environmental characteristics of urbanization, and that the spatiotemporal variation of the decoupling states was related to the spatial variation of urbanization levels in PRDUA. The formulation of future ecological policies in the PRDUA must consider the differences in urbanization levels and the differences in the trade-offs between urbanized environments and ecosystems to precisely formulate ecological control and restoration plans and improve the efficiency and implementation effects of ecological planning.


Assuntos
Ecossistema , Rios , China , Cidades , Conservação dos Recursos Naturais , Temperatura Alta , Urbanização
6.
World J Gastrointest Oncol ; 12(7): 719-731, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32864040

RESUMO

BACKGROUND: Overexpression of SQSTM1 (sequestosome 1, P62) and nuclear factor-κB (NF-κB) plays an important role in the invasion and metastasis of a variety of malignant tumors. AIM: To explore the expression of P62 and NF-κB in pancreatic cancer and their relationship with clinicopathological features. METHODS: The expression levels of P62 and NF-κB were analyzed by immunohistochemistry with a tissue chip containing 40 cases of human pancreatic carcinoma. Then we analyzed the correlation among P62 expression, phospho-P65 expression, and clinicopathological features of pancreatic carcinoma samples. RESULTS: P62 expression was mainly observed in the cytoplasm of pancreatic carcinoma cells. Phosphorylated P65 (phospho-P65) was mainly expressed in the nucleus and cytoplasm of pancreatic carcinoma cells. There was a significant difference in P62 expression among T stages. And a significant difference in phosphor-P65 expression among pathology types was noted. In the cases with strongly positive P62 expression, significant differences were found in age. And there were significant differences in T stage and tumor-node-metastasis stage in the cases with strongly positive phosphor-P65 expression. CONCLUSION: In pancreatic carcinoma, P62 expression is significantly correlated with T stage. It may be a valuable malignant indicator for human pancreatic carcinoma.

7.
World J Gastrointest Oncol ; 12(8): 877-892, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32879665

RESUMO

BACKGROUND: Kras mutant colon cancer shows abnormal activation of the nuclear factor kappa-B (NF-κB) pathway, resulting in the proliferation of tumor cells. Treatment with fluorouracil (5-FU) might not achieve the expected inhibition of proliferation of malignant cells based on the fluorouracil-induced activation of the NF-κB pathway. AIM: To detect whether interleukin (IL)-1 receptor antagonist (IL-1RA) could increase the chemosensitivity to 5-FU by decreasing the activation of the NF-κB pathway and reducing the proliferation of colon cancer cells. METHODS: Western blot analysis was performed to detect the persistent activation of the NF-κB pathway in colon cancer cell lines. Reverse transcription-polymerase chain reaction was used to detect the IL-1RA-reduced expression levels of IL-6, IL-8, IL-17, IL-21 and TLR4 in colon cancer cell lines. We used a xenograft nude mouse model to demonstrate the downregulation of the NF-κB pathway by blocking the NF-κB-regulated IL-1α feedforward loop, which could increase the efficacy of chemotherapeutic agents in inhibiting tumor cell growth. RESULTS: IL-1 receptor antagonist could decrease the expression of IL-1α and IL-1ß and downregulate the activity of the NF-κB pathway in Kras mutant colon cancer cells. Treatment with 5-FU combined with IL-1RA could increase the chemosensitivity of the SW620 cell line, and decreased expression of the TAK1/NF-κB and MEK pathways resulted in limited proliferation in the SW620 cell line. CONCLUSION: Adjuvant chemotherapy with IL-1RA and 5-FU has a stronger effect than single chemotherapeutic drugs. IL-1RA combined with fluorouracil could be a potential neoadjuvant chemotherapy in the clinic.

8.
World J Gastroenterol ; 24(3): 360-370, 2018 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-29391758

RESUMO

AIM: To investigate the effect of ischaemia and reperfusion (I/R) injury on the Ca2+-ATPase activation in the intestinal tissue of a rat autologous orthotopic liver transplantation model and to determine if hypoxia preconditioning (HP) therapy induces HIF-1α to protect rat intestinal tissue against I/R injury. METHODS: Rats received non-lethal hypoxic preconditioning therapy to induce HIF-1α expression. We used an autologous orthotopic liver transplantation model to imitate the I/R injury in intestinal tissue. Then, we detected the microstructure changes in small intestinal tissues, Ca2+-ATPase activity, apoptosis, and inflammation within 48 h postoperatively. RESULTS: HIF-1α expression was significantly increased in intestinal tissue at 12 h postoperatively in rats that were exposed to a hypoxic environment for 90 min compared with a non-HP group (HP vs AT, P = 0.0177). Pathological analysis was performed on the intestinal mucosa cells, and the cells in the HP group appeared healthier than the cells in the AT group. The Ca2+-ATPase activity in the small intestinal cells in the AT group was significantly lower after the operation, and the Ca2+-ATPase activity in the HP group recovered faster than that in the AT group at 6 h postoperatively (HP vs AT, P = 0.0106). BCL-2 expression in the HP group was significantly higher than that in the AT group at 12 h postoperatively (HP vs AT P = 0.0010). The expression of the inflammatory factors NO, SOD, IL-6, and TNF-α was significantly lower in the HP group than in the AT group. CONCLUSION: Hypoxia-induced HIF-1α could protect intestinal mucosal cells against mitochondrial damage after I/R injury. HP could improve hypoxia tolerance in small intestinal mucosal cells and increase Ca2+-ATPase activity to reduce the apoptosis of and pathological damage to intestinal cells. HP could be a useful way to promote the earlier recovery of intestinal function after graft procedure.


Assuntos
ATPases Transportadoras de Cálcio/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Precondicionamento Isquêmico/métodos , Transplante de Fígado/efeitos adversos , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose , Hipóxia Celular/fisiologia , Modelos Animais de Doenças , Mucosa Intestinal/citologia , Mucosa Intestinal/patologia , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Fator de Necrose Tumoral alfa/metabolismo
9.
Cancer Lett ; 379(1): 1-11, 2016 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-27233476

RESUMO

Nicotinamide adenine dinucleotide (NAD) is a crucial cofactor for the redox reactions in the metabolic pathways of cancer cells that have elevated aerobic glycolysis (Warburg effect). Cancer cells are reported to rely on NAD recycling and inhibition of the NAD salvage pathway causes metabolic collapse and cell death. However, the underlying regulatory mechanisms and clinical implications for the NAD salvage pathway in pancreatic ductal adenocarcinoma (PDAC) remain unclear. This study showed that the expression of Nampt, the rate-limiting enzyme of the NAD salvage pathway, was significantly increased in PDAC cells and PDAC tissues. Additionally, inhibition of Nampt impaired tumor growth in vitro and tumorigenesis in vivo, which was accompanied by a decreased cellular NAD level and glycolytic activity. Mechanistically, the Nampt expression was independent of Kras and p16 status, but it was directly regulated by miR-206, which was inversely correlated with the expression of Nampt in PDAC tissues. Importantly, pharmacological inhibition of Nampt by its inhibitor, FK866, significantly enhanced the antitumor activity of gemcitabine in PDAC cells and in orthotopic xenograft mouse models. In conclusion, the present study revealed a novel regulatory mechanism for Nampt in PDAC and suggested that Nampt inhibition may override gemcitabine resistance by decreasing the NAD level and suppressing glycolytic activity, warranting further clinical investigation for pancreatic cancer treatment.


Assuntos
Acrilamidas/farmacologia , Antimetabólitos Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Citocinas/antagonistas & inibidores , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Piperidinas/farmacologia , Regiões 3' não Traduzidas , Animais , Sítios de Ligação , Carcinoma Ductal Pancreático/enzimologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Glicólise/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/genética , MicroRNAs/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Interferência de RNA , Fatores de Tempo , Transfecção , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
10.
World J Gastroenterol ; 22(14): 3852-9, 2016 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-27076771

RESUMO

AIM: To investigate the expression of integrin αvß6 and matrix metalloproteinase 9 (MMP-9), their association with prognostic factors and to assess their predictive role in gastric cancer patients. METHODS: Immunohistochemistry was used to determine the expressions of integrin αvß6 and MMP-9 in 126 specimens from patients with primary gastric carcinoma. Associations between immunohistochemical staining and various clinic pathologic variables of tissue specimens were evaluated by the χ(2) test and Fisher's exact test. Expression correlation of αvß6 and MMP-9 was assessed using bivariate correlation analysis. The patients were followed-up every 3 mo in the first two years and at least every 6 mo afterwards, with a median follow-up of 56 mo (ranging from 2 mo to 94 mo). Four different combinations of αvß6 and MMP-9 levels (that is, both markers positive, both markers negative, αvß6 positive with MMP-9 negative, and αvß6 negative with MMP-9 positive) were evaluated for their relative effect on survival. The difference in survival curves was evaluated with a log-rank test. Survival analysis was conducted using the Kaplan-Meier survival and Cox proportional hazards model analysis. RESULTS: The expressions of integrin αvß6 and MMP-9 were investigated in 126 cases, among which 34.92% were positive for αvß6 expression, and 42.06% for MMP-9 expression. The expression of αvß6 was associated with Lauren type, differentiation, N stage, and TNM stage (the P values were 0.006, 0.038, 0.016, and 0.002, respectively). While MMP-9 expression was associated with differentiation, T stage, N stage, and TNM stage (the P values were 0.039, 0.014, 0.033, and 0.008, respectively). The positive correlation between αvß6 and MMP-9 in gastric cancer was confirmed by a correlation analysis. The Kaplan-Meier survival analysis showed that patients with expression of αvß6 or MMP-9 alone died earlier than those with negative expression and that patients who were both αvß6 and MMP-9 positive had a shorter overall survival than those with the opposite pattern (both αvß6 and MMP-9 negative) (P = 0.000). A Cox model indicated that positive expression of αvß6 and MMP-9, diffuse Lauren type, as well as a senior grade of N stage, M stage, and TNM stage were predictors of a poor prognosis in univariate analysis. Only αvß6 and MMP-9 retained their significance when adjustments were made for other known prognostic factors in multivariate analysis (RR = 2.632, P = 0.003 and RR = 1.813, P = 0.007). CONCLUSION: The expression of αvß6 and MMP-9 are closely correlated, and the combinational pattern of αvß6 and MMP-9 can serve as a more effective prognostic index for gastric cancer patients.


Assuntos
Antígenos de Neoplasias/análise , Biomarcadores Tumorais/análise , Integrinas/análise , Metaloproteinase 9 da Matriz/análise , Neoplasias Gástricas/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Fatores de Risco , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Fatores de Tempo , Resultado do Tratamento
11.
Eur J Radiol ; 85(3): 607-15, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26860674

RESUMO

PURPOSE: To investigate whether global spontaneous brain activity changes in type 2 diabetes mellitus (T2DM) patients and these changes vary according to the degree of microangiopathy. MATERIALS AND METHODS: T2DM patients with (M(+), n=26) and without (M(-), n=22) microangiopathy as well as 28 healthy nondiabetic subjects were enrolled in this study. All the subjects completed a resting-state functional magnetic resonance imaging (rs-fMRI) examination and neuropsychological assessment. Regional homogeneity (ReHo) values, representing spontaneous brain activity, were calculated and compared between M(+) and M(-) T2DM patients and nondiabetic controls. RESULTS: In both M(+) and M(-) T2DM patients, ReHo values were decreased in the occipital lobe, temporal lobe, postcentral gyrus, and cerebellum, while increased in the bilateral precuneus, superior/middle frontal gyrus, and insula. Compared with the M(-) group, M(+) patients showed decreased ReHo values in the left cuneus and superior occipital gyrus. The ReHo values in the lingual gyrus/calcarine cortex and MTG were related to clinical parameters in T2DM patients. CONCLUSION: The abnormalities of spontaneous brain activity revealed by ReHo values in both M(+)and M(-) T2DM patients may provide insights into the neurological pathophysiology underlying diabetes-related cognitive impairments. M(+) patients showed more decreased brain activity related to severely impaired function of visual processing and visual memory.


Assuntos
Mapeamento Encefálico/métodos , Encéfalo/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
12.
Mol Cancer Ther ; 14(3): 788-98, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25527634

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) frequently develops therapeutic resistances, which can be divided into extrinsic and intrinsic resistance. The extrinsic resistance that arises from the surrounding dense tumor stroma is much better understood. However, the mechanisms of intrinsic resistance are not well understood. Here, we report that reactive oxygen species (ROS) induced by gemcitabine treatment, a newly discovered cytotoxic activity, served as a probe in our study to reveal the mechanisms of the intrinsic therapeutic resistance. Our results showed that gemcitabine-induced ROS is generated by NOX and through the increase of p22(-phox) expression via NF-κB activation. As a feedback mechanism, nuclear translocation of Nrf2 stimulated the transcription of cytoprotective antioxidant genes, especially genes encoding enzymes that catalyze glutathione (GSH) production to reduce elevated ROS as an intrinsic resistance countermeasure. RNAi-mediated depletion of Nrf2 or addition of ß-phenylethyl isothiocyanate inhibited the ROS detoxification process by reducing GSH levels, which, in turn, increased the efficacy of gemcitabine in vitro and in vivo. Thus, our study suggests that a redox-mediated pathway contributes to the intrinsic resistance of PDAC to gemcitabine and provides a basis for developing strategies to preferentially kill PDAC cells through ROS-mediated mechanism. The combination of gemcitabine and PEITC has a selective cytotoxic effect against pancreatic cancer cells in vivo and could thus prove valuable as a cancer treatment.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/fisiologia , Oxirredução/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/metabolismo , Animais , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Desoxicitidina/farmacologia , Glutationa/metabolismo , Humanos , Isotiocianatos/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Neoplasias Pancreáticas/metabolismo , Interferência de RNA/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Gencitabina
13.
Head Neck ; 37(10): 1439-47, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24844802

RESUMO

BACKGROUND: Overexpression of integrin ß6 plays an important role in a variety of malignant tumor invasion and metastasis. METHODS: The expression levels of integrin ß6, matrix metalloproteinase (MMP)-2 and MMP-9 were analyzed by immunohistochemistry with human follicular thyroid carcinomas. Then we investigated their correlation with clinical outcomes parameters, relationship, and the survival time. RESULTS: The integrin ß6 staining was expressed in cellular membrane and cytoplasm of follicular thyroid carcinoma cells. The MMP-2 and MMP-9 expressions were mainly found in cellular cytoplasm. In correlation with the clinical outcome parameters of 60 patients, there were significant statistical differences of integrin ß6, MMP-2, and MMP-9 expression levels in different size of tumor. Integrin ß6 and MMP-9 expressions have significant statistical differences in T classifications. MMP-2 and MMP-9 expressions have significant statistical differences in different M classification. Other clinical outcome parameters had no significant statistical differences. CONCLUSION: Integrin ß6 expression correlated significantly with MMP-9 expression, and may be a valuable recurrence indicator for follicular thyroid carcinomas.


Assuntos
Adenocarcinoma Folicular/metabolismo , Biomarcadores Tumorais/metabolismo , Cadeias beta de Integrinas/metabolismo , Recidiva Local de Neoplasia/metabolismo , Adenocarcinoma Folicular/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Prognóstico , Adulto Jovem
14.
World J Gastrointest Surg ; 6(7): 122-8, 2014 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-25068009

RESUMO

Hepatic ischemia-reperfusion injury (IRI) is a pathophysiological event post liver surgery or transplantation and significantly influences the prognosis of liver function. The mechanisms of IRI remain unclear, and effective methods are lacking for the prevention and therapy of IRI. Several factors/pathways have been implicated in the hepatic IRI process, including anaerobic metabolism, mitochondria, oxidative stress, intracellular calcium overload, liver Kupffer cells and neutrophils, and cytokines and chemokines. The role of nitric oxide (NO) in protecting against liver IRI has recently been reported. NO has been found to attenuate liver IRI through various mechanisms including reducing hepatocellular apoptosis, decreasing oxidative stress and leukocyte adhesion, increasing microcirculatory flow, and enhancing mitochondrial function. The purpose of this review is to provide insights into the mechanisms of liver IRI, indicating the potential protective factors/pathways that may help to improve therapeutic regimens for controlling hepatic IRI during liver surgery, and the potential therapeutic role of NO in liver IRI.

15.
Artigo em Inglês | MEDLINE | ID: mdl-24527057

RESUMO

A Chinese medicine granule, Shu-Feng-Xuan-Fei (SFXF), is critical for viral clearance in early phase of influenza virus infection. In this study, 72 ICR mice were randomly divided into six groups: normal control group, virus control group, Oseltamivir group, low-dose SFXF, medium-dose SFXF, and high-dose SFXF. Mice were anesthetized and inoculated with 4LD50 of influenza virus A (H1N1) except normal control group. Oseltamivir group received 11.375 mg·kg(-1) ·d(-1) Oseltamivir Phosphate. SFXF 3.76, 1.88 and 0.94 g·kg(-1) ·d(-1) were administrated to mice in all SFXF groups. Each group was in equal dose of 0.2ml daily for 4 consecutive days. Mice were sacrificed and then total RNA was extracted in lung tissue. Some genes involved in T-cell-mediated immunity were selected by DNA microarray. These candidate genes were verified by Real-Time PCR and western immunoblotting. Compared with virus control group, in Toll-like receptor signaling pathway, 12 virus-altered genes were significantly reduced following medium-dose SFXF treatment. Eighteen antigen processing presentation-associated genes were upregulated by medium-dose SFXF. In the process of T cell receptor signaling pathway, 19 genes were downregulated by medium-dose SFXF treatment. On exploration into effector T cells activation and cytokines, all of altered genes in virus control group were reversed by medium-dose SFXF. Real-time PCR and western immunoblotting showed that the regulation of medium-dose SFXF in IL-4, IFN-γ, TNF-α, IL-1ß, TLR7, MyD88, p38, and JNK was superior to Oseltamivir and high-dose SFXF group. Therefore, SFXF granules could reduce influenza infected cells and activation of T cells.

16.
Zhonghua Yu Fang Yi Xue Za Zhi ; 42(5): 324-8, 2008 May.
Artigo em Chinês | MEDLINE | ID: mdl-18844081

RESUMO

OBJECTIVE: In order to investigate Hantavirus (HV) infection of captured rodents and to understand the genotypes and the molecular characteristic of Hantaviruses in Shenzhen. METHODS: The captured rodents were classified and the density of distribution was calculated. A total of 472 animals were captured, among which Rattus norvegicus was the dominant group. The total viral RNA was extracted from the lung tissues positive with HV antigens by immunofluorescent assay and gene sequence of M fragment was amplified with RT-nested-PCR by using the Hantavirus genotype specific primers. The amplified genes were then sequenced, and subjected to genotyping and homology analysis. RESULTS: The results of genotype analysis showed that the Hantaviruses taken from twenty-one lung specimens in Rattus norvegicus in Shenzhen city belonged to the Hantavirus type II (SEOV). Results in homology analysis suggested that the homology among twenty-one samples should be rather high with 95.4% of nucleotide sequence identity and they belonged to the same subtype. Phylogenetic tree analysis showed that they were branched into at least six different lineages, and were highly homologized with SZ2083. We also found that these virus strains had not shown more highly homology of nucleotide sequence in nearest district, whereas revealed consistency in farther district. CONCLUSION: The major hosts of Hantaviruses in Shenzhen city were Rattus norvegicus and the epidemic strains were genotyped as SEO-type. Nucleotide sequence and deduced amino acid sequence from different rodents were highly homologous, while nucleotide mutation had also been observed. Further studies are required to explore the possible viruses' sequence mutation.


Assuntos
Infecções por Hantavirus/epidemiologia , Infecções por Hantavirus/veterinária , Orthohantavírus/genética , Doenças dos Roedores/epidemiologia , Doenças dos Roedores/virologia , Animais , China/epidemiologia , Primers do DNA , DNA Viral , Genótipo , Orthohantavírus/classificação , Infecções por Hantavirus/virologia , Reação em Cadeia da Polimerase , RNA Viral , Ratos , Homologia de Sequência
17.
Zhonghua Zheng Xing Wai Ke Za Zhi ; 24(2): 112-5, 2008 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-18590211

RESUMO

OBJECTIVE: To apply the scapular free flap extended to the upper arm for resurfacing the face and neck, as well as the upper lip in one stage. METHODS: The scapular free flap was designed with extended portion to the posterior and interior part of the upper arm. Then the free flap was transferred to resurface the face and neck with the routine portion and to resurface the upper lip with the extended portion. RESULTS: 6 cases with extensive upper lip, facial and cervical burn scar were treated with the extended scapular free flaps. The flap size ranged from 22 cm x 11 cm to 40 cm x 9.5 cm (36.57 cm x 10.20 cm in average) for the routine portion and from 7 cm x 4 cm to 12 cm x 4 cm (10.32 cm x 3.67 cm in average) for the extended portion. All flaps survived completely. CONCLUSIONS: There are direct communicating branches ("choke vessel") between the circumflex scapular artery (CSA) and the posterior humeral circumflex artery (PHCA). When the blood supply of PHCA is cut off, the CSA can provide blood supply through the communicating branches to the upper arm skin area previously nourished by PHCA. So the blood supply of the extended portion of the scapular free flap is not only from the branches of CSA, but also from the direct communicating branches between the CSA and PHCA. The extended scapular free flap has a reliable blood supply and can be applied to construct the facial and cervical scar contraction with the extended portion to resurface the upper lip. The satisfactory result can be expected.


Assuntos
Cicatriz/cirurgia , Transplante de Pele/métodos , Retalhos Cirúrgicos , Adulto , Braço/cirurgia , Humanos , Masculino , Pescoço , Escápula , Adulto Jovem
18.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-325895

RESUMO

<p><b>OBJECTIVE</b>To apply the scapular free flap extended to the upper arm for resurfacing the face and neck, as well as the upper lip in one stage.</p><p><b>METHODS</b>The scapular free flap was designed with extended portion to the posterior and interior part of the upper arm. Then the free flap was transferred to resurface the face and neck with the routine portion and to resurface the upper lip with the extended portion.</p><p><b>RESULTS</b>6 cases with extensive upper lip, facial and cervical burn scar were treated with the extended scapular free flaps. The flap size ranged from 22 cm x 11 cm to 40 cm x 9.5 cm (36.57 cm x 10.20 cm in average) for the routine portion and from 7 cm x 4 cm to 12 cm x 4 cm (10.32 cm x 3.67 cm in average) for the extended portion. All flaps survived completely.</p><p><b>CONCLUSIONS</b>There are direct communicating branches ("choke vessel") between the circumflex scapular artery (CSA) and the posterior humeral circumflex artery (PHCA). When the blood supply of PHCA is cut off, the CSA can provide blood supply through the communicating branches to the upper arm skin area previously nourished by PHCA. So the blood supply of the extended portion of the scapular free flap is not only from the branches of CSA, but also from the direct communicating branches between the CSA and PHCA. The extended scapular free flap has a reliable blood supply and can be applied to construct the facial and cervical scar contraction with the extended portion to resurface the upper lip. The satisfactory result can be expected.</p>


Assuntos
Adulto , Humanos , Masculino , Adulto Jovem , Braço , Cirurgia Geral , Cicatriz , Cirurgia Geral , Pescoço , Escápula , Transplante de Pele , Métodos , Retalhos Cirúrgicos
19.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-352478

RESUMO

<p><b>OBJECTIVE</b>In order to investigate Hantavirus (HV) infection of captured rodents and to understand the genotypes and the molecular characteristic of Hantaviruses in Shenzhen.</p><p><b>METHODS</b>The captured rodents were classified and the density of distribution was calculated. A total of 472 animals were captured, among which Rattus norvegicus was the dominant group. The total viral RNA was extracted from the lung tissues positive with HV antigens by immunofluorescent assay and gene sequence of M fragment was amplified with RT-nested-PCR by using the Hantavirus genotype specific primers. The amplified genes were then sequenced, and subjected to genotyping and homology analysis.</p><p><b>RESULTS</b>The results of genotype analysis showed that the Hantaviruses taken from twenty-one lung specimens in Rattus norvegicus in Shenzhen city belonged to the Hantavirus type II (SEOV). Results in homology analysis suggested that the homology among twenty-one samples should be rather high with 95.4% of nucleotide sequence identity and they belonged to the same subtype. Phylogenetic tree analysis showed that they were branched into at least six different lineages, and were highly homologized with SZ2083. We also found that these virus strains had not shown more highly homology of nucleotide sequence in nearest district, whereas revealed consistency in farther district.</p><p><b>CONCLUSION</b>The major hosts of Hantaviruses in Shenzhen city were Rattus norvegicus and the epidemic strains were genotyped as SEO-type. Nucleotide sequence and deduced amino acid sequence from different rodents were highly homologous, while nucleotide mutation had also been observed. Further studies are required to explore the possible viruses' sequence mutation.</p>


Assuntos
Animais , Ratos , China , Epidemiologia , Primers do DNA , DNA Viral , Genótipo , Orthohantavírus , Classificação , Genética , Infecções por Hantavirus , Epidemiologia , Virologia , Reação em Cadeia da Polimerase , RNA Viral , Doenças dos Roedores , Epidemiologia , Virologia , Homologia de Sequência
20.
Zhonghua Zheng Xing Wai Ke Za Zhi ; 23(3): 187-90, 2007 May.
Artigo em Chinês | MEDLINE | ID: mdl-17649933

RESUMO

OBJECTIVE: To provide an ideal method for flap prefabrication. METHODS: The superficial temporal fascial flap has been elevated based on the superficial temporal vessels during the first-stage procedure. A subcutaneous tissue pocket with appropriate site was formed in the retroauricular and mastoid process region. The fascial flap was transferred into the pocket and fixed properly. The tissue expander was placed under the fascial flap. When the expanding process has been finished, the expander was removed and the expanded induced prefabricated skin flap of the retroauricular and mastoid process region pedicled on the superficial temporal vascular bundle was elevated and transferred to repair the facial skin defect. RESULTS: There were nine cases in the group. Facial defects after resection of the melanotic nevus was repaired in 2 cases and facial defects after resection of the facial haemangioma and scar were repaired in 2 and 5 cases respectively. Pedicle length of the superficial temporal fascial flap was ranged from 5.5 cm to 7 cm (mean length 6.2 cm). The size of the fascial flaps was ranged from 4 cm x 3 cm to 7 cm x 7 cm (mean size 5.7 cm x 4.9 cm). The size of the prefabricated skin flaps was ranged from 5 cm x 5 cm to 8.0 cm x 7.5 cm (mean size 6.4 cm x 6.1 cm). The average time of the tissue expansion process is 16.1 weeks. All flaps survived postoperatively and the donor sites of the flaps were appropriated directly in 5 cases. The split-thickness skin grafting was used to recover the donor site defects in 4 cases. CONCLUSIONS: The superficial temporal fascial flap owns the following advantages: the vascular pedicle is much longer and vascular supply is plentiful, and it is convenient to transfer. Meanwhile, the skin of the retroauricular and mastoid process region is most similar to that of the face in texture, color and depth. For the patients selected strictly, the technique mentioned above is somewhat an ideal method for facial defect repair.


Assuntos
Orelha Externa/cirurgia , Traumatismos Faciais/cirurgia , Transplante de Pele/métodos , Lesões dos Tecidos Moles/cirurgia , Adolescente , Adulto , Criança , Fáscia/transplante , Feminino , Humanos , Masculino , Retalhos Cirúrgicos , Expansão de Tecido , Resultado do Tratamento , Adulto Jovem
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