Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 40
Filtrar
Filtros adicionais











País/Região como assunto
Intervalo de ano
1.
Cancer Res ; 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484669

RESUMO

The genetic events occuring in recurrent nasopharyngeal carcinoma (rNPC) are poorly understood. Here, we performed whole-genome and whole-exome sequencing in 55 rNPC and 44 primarily diagnosed NPC (pNPC) patients; with 7 patients having paired rNPC and pNPC samples. Previously published pNPC exome data were integrated for analysis. rNPC and pNPC tissues had similar mutational burdens, however, the number of clonal mutations was increased in rNPC samples. TP53 and three NF-κB pathway components (TRAF3, CYLD and NFKBIA) were significantly mutated in both pNPC and rNPC. Notably, mutations in TRAF3, CYLD and NFKBIA were all clonal in rNPC, however, 55.6-57.9% of them were clonal in pNPC. In general, the number of clonal mutations in NF-κB pathway-associated genes was significantly higher in rNPC than in pNPC. The NF-κB mutational clonality was selected and/or enriched during NPC recurrence. The amount of NF-κB translocated to the nucleus in samples with clonal NF-κB mutants was significantly higher than that in samples with subclonal NF-κB mutants. Moreover, the nuclear abundance of NF-κB protein was significantly greater in pNPC samples with local regional relapse than in those without relapse. Further, high nuclear NF-κB levels were an independent negative prognostic marker for locoregional relapse-free survival in pNPC. Lastly, inhibition of NF-κB enhanced both radiosensitivity and chemosensitivity in vitro and in vivo. In conclusion, NF-κB pathway activation by clonal mutations plays an important role in promoting the recurrence of NPC. Moreover, nuclear accumulation of NF-κB is a prominent biomarker for predicting locoregional relapse-free survival.

2.
Theranostics ; 9(12): 3541-3554, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281496

RESUMO

Rationale: Advanced nasopharyngeal carcinoma (NPC) is an aggressive disease with no targeted therapies and poor outcomes. New innovative targets are urgently needed. KLF4 has been extensively studied in the context of tumors, and current data suggest that it can act as either a tissue-specific tumor-inhibiting or a tumor-promoting gene. Here, we found that KLF4 played as a tumor-promoting gene in NPC, and could be mediated by PLK1. Methods: Tissue immunohistochemistry (IHC) assay was performed to identify the role of KLF4 in NPC. Global gene expression experiments were performed to explore the molecular mechanisms underlying KLF4-dependent tumorigenesis. Small-molecule kinase inhibitor screening was performed to identify potential upstream kinases of KLF4. The pharmacologic activity of polo-like kinase inhibitor volasertib (BI6727) in vitro and in vivo was determined. Result: Our investigation showed that high expression of KLF4 was correlated with poor prognosis in NPC. Moreover, genome-wide profiling revealed that KLF4 directly activated oncogenic programmes, including gene sets associated with KRAS, VEGF, and MYC signalling. We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization. Moreover, KLF4 could enhance TRAF6 expression at the transcriptional level, thus initiating a KLF4-TRAF6 feed-forward loop. Treatment with the PLK1 inhibitor volasertib (BI6727) significantly inhibited tumor growth in nude mice. Conclusion: Our study unveiled a new PLK1-TRAF6-KLF4 feed-forward loop. The resulting increase in KLF4 ubiquitination leads to stabilization and upregulation of KLF4, which leads to tumorigenesis in NPC. These results expand our understanding of the role of KLF4 in NPC and validate PLK1 inhibitors as potential therapeutic agents for NPC, especially cancer patients with KLF4 overexpression.

3.
World J Gastroenterol ; 25(15): 1840-1853, 2019 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-31057298

RESUMO

BACKGROUND: Colorectal cancer (CRC) is one of the main causes of cancer-related deaths in China and around the world. Advanced CRC (ACRC) patients suffer from a low cure rate though treated with targeted therapies. The response rate is about 50% to chemotherapy and cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR) and used for ACRC with wild-type KRAS. It is important to identify more predictors of cetuximab efficacy to further improve precise treatment. Autophagy, showing a key role in the cancer progression, is influenced by the EGFR pathway. Whether autophagy can predict cetuximab efficacy in ACRC is an interesting topic. AIM: To investigate the effect of autophagy on the efficacy of cetuximab in colon cancer cells and ACRC patients with wild-type KRAS. METHODS: ACRC patients treated with cetuximab plus chemotherapy, with detailed data and tumor tissue, at Sun Yat-sen University Cancer Center from January 1, 2005, to October 1, 2015, were studied. Expression of autophagy-related proteins [Beclin1, microtubule-associated protein 1A/B-light chain 3 (LC3), and 4E-binding protein 1 (4E-BP1)] was examined by Western blot in CRC cells and by immunohistochemistry in cancerous and normal tissues. The effect of autophagy on cetuximab-treated cancer cells was confirmed by MTT assay. The associations between Beclin1, LC3, and 4E-BP1 expression in tumor tissue and the efficacy of cetuximab-based therapy were analyzed. RESULTS: In CACO-2 cells exposed to cetuximab, LC3 and 4E-BP1 were upregulated, and P62 was downregulated. Autophagosome formation was observed, and autophagy increased the efficacy of cetuximab. In 68 ACRC patients, immunohistochemistry showed that Beclin1 levels were significantly correlated with those of LC3 (0.657, P < 0.001) and 4E-BP1 (0.211, P = 0.042) in ACRC tissues. LC3 was significantly overexpressed in tumor tissues compared to normal tissues (P < 0.001). In 45 patients with wild-type KRAS, the expression levels of these three proteins were not related to progression-free survival; however, the expression levels of Beclin1 (P = 0.010) and 4E-BP1 (P = 0.005), pathological grade (P = 0.002), and T stage (P = 0.004) were independent prognostic factors for overall survival (OS). CONCLUSION: The effect of cetuximab on colon cancer cells might be improved by autophagy. LC3 is overexpressed in tumor tissues, and Beclin1 and 4E-BP1 could be significant predictors of OS in ACRC patients treated with cetuximab.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Autofagia , Biomarcadores Tumorais/metabolismo , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteína Beclina-1/metabolismo , Cetuximab/farmacologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Humanos , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fosfoproteínas/metabolismo , Prognóstico , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas p21(ras)/genética , Regulação para Cima , Adulto Jovem
4.
Cancer Manag Res ; 10: 2499-2507, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30122999

RESUMO

Background: Skeletal muscle depletion is a prognostic factor in patients with cancer. Here, we evaluated the association between the skeletal muscle index (SMI) and local and systemic responses in patients with colon cancer. Patients and methods: We analyzed the relationships of the SMI with neutrophil, lymphocyte, monocyte, and platelet counts; the neutrophil-to-lymphocyte ratio; albumin levels; and C-reactive protein levels in a cohort of 561 patients, and with the circulating levels of 39 cytokines in a cohort of 125 patients. We also studied the association between the SMI and tumor local inflammatory response and the effect of SMI on survival. Results: The median SMIs for male and female subjects were 44.1 and 34.2 cm2/m2, respectively. We observed positive correlations of the SMI with neutrophil (p=0.022), lymphocyte (p=0.001), and monocyte counts (p=0.003). A low SMI correlated significantly with an increased platelet count (p=0.017), decreased albumin level (p=0.006), neutrophil-to-lymphocyte ratio >3 (p=0.021), and an increased interferon γ-induced protein 10 level (IP-10, r = -0.276, p=0.002). The SMI did not correlate significantly with local inflammatory reactions or the C-reactive protein level. Finally, the SMI was a significant prognosticator in patients with stage III colon cancer (3-year disease-free survival rates: 35.1% for the low SMI arms versus 46.0% in the high SMI arms; HR =2.036; p=0.034). Conclusion: This study highlights the association of a low SMI with a high systematic inflammatory response and IP-10 levels. Furthermore, low SMI is a predictor of poor disease-free survival in patients with stage III colon cancer.

5.
Neurosurgery ; 2018 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-29893910

RESUMO

BACKGROUND: Brief electrical stimulation (ES) therapy to the nerve may improve outcome in lacerated, repaired nerves. However, most human nerve injuries leave the nerve in continuity with variable and often poor functional recovery from incomplete axon regeneration and reinnervation. OBJECTIVE: To evaluate the effect of brief ES in an experimental model for neuroma-in-continuity (NIC) injuries in rodents. METHODS: Lewis rats were randomly assigned to 1 of 4 groups: NIC injury immediately followed by brief (1 h) ES; NIC injury without ES; sham-operated controls; sciatic nerve transection without repair. Outcome measures included serial behavioral evaluation and electrophysiology together with terminal retrograde spinal cord motor neuron labeling and histomorphological analysis for axonal regeneration. RESULTS: Applying brief ES immediately after in-continuity nerve injury resulted in earlier recovery and significantly improved locomotion function at 4 and 6 wk. At 8 wk, brief ES resulted in higher compound action potential amplitude. By 12 wk there was no significant difference between the 2 groups in behavior or electrophysiology. Histomorphological analysis demonstrated a significantly higher percentage of neural tissue in the brief ES group. Spinal cord motor neuron pool cell counts revealed a preference for regeneration into a motor over a sensory nerve, for the group receiving ES. CONCLUSION: The application of brief ES for in-continuity nerve injury promotes faster recovery, although in a rat model where regeneration distances are short the control group ultimately recovers to a similar degree. Brief EF requires further evaluation as a promising therapy for in-continuity nerve injuries in humans.

6.
J Neurosurg ; : 1-10, 2018 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-29775143

RESUMO

OBJECTIVE Supercharge end-to-side (SETS) transfer, also referred to as reverse end-to-side transfer, distal to severe nerve compression neuropathy or in-continuity nerve injury is gaining clinical popularity despite questions about its effectiveness. Here, the authors examined SETS distal to experimental neuroma in-continuity (NIC) injuries for efficacy in enhancing neuronal regeneration and functional outcome, and, for the first time, they definitively evaluated the degree of contribution of the native and donor motor neuron pools. METHODS This study was conducted in 2 phases. In phase I, rats (n = 35) were assigned to one of 5 groups for unilateral sciatic nerve surgeries: group 1, tibial NIC with distal peroneal-tibial SETS; group 2, tibial NIC without SETS; group 3, intact tibial and severed peroneal nerves; group 4, tibial transection with SETS; and group 5, severed tibial and peroneal nerves. Recovery was evaluated biweekly using electrophysiology and locomotion tasks. At the phase I end point, after retrograde labeling, the spinal cords were analyzed to assess the degree of neuronal regeneration. In phase II, 20 new animals underwent primary retrograde labeling of the tibial nerve, following which they were assigned to one of the following 3 groups: group 1, group 2, and group 4. Then, secondary retrograde labeling from the tibial nerve was performed at the study end point to quantify the native versus donor regenerated neuronal pool. RESULTS In phase I studies, a significantly increased neuronal regeneration in group 1 (SETS) compared with all other groups was observed, but with modest (nonsignificant) improvement in electrophysiological and behavioral outcomes. In phase II experiments, the authors discovered that secondary labeling in group 1 was predominantly contributed from the donor (peroneal) pool. Double-labeling counts were dramatically higher in group 2 than in group 1, suggestive of hampered regeneration from the native tibial motor neuron pool across the NIC segment in the presence of SETS. CONCLUSIONS SETS is indeed an effective strategy to enhance axonal regeneration, which is mainly contributed by the donor neuronal pool. Moreover, the presence of a distal SETS coaptation appears to negatively influence neuronal regeneration across the NIC segment. The clinical significance is that SETS should only employ synergistic donors, as the use of antagonistic donors can downgrade recovery.

7.
J Cancer ; 8(17): 3548-3554, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29151940

RESUMO

Background: Given recent results indicating that diminished LKB1 expression in laryngeal cancer correlates with shorter survival. We aim to perform an analysis estimate the role of decreased liver kinase B1(LKB1) and in the prognostication of human laryngeal squamous cell carcinoma (LSCC). Methods: We conducted a retrospective study and evaluate the expression of LKB1 and p16INK4a (p16) in 208 clinical advanced-stage LSCC tissue samples by using immunohistochemistry. The specimens were received at Sun Yat-sen University Cancer Center (Guangzhou, China). To evaluate the independent prognostic relevance of LKB1, univariate and multivariate Cox regression models were used, overall survival (OS) and distant metastasis-free survival (DMFS) were compared using the Kaplan-Meier method. Results: Immunohistochemical analyses revealed that 80/208 (38.5%) of the LSCC tissue samples expressed high LKB1. Low LKB1 expression was associated with a significantly shorter OS and DMFS than high LKB1 expression (P = 0.041 and 0.028, respectively; log-rank test), and there was a poorer OS in the p16-positive than p16-negative group. In the subgroup stratified by p16 status, the shorter OS were also seen with low LKB1 expression. Multivariate survival analysis indicated that high LKB1 expression was an independent prognostic factor for OS (hazard ratio [HR]: 1.628, 95% confidence interval [CI]: 1.060-2.500, P = 0.026) and DMFS (HR: 2.182, 95% CI: 1.069-4.456, P = 0.032). Conclusions: Our data indicated that low expression of LKB1 was significantly associated with poor prognosis and it may represent a marker of tumor metastasis in patients with LSCC. When combined with p16, LKB1 was also of prognostic value.

8.
J Cancer ; 8(12): 2410-2416, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28819445

RESUMO

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is known to function in several types of cancer. In this study, we investigated the expression and clinicopathologic significance of DNA-PKcs in laryngeal squamous cell carcinoma (LSCC). Methods: We conducted a retrospective study of 208 patients with advanced-stage LSCC treated at Sun Yat-sen University Cancer Center, Guangzhou, China. We assessed DNA-PKcs and p16INK4a (p16) status using immunohistochemistry. We examined the association between DNA-PKcs expression and clinicopathologic features and survival outcomes. To evaluate the independent prognostic relevance of DNA-PKcs, we used univariate and multivariate Cox regression models. We estimated overall survival (OS) and distant metastasis-free survival (DMFS) using the Kaplan-Meier method. Results: Immunohistochemical analyses revealed that 163/208 (78.4%) of the LSCC tissue samples exhibited high DNA-PKcs expression. High DNA-PKcs expression was significantly associated with survival outcomes (P = 0.016) and distant metastasis (P = 0.02; chi-squared test). High DNA-PKcs expression was associated with a significantly shorter OS and DMFS than low DNA-PKcs expression (P = 0.029 and 0.033, respectively; log-rank test), and was associated with poor OS in the p16-positive subgroup (P = 0.047). Multivariate analysis identified DNA-PKcs as an independent prognostic indicator of OS and DMFS in all patients (P = 0.039 and 0.037, respectively). Conclusions: Our results suggest that patients with LSCC in whom DNA-PKcs expression is elevated have a higher incidence of distant metastasis and a poorer prognosis. DNA-PKcs may represent a marker of tumor progression in patients with p16-positive LSCC.

9.
Chin J Integr Med ; 23(2): 153-160, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27041332

RESUMO

Brucea javanica, a Chinese herbal medicine, combined with conventional anticancer modalities, has been widely used for treatment of various cancers. Based on researches over the last decades, authors briefly summarized its active constituents, molecular mechanisms and clinical application for cancer treatment.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Pesquisa Biomédica/tendências , Brucea/química , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias/tratamento farmacológico , Apoptose/efeitos dos fármacos , Pesquisa Biomédica/métodos , Humanos , Neoplasias/patologia , Fitoterapia
10.
J Neurosci Methods ; 273: 86-95, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27546200

RESUMO

BACKGROUND: To optimize survival evaluation of Schwann cells (SCs) in vivo, we tested fluorescent labeling of the nucleus as an improved method of tracking and counting the transplanted SCs at sciatic nerve injury sites in rodents. We also investigated if co-administering cells with the glial growth factor Neuregulin-1 ß (NRG1ß) improves in vivo survival. NEW METHOD: We transduced SCs using a Lentiviral vector with a nuclear localization signal (NLS) fused with mCherry and transplanted them in the sciatic nerve of rat post-crush injury (bilateral) either in the presence or absence of NRG1ß in the injectate media. For comparison, in a separate group of similar injury, GFP-labeled cells were transplanted. After 10 days, nerves were harvested and sections (14µm) were counterstained with Hoechst and imaged. Cells showing co-localization with Hoechst and GFP or mCherry were exhaustively counted and data analyzed. RESULTS: Percentage cells counted in with- and without-NRG condition in both the groups were 0.83±0.13% and 0.06±0.04% (Group 1) & 2.83*±1.95% and 0.23*±0.29% (Group 2). COMPARISON TO EXISTING METHOD: We are introducing fluorescent labeling of the nucleus as a reliable and efficient technique to perform survival assessments in Schwann cell based treatment studies in animal model. This method can overcome the challenges and limitations of the existing method that could result in underestimation of the therapeutic outcome. CONCLUSIONS: Nucleus-restricted fluorescent labeling technique offer improved method of tracking as well as accurately counting transplanted SCs in vivo while NRG1ß in the injectate media can improve survival.


Assuntos
Proteínas de Fluorescência Verde/metabolismo , Proteínas Luminescentes/metabolismo , Células de Schwann/metabolismo , Células de Schwann/transplante , Neuropatia Ciática/cirurgia , Animais , Animais Recém-Nascidos , Contagem de Células , Sobrevivência Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/genética , Proteínas Luminescentes/genética , Masculino , Sinais de Localização Nuclear/metabolismo , Sinais de Localização Nuclear/farmacologia , Ratos , Ratos Endogâmicos Lew , Células de Schwann/efeitos dos fármacos , Transdução Genética
11.
Chin J Cancer ; 35(1): 58, 2016 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-27357402

RESUMO

BACKGROUND: It remains controversial whether palliative primary tumor resection (PPTR) can provide survival benefits to the patients with metastatic colorectal cancer (mCRC) who have unresectable metastases. The aim of this study was to evaluate whether PPTR could improve the survival of patients with mCRC. METHODS: We conducted a retrospective study on consecutive mCRC patients with unresectable metastases who were diagnosed at Sun Yat-sen University Cancer Center in Guangzhou, Guangdong, China, between January 2005 and December 2012. Overall survival (OS) and progression-free survival (PFS) after first-line chemotherapy failure were compared between the PPTR and non-PPTR patient groups. RESULTS: A total of 387 patients were identified, including 254 who underwent PPTR and 133 who did not. The median OS of the PPTR and non-PPTR groups was 20.8 and 14.8 months (P < 0.001), respectively. The median PFS after first-line chemotherapy was 7.3 and 4.8 months (P < 0.001) in the PPTR and non-PPTR groups, respectively. A larger proportion of patients in the PPTR group (219 of 254, 86.2%) showed local progression compared with that of patients in the non-PPTR group (95 of 133, 71.4%; P < 0.001). Only patients with normal lactate dehydrogenase (LDH) levels and with carcinoembryonic antigen (CEA) levels <70 ng/mL benefited from PPTR (median OS, 22.2 months for the PPTR group and 16.2 months for the non-PPTR group; P < 0.001). CONCLUSIONS: For mCRC patients with unresectable metastases, PPTR can improve OS and PFS after first-line chemotherapy and decrease the incidence of new organ involvement. However, PPTR should be recommended only for patients with normal LDH levels and with CEA levels <70 ng/mL.


Assuntos
Antígeno Carcinoembrionário/sangue , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , L-Lactato Desidrogenase/sangue , Cuidados Paliativos/métodos , Idoso , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
12.
Onco Targets Ther ; 9: 877-83, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26966375

RESUMO

PURPOSE: To investigate the prognostic relevance of preoperative peripheral neutrophil- to-lymphocyte ratio (NLR) in gastrointestinal stromal tumor (GIST) patients. MATERIALS AND METHODS: We enrolled 129 consecutive GIST patients who underwent initial curative surgical resection with or without adjuvant/palliative imatinib treatment in our study. Blood NLR was calculated as neutrophil count (number of neutrophils ×10(9)/L) divided by lymphocyte count (number of lymphocytes ×10(9)/L). Survival curves were constructed by using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazard regression models were performed to identify associations with outcome variable. All tests were two-sided, and P<0.05 was considered statistically significant. RESULTS: The optimal cut-off value of NLR was 2.07 in the receiver operating characteristic curve analysis. The median overall survival (OS) of high NLR group was 113.0 months, whereas that of the low NLR group had not reached the median OS both in the general (P<0.001) and subgroup analyses. The elevated NLR suggested shorter OS in the high malignant potential groups (P=0.01) and the combined low and moderate groups (P=0.02). Increased NLR indicated poor OS in patients regardless of whether if received imatinib treatment or not (P=0.005, and P=0.032, respectively). High NLR indicated poor OS of patients in stage I and II disease (P=0.005) and a clear tendency that increased level of NLR is inimical to OS. CONCLUSION: Elevated NLR was detected as an independent adverse prognostic factor. Elevated preoperative NLR predicts poor clinical outcome in GIST patients and may serve as a cost-effective and broadly available independent prognostic biomarker.

13.
Eur J Neurosci ; 43(3): 365-75, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26121489

RESUMO

Skin-derived precursor Schwann cell (SKPSC) therapy has been identified as a potentially beneficial treatment for peripheral nerve injuries. One hypothesised mechanism by which SKPSCs enhance recovery is via the modulation of macrophages. In the present study, we investigated the immunomodulatory properties of adult rat SKPSCs, and demonstrated that these cells expressed a battery of cytokines, including interferon-γ (IFN-γ), interleukin (IL)-1ß, and, most abundantly, IL-6. Whereas macrophages exposed to depleted or fibroblast-conditioned medium secreted minimal amounts of tumor necrosis factor-α (TNF-α), in the presence of SKPSC-conditioned medium, macrophages secreted > 500 pg/mL TNF-α. Following the transplantation of SKPSCs into injured rat sciatic nerves, we observed an SKPSC density-dependent increase in the number of macrophages (Pearson's r = 0.66) and an SKPSC density-dependent decrease in myelin debris (Pearson's r = -0.68). To determine the effect of IL-6 in a proinflammatory context, macrophage cultures were primed with either lipopolysaccharide (LPS)/IFN-γ/IL-1ß or LPS/IFN-γ/IL-1ß + IL-6, and this showed a 212% and 301% increase in the number of inducible nitric oxide synthase (iNOS)-positive proinflammatory macrophages respectively. In contrast to neurons exposed to conditioned medium from unprimed macrophages, neurons treated with conditioned medium from proinflammatory-primed macrophages showed a 13-26% reduction in neurite outgrowth. Anti-IL-6 antibody combined with SKPSC transplant therapy following nerve injury did not alter macrophage numbers or debris clearance, but instead reduced iNOS expression as compared with SKPSC + IgG-treated rats. SKPSC + anti-IL-6 treatment also resulted in a two-fold increase in gastrocnemius compound muscle action potential amplitudes as compared with SKPSC + IgG treatment. Understanding the mechanisms underlying immunomodulatory aspects of SKPSC therapy and developing approaches to manipulate these responses are important for advancing Schwann cell-based therapies.


Assuntos
Células-Tronco Adultas/citologia , Citocinas/metabolismo , Regeneração Nervosa , Traumatismos dos Nervos Periféricos/terapia , Células de Schwann/transplante , Animais , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Citocinas/genética , Macrófagos/metabolismo , Masculino , Bainha de Mielina/metabolismo , Neurônios/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew , Células de Schwann/citologia , Células de Schwann/imunologia , Pele/citologia
14.
Exp Neurol ; 271: 493-505, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26210874

RESUMO

Intrinsic molecular determinants of neurodevelopmental outcomes assume new, albeit related roles during adult neural regeneration. Here we studied and identified a facilitatory role for Sonic hedgehog protein (Shh), a morphogen that influences motor neuron floor plate architecture, during adult peripheral neuron regeneration. Shh and its receptors were expressed in adult dorsal root ganglia (DRG) neurons, axons and glia and trended toward higher levels following axotomy injury. Knockdown of Shh in adult sensory neurons resulted in decreased outgrowth and branching in vitro, identifying a role for Shh in facilitating outgrowth. The findings argued for an intrinsic action to support neuron regeneration. Support of advancement and turning however, were not identified in adult sensory neuron growth cones in response to local extrinsic gradients of Shh. That intrinsic Shh supported the regrowth of peripheral nerves after injury was confirmed by the analysis of axon regrowth from the proximal stumps of transected sciatic nerves. By exposing regenerating axons to local infusions of Shh siRNA in vivo within a conduit bridging the transected proximal and distal stumps, we achieved local knockdown of Shh. In response, there was attenuated axonal and Schwann cell outgrowth beyond the transection zone. Unlike its role during neurodevelopment, Shh facilitates but does not confer regenerative outgrowth properties to adult neurons alone. Exploring the differing properties of morphogens and related proteins in the adult nervous system identifies new and important roles for them.


Assuntos
Proteínas Hedgehog/metabolismo , Regeneração Nervosa/fisiologia , Neuropatia Ciática/fisiopatologia , Células Receptoras Sensoriais/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Gânglios Espinais/citologia , Proteínas Hedgehog/genética , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuritos/fisiologia , Receptores Patched , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Neuropatia Ciática/patologia , Células Receptoras Sensoriais/citologia
15.
Mol Cell Neurosci ; 67: 1-12, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25979201

RESUMO

Perineuronal satellite cells have an intimate anatomical relationship with sensory neurons that suggests close functional collaboration and mutual support. We examined several facets of this relationship in adult sensory dorsal root ganglia (DRG). Collaboration included the support of process outgrowth by clustering of satellite cells, induction of distal branching behavior by soma signaling, the capacity of satellite cells to respond to distal axon injury of its neighboring neurons, and evidence of direct neuron-satellite cell exchange. In vitro, closely adherent coharvested satellite cells routinely clustered around new outgrowing processes and groups of satellite cells attracted neurite processes. Similar clustering was encountered in the pseudounipolar processes of intact sensory neurons within intact DRG in vivo. While short term exposure of distal growth cones of unselected adult sensory neurons to transient gradients of a PTEN inhibitor had negligible impacts on their behavior, exposure of the soma induced early and substantial growth of their distant neurites and branches, an example of local soma signaling. In turn, satellite cells sensed when distal neuronal axons were injured by enlarging and proliferating. We also observed that satellite cells were capable of internalizing and expressing a neuron fluorochrome label, diamidino yellow, applied remotely to distal injured axons of the neuron and retrogradely transported to dorsal root ganglia sensory neurons. The findings illustrate a robust interaction between intranganglionic neurons and glial cells that involve two way signals, features that may be critical for both regenerative responses and ongoing maintenance.


Assuntos
Células Satélites Perineuronais/fisiologia , Células Receptoras Sensoriais/fisiologia , Animais , Transporte Axonal , Axônios/metabolismo , Axônios/fisiologia , Células Cultivadas , Gânglios Espinais/citologia , Gânglios Espinais/fisiologia , Cones de Crescimento/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/metabolismo
16.
Oncol Lett ; 9(3): 1425-1431, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25663926

RESUMO

Brucea javanica oil emulsion (BJOE), the petroleum ether extract of B. javanica emulsified by phospholipid, is widely used in China as an anticancer agent. The extracts from B. javanica induce cancer cell death by various mechanisms; however, it is not known whether these mechanisms involve autophagy, which is an important process in cancer development and treatment. Thus, the current study aimed to investigate whether BJOE modulates autophagy in HCT116 human colon cancer cells and whether modulation of autophagy is an anticancer mechanism of BJOE. Immunoblotting was employed to analyze the protein expression levels of microtubule-associated protein light-chain 3 (LC3), a specific protein marker of autophagy, in HCT116 cancer cells following exposure to BJOE. The apoptosis rate of the HCT116 cancer cells was detected by performing an Annexin V-fluorescein isothiocyanate/propidium iodide assay. According to the effect of BJOE administration on autophagy in the HCT116 cancer cells (induction or suppression), a functionally opposite agent (autophagy suppressor or inducer) was applied to counteract this effect, and the apoptosis rate of the cancer cells was detected again. The role of autophagy (pro-survival or pro-death) was demonstrated by comparing the rates of apoptotic cancer cells prior to and following the counteraction. The results revealed that BJOE suppressed the protein expression levels of LC3, including the LC3-I and LC3-II forms, and induced apoptosis in the HCT116 cancer cells with a high level of basal LC3. The apoptosis-inducing activity of BJOE was significantly attenuated when autophagy was induced by the administration of trehalose, an autophagy inducer. The data indicates that autophagy inhibition is involved in BJOE-induced cancer cell death, and that this inhibition may be a potential anticancer mechanism of BJOE.

17.
Asian Pac J Cancer Prev ; 15(17): 7327-31, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25227837

RESUMO

BACKGROUND: We had previously showed that the neutrophil lymphocyte ratio (NLR), γ-glutamyl transpeptidase (GGT) and carcinoembryonic antigen (CEA) are prognostic factors for metastatic colorectal cancer (mCRC) patients. In this study we developed a prognostic model based on these three indices. MATERIALS AND METHODS: A total of 243 patients who were initially diagnosed as mCRC between 2005 and 2010 in the Sun Yat-sen University Cancer Center were studied. The endpoint was overall survival (OS). RESULTS: NLR>3, elevated GGT and elevated CEA were confirmed as independent risk factors which could predict poor prognosis. Patients could be divided into three groups according to the number of risk factors they had. Those with two or three were defined as the high risk group, individuals with one risk factor as the modest risk group and patients without risk factor as the low risk group. The OS values for these three groups were 16.2 months (2.80~68.8), 24.2 months (4.07~79.0), and 37.2 months (12.6~87.8), respectively (p<0.001). CONCLUSIONS: We developed a simple but useful model based on NLR, GGT and CEA to provide prognostic information to clinical practice in highly selected mCRC patients. Further prospective and multi-center studies are warranted to test our model.


Assuntos
Biomarcadores Tumorais/sangue , Antígeno Carcinoembrionário/sangue , Carcinoma/sangue , Neoplasias Colorretais/sangue , gama-Glutamiltransferase/sangue , Carcinoma/mortalidade , Carcinoma/patologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Humanos , Contagem de Linfócitos , Masculino , Modelos Estatísticos , Metástase Neoplásica , Neutrófilos/citologia , Prognóstico , Estudos Retrospectivos , Medição de Risco
18.
J Neuropathol Exp Neurol ; 73(9): 820-36, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25101700

RESUMO

An overlapping population of adult primary sensory neurons that innervate the skin express the glial cell-derived neurotrophic factor coreceptor α1 (GFRα1), the lectin IB4, and the "regenerative brake" phosphatase and tensin homolog deleted on chromosome 10. Using an adapted turning and growth assay, we analyzed the growth cone behavior of adult immunoselected GFRα1 sensory neurons. These neurons had less robust baseline growth and reluctant responsiveness to individual growth factors but responded to synergistic types of input from glial cell-derived neurotrophic factor, hepatocyte growth factor, a phosphatase and tensin homolog deleted on chromosome 10 inhibitor, or a downstream Rho kinase inhibitor. Hepatocyte growth factor and the phosphatase and tensin homolog deleted on chromosome 10 inhibitor were associated with growth cone turning. A gradient of protein extracted from skin samples, a primary target of GFRα1 axons, replicated the impact of synergistic support. Within the skin, glial cell-derived neurotrophic factor was expressed within epidermal axons, indicating an autocrine role accompanying local hepatocyte growth factor synthesis. Taken together, our findings identify unique growth properties and plasticity of a distinct population of epidermal axons that are relevant to neurologic repair and skin reinnervation.


Assuntos
Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Cones de Crescimento/fisiologia , Células Receptoras Sensoriais/fisiologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Gânglios Espinais/citologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Cones de Crescimento/efeitos dos fármacos , Masculino , Neuritos/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Lectinas de Plantas/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Ribossômicas/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos
19.
Asian Pac J Cancer Prev ; 15(13): 5493-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25041024

RESUMO

OBJECTIVE: To compare the efficacy of taxane-based regimens in the first line setting retrospectively in Chinese patients with recurrent and/or metastatic esophageal cancer. METHODS: We analyzed 102 recurrent and/or metastatic esophageal cancer patients who received taxanes-based regimens in a first-line setting from January 2009 to December 2013. Sixteen (15.7%) patients were administered Nab-PTX based chemotherapy and 86 patients (84.3%) received paclitaxel (PTX) or docetaxel (DTX) based chemotherapy. Patients in the PTX/DTX group could be further divided into TP (71 patients) and TPF (15 patients) groups. RESULTS: The objective response rate (ORR) of all patients was 20.6%, and the disease control rate (DCR) was 67.6%. The median overall survival (OS) was 10.5 months (95% CI 10.1-16.4) and the median progression-free survival (PFS) was 6.04 months (95% CI 5.09-7.91). The DCR was higher in the TPF group than the TP group (93.3% vs. 59.1%; p = 0.015 ). There were no significant differences in ORR, OS, and PFS among Nab-PTX, TPF and TP groups. CONCLUSIONS: The three regimens of Nab-PTX based, TP and TPF proved active in a first line setting of Chinese patients with recurrent and/or metastatic esophageal cancer, and should thus be regarded as alternative treatments.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Intervalo Livre de Doença , Docetaxel , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Estudos Retrospectivos , Taxoides/administração & dosagem
20.
J Surg Res ; 187(2): 596-604, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24331940

RESUMO

BACKGROUND: Mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) signaling pathways are pleiotropic regulator of many genes involved in lipopolysaccharide (LPS)-induced acute lung injury (ALI). The present study aimed to reveal the protective effect of isotetrandrine (ITD), a small molecule inhibitor, on various aspects of LPS-induced inflammation in vitro and in vivo. METHODS: In vitro, RAW 264.7 cells were pretreated with different dose of ITD 1 h before treatment with 1 mg/L of LPS. In vivo, to induce ALI, male BALB/c mice were injected intranasally with LPS and treated with ITD (20 and 40 mg/kg) 1 h before LPS. RESULTS: In vitro, the cytokine levels of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 in supernatant were reduced by ITD. Meanwhile, in vivo, pulmonary inflammatory cell infiltration, myeloperoxidase activity, total cells, neutrophils, macrophages, along with the levels of tumor necrosis factor-α, IL-1ß, and IL-6 in bronchoalveolar lavage fluid were dose-dependently attenuated by ITD. Furthermore, our data showed that ITD significantly inhibited the activation of MAPK and NF-κB, which are induced by LPS in ALI model. CONCLUSIONS: These results suggested that ITD dose-dependently suppressed the severity of LPS-induced ALI by inactivation of MAPK and NF-κB, which may involve the inhibition of tissue oxidative injury and pulmonary inflammatory process.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Benzilisoquinolinas/farmacologia , Imunossupressores/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Animais , Benzilisoquinolinas/química , Líquido da Lavagem Broncoalveolar , Linhagem Celular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Imunossupressores/química , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Peroxidase/metabolismo , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/tratamento farmacológico , Edema Pulmonar/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA