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1.
Carcinogenesis ; 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32034405

RESUMO

Pancreatic cancer is a lethal and devastating disease in the worldwide. Recognized risk factors for pancreatic cancer include cigarette smoking, obesity, typeⅡdiabetes and chronic pancreatitis. Other factors such as variant ABO blood type and Helicobacter pylori may also play an important role in pancreatic carcinogenesis. Recently, growing evidence suggests that the association between bacteria and pancreatic cancer is positive and related immune/inflammation activation and increased nitrosamine exposure may be its potential mechanism. Interestingly, it is debatable whether the relationship of bacteria and pancreatic cancer is causative, reactive or parallel and future studies are in progress. Here we review recent progress in pancreatic cancer and its related bacteria.

2.
Cell Death Dis ; 10(12): 957, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31862870

RESUMO

Radiation-induced lung injury (RILI) is one of the most common and fatal complications of thoracic radiotherapy, whereas no effective interventions are available. Andrographolide, an active component extracted from Andrographis paniculate, is prescribed as a treatment for upper respiratory tract infection. Here we report the potential radioprotective effect and mechanism of Andrographolide on RILI. C57BL/6 mice were exposed to 18 Gy of whole thorax irradiation, followed by intraperitoneal injection of Andrographolide every other day for 4 weeks. Andrographolide significantly ameliorated radiation-induced lung tissue damage, inflammatory cell infiltration, and pro-inflammatory cytokine release in the early phase and progressive fibrosis in the late phase. Moreover, Andrographolide markedly hampered radiation-induced activation of the AIM2 inflammasome and pyroptosis in vivo. Furthermore, bone marrow-derived macrophages (BMDMs) were exposed to 8 Gy of X-ray radiation in vitro and Andrographolide significantly inhibited AIM2 inflammasome mediated-pyroptosis in BMDMs. Mechanistically, Andrographolide effectively prevented AIM2 from translocating into the nucleus to sense DNA damage induced by radiation or chemotherapeutic agents in BMDMs. Taken together, Andrographolide ameliorates RILI by suppressing AIM2 inflammasome mediated-pyroptosis in macrophage, identifying Andrographolide as a novel potential protective agent for RILI.

3.
Medicine (Baltimore) ; 98(44): e17462, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689749

RESUMO

RATIONALE: Oxaliplatin is a key part of the standard treatment for colorectal cancer which is formally contraindicated in patients with severe renal dysfunction. Here, we investigated a safe and efficient dosing schedule of oxaliplatin in folinic acid, fluorouracil, and oxaliplatin (FOLFOX) regimen by monitoring total and free platinum concentrations in plasma. PATIENT CONCERNS: A 47-year-old female with chronic hemodialysis was diagnosed with left-sided colon cancer and underwent colectomy. One year later, she was presented with omentum metastasis and needed further treatment. DIAGNOSES: The computed tomography (CT) scanning revealed multiple omental nodules. Positron emission tomography-CT (PET-CT) showed increased uptake of the nodules. INTERVENTIONS: The patient was treated with FOLFOX therapy every 3 weeks. The oxaliplatin began with 50 mg/m and gradually increased 85 mg/m as in the standard regimen. A 4-hour dialysis was started 1 hour after the end of oxaliplatin infusion. OUTCOMES: The free platinum concentration time curve showed a biomodel pattern. The Cmax of the 1st peak we observed in our patients at the standard dose is comparable to patients with normal renal function. This patient was treated with FOLFOX for 12 courses. No apparent adverse effect was observed during the treatment. LESSONS: The FOLFOX can be safely administered in hemodialysis patients on a long-term basis. Dose reduction of oxaliplatin is not necessarily needed if hemodialysis is performed soon after the infusion. Further studies are needed to distinguish between active and inactive oxaliplatin products during the 2nd peak of the free platinum concentration curve in this population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Glomerulonefrite/terapia , Oxaliplatina/uso terapêutico , Diálise Renal/métodos , Doença Crônica , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina/administração & dosagem
4.
EBioMedicine ; 48: 169-177, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31521609

RESUMO

BACKGROUND: Tumor mutations and tumor microenvironment are associated with resistance to cancer immunotherapies. However, peripheral T cell in effective anti-programmed death 1 (PD-1) antibody treatment is poorly understood. METHODS: Mass spectrometry and conventional flow cytometry were used to investigate peripheral blood cells isolated from patients. Furthermore, melanoma mouse model was performed to assess the role of CXCR3 signaling in anti-PD-1 antibody treatment. FINDINGS: We revealed a marked increase in the percentage of CXCR3+ T cells in the blood of cancer patients after the first pembrolizumab infusion. This percentage decreased after the second infusion in responsive patients, whereas a sustained high percentage of CXCR3+ T cells was observed in patients with progressive disease. A low percentage of CXCR3+ T cells presented in patients with stable disease or a partial response was confirmed by conventional flow cytometry. Intriguingly, blockade of CXCR3 signaling exacerbated tumor growth in mice. Intratumoral injection with recombinant CXCL9/10 plus intraperitoneal injection of anti-PD1 antibody inhibited the tumor growth in mice. INTERPRETATION: The dynamic changes in CXCR3+ T cells in blood may be a prognostic factor in anti-PD-1 immunotherapy, and promotion of CXCR3-mediated signaling may be beneficial to the anti-PD-1 therapy. FUND: This work was supported by the National Natural Science Foundation of China (Nos. 81722047, 81871944, 81670553, 81874317, 81572389, 81730100) and Jiangsu province key medical talents (Nos. ZDRCA2016026), The "Deng Feng" Distinguished Scholars Program, National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China (Number: 2018ZX09201002), and the Fundamental Research Funds for the Central Universities (020814380117).

5.
Cell Death Dis ; 10(8): 618, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409769

RESUMO

Valine catabolism is known to be essential for cancer cells but the detailed mechanism remains unclear. This study is to explore the critical roles of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) in colorectal cancers (CRC) and to develop a new therapy returning valine metabolism homeostasis. High HIBCH expression was first confirmed to correlate with poor survival in patients with CRC, which was then linked to the increased cell growth, resistant apoptosis, and decreased autophagy in CRC cells. The functions of HIBCH in CRC were dependent on its mitochondrial localization. High HIBCH level was further demonstrated to promote the metabolism of tricarboxylic acid cycle as well as oxidative phosphorylation in CRC cells. Based on above findings, we further discovered a novel valine catabolism inhibitor SBF-1. The pharmacological blockade of HIBCH mitochondrial localization with SBF-1 resulted in decreased cancer cell growth and increased autophagy, collectively contributing to the antitumor effect both in vitro and in vivo. Moreover, anti-VEGF therapy with bevacizumab increased HIBCH level in CRC cells, which in turn caused the resistance to the therapy. The interference with HIBCH function by SBF-1 significantly increased the antitumor efficacy of bevacizumab and led to a robust survival benefit. The present study identified HIBCH as a critical enzyme of valine catabolism in CRC progression and resistance to anti-VEGF therapy. We also provided a novel HIBCH inhibitor SBF-1, which highlighted the combined therapy using valine catabolic inhibitor along with anti-VEGF drugs, to control progression of CRC.

6.
Nat Commun ; 10(1): 3190, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320627

RESUMO

Brain metastases (BM) of colorectal cancer (CRC) are rare but lethal, and an understanding of their genomic landscape is lacking. We conduct an analysis of whole-exome sequencing (WES) and whole-genome sequencing (WGS) data on 19 trios of patient-matched BMs, primary CRC tumors, and adjacent normal tissue. Compared with primary CRC, BM exhibits elevated mutational signatures of homologous recombination deficiency (HRD) and mismatch repair deficiency (MMRD). Further analysis reveals two DNA damage response (DDR) signatures could emerge early and are enhanced in BM tissues but are eliminated eventually in matched primary CRC tissues. BM-specific mutations in DDR genes and elevated microsatellite instability (MSI) levels support the importance of DDR in the brain metastasis of CRC. We also identify BM-related genes (e.g., SCN7A, SCN5A, SCN2A, IKZF1, and PDZRN4) that carry frequent BM-specific mutations. These results provide a better understanding of the BM mutational landscape and insights into treatment.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Colorretais/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Neoplasias Colorretais/patologia , Dano ao DNA/genética , Reparo de Erro de Pareamento de DNA/genética , Recombinação Homóloga/genética , Humanos , Instabilidade de Microssatélites , Mutação/genética , Sequenciamento Completo do Exoma
7.
Technol Cancer Res Treat ; 18: 1533033819853237, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31159706

RESUMO

BACKGROUND: Non-coding RNAs are competing endogenous RNAs in the occurrence and development of tumorigenesis; numerous microRNAs are aberrantly expressed in colon cancer tissues and play significant roles in oncogenesis development and metastasis. However, large clinical and RNA data are lacking to further confirm the exact role of these RNAs in tumors. This study aimed to ascertain differential RNA expression between colon cancer and normal colon tissues. MATERIALS AND METHODS: RNA sequencing and clinical data of patients with colon cancer were procured from The Cancer Genome Atlas database; differentially expressed long non-coding RNA, differentially expressed messenger RNAs, and differentially expressed microRNAs were achieved using the limma package in edgeR to generate competing endogenous RNAs networks. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were conducted with ggplot2 package, the Kaplan-Meier survival method was used to predict survival in patients with colon cancer. RESULTS: In total, 1174 differentially expressed long non-coding RNAs, 2068 differentially expressed messenger RNAs, and 239 differentially expressed microRNAs were generated between 480 colon cancer and 41 normal colon tissue samples. Three competing endogenous RNA networks were established. Gene Ontology analysis indicated that the genes of the up-regulated microRNA network were involved in negative regulation of transcription, DNA-template, and those of down-regulated microRNA network were involved in transforming growth factor ß receptor signaling pathways, response to hypoxia, cell migration, while Kyoto Encyclopedia of Genes and Genomes analyses of these networks turned out to be negative. Three long non-coding RNAs (AP004609.1, ARHGEF26-AS1, and LINC00491), 3 microRNAs (miRNA-141, miRNA-216a, and miRNA-193b) and 3 RNAs (ULBP2, PHLPP2, and TPM2) were detected to be associated with prognosis by the Kaplan-Meier survival analysis. Additionally, univariate and multivariate Cox regression analyses showed that the microRNA-216a of the competing endogenous RNA might be an independent prognostic factor in colon cancer. CONCLUSIONS: This study constructed the non-coding RNA-related competing endogenous RNA networks in colon cancer and sheds lights on underlying biomarkers for colon cancer cohorts.


Assuntos
Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , MicroRNAs/genética , Interferência de RNA , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Adulto , Idoso , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/mortalidade , Biologia Computacional , Ontologia Genética , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico
8.
Polymers (Basel) ; 11(5)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083352

RESUMO

The corrosion behavior of zinc-rich epoxy primers or paints (ZRPs) with different conducting polyaniline-grafted graphene (PANI/Gr) contents was investigated. Conductivity of the formed PANI/Gr nanosheets was significantly improved by employing the Gr as the inner template to synthesize the PANI. The protective properties and electrochemical behavior of coatings with artificial defects were investigated by monitoring the free corrosion potential versus time and by using localized electrochemical impedance spectroscopy (LEIS). A synergetic enhancement of the physical barrier role of the coating and the zinc sacrificial cathodic protection was achieved in the case of ZRP including PANI/Gr nanosheets. In addition, the ZRP mixed with the PANI/Gr at a content of 0.6% exhibited the best anticorrosion performance across the range of investigated PANI/Gr contents.

9.
Cancer Biol Med ; 16(1): 189-204, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31119060

RESUMO

Next-generation sequencing (NGS) technology is capable of sequencing millions or billions of DNA molecules simultaneously. Therefore, it represents a promising tool for the analysis of molecular targets for the initial diagnosis of disease, monitoring of disease progression, and identifying the mechanism of drug resistance. On behalf of the Tumor Biomarker Committee of the Chinese Society of Clinical Oncology (CSCO) and the China Actionable Genome Consortium (CAGC), the present expert group hereby proposes advisory guidelines on clinical applications of NGS technology for the analysis of cancer driver genes for precision cancer therapy. This group comprises an assembly of laboratory cancer geneticists, clinical oncologists, bioinformaticians, pathologists, and other professionals. After multiple rounds of discussions and revisions, the expert group has reached a preliminary consensus on the need of NGS in clinical diagnosis, its regulation, and compliance standards in clinical sample collection. Moreover, it has prepared NGS criteria, the sequencing standard operation procedure (SOP), data analysis, report, and NGS platform certification and validation.

10.
Langmuir ; 35(20): 6735-6741, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31030507

RESUMO

Titanium and its alloys have long been used as implantable biomaterials in orthopedics; however, to the best of our knowledge, few studies were reported to investigate surface functionalization of titanium for enhanced lubrication and sustained drug release. In the present study, titania nanotube arrays (TNTs) were prepared by anodization as effective drug nanocarriers, using titanium as the substrate. Meanwhile, motivated by articular cartilage-inspired superlubricity and mussel-inspired adhesion, a copolymer containing both dopamine methacrylamide and 2-methacryloyloxyethyl phosphorylcholine was synthesized (DMA-MPC) and spontaneously grafted onto the TNT surface, which was validated by characterization techniques such as scanning electron microscopy, water contact angle measurements, and X-ray photoelectron spectroscopy. Additionally, the lubrication test showed that copolymer-grafted TNTs have remarkably reduced friction coefficients compared with bare TNTs. Furthermore, the drug release test demonstrated that copolymer-grafted TNTs inhibited burst drug release and achieved sustained drug release in comparison with bare TNTs. In conclusion, the bioinspired surface functionalization strategy developed here, namely DMA-MPC copolymer-grafted TNTs, can be applied to modify orthopedic biomaterials (such as titanium) for enhanced lubrication and sustained drug release.

11.
Transl Oncol ; 12(6): 828-835, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30981094

RESUMO

BACKGROUND: Pembrolizumab shows robust antitumor activity and favorable safety in metastatic melanoma. KEYNOTE-151 evaluated pembrolizumab in Chinese patients, who have more aggressive melanoma subtypes than other populations. METHODS: Chinese patients aged ≥18years with advanced melanoma previously treated with one line of therapy received pembrolizumab 2 mg/kg every 3 weeks for 35 cycles or until confirmed disease progression, intolerable toxicity, or study withdrawal. Primary end points were objective response rate (ORR) per RECIST v1.1 by blinded independent central review and safety. Key secondary end points included duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 and overall survival (OS). RESULTS: Median age was 52 years (N=103); 37.9% had acral and 14.6% had mucosal melanoma. Median follow-up was 7.9months at data cutoff (December 27, 2017). ORR was 16.7% (95% CI, 10.0-25.3%) (1 complete, 16 partial responses). Disease control rate was 38.2%. ORR was 15.8% for acral, 13.3% for mucosal melanoma. Median DOR was 8.4months; 65.6% of patients had response duration ≥6months. Median PFS was 2.8months (95% CI, 2.7-3.5months); 6-month rate was 20.4%. Median OS was 12.1months (95% CI, 9.6months-not reached); 6-month rate, 75.7%; 12-month rate, 50.6%. Treatment-related AEs (TRAEs) occurred in 87 (84.5%) patients; 9 (8.7%) experienced grade 3/4 TRAE and 2 (1.9%) discontinued because of TRAE; none died. Two deaths occurred that were unrelated to treatment. CONCLUSIONS: Pembrolizumab was well tolerated and provided clinically meaningful antitumor activity as second-line therapy in Chinese patients with advanced melanoma.

12.
Acta Pharm Sin B ; 9(2): 304-315, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30972278

RESUMO

Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both in vitro and in vivo. However, whether SHP099-mediated SHP2 inhibition retards tumor growth in vivo via anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099. Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system. SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8+IFN-γ + T cells and the upregulation of cytotoxic T-cell related genes including Granzyme B andPerforin, which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and anti-PD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.

13.
Oncologist ; 24(7): 883-e407, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30877190

RESUMO

LESSONS LEARNED: Patients with metastatic colorectal cancer with good performance status or no liver metastasis could benefit from apatinib.Circulating tumor DNA abundance may be a predictor in serial monitoring of tumor load. BACKGROUND: Apatinib, an oral vascular endothelial growth factor (VEGF) receptor-2 inhibitor, has been approved as third-line treatment for metastatic gastric cancer in China. The aim of this study was to evaluate the efficacy and safety of apatinib, in the treatment of patients with refractory metastatic colorectal cancer after failure of two or more lines of chemotherapy. METHODS: In this open-label, single-arm, phase II study, patients with histological documentation of adenocarcinoma of the colon or rectum were eligible if they had received at least two prior regimens of standard therapies including fluoropyrimidine, oxaliplatin, and irinotecan. These patients were treated with apatinib in a daily dose of 500 mg, p.o., in the third-line or higher setting. Capture sequencing was dynamically performed to identify somatic variants in circulating tumor DNA (ctDNA) with a panel of 1,021 cancer-related genes. The primary endpoint was progression-free survival (PFS) and the tumor response was determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Interim analysis was applied as predefined. RESULTS: From June 1, 2016 to December 31, 2017, 26 patients were enrolled. The median PFS of the whole group was 3.9 months (95% confidence interval [CI]: 2.1-5.9). The median overall survival (OS) was 7.9 months (95% CI: 4.6-10.1+). Patients with performance status (PS) 0-1 had longer PFS than those with PS 2 (4.17 months vs. 1.93 months, p = .0014). Patients without liver metastasis also had longer PFS than those who had live metastasis (5.87 months vs. 3.33 months, p = .0274). The common side effects of apatinib were hypertension, hand-foot syndrome, proteinuria, and diarrhea. The incidence of grade 3-4 hypertension, hand-foot syndrome, proteinuria, and diarrhea was 76.92%, 11.54%, 73.08%, and 23.08%, respectively. All of the patients received dose reduction because of adverse effect. Results of capture sequencing showed APC, TP53, and KRAS were most frequently mutant genes. ctDNA abundance increased before the radiographic assessment in ten patients. CONCLUSION: Apatinib monotherapy showed promising efficiency for patients with refractory colorectal cancer, especially in patients with PS 0-1 or no liver metastasis. ctDNA abundance may be a predictor in serial monitoring of tumor load.

14.
Clin Lab ; 65(1)2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30775879

RESUMO

BACKGROUND: Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) has been proven to be involved in various human cancers; however, the function of PLOD3 in gastric cancer (GC) remains unclear. In this study, the role of PLOD3 in GC was evaluated. METHODS: The expression of PLOD3 in GC tissues and normal tissues was predicted by The Cancer Genome Atlas (TCGA). The kmplot online tool was performed to evaluate the impact of PLOD3 expression on GC patients' survival. Real-time PCR was conducted to verify PLOD3 expression in our own clinical samples and GC cells. The Cell Counting Kit-8 and the colony formation assay were used to detect GC cell proliferation ability. RESULTS: PLOD3 was upregulated in human GC tissues (compared to adjacent normal tissues, p < 0.001) and GC cells. High expression of PLOD3 was significantly correlated with larger tumor size (p = 0.007) and poor prognosis. Inhibition of PLOD3 could suppress cell proliferation in GC. CONCLUSIONS: These results revealed that PLOD3 may promote the progression of GC.


Assuntos
Regulação Neoplásica da Expressão Gênica , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/genética , Neoplasias Gástricas/genética , Regulação para Cima , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/metabolismo , Prognóstico , Interferência de RNA , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
15.
J Hematol Oncol ; 12(1): 16, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30764882

RESUMO

The lungs are the second most common site of metastasis for colorectal cancer (CRC) after the liver. Rectal cancer is associated with a higher incidence of lung metastases compared to colon cancer. In China, the proportion of rectal cancer cases is around 50%, much higher than that in Western countries (nearly 30%). However, there is no available consensus or guideline focusing on CRC with lung metastases. We conducted an extensive discussion and reached a consensus of management for lung metastases in CRC based on current research reports and the experts' clinical experiences and knowledge. This consensus provided detailed approaches of diagnosis and differential diagnosis and provided general guidelines for multidisciplinary therapy (MDT) of lung metastases. We also focused on recommendations of MDT management of synchronous lung metastases and initial metachronous lung metastases. This consensus might improve clinical practice of CRC with lung metastases in China and will encourage oncologists to conduct more clinical trials to obtain high-level evidences about managing lung metastases.

16.
Cell Prolif ; 52(2): e12551, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30485570

RESUMO

OBJECTIVES: To investigate the function and regulatory mechanism of Krüppel-like factor 3 (KLF3) in lung cancer. MATERIALS AND METHODS: KLF3 expression was analysed by qRT-PCR and Western blot assays. The proliferation, migration, invasion, cycle and apoptosis were measured by CCK-8 and EdU, wound-healing and Transwell, and flow cytometry assays. The tumour growth was detected by nude mouse tumorigenesis assay. In addition, the interaction between KLF3 and Sp1 was accessed by luciferase reporter, EMSA and ChIP assay. JAK2, STAT3, PI3K and p-AKT levels were evaluated by Western blot and IHC assays. RESULTS: The results indicated that KLF3 expression was elevated in lung cancer tissues. Knockdown of KLF3 inhibited lung cancer cell proliferation, migration and invasion, and induced cell cycle arrest and apoptosis. In addition, the downregulation of KLF3 suppressed tumour growth in vivo. KLF3 was transcriptionally activated by Sp1. miR-326 could bind to 3'UTR of Sp1 but not KLF3 and decreased the accumulation of Sp1, which further indirectly reduced KLF3 expression and inactivated JAK2/STAT3 and PI3K/AKT signaling pathways in vitro and in vivo. CONCLUSIONS: Our data demonstrate that miR-326/Sp1/KLF3 regulatory axis is involved in the development of lung cancer, which hints the potential target for the further therapeutic strategy against lung cancer.


Assuntos
Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição Kruppel-Like/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Fator de Transcrição Sp1/genética , Células A549 , Idoso , Animais , Apoptose , Movimento Celular , Proliferação de Células , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia
17.
Medicine (Baltimore) ; 97(47): e13286, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30461637

RESUMO

RATIONALE: Thymic carcinoids are a rare type of malignant neuroendocrine tumors which have a poor prognosis due to their distant metastasis, invasive behaviour, and postoperative recurrence. Surgical resection is still the fundamental mode for treating thymic carcinoids. Here, we report the rapid shrinkage of an atypical thymic carcinoid with multiple metastases following chemoradiation plus octreotide as a first-line therapy PATIENT CONCERNS:: A 39-year-old Chinese man presented with chest tightness, dyspnea with a history of lumbago and untreated malignant thymoma. DIAGNOSIS: Thoracic computed tomography (CT) scan revealed an anterior mediastinal mass with pulmonary and multiple bone metastases as well as bilateral pleural and pericardial effusions. Percutaneous needle biopsy was performed on the mediastinal mass and the pathological diagnosis was neuroendocrine carcinoma of moderately differentiation (atypical carcinoid) INTERVENTIONS:: The tumor was considered unresectable because of extensive invasion into the lung and various bones. The patient was started on paclitaxel and oxaliplatin per 21 days for 4 cycles, and on 20 mg of depot formulation of octreotide once per 21 days. After 2 cycles of chemotherapy, the patient received concurrently mediastinal radiotherapy (39.6 Gy × 22 fractions). OUTCOMES: A follow-up CT of the chest at the completion of his fourth chemotherapy regimen demonstrated, approximately 22% of tumor shrinkage. There were no signs of disease progression but the patient refused further chemoradiation treatment. The patient received monthly treatment of octreotide and zoledronate and his progression-free survival reached 18 months. Due to uncontrollable disease progression, the patient expired. LESSONS: Early diagnosis and radical surgery of thymic carcinoid are very important. However, radiotherapy (combined/noncombined chemotherapy) must be considered if radical resection is not performed. We believe that further study of chemoradiation and octreotide with the palliative intent of preparing tumors for shrinkage is warranted as a strategy to improve curative management of neuroendocrine tumors.


Assuntos
Neoplasias Ósseas , Tumor Carcinoide , Neoplasias Pulmonares , Mediastino/diagnóstico por imagem , Octreotida/administração & dosagem , Neoplasias do Timo , Adulto , Antineoplásicos Hormonais/administração & dosagem , Biópsia/métodos , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/secundário , Tumor Carcinoide/patologia , Tumor Carcinoide/terapia , Quimiorradioterapia/métodos , Terapia Combinada/métodos , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Masculino , Estadiamento de Neoplasias , Neoplasias do Timo/patologia , Neoplasias do Timo/terapia , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
18.
Onco Targets Ther ; 11: 2533-2543, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29765232

RESUMO

Background: Biliary tract cancers (BTCs) are uncommon but fatal, with a low 5-year survival rate after surgical resection. This study was designed to investigate the prognostic factors for operable BTC. Methods: Baseline demographics at diagnosis were retrospectively evaluated in 341 BTC patients undergoing radical surgery at The First Affiliated Hospital of Nanjing Medical University from January 2011 to December 2015. The association between prognostic factors and overall survival (OS) was determined by multivariate analysis using the Cox proportional hazards regression model. Results: Our study showed that 341 patients were included in the analysis, of which 166 (48.7%) were males and 175 (51.3%) were females. Older age, depth of tumor invasion, positive surgical margin, lower hemoglobin, and higher lactic dehydrogenase (LDH) were associated with significantly worse OS using multivariate analysis. In the entire cohort, the estimate of median OS in patients with LDH <271 U/L was 36.291 months (95% CI; 30.989-41.594 months), and 30.736 months (95% CI; 19.154-42.318 months) in patients with LDH ≥271 U/L (adjusted HR-1.505, 95% CI; 1.009-2.245, P = 0.045). Moreover, it was investigated whether serum LDH retained its significance as a prognostic marker in BTC subgroups separately. The results showed that LDH was prognostic in patients with distal bile duct (DBD) carcinoma undergoing radical surgery (HR-2.452, 95% CI; 1.167-5.152, P = 0.018). However, there were no statistical differences between LDH and OS in multivariate analysis in the other three individual subgroups except for DBD carcinoma. This may be due to the limited number of patients in the study, indicating that a greater number of patients may be required for statistical significance. Conclusion: Older age, depth of tumor invasion, positive surgical margin status, lower hemoglobin levels, and elevated serum LDH level are associated with poor survival in operable BTC patients. Serum LDH level is a cost-effective prognostic biomarker in patients with operable BTC and especially DBD carcinoma.

19.
Am J Transl Res ; 10(3): 771-783, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29636867

RESUMO

Circular RNAs (circRNAs) are novel noncoding RNAs with a wide range of physiological and pathological activities. However, the expression profile and roles in lung squamous cell carcinoma (LSCC) remain largely unknown. Therefore, we investigated the expression profile of circRNAs in three LSCC and matched adjacent normal tissues using microarray. Total 216 differentially expressed circRNAs were identified, including 135 upregulated and 81 downregulated ones in LSCC tissues. Bioinformatics analysis revealed that these differentially expressed circRNAs were potentially implicated in carcinogenesis using Gene ontology (GO) and KEGG pathway analyses. By constructing miRNA-circRNA interaction network, a total of ten key circRNAs, including 6 upregulated and 4 downregulated circRNAs were further screened and then confirmed using qRT-PCR analysis in another 40 paired of LSCC tissues and adjacent normal tissues. In addition, Kaplan-Meier survival analysis demonstrated that the overall survival time of LSCC patients with high hsa_circRNA_103827 expression and low hsa_circRNA_000122 was significantly shorter (P<0.001). In conclusion, this study provides evidence that circRNAs are differentially expressed in LSCC and closely related to the carcinogenesis of LSCC. Among these, hsa_circRNA_103827 and hsa_circRNA_000122 might be served as potential prognostic biomarkers and therapeutic target for LSCC.

20.
BMC Cancer ; 18(1): 479, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29703253

RESUMO

BACKGROUND: Cetuximab, an anti-EGFR monoclonal antibody, is used in combination with chemotherapy in clinic to enhance the outcome in metastatic colorectal cancer (mCRC) patients with only ~ 20% response rate. To date only activating mutations in KRAS and NRAS have been identified as poor prognosis biomarkers in cetuximab-based treatment, which makes an urgent need for identification of novel prognosis biomarkers to precisely predict patients' response in order to maximize the benefit. METHODS: In this study, we analysed the mutation profiles of 33 Chinese mCRC patients using comprehensive next-generation sequencing (NGS) targeting 416 cancer-relevant genes before cetuximab treatment. Upon receiving cetuximab-based therapy, patients were evaluated for drug response, and the progression-free survival (PFS) was monitored. The association of specific genetic alterations and cetuximab efficacy was analyzed. RESULTS: Patients carrying SMAD4 mutations (SMAD4mut, n = 8) or NF1 mutations (NF1mut, n = 4) had significantly shorter PFS comparing to those carrying wildtype SMAD4 (SMAD4wt, n = 25) (P = 0.0081) or wildtype NF1 (NF1wt, n = 29) (P = 0.0028), respectively. None of the SMAD4mut or NF1mut patients showed response to cetuximab when assessed at 12-week post-treatment. Interestingly, two patients carrying both SMAD4mut and NF1mut showed the shortest PFS among all the patients. CONCLUSIONS: Our results demonstrated that SMAD4 and NF1 mutations can serve as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese mCRC patients.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Mutação , Neurofibromina 1/genética , Proteína Smad4/genética , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética
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