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1.
World J Clin Cases ; 10(4): 1226-1241, 2022 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-35211556

RESUMO

BACKGROUND: The number of elderly individuals with diabetes is dramatically increasing. Diabetes is a long-term condition and a noncommunicable disease and requires intensive daily self-management. Understanding of self-management from the patients' perspectives is important to nurses, healthcare providers, and researchers and benefits people by improving their self-management skills. AIM: To examine and synthesize qualitative studies that explore the experiences of elderly people in self-managing diabetes. METHODS: Electronic databases were searched, including MEDLINE, CINAH, PsycINFO, PubMed, CNKI, and WANFADATA. Relevant research was identified by manually searching reference lists and gray literature. Only English and Chinese publications were included. The Critical Appraisal Skills Program was used to assess the quality of the research. The Confidence in the Evidence from Reviews of Qualitative research approach was used to assess the confidence of the findings. RESULTS: A total of 10 qualitative studies were included, and content analysis was performed. Five themes were identified: The need for knowledge about diabetes care, support systems, functional decline, attitudes toward diabetes, and healthy lifestyle challenges. CONCLUSION: This present review provides a deep and broad understanding of the experiences in the self-management of diabetes and can be valuable to nursing practice and provide recommendations for future research.

2.
Nat Commun ; 13(1): 2342, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35487942

RESUMO

The genetic basis of colorectal cancer (CRC) and its clinical associations remain poorly understood due to limited samples or targeted genes in current studies. Here, we perform ultradeep whole-exome sequencing on 1015 patients with CRC as part of the ChangKang Project. We identify 46 high-confident significantly mutated genes, 8 of which mutate in 14.9% of patients: LYST, DAPK1, CR2, KIF16B, NPIPB15, SYTL2, ZNF91, and KIAA0586. With an unsupervised clustering algorithm, we propose a subtyping strategy that classisfies CRC patients into four genomic subtypes with distinct clinical characteristics, including hypermutated, chromosome instability with high risk, chromosome instability with low risk, and genome stability. Analysis of immunogenicity uncover the association of immunogenicity reduction with genomic subtypes and poor prognosis in CRC. Moreover, we find that mitochondrial DNA copy number is an independent factor for predicting the survival outcome of CRCs. Overall, our results provide CRC-related molecular features for clinical practice and a valuable resource for translational research.


Assuntos
Neoplasias Colorretais , Exoma , Instabilidade Cromossômica , Neoplasias Colorretais/genética , Exoma/genética , Genômica , Humanos , Sequenciamento Completo do Exoma/métodos
3.
Genome Med ; 14(1): 45, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35488273

RESUMO

BACKGROUND: Although immune checkpoint inhibitor (ICI) is regarded as a breakthrough in cancer therapy, only a limited fraction of patients benefit from it. Cancer stemness can be the potential culprit in ICI resistance, but direct clinical evidence is lacking. METHODS: Publicly available scRNA-Seq datasets derived from ICI-treated patients were collected and analyzed to elucidate the association between cancer stemness and ICI response. A novel stemness signature (Stem.Sig) was developed and validated using large-scale pan-cancer data, including 34 scRNA-Seq datasets, The Cancer Genome Atlas (TCGA) pan-cancer cohort, and 10 ICI transcriptomic cohorts. The therapeutic value of Stem.Sig genes was further explored using 17 CRISPR datasets that screened potential immunotherapy targets. RESULTS: Cancer stemness, as evaluated by CytoTRACE, was found to be significantly associated with ICI resistance in melanoma and basal cell carcinoma (both P < 0.001). Significantly negative association was found between Stem.Sig and anti-tumor immunity, while positive correlations were detected between Stem.Sig and intra-tumoral heterogenicity (ITH) / total mutational burden (TMB). Based on this signature, machine learning model predicted ICI response with an AUC of 0.71 in both validation and testing set. Remarkably, compared with previous well-established signatures, Stem.Sig achieved better predictive performance across multiple cancers. Moreover, we generated a gene list ranked by the average effect of each gene to enhance tumor immune response after genetic knockout across different CRISPR datasets. Then we matched Stem.Sig to this gene list and found Stem.Sig significantly enriched 3% top-ranked genes from the list (P = 0.03), including EMC3, BECN1, VPS35, PCBP2, VPS29, PSMF1, GCLC, KXD1, SPRR1B, PTMA, YBX1, CYP27B1, NACA, PPP1CA, TCEB2, PIGC, NR0B2, PEX13, SERF2, and ZBTB43, which were potential therapeutic targets. CONCLUSIONS: We revealed a robust link between cancer stemness and immunotherapy resistance and developed a promising signature, Stem.Sig, which showed increased performance in comparison to other signatures regarding ICI response prediction. This signature could serve as a competitive tool for patient selection of immunotherapy. Meanwhile, our study potentially paves the way for overcoming immune resistance by targeting stemness-associated genes.


Assuntos
Neoplasias , RNA , Biomarcadores Tumorais/genética , Proteínas de Transporte/genética , Humanos , Imunoterapia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas de Ligação a RNA/genética , Análise de Sequência de RNA , Sequenciamento Completo do Exoma
4.
Clin Epigenetics ; 13(1): 232, 2021 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-34961566

RESUMO

BACKGROUND: Circulating tumor DNA (ctDNA) is a promising diagnostic and prognostic marker for many cancers and has been actively investigated in recent years. Previous studies have already demonstrated the potential use of ctDNA methylation markers in the diagnosis and prognostication of colorectal cancer (CRC). This retrospective study validated the value of methylation biomarker MYO1-G (cg10673833) in CRC diagnosis and disease monitoring using digital droplet PCR (ddPCR), a biomarker selected from our previous study due to its highest diagnostic efficiency. METHODS: Blood samples of CRC and control samples from tumor-free individuals at two institutions were collected to quantify the methylation ratio using ddPCR. Area under curve (AUC) was calculated after constructing receiver operating characteristic curve (ROC) for CRC diagnosis. Sensitivity and specificity were estimated and comparisons of methylation ratio in different groups were performed. RESULTS: We collected 673 blood samples from 272 patients diagnosed with stage I-IV CRC and 402 normal control samples. The methylation biomarker discriminated patients with CRC from normal controls with high accuracy (area under curve [AUC] = 0.94) and yielded a sensitivity of 84.3% and specificity of 94.5%. Besides, methylation ratio of MYO1-G was associated with tumor burden and treatment response. The methylation ratio was significantly lower in patients after their radical operation than when compared with those before surgeries (P < 0.001). Methylation ratio was significantly higher in patients with disease progression than those with stable disease (P = 0.002) and those with complete response or partial response (P = 0.009). CONCLUSIONS: Together, our study indicated that this methylation marker can serve as a potential biomarker for diagnosing and monitoring CRC.


Assuntos
DNA Tumoral Circulante/análise , Neoplasias Colorretais/sangue , Antígenos de Histocompatibilidade Menor/análise , Miosinas/análise , Adulto , Área Sob a Curva , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , China/epidemiologia , DNA Tumoral Circulante/sangue , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Metilação de DNA/genética , Metilação de DNA/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor/sangue , Miosinas/sangue , Curva ROC
5.
Cell Rep Med ; 2(9): 100383, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34622226

RESUMO

This is a phase Ib/II study of regorafenib plus toripalimab for colorectal cancer. The objective response rate (ORR) is 15.2% and the disease control rate is 36.4% in evaluable patients with recommended phase II dose (80 mg regorafenib plus toripalimab). The median progression-free survival (PFS) and the median overall survival are 2.1 months and 15.5 months, respectively. Patients with liver metastases have lower ORR than those without (8.7% versus 30.0%). All patients (3/3) with lung-only metastasis respond, whereas no patients (0/4) with liver-only metastasis respond. 94.9% and 38.5% of patients have grade 1 and grade 3 treatment-related adverse events, respectively. Gut microbiome analysis of the baseline fecal samples shows significantly increased relative abundance and positive detection rate of Fusobacterium in non-responders than responders. Patients with high-abundance Fusobacterium have shorter PFS than those with low abundance (median PFS = 2.0 versus 5.2 months; p = 0.002).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/microbiologia , Microbioma Gastrointestinal , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacologia , Piridinas/efeitos adversos , Piridinas/farmacologia , Resultado do Tratamento
6.
Gut ; 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489309

RESUMO

OBJECTIVE: Circulating tumour DNA (ctDNA) sequencing is increasingly used in the clinical management of patients with colorectal cancer. However, the genomic heterogeneity in ctDNA during treatments and its impact on clinical outcomes remain largely unknown. DESIGN: We conducted a prospective cohort study (NCT04228614) of 171 patients with unresectable metastatic colorectal cancer (mCRC) who underwent first-line treatment and prospectively collected blood samples with or without tumour samples from patients at baseline and sequentially until disease progression or last follow-up. RESULTS: The RAS/BRAF alterations in paired baseline tissue and plasma samples from 63 patients displayed a favourable concordance (81.0%, 51/63). After a period of first-line treatment (median time between baseline and last liquid biopsy, 4.67 months), 42.6% (26/61) of RAS-mutant patients showed RAS clearance and 50.0% (5/10) of BRAF-mutant patients showed BRAF clearance, while 3.6% (3/84) and 0.7% (1/135) of patients showed new RAS or BRAF mutations in ctDNA. Patients with plasma RAS/BRAF clearance showed similar progression-free survival (PFS) and overall survival (OS) with patients who remained RAS/BRAF wild-type, while much better outcomes than those who remained RAS/BRAF mutant. Patients who gained new RAS/BRAF mutations showed similar prognosis as those who maintained RAS/BRAF mutations, and shorter PFS and OS than those who remained RAS/BRAF wild-type. CONCLUSION: This prospective, serial and large-scale ctDNA profiling study reveals the temporal heterogeneity of mCRC-related somatic variants, which should be given special attention in clinical practice, as evidenced by the finding that the shift in plasma RAS/BRAF mutational status can yield a drastic change in survival outcomes.

8.
JAMA Netw Open ; 4(4): e215250, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33835174

RESUMO

Importance: The prevention of chemotherapy-induced nausea and vomiting has an important role in the overall management of cancer treatment. Objective: To evaluate whether adding aprepitant to palonosetron and dexamethasone can further prevent the incidence and severity of nausea and vomiting caused by FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX (fluorouracil, leucovorin, and oxaliplatin) chemotherapy regimens among women with gastrointestinal cancer at higher risk. Design, Setting, and Participants: This phase 3, double-blind, placebo-controlled randomized clinical trial recruited young women (age ≤50 years) who drank little or no alcohol and had gastrointestinal cancer for which they received FOLFOX or FOLFIRI chemotherapy. A total of 248 women were enrolled and assigned in the ratio 1:1 to intervention and control groups from August 4, 2015, to March 31, 2020. Intention-to-treat analysis was used to evaluate patient baseline characteristics and efficacy. The analysis was conducted on October 30, 2020. Interventions: Patients were randomly assigned to the aprepitant group (aprepitant, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 6 mg, orally 30 minutes before chemotherapy initiation on day 1) or the placebo group (placebo, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally on each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 12 mg, orally 30 minutes before chemotherapy initiation on day 1). Main Outcomes and Measures: The primary end point was the complete response (CR) rate, defined as the proportion of patients without emesis episodes or rescue medication use during the overall phase of the first cycle. Other efficacy indicators, such as no vomiting and no nausea, were measured as the secondary and exploratory end points. Results: A total of 248 women from 4 clinical centers in China entered this study, and 243 patients (aprepitant regimen, 125 patients [51.4%]; placebo regimen, 118 patients [48.5%]) were evaluable for efficacy and safety; mean (SD) age of the total population was 40.1 (7.3) years. The CR rate was significantly higher in the aprepitant group vs the control group overall (107 [87.0%] vs 80 [66.7%]; P < .001) and in the acute (114 [92.7%] vs 91 [75.8%]; P = .001) and delayed (109 [88.6%] vs 84 [70.0%]; P = .001) phases of the trial. The incidence of adverse events was similar between the 2 groups (100 [80.0%] vs 96 [81.3%]; P = .79), and no grade 3 or 4 aprepitant treatment-related adverse events were observed. Multivariable analysis revealed that aprepitant use was the only independent factor associated with CR during the overall phase. Conclusions and Relevance: The combination of aprepitant with palonosetron and dexamethasone provided increased antiemetic efficacy in the FOLFOX or FOLFIRI chemotherapy regimen and was well tolerated by younger women with gastrointestinal cancer who have a history of little or no alcohol consumption. Trial Registration: ClinicalTrials.gov Identifier: NCT03674294.


Assuntos
Antieméticos/administração & dosagem , Antineoplásicos/efeitos adversos , Aprepitanto/administração & dosagem , Náusea/prevenção & controle , Neoplasias Gástricas/tratamento farmacológico , Vômito/prevenção & controle , Adulto , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , China , Método Duplo-Cego , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Pessoa de Meia-Idade , Náusea/etiologia , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Vômito/etiologia
9.
J Transl Med ; 19(1): 150, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33858440

RESUMO

BACKGROUND: Sidedness (right/left) of colorectal cancer (CRC) is essential for treatment. Whether carcinogenesis of tobacco varies by sidedness remains unclear. The present study aims to evaluate the sidedness tendency of cigarette smoking and to explore its impact on prognosis. METHODS: In the multi-center retrospective study, data on 46 166 Chinese CRC patients were extracted from a big-data platform. Logistic regression analyses were performed to evaluate qualitative and quantitative associations between smoking and tumor sidedness. Survival analyses were conducted in metastatic CRC. RESULTS: History of smoking was associated with left-sided CRC (LSCRC; Adjusted odds ratio, 1.25; 95% CI, 1.16 - 1.34; P < .001). The sidedness tendency towards LSCRC increased from non-smokers, to ex-smokers, and to current smokers (P for trend < .001). Longer duration (P for trend < .001) and larger total amount of cigarette smoking (P for trend < .001) were more associated with LSCRC, respectively. The association was confirmed in both left-sided colon cancer and rectal cancer, but was stronger for rectal cancer (P = .016). Alcoholism significantly enhanced the association by 7% (P = .027). Furthermore, prognostic advantage of metastatic LSCRC diminished among ever-smokers, with contrary survival impacts of smoking on either side of CRC. CONCLUSIONS: History of smoking was associated with LSCRC in a positive dose-response relationship, and presented opposite prognostic impacts on right- and left-sided tumors. Smoking potentially plays an instrumental role in the mechanism for sidedness heterogeneity in CRC.


Assuntos
Fumar Cigarros , Neoplasias do Colo , Neoplasias Colorretais , Humanos , Estudos Retrospectivos , Tabaco
10.
BMC Med ; 19(1): 26, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33526018

RESUMO

BACKGROUND: A critical and challenging process in immunotherapy is to identify cancer patients who could benefit from immune checkpoint inhibitors (ICIs). Exploration of predictive biomarkers could help to maximize the clinical benefits. Eph receptors have been shown to play essential roles in tumor immunity. However, the association between EPH gene mutation and ICI response is lacking. METHODS: Clinical data and whole-exome sequencing (WES) data from published studies were collected and consolidated as a discovery cohort to analyze the association between EPH gene mutation and efficacy of ICI therapy. Another independent cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was adopted to validate our findings. The Cancer Genome Atlas (TCGA) cohort was used to perform anti-tumor immunity and pathway enrichment analysis. RESULTS: Among fourteen EPH genes, EPHA7-mutant (EPHA7-MUT) was enriched in patients responding to ICI therapy (FDR adjusted P < 0.05). In the discovery cohort (n = 386), significant differences were detected between EPHA7-MUT and EPHA7-wildtype (EPHA7-WT) patients regarding objective response rate (ORR, 52.6% vs 29.1%, FDR adjusted P = 0.0357) and durable clinical benefit (DCB, 70.3% vs 42.7%, FDR adjusted P = 0.0200). In the validation cohort (n = 1144), significant overall survival advantage was observed in EPHA7-MUT patients (HR = 0.62 [95% confidence interval, 0.39 to 0.97], multivariable adjusted P = 0.0367), which was independent of tumor mutational burden (TMB) and copy number alteration (CNA). Notably, EPHA7-MUT patients without ICI therapy had significantly worse overall survival in TCGA cohort (HR = 1.33 [95% confidence interval, 1.06 to 1.67], multivariable adjusted P = 0.0139). Further gene set enrichment analysis revealed enhanced anti-tumor immunity in EPHA7-MUT tumor. CONCLUSIONS: EPHA7-MUT successfully predicted better clinical outcomes in ICI-treated patients across multiple cancer types, indicating that EPHA7-MUT could serve as a potential predictive biomarker for immune checkpoint inhibitors.


Assuntos
Inibidores de Checkpoint Imunológico/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptor EphA7/metabolismo , Biomarcadores Tumorais/genética , Estudos de Coortes , Variações do Número de Cópias de DNA , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Mutação
11.
Am J Cancer Res ; 10(9): 2946-2954, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042628

RESUMO

In the REGONIVO study, regorafenib combined with nivolumab was effective in the treatment of microsatellite stable (MSS) metastatic colorectal cancer (mCRC), which indicated anti-angiogenic drugs may enhance the efficacy of immune checkpoint inhibitors. Therefore, we designed a single-arm, single-center, open-label, phase II trial to determine the toxicity and efficacy of SHR-1210 (an anti-PD-1 antibody) plus apatinib in MSS mCRC. The sample size was estimated using a Simon Optimum two-stage design. 10 patients were included at the first stage and if one effective patient observed, an additional 19 patients would be added. Patients with MSS mCRC who refractory to second-line treatment or intolerant to standard treatment were given SHR-1210 200 mg every 2 weeks and apatinib 250-375 mg once daily until unacceptable toxicity or disease progression occurred. In our study, the objective response rate was 0% and the disease control rate was 22.2%. The median progression-free survival was 1.83 months (95% confidence interval (CI) 1.80-1.86 months), and the median overall survival was 7.80 months (95% CI 0-17.07). Treatment-related adverse events (AEs) occurred in all patients (100%). The most common treatment-related AEs were hypertension and proteinuria (70% each). Grade 3 AEs were observed in nine patients (9/10, 90%), and the commonest was hypertension (30%). In conclusion, SHR-1210 combined with apatinib has failed to improve the efficacy of treatment of MSS mCRC, and the intolerable toxicity may be the leading cause.

12.
Am J Cancer Res ; 10(9): 3037-3046, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042632

RESUMO

Gastric cancer (GC) is the second most common cancer in China. The ToGA study showed that trastuzumab in combination with fluoropyrimidine plus cisplatin prolonged overall survival (OS) in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced GC (AGC). However, some patients may not be able to receive this regimen. We conducted a clinical study to evaluate the efficacy and safety of trastuzumab in combination with docetaxel+capecitabine (DX) in patients with HER2-positive AGC. This phase II, multi-center, open-label, single arm study enrolled patients with HER2-positive AGC who had not received prior treatment for metastatic disease. Patients were treated with a regimen of trastuzumab (8 mg/kg loading dose followed by 6 mg/kg, day 1), capecitabine (1000 mg/m2 twice daily, days 1-14) and docetaxel (60 mg/m2, day 1 for 6 cycles) every 3 weeks. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR), OS and safety profiles. Sixty-seven patients with AGC were enrolled from 14 centers. 64 were included in the full analysis set (FAS). The median PFS was 8.1 months (95% confidence interval [CI]: 5.6-12.8) and the median OS was 20.9 months (95% CI: 15.1-33.0). Response was evaluated in 59 patients. The ORR was 67.8%. The most common adverse events of Grade ≥3 were neutropenia, leukopenia, hand-foot syndrome, febrile neutropenia and anemia. We concluded that combination treatment with trastuzumab and DX was well-tolerated and highly effective in patients with HER2-positive AGC, and may offer an alternative to current treatments.

13.
Mol Cancer ; 19(1): 154, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126883

RESUMO

A more common and noninvasive predicting biomarker for programmed cell death 1 (PD-1) antibody remains to be explored. We assessed 46 patients with advanced gastric cancer who received PD-1 antibody immunotherapy and 425-genes next-generation sequencing (NGS) testing. Patients who had a > 25% decline in maximal somatic variant allelic frequency (maxVAF) had a longer progression free survival (PFS) and higher response rate than those who did not (7.3 months vs 3.6 months, p = 0.0011; 53.3% vs 13.3%, p = 0.06). The median PFS of patients with undetectable and detectable post-treatment circulating tumor DNA (ctDNA) was 7.4 months vs. 4.9 months (p = 0.025). Mutation status of TGFBR2, RHOA, and PREX2 in baseline ctDNA influenced the PFS of immunotherapy (p < 0.05). Patients with alterations in CEBPA, FGFR4, MET or KMT2B (p = 0.09) gene had greater likelihood of immune-related adverse events (irAEs). ctDNA can serve as a potential biomarker of the response to immunotherapy in advanced gastric cancers, and its potential role in predicting irAEs worth further exploration.


Assuntos
Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Gástricas/patologia , DNA Tumoral Circulante/sangue , Feminino , Humanos , Masculino , Prognóstico , Neoplasias Gástricas/sangue , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Taxa de Sobrevida
15.
Signal Transduct Target Ther ; 5(1): 183, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32900990

RESUMO

The acidic tumor microenvironment provides an energy source driving malignant tumor progression. Adaptation of cells to an acidic environment leads to the emergence of cancer stem cells. The expression of the vitamin D receptor (VDR) is closely related to the initiation and development of colorectal carcinoma (CRC), but its regulatory mechanism in CRC stem cells is still unclear. Our study revealed that acidosis reduced VDR expression by downregulating peroxisome proliferator-activated receptor delta (PPARD) expression. Overexpression of VDR effectively suppressed the stemness and oxaliplatin resistance of cells in acidosis. The nuclear export signal in VDR was sensitive to acidosis, and VDR was exported from the nucleus. Chromatin immunoprecipitation (ChIP) and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) analyses showed that VDR transcriptionally repressed SRY-box 2 (SOX2) by binding to the vitamin D response elements in the promoter of SOX2, impairing tumor growth and drug resistance. We demonstrated that a change in the acidic microenvironment combined with overexpression of VDR substantially restricted the occurrence and development of CRC in vivo. These findings reveal a new mechanism by which acidosis could affect the stemness of CRC cells by regulating the expression of SOX2 and show that abnormal VDR expression leads to ineffective activation of vitamin D signaling, resulting in a lack of efficacy of vitamin D in antineoplastic process.


Assuntos
Neoplasias Colorretais/genética , PPAR delta/genética , Receptores de Calcitriol/genética , Fatores de Transcrição SOXB1/genética , Acidose/genética , Acidose/patologia , Ácidos/metabolismo , Proliferação de Células/genética , Cromatina/genética , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células HCT116 , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Compostos Organoplatínicos/farmacologia , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Cancer Commun (Lond) ; 40(8): 345-354, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32589350

RESUMO

BACKGROUND: Several programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) antibodies have been approved for cancer treatment worldwide. Their pharmacokinetic and pharmacodynamic characteristics have been reported mainly in western countries, but related data in Chinese patients are limited. This study was conducted to investigate the safety, efficacy, pharmacokinetics, and pharmacodynamics of an anti-PD-1 antibody, toripalimab, in Chinese patients. METHODS: A single-center phase I study was conducted in Sun Yat-sen University Cancer Center. Eligible patients were adults with histologically confirmed, treatment-refractory, advanced, solitary malignant tumors. Toripalimab was intravenously infused every 2 weeks in dose-escalating cohorts at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg. The study followed standard 3 + 3 design. RESULTS: Between 15th March 2016 and 27th September 2016, 25 patients were enrolled, of whom 3 (12.0%), 7 (28.0%), 6 (24.0%), 6 (24.0%), 3 (12.0%) received 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg toripalimab, respectively. After a median follow-up time of 5.0 months (range: 1.5-19.8 months), we observed that the commonest treatment-related adverse events (TRAEs) were fatigue (64.0%) and rash (24.0%). No grade 3 or higher TRAEs were observed. No dose-limiting toxicity, treatment-related serious adverse events (SAEs), or treatment-related death occurred. Objective response rate was 12.5%. The half-life of toripalimab was 150-222 h after a single dose infusion. Most patients, including those from the 0.3 mg/kg group, maintained complete PD-1 receptor occupancy (> 80%) on activated T cells since receiving the first dose of toripalimab. CONCLUSIONS: Toripalimab is a promising anti-PD-1 antibody, which was well tolerated and demonstrated anti-tumor activity in treatment-refractory advanced solitary malignant tumors. Further exploration in various tumors and combination therapies is warranted.


Assuntos
Adenocarcinoma , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Melanoma , Adenocarcinoma/tratamento farmacológico , Adulto , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Feminino , Humanos , Masculino , Melanoma/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Faríngeas/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Neoplasias da Língua/tratamento farmacológico
17.
Theranostics ; 10(2): 498-515, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31903134

RESUMO

Rationale: STING is a critical player in the innate and adaptive immune system, sensing cytosolic DNA to activate the expression of interferon genes and regulate T lymphocytes, which drives immunogenic responses to cancer cells. Tumor-associated macrophages (TAMs), abundantly present in the tumor microenvironment, play a key role in cancer development. Gastric cancer is one of the most common and leading causes in cancer-related death worldwide. However, studies on the function and regulation of STING in TAMs and their roles in gastric cancer progression are still limited. Methods: We analyzed STING and CD68 expression of 200 pairs of gastric cancer and adjacent normal tissues by immunohistochemistry to identify the prognostic values of STING, as well as the correlations between STING and CD68 in gastric cancer. The characteristics of STING-altered macrophages, as well as their effects on cancer cell apoptosis and T cell differentiation were examined by flow cytometry. Cytokines secreted by STING-altered macrophages were identified by the Human Inflammation Array3 kit. Concentrations of soluble IL24 and IFN-ß were measured by ELISA. In vivo models, including spontaneous gastric cancer in p53+/- mice and cell line-based xenografts, were established, and clinical benefits of STING-altered macrophages were examined. Results: Our study identifies STING as a prognostic factor for gastric cancer, and for the first time demonstrated that knocking-down STING and STING activation by 2'3'-c-GAMP both promote TAMs polarizing into pro-inflammatory subtype and induce apoptosis of gastric cancer cells, mechanistically through IL6R-JAK-IL24 pathway. Conclusions : This study evaluated effects of targeting STING in TAMs in anti-gastric-cancer therapies. Moreover, we unveil a novel function of STING to activate the IL6R-JAK-IL24 pathway in macrophages.


Assuntos
Biomarcadores Tumorais/metabolismo , Imunidade Inata , Proteínas de Membrana/metabolismo , Receptores de Interleucina-6/metabolismo , Neoplasias Gástricas/imunologia , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Interleucinas/metabolismo , Janus Quinases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Proteína Supressora de Tumor p53/genética , Macrófagos Associados a Tumor/metabolismo
18.
Medicine (Baltimore) ; 98(40): e17332, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577727

RESUMO

To predict the survival of appendiceal mucinous adenocarcinoma (AMA) by prognostic nomogram.A total of 3234 patients with AMA were collected from the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2015. Univariate and multivariate Cox proportional hazards (PH) regression analyses were used to generate independent prognostic factors. These variables were included in the nomogram to predict overall survival (OS) and disease-specific survival (DSS) at 1-, 3-, and 5- years. These data are validated both internally and externally. The consistency index (C-index) and calibration chart were used to estimate the accuracy of the nomogram.The study cohort was randomly divided into the training (n = 2155) and validation group (n = 1799). According to univariate and multivariate analyses, age at diagnosis, marital status, sex, histological differentiation, SEER extent of disease, number of local lymph nodes examined, whether they were positive, and surgical methods were independent prognostic factors for OS and DSS. These factors were incorporated into the nomogram. Internal validation in the training cohort showed that the C-index values for nomogram predictions of OS and DSS were 0.73 (95% CI 0.70-0.76) and 0.77 (95% CI 0.73-0.81), respectively. Similarly, the corresponding C-index values in the external validation cohort were 0.76 (95% CI 0.70-0.81) and 0.75 (95% CI 0.71-0.80). The Calibration plots revealed that the actual survival and nomogram prediction had a good consistency.Build a nomogram in the SEER database to predict OS and DSS in patients with AMA. It can provide accurate and personalised survival prediction for clinicians and patients.


Assuntos
Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Neoplasias do Apêndice/mortalidade , Neoplasias do Apêndice/patologia , Nomogramas , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Modelos de Riscos Proporcionais , Programa de SEER , Fatores Sexuais , Fatores Socioeconômicos , Análise de Sobrevida
20.
J Natl Compr Canc Netw ; 17(7): 805-811, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31319395

RESUMO

BACKGROUND: Previous meta-analyses have suggested primary tumor location as a predictive factor for efficacy of anti-epidermal growth factor receptor (EGFR) therapies in patients with metastatic colorectal cancer (mCRC). However, the recent phase III TAILOR trial addressing this issue was not included in those analyses. This meta-analysis incorporated data from the TAILOR trial to evaluate the efficacy of chemotherapy plus anti-EGFR agents (cetuximab [Cet] or panitumumab [Pani]) versus chemotherapy alone for RAS wild-type (wt) right- and left-sided mCRC. PATIENTS AND METHODS: A PubMed-based literature search was conducted to identify randomized controlled trials (RCTs) studying the additional efficacy of Cet/Pani in combination with chemotherapy versus chemotherapy alone in RAS wt left- and right-sided mCRC. Study-level pooled analyses of hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and odds ratios (ORs) for objective response rate (ORR) were performed. RESULTS: Three first-line RCTs (CRYSTAL, PRIME, and TAILOR) and one second-line RCT (20050181) were included. Significant OS benefits from Cet/Pani were observed in the left-sided (HR, 0.76; 95% CI, 0.66-0.86) but not right-sided subgroups (HR, 0.99; 95% CI, 0.78-1.27). However, the addition of Cet/Pani to chemotherapy significantly improved PFS and ORR in both the left-sided (HR, 0.70; 95% CI, 0.57-0.86, and OR, 3.28; 95% CI, 1.95-5.51, respectively) and right-sided subgroups (HR, 0.76; 95% CI, 0.59-0.99, and OR, 1.78; 95% CI, 1.08-2.93, respectively). CONCLUSIONS: The addition of Cet/Pani to chemotherapy significantly benefits PFS and ORR in patients with RAS wt right-sided mCRC, indicating that anti-EGFR therapies may remain an option for selected patients.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Tratamento Farmacológico , Anticorpos Monoclonais/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Humanos , Mutação , Metástase Neoplásica , Panitumumabe/uso terapêutico , Modelos de Riscos Proporcionais
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