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1.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(9): 1128-1132, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31657338

RESUMO

OBJECTIVE: To investigate the effect of circadian heart rate variation on short-term and long-term mortality in intensive care unit (ICU) patients. METHODS: A retrospective cohort study was conducted. A total of 32 536 ICU patients were recorded from 2001 to 2008 published by Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC-II v2.6) in April 2011. The circadian heart rate variation was defined as the ratio of mean nighttime (23:00 to 07:00) heart rate to mean daytime (07:00 to 23:00) heart rate. The 28-day mortality and 1-year mortality were defined as outcome events. The information such as age, gender, ethnicity, first sequential organ failure assessment (SOFA) score, first simplified acute physiology score I (SAPS I), usage of sedatives and catecholamines within 24 hours admission of ICU, clinical complications [hypertension, chronic obstructive pulmonary disease (COPD), diabetes with or without complications, congestive heart failure, liver disease, renal failure, etc.], and the complete heart rate records within 24 hours after ICU admission were collected. Cox proportional risk regression models were used to investigate the association between circadian heart rate variation and 28-day mortality and 1-year mortality in ICU patients. Besides, subgroup analysis was also performed in patients with different first SOFA scores. RESULTS: Totally 15 382 ICU patients in MIMIC-II database were enrolled, excluding the patients without heart rate records or death records, using pacemaker with arrhythmia, without SOFA or SAPS I score records. Finally, 9 439 patients were enrolled in the study cohort. (1) Cox regression analysis of the whole patient showed that the higher circadian heart rate variation was correlated with the increased 28-day mortality [hazard ratio (HR) = 1.613, 95% confidence interval (95%CI) was 1.338-1.943, P < 0.001] and 1-year mortality (HR = 1.573, 95%CI was 1.296-1.908, P < 0.001). After adjustment for demographic factors (age, gender and ethnicity), severity of illness (SOFA and SAPS I scores), clinical complications (hypertension, COPD, diabetes with or without complications, congestive heart failure, liver disease, renal failure, etc.), and influence of medications (sedatives and catecholamines), the night-day heart rate ratio was also correlated with 28-day mortality (HR = 1.256, 95%CI was 1.018-1.549, P = 0.033) and 1-year mortality (HR = 1.249, 95%CI was 1.010-1.545, P = 0.040). (2) According to the SOFA score (median value of 5), the patients were divided into two subgroups, in which 5 478 patients with SOFA score ≤ 5 and 3 961 patients with SOFA score > 5. Cox regression subgroup analysis showed that circadian heart rate variation was related with higher 28-day mortality (HR = 1.430, 95%CI was 1.164-1.756, P = 0.001) and 1-year mortality (HR = 1.393, 95%CI was 1.123-1.729, P = 0.003) in patients with SOFA score > 5. After adjustment for covariates, the 28-day mortality (HR = 1.279, 95%CI was 1.032-1.584, P = 0.025) and 1-year mortality (HR = 1.255, 95%CI was 1.010-1.558, P = 0.040) also increased with the increasing of night-day heart rate ratio in patients with SOFA score > 5. However, the relationships did not exist in patients with SOFA score ≤ 5. CONCLUSIONS: In ICU patients, the 28-day mortality and 1-year mortality increase with the higher circadian heart rate variation, which indicates that the circadian heart rate variation in ICU patients is positively correlated with the short-term and long-term mortality, especially in patients with relatively severe illness.


Assuntos
Relógios Circadianos , Frequência Cardíaca/fisiologia , Unidades de Terapia Intensiva , Mortalidade/tendências , Cuidados Críticos , Humanos , Escores de Disfunção Orgânica , Prognóstico , Estudos Retrospectivos
2.
Theranostics ; 9(21): 6143-6156, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534542

RESUMO

Purpose: Angiogenesis in liver cancers can be characterized by hepatic functional perfusion imaging (FPI) on the basis of dynamic contrast-enhanced ultrasound (DCEUS). However, accuracy is limited by breathing motion which results in out-of-plane image artifacts. Current hepatic FPI studies do not correct for these artifacts and lack the evaluation of correction accuracy. Thus, a hepatic DCEUS-based dual-phase multi-parametric FPI (DM-FPI) scheme using a derivative principal component analysis (PCA) respiratory gating is proposed to overcome these limitations. Materials and Methods: By considering severe 3D out-of-plane respiratory motions, the proposed scheme's accuracy was verified with in vitro DCEUS experiments in a flow model mimicking a hepatic vein. The feasibility was further demonstrated by considering in vivo DCEUS measurements in normal rabbit livers, and hepatic cavernous hemangioma and hepatocellular carcinoma in patients. After respiratory kinetics was extracted through PCA of DCEUS sequences under free-breathing condition, dual-phase respiratory gating microbubble kinetics was identified by using a derivative PCA zero-crossing dual-phase detection, respectively. Six dual-phase hemodynamic parameters were estimated from the dual-phase microbubble kinetics and DM-FPI was then reconstructed via color-coding to quantify 2.5D angiogenic hemodynamic distribution for live tumors. Results: Compared with no respiratory gating, the mean square error of respiratory gating DM-FPI decreased by 1893.9 ± 965.4 (p < 0.05), and mean noise coefficients decreased by 17.5 ± 7.1 (p < 0.05), whereas correlation coefficients improved by 0.4 ± 0.2 (p < 0.01). DM-FPI observably removed severe respiratory motion artifacts on PFI and markedly enhanced the accuracy and robustness both in vitro and in vivo. Conclusions: DM-FPI precisely characterized and distinguished the heterogeneous angiogenic hemodynamics about perfusion volume, blood flow and flow rate within two anatomical sections in the normal liver, and in benign and malignant hepatic tumors. DCEUS-based DM-FPI scheme might be a useful tool to help clinicians diagnose and provide suitable therapies for liver tumors.

3.
J Orthop Surg Res ; 14(1): 215, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311601

RESUMO

In the original publication of this article [1], the Gene Expression Omnibus (GEO) accession code GSE79772 is wrong. The correct accession code should be GSE86213.

4.
J Exp Clin Cancer Res ; 38(1): 331, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358019

RESUMO

In the original publication of this article [1], the Gene Expression Omnibus (GEO) accession code GSE79772 is wrong. The correct accession code should be GSE86213.

5.
Neuro Oncol ; 21(11): 1423-1435, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31232447

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most malignant primary brain tumor, with dismal median survival. Treatment of GBM is particularly challenging given the intrinsic resistance to chemotherapy and difficulty of drugs to reach the tumor beds due to the blood-brain barrier. Here, we examined the efficacy of SHP099, a potent, selective, and oral SHP-2 inhibitor for treating GBM with activated platelet derived growth factor receptor alpha (PDGFRα) signaling. METHODS: The effects of SHP099 on cell survival of neural progenitor cells (NPCs), GBM cell lines, and patient-derived glioma stem-like cells (GSCs) were evaluated. Brain and plasma pharmacokinetics of SHP099 and its ability to inhibit SHP-2 signaling were assessed. SHP099 efficacy as a single agent or in combination with temozolomide (TMZ) was assessed using transformed mouse astrocyte and GSC orthotopic xenograft models. RESULTS: Activated PDGFRα signaling in established GBM cells, GSCs, and transformed mouse astrocytes was significantly inhibited by SHP099 compared with NPCs in vitro and in vivo through targeting SHP-2-stimulated activation of extracellular signal-regulated protein kinases 1 and 2 in GBM. SHP099 treatment specifically inhibited expression of JUN, a downstream effector of PDGFR signaling, thereby attenuating cell cycle progression in GBM cells with activated PDGFRα. Moreover, SHP099 accumulated at efficacious concentrations in the brain and effectively inhibited orthotopic GBM tumor xenograft growth. SHP099 exhibited antitumor activity either as a single agent or in combination with TMZ and provided significant survival benefits for GBM tumor xenograft-bearing animals. CONCLUSIONS: Our data demonstrate the utility and feasibility of SHP099 as a potential therapeutic option for improving the clinical treatment of GBM in combination with TMZ.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31118956

RESUMO

Background: The prevalence of overweight/obesity in adults is raised to 39%, which is nearly tripled more than 1975. The alteration of the gut microbiome has been widely accepted as one of the main causal factors. To find an effective strategy for the prevention and treatment of overweight/obesity, a systematic review and meta-analysis were designed. Methods: In this study, we systematically reviewed the article published from January 2008 to July 2018 and conducted a meta-analysis to examine the effects of probiotics on body weight control, lipid profile, and glycemic control in healthy adults with overweight or obesity. The primary outcomes were body weight, body mass index (BMI), waist circumference, fat mass, fat percentages, plasma lipid profiles, and glucose metabolic parameters. Results: We systematically searched PubMed, Embase, and the Web of Science and identified 1248 articles, and 7 articles which were manually searched by the references of included studies and previously systematic reviews. Twelve randomized controlled trials (RCTs), including 821 participants, were included in the meta-analysis via full-text screening. Probiotics supplementation resulted in a statistical reduction in body weight (WMD [95% CI]; -0.55 [-0.91, -0.19] kg), BMI (WMD [95% CI]; -0.30 [-0.43, -0.18] kg m-2), waist circumference (WMD [95% CI]; -1.20 [-2.21, -0.19] cm), fat mass (WMD [95% CI]; -0.91 [-1.19, -0.63] kg), and fat percentage (WMD [95% CI]; -0.92 [-1.27, -0.56] %) compared with control groups. As expected, the metabolic parameters were improved significantly, with a pooled standardized mean difference in TC (SMD [95% CI]; -0.43 [-0.80, -0.07]), LDL-C (SMD [95% CI]; -0.41 [-0.77, -0.04]), FPG (SMD [95% CI]; -0.35 [-0.67, -0.02]), insulin (SMD [95% CI]; -0.44 [-0.84, -0.03]), and HOMA-IR (SMD [95% CI]; -0.51 [-0.96, -0.05]), respectively. The changes in TG (SMD [95% CI]; 0.14 [-0.23, 0.50]), HDL-C (SMD [95% CI]; -0.31 [-0.70, 0.07]), and HbA1c (SMD [95% CI]; -0.23 [-0.46, 0.01]) were not significant. Conclusion: This study suggests that the probiotics supplementation could potentially reduce the weight gain and improve some of the associated metabolic parameters, which may become an effective strategy for the prevention and treatment of obesity in adult individuals.

7.
J Exp Clin Cancer Res ; 38(1): 147, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953555

RESUMO

BACKGROUND: Ionizing radiation (IR) therapy is the standard first-line treatment for newly diagnosed patients with glioblastoma (GBM), the most common and malignant primary brain tumor. However, the effects of IR are limited due to the aberrant radioresistance of GBM. METHODS: Transcriptome analysis was performed using RNA-seq in radioresistant patient-derived glioma stem-like cells (GSCs). Survival of glioma patient and mice bearing-brain tumors was analyzed by Kaplan-Meier survival analysis. Lipid droplet and γ-H2AX foci-positive cells were evaluated using immunofluorescence staining. RESULTS: Lipolytic inhibitor G0/G1 switch gene 2 (G0S2) is upregulated in radioresistant GSCs and elevated in clinical GBM. GBM patients with high G0S2 expression had significantly shorter overall survival compared with those with low expression of G0S2. Using genetic approaches targeting G0S2 in glioma cells and GSCs, we found that knockdown of G0S2 promoted lipid droplet turnover, inhibited GSC radioresistance, and extended survival of xenograft tumor mice with or without IR. In contrast, overexpression of G0S2 promoted glioma cell radiation resistance. Mechanistically, high expression of G0S2 reduced lipid droplet turnover and thereby attenuated E3 ligase RNF168-mediated 53BP1 ubiquitination through activated the mechanistic target of rapamycin (mTOR)-ribosomal S6 kinase (S6K) signaling and increased 53BP1 protein stability in response to IR, leading to enhanced DNA repair and glioma radioresistance. CONCLUSIONS: Our findings uncover a new function for lipolytic inhibitor G0S2 as an important regulator for GSC radioresistance, suggesting G0S2 as a potential therapeutic target for treating gliomas.


Assuntos
Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular/genética , Glioma/genética , Tolerância a Radiação/fisiologia , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular , Glioma/patologia , Humanos , Camundongos , Transfecção
8.
Int J Oncol ; 54(4): 1466-1480, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30968148

RESUMO

It is well-known that the activation status of the P53, signal transducer and activator of transcription (Stat)3 and nuclear factor (NF)­κB signaling pathways determines the radiosensitivity of cancer cells. However, the function of these pathways in radiosensitive vs radioresistant cancer cells remains elusive. The present study demonstrated that adaptive expression of epidermal growth factor (EGF) following exposure to ionizing radiation (IR) may induce radiosensitization of pancreatic cancer (PC) cells through induction of the cyclin D1/P53/poly(ADP­ribose) polymerase pathway. By contrast, adaptively expressed interleukin (IL)­6 and insulin­like growth factor (IGF)­1 may promote radioresistance of PC cells, likely through activation of the Stat3 and NF­κB pathways. In addition, cyclin D1 and survivin, which are specifically expressed in the G1/S and G2/M phase of the cell cycle, respectively, are mutually exclusive in radiosensitive and radioresistant PC cells, while Bcl­2 and Bcl­xL expression does not differ between radiosensitive and radioresistant PC cells. Therefore, adaptively expressed EGF and IL­6/IGF­1 may alter these pathways to promote the radiosensitivity of PC cancers. The findings of the present study highlight potential makers for the evaluation of radiosensitivity and enable the development of effective regimens for cancer radiotherapy.


Assuntos
Carcinoma Ductal Pancreático/radioterapia , Fator de Crescimento Epidérmico/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Neoplasias Pancreáticas/radioterapia , Transdução de Sinais/efeitos da radiação , Apoptose/efeitos da radiação , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Humanos , Neoplasias Pancreáticas/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Tolerância a Radiação , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos da radiação
9.
Front Immunol ; 10: 108, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30778352

RESUMO

Background: We performed a systematic review and meta-analysis to evaluate the risk of pneumonitis and pneumonia associated with immune checkpoint inhibitors (ICIs) for solid tumors. Methods: The following keywords were used in searching the Embase and PubMed database: pneumonitis, pneumonia, and immune checkpoint inhibitors. The data was analyzed by using the R software and Metafor package. Results: Among 3,436 studies, 23 randomized clinical trials (RCTs) met our selection criteria which included data from 12,876 patients. Compared with chemotherapy, PD-1 inhibitors showed significant increase in grade 1-5 and grade 3-5 pneumonitis (RR, 5.17, 95% CI: 2.82-9.47, p < 0.001; RR, 4.14, 95% CI: 1.82-9.42, p < 0.001), but not in pneumonia. PD-L1 inhibitors showed significant increase in grade 1-5 pneumonitis and pneumonia (RR, 3.25, 95% CI: 1.61-6.57, p < 0.001; RR, 2.11, 95% CI: 1.20-3.70, p < 0.001). There was no significant difference in any grade pneumonitis and pneumonia in cytotoxic T lymphocyte-associated protein 4 (CTLA4) inhibitors subgroup. Programmed cell death protein 1 (PD-1) inhibitor (nivolumab and pembrolizumab) both showed significant increase in grade 1-5 pneumonitis, and pembrolizumab specially tended to increase grade 3-5 pneumonitis. (RR, 5.64 95% CI: 1.94-16.38, p < 0.001). Compared with PD-1 inhibitor (nivolumab) or CTLA-4 inhibitor (ipilimumab) monotherapy, PD-1 inhibitor, and CTLA-4 inhibitor (nivolumab plus ipilimumab) combination therapies showed significant increase in grade 1-5 and grade 3-5 pneumonitis (RR 3.47, 95%CI:1.76-6.83, p < 0.001; RR 3.48, 95%CI: 1.10-11.02, p < 0.001). Conclusions: PD-1/PD-L1 inhibitors treatment could increase the risk of all-grade pneumonitis. CTLA4 inhibitor ipilimumab treatment alone could not increase the risk of pneumonitis but could augment the risk of pneumonitis in PD-1/PD-L1 inhibitor treated patients. There was no significant increase in the risk of pneumonia after either PD-1/PDL-1inhibitor or CTLA4 inhibitor treatment alone or in combination.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Pneumonia/etiologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Conscientização , Quimioterapia Combinada/efeitos adversos , Humanos , Neoplasias/tratamento farmacológico , Oncologistas/psicologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Risco
10.
Blood Adv ; 2(21): 2814-2828, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30373888

RESUMO

Systemic mastocytosis (SM) is a highly heterogeneous disease with indolent and aggressive forms, with the mechanisms leading to malignant transformation still remaining to be elucidated. Here, we investigated the presence and frequency of genetic variants in 34 SM patients with multilineal KIT D816V mutations. Initial screening was performed by targeted sequencing of 410 genes in DNA extracted from purified bone marrow cells and hair from 12 patients with nonadvanced SM and 8 patients with advanced SM, followed by whole-genome sequencing (WGS) in 4 cases. Somatic mutations were further investigated in another 14 patients with advanced SM. Despite the fact that no common mutation other than KIT D816V was found in WGS analyses, targeted next-generation sequencing identified 67 nonsynonymous genetic variants involving 39 genes. Half of the mutations were somatic (mostly multilineal), whereas the other half were germline variants. The presence of ≥1 multilineal somatic mutation involving genes other than KIT D816V, ≥3 germline variants, and ≥1 multilineal mutation in the SRSF2, ASXL1, RUNX1, and/or EZH2 genes (S/A/R/E genes), in addition to skin lesions, splenomegaly, thrombocytopenia, low hemoglobin levels, and increased alkaline phosphatase and ß2-microglobulin serum levels, were associated with a poorer patient outcome. However, the presence of ≥1 multilineal mutation, particularly involving S/A/R/E genes, was the only independent predictor for progression-free survival and overall survival in our cohort.


Assuntos
Mastocitose Sistêmica/diagnóstico , Proteínas Proto-Oncogênicas c-kit/genética , Adolescente , Adulto , Idoso , Fosfatase Alcalina/sangue , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Criança , Intervalo Livre de Doença , Feminino , Variação Genética , Mutação em Linhagem Germinativa , Hemoglobinas/análise , Humanos , Recém-Nascido , Masculino , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/mortalidade , Mastocitose Sistêmica/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Microglobulina beta-2/sangue
11.
Oncol Lett ; 16(1): 1332-1340, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30061953

RESUMO

Insulin-like growth factor-1 receptor (IGF-1R) is a cell membrane receptor involved in cell proliferation and apoptosis, which is highly expressed in lung squamous cell carcinoma (SCC). The present study aimed to observe the influence of IGF-1R silencing on the radiosensitivity of SCC and investigate the potential mechanisms involved. Human lung SCC H520 cells with relatively high expression of IGF-1R were used. IGF-1R expression was silenced using short hairpin RNA. The influence of IGF-1R silencing on radiosensitivity and apoptosis was assessed using a clone formation assay and flow cytometry. The expression levels of proteins relevant in DNA damage repair and hypoxic signaling pathways were analyzed using western blotting. Decreased expression of IGF-1R led to an increase in the sensitivity of H520 cells to irradiation. Molecular analysis showed that the reduced expression of IGF-1R decreased the protein expression of ataxia-telangiectasia mutated (ATM), H2A histone family member X (H2AX) and p53 binding protein 1 (53BP1), which are associated with the DNA repair pathway. Furthermore, 53BP1 is also known to be involved in apoptosis. Proteins involved in the hypoxic pathway, including hypoxia inducible factor 1 α (HIF-1α), matrix metallopeptidase 9 (MMP-9) and vascular endothelial growth factor A (VEGFA) were also involved in the radiosensitivity. In conclusion, decreased expression of IGF-1R leads to improved radiosensitivity of SCC cells, and the underlying mechanism may be associated with the decreased expression of proteins involved in ATM/H2AX/53BP1 DNA damage repair and the HIF-1α/MMP-9 hypoxic pathway, which results in the induction of apoptosis and increased radiosensitivity. These findings suggest that targeting of IGF-1R may represent a novel approach for lung SCC radiation treatment.

12.
J Immunol Res ; 2018: 1027323, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29971244

RESUMO

We performed a systematic review and meta-analysis to determine the risk of immune-related pancreatitis associated with the treatment by immune checkpoint inhibitors (ICIs) for solid tumors. Eligible studies were selected from multiple databases including phase II/III randomized controlled trials (RCTs) with ICIs in solid tumor patients. The data were analyzed with Stata version 12.0 software. After excluding ineligible studies, a total of 15 clinical trials were considered eligible for the meta-analysis, which included 9099 patients. Compared with chemotherapy or placebo, the risk ratio (RR) for all-grade lipase elevation after CTLA-4 inhibitor treatment was 1.05 (95% confidence interval (CI): 1.01-2.24, p = 0.047). However, the risk for pancreatitis after ICI treatment in any subgroup was not significantly higher than that after control therapy. In addition, compared with ipilimumab/nivolumab alone, the RR for all-grade and high-grade lipase elevation under combination treatment of nivolumab and ipilimumab was 6.43 (95% CI: 1.43-28.99, p = 0.015) and 6.44 (95% CI: 1.39-29.79, p = 0.017), respectively, and the RR for all-grade amylase elevation under combination treatment was 6.08 (95% CI: 1.51-24.44, p = 0.011). Our meta-analysis has demonstrated that both CTLA-4 inhibitors alone and combination treatment of nivolumab and ipilimumab could increase the risk of amylase or lipase elevation, but not significantly increase the risk of pancreatitis when compared with controls.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Neoplasias/tratamento farmacológico , Pancreatite/induzido quimicamente , Amilases/sangue , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Quimioterapia Combinada/efeitos adversos , Humanos , Imunoterapia , Lipase/sangue , Neoplasias/sangue , Pancreatite/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Risco
13.
J Cancer ; 9(9): 1614-1622, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29760800

RESUMO

Background: We performed a meta-analysis to evaluate the risk of immune-related colitis associated with PD1/PD-L1 inhibitors as compared to chemotherapy in solid tumor patients. Methods: Eligible studies were identified through a comprehensive search of multiple databases and included solid tumor patients in randomized controlled trials (RCTs) with PD-1/PD-L1 inhibitors. The data was analyzed by Stata version 12.0 software. Results: After exclusion of ineligible studies, 11 clinical trials were considered eligible for the meta-analysis, including 5751 patients. Compared with chemotherapy, the risk ratios (RRs) of all-grade colitis were significant for the PD-1 inhibitor subgroup (RR 2.69, 95% confidence interval (CI): 1.15-6.29, p=0.023), and for pembrolizumab subgroup (RR 3.17, 95% CI: 1.08-9.37, p=0.037), but not for nivolumab treatment and PD-L1 inhibitor (atezolizumab) treatment (RR 2.05, 95% CI: 0.52-8.13, p=0.305; RR 4.75,95% CI: 0.56-40.50, p=0.154, respectively). The RR of all-grade colitis was significant for PD-1/PD-L1 inhibitor in NSCLC (RR 4.34, 95% CI: 1.37-13.82, p=0.013), and not significant in melanoma (RR 2.11, 95% CI: 0.54-8.34, p=0.285). Moreover, the RRs of all-grade diarrhea were significant for the PD-1 inhibitor subgroup (RR 0.61, 95% CI: 0.44-0.83, p=0.002), for the nivolumab subgroup (RR 0.54, 95% CI: 0.34-0.87, p=0.012), and for atezolizumab subgroup (RR 0.48, 95% CI: 0.25-0.89, p=0.021). The RR of high-grade diarrhea was significant for atezolizumab subgroup (RR 0.34, 95% CI: 0.12-0.94, p=0.037). Conclusions: Our meta-analysis demonstrates that compared with chemotherapy, pembrolizumab may result in a higher risk of all-grade immune-mediated colitis. PD-1/PD-L1 inhibitor treatment in NSCLC patients, but not in melanoma patients, increases the risk of all-grade colitis incidence.

14.
Int Immunopharmacol ; 59: 328-338, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29679857

RESUMO

BACKGROUND: We performed a systematic review and meta-analysis to evaluate the risk of immune-related endocrine disorders associated with PD-1 inhibitors therapy for solid tumors. METHODS: An Embase and PubMed search through December 6, 2017, using the following keywords was performed: immune-related endocrine disorders, and PD-1 inhibitors, etc. The data were analyzed using R 3.4.3 (R Project) and the metafor package. Patients treated with chemotherapy alone were used as control for the purpose of comparison. RESULTS: A total of 12 clinical trials including 5577 patients were found eligible for the meta-analysis. Compared with chemotherapy, the risk ratios of all-grade endocrine disorders are 13.89, (95% CI: 5.35-36.05, p < 0.001) for nivolumab therapy, and 9.85, (95% CI: 5.65-17.17, p < 0.001) for pembrolizumab therapy. The risk of all-grade hypothyroidism and hyperthyroidism incidence was increased for nivolumab therapy (hypothyroidism: RR 10.07, 95% CI: 3.37-30.11, p < 0.001; hyperthyroidism: RR 4.29, 95% CI: 1.13-16.30, p = 0.034) and for pembrolizumab therapy (hypothyroidism: RR 7.73, 95% CI: 3.86-15.49, p < 0.001; hyperthyroidism: RR 5.09, 95% CI: 2.36-10.97, p < 0.001). There was a significant increase in the risk of grade 1-5 endocrine disorders incidence for ipilimumab-nivolumab combination therapy (versus ipilimumab, RR 3.20, 95% CI: 2.08-4.91, p < 0.001; versus nivolumab, RR 2.54, 95% CI: 1.70-3.80, p < 0.001). CONCLUSIONS: Both nivolumab and pembrolizumab therapy could result in a higher risk of all-grade immune-related endocrine disorders than chemotherapy. Nivolumab and ipilimumab combination therapy could result in an even higher risk of all-grade immune-related endocrine disorders than ipilimumab or nivolumab alone. Awareness of these side effects could guide clinicians to better manage the patients treated with anti-PD-1 inhibitors therapy for solid tumors.


Assuntos
Antineoplásicos/efeitos adversos , Doenças do Sistema Endócrino/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Risco
15.
Genet Med ; 20(1): 159-163, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28640241

RESUMO

PurposeCurrent clinical genomics assays primarily utilize short-read sequencing (SRS), but SRS has limited ability to evaluate repetitive regions and structural variants. Long-read sequencing (LRS) has complementary strengths, and we aimed to determine whether LRS could offer a means to identify overlooked genetic variation in patients undiagnosed by SRS.MethodsWe performed low-coverage genome LRS to identify structural variants in a patient who presented with multiple neoplasia and cardiac myxomata, in whom the results of targeted clinical testing and genome SRS were negative.ResultsThis LRS approach yielded 6,971 deletions and 6,821 insertions > 50 bp. Filtering for variants that are absent in an unrelated control and overlap a disease gene coding exon identified three deletions and three insertions. One of these, a heterozygous 2,184 bp deletion, overlaps the first coding exon of PRKAR1A, which is implicated in autosomal dominant Carney complex. RNA sequencing demonstrated decreased PRKAR1A expression. The deletion was classified as pathogenic based on guidelines for interpretation of sequence variants.ConclusionThis first successful application of genome LRS to identify a pathogenic variant in a patient suggests that LRS has significant potential for the identification of disease-causing structural variation. Larger studies will ultimately be required to evaluate the potential clinical utility of LRS.


Assuntos
Estudos de Associação Genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Variação Genética , Genoma Humano , Genômica , Análise de Sequência de DNA , Criança , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Ecocardiografia , Genômica/métodos , Humanos , Masculino , Fenótipo , Análise de Sequência de DNA/métodos , Deleção de Sequência
16.
J Nematol ; 50(4): 495-506, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-31094152

RESUMO

Beneficial nematodes are used as biological control agents. Low-cost mass production of entomopathogenic nematodes (EPNs) is an important prerequisite toward their successful commercialization. EPNs can be grown via in vivo methods or in sold or liquid fermentation. For solid and liquid approaches, media optimization is paramount to maximizing EPN yield and quality. In solid media, the authors investigated the effects of incorporating pulverized insect powder from larvae of three insects (Galleria mellonella, Tenebrio molitor, and Lucillia sericata) at three dose levels (1, 3, and 5%). The impact of insect powder was assessed on infective juvenile (IJ) yield in solid media. Additionally, IJs produced in solid culture were subsequently assessed for virulence, and progeny production in a target insect, Spodoptera litura. The dose level of larval powder had a significant effect on IJ yield in both trials, whereas insect type had significant effect on IJ yield in trial 1 but not in trial 2. The maximum solid culture yield was observed in T. molitor powder at the highest dose in both trials. Moreover, the time-to-death in S. litura was substantially shortened in trial 1 and in trial 2 when IJs from the T. molitor powder treatment were applied. There was no significant effect of combining two insect powders relative to addition of powder from a single insect species. These findings indicate that addition of insect powder to solid media leads to high mass production yields, and the fitness of the IJs produced (e.g., in virulence and reproductive capacity) can be enhanced as well.Beneficial nematodes are used as biological control agents. Low-cost mass production of entomopathogenic nematodes (EPNs) is an important prerequisite toward their successful commercialization. EPNs can be grown via in vivo methods or in sold or liquid fermentation. For solid and liquid approaches, media optimization is paramount to maximizing EPN yield and quality. In solid media, the authors investigated the effects of incorporating pulverized insect powder from larvae of three insects (Galleria mellonella, Tenebrio molitor, and Lucillia sericata) at three dose levels (1, 3, and 5%). The impact of insect powder was assessed on infective juvenile (IJ) yield in solid media. Additionally, IJs produced in solid culture were subsequently assessed for virulence, and progeny production in a target insect, Spodoptera litura. The dose level of larval powder had a significant effect on IJ yield in both trials, whereas insect type had significant effect on IJ yield in trial 1 but not in trial 2. The maximum solid culture yield was observed in T. molitor powder at the highest dose in both trials. Moreover, the time-to-death in S. litura was substantially shortened in trial 1 and in trial 2 when IJs from the T. molitor powder treatment were applied. There was no significant effect of combining two insect powders relative to addition of powder from a single insect species. These findings indicate that addition of insect powder to solid media leads to high mass production yields, and the fitness of the IJs produced (e.g., in virulence and reproductive capacity) can be enhanced as well.

17.
Cancer Res ; 77(22): 6190-6201, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-29021135

RESUMO

Lysine acetyltransferase KAT6A is a chromatin regulator that contributes to histone modification and cancer, but the basis of its actions are not well understood. Here, we identify a KAT6A signaling pathway that facilitates glioblastoma (GBM), where it is upregulated. KAT6A expression was associated with GBM patient survival. KAT6A silencing suppressed cell proliferation, cell migration, colony formation, and tumor development in an orthotopic mouse xenograft model system. Mechanistic investigations demonstrated that KAT6A acetylates lysine 23 of histone H3 (H3K23), which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Overexpressing activated AKT or PIK3CA rescued the growth inhibition due to KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogated the growth-promoting effect of KAT6A. Overexpression of KAT6A or TRIM24, but not KAT6A acetyltransferase activity-deficient mutants or TRIM24 mutants lacking H3K23ac-binding sites, promoted PIK3CA expression, AKT phosphorylation, and cell proliferation. Taken together, our results define an essential role of KAT6A in glioma formation, rationalizing its candidacy as a therapeutic target for GBM treatment. Cancer Res; 77(22); 6190-201. ©2017 AACR.


Assuntos
Proteínas de Transporte/metabolismo , Histona Acetiltransferases/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Western Blotting , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Histona Acetiltransferases/genética , Humanos , Camundongos Nus , Fosforilação , Ligação Proteica , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Heterólogo
18.
Cancer Genet ; 216-217: 10-15, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29025582

RESUMO

FLT3 fusions are associated with myeloid and lymphoid neoplasms with eosinophilia. We describe a patient presenting with clinicopathologic features of both chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) and systemic mastocytosis (SM). The bone marrow demonstrated a myeloproliferative neoplasm with eosinophilia and aggregates of atypical mast cells. Cytogenetic analysis revealed a t(13;14)(q12;q32), which was subsequently molecularly characterized as a novel TRIP11-FLT3 rearrangement. A KIT D816V mutation was also identified. The patient rapidly transformed to T-lymphoblastic leukemia/lymphoma and expired shortly after diagnosis. This is the fifth FLT3 fusion gene described in the literature; the presence of both myeloid and lymphoid neoplasms implicates involvement of an early hematopoietic progenitor by rearranged FLT3. We suggest that leukemias and lymphomas with FLT3 fusion genes exhibit similar clinicopathologic features to, and should be included in, the WHO category of "Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2."


Assuntos
Eosinofilia/complicações , Linfoma/complicações , Linfoma/genética , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/genética , Proteínas de Fusão Oncogênica/genética , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
Oncotarget ; 8(35): 59677-59689, 2017 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-28938671

RESUMO

Meta-analysis was conducted to systematically assess the effectiveness and safety of programmed cell death protein-1 or ligand-1 (PD-1 or PD-L1) antibodies versus docetaxel alone in advanced non small cell lung cancer (NSCLC). In addition, the prognostic significance of PD-L1 expression in advanced NSCLC was also investigated. 5 eligible studies including 3579 patients were identified through comprehensive search of multiple databases. The results showed that pooled hazard ratios (HR) for overall survival (OS) and progression free survival (PFS) were 0.69 (95% CI: 0.63-0.75; p < 0.001) and 0.87 (95% CI: 0.80-0.94; p < 0.001), between PD-1/PD-L1 antibodies and docetaxel treatment arms, respectively. The pooled relative risk (RR) value for objective response rate (ORR) was 1.53, (95% CI: 1.16-2.01, p = 0.003). Further, subgroup analysis based on PD-L1 expression indicated that pooled HR for OS was significant with 0.66(95% CI: 0.59-0.74, p < 0.001) for PD-L1≥1%. However, PD-L1 < 1% had HR value of 0.79 (95% CI: 0.67-0.93, p = 0.006). Our study concluded that advanced NSCLC patients benefited more with PD-1/PD-L1 antibodies than docetaxel in the second line treatment. PD-L1≥10% in tumor tissues is sufficient to show significant improvement in patient's outcome with PD-1/PD-L1 antibodies compared to docetaxel. Moreover, PD-1/PD-L1 antibodies treatment showed significant decrease in conventional chemotherapy adverse events, but increased immune-associated adverse effects.

20.
J Crit Care ; 42: 65-68, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28688239

RESUMO

Toxic epidermal necrolysis (TEN) is a rare, severe, life-threatening skin disease and it requires urgent critical care, including admission to the intensive care unit (ICU). It is characterized by fatal sequelae and high mortality. Currently, insufficient evidence exists to support the use of any systemic adjuvant therapy, such as cyclophosphamide, intravenous immunoglobulin (IVIg), or corticosteroids. However, plasmapheresis has been increasingly valued by clinicians due to its significant efficacy and little adverse side effects. To assess the efficacy of such treatment, 28 patients who were diagnosed with TEN or SJS/TEN overlap were continuously recruited in the ICU from February 2009 to August 2016. These patients including both children and adults were randomly divided into two groups based on whether or not plasmapheresis therapy was performed after admission, which resulted in a plasmapheresis group (n=13) and a non-plasmapheresis group (n=15). Severity of the disease and the efficacy of treatments were evaluated by the severity-of-illness score for TEN. The results indicated that plasmapheresis may be superior to conventional therapies, such as IVIg or corticosteroids. Furthermore, plasmapheresis combined with other treatments might not be advantageous compared to the effect of plasmapheresis alone.


Assuntos
Plasmaferese/métodos , Síndrome de Stevens-Johnson/terapia , Adolescente , Corticosteroides/uso terapêutico , Adulto , Criança , Terapia Combinada , Cuidados Críticos/estatística & dados numéricos , Progressão da Doença , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Tempo de Internação/estatística & dados numéricos , Masculino , Estudos Prospectivos , Resultado do Tratamento
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