Trends in innovative pediatric drug development in China based on clinical trial registration data.

In China, the focus of drug research and development has gradually shifted from generic to innovative drugs. Using the Chinese Clinical Trials Registry and Information Transparency Platform, we retrospectively analyzed clinical trials of innovative pediatric drugs conducted in mainland China over the last decade. The goal of this work was to better understand the characteristics of and historical changes in innovative pediatric drug research and development (R&D) in China and to provide effective data support for policy makers and other stakeholders. This study included 198 innovative pediatric drug clinical trials. The data showed that, although some progress has been made in the R&D of innovative pediatric drugs in China, many factors limiting this progress still exist, such as concentrated R&D areas, inadequate pediatric participants, and unbalanced source distributions. The level of innovative pediatric drug R&D in China currently lags behind the global level and has not kept pace with anti-neoplastic drug R&D in China. To promote the innovative development of pediatric drugs in China, the Chinese government must develop an R&D supervision framework, improve the motivation and innovation capabilities of pharmaceutical companies, and optimize the source distribution between regions.

Risk factors associated with the comprehensive needs of cancer caregivers in China.

BACKGROUND: Cancer incidence and mortality rates have been rising in developing countries, especially in Asia. Cancer caregivers face unique challenges which put them at risk for burden, poor quality of life, and burnout. The purpose of this study was to investigate the comprehensive needs and associated factors of cancer caregivers, and explore the correlation with cancer patients. METHODS: In Mainland China, 200 cancer patient-caregiver dyads were chosen and interviewed for a cross-sectional questionnaire survey by convenient sampling method. Cancer caregivers' comprehensive needs were assessed with Comprehensive Needs Assessment Tool in cancer for Caregivers(CNAT-C), including seven domains (health and psychological problems, family and social support, healthcare staffs, information, religious/spiritual support, hospital facilities and services, and practical support). The comprehensive needs assessment tool in cancer for patients (CNAT) was used to assess patients' comprehensive needs. The sociodemographic survey was completed by both cancer patients and caregivers. The mean differences in domain scores for different groups of characteristics were compared by one-way ANOVA or non-parametric analyses, and those factors that had significant differences were selected for the multivariate regression analysis to determine the final influencing factors. The correlation between cancer patients' and caregivers' needs was evaluated by Spearman's correlation analysis. RESULTS: The cancer caregivers' need for healthcare staff (82.60±19.56) was the highest among the seven domains, followed by the need for information (72.17±14.61) and the need for hospital facilities and services (56.44±18.22). The lowest score was the need for religious/spiritual support (28.33±16.05). Caregivers who were younger, highly educated, with high household income, and less than 1 year since diagnosis had higher scores of CNAT-C. Also sociodemographic characteristics were associated with each domain of cancer caregivers' need. Correlations between patients' and caregivers' comprehensive needs were low to moderate (0.013~0.469). CONCLUSION: Cancer caregivers experience high levels of comprehensive needs, which are closely related to their sociological characteristics. The tailored interventions and mobilization of social and health care support may thus provide multiple levels of benefit across cancer trajectories. The patient-caregiver dyad should be regarded as a unit for treatment in cancer care.

Long-read genome assemblies reveal a cis-regulatory landscape associated with phenotypic divergence in two sister Siniperca fish species.

Due to the difficulty in accurately identifying structural variants (SVs) across genomes, their impact on cis-regulatory divergence of closely related species, especially fish, remains to be explored. Recently identified broad H3K4me3 domains are essential for the regulation of genes involved in several biological processes. However, the role of broad H3K4me3 domains in phenotypic divergence remains poorly understood. Siniperca chuatsi and S. scherzeri are closely related but divergent in several phenotypic traits, making them an ideal model to study cis-regulatory evolution in sister species. Here, we generated chromosome-level genomes of S. chuatsi and S. scherzeri, with assembled genome sizes of 716.35 and 740.54 Mb, respectively. The evolutionary histories of S. chuatsi and S. scherzeri were studied by inferring dynamic changes in ancestral population sizes. To explore the genetic basis of adaptation in S. chuatsi and S. scherzeri, we performed gene family expansion and contraction analysis and identified positively selected genes (PSGs). To investigate the role of SVs in cis-regulatory divergence of closely related fish species, we identified high-quality SVs as well as divergent H3K27ac and H3K4me3 domains in the genomes of S. chuatsi and S. scherzeri. Integrated analysis revealed that cis-regulatory divergence caused by SVs played an essential role in phenotypic divergence between S. chuatsi and S. scherzeri. Additionally, divergent broad H3K4me3 domains were mostly associated with cancer-related genes in S. chuatsi and S. scherzeri and contributed to their phenotypic divergence.

Changes in the renal artery and renal volume and predictors of renal atrophy in patients with complicated type B aortic dissection after thoracic endovascular aortic repair.

Background: For complicated Stanford type B aortic dissection (TBAD), thoracic endovascular aortic repair (TEVAR) is the recommended treatment; however, the type of renal artery that should be repaired remains controversial. The study aimed to investigate the changes in the renal artery and renal volume in complicated TBAD after TEVAR and the predictors of renal atrophy. Methods: The cohort study retrospectively enrolled patients with acute and subacute complicated TBAD who underwent aortic computed tomography angiography (CTA) 1 month before as well as 1 week and half a year after TEVAR from January 2010 to May 2017. According to the source of blood supply shown in preoperative CT, the renal artery was classified in 3 ways: type 1, supplied by the aortic true lumen; type 2, supplied by the aortic false lumen; or type 3, supplied by both the true and false lumen. Results: A total of 91 patients (81 men and 10 women) with an average age of 48.12±10.35 years were enrolled. Renal arteries were classified as type 1 (n=91), type 2 (n=35), and type 3 (n=56). There was no difference in the distribution of the 3 types on the left and right sides (type 1 vs. type 2 vs. type 3: 52:39 vs. 15:20 vs. 24:32; P=0.152). After TEVAR, type 3 was more likely to have spontaneous healing than type 2 (16.1% vs. 2.9%; P=0.049). There was no significant difference in the preoperative volume of kidneys of the 3 types (type 1 vs. type 2 vs. type 3: 198.23±38.68 vs. 197.37±41.77 vs. 195.10±36.11 mL; P=0.893). The postoperative volume of types 2 and 3 was smaller than that of type 1 (type 1 vs. type 2 vs. type 3: 190.09±43.25 vs. 165.15±52.63 vs. 170.70±45.28 mL; P=0.006). The renal volume was reduced in all 3 types of renal artery, especially in type 2 (the change of renal volume for type 1 vs. type 2 vs. type 3: -8.14±29.31 vs. -32.22±41.59 vs. -24.41±38.44 mL; P=0.001). The relative change of renal volume for type 1 vs. type 2 vs. type 3: (-3.64±15.69)% vs. (-16.00±21.29)% vs. (-11.97±18.22)%; P=0.001). During the median follow-up of 668 days, 7 patients (7.7%) belonging to types 2 and 3 developed renal atrophy. False lumen thrombosis in the abdominal aorta and/or the renal artery was the predictor of renal atrophy [hazard ratio (HR) =17.757; P=0.008]. Conclusions: Patients with type 2 or 3 renal artery and false lumen thrombosis in the abdominal aorta and/or renal artery should be monitored closely and actively intervened to prevent renal atrophy.

Unstable plaques hide in heavily calcified coronary arteries.

Background: The napkin-ring sign (NRS) was accepted as unstable plaques at coronary computed tomography angiography (CCTA). However, the incidence is relatively low. We sought to assess whether the newly defined diamond-attenuation-sign [DAS, defined as a qualitative plaque feature in a mixed plaque (MP) on CCTA cross-section images by the presence of two features: a visual calcification (in the shape of a diamond) accompanied by an annular-shape lower attenuation plaque tissue surrounding the lumen like a ring], could be accurately identified as unstable atherosclerotic plaques. Methods: Eight heart transplant recipients (8 male; mean age, 48.5±11.6 years; range, 37-65 years) underwent CCTA exams prior to heart transplant surgery. Segment-based CCTA sections were independently evaluated for various plaque patterns including non-calcified plaque (NCP) with NRS (NCP-NRS), NCP without NRS (NCP-non-NRS), MP with DAS (MP-DAS), MP without DAS sign (MP-non-DAS), and calcified plaque (CP). Results: NCP-NRS plaques in 6.4% (23/358), NCP-non-NRS plaques in 24.0% (86/358), MP-DAS plaques in 18.2% (65/358), MP-non-DAS plaques in 20.1% (72/358), and calcified-plaques in 7.0% (25/358) of all cases. The specificity and positive predictive values of the MP-DAS and NCP-NRS signs to identify unstable plaque features were excellent (97.1% vs. 98.6%, 90.8% vs. 87.0%, respectively). DAS plaques were more frequently seen on CCTA exams than that of NRS (39.3% vs. 13.3%, respectively, P=0.001). The diagnostic performance of MP-DAS to identify unstable coronary lesions was superior compared to NCP-NRS [area under the receiver operating characteristic curve (ROC), 0.756; 95% CI: 0.717-0.791 vs. 0.558; 95% CI: 0.514-0.600, respectively, P<0.001]. Conclusions: Both the DAS and NRS had a high specificity and positive predictive value for the presence of unstable lesions. DAS was a better identification of unstable atherosclerotic plaques in the assessment of plaque-calcification-pattern (PCP).

Rational application of gefitinib in NSCLC patients with sensitive EGFR mutations based on pharmacokinetics and metabolomics.

Gefitinib has been available in the market for 20 years, but its pharmacokinetic mechanism of response is little known. In this study, we examined the pharmacokinetic and metabolomic profiles in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. A total of 216 advanced NSCLC patients were enrolled, and administered gefitinib at the standard dosage of 250 mg/day, which was established in heterogeneous subjects with non-sensitive mutations. We identified and quantified three main metabolites (named as M1, M2 and M3) in the plasma of patients, the correlations between the concentration of gefitinib/metabolites and efficacy were analyzed. In exploratory and validation set, gefitinib concentration was not correlated with clinical effects. Considering the result that the therapeutic effects of 250 mg/2-day was better than that of 250 mg/day in a multiple center clinical trial, the standard dose might be higher than that for maximal efficacy according to the hypothetical dose-response curve. Among the three metabolites, the IC50 of M2 in HCC827 and PC9 cell lines was significantly lower, and Conc.brain/Conc.plasma of M2 in mice was significantly higher than those of gefitinib, suggesting its higher potential to penetrate blood-brain barrier and might be more effective in the treatment of brain metastatic tumor than gefitinib. Consistently and attractively, higher M2 plasma concentration was found to be correlated with better clinical outcome in patients with brain metastases (the median PFS of CM2 < 12 ng/mL and CM2 ≥ 12 ng/mL were 17.0 and 27.1 months, respectively, P = 0.038). The plasma concentration of M2 ≥ 12 ng/mL was a strong predictor of the PFS of NSCLC patients. In conclusion, for NSCLC patients with EGFR sensitive mutations, the standard dose is suspectable and could be decreased reasonably. M2 plays an important role in efficacy and may be more effective in the treatment of metastatic tumor than gefitinib.

Impact of STAT1 polymorphisms on crizotinib-induced hepatotoxicity in ALK-positive non-small cell lung cancer patients.

PURPOSE: Crizotinib is the first-line small molecule tyrosine kinase inhibitor for ALK-positive non-small cell lung cancer. In this study, a retrospective pharmacogenomics investigation was conducted to explore the relationship between genes related to RTK downstream signaling pathways and crizotinib-induced hepatic toxicity in ALK-positive NSCLC patients. METHODS: The variable importance analysis of random forest algorithm was applied to identify the significant features which contribute to the crizotinib sensitivity in Cancer Cell Line Encyclopedia (CCLE) database. The KEGG and reactome pathway enrichment analysis were conducted with EnrichR. The differential expression genes were identified with R package DESeq2 in CCLE liver derived cell lines between crizotinib sensitive and resistant groups. From 2012 to 2015, 42 NSCLC patients were enrolled in this study. 90 polymorphisms were genotyped using the Sequenom Massarray system. Sequencing of HGFR (c-Met) genes was carried out on the Ion Torrent Proton. RESULTS: In total, 66.7% NSCLC patients suffered from crizotinib-induced liver toxicity and 11.9% progressed to severe hepatic toxicity. The features with the top importance from classification and regression random forest model were enriched in RTK downstream signaling pathways (JAK/STAT, RAS/RAF/MAPK, PI3K/AKT pathways) and immune system-related pathways. Collagen family genes (COL1A1, COL1A2, COL6A1, COL5A1) and other extracellular matrix protein (TNC, TAGLN, TENM2, EDIL3, VCAN, CNN1, SH3BP4, TAGLN), which were closely related to MAPK-ERK signaling pathways, were significantly enriched in crizotinib resistant cell lines. In multiple logistic regression, STAT1 rs10208033 (T > C) was significantly associated with crizotinib-induced liver toxicity (OR = 6.733, 95% CI 1.406-32.24, P = 0.017). Compared with non-CC, OR is 5.5 (95% CI 1.219-24.81, P = 0.027) for STAT1 rs10208033 CC genotype to develop crizotinib-induced liver toxicity. Further cell viability test in human fetal hepatocyte line, L-02, reveals that the STAT1 inhibitor might protect hepatocyte cells from the toxicity caused by crizotinib. CONCLUSION: Polymorphism of rs10208033 is a potential biomarker for predicting crizotinib-induced hepatotoxicity. These results suggest that STAT1 plays an important role in crizotinib-induced hepatotoxicity. Further studies are needed to confirm our finding and understand the underlying mechanisms.

Establishment and application of a predictive model for gefitinib-induced severe rash based on pharmacometabolomic profiling and polymorphisms of transporters in non-small cell lung cancer.

BACKGROUND: Rash is a well-known predictor of survival for patients with gefitinib therapy with non-small cell lung cancer (NSCLC). However, whether patients with more severe rash obtain the more survival benefits from gefitinib is still unknown, and predicted model for severe rash is needed. METHODS: The relationship between gefitinib-induced rash and progression free survival (PFS) was primarily explored in the retrospective cohort. The association between rash and gefitinib/metabolites concentration and genetic polymorphisms were determined by pharmacometabolomic and pharmacogenomics methods in the exploratory cohort and validated in an external cohort. RESULTS: The survival for patients with rash was significantly higher than that of patients without rash (p = 0.0002, p = 0.0089), but no difference was found between grade 1/2 or grade 3/4. Only the concentration of gefitinib, but not its metabolites, was found to be associated with severe rash, and the cutoff value of gefitinib was 204.6 ng/mL conducted by ROC curve analysis (AUC=0.685). A predictive model for severe rash was established: gefitinib concentration (OR = 11.523, 95% CI = 2.898-64.016, p = 0.0016), SLC22A8 rs4149179(CT vs CC, OR = 3.156, 95% CI = 0.958-11.164, p = 0.0629), SLC22A1 rs4709400(CG vs CC, OR = 10.267, 95% CI = 2.067-72.465, p = 0.0087; GG vs CC, OR = 5.103, 95% CI = 1.032-33.938, p = 0.061). This model was confirmed in the validation cohort with an excellent predictive ability (AUC = 0.749, 95% CI = 0.710-0.951). CONCLUSIONS: Our finding demonstrated that the incidence, not the severity, of gefitinib-induced rash predicted improved survival, the gefitinib concentration and polymorphisms of SLC22A8 and SLC22A1 were recommended to manage severe rash.

Polymorphisms of NF-κB pathway genes influence adverse drug reactions of gefitinib in NSCLC patients.

Gefitinib is a widely used targeted therapeutic drug in East Asian non-small cell lung cancer (NSCLC) patients. This research retrospectively investigated the relationship between the polymorphisms of genes involved in NF-κB pathways and gefitinib-related Adverse Drug Reactions (ADRs). From 2011 to 2016, 109 NSCLC patients were enrolled in this study. Thirty-two SNPs of 15 genes were genotyped with a Sequenom MassARRAY system. We collected 34 paired RNA samples before and after gefitinib administration for the detection of whole blood RNA expression of genes in NF-κB pathways (NFKBIA, NFKB1, NFKB2, RELA, RELB, and TNFAIP3). IKBKB rs2272733 (CC vs non-CC: OR = 0.256, 95% CI 0.087-0.753, P = 0.013) and IKBKE rs12142086 (CC vs non-CC: OR = 3.640, 95% CI 1.320-10.039, P = 0.013) were significantly associated with gefitinib-induced skin toxicity. IKBKE rs2151222 was associated with diarrhea with the odds ratio of non-TT vs TT as 0.162 (non-TT vs TT: 95% CI 0.034-0.775, P = 0.023). Furthermore, RELA rs11227247 was a predictor for hepatic toxicity (GG vs non-GG: OR = 0.212, 95% CI 0.062-0.726, P = 0.013). None of the gene expression levels after drug administration were determined to be significant predictors for adverse drug reactions by a logistics regression analysis. Polymorphisms of IKBKB, IKBKE, and RELA are potential biomarkers for predicting gefitinib-related ADRs. Further studies are needed to understand the underlying mechanisms for diagnostic and prophylactic therapy applications.

Retraction: Activation of endoplasmic reticulum stress promotes autophagy and apoptosis and reverses chemoresistance of human small cell lung cancer cells by inhibiting the PI3K/AKT/mTOR signaling pathway.

[This retracts the article DOI: 10.18632/oncotarget.12718.].

Prevalence and risk factors associated with the comprehensive needs of cancer patients in China.

BACKGROUND: The incidence and mortality rates of cancer have been increasing in developing countries, particularly in Asia. Therefore to provide optimal comprehensive care to the cancer patients, the care plan must focus on the comprehensive needs of cancer patients. The purpose of this study was to investigate the comprehensive needs of cancer patients, and explore the associated factors. METHODS: In a cross-sectional questionnaire study, a total of 200 cancer patient-caregiver dyads were selected and interviewed in Mainland China by convenient sampling method. Patients' comprehensive needs were assessed with Comprehensive Needs Assessment Tool in cancer for Patients (CNAT), including seven domains (Information, Psychological Problems, Health Care Staffs, Physical Symptoms, Hospital Facilities and Services, Social/Religious/Spiritual Support and Practical Support). Both cancer patients and caregivers completed the sociodemographic survey. The mean differences in domain scores for different characteristics groups were compared by one-way ANOVA or non-parametric analyses, and influencing factors defined with multivariate regression analysis. RESULTS: The cancer patients' need for Health Care Staffs (78.35 ± 13.08) was the highest among the seven domains, followed by the need for Information (71.18 ± 17.39) and the need for Hospital Facilities and Services (52.65 ± 13.35). The lowest score was the need for Physical Symptoms (35.12 ± 16.68). Patients who were female, with low family monthly income, at their own expense, and with highly educated caregivers had higher score of CNAT. Also sociodemographic characteristics were associated with each domain need of cancer patients. CONCLUSION: This study shows that cancer patients experience high levels of needs for health-care staff and information, and the different needs are closely related to their sociological characteristics. The provision of health care can be adapted to meet the different needs of cancer patients of different epidemiological characteristics at different times during the course of treatment.

Development and validation of a sensitive LC-MS/MS method for determination of gefitinib and its major metabolites in human plasma and its application in non-small cell lung cancer patients.

Gefitinib, the first approved oral epidermal growth factor receptor (EGFR) inhibitor, has been demonstrated effective in cancers with EGFR active mutations. In this study, we established and validated a method for determining gefitinib and its main metabolites, M605211, M387783, M537194 and M523595 in patients with non-small cell lung cancer (NSCLC) by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The mobile phase was water: acetonitrile (35:65, v/v) with 0.1% formic acid at a flow-rate of 0.35 mL/min, within a 3 min run time. Gefitinib and its main metabolites were separated on a X-Terra RP18 column (50 × 2.1 mm, 3.5 µm) at 40 ℃ and subjected to mass analysis using positive electro-spray ionization (ESI). The calibration ranges of gefitinib and M523595 were 0.5-1000 ng/mL, and other compounds were 0.05-100 ng/mL with the correlation coefficients (r2) ≥ 0.99. Accuracies ranged from 92.60%-107.58 and the inter- and intra-assay precision were less than 15% for all analytes in quality control samples. There was no significant matrix effect. The ranges of extraction recoveries were 86-105% for all analytes and IS. Thirty plasmas were obtained from Sun Yat-sen university cancer center. The mean plasma concentration of (± SD) of gefitinib M537194, M523595, M387783 and M605211 were 247.18 (± 140.39) ng/mL, 7.78 (± 6.74) ng/mL, 101.09 (± 93.44) ng/mL, 1.6 (± 0.9) ng/mL and 11.63 (± 4.98) ng/mL, respectively. The validated LC/MS/MS method was effectively used in the determination of gefitinib and its four metabolites in NSCLC patients.

The analysis of pharmacokinetic and pharmacogenomic impact on gefitinib efficacy in advanced non-small cell lung cancer patients: results from a prospective cohort study.

BACKGROUND: The current study is aimed to examine the impact of pharmacokinetics and gene polymorphisms of enzymes involving in absorption, distribution, metabolism and excretion (ADME) on the efficacy of gefitinib in non-small cell lung cancer (NSCLC) patients. METHODS: Eligible patients with indication of gefitinib treatment were prospectively enrolled in this study. Two peripheral blood samples at baseline and before cycle 2 day 1 were collected for the detection of single nucleotide polymorphisms (SNPs) of drug ADME enzymes and trough drug concentration (Ctrough) at steady state. Thirteen SNPs were genotyped using the Sequenom Massarray system. Ctrough was determined by validated high-performance liquid chromatographic method with tandem mass spectrometric (LC-MS/MS). RESULTS: Fifty-eight NSCLC patients were enrolled in this study. The median of Ctrough was 175ng/mL (range from 47.8 to 470 ng/mL). The trough concentration was not associated with either objective response or progression free survival (PFS). Ctrough was significantly lower in CYP3A4 rs2242480 CC + CT genotype than in TT genotype (P=0.019) and in ABCG2 rs2231142 AA genotype than in AC + CC genotype (P=0.031). ABCB1 rs2032582 dominant model was significantly correlated with overall response rate (ORR) and patients with GG phenotype respond better than patients with GT + TT phenotypes (84.6% vs. 51.2%, P=0.032). ABCB1 rs10256836 recessive model was significantly correlated with PFS and patients with GG phenotype achieved longer PFS than patients with GC + CC phenotypes (17.40 vs. 10.33 months, P=0.040). CONCLUSIONS: The Ctrough of gefitinib was significantly different between CYP3A4 and ABCG2 genotypes, but not with the efficacy of gefitinib treatment. ABCB1 rs2032582 and rs10256836 polymorphisms were correlated treatment outcome. Polymorphisms analysis of ABCB1 could be a predictive biomarker for gefitinib treatment.

Can therapeutic drug monitoring increase the safety of Imatinib in GIST patients?

Imatinib at 400 mg daily is the standard treatment for patients affected with CML and GIST. The intervariability in plasma concentration is very significant. In many reports, a good therapeutic effect is attributed to an adequate concentration of Imatinib. However, few studies have been conducted to investigate the association between plasma concentration and side effects. Besides, no upper concentration limit of Imatinib plasma concentration detection has been established. The correlation of Imatinib trough concentrations (Cmin ) with adverse effects (AEs) was described here. Plasma samples were obtained from patients after 3 months treatment with Imatinib (steady state, n = 122). Liquid chromatography/ tandem mass spectrometry was used to determine the concentration of Imatinib and its metabolite NDI. The incidence of myelosuppression was increased significantly with the increased Imatinib trough plasma concentration. The plasma level of Imatinib and NDI in patients who developed myelosuppression are 1698.3 ± 598.6 ng/mL and 242.1 ng/mL, respectively, which were significantly higher than those in patients who did not (1327.2 ± 623.4 ng/mL, P = 1.75 × 10-4 ; 206.3 ng/mL, P = 0.006). Estimated exposure thresholds of Imatinib and NDI were 1451.6 ng/mL with ROCAUC (95%CI) of 0.693 (0.597-0.789) and 207.1 ng/mL with ROCAUC (95%CI) of 0.646 (0.546-0.745), respectively. Multivariate regression confirmed the correlation of Imatinib Cmin with myelosuppression. Other side effects such as fluid retention and rash were not found to be correlated with Imatinib concentrations. These results suggest that trough concentration of Imatinib should be taken into consideration to increase the safety of Imatinib therapy in GIST patients.

Activation of endoplasmic reticulum stress promotes autophagy and apoptosis and reverses chemoresistance of human small cell lung cancer cells by inhibiting the PI3K/AKT/mTOR signaling pathway.

OBJECTIVE: This study aims to investigate the effects of endoplasmic reticulum stress (ERS) on autophagy, apoptosis and chemoresistance of human small cell lung cancer (SCLC) cells via the PI3K/AKT/mTOR signaling pathway. RESULTS: The expressions of ERS-related proteins (PEAK, eIF2α and CHOP) up-regulated, autophagy-related proteins (LC3, LC3-II and Beclin1) and apoptosis-related proteins (Bax and procaspase-3) down-regulated in NCI-H446 and H69 cells after tunicamycin treatment for 24 h. Compared with the blank group, the tunicamycin, BEZ235 and tunicamycin + BEZ235 groups exhibited decreased expressions of p-PI3K, p-AKT and p-mTOR, and increased expressions of autophagy-related proteins (LC3, LC3-II and Beclin1) and apoptosis proteins (Bax and procaspase-3), and the most obvious changes were observed in the tunicamycin + BEZ235 group. MATERIALS AND METHODS: CCK-8 assay was applied to select the best cell line from five SCLC cell lines (NCI-H446, H69, H526, H146 and H209). Finally, NCI-H446 and H69 cells were selected for further experiments. NCI-H446/CDDP and H69/CDDP were selected and divided into the blank group, tunicamycin (an ESR inducer) group, BEZ235 (inhibitors of PI3K/AKT/mTOR pathway) group and tunicamycin + BEZ235 group. Cell apoptosis was detected by flow cytometry. Autophagy was observed by fluorescence microscopy and flow cytometry. Western blotting was used to detect the expressions of ERS-related proteins, autophagy-related proteins, apoptosis-related proteins and PI3K/AKT/mTOR pathway-related proteins. CONCLUSIONS: Our findings provide evidence that the activation of ERS could promote autophagy and apoptosis and reverse chemoresistance of human SCLC cells by inhibiting the PI3K/AKT/mTOR pathway.

The effects of miR-1207-5p expression in peripheral blood on cisplatin-based chemosensitivity of primary gallbladder carcinoma.

OBJECTIVE: The aim of this study was to investigate the association between miR-1207-5p expression in peripheral blood and the chemosensitivity of primary gallbladder carcinoma (PGBC). METHODS: A total of 85 patients with PGBC undergoing preoperative chemotherapy were divided into effective (n=18) and ineffective (n=67) groups. Another 70 healthy individuals were selected as the control group. An miR-1207-5p mimic (mimic group), an inhibitor (inhibitor group), and a negative control (NC group) sequence were transfected into human gallbladder carcinoma GBC-SD cells. Real-time quantitative polymerase chain reaction was used to determine miR-1207-5p expression. After 48 hours of cisplatin treatment, CCK-8 method was used to detect cell proliferation and flow cytometry were performed to examine cell apoptosis. RESULTS: miR-1207-5p expression in peripheral blood was significantly associated with tumor node metastasis staging of PGBC (P<0.05). Before chemotherapy, miR-1207-5p expression in patients was higher than in healthy individuals (P<0.05). After chemotherapy, the effective group had lower miR-1207-5p expression than the ineffective group (P<0.05). The rates of positive expression of Ki67 protein in the effective group were significantly lower than those in the ineffective group (P<0.05). Receiver operating characteristic curves showed that the area under curve, sensitivity, and specificity of miR-1207-5p used to diagnose PGBC were 0.898, 77.6%, and 97.1% at a cutoff of 1.470, respectively. After 48 hours of cisplatin treatment, compared with the NC group and nontransfected (non-T) group, the mimic group had decreased rates of cell inhibition and apoptosis, but the inhibitor group had increased rates (all P<0.05). The expression levels of caspase3 protein were increased in the mimic group and decreased in the inhibitor group. Cell survival rates in the mimic group at different time points after cisplatin treatment were significantly higher than the corresponding rates in the NC and non-T groups, whereas the cell survival rates in the inhibitor group were significantly lower than the rates in the NC and non-T groups (all P<0.05). The concentration and action time of cisplatin were negatively associated with the cell survival rate in each group (all P<0.05). CONCLUSION: Cisplatin-based chemosensitivity of PGBC increased as expression of miR-1207-5p in peripheral blood declined. Thus, miR-1207-5p appears to be a promising and novel chemosensitizer for the treatment of PGBC.

The Dissociation of Gefitinib Trough Concentration and Clinical Outcome in NSCLC Patients with EGFR Sensitive Mutations.

Gefitinib is an essential drug for NSCLC patients harboring EGFR sensitive mutations. The approved dose 250 mg/day is based on limited clinical trials, this research aims to explore the relationship between drug exposure and gefitinib response. C trough of 87 NSCLC patients harboring EGFR sensitive mutations were determined by LC-MS/MS. The median of C trough was 173.9 ng/ml (P25-P75, 130.5-231.2 ng/ml), and cutoff value 200 ng/ml was determined by X-Tile. The PFS between C trough < 200 ng/ml and C trough ≥ 200 ng/ml groups were not significantly different (17.3 VS 14.8 months; p = 0.258). C trough was not significantly associated with rash, diarrhea and hepatotoxicity. Non-smokers enjoyed longer PFS than smokers (18.7 VS 9.3 months; p = 0.025). The results showed that, for NSCLC patients with EGFR sensitive mutations, the PFS in lower trough concentration group were not inferior to that in higher trough concentration group and dose reduction is a rational suggestion for adjustment of dose regimen for aforementioned patients. More clinical trials are warranted to explore the precision dose schedule of gefitinib.

Association of LEPR and ANKK1 Gene Polymorphisms with Weight Gain in Epilepsy Patients Receiving Valproic Acid.

BACKGROUND: Weight gain is the most frequent adverse effect of valproic acid (VPA) treatment, resulting in poor compliance and many endocrine disturbances. Similarities in the weight change of monozygotic twins receiving VPA strongly suggests that genetic factors are involved in this effect. However, few studies have been conducted to identify the relevant genetic polymorphisms. Additionally, the causal relationship between the VPA concentration and weight gain has been controversial. Thus, we investigated the effects of single nucleotide polymorphisms (SNPs) in several appetite stimulation and energy homeostasis genes and the steady state plasma concentrations (Css) of VPA on the occurrence of weight gain in patients. METHODS: A total of 212 epilepsy patients receiving VPA were enrolled. Nineteen SNPs in 11 genes were detected using the Sequenom MassArray iPlex platform, and VPA Css was determined by high-performance liquid chromatography (HPLC). RESULTS: After 6 months of treatment, 20.28% of patients were found to gain a significant amount of weight (weight gained ≥7%). Three SNPs in the leptin receptor (LEPR), ankyrin repeat kinase domain containing 1 (ANKK1), and α catalytic subunit of adenosine monophosphate-activated protein kinase (AMPK) showed significant associations with VPA-induced weight gain (p < 0.001, p = 0.017 and p = 0.020, respectively). After Bonferroni correction for multiple tests, the genotypic association of LEPR rs1137101, the allelic association of LEPR rs1137101, and ANKK1 rs1800497 with weight gain remained significant. However, the VPA Css in patents who gained weight were not significantly different from those who did not gain weight (p = 0.121). CONCLUSIONS: LEPR and ANKK1 genetic polymorphisms may have value in predicting VPA-induced weight gain.

Cross-cultural adaptation and psychometric assessment of the Chinese version of the comprehensive needs assessment tool for cancer caregivers (CNAT-C).

PURPOSE: The comprehensive needs assessment tool for cancer caregivers (CNAT-C) is a systematic and comprehensive needs assessment tool for the family caregivers. The purpose of this project was twofold: (1) to adapt the CNAT-C to Mainland China's cultural context and (2) to evaluate the psychometric properties of the newly adapted Chinese CNAT-C. METHODS: Cross-cultural adaptation of the original CNAT-C was performed according to published guidelines. A pilot study was conducted in Mainland China with 30 Chinese family cancer caregivers. A subsequent validation study was conducted with 205 Chinese cancer caregivers from Mainland China. Construct validity was determined through exploratory and confirmatory factor analyses. Reliability was determined using internal consistency and test-retest reliability. RESULTS: The split-half coefficient for the overall Chinese CNAT-C scale was 0.77. Principal component analysis resulted in an eight-factor structure explaining 68.11 % of the total variance. The comparative fit index (CFI) was 0.91 from the modified model confirmatory factor analysis. The Chi-square divided by degrees of freedom was 1.98, and the root mean squared error of approximation (RMSEA) was 0.079. In relation to the known-group validation, significant differences were found in the Chinese CNAT-C scale according to various caregiver characteristics. Internal consistency was high for the Chinese CNAT-C reaching a Cronbach α value of 0.94. Test-retest reliability was 0.85. CONCLUSIONS: The newly adapted Chinese CNAT-C scale possesses adequate validity, test-retest reliability, and internal consistency and therefore may be used to ascertain holistic health and support needs of cancer patients' family caregivers in Mainland China.

Effects and safety of iron-based phosphate binders in dialysis patients: a systematic review and meta-analysis.

AIM: To assess the effects and safety of iron-based phosphate binders in adult patients receiving dialysis. METHODS: We electronically searched MEDLINE, EMBASE, CENTRAL, and CBM for randomized controlled trials about iron-based phosphate binders in adult dialysis patients. Study quality was assessed using the criteria outlined in the Cochrane Handbook for Systematic Reviews of intervention. Meta-analysis was conducted by RevMan 5.3. RESULTS: Eight studies with 2018 participants were eligible for our meta-analysis. Iron-based phosphate binders were superior to placebo (MD = -2.43 mg/dL, 95% CI: -3.18 to -1.68, p < 0.00001) and as efficient as sevelamer (MD = 0.04 mg/dL, 95% CI: -0.29 to 0.36, p = 0.83) in reducing serum phosphorus in dialysis patients. No significant differences were found in all adverse events (OR = 1.30, 95% CI: 0.77 to 2.20, p = 0.32) between iron-based phosphate binders and placebo. Iron-based phosphate binders were associated with significant higher serum iron (MD = 9.39 ng/mL, 95% CI 1.48 to 17.30, p = 0.02), higher serum transferring saturation (MD = 6.29%, 95% CI 2.72 to 9.87, p = 0.0006) and lower serum total iron binding capacity (MD = -23.13 µg/dL, 95% CI -35.69 to -10.58, p = 0.0003) in comparison to placebo. CONCLUSION: Iron-based phosphate binders are as effective as sevelamer and well tolerated for hyperphosphatemia in dialysis patients. Iron-based phosphate binders appear to have a beneficial effect on renal anemia in patients receiving dialysis. Therefore, iron-based phosphate binders may represent a new treatment option for dialysis patients.