Bioactivity and mechanism of action of sanguinarine and its derivatives in the past 10 years.

Sanguinarine is a quaternary ammonium benzophenanthine alkaloid found in traditional herbs such as Chelidonium, Corydalis, Sanguinarum, and Borovula. It has been proven to possess broad-spectrum biological activities, such as antitumor, anti-inflammatory, antiosteoporosis, neuroprotective, and antipathogenic microorganism activities. In this paper, recent progress on the biological activity and mechanism of action of sanguinarine and its derivatives over the past ten years is reviewed. The results showed that the biological activities of hematarginine and its derivatives are related mainly to the JAK/STAT, PI3K/Akt/mTOR, NF-κB, TGF-ß, MAPK and Wnt/ß-catenin signaling pathways. The limitations of using sanguinarine in clinical application are also discussed, and the research prospects of this subject are outlined. In general, sanguinarine, a natural medicine, has many pharmacological effects, but its toxicity and safety in clinical application still need to be further studied. This review provides useful information for the development of sanguinarine-based bioactive agents.

Thyroid dysfunction (TD) induced by PD-1/PD-L1 inhibitors in advanced lung cancer.

Background: Thyroid Dysfunction (TD) is a common immune-related adverse events (irAEs) in the treatment of advanced lung cancer with programmed cell death protein 1 (PD-1) and programmed death 1 ligand (PD-L1) inhibitors, with incidence accounting for 6-8% of all irAEs. The incidence of TD is receiving increasing attention from clinicians, given its potential impact on clinical efficacy. However, the molecular mechanisms, biomarkers, and clinical impact of TD resulting from PD-1/PD-L1 inhibitor treatment in advanced lung cancer are unclear. Objective: To present a comprehensive review of current advancements in research about the molecular mechanisms, influential factors, and clinical manifestations in the treatment of advanced lung cancer with PD-1 and PD-L1 inhibitors, as well as the correlation between TD and the efficacy of PD-1 and PD-L1 inhibitors. Methods: A systematic search was conducted using PubMed, Web of Science, Cochrane Library, Embase and Google Scholar databases, with the keywords including thyroid dysfunction, efficacy, mechanisms, immune checkpoint inhibitors, PD-1/PD-L1 inhibitors, and advanced lung cancer. Results: PD-1/PD-L1 inhibitors can induce T cell-mediated destructive thyroiditis, thyroid autoantibody-mediated autoimmunity, and a decrease in the number of immunosuppressive monocytes (circulating cluster of differentiation (CD)14+ human leukocyte antigen (HLA)-DRlow/negatives monocytes, CD14+ HLA-DR + lo/neg), leading to TD. Several factors, including peripheral blood inflammatory markers, body mass index (BMI), baseline thyroid-stimulating hormone (TSH) level, gender, smoking history, hypertension, and previous opioid use, may also contribute to the development of TD. However, there is currently a lack of reliable predictive biomarkers for TD, although anti-thyroid antibodies, TSH levels, and peripheral blood inflammatory markers are expected to be predictive.Interestingly, some studies suggested a positive correlation between TD and clinical efficacy, i.e., patients experiencing TD showed better outcomes in objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), compared with those without TD. However, most of these studies were single-center and had small sample sizes, so more multi-center studies are needed to provide further data support. Conclusion: TD resulting from PD-1/PD-L1 inhibitor treatment in advanced lung cancer may be associated with good clinical outcomes. The clarification of the molecular mechanisms underlying TD and the identification of reliable predictive biomarkers will guide clinicians in managing TD in this patient population.

AKT/FOXM1/STMN1 signaling pathway activation by SMC1A promotes tumor growth in breast cancer.

BACKGROUND: Upregulation of SMC1A (Structural maintenance of chromosomes 1A) is linked with many types of cancer and its oncogenic function, which has been associated with crucial cellular mechanisms (cell division, cell cycle checkpoints regulation and DNA repair). Recent studies have shown that SMC1A was involved in breast cancer, although the exact mechanisms of SMC1A remain to be determined. METHODS: Using The Cancer Genome Atlas (TCGA) database, we examined SMC1A expression and its relation to other genes, including FOXM1 and STMN1. Short hairpin RNA was used to subsequently examine the biological roles of SMC1A in MDA-MB-231 and MDA-MB-468 cell lines. Bioinformatics were performed to identify the SMC1A-related gene FOXM1. RESULTS: Here, we used the TCGA database to show that SMC1A is overexpressed in breast cancer. Later investigations showed SMC1A's role in breast cancer cell survival, apoptosis and invasion. Using bioinformatics and western blot assays, we confirmed that FOXM1 acted as the downstream of SMC1A, and SMC1A knockdown significantly downregulated the FOXM1 expression via the AKT signal pathway. Interestingly, the inhibition effects induced by SMC1A downregulation could be reversed by FOXM1 overexpression. In the clinic, SMC1A expression is favorably linked with FOXM1 expression in breast cancer tumor tissues. CONCLUSIONS: Collectively, our results not only enhance our knowledge of SMC1A's molecular pathways in breast cancer, but also suggest a potential new therapeutic target.

Effect of Radioactive Iodine Therapy on Cancer-Specific Survival of Papillary Thyroid Cancer Tall Cell Variant.

CONTEXT: Radioactive iodine (RAI) therapy is often used as an adjuvant treatment to reduce the risk of recurrence in patients with papillary thyroid cancer (PTC). However, the effect of RAI therapy on cancer-specific survival (CSS) in patients with tall cell variant (TCV) remains controversial. OBJECTIVE: This study aimed to investigate the impact of RAI therapy on CSS in patients with TCV-PTC by analyzing data from the Surveillance, Epidemiology, and End Results database. METHODS: We identified 1281 patients with TCV-PTC in the SEER database who underwent total thyroidectomy between 2004 and 2019. Of these, 866 (67.6%) patients received RAI therapy and 415 (32.4%) did not. Propensity score matching was conducted to balance the baseline characteristics between the 2 groups. Cox proportional hazards regression models were used to estimate the hazard ratio (HR) and 95% CI for the effect of RAI therapy on CSS. RESULTS: After propensity score matching, 373 pairs of patients were included in the analysis. The results showed no significant difference in CSS between the RAI therapy group and the non-RAI therapy group (HR 0.54, 95% CI 0.25-1.17, P = .120). Subgroup analyses indicated similar results. CONCLUSION: RAI therapy may not improve CSS in patients with TCV-PTC after total thyroidectomy. Future studies with larger sample sizes, longer follow-up periods, and better study designs are needed to confirm or refine our research findings.

Multi-Slice CT Features Predict Pathological Risk Classification in Gastric Stromal Tumors Larger Than 2 cm: A Retrospective Study.

BACKGROUND: The Armed Forces Institute of Pathology (AFIP) had higher accuracy and reliability in prognostic assessment and treatment strategies for patients with gastric stromal tumors (GSTs). The AFIP classification is frequently used in clinical applications. But the risk classification is only available for patients who are previously untreated and received complete resection. We aimed to investigate the feasibility of multi-slice MSCT features of GSTs in predicting AFIP risk classification preoperatively. METHODS: The clinical data and MSCT features of 424 patients with solitary GSTs were retrospectively reviewed. According to pathological AFIP risk criteria, 424 GSTs were divided into a low-risk group (n = 282), a moderate-risk group (n = 72), and a high-risk group (n = 70). The clinical data and MSCT features of GSTs were compared among the three groups. Those variables (p < 0.05) in the univariate analysis were included in the multivariate analysis. The nomogram was created using the rms package. RESULTS: We found significant differences in the tumor location, morphology, necrosis, ulceration, growth pattern, feeding artery, vascular-like enhancement, fat-positive signs around GSTs, CT value in the venous phase, CT value increment in the venous phase, longest diameter, and maximum short diameter (all p < 0.05). Two nomogram models were successfully constructed to predict the risk of GSTs. Low- vs. high-risk group: the independent risk factors of high-risk GSTs included the location, ulceration, and longest diameter. The area under the receiver operating characteristic curve (AUC) of the prediction model was 0.911 (95% CI: 0.872-0.951), and the sensitivity and specificity were 80.0% and 89.0%, respectively. Moderate- vs. high-risk group: the morphology, necrosis, and feeding artery were independent risk factors of a high risk of GSTs, with an AUC value of 0.826 (95% CI: 0.759-0.893), and the sensitivity and specificity were 85.7% and 70.8%, respectively. CONCLUSIONS: The MSCT features of GSTs and the nomogram model have great practical value in predicting pathological AFIP risk classification between high-risk and non-high-risk groups before surgery.

Transplantation of Chemical Compound-Induced Cells from Human Fibroblasts Improves Locomotor Recovery in a Spinal Cord Injury Rat Model.

The development of regenerative medicine using cell therapy is eagerly awaited for diseases such as spinal cord injury (SCI), for which there has been no radical cure. We previously reported the direct conversion of human fibroblasts into neuronal-like cells using only chemical compounds; however, it is unclear whether chemical compound-induced neuronal-like (CiN) cells are clinically functional. In this study, we partially modified the method of inducing CiN cells (termed immature CiN cells) and examined their therapeutic efficacy, in a rat model of SCI, to investigate whether immature CiN cells are promising for clinical applications. Motor function recovery, after SCI, was assessed using the Basso, Beattie, and Bresnahan (BBB) test, as well as the CatWalk analysis. We found that locomotor recovery, after SCI in the immature CiN cell-transplanted group, was partially improved compared to that in the control group. Consistent with these results, magnetic resonance imaging (MRI) and histopathological analyses revealed that nerve recovery or preservation improved in the immature CiN cell-transplanted group. Furthermore, transcriptome analysis revealed that immature CiN cells highly express hepatocyte growth factor (HGF), which has recently been shown to be a promising therapeutic agent against SCI. Our findings suggest that immature CiN cells may provide an alternative strategy for the regenerative therapy of SCI.

The activation of SIRT1 by resveratrol reduces breast cancer metastasis to lung through inhibiting neutrophil extracellular traps.

Neutrophil extracellular traps (NETs) play a crucial role in breast cancer metastasis. However, the therapeutic target of NETs in breast cancer metastasis is still unknown. Using a natural metabolite library and single-cell sequencing data analysis, we identified resveratrol (RES), a polyphenolic natural phytoalexin, and agonist of silent information regulator-1 (SIRT1) that suppressed NETs formation after cathepsin C (CTSC) treatment. In vivo, RES significantly hindered breast cancer metastasis in a murine orthotopic 4T1 breast cancer model. Serum levels of myeloperoxidase-DNA and neutrophil elastase-DNA in mouse breast cancer model were significantly lower after RES treatment. Correspondingly, the tumour infiltrated CD8+T cells in the lungs increased after the treatment. Mechanistically, RES targets SIRT1 in neutrophils and significantly inhibits the citrullination of histones H3, which is essential for chromatin decondensation and NETs formation. Furthermore, we identified that the NETs were suppressed by RES in bone marrow neutrophils after CTSC treatment, while specific deficiency of SIRT1 in neutrophils promoted NETs formation and breast cancer to lung metastasis. Thus, our results revealed that RES could be potentially identified as a viable therapeutic drug to prevent neutrophil cell death and breast cancer metastasis.

Isolation of new compounds related to xyloketals biosynthesis implies an alternative pathway for furan-fused-chromene formation.

In fungi, there is a rare group of natural products harboring the 2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromene skeleton, represented by xyloketal B, which display a wide range of biological activities and have drawn significant attention. In this work, four new analogues simpliketals A-D (1-4), as well as two other new compounds simplilactones A and B (5 and 6), were isolated from Simplicillium sp. AHK071-01. Their structures were elucidated by extensive NMR spectroscopic methods, 13C NMR calculation, single-crystal X-ray diffraction, and ECD calculation. In addition, five known compounds (7-11) including alboatrin (7) were also obtained. Based on the structural similarity of the above compounds, we inferred that compounds 5, 6, and 8-11 might be biosynthetically related with 1-4 and 7, which allowed us to propose an alternative biosynthetic route to generate the furan-fused chromene skeleton of this class of compounds, instead of a previously presumed polyketide-terpenoid hybrid pathway. Finally, cytotoxicity assays showed that 1-4 exhibited weak inhibitory activity on PANC-1 cells and that 2 and 3 possessed moderate activity against SH-SY5Y cells.

Expression and clinical significance of NCOA5 in epithelial ovarian cancer.

Background: Nuclear receptor coactivator 5 (NCOA5) plays a significant role in the progression of human cancer. However, its expression in epithelial ovarian cancer (EOC) is unknown. The current study was designed to explore to investigate the clinical significance of NCOA5 and its correlation with the prognosis of EOC. Methods: Immunohistochemistry was used to detect the expression of NCOA5 in 60 patients with EOC in this retrospective study and statistical analysis was performed to assess its relevance to clinicopathologic features and survival. Results: NCOA5 expression was significantly higher in EOC than in normal ovarian tissues (P < 0.001). Its expression level was significantly correlated with FIGO stage (P <0. 05) and subtypes of ovarian cancer (P < 0.001), while not correlation with age , differentiation and lymph node metastasis (P>0.05). Correlation analysis showed that NCOA5 was significantly correlated with CA125 (P < 0.001) and HE4 (P < 0.01). In a Kaplan-Meier analysis of overall survival rates, the patients with low expression of NCOA5 had significantly longer survival than high expression of NCOA5 (p=0.038). Conclusion: NCOA5 high expression is associated with EOC progression and can be an independent factor affecting the prognosis of EOC patients.

Echocardiographic evaluation of left atrial strain for predicting iron overload in pediatric patients with ß-thalassemia with preserved ejection fraction.

Pediatric patients with ß-thalassemia (ß-TM) with preserved ejection fraction may experience early myocardial damage. This prospective study aimed to investigate left atrial (LA) function restructure in pediatric patients with ß-TM by two-dimensional speckle tracking echocardiography (2D-STE) and evaluate the value of LA strain for predicting myocardial iron overload (MIO). We recruited 50 ß-TM pediatric patients and 30 healthy children aged 3-14 years. The patients were assigned to a normal left ventricular (LV) lesion group (n = 20) and an enlarged LV lesion group (n = 30). Subjects all underwent echocardiography to measure conventional cardiac function parameters and LA strain parameters. The results displayed that LA reservoir strain (LASr), conduit strain (LAScd), contractile strain (LASct) and strain rate were significantly reduced in pediatric patients with ß-TM with preserved ejection fraction. LASr, LAScd, and LASct were negatively correlated with the E/e' ratio, of which LASr had the most significant correlation (r = - 0.69, P < 0.001). LASr and LASct correlated positively with T2* (r = 0.70 and 0.62, respectively, all P < 0.001). In the multiple regression, LASr and LASct were independent predictors for T2*. The areas under the curve for LASr and LASct were 0.87 (P < 0.001) and 0.78 (P = 0.004), respectively. Our results demonstrated that LA strains were dramatically impaired in pediatric patients with ß-TM, and LASr is an efficient indicator for detecting LV early diastolic dysfunction in ß-TM pediatric patients and reflects early myocardial damage. LASr and LASct were independently predictive of MIO, but LASr was a more sensitive predictor.

Mitochondrial Energy Metabolism in the Regulation of Thermogenic Brown Fats and Human Metabolic Diseases.

Brown fats specialize in thermogenesis by increasing the utilization of circulating blood glucose and fatty acids. Emerging evidence suggests that brown adipose tissue (BAT) prevents the incidence of obesity-associated metabolic diseases and several types of cancers in humans. Mitochondrial energy metabolism in brown/beige adipocytes regulates both uncoupling protein 1 (UCP1)-dependent and -independent thermogenesis for cold adaptation and the utilization of excess nutrients and energy. Many studies on the quantification of human BAT indicate that mass and activity are inversely correlated with the body mass index (BMI) and visceral adiposity. Repression is caused by obesity-associated positive and negative factors that control adipocyte browning, de novo adipogenesis, mitochondrial energy metabolism, UCP1 expression and activity, and noradrenergic response. Systemic and local factors whose levels vary between lean and obese conditions include growth factors, inflammatory cytokines, neurotransmitters, and metal ions such as selenium and iron. Modulation of obesity-associated repression in human brown fats is a promising strategy to counteract obesity and related metabolic diseases through the activation of thermogenic capacity. In this review, we highlight recent advances in mitochondrial metabolism, thermogenic regulation of brown fats, and human metabolic diseases.

FBP1 induced by ß-elemene enhances the sensitivity of gefitinib in lung cancer.

BACKGROUND: ß-elemene is known to play a critical role in tumorigenesis as well as tyrosine kinase inhibitor (TKI) resistance in lung cancer. However, the biological function and molecular mechanism remain largely unknown. METHODS: In this study, the common genes involved in gefitinib resistance and ß-elemene were identified using bioinformatic analysis. The expression of FBP1 was examined by qRT-PCR and Western blot analysis. Cell proliferation, flow cytometry, clone formation and IC50 assays were performed to assess the effects of ß-elemene and FBP1. Western blot analysis was used to evaluate apoptosis-related gene expression. Finally, in vivo experiments were conducted to assess the crucial role of FBP1 in gefitinib-resistant HCC827/GR cells in nude mice. RESULTS: Screening analysis demonstrated that fructose-1,6-bisphosphatase (FBP1) was induced by ß-elemene and downregulated in gefitinib-resistant lung cells. Functionally, overexpression of FBP1 inhibited proliferation and gefitinib resistance and promoted apoptosis of PC9/GR and HCC827/GR cells in vitro. Mechanistically, FBP1 impeded the nuclear translocation of p-STAT3. The FBP1/STAT3 axis was required for FBP1-mediated apoptosis-related gene expression. In vivo experiments further confirmed the enhanced effects of FBP1 on lung cancer cell sensitivity to gefitinib. CONCLUSION: Our research indicated that ß-elemene suppressed proliferation and enhanced sensitivity to gefitinib by inducing apoptosis through the FBP1/STAT3 axis in gefitinib-resistant lung cancer cells.

Size-transformable gelatin/nanochitosan/doxorubicin nanoparticles with sequentially triggered drug release for anticancer therapy.

The translation of nanoparticles in cancer treatment is limited by their low drug-loading capacity, poor colloidal stability, insufficient tumor penetration, and uncontrolled drug release. Herein, gelatin/nanochitosan/doxorubicin nanoparticles (GND) are developed by crosslinking nanochitosan (NCT) with gelatin for doxorubicin delivery. The hydrophilicity and stability properties of GND allow it to be protected and have a long circulation time in blood. The GND formulation exhibited shedding and triggered release effects as well as improved colloidal stability. When reaching the tumor site, matrix metallopeptidase-2 (MMP-2) from the tumor environment degrades gelatin from 178-nm GND to release smaller 4 nm nanochitosan/doxorubicin (ND) nanoparticles for deep tumor penetration and efficient tumor cell endocytosis. Following endocytosis by tumor cells, the intracellular low pH and MMP-2 further trigger doxorubicin release, resulting in superior inhibitory capacity against cancer cells. Using a mouse tumor-bearing model, the superior anticancer activity and good in vivo biocompatibility of GND were verified. The rational design of tumor-penetrating GND enables MMP-2/pH sequentially triggered intelligent drug delivery, providing a practical approach for anticancer therapy.

GE11 Modified PLGA/TPGS Nanoparticles Targeting Delivery of Salinomycin to Breast Cancer Cells.

Salinomycin (Sal) is a potent inhibitor with effective anti-breast cancer properties in clinical therapy. The occurrence of various side effect of Sal greatly limits its application. The epidermal growth factor receptor (EGFR) family is a family of receptors highly expressed in most breast cancer cells. GE11 is a dodecapeptide which shows excellent EGFR affinity. A series of nanoparticles derivatives with GE11 peptide conjugated PLGA/TPGS were synthesized. Nanoprecipitation method was used to prepare the Sal loaded nanoparticles at the optimized concentration. The characterization, targeting efficacy, and antitumor activity were detected both in vitro and in vivo. Encapsulation of Sal in GE11 modified PLGA/TPGS nanoparticles shows an improved therapy efficacy and lower systemic side effect. This represents the delivery system a promising strategy to enhance the therapeutic effect against EGFR highly expressed breast cancer.

Transcriptome analysis reveals brown adipogenic reprogramming in chemical compound-induced brown adipocytes converted from human dermal fibroblasts.

Brown adipogenesis contributes to controlling systemic energy balance by enhancing glucose and lipid consumptions. We have previously reported chemical compound-induced brown adipocytes (ciBAs) directly converted from human dermal fibroblasts using a serum-free medium. In this study, genome-wide transcriptional analysis was performed in ciBAs in comparison with the control fibroblasts. A broad range of integrated gene expression was enhanced in functional groups including tricarboxylic acid cycle, electron transfer chain, triglycerides metabolism, fatty acid and glucose metabolism, and adaptive thermogenesis. The results suggested that the chemical conversion underwent metabolic and mitochondrial reprogramming closely associated with functions in brown/beige adipocytes. Moreover, we also compared the transcriptional changes to those of adipocyte browning in adipose tissue-derived mesenchymal stem cells (AdMSCs). Transcriptome analysis indicated that the same sets of metabolic and mitochondria-related genes were similarly changed in the adipocyte browning. Interestingly, ciBAs more expressed Ucp1, while AdMSC-derived adipocytes predominantly expressed Ucp2. UCP1 protein was also more expressed in ciBAs than in AdMSC-derived adipocytes. Based on the evidence that UCP1, but not UCP2, is responsible for adrenergic thermogenesis, ciBAs could be a promising model for human beige adipocytes applicable for basic research, drug development, and clinical uses.

Specific TP53 subtype as biomarker for immune checkpoint inhibitors in lung adenocarcinoma.

BACKGROUND: Although TP53 co-mutation with KRAS/ATM/EGFR/STK11 have been proved to have predictive value for response to immune checkpoint inhibitors (ICIs), not all TP53 mutations are equal in this context. As the main part of TP53 mutant types, Missense and Nonsense alternations in TP53 as independent factors to predict the response to ICIs within Lung Adenocarcinoma (LUAD) patients have not yet been reported. METHODS: An integrated analysis based on multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from published lung adenocarcinoma data and local database of LUAD taking immune checkpoint inhibitors. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Single-sample GSEA (GSVA) is conducted to calculate the score for enrichment of a set of genes regulating DNA damage repair (DDR) pathway. FINDINGS: The TP53-missense-mutation group showed increased PD-L1 (CD274) level and enriched IFN-γ signatures compared with the TP53-wild-type subgroup, but no differences were noted in patients with nonsense-mutant vs wild-type p53. Furthermore, a group of suppressor Immune cells like M2 Macrophage and Neutrophils are found enriched in nonsense group. On the other-side, both TP53 missense and nonsense mutations are associated with elevated TMB and neoantigen levels and contribute equally to DNA damage repair deficiency. The distribution regarding to multi-dimensional factors determining the efficacy of ICIs finally transformed into diverse clinical benefits for LUAD. TP53 missense but not -nonsense Mutants are associated with better clinical benefits taking antiPD-1/1L. However, all such TP53 subgroups responds well to nivolumab (antiPD-L1) plus ipilimumab (antiCTLA-4) therapy. INTERPRETATION: Our study demonstrated that not all TP53 mutations are equal in predicting efficacy in patients with LUAD treated with ICIs. Multi-center data showed that TP53 missense and nonsense mutations were significantly different in terms of associations with PD-L1 expression, IFN-γ signatures and TME composition. Special attention should be paid to potential TP53 mutation heterogeneity when evaluating TP53 status as biomarker for ICIs. FUNDING: The study was supported by Key Lab System Project of Guangdong Science and Technology Department - Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120, to Yi-Long WU).

Chemical compound-based direct reprogramming for future clinical applications.

Recent studies have revealed that a combination of chemical compounds enables direct reprogramming from one somatic cell type into another without the use of transgenes by regulating cellular signaling pathways and epigenetic modifications. The generation of induced pluripotent stem (iPS) cells generally requires virus vector-mediated expression of multiple transcription factors, which might disrupt genomic integrity and proper cell functions. The direct reprogramming is a promising alternative to rapidly prepare different cell types by bypassing the pluripotent state. Because the strategy also depends on forced expression of exogenous lineage-specific transcription factors, the direct reprogramming in a chemical compound-based manner is an ideal approach to further reduce the risk for tumorigenesis. So far, a number of reported research efforts have revealed that combinations of chemical compounds and cell-type specific medium transdifferentiate somatic cells into desired cell types including neuronal cells, glial cells, neural stem cells, brown adipocytes, cardiomyocytes, somatic progenitor cells, and pluripotent stem cells. These desired cells rapidly converted from patient-derived autologous fibroblasts can be applied for their own transplantation therapy to avoid immune rejection. However, complete chemical compound-induced conversions remain challenging particularly in adult human-derived fibroblasts compared with mouse embryonic fibroblasts (MEFs). This review summarizes up-to-date progress in each specific cell type and discusses prospects for future clinical application toward cell transplantation therapy.

Diagnosis related group grouping study of senile cataract patients based on E-CHAID algorithm.

AIM: To figure out the contributed factors of the hospitalization expenses of senile cataract patients (HECP) and build up an area-specified senile cataract diagnosis related group (DRG) of Shanghai thereby formulating the reference range of HECP and providing scientific basis for the fair use and supervision of the health care insurance fund. METHODS: The data was collected from the first page of the medical records of 22 097 hospitalized patients from tertiary hospitals in Shanghai from 2010 to 2012 whose major diagnosis were senile cataract. Firstly, we analyzed the influence factors of HECP using univariate and multivariate analysis. DRG grouping was conducted according to the exhaustive Chi-squared automatic interaction detector (E-CHAID) model, using HECP as target variable. Finally we evaluated the grouping results using non-parametric test such as Kruskal-Wallis H test, RIV, CV, etc. RESULTS: The 6 DRGs were established as well as criterion of HECP, using age, sex, type of surgery and whether complications/comorbidities occurred as the key variables of classification node of senile cataract cases. CONCLUSION: The grouping of senile cataract cases based on E-CHAID algorithm is reasonable. And the criterion of HECP based on DRG can provide a feasible way of management in the fair use and supervision of medical insurance fund.

Efficacy and safety of COX-2 inhibitors for advanced non-small-cell lung cancer with chemotherapy: a meta-analysis.

BACKGROUND: The study of cyclooxygenase-2 (COX-2) inhibitors is now mired in controversy. We performed a meta-analysis to assess the efficacy and safety profile of COX-2 inhibitors in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A literature search of PubMed, EMBASE, the Cochrane Central databases, and ClinicalTrials.gov, up until March 26, 2017, identified relevant randomized controlled trials. Data analysis was performed using Stata 12.0. RESULTS: Six eligible trials (1,794 patients) were selected from the 407 studies that were identified initially. A significant difference, favoring COX-2 inhibitors plus chemotherapy over chemotherapy alone, was observed in the overall response rate (relative risk [RR] =1.25, 95% confidence interval [CI]: 1.06-1.48). Further, we conducted two subgroup analyses according to the type of COX-2 inhibitors (celecoxib, rofecoxib, or apricoxib) and treatment line (first or second chemotherapy). The first-line treatment includes: NP (changchun red bean + cisplatin or carboplatin), GP (double fluorine cytidine + cisplatin or carboplatin), or TP (paclitaxel + cisplatin or carboplatin, docetaxel + cisplatin or carboplatin). The second-line treatment includes two internationally recognized compounds, one is docetaxel and the other is the pemetrexed, both of which are individually selected. In subgroup analysis, significantly increased overall response rate (ORR) results were found for rofecoxib plus chemotherapy (RR =1.56, 95% CI: 1.08-2.25) and COX-2 inhibitor given with first-line chemotherapy (RR =1.27, 95% CI: 1.07-1.50). However, there was no difference between COX-2 inhibitors plus chemotherapy and chemotherapy alone in overall survival (hazard ratio [HR] =1.04, 95% CI: 0.91-1.18), progression-free survival (HR =0.97, 95% CI: 0.86-1.10), and 1-year survival rate (RR =1.03, 95% CI: 0.89-1.20). Toxicity did not differ significantly between COX-2 inhibitors plus chemotherapy and chemotherapy alone with the exception of leukopenia (RR =1.21, 95% CI: 1.03-1.42), thrombocytopenia (RR =1.32, 95% CI: 1.04-1.67), and cardiovascular events (RR =2.39, 95% CI: 1.06-5.42). The results of the Egger's test indicated no significant difference in primary outcomes. CONCLUSION: COX-2 inhibitors improved ORR of advanced NSCLC with chemotherapy, but had no effect on survival indices. Moreover, COX-2 inhibitors may lead to higher rates of hematologic toxicities and cardiovascular events.

Direct conversion of human fibroblasts to brown adipocytes by small chemical compounds.

Brown adipocytes play an important role in human energy metabolism and prevention of obesity and diabetes. Induced pluripotent stem cells (iPSCs) represent a promising source for brown adipocytes; however, exogenous gene induction is generally required for iPSCs generation, which might cause undesired effects particularly in long-term treatment after transplantation. We have previously reported a cocktail of six small chemical compounds that enables a conversion of human fibroblasts into chemical compound-induced neuronal cells (CiNCs). Here, we report that modified combinations of the chemical compounds and rosiglitazone, a PPARγ agonist, afforded direct conversion of human fibroblasts into brown adipocytes. The chemical compound-induced brown adipocytes (ciBAs) exhibit induction of human brown adipocyte-specific genes such as Ucp1, Ckmt1, Cited1 and other adipocyte-specific genes such as Fabp4, AdipoQ, and Pparγ. Treatment with either isoproterenol or Forskolin further induced the expression of Ucp1, suggesting that ß adrenergic receptor signalling in ciBAs could be functional for induction of thermogenic genes. Moreover, oxygen consumption rates were elevated in ciBAs along with increase of cellular mitochondria. Our findings might provide an easily accessible approach for generating human brown adipocytes from fibroblasts and offer therapeutic potential for the management of obesity, diabetes, and related metabolic disorders.