Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin-4-IgG4-Fc in healthy subjects: A phase 1, single-centre, randomized, double-blind, dose escalation study.

AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.

Efficacy observation, complications and nursing of enteral nutrition suspension in patients with acute ischemic stroke.

OBJECTIVE: This study focuses on exploring the efficacy observation, complications and nursing aspects of using enteral nutrition suspension in patients with acute ischemic stroke. METHODS: This study retrospectively analyzed clinical data from 188 patients with acute ischemic stroke treated in the Neurology Department of our hospital from October 2022 to September 2023. Patients who received intermittent enteral nutrition and nursing interventions were included in the control group (n=96), while patients who received continuous enteral nutrition and nursing interventions were included in the treatment group (n=92). Relevant indicators data changes before and after treatment were recorded for each patient, along with the occurrence of complications in both groups, and statistical analysis was conducted. RESULTS: The treatment group had fewer days in the ICU and total hospitalization days compared to the control group, with p < .05. Patients in the treatment group had higher levels of serum albumin and serum prealbumin than those in the control group, with p < .05. The occurrence of abdominal pain, diarrhea, constipation, bloating and acid reflux in the treatment group was lower than in the control group, with p < .05. There was no significant difference in the occurrence of adverse outcomes at discharge, death at discharge, cerebral hemorrhage, lung infection and gastrointestinal bleeding between the two groups (p > .05). CONCLUSION: The application of enteral nutrition suspension in patients with acute ischemic stroke effectively provides the necessary nutrients, maintains nutritional balance, promotes tissue repair and recovery and reduces the length of hospital stay.

Rapid qualitative and quantitative detection of Salmonella typhimurium using a single-step dual photometric/fluorometric assay.

A dual-signal photometric/fluorometric assay was established for rapid, qualitative, and quantitative detection of Salmonella typhimurium (S. typhimurium). This method was composed of two parts: (1) a single-step photometric (SSC) assay containing gold nanoparticles (AuNPs), poly-diallyldimethylammonium chloride (PDDA), and S. typhimurium-specific aptamer, and (2) a fluorescence (FL) assay containing carboxyl-modified CdSe/ZnS quantum dots (QDs-COOH). Users just need to drop samples contaminated with S. typhimurium into SSC assay; the apparent color change from red to blue can be observed in a short time (20 min). A smartphone app was developed to read the semiquantitative result. By subsequently adding one drop of FL assay into the reaction mixture, the generated fluorescence intensity reflected the concentration of S. typhimurium. The naked eye limit of detection (LOD) and fluorescent LOD were 103 cfu/mL and 10 cfu/mL, respectively. This method exhibited good selectivity. The reliability and practicability were verified by testing contaminated food, drinking water, and pets' urine.

Deubiquitylation and stabilization of ARMC5 by ubiquitin-specific processing protease 7 (USP7) are critical for RCC proliferation.

The ubiquitin-proteasome system is an essential regulator of ARMC5, which serves as a new tumour suppressor protein for inhibiting meningiomas and hereditary adrenocortical tumorigenesis. However, the precise mechanism for the deubiquitination of ARMC5 is still not fully understood. A Western blot analysis of ARMC5 was performed and showed that the expression of ARMC5 was decreased in the renal cancer cell tissues and lines. By screening a deubiquitinase library, we identified USP7 as a potential ARMC5 associated deubiquitinase. In this paper, we demonstrated that there was an interaction between USP7 and ARMC5 in vivo and in vitro. Employing the overexpression and knockdown assay indicated that USP7 could greatly increase the steady state of ARMC5 through the ubiquitin-proteasome pathway and regulate ARMC5 ubiquitination. Moreover, USP7 altered cell cycle G1/S phases and regulated renal cancer cell proliferation by targeting ARMC5. Together, these results suggest that USP7 plays an important role in the RCC proliferation through modulating ARMC5 stability.

Conservation and diversification of the miR166 family in soybean and potential roles of newly identified miR166s.

BACKGROUND: microRNA166 (miR166) is a highly conserved family of miRNAs implicated in a wide range of cellular and physiological processes in plants. miR166 family generally comprises multiple miR166 members in plants, which might exhibit functional redundancy and specificity. The soybean miR166 family consists of 21 members according to the miRBase database. However, the evolutionary conservation and functional diversification of miR166 family members in soybean remain poorly understood. RESULTS: We identified five novel miR166s in soybean by data mining approach, thus enlarging the size of miR166 family from 21 to 26 members. Phylogenetic analyses of the 26 miR166s and their precursors indicated that soybean miR166 family exhibited both evolutionary conservation and diversification, and ten pairs of miR166 precursors with high sequence identity were individually grouped into a discrete clade in the phylogenetic tree. The analysis of genomic organization and evolution of MIR166 gene family revealed that eight segmental duplications and four tandem duplications might occur during evolution of the miR166 family in soybean. The cis-elements in promoters of MIR166 family genes and their putative targets pointed to their possible contributions to the functional conservation and diversification. The targets of soybean miR166s were predicted, and the cleavage of ATHB14-LIKE transcript was experimentally validated by RACE PCR. Further, the expression patterns of the five newly identified MIR166s and 12 target genes were examined during seed development and in response to abiotic stresses, which provided important clues for dissecting their functions and isoform specificity. CONCLUSION: This study enlarged the size of soybean miR166 family from 21 to 26 members, and the 26 soybean miR166s exhibited evolutionary conservation and diversification. These findings have laid a foundation for elucidating functional conservation and diversification of miR166 family members, especially during seed development or under abiotic stresses.

Recent Progress of Layered Double Hydroxide-Based Materials in Wastewater Treatment.

Layered double hydroxides (LDHs) can be used as catalysts and adsorbents due to their high stability, safety, and reusability. The preparation of modified LDHs mainly includes coprecipitation, hydrothermal, ion exchange, calcination recovery, and sol-gel methods. LDH-based materials have high anion exchange capacity, good thermal stability, and a large specific surface area, which can effectively adsorb and remove heavy metal ions, inorganic anions, organic pollutants, and oil pollutants from wastewater. Additionally, they are heterogeneous catalysts and have excellent catalytic effect in the Fenton system, persulfate-based advanced oxidation processes, and electrocatalytic system. This review ends with a discussion of the challenges and future trends of the application of LDHs in wastewater treatment.

Discourse markers in TV interviews: A corpus-based comparative study of Chinese and the western media.

This article, which is part of an on-going large-scale study, quantitatively explores and compares the frequency, patterns, and positions of the three most frequently used discourse markers (DMs): so, and, but in TV interviews. The data comprise three corpora consisting of three media programs from China, the US, and the UK. Results show that there is a statistically significant difference in the frequency of the DM so and the DM and, with each DM having the highest frequency in a specific corpus. Four co-occurring strings ("and so," "and but," "so but," "but so") are identified in the three corpora with the DM co-occurrence "and so" having the highest frequency in the American program, supporting the claim that this combination is a typical use in American English. The general positional distribution of the three DMs is similar with the highest tendency in the initial position, which can be attributed to the program's interactivity. The findings will enhance our understanding of the three DMs used in media discourse and should be of practical significance to media hosts and guests in achieving better bilateral communication.

Effects of Oxytetracycline/Lead Pollution Alone and in the Combined Form on Antibiotic Resistance Genes, Mobile Genetic Elements, and Microbial Communities in the Soil.

The application of livestock manure is the leading cause of antibiotic and heavy metal pollution in agricultural soil. However, the effects of oxytetracycline (OTC) and lead (Pb) pollution in the single or combined form on antibiotic resistance genes (ARGs) in the soil need to be further studied. This study was planned to investigate the effects of OTC and Pb application on ARGs, mobile genetic elements (MGEs), and bacterial abundance in the soil. The relative abundance of ARGs and MGEs increased by 0.31-fold and 0.03-fold after the addition of 80 mg kg-1 Pb to the soil, and by 0.49-fold and 0.03-fold after the addition of 160 mg kg-1 Pb. In addition, under the premise of the existence of OTC, the inhibitory effect of a low concentration of Pb on ARG is stronger than that of a high concentration of Pb, resulting in a lower abundance of ARGs. The abundance of ARGs and MGEs increased by 0.11-fold and 0.17-fold after the addition of OTC (30 mg kg-1) to the soil at a Pb concentration of 80 mg kg-1 and by 0.18-fold and 0.04-fold at a Pb concentration of 160 mg kg-1. The addition of OTC and Pb in the soil also decreased the many bacterial communities such as Bacteroidetes, Proteobacteria, Acidobacteria, and Firmicutes. Redundancy analysis (RDA) showed that organic matter content and pH were positively correlated with the abundance of ARGs and MGEs. At the same time, electrical conductivity (EC) had a negative correlation with the abundance of ARGs and MGEs in the soil. Intl1 was significantly associated with tetB, sul1, tetQ, sul2, and sul3. Network analysis illustrated that Actinobacteria, Bacteroidetes, and Proteobacteria were the main host bacteria causing changes in the abundance of ARGs and MGEs, and they were also predominant phylum in the culture environment. This conclusion can provide a reference for the related research of ARGs in soil.

Degradation of chloramphenicol by Ti/PbO2-La anodes and alteration in bacterial community and antibiotics resistance genes.

Antibiotics accumulation in the environment has given rise to multi-drug resistant 'superbugs' and antibiotics resistence genes (ARGs). Chloramphenicol (CAP), a kind of widely used antibiotics, was chosen as the model compound to investigate its degradation during electrochemical treatment process. The prepared Ti/PbO2-La electrodes had a denser surface and a more complete PbO2 crystal structure than Ti/PbO2 electrode. The doping of La increased the onset potential and the overpotential, increased the current value of the oxidation peak and the reduction peak, reduced the impedance, and increased the lifetime. The reactions CAP degradation and TOC removal on Ti/PbO2-La electrode was both primary kinetic reactions. CAP degradation rate increased with current density, and TOC obtained the highest removal at current density of 25 mA cm-2. The electrolyte concentration had a small effect in the range of 0.050-0.150 mol L-1. The effects under acidic and neutral conditions were better than under alkaline conditions. CAP was mainly directly oxidized at the electrode surface and indirect oxidation also took place via generated ·OH and SO4·-. 15 intermediates and 2 degradation pathways have been postulated. The entry of CAP and CAP intermediates into the environment caused the alteration in bacterial community and ARGs, while complete degradation products had little effect on them. Redundancy analysis showed that intI1 was the dominant factor affecting ARGs, and Actinobacteria and Patescibacteria were the main factors affecting the abundances of ARGs in the microbial community.

A cascade amplification strategy for ultrasensitive Salmonella typhimurium detection based on DNA walker coupling with CRISPR-Cas12a.

Salmonella typhimurium (S. typhimurium) infection is one of leading causes of severe foodborne illness, which poses grievous threats to public health. Thus, the detection with ultra-sensitivity is highly demanded for timely prevention and diagnosis of S. typhimurium. In this study, we developed a novel detection machinery based on DNA walker and CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-Cas12a technologies. Mechanistically, the S. typhimurium specific sequence triggers Nt.AlwI nicking endonuclease and produces particular signaling nucleotide, which further activates Cas12a for strong fluorescence signal output. This cascade amplification strategy exhibits excellent specificity and successfully decreases the limit of detection (LOD) of DNA walker by 2,000 folds to 5 CFU/mL. Collectively, this combinatorial approach offers great promises to effectively reduce foodborne diseases by ultrasensitive detection of S. typhimurium. As a proof of concept, this innovative design also shows prominent potential in detections of other biomolecules, cells and pathogens.

Targeting glycolysis in non-small cell lung cancer: Promises and challenges.

Metabolic disturbance, particularly of glucose metabolism, is a hallmark of tumors such as non-small cell lung cancer (NSCLC). Cancer cells tend to reprogram a majority of glucose metabolism reactions into glycolysis, even in oxygen-rich environments. Although glycolysis is not an efficient means of ATP production compared to oxidative phosphorylation, the inhibition of tumor glycolysis directly impedes cell survival and growth. This review focuses on research advances in glycolysis in NSCLC and systematically provides an overview of the key enzymes, biomarkers, non-coding RNAs, and signaling pathways that modulate the glycolysis process and, consequently, tumor growth and metastasis in NSCLC. Current medications, therapeutic approaches, and natural products that affect glycolysis in NSCLC are also summarized. We found that the identification of appropriate targets and biomarkers in glycolysis, specifically for NSCLC treatment, is still a challenge at present. However, LDHB, PDK1, MCT2, GLUT1, and PFKM might be promising targets in the treatment of NSCLC or its specific subtypes, and DPPA4, NQO1, GAPDH/MT-CO1, PGC-1α, OTUB2, ISLR, Barx2, OTUB2, and RFP180 might be prognostic predictors of NSCLC. In addition, natural products may serve as promising therapeutic approaches targeting multiple steps in glycolysis metabolism, since natural products always present multi-target properties. The development of metabolic intervention that targets glycolysis, alone or in combination with current therapy, is a potential therapeutic approach in NSCLC treatment. The aim of this review is to describe research patterns and interests concerning the metabolic treatment of NSCLC.

Biochar and Hyperthermophiles as Additives Accelerate the Removal of Antibiotic Resistance Genes and Mobile Genetic Elements during Composting.

Sewage treatment plants are known as repositories of antibiotic resistance genes (ARGs). Adding biochar and inoculating with exogenous microbial agents are common ways to improve the quality of compost. However, little is known about the effects of these exogenous additives on the fate of ARGs during composting and the related mechanisms. In this study, municipal sludge was taken as the research object to study the ARG-removal effects of four composting methods: ordinary compost (CT), compost with hyperthermophiles (HT), compost with hyperthermophiles and 2.0% biochar (HT2C) and compost with hyperthermophiles and 5.0% biochar (HT5C). Real-time quantitative PCR (qPCR) and 16S rRNA high-throughput sequencing were conducted to analyze the ARGs, MGEs and bacterial community. After composting, the abundance of ARGs in CT was reduced by 72.7%, while HT, HT2C and HT5C were reduced by 80.7%, 84.3% and 84.8%, respectively. Treatments with different proportions of biochar added (HT2C, HT5C) had no significant effect on the abundance of ARGs. Network analysis showed that Firmicutes and Nitrospirae were positively associated with most ARGs and may be potential hosts for them. In addition, redundancy analysis further showed that the class 1 integrase gene (intI1), pH and organic carbon had a greater effect on ARGs. Our findings suggested that the combination of hyperthermophiles and biochar during the composting process was an effective way to control ARGs and mobile genetic elements (MGEs), thus inhibiting the spread and diffusion of ARGs in the environment and improving the efficiency of treating human and animal diseases.

Bioinformatics and Network Pharmacology-Based Approaches to Explore the Potential Mechanism of the Antidepressant Effect of Cyperi Rhizoma through Soothing the Liver.

Major depressive disorder (MDD) has become the second most common disease worldwide, making it a threat to human health. Cyperi Rhizoma (CR) is a traditional herbal medicine with antidepressant properties. Traditional Chinese medicine theory states that CR relieves MDD by dispersing stagnated liver qi to soothe the liver, but the material basis and underlying mechanism have not been elucidated. In this study, we identified the active compounds and potential anti-MDD targets of CR by network pharmacology-based approaches. Through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, we hypothesized that the anti-MDD effect of CR may be mediated by an altered response of the liver to lipopolysaccharide (LPS) and glucose metabolism. Through bioinformatics analysis, comparing normal and MDD liver tissue in rats with spontaneous diabetes, we identified differentially expressed genes (DEGs) and selected PAI-1 (SERPINE1) as a target of CR in combating MDD. Molecular docking and molecular dynamics analysis also verified the binding of the active compound quercetin to PAI-1. It can be concluded that quercetin is the active compound of CR that acts against MDD by targeting PAI-1 to enhance the liver response to LPS and glucose metabolism. This study not only reveals the material basis and underlying mechanism of CR against MDD through soothing the liver but also provides evidence for PAI-1 as a potential target and quercetin as a potential agent for MDD treatment.

Jinfukang induces cellular apoptosis through activation of Fas and DR4 in A549 cells.

The traditional Chinese medicine Jinfukang (JFK) has been shown as a valuable drug to treat non-small cell lung cancer (NSCLC). Previously, it was reported that JFK-induced epigenetic alteration is involved in anti-lung cancer activity. In the present study, the effect of JFK on lung cancer cell lines was examined with the aim to further understand the underlying mechanisms of JFK-induced anti-lung cancer activity by transcriptome profiling analysis. JFK was observed to decrease lung cancer cell viability and simultaneously induce cellular morphology alteration. Additionally, this causes cell cycle arrest and apoptosis in A549 cells. The present RNA-seq analysis identified 5,281 genes with differential expression (P<0.05). Gene ontology analysis indicated that genes involved in the cell cycle pathway are downregulated, including cyclin-dependent kinase 2, cyclin-dependent kinase 4, cyclin B1 and cyclin A2, and apoptosis-associated genes are upregulated, including Fas, death receptor 4 (DR4), tumor protein P53 binding protein 2 and BCL2 interacting protein 3 like. Particularly, the present results indicate knockdown of Fas and DR4 attenuates JFK-induced apoptosis in A549 cells. Overall, the present study suggests JFK induces cellular apoptosis through activation of Fas and DR4 in A549 cells and provides an insight for understanding the antitumor mechanisms of this Chinese traditional medicine.

Evaluation of Bone Cancer Pain Induced by Different Doses of Walker 256 Mammary Gland Carcinoma Cells.

BACKGROUND: Cancer pain is a complex medical syndrome. Understanding its underlying mechanisms relies on the use of animal models which can mimic the human condition. A crucial component of this model is the quantity of tumor cells; however, the exact relationship between the doses of tumor cells on bone cancer pain is yet unknown. OBJECTIVE: We explored the relationship of different doses of Walker 256 carcinoma cells using a bone cancer pain model in rats, and evaluated its success and stability. STUDY DESIGN: Experimental animal study using a comparative design. SETTING: Experimental Animal Center and Tumor Institute of Traditional Chinese Medicine. METHODS: We constructed the bone cancer pain model by implanting Walker 256 carcinoma cells into the right tibia of Sprague-Dawley (SD) rats (150 - 170 g). Spontaneous pain, mechanical threshold, and paw withdrawal latency (PWL) were measured and x-ray, bone mineral density (BMD), histological, interleukin-1 beta (IL-1beta) mRNA, carboxyterminal telopeptide of type I collagen (ICTP), and bone alkaline phosphatase (BAP) were analyzed for bone pain model evaluation. RESULTS: The results showed that: (1) the 3 doses (3×105, 3.5×105, 4×105) of Walker 256 carcinoma cells can induce bone cancer pain from day 7 to day 21 after implantation into the right tibia of SD rats; (2) compared to the control group, 3×105, 3.5×105, and 4×105 Walker 256 carcinoma cells produced different pain manifestations, where the 3.5×105 dose of Walker 256 carcinoma cells resulted in the greatest bone cancer pain response; (3) the 3.5×105 dose induced the lowest mortality rate in rats; (4) Walker 256 carcinoma cells (3×105, 3.5×105, and 4×105) resulted in a significant decrease in the general condition and body weight of rats, where the 3.5×105 and 4×105 doses of carcinoma cells produced a greater effect than 3×105 dose of carcinoma cells; (5) progressive spontaneous pain, PWL, and mechanical threshold were exacerbated by 3.5×105 and 4×105 doses of carcinoma cells; (6) implantation of 3.5×105 and 4×105 doses of carcinoma cells induced progressive bone destruction and decrease in BMD; (7) ICTP and BAP were significantly increased following the implantation of 3.5×105 and 4×105 doses of carcinoma cells; (8) IL-1beta mRNA was significantly up-regulated in the spinal cord of rats implanted with 3.5×105 and 4×105 doses of carcinoma cells. LIMITATIONS: One limitation of this study was the small sample size; therefore, additional research is needed to provide better validation. Another limitation is the unavailability of small animal Micro computed tomography (CT), which is a more advanced and precise technique in determining bone marrow density than the x-ray imaging system we used. In addition, ethology experiments during late-stage tumor progression can be more objective. CONCLUSION: This study provides evidence that implantation of 3.5×105 and 4×105 dose of Walker 256 carcinoma cells produced the greatest effects in relation to the bone cancer pain model in SD rats, and 3.5×105 dose induced the lowest mortality rate. KEY WORDS: Bone cancer pain model, Walker 256 carcinoma cells, different doses.

Rapid generation of functional hepatocyte-like cells from human adipose-derived stem cells.

BACKGROUND: Liver disease is a major cause of death worldwide. Orthotropic liver transplantation (OLT) represents the only effective treatment for patients with liver failure, but the increasing demand for organs is unfortunately so great that its application is limited. Hepatocyte transplantation is a promising alternative to OLT for the treatment of some liver-based metabolic disorders or acute liver failure. Unfortunately, the lack of donor livers also makes it difficult to obtain enough viable hepatocytes for hepatocyte-based therapies. Currently, a fundamental solution to this key problem is still lacking. Here we show a novel non-transgenic protocol that facilitates the rapid generation of functional induced hepatocytes (iHeps) from human adipose-derived stem cells (hADSCs), providing a source of available cells for autologous hepatocytes to treat liver disease. METHODS: We used collagenase digestion to isolate hADSCs. The surface marker was detected by flow cytometry. The multipotential differentiation potency was detected by induction into adipocytes, osteocytes, and chondrocytes. Passage 3-7 hADSCs were induced into iHeps using an induction culture system composed of small molecule compounds and cell factors. RESULTS: Primary cultured hADSCs presented a fusiform or polygon appearance that became fibroblast-like after passage 3. More than 95 % of the cells expressed the mesenchymal cell markers CD29, CD44, CD166, CD105, and CD90. hADSCs possessed multipotential differentiation towards adipocytes, osteocytes, and chondrocytes. We rapidly induced hADSCs into iHeps within 10 days in vitro; the cellular morphology changed from fusiform to close-connected cubiform, which was similar to hepatocytes. After induction, most of the iHeps co-expressed albumin and alpha-1 antitrypsin; they also expressed mature hepatocyte special genes and achieved the basic functions of hepatocyte. Moreover, iHep transplantation could improve the liver function of acute liver-injured NPG mice and prolong life. CONCLUSIONS: We isolated highly purified hADSCs and rapidly induced them into functional hepatocyte-like cells within 10 days. These results provide a source of available cells for autologous hepatocytes to treat liver disease.

Meta-analysis comparing doublet and single cytotoxic agent therapy as first-line treatment in elderly patients with advanced nonsmall-cell lung cancer.

OBJECTIVE: To perform a systematic review and meta-analysis comparing doublet versus single agent therapy in elderly patients with advanced nonsmall-cell lung cancer (NSCLC). METHODS: PubMed® and Cochrane databases, and American Society of Clinical Oncology, World Congress of Lung Cancer, and European Society of Medical Oncology abstracts were searched. Endpoints were overall survival (OS), 1-year survival rate (1-year SR), overall response rate (ORR), and grade 3/4 adverse events. Subgroup analyses were based on chemotherapy regimens and race. RESULTS: Out of 11 studies (13 randomized trials; n = 2782), doublet therapy was associated with significantly increased OS (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.83, 0.95), 1-year SR (risk ratio [RR] 1.15, 95% CI 1.04, 1.28), and ORR (RR 1.39, 95% CI 1.39, 1.86) versus single-agents. Chemotherapy regimen-based subgroup analyses favoured platinum-based doublet therapy for OS (RR 0.71, 95% CI 0.60, 0.84), 1-year SR (RR 1.28, 95% CI 1.11, 1.47), and ORR (RR 1.88, 95% CI 1.49, 2.38). Race-based subgroup analyses revealed increased benefit from doublet therapy in Asian populations for ORR (RR 1.70, 95% CI 1.29, 2.23) but not increased survival benefit. Higher incidences of grade 3/4 anaemia (RR 2.23, 95% CI 1.61, 3.09), thrombocytopenia (RR 2.47, 95% CI 1.17, 5.20), and fatigue (RR 1.36, 95% CI 1.06, 1.74) were observed with doublet versus single-agent therapy. CONCLUSIONS: Doublet therapy was associated with significantly increased OS, 1-year SR and ORR compared with single agent therapy. Race may be considered when choosing doublet versus single-agent therapy as first-line treatment of NSCLC in elderly patients.

Rapid and high-efficiency generation of mature functional hepatocyte-like cells from adipose-derived stem cells by a three-step protocol.

The generation of functional hepatocytes is a major challenge for regenerative medicine and drug discovery. Here we show a method that facilitates generation of induced functional hepatocytes (iHeps) from adipose-derived stem cells (ADSCs) within 9 days. iHeps express hepatocytic gene programs and display functions characteristic of mature hepatocytes, including cytochrome P450 enzyme activity. Upon transplantation into mice with carbon tetrachloride (CCl4)-induced acute fulminant liver failure, iHeps restore the liver function and prolong survival. The work could contribute to the development of alternative strategies to obtain nonhepatic cell-derived mature hepatocytes with potential for biomedical and pharmaceutical applications.