Exosomal microRNA-140-3p from human umbilical cord mesenchymal stem cells attenuates joint injury of rats with rheumatoid arthritis by silencing SGK1.

OBJECTIVE: Over the years, microRNAs (miRNAs) have been involved in the pathogenesis of rheumatoid arthritis (RA). We aim to investigate the role of human umbilical cord mesenchymal stem cells (HUCMSCs)-derived exosomal miR-140-3p in RA development. METHODS: Exosomes(exo) were isolated from human umbilical cord-derived mesenchymal stem cells (HUCMSCs), and this isolation was followed by the transfer of miR-140-3p. RA rat models were constructed by collagen II adjuvant and respectively treated with HUCMSCs-exo or HUCMSCs-exo carrying miR-140-3p mimic/inhibitor, and expression of miR-140-3p and serum- and glucocorticoid-inducible kinase 1 (SGK1) was assessed. Then, RA score and inflammation scoring, fibrosis degree and apoptosis, serum inflammatory response and oxidative stress in joint tissues were determined. The RA synovial fibroblasts (RASFs) were extracted from rats and identified. Conducted with relative treatment, the migration, proliferation and apoptosis in RASFs were determined. RESULTS: MiR-140-3p was decreased while SGK1 was increased in RA rats. HUCMSCs-exo or upregulated exosomal miR-140-3p improved pathological changes and suppressed inflammation, oxidative stress and fibrosis in RA rats, and also constrained and RASF growth. Overexpression of SGK1 reversed the inhibition of RASF growth caused by overexpression of miR-140-3p. CONCLUSION: Upregulated exosomal miR-140-3p attenuated joint injury of RA rats by silencing SGK1. This research provided further understanding of the role of exosomal miR-140-3p in RA development.

Associations between comorbidities and annual incidence plus frequency of asthma exacerbation hospitalisation during the past year: data from CARN study.

PURPOSE: While asthma comorbidities are associated with higher health care utilisation, lower quality of life and poorer asthma control, the impact of asthma comorbidities on hospitalisation for asthma exacerbation (H-AX) remains less recognised. We aim to analyse the impact of asthma comorbidities on H-AX. METHODS: Based on a national survey on asthma control and disease perception (CARN 2015 study), we analysed the impact of comorbidities on annual incidence and frequency of H-AX in China. Information on demographic characteristics, asthma comorbidities and annual incidence and frequency of H-AX were presented in this study. RESULTS: Among 3875 ambulatory asthma patients, 75.9% (2941/3875) had comorbidities, and 26.4% (1017/3858) experienced H-AX during past year. After adjusting for confounding factors such as demographic data, smoking status and asthma control, COPD [OR = 2.189, 95% CI (1.673, 2.863)] and coronary heart disease [OR = 1.387, 95% CI (1.032, 1.864)] were associated with higher annual incidence, while allergic rhinitis [OR = 0.692, 95% CI (0.588, 0.815)] was associated with lower annual incidence, of H-AX. In terms of frequency, allergic rhinitis [OR = 1.630, 95% CI (1.214, 2.187)], COPD [OR = 1.472, 95% CI (1.021, 2.122)] and anxiety [OR = 2.609, 95% CI (1.051, 6.477)] showed statistically significant correlation with frequent H-AX. CONCLUSIONS: COPD and coronary heart disease were associated with higher annual incidence, while allergic rhinitis was associated with lower annual incidence of H-AX. Allergic rhinitis, COPD and anxiety were associated with frequent H-AX. Comorbidities may have an important role in the risk and frequency of annual hospitalisations due to asthma exacerbation. The goal of asthma control should rely on a multi-disciplinary treatment protocol.

Efficacy and safety of omalizumab in patients with moderate-to-severe asthma: An analytic comparison of data from randomized controlled trials between Chinese and Caucasians.

BACKGROUND: Omalizumab has > 15 years of real-world evidence of effectiveness in Caucasian patients. In August 2017, it was approved as an add-on therapy for the management of moderate-to-severe asthma in China. OBJECTIVE: To compare the efficacy and safety of omalizumab in Chinese and Caucasian patients. METHODS: This analysis included clinical trial data from a Chinese study (NCT01202903) and four studies with predominantly Caucasian patients (008, 009, EXTRA and INNOVATE). The following outcomes were analyzed: change from baseline in morning peak expiratory flow (mPEF), percentage predicted forced expiratory volume in one second (FEV1), patient-reported outcomes (PROs), asthma exacerbation and safety. Further, a population pharmacokinetic/pharmacodynamic (PK/PD) was also assessed. RESULTS: In the Chinese study, omalizumab significantly improved the mPEF from baseline vs placebo at Weeks > 4-8 through > 16-20; however, the change in mPEF did not reach statistical significance at Week 24. A similar trend towards improvement in mPEF was observed in the studies with Caucasians (INNOVATE, 008 and 009). In all studies, omalizumab showed greater improvement in %predicted FEV1, AQLQ score, and GETE score vs placebo. In addition, asthma symptom scores and seasonal exacerbations were lower, especially during winter, in the Chinese study, and was comparable to studies in Caucasians. PK/PD analyses showed that steady-state PK of omalizumab; free or total immunoglobulin E levels were similar in all studies. CONCLUSIONS: The clinical efficacy and safety of omalizumab was comparable among Chinese and Caucasian patients with moderate-to-severe asthma supporting therapeutic effectiveness, irrespective of race, ethnicity and geographical factors.

Bone marrow mesenchymal stem cell-derived exosomal miR-206 promotes osteoblast proliferation and differentiation in osteoarthritis by reducing Elf3.

MicroRNAs (miRNAs) serve as gene silencers involved in essential cell functions. The role of miR-206 and E74-like factor 3 (Elf3) has been identified in osteoarthritis (OA), while the effect of exosomal miR-206 from bone marrow mesenchymal stem cells (BMSCs) in OA remains largely unknown. Thus, we aim to explore the role of exosomal miR-206 from BMSCs in OA with the involvement of Elf3. BMSCs and BMSC-derived exosomes (BMSC-exos) were obtained and identified. OA mouse models were constructed by anterior cruciate ligament transection and then treated with BMSC-exos or BMSC-exos containing miR-206 mimic/inhibitor. The expression of miR-206, Elf3, inflammatory factors, osteocalcin (OCN) and bone morphogenetic protein 2 (BMP2) in mouse femoral tissues was assessed. The pathological changes in mouse femur tissues were observed. The mouse osteoblasts were identified and treated with untransfected or transfected BMSC-exos, and then, the expression of miR-206, Elf3, OCN and BMP2 was determined. The alkaline phosphatase (ALP) activity, calcium deposition level, OCN secretion, proliferation, apoptosis and cell cycle arrest in osteoblasts were measured. MiR-206 was down-regulated while Elf3 was up-regulated in OA animal and cellular models. Exosomal miR-206 ameliorated inflammation and increased expression of OCN and BMP2 in mouse femoral tissues. Moreover, exosomal miR-206 promoted ALP activity, calcium deposition level, OCN secretion and proliferation and inhibited apoptosis in OA osteoblasts. Overexpressed Elf3 reversed miR-206 up-regulation-induced effects on OA osteoblasts. BMSC-derived exosomal miR-206 promotes proliferation and differentiation of osteoblasts in OA by reducing Elf3. Our research may provide novel targets for OA treatment.

Synergistic interaction of hTGF-ß3 with hBMP-6 promotes articular cartilage formation in chitosan scaffolds with hADSCs: implications for regenerative medicine.

BACKGROUND: Human TGF-ß3 has been used in many studies to induce genes coding for typical cartilage matrix components and accelerate chondrogenic differentiation, making it the standard constituent in most cultivation media used for the assessment of chondrogenesis associated with various stem cell types on carrier matrices. However, in vivo data suggests that TGF-ß3 and its other isoforms also induce endochondral and intramembranous osteogenesis in non-primate species to other mammals. Based on previously demonstrated improved articular cartilage induction by a using hTGF-ß3 and hBMP-6 together on hADSC cultures and the interaction of TGF- ß with matrix in vivo, the present study investigates the interaction of a chitosan scaffold as polyanionic polysaccharide with both growth factors. The study analyzes the difference between chondrogenic differentiation that leads to stable hyaline cartilage and the endochondral ossification route that ends in hypertrophy by extending the usual panel of investigated gene expression and stringent employment of quantitative PCR. RESULTS: By assessing the viability, proliferation, matrix formation and gene expression patterns it is shown that hTGF-ß3 + hBMP-6 promotes improved hyaline articular cartilage formation in a chitosan scaffold in which ACAN with Col2A1 and not Col1A1 nor Col10A1 where highly expressed both at a transcriptional and translational level. Inversely, hTGF-ß3 alone tended towards endochondral bone formation showing according protein and gene expression patterns. CONCLUSION: These findings demonstrate that clinical therapies should consider using hTGF-ß3 + hBMP-6 in articular cartilage regeneration therapies as the synergistic interaction of these morphogens seems to ensure and maintain proper hyaline articular cartilage matrix formation counteracting degeneration to fibrous tissue or ossification. These effects are produced by interaction of the growth factors with the polysaccharide matrix.

Computational analysis of receptor tyrosine kinase inhibitors and cancer metabolism: implications for treatment and discovery of potential therapeutic signatures.

BACKGROUND: Receptor tyrosine kinase (RTK) inhibitors are frequently used to treat cancers and the results have been mixed, some of these small molecule drugs are highly successful while others show a more modest response. A high number of studies have been conducted to investigate the signaling mechanisms and corresponding therapeutic influence of RTK inhibitors in order to explore the therapeutic potential of RTK inhibitors. However, most of these studies neglected the potential metabolic impact of RTK inhibitors, which could be highly associated with drug efficacy and adverse effects during treatment. METHODS: In order to fill these knowledge gaps and improve the therapeutic utilization of RTK inhibitors a large-scale computational simulation/analysis over multiple types of cancers with the treatment responses of RTK inhibitors was performed. The pharmacological data of all eight RTK inhibitor and gene expression profiles of 479 cell lines from The Cancer Cell Line Encyclopedia were used. RESULTS: The potential metabolic impact of RTK inhibitors on different types of cancers were analyzed resulting in cancer-specific (breast, liver, pancreas, central nervous system) metabolic signatures. Many of these are in line with results from different independent studies, thereby providing indirect verification of the obtained results. CONCLUSIONS: Our study demonstrates the potential of using a computational approach on signature-based-analysis over multiple cancer types. The results reveal the strength of multiple-cancer analysis over conventional signature-based analysis on a single cancer type.

Induction of Articular Chondrogenesis by Chitosan/Hyaluronic-Acid-Based Biomimetic Matrices Using Human Adipose-Derived Stem Cells.

Cartilage repair using tissue engineering is the most advanced clinical application in regenerative medicine, yet available solutions remain unsuccessful in reconstructing native cartilage in its proprietary form and function. Previous investigations have suggested that the combination of specific bioactive elements combined with a natural polymer could generate carrier matrices that enhance activities of seeded stem cells and possibly induce the desired matrix formation. The present study sought to clarify this by assessing whether a chitosan-hyaluronic-acid-based biomimetic matrix in conjunction with adipose-derived stem cells could support articular hyaline cartilage formation in relation to a standard chitosan-based construct. By assessing cellular development, matrix formation, and key gene/protein expressions during in vitro cultivation utilizing quantitative gene and immunofluorescent assays, results showed that chitosan with hyaluronic acid provides a suitable environment that supports stem cell differentiation towards cartilage matrix producing chondrocytes. However, on the molecular gene expression level, it has become apparent that, without combinations of morphogens, in the chondrogenic medium, hyaluronic acid with chitosan has a very limited capacity to stimulate and maintain stem cells in an articular chondrogenic state, suggesting that cocktails of various growth factors are one of the key features to regenerate articular cartilage, clinically.

[XP gene polymorphisms and haplotypes with genetic susceptibility to lung cancer].

OBJECTIVE: To investigate the association of DNA repair gene XPB, XPD and XPG gene polymorphisms and haplotypes with genetic susceptibility to lung cancer. METHODS: A case-control study was conducted, the case group was 100 lung cancer patients in Hainan Province, while the control group was 100 cases of respiratory diseases in Hainan Province. The polymorphism of XPB gene rs4150441 and rs4150434 loci, the polymorphism of the rs171140 and rs11878544 loci of the XPD gene, the XPG gene rs4771436, and the polymorphism of the rs2094258 and rs17655 loci were detected by mass spectrometry. Halopview software was used to investigate the association between XP gene polymorphism and haplotype and genetic susceptibility to lung cancer. RESULTS: The experimental result showed that the rs4150434 locus of XPB gene, the rs4771436 locus of XPG gene and the rs2094258 locus of XPG gene were associated with the genetic susceptibility of lung cancer(P < 0. 05). Among the rs4150434 loci of XPB gene, the susceptibility of individuals carrying heterozygous GA to lung cancer was 2. 071 times than wild type GG(OR = 2. 071, 95% CI = 1. 055-4. 067). The susceptibility of individuals with mutant AA to lung cancer was 2. 535 times than wild type GG(OR =2. 535, 95%CI = 1. 063-6. 044). In the rs4771436 locus of XPG gene, the susceptibility of individuals carrying mutant GG to lung cancer was 2. 494 times than wild type TT(OR = 2. 494, 95% CI = 1. 038-5. 992). In the rs2094258 locus of XPG gene, the susceptibility of individuals carrying mutant AA to lung cancer was 3. 020 times than wild type GG(OR = 3. 020, 95%CI = 1. 015-8. 980). As haplotype result show, compared with GG haplotypes of rs4150441-rs4150434 loci in XPB gene, the risk of lung cancer in GA haplotype was 3. 643 times than GG haplotype(OR = 3. 643, 95% CI = 1. 113-11. 921). Compared with GTC haplotypes of rs2094258-rs4771436-rs17655 loci in XPG gene, the risk of lung cancer in ATC haplotype was 3. 800 times than GTC haplotype(OR = 3. 800, 95%CI = 1. 073-13. 459). CONCLUSION: XPB rs4150434, XPG rs4771436, XPG rs2094258 locus polymorphism and haplotype are associated with the genetic susceptibility to lung cancer.

The Efficacy and Safety of Once-daily Fluticasone Furoate/Umeclidinium/Vilanterol Versus Twice-daily Budesonide/Formoterol in a Subgroup of Patients from China with Symptomatic COPD at Risk of Exacerbations (FULFIL Trial).

The FULFIL study evaluated once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100 µg/62.5 µg/25 µg versus twice-daily budesonide/formoterol (BUD/FOR) 400 µg/12 µg in patients with symptomatic COPD at risk of exacerbations. FULFIL demonstrated clinically meaningful and statistically significant improvements at Week 24 in trough forced expiratory volume in 1 second (FEV1), St George's Respiratory Questionnaire (SGRQ) Total scores and reduced exacerbation frequency. Predefined analyses were performed to evaluate treatment effects in a subgroup of patients recruited in China (China subgroup; FF/UMEC/VI, n = 32; BUD/FOR, n = 29). Analyses included treatment by region (China versus non-China) to allow estimated treatment effects in patients from China to be compared with those of the non-China subgroup and the overall FULFIL intent-to-treat (ITT) population. In the China subgroup at Week 24: the mean change from baseline in trough FEV1 was 125 mL (95% confidence interval [CI] 36, 214) for FF/UMEC/VI and -70 mL (95% CI -163, 23) BUD/FOR (between-treatment difference: 195 mL [95% CI 67, 323]; p = 0.003) and in SGRQ Total score was -5.6 units (95% CI -10.5, -0.7) and -0.3 units (95% CI -5.4, 4.7), respectively (between-treatment difference: -5.3 [95% CI -12.3, 1.7]; p = 0.140). Fewer moderate/severe exacerbations occurred with FF/UMEC/VI than BUD/FOR (16% and 28%, respectively). The overall incidence of adverse events was similar between arms (FF/UMEC/VI: 38%; BUD/FOR: 31%). This prespecified subgroup analysis of patients recruited in China to FULFIL demonstrated comparable efficacy and safety to that observed in the non-China and in the overall ITT populations, for FF/UMEC/VI versus BUD/FOR.

Antibiotic drug rifabutin is effective against lung cancer cells by targeting the eIF4E-ß-catenin axis.

The essential roles of overexpression of eukaryotic translation initiation factor 4E (eIF4E) and aberrant activation of ß-catenin in lung cancer development have been recently identified. However, whether there is a direct connection between eIF4E overexpression and ß-catenin activation in lung cancer cells is unknown. In this study, we show that antibiotic drug rifabutin targets human lung cancer cells via inhibition of eIF4E-ß-catenin axis. Rifabutin is effectively against lung cancer cells in in vitro cultured cells and in vivo xenograft mouse model through inhibiting proliferation and inducing apoptosis. Mechanistically, eIF4E regulates ß-catenin activity in lung cancer cells as shown by the increased ß-catenin phosphorylation and activity in cells overexpressing eIF4E, and furthermore that the regulation is dependent on phosphorylation at S209. Rifabutin suppresses eIF4E phosphorylation, leads to decreased ß-catenin phosphorylation and its subsequent transcriptional activities. Depletion of eIF4E abolishes the inhibitory effects of rifabutin on ß-catenin activities and overexpression of ß-catenin reverses the inhibitory effects of rifabutin on cell growth and survival, further confirming that rifabutin acts on lung cancer cells via targeting eIF4E- ß-catenin axis. Our findings identify the eIF4E- ß-catenin axis as a critical regulator of lung cancer cell growth and survival, and suggest that its pharmacological inhibition may be therapeutically useful in lung cancer.

Feasibility and Safety of 2-Day Discharge After Fast-Track Total Hip Arthroplasty: A Chinese Experience.

BACKGROUND: A fast-track program (FT) can shorten hospital stay after total hip arthroplasty. The aim of this prospective randomized study was to investigate the feasibility and safety of 2-day discharge after fast-track total hip arthroplasty in a Chinese population. METHODS: A total of 258 selected patients who underwent unilateral primary total hip arthroplasty were enrolled into the final cohort and were randomized into the FT (n = 126) and standard program group (n = 132). In the FT group, the patients received a multidisciplinary FT, whereas the patients in the standard program group only followed a standard care program. After setting restricted discharge criteria, we undertook follow-up evaluations to investigate the length of hospital stay, clinical performance, 30-day and 90-day complications, and 90-day admissions in both groups. A multivariate regression model was used to assess independent predictors of delayed discharge (>2 days). RESULTS: The mean length of stay was reduced from 5.8 to 2.1 days after implementation of our FT (P < .001). Most patients in the FT group (82.5%) were discharged within 2 days postoperatively. However, the complications and readmissions appeared no difference between the two groups. The multivariate regression analysis identified age (P = .041), operative time (P < .001), intraoperative blood loss (P = .026), and total blood loss (P < .001) as the predictive factors for delayed discharge. CONCLUSION: A 2-day discharge protocol after fast-track total hip arthroplasty can be safe and feasible in selected patients, without increasing the risk of complications and readmissions. Further efforts are needed to shorten operative time and reduce perioperative blood loss and eventually to shorten hospital stay.

Effect of nitrogen and temperature on the transcription of an ACAT gene in Isochrysis galbana.

Thiolases are functionally divided into two groups: 3-ketoacyl-CoA thiolase and acetoacetyl-CoA thiolase (ACAT). Acetoacetyl-CoA thiolase plays a key role in the mevalonate pathway. In this study, a novel gene, IgACAT, which encodes ACAT was cloned from Isochrysis galbana and characterized. The cDNA of IgACAT was 1551 bp in length, consisting of an open reading frame of 1173 bp, a 5' untranslated region of 69 bp and a 3' untranslated region of 309 bp. The deduced amino acid sequence of IgACAT was 390 amino acid residues in length with a predicted molecular weight of 53.59 kDa and an isoelectric point of pH 9.04. The triterpenes content and the expression of IgACAT under nitrogen and temperature stress were analyzed. When I. galbana was treated with excessive nitrogen and at 35 °C, respectively, both the triterpenes content and the abundance of IgACAT gene transcript increased. Our findings will facilitate the regulation of gene expression and genetic modification of the triterpenes synthesis pathway of I. galbana.

Overexpression of NgAUREO1, the gene coding for aurechrome 1 from Nannochloropsis gaditana, into Saccharomyces cerevisiae leads to a 1.6-fold increase in lipid accumulation.

Aureochrome-1 (AUREO1) is a transcription factor that is induced by blue light and controls branching of Vaucheria frigida. We have cloned the gene, NgAUREO1, coding for AUREO1 from Nannochloropsis gaditana, and report that the lipid content in recombinant Saccharomyces cerevisiae was 1.6-fold more than in wild-type S. cerevisiae (6.3 % lipid increased to 10 %). Over-expression of AUREO1 in S. cerevisiae up-regulated the expression of acetyl-CoA carboxylase and acyl-CoA:diacylglycerol acyl-transferase but down-regulated the expression of long-chain-acyl CoA synthetase. This enhanced the accumulation of lipid. This study highlights a novel function of AUREO1 and allows a better understanding of the regulation mechanism of fatty acid metabolism.

Cloning, expression and stress-respondent transcription of long-chain acyl-coenzyme A synthetase cDNA gene of Nannochloropsis gaditana and its involvement in the biosynthesis of eicosapentaenoic and decosahexaenoic acids.

A novel cDNA gene, NgLACS, that encodes a long-chain acyl-CoA sythetase (LACS), was cloned from Nannochloropsis gaditana and characterized. The cDNA was 2,360 bp in length, consisting of an ORF of 1,950 bp, a 5'-untranslated region of 88 bp and a 3'-untranslated region of 322 bp. The deduced amino acid sequence of LACS was 649 amino acid residues in length with a predicted molecular weight of 71 kDa and an isoelectric point of pH 7.8. When the alga was treated with excessive nitrogen and iron, and at 15 °C, the proportion of long-chain polyunsaturated acyl-CoAs in the total acyl-CoAs and the abundance of NgLACS cDNA gene transcript were up-regulated. Over-expression of NgLACS in Saccharomyces cerevisiae caused the accumulation of eicosapentaenoic acid and docosahexaenoic acid.

The treatment of osteoporotic thoracolumbar severe burst fractures with short pedicle screw fixation and vertebroplasty.

BACKGROUND: To investigate the clinical and radiological results of short pedicle screw fixation and vertebroplasty in osteoporotic thoracolumbar severe burst fractures. METHODS: From September 2006 to August 2010, 19 consecutive patients sustained osteoporotic thoracolumbar severe burst fractures with or without neurologic deficit and were included in this prospective study. All patients underwent short pedicle screw fixation and vertebroplasty. Segmental kyphosis, AVBHr and PVBHr, and Canal compromise were calculated on radiographs pre-operatively, post-operative and at final follow up. VAS, ODI and SF-36 were calculated pre-operatively and at final follow up. RESULTS: Mean operative time was 70.8 min (range 60~100 min) and mean blood loss was 92 ml (range 60~160 ml). The mean duration of their hospital stay was 4.5 days (range 3-7 days). The operative incisions were healing well. Average follow up time was 40.1 months (range 24~72 months). The AVBHr was corrected from preoperative (48.1 ± 6.8) % to postoperative (94.1 ± 1.7) % (P < 0.001). The PVBHr was corrected from preoperative (62.7 ± 4.8) % to postoperative (92.8 ± 1.8) % (P < 0.001). Canal compromise was corrected from preoperative (37.3 ± 5.8) % to postoperative (5.9 ± 2.3) % (P < 0.001). The segmental kyphosis was corrected from preoperative (20.6 ± 5.3) degree to postoperative (2.0 ± 3.2) degree (P < 0.001). VAS scores were reduced from preoperative 7.21 ± 0.86 to 2.21 ± 0.98 at final follow up (P < 0.001). SF-36 Bodily pain was reduced from preoperative 75.31 ± 13.85 to 13.74 ± 13.24 at final follow up (P < 0.001), and SF-36 Role Physical was reduced from preoperative 59.21 ± 26.63 to 19.74 ± 22.94 at final follow up (P < 0.001). The ODI scores were reduced from preoperative 81.68 ± 4.44 to 15.37 ± 5.54 at final follow up (P < 0.001). All 4 patients with partial neurological deficit initially had improvement. Cement leakage was observed in 3 cases (two anterior to vertebral body and one into the disc without sequela). There were no instances of instrumentation failure and no patient had persistent postoperative back pain. CONCLUSIONS: Vertebroplasty and short pedicle screw fixation has the advantages of both radiographic and functional results for treating osteoporotic thoracolumbar severe burst fractures using a purely posterior approach.

Sunvozertinib for patients in China with platinum-pretreated locally advanced or metastatic non-small-cell lung cancer and EGFR exon 20 insertion mutation (WU-KONG6): single-arm, open-label, multicentre, phase 2 trial.

BACKGROUND: Sunvozertinib is an oral, irreversible, and selective tyrosine kinase inhibitor that has a favourable safety profile and encouraging antitumour activity, as shown in phase 1 studies of patients with heavily pretreated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation (exon20ins). We aimed to assess the antitumour efficacy of sunvozertinib in patients with platinum-pretreated locally advanced or metastatic NSCLC with EGFR exon20ins. METHODS: WU-KONG6 is a single-group, open-label, multicentre phase 2 trial of sunvozertinib monotherapy, conducted across 37 medical centres in China. We enrolled adult patients with pathologically or cytologically confirmed locally advanced or metastatic NSCLC whose tumour tissue carried an EGFR exon20ins mutation. All patients had received at least one line of previous systemic therapy, with at least one line containing platinum-based chemotherapy. The primary endpoint was objective response rate (ORR), as assessed by the independent review committee. The ORR was defined as the percentage of patients who achieved complete or partial response, confirmed by two separate assessments with at least 4-week time interval, until disease progression or initiation of any new anti-cancer therapy. Enrolled patients received sunvozertinib 300 mg once daily until meeting discontinuation criteria per the protocol. Patients who received at least one dose of treatment and were evaluable for efficacy analysis were included in the primary analysis, and all patients who received at least one dose of treatment were included in the safety analysis. This study is registered with ChinaDrugTrials.org, CTR20211009, and ClinicalTrials.gov, NCT05712902, and efficacy and safety follow-up are ongoing. FINDINGS: Between July 19, 2021, and May 6, 2022, 104 patients were enrolled. At data cutoff (Oct 17, 2022), the last enrolled patient had been followed up for about 6 months. Among 97 patients evaluable for efficacy analysis, 59 (61%) patients achieved tumour response, with a confirmed ORR of 61% (95% CI 50-71). All tumour responses were partial responses. Tumour responses were observed irrespective of age, sex, smoking history, EGFR exon20ins subtypes, brain metastasis at baseline, previous lines of therapy, and history of onco-immunotherapy. In total, 19 death events occurred over a median follow-up period of 7·6 months (IQR 6·1-9·4). Sunvozertinib was well tolerated at 300 mg once daily. The most common grade 3 or worse treatment-related adverse events were blood creatine phosphokinase increased (18 [17%] of 104), diarrhoea (eight [8%]), and anaemia (six [6%]). The most common serious treatment-related adverse events were interstitial lung disease (five [5%] of 104), anaemia (three [3%]), vomiting (two [2%]), nausea (two [2%]) and pneumonia (two [2%]). INTERPRETATION: In this phase 2 study, sunvozertinib demonstrated antitumour efficacy in patients with platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins, with a manageable safety profile. A multinational randomised, phase 3 study of sunvozertinib versus platinum-doublet chemotherapy in EGFR exon20ins NSCLC is ongoing (NCT05668988). FUNDING: Dizal Pharmaceutical.

A multicentre, randomised, double-blind, double-dummy, parallel-controlled, phase 3 clinical trial assessing the efficacy and safety of intravenous nemonoxacin malate versus levofloxacin for community-acquired pneumonia in adult patients.

BACKGROUND: Nemonoxacin malate is a novel non-fluorinated quinolone for oral and intravenous (IV) administration. This phase 3 multicentre, randomised, double-blind, double-dummy, parallel-controlled clinical trial (NCT02205112) evaluated the efficacy and safety of IV nemonoxacin versus levofloxacin for treatment of community-acquired pneumonia (CAP) in adult patients. METHODS: The eligible patients were randomised to receive 500 mg nemonoxacin or levofloxacin via IV infusion, once daily for 7-14 days. The primary endpoint was the clinical cure rate at test of cure (TOC) visit in the modified intent-to-treat (mITT) population. The efficacy and safety were also compared between nemonoxacin and levofloxacin in terms of secondary efficacy and safety endpoints. RESULTS: Overall, 525 patients were randomised and treated with nemonoxacin (n=349) or levofloxacin (n=176). The clinical cure rate was 91.8% (279/304) for nemonoxacin and 85.7% (138/161) for levofloxacin in the mITT population (P> 0.05). The clinical efficacy of nemonoxacin was noninferior to levofloxacin in treatment of CAP. Nemonoxacin achieved microbiological success rate of 88.8% (95/107), while levofloxacin achieved 87.8% (43/49) (P > 0.05) at TOC visit in the bacteriological mITT population. The incidence of drug-related adverse events (AEs) was 37.1% in nemonoxacin group and 22.2% in levofloxacin group, mostly local reactions at the infusion site, nausea, elevated ALT/AST, and QT interval prolongation. The nemonoxacin-related AEs were mostly mild and resolved after discontinuation of nemonoxacin. CONCLUSIONS: Nemonoxacin 500 mg IV once daily for 7-14 days is effective and safe and noninferior to levofloxacin for treating CAP in adult patients.

A multicentre clinical study on the injection of ceftriaxone/sulbactam compared with cefoperazone/sulbactam in the treatment of respiratory and urinary tract infections.

OBJECTIVE: This clinical study was designed to evaluate the efficacy and safety of this therapy in the treatment of respiratory and urinary infections caused by ceftriaxone-resistant bacteria in comparison with the effect of cefoperazone/sulbactam on cefoperazone-resistant bacteria. METHODS: A total of 285 patients aged from 18 to 65 years old, with a respiratory or urinary tract bacterial infection, were enrolled into this multicentre, open-label, controlled clinical study, and bacteria that were either ceftriaxone-resistant or cefoperazone-resistant were isolated from the patients, whose condition had not improved after three days of treatment with ceftriaxone or cefoperazone. To be selected for the study, bacterial cultures obtained from the patients had to be positive before enrolment, and all of the isolates were required to be ß-lactamase-positive. Of these patients, 253 completed the trial, and 263 were enrolled into the intention-to-treat (ITT) analysis. All of the 285 patients were included in the safety analysis. RESULTS: The cure and effective rates were 39.55% and 85.07% in the ceftriaxone/sulbactam group and 36.43% and 79.84% in the cefoperazone/sulbactam group; the bacterial eradication rates were 83.58% and 83.72%; and the adverse-event rates were 7.48% and 7.80%, respectively. There were no significant differences between the two groups (p > 0.05). CONCLUSION: Ceftriaxone/sulbactam is as effective and well-tolerated as cefoperazone/sulbactam for the treatment of intermediate and severe bacterial infections caused by resistant strains.

Efficacy and Safety of Ceftaroline Fosamil in Hospitalized Patients with Community-Acquired Pneumonia in China: Subset Analysis of an International Phase 3 Randomized Controlled Trial.

BACKGROUND: Ceftaroline fosamil has demonstrated superior clinical efficacy versus ceftriaxone for hospitalized adults with moderate-to-severe community-acquired pneumonia (CAP) in a Phase 3 trial in Asia and in a meta-analysis of three trials in Asia, North America, and Europe. Efficacy and safety outcomes for the subset of patients in China in the ASIA CAP trial were analyzed to determine if the same conclusions hold in the China subpopulation. METHODS: Hospitalized adults with Pneumonia Outcomes Research Team risk class III-IV CAP were randomized (1:1) to receive either intravenous ceftaroline fosamil 600 mg every 12 h or ceftriaxone 2 g every 24 h for 5-7 days. The primary efficacy variable was clinical response at test-of-cure (TOC) in the clinically evaluable (CE) population. Secondary endpoints included microbiological responses and safety. RESULTS: Of 302 patients randomized in China, 205 were included in the CE population. Clinical cure rates at TOC were 80/105 (76.2%) for ceftaroline fosamil and 61/100 (61.0%) for ceftriaxone (difference 15.2%, 95% CI 2.5, 27.6), thereby meeting predefined non-inferiority and superiority criteria for the overall study. Subgroup analyses of the primary endpoint demonstrated consistency of favourable efficacy of ceftaroline fosamil across age groups, Pneumonia Outcomes Research Team risk classes and CURB-65 scores. Microbiological responses were presumed from clinical outcomes. Adverse events were consistent with the study treatments' known safety profiles. CONCLUSION: The China subset results are consistent with the overall study population, despite the smaller sample size. Ceftaroline fosamil was both non-inferior and superior to ceftriaxone for empiric treatment of Chinese patients with moderate-to-severe CAP. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01371838.

Asthma Management Using the Mobile Asthma Evaluation and Management System in China.

PURPOSE: As stated in the Global Initiative for Asthma, there are still some asthmatic patients who have not achieved asthma control. Mobile is a useful tool for asthma management. We aimed to compare the advantages of mobile management with traditional management in improving adherence and control of asthma. METHODS: In this prospective, multicentre, randomized, controlled and parallel-group study, we enrolled patients with poor adherence and uncontrolled asthma at 32 hospitals in 28 provinces in China. Patients were randomly assigned to the mobile management or traditional management groups for 12 months. The primary endpoint was the proportion of patients with good adherence (Medication Adherence Report Scale for Asthma [MARS-A] score ≥ 45) for 6 months. This study is registered at ClinicalTrials.gov (NCT02917174). RESULTS: Between April 2017 and April 2018, 923 patients were eligible for randomization (mobile group, n = 461; traditional group, n = 462). Dropout was 84 (18.2%) in the mobile management group and 113 (24.4%) patients in the traditional management group. The proportion of patients with good adherence was significantly higher in the mobile management group than in the traditional management group (66.0% vs. 58.99%, P = 0.048). The mobile management group showed higher mean MARS-A score (at 1, 6, 9, and 12 months) and asthma control test scores (at 6 and 9 months), and lower total lost rate to follow-up within 12 months than the traditional management group. CONCLUSIONS: Mobile asthma management can improve adherence and asthma control compared to traditional management. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02917174.