In situ Transformation of Amorphous Supramolecular Coating to Hydrogen-Bonded Organic Framework Membrane to Trigger Selective Gas Permeation.

We introduce a "solution-processing-transformation" strategy, deploying solvent vapor as scaffolds, to fabricate high-quality hydrogen-bonded organic framework (HOF) membranes. This strategy can overcome the mismatch in processing conditions and crystal growth thermodynamics faced during the facile solution processing of the membrane. The procedure includes the vapor-trigged in-situ transformation of dense amorphous supramolecules to crystalline HOF-16, with HOF-11 as the transient state. The mechanism involves a vapor-activated dissolution-precipitation equilibrium shifting and hydrogen bonding-guided molecule rearrangement, elucidated through combined experimental and theoretical analysis. Upon removal of the molecular scaffolds, the resulting HOF-16 membranes showcase significant improvement in hydrogen separation performance over their amorphous counterparts and previously reported HOF membranes. The method's broad applicability is evidenced by successfully extending it to other substrates and HOF structures. This study provides a fundamental understanding of guest-induced ordered supramolecular assembly and paves the way for the advanced manufacture of high-performance HOF membranes for gas separation processes.

Hollow STW-Type Zeolite Single Crystals with Aluminum Gradient for Highly Selective Production of p-Xylene from Methanol-Toluene Alkylation.

Zeolites with uniform micropores are important shape-selective catalysts. However, the external acid sites of zeolites have a negative impact on shape-selective catalysis, and the microporosity may lead to serious diffusion limitation. Herein, we report on the direct synthesis of hierarchical hollow STW-type zeolite single crystals with a siliceous exterior. In an alkalinous fluoride medium, the nucleation of highly siliceous STW zeolites takes place first, and the nanocrystals are preferentially aligned on the outer surface of the gel agglomerates to grow into single crystalline shells upon crystallization. The lagged crystallization of the internal Al-rich amorphous gels onto the inner surface of nanocrystalline zeolite shells leads to the formation of hollow cavities in the core of the zeolite crystals. The hollow zeolite single crystals possess a low-to-high aluminum gradient from the surface to the core, resulting in an intrinsic inert external surface, and exhibit superior catalytic performance in toluene methylation reactions.

Efficacy and safety of once-weekly efpeglenatide in people with suboptimally controlled type 2 diabetes: The AMPLITUDE-D, AMPLITUDE-L and AMPLITUDE-S randomized controlled trials.

AIM: To evaluate the efficacy and safety of once-weekly (QW) efpeglenatide in people with type 2 diabetes (T2D) suboptimally controlled with oral glucose-lowering drugs and/or basal insulin (BI). MATERIALS AND METHODS: Three phase 3, multicentre, randomized controlled trials compared the efficacy and safety of QW efpeglenatide versus dulaglutide when added to metformin (AMPLITUDE-D), efpeglenatide versus placebo when added to BI ± oral glucose-lowering drugs (AMPLITUDE-L) or metformin ± sulphonylurea (AMPLITUDE-S). All trials were terminated early by the sponsor because of funding rather than safety or efficacy concerns. RESULTS: In AMPLITUDE-D, non-inferiority of efpeglenatide to dulaglutide 1.5 mg was shown in HbA1c reduction from baseline to week 56, least squares mean treatment difference (95% CI): 4 mg, -0.03% (-0.20%, 0.14%)/-0.35 mmol/mol (-2.20, 1.49); 6 mg, -0.08% (-0.25%, 0.09%)/-0.90 mmol/mol (-2.76, 0.96). The reductions in body weight (approximately 3 kg) from baseline to week 56 were similar across all treatment groups. In AMPLITUDE-L and AMPLITUDE-S, numerically greater reduction in HbA1c and body weight were observed at all doses of efpeglenatide than placebo. American Diabetes Association level 2 hypoglycaemia (< 54 mg/dL [< 3.0 mmol/L]) was reported in few participants across all treatment groups (AMPLITUDE-D, ≤ 1%; AMPLITUDE-L, ≤ 10%; and AMPLITUDE-S, ≤ 4%). The adverse events profile was consistent with other glucagon-like peptide-1 receptor agonists (GLP-1 RAs); gastrointestinal adverse events were most frequent in all three studies. CONCLUSIONS: In people with T2D suboptimally controlled with oral glucose-lowering drugs and/or BI, QW efpeglenatide was non-inferior to dulaglutide in terms of HbA1c reduction and showed numerically greater improvements than placebo in glycaemic control and body weight, with safety consistent with the GLP-1 RA class.

Multi-omics Analysis Reveals the Crucial Mediators of DJB in the Treatment of Type 2 Diabetes.

PURPOSE: Duodenal-jejunal bypass (DJB) has a definite hypoglycemic effect; however, the intrinsic mechanisms remain unclear. The purpose of this study was to determine whether DJB may cause changes in the gut microbiota and metabolite of portal venous blood and to explore the effects of DJB on blood glucose metabolism. METHODS: T2DM was induced in rats with a high-fat diet and a low dose of streptozotocin, which were randomly divided into two groups: Sham operation and DJB. RESULTS: DJB significantly improved several diabetic parameters. 16S rRNA analyses showed that the compositions of the gut microbiota were significantly different between the two groups. The results of metabolomics showed that DJB could significantly regulate the metabolites, among which diaminopimelic acid and isovaleric acid had a significant down-regulation in the DJB group. Transcriptomic analysis showed that DJB can regulate the expression of hepatic genes related to abnormal glucose metabolism, such as Ltc4s, Alox15, Ggt1, Gpat3, and Cyp2c24. Correlation analyses showed that diaminopimelic acid was positively associated with Allobaculum, Serratia, and Turicibacter. There was a significant correlation between diaminopimelic acid and Gpat3, and its Spearman correlation coefficient was the highest among metabolite-DEG pairs (ρ=0.97). DISCUSSIONS: These results suggest an important cue of the relation between the diaminopimelic acid, Gpat3, and gut microbiome in the mechanism by which DJB can improve glucose metabolism.

Stem cell-derived extracellular vesicles: A novel and potential remedy for primary ovarian insufficiency.

Primary ovarian insufficiency (POI) is an essential cause of young female fertility loss. At present, there are many treatments for primary ovarian insufficiency, but due to the complexity of the pathogenesis of primary ovarian insufficiency, the efficacy still could not be satisfactory. Stem cell transplantation is a feasible intervention protocol for primary ovarian insufficiency. However, its wide application in the clinic is limited by some defects such as tumorigenic and controversial ethical issues. Stem cell-derived extracellular vesicles (EVs) represent an important mode of intercellular communication attracting increasing interest. It is well documented that stem cell-derived extracellular vesicles for primary ovarian insufficiency with exciting therapeutic effects. Studies have found that stem cell-derived extracellular vesicles could improve ovarian reserve, increase the growth of follicles, reduce follicle atresia, and restore hormone levels of FSH and E2. Its mechanisms include inhibiting ovarian granulosa cells (GCs) apoptosis, reactive oxygen species, and inflammatory response and promoting granulosa cells proliferation and angiogenesis. Thus, stem cell-derived extracellular vesicles are a promising and potential method for primary ovarian insufficiency patients. However, stem cell-derived extracellular vesicles are still a long way from clinical translation. This review will provide an overview of the role and the mechanisms of stem cell-derived extracellular vesicles in primary ovarian insufficiency, and further elaborate on the current challenges. It may suggest new directions for future research.

METTL3-IGF2BP3-axis mediates the proliferation and migration of pancreatic cancer by regulating spermine synthase m6A modification.

Spermine synthase (SMS) is an enzyme participating in polyamine synthesis; however, its function and role in pancreatic cancer remains elusive. Here we report that SMS is upregulated in pancreatic cancer and predicts a worse overall survival and significantly promotes the proliferation and migration of pancreatic cancer cells. Excessive SMS reduces the accumulation of spermidine by converting spermidine into spermine, which activates the phosphorylation of serine/threonine kinase (AKT) and epithelial-mesenchymal transition (EMT) signaling pathway, thereby inhibiting pancreatic cancer cell proliferation and invasion. Moreover, SMS was identified as the direct target of both methyltransferase like 3 (METTL3) and insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), which directly bind to the m6A modification sites of SMS and inhibit mRNA degradation. Knockdown of METTL3 or IGF2BP3 significantly reduced the SMS protein expression and inhibited the migration of pancreatic cancer. We propose a novel regulatory mechanism in which the METTL3-IGF2BP3 axis mediates the mRNA degradation of SMS in an m6A-dependent manner to regulate spermine/spermidine conversion, which regulates AKT phosphorylation and EMT activation, thereby inducing tumor progression and migration in pancreatic cancer.

Effects of Artemisia annua L. Essential Oil on Osteoclast Differentiation and Function Induced by RANKL.

Objective: This study aimed to assess the main components of Artemisia annua L. essential oil (AEO) and determine their effect on the proliferation and differentiation of RAW264.7 cells induced by receptor activator for nuclear factor-ligand (RANKL) in vitro. Then, we tried to explain part of the function of its possible mechanisms. Materials and Methods: Essential oil was extracted from Artemisia annua L. Osteoclasts were induced in vitro by RANKL in mouse RAW264.7 cells. The experimental group was treated with different concentrations of AEO, while the control group was not treated with AEO. CCK8 was used to detect osteoclast proliferation. The osteoclasts were stained with TRAP. Western blot was used to detect protein in the MAPK pathway and the NF-κB pathway after treatment with different concentrations of AEO. RT-PCR was used to determine the expression of osteoclast-related mRNA in cells. Results: The GC-MS analysis was used to obtain the main components of AEO, including camphor, borneol, camphor, borneol, terpinen-4-ol, p-cymene, eucalyptol, deoxyartemisinin, and artemisia ketone. The CCK8 results showed that the AEO volume ratio of 1 : 4000, 1 : 5000, and 1 : 6000 did not affect the proliferation of RAW264.7 cells. However, TRAP staining showed that AEO decreased osteoclast formation. Western blot results showed that the expression of protein TRAF6, p-p38, p-ERK, p-p65, and NFATc1 decreased in the MAPK pathway and the NF-κB pathway affected by AEO. Furthermore, RT-PCR results showed that the expression of osteoclast resorption-related mRNAs (MMP-9, DC-STAMP, TRAP, and CTSK) and osteoclast differentiation-related mRNAs (OSCAR, NFATc1, c-Src, and c-Fos) also decreased in the experimental group. Conclusions: AEO inhibits osteoclast differentiation in vitro, probably by reducing TRAF6 activation, acting on the MAPK pathway and NF-κB pathway, and inhibiting the expression of osteoclast-related genes.

The Role of Preoperative Breast Reconstruction Information in Selection of Immediate Reconstruction After Modified Radical Mastectomy-A Randomized Study.

BACKGROUND: Immediate breast reconstruction has become an important supplement after modified radical mastectomy. The role of preoperative breast reconstruction information has not been widely popularized in China. It may play an important role in choosing immediate breast reconstruction. In this paper, we investigated whether there was an effect of the role of preoperative breast reconstruction information on the difference about choosing immediate breast reconstruction after modified radical mastectomy at signing the operation consent. METHODS: From 2015 January to March 2018, newly admitted 100 patients with breast carcinoma must receive modified radical mastectomy. All these patients' conditions met the requirements of immediate breast reconstruction. Patient age, breast reconstruction cognition, marital status, education, and family economics were recorded. They were randomly classified into two groups (A & B). Preoperative breast reconstruction information was designed and prepared. When it came to signing operation consent, Group A received preoperative breast reconstruction information and Group B did not receive it. We recorded whether they were willing to receive immediate breast reconstruction in different groups. RESULTS: There was no significant difference in patient age, breast reconstruction cognition, marital status, education, and family economics (P > 0.05). Thirty-two patients agreed to receive breast reconstruction and 18 patients did not agree to receive breast reconstruction in Group A when 24 patients agreed to receive breast reconstruction and 26 patients did not agree to receive breast reconstruction in Group B. There was a statistical significance (P < 0.05) between the above two groups. CONCLUSION: Preoperative breast reconstruction information may be a vital role for explaining about choosing immediate breast reconstruction after modified radical mastectomy at signing the operation consent. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

4-in-1 Fe3O4/g-C3N4@PPy-DOX nanocomposites: Magnetic targeting guided trimode combinatorial chemotherapy/PDT/PTT for cancer.

At present, cancer has become a major disease threatening human health worldwide. Therefore, developing targeting guided multimode synergetic therapy has become one of the hot spots in current antitumor research and is also a great challenge. Herein, a new Fe3O4/g-C3N4@PPy-DOX nanocomposite containing magnetic iron oxide (Fe3O4) nanoparticles (NPs), lamellar structure of graphite-like carbon nitride (g-C3N4) and polypyrrole (PPy) shell with the loaded anti-tumor drug doxorubicin hydrochloride (DOX) was designed and prepared. The monodisperse Fe3O4 nanoparticles (NPs) with the diameter of 20 nm endowed the nanocomposite with the magnetic targeting ability, reducing damage to normal tissues. It is very interesting that the Fe3O4 NPs also possessed photosensitizer function for photodynamic therapy (PDT). The g-C3N4 sheets as the photocatalysis towards the degradation of water for generating O2 could effectively improve the hypoxia of solid tumors and increase the efficiency of PDT. In addition, PPy has high light-to-heat conversion efficiency, so was chosen for the cancer photothermal therapy (PTT). Finally, an anticancer drug (DOX) was loaded on the nanocomposite because the presence of mesoporous structure. Thus, the prepared Fe3O4/g-C3N4@PPy-DOX nanocomposites exhibit synergetic chemotherapy/PTT/enhanced PDT antitumor effect. This study provides an inspiration for combining targeting and multimodality to improve the anticancer efficiency.

Micelles of Mesoporous Silica with Inserted Iron Complexes as a Platform for Constructing Efficient Electrocatalysts for Oxygen Reduction.

Iron, N-codoped carbon materials (Fe-N-C) are promising electrocatalysts toward oxygen reduction reactions due to their high atom utilization efficiency and intrinsic activity. Nanostructuring of the Fe-N-C materials, such as introducing porosity into the carbon structure, would be conducive to further increasing the exposure of active sites as well as improving the mass transfer. Herein, we explore the potential of iron complex-functionalized micelles of mesoporous SiO2 as a platform for constructing porous Fe-N-C materials. The classical three-dimensional MCM-48 was selected as a proof-of-concept example, which was utilized as the hard template, and cetyltrimethylammonium bromide micelles inside it played the role of the main carbon source. Fe-Nx sites were derived from Fe-1,10-phenanthroline complexes in the micelles introduced by in situ incorporation of 1,10-phenanthroline and post Fe2+ insertion in an aqueous solution. After thermal annealing in a nitrogen atmosphere and subsequent removal of the MCM-48 framework, a carbon material that possesses porous structural features with uniformly dispersed Fe-Nx sites (MPC@PhFe) was obtained, which shows superior ORR activity in a 0.1 M KOH solution and great potential for Zn-air battery applications as well. This work demonstrates the feasibility as well as the effectiveness of turning micelles of mesoporous SiO2 into porous carbon structures and might offer a universal strategy for manufacturing carbon materials for future application in energy storage and conversion.

Web-Based Medical Information Searching by Chinese Patients With Breast Cancer and its Influence on Survival: Observational Study.

BACKGROUND: The internet allows patients to easily look for health information. However, how Chinese patients with breast cancer use the internet has rarely been investigated, and there is a scarcity of information about the influence of internet use on survival. OBJECTIVE: This observational study aimed to investigate the details of online medical information searching by Chinese patients with breast cancer and to determine whether internet use has any survival benefits. METHODS: Patients who were diagnosed with invasive breast cancer at Peking Union Medical College Hospital between January 2014 and December 2015 were enrolled. We obtained information on their internet-searching behavior and gathered data from the patients' medical and follow-up records. The associations between internet use and other clinic-pathological factors were analyzed. A Cox proportional-hazards model and the Kaplan-Meier method were used for disease-free survival (DFS) analyses. RESULTS: A total of 973 patients with invasive breast cancer who underwent definitive surgery took part in the study. Among them, 477 cases (49.0%) performed web-based breast cancer information searching before the initial treatment. A multivariate logistic regression analysis suggested that web-based breast cancer information searching was significantly associated with younger age (odds ratio [OR] 0.95, 95% CI 0.94-0.97, P<.001), higher education level (OR 1.37, 95% CI 1.01-1.86, P=.04), and breast conserving surgery (OR 1.35, 95% CI 1.04-1.77, P=.03). Baidu (73.4%, 350/477) and WeChat (66.7%, 318/477) were the two most popular online information sources for breast cancer; however, only 44.9% (214/477) felt satisfied with the online information. In contrast to the nonweb searching group, the web-using patients who were satisfied with online information showed significantly improved DFS (hazard ratio 0.26; 95% CI 0.08-0.88, P=.03). CONCLUSIONS: The patients who were most likely to search the internet for breast cancer information were younger and well-educated, and they were more likely to have breast conserving therapy. Web-using patients who were satisfied with the internet information showed significantly improved DFS. Patients should browse credible websites offering accurate and updated information, and website developers should provide high-quality and easy-to-understand information to better meet the needs of patients with breast cancer.

Different Types of Breast Deformity Induced by Two Types of Polyacrylamide Hydrogel and Corresponding Treatment.

BACKGROUND: Polyacrylamide hydrogel (PAAG) was once used as an important injection for breast augmentation though it has been banned in China for more than 10 years. Secondary breast deformity after removing PAAG poses a challenging problem. The aim of this article is to introduce types of breast deformity induced by two types of PAAG based on MRI examination and corresponding treatment strategies. METHODS: From 2008 to 2017, 300 patients with the history of injectable PAAG were reviewed. From their medical history, two types of PAAG injections were imported Interfall and domestic Amazingel, 182 patients received Interfall injection and 118 patients received Amazingel injection. MRI was used as a regular examination preoperatively. According to MRI examinations, breast deformities were classified into nodular type, flow type and mixed type. RESULTS: All of them underwent PAAG removal operations. In the 182 patients with Interfall injection: There were only 5 cases of nodular type, 3 cases received immediate breast augmentation and 2 cases received second-stage breast augmentation, and none of cases received breast augmentation; there were 170 cases of flow type, 165 cases received immediate breast augmentation and 5 cases received second-stage breast augmentation, and none of cases received breast augmentation; there were 7 cases of mixed type, 5 cases received immediate breast augmentation, 1 case received second-stage breast augmentation and 1 case did not receive breast augmentation; in the 118 patients with Amazingel injection: There were 111 cases of nodular type, 20 cases received immediate breast augmentation, 51 cases received second-stage breast augmentation and 40 cases did not receive breast augmentation; there were 4 cases of flow type, 2 cases received immediate breast augmentation, 1 case received second-stage breast augmentation and 1 case did not receive breast augmentation; there were 2 cases of mixed type, 1 case received second-stage breast augmentation and 1 case did not receive breast augmentation, and none of cases received immediate breast augmentation . CONCLUSIONS: Breast deformity induced by two types of PAAG can be classified into three types based on MRI examinations, which is very critical for preoperative evaluation and classification. Each type of deformity has its own characteristics, which serves as a guide for whether a first-stage or a second-stage prosthesis implant can be implemented. The proportion of patients who can have breast augmentation in the first or second phase after injection of Interfall is significantly higher than that of patients who have injections of Amazingel. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Cross-Linking between Sodalite Nanoparticles and Graphene Oxide in Composite Membranes to Trigger High Gas Permeance, Selectivity, and Stability in Hydrogen Separation.

Thin membranes (900 nm) were prepared by direct transformation of infiltrated amorphous precursor nanoparticles, impregnated in a graphene oxide (GO) matrix, into hydroxy sodalite (SOD) nanocrystals. The amorphous precursor particles rich in silanols (Si-OH) enhanced the interactions with the GO, thus leading to the formation of highly adhesive and stable SOD/GO membranes via strong bonding. The cross-linking of SOD nanoparticles with the GO in the membranes promoted both the high gas permeance and enhanced selectivity towards H2 from a mixture containing CO2 and H2 O. The SOD/GO membranes are moisture resistance and exhibit steady separation performance (H2 permeance of about 4900 GPU and H2 /CO2 selectivity of 56, with no degradation in performance during the test of 50 h) at high temperature (200 °C) under water vapor (4 mol %).

Fabrication of a Hydrogen-Bonded Organic Framework Membrane through Solution Processing for Pressure-Regulated Gas Separation.

Ordered and flexible porous frameworks with solution processability are highly desirable to fabricate continuous and large-scale membranes for the efficient gas separation. Herein, the first microporous hydrogen-bonded organic framework (HOF) membrane has been fabricated by an optimized solution-processing technique. The framework exhibits the superior stability because of the abundant hydrogen bonds and strong π-π interactions. Thanks to the flexible HOF structure, the membrane possesses the unprecedented pressure-responsive H2 /N2 separation performance. Furthermore, the scratched membrane can be healed by the treatment of solvent vapor, achieving the recovery of separation performance.

Evaluation of selected traditional Chinese medical extracts for bone mineral density maintenance: A mechanistic study.

OBJECTIVE: To investigate the development of a minimal traditional Chinese medicine (TCM) formula using selected TCM ingredients and evaluating their biological activity with bone-specific in vitro tests. Finally, determining if the minimal formula can maintain bone mineral density (BMD) in a low bone mass (LBM)/osteoporosis (OP) model system. METHODS AND RESULTS: Sixteen different TCM plant extracts were tested for estrogenic, osteogenic and osteoclastic activities. Despite robust activation of the full-length estrogen receptors α and ß by Psoralea corylifolia and Epimedium brevicornu, these extracts do not activate the isolated estrogen ligand binding domains (LBD) of either ERα or ERß; estrogen (17-ß estradiol) fully activates the LBD of ERα and ERß. E. brevicornu and Drynaria fortunei extracts activated cyclic AMP response elements (CRE) individually and when combined these ingredients stimulated the production of osteoblastic markers Runx2 and Bmp4 in MC3T3-E1 cells. E. brevicornu, Salvia miltiorrhiza, and Astragalus onobrychis extracts inhibited the Il-1ß mediated activation of NF-κß and an E. brevicornu/D. fortunei combination inhibited the development of osteoclasts from precursor cells. Further, a minimal formula containing the E. brevicornu/D. fortunei combination with or without a third ingredient (S. miltiorrhiza, Angelica sinensis, or Lycium barbarum) maintained bone mineral density (BMD) similar to an estradiol-treated control group in the ovariectomized rat; a model LBM/OP system. CONCLUSION: A minimal formula consisting of TCM plant extracts that activate CRE and inhibit of NF-κß activation, but do not behave like estrogen, maintain BMD in a LBM/OP model system.

Fe3O4@MnO2@PPy nanocomposites overcome hypoxia: magnetic-targeting-assisted controlled chemotherapy and enhanced photodynamic/photothermal therapy.

Considering traditional treatment methods, such as chemotherapy, with their potential side effects and lack of targeting, photodynamic therapy (PDT) and photothermal therapy (PTT), being innovative, with less side effects, and light-controlled strategies for antitumour applications, have received extensive attention, but the efficacy of PDT is seriously hindered by the hypoxia tumour microenvironment. Here, a multifunctional nanocomposite composed of an iron oxide (Fe3O4) core and two shells of manganese dioxide (MnO2) and polypyrrole (PPy) was successfully prepared and used to solve these issues. PPy, simultaneously as the photothermal agent and photosensitizer, was first combined with MnO2 to coat magnetic Fe3O4 for achieving an increase in the intracellular O2 concentration and to improve the generation ability of singlet oxygen upon laser irradiation, so that enhanced PDT/PTT could be obtained. After the efficient loading of doxorubicin (DOX) on the Fe3O4@MnO2@PPy nanocomposite, an acid controlled-release behaviour for DOX as well as magnetic-targeting-assisted synergistic effects of chemotherapy and improved PDT/PTT for tumour cells could be realized, which could also protect normal cells from damage. All these features may render our nanocomposite a promising platform to reverse hypoxia-triggered PDT resistance and chemotherapy-caused side effects in cancer therapy and other biomedical applications.

Lixisenatide Therapy in Older Patients With Type 2 Diabetes Inadequately Controlled on Their Current Antidiabetic Treatment: The GetGoal-O Randomized Trial.

OBJECTIVE: To evaluate the efficacy and safety of lixisenatide versus placebo on glycemic control in older patients with type 2 diabetes uncontrolled on their current antidiabetic treatment. RESEARCH DESIGN AND METHODS: In this phase III, double-blind, randomized, placebo-controlled, two-arm, parallel-group, multicenter trial, patients aged ≥70 years were randomized to receive once-daily lixisenatide 20 µg or placebo before breakfast concomitantly with their existing antidiabetic therapy (including insulin) for 24 weeks. Patients at risk for malnutrition or with moderate to severe cognitive impairment were excluded. The primary end point was absolute change in HbA1c from baseline to week 24. Secondary end points included change from baseline to week 24 in 2-h postprandial plasma glucose (PPG) and body weight. RESULTS: A total of 350 patients were randomized. HbA1c decreased substantially with lixisenatide (-0.57% [6.2 mmol/mol]) compared with placebo (+0.06% [0.7 mmol/mol]) from baseline to week 24 (P < 0.0001). Mean reduction in 2-h PPG was significantly greater with lixisenatide (-5.12 mmol/L) than with placebo (-0.07 mmol/L; P < 0.0001). A greater decrease in body weight was observed with lixisenatide (-1.47 kg) versus placebo (-0.16 kg; P < 0.0001). The safety profile of lixisenatide in this older population, including rates of nausea and vomiting, was consistent with that observed in other lixisenatide studies. Hypoglycemia was reported in 17.6% of patients with lixisenatide versus 10.3% with placebo. CONCLUSIONS: In nonfrail older patients uncontrolled on their current antidiabetic treatment, lixisenatide was superior to placebo in HbA1c reduction and in targeting postprandial hyperglycemia, with no unexpected safety findings.

Efficacy and Safety of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide in Type 2 Diabetes Inadequately Controlled on Basal Insulin and Metformin: The LixiLan-L Randomized Trial.

OBJECTIVE: This study was conducted to demonstrate the efficacy and safety of LixiLan (iGlarLixi), a novel, titratable, fixed-ratio combination of insulin glargine (iGlar) (100 units) and lixisenatide, compared with iGlar in patients with type 2 diabetes inadequately controlled on basal insulin with or without up to two oral glucose-lowering agents. RESEARCH DESIGN AND METHODS: After a 6-week run-in when iGlar was introduced and/or further titrated, and oral antidiabetic drugs other than metformin were stopped, 736 basal insulin-treated patients (mean diabetes duration 12 years, BMI 31 kg/m2) were randomized 1:1 to open-label, once-daily iGlarLixi or iGlar, both titrated to fasting plasma glucose <100 mg/dL (<5.6 mmol/L) up to a maximum dose of 60 units/day. The primary outcome was change in HbA1c levels at 30 weeks. RESULTS: HbA1c decreased from 8.5% (69 mmol/mol) to 8.1% (65 mmol/mol) during the run-in period. After randomization, iGlarLixi showed greater reductions in HbA1c from baseline compared with iGlar (-1.1% vs. -0.6%, P < 0.0001), reaching a mean final HbA1c of 6.9% (52 mmol/mol) compared with 7.5% (58 mmol/mol) for iGlar. HbA1c <7.0% (53 mmol/mol) was achieved in 55% of iGlarLixi patients compared with 30% on iGlar. Mean body weight decreased by 0.7 kg with iGlarLixi and increased by 0.7 kg with iGlar (1.4 kg difference, P < 0.0001). Documented symptomatic hypoglycemia (≤70 mg/dL) was comparable between groups. Mild gastrointestinal adverse effects were very low but more frequent with iGlarLixi. CONCLUSIONS: Compared with iGlar, a substantially higher proportion of iGlarLixi-treated patients achieved glycemic targets with a beneficial effect on body weight, no additional risk of hypoglycemia, and low levels of gastrointestinal adverse effects in inadequately controlled, basal insulin-treated, long-standing type 2 diabetes.

Changes of mesenchymal stromal cells mobilization and bone turnover in an experimental bone fracture model in ovariectomized mice.

OBJECTIVE: The aim of this study was to characterize the mesenchymal stromal cells (MSCs) and endothelial progenitor cells (EPCs) mobilization, and bone turnover in osteoporotic fracture healing in ovariectomized mice. METHODS: In total, 112 female C57/BL mice were divided into two groups. The first group was sham-operated (SO), and the other group was ovariectomized (OVX). After three weeks, the right femora of the mice were fractured under anesthesia and internally fixed with steel pin. Peripheral blood and bone marrow were was collected for flow cytometry analysis, at 0 hours (h), 12 h, 24 h, 72 h and 168 h after fracture. MSCs and EPCs levels were assessed using cell surface antigens in different combinations (CD44+ CD34-CD45-, and CD34+ KDR+CD45-) by flow cytometry. At 0, 14, 28 and 42 days after fracture, sera were assayed for circulating levels of procollagen type I-N-terminal propeptide (P1NP) and C-terminal telopeptide of type I-collagen (CTX) by ELISA. Femurs were harvested at 2 weeks and 6 weeks after fracture for X-ray radiography, micro-computed tomography (micro-CT) and histology. RESULTS: Our results showed that bone marrow and peripheral blood MSCs numbers of the OVX mice were significantly lower than the SO mice, at 12 h, 24 h and 72 h after fracture. In addition, circulating P1NP and CTX levels of the OVX mice were significantly higher than the SO mice, at 2 and 4 weeks. CONCLUSION: Results of the present study revealed disorders of bone marrow MSCs mobilization and bone turnover may partially account for the delay of osteoporotic fracture healing.

[Experimental study on the mechanism of icariin improving human osteoblasts proliferation and the expression of OPG protein].

OBJECTIVE: To establish the human osteoblasts culture system in vitro, observe the effects of icariin on human osteoblasts proliferation and expression of OPG protein, and to explore the mechanism of promoting bone formation about human osteoblast in icariin. METHODS: The femoral cancellous bone pieces were obtained from the operation. The enzyme digestion method was used for culturing. The third passage of human osteoblast was taken for experiments. The cells were divided into four groups, the control group was treated with 15% NCS-DMEM-F12 (1:1), the experimental groups were respectively treated with 10(-6), 10(-8), 10(-10) mol/L icariin. The MTT method was used to observe the proliferation of human osteoblast on 1, 3, 5, 7, 9 d; in 8, 10, 12 d, western blot was used to determine the expression of OPG protein on human osteoblast. RESULTS: 1) Results of MTT: the icariin promoted the proliferation of human osteoblast. There was a concentration-response relation,while with the concentration of icariin increased, the ability was more obvious. There was statistically difference between 10(-6) mol/L icariin group (0.402 +/- 0.033) and the control group (0.268 +/- 0.031) (P<0.05). In the timely research, as the time prolong, the number of human osteoblast were more. At the fifth day, the human osteoblast entered rapid growth period, and access the growth platform stage; the icariin began to promote the proliferation of human osteoblast from the fifth day, which almost maintained to the 7th day and the 9th day, and most obvious in the 9th day. There was statistically difference between 10(-6) mol/L icariin group (0.402 +/- 0.033) and the control group (0.268 +/- 0.031) at the 9th day. (The results of OPG protein expression: in the control group, the expression of OPG protein was detected at the 8th day (1.01 +/- 0.08), and reached the expression peak (1.80 +/- 0.10), there was statistically different (P<0.05). In the different days and different concentration icariin groups, the expressions of OPG protein were all inferior to the control group. While the concentration decreasing, the expression was less. There were statistically difference (P<0.05). At the day 12, there was no significant difference of OPG protein expression between the 10(-6) mol/L icariin group and the 10(-8) mol/L icariin group (P>0.05). CONCLUSION: The effect of icariin promoting the proliferation of human osteoblast maybe is one of the mechanisms of improving the bone formation on human osteoblast.