In situ growth of imine-based covalent organic framework as stationary phase for open-tubular capillary electrochromatographic separation.

Designing advanced stationary phases to improve separation efficiency is essential in capillary electrochromatography. Due to their outstanding performance, covalent organic frameworks have recently demonstrated considerable promise in the field of separation science. Herein, an open-tubular capillary electrochromatography method was reported using porous imine-based covalent organic framework with sufficiently available interaction sites as stationary phase. The imine-based covalent organic framework coated capillary was easily prepared via an in situ growth method at room temperature, and its separation performance was evaluated, indicating the high separation efficiency for three types of analytes, including herbicides, polybrominated dibenzofurans, and bisphenols. Moreover, the imine-based covalent organic framework coated capillary showed good reproducibility and stability, with intraday (n = 3), interday (n = 3), and column-to-column (n = 3) relative standard deviations of retention time and peak areas of less than 5%. The separation efficiency of the coated capillary remained unchanged even after 200 runs and the maximum theoretical plates reached up to 85 595 N/m for 4,4'-ethylidenebisphenol. It was predicted that the imine-based covalent organic framework stationary phase would be a strong contender for chromatographic separation with high efficiency.

Radiomic biomarkers for platinum-refractory head and neck cancer in the era of immunotherapy.

OBJECTIVE: Immune checkpoint inhibitors (ICI) are recommended as the first-line therapy for platinum-refractory head and neck squamous cell carcinoma (HNSCC), a disease with a poor prognosis. However, biomarkers in this situation are rare. The objective was to identify radiomic features-associated biomarkers to guide the prognosis and treatment opinions in the era of ICI. METHODS: A total of 31 platinum-refractory HNSCC patients were retrospectively enrolled. Of these, 65.5% (20/31) received ICI-based therapy and 35.5% (11/31) did not. Radiomic features of the primary site at the onset of recurrent metastatic (R/M) status were extracted. Prognostic and predictive radiomic biomarkers were analysed. RESULTS: The median overall survival from R/M status (R/M OS) was 9.6 months. Grey-level co-occurrence matrix-associated texture features were the most important in identifying the patients with or without 9-month R/M death. A radiomic risk-stratification model was established and equally separated the patients into high-, intermittent- and lower-risk groups (1-year R/M death rate, 100.0% vs. 70.8% vs. 27.1%, p = 0.001). Short-run high grey-level emphasis (SRHGE) was more suitable than programmed death ligand 1 (PD-L1) expression in selecting whether patients received ICI-based therapy. CONCLUSIONS: Radiomic features were effective prognostic and predictive biomarkers. Future studies are warranted.

Colorimetric detection of alkaline phosphatase based on the off-on effect of light-responsive oxidase mimicking activity of covalent organic framework (Cu-TpBpy-COF) under near-neutral condition.

A colorimetric strategy has been developed for the detection of alkaline phosphatase (ALP) activity based on the off-on effect of the catalytic activity of light-responsive oxidase mimics covalent organic framework (Cu-TpBpy-COF) in near-neutral condition. Cu-TpBpy-COF can effectively catalyze the oxidation of the colorless substrate 3,3',5,5'-tetramethylbenzidine (TMB) by oxygen to form a blue oxidized product (oxTMB) with an absorption peak at 652 nm. Cu2+ is the active center of Cu-TpBpy-COF and pyrophosphate (PPi) can form a complex with Cu2+ to weaken the catalytic activity of Cu-TpBpy-COF. In the presence of ALP, PPi is hydrolyzed into orthophosphates (Pi) with low affinity to Cu2+, thus resulting in absorbance restoration. The absorbance at 652 nm is related to ALP activity in the linear range 10-150 U·L-1 with a detection limit of 7.17 U·L-1. The recoveries of ALP in serum samples are in the range 94.7~107.0% with relative standard deviations (RSD) lower than 5%. The decisive role of Cu2+ on the enhancing catalytic activities of Cu-TpBpy-COF in neutral condition was verified by TpBpy-COF and TpBD-COF as controls, in which the main difference between them is that TpBpy-COF contains pyridine nitrogen. Upon Cu2+ modification, Cu-TpBpy-COF has better catalytic activity than TpBpy-COF in a broader pH range because of the in situ generation of Cu+ under irradiation.

Clinical practice consensus for the diagnosis and management of melanoma in Taiwan.

Melanoma is rare in Taiwan. Asian melanoma is distinct from Western melanoma because acral and mucosal melanoma accounts for the majority of melanoma cases, leading to distinct tumor behaviors and genetic profiling. With consideration of the clinical guidelines in Western countries, Taiwanese experts developed a local clinical practice consensus guideline. This consensus includes diagnosis, staging, and surgical and systemic treatment, based only on clinical evidence, local epidemiology, and available resources evaluated by experts in Taiwan. This consensus emphasizes the importance of surgical management, particularly for sentinel lymph node biopsies. In addition, molecular testing for BRAF is mandatory for patients before systemic treatment. Furthermore, immunotherapy and targeted therapy are prioritized for systemic treatment. This consensus aimed to assist clinicians in Taiwan in diagnosing and treating patients according to available evidence.

Enhancing Targeted Therapy in Hepatocellular Carcinoma through a pH-Responsive Delivery System: Folic Acid-Modified Polydopamine-Paclitaxel-Loaded Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) Nanoparticles.

Currently, there is an inherent contradiction between the multifunctionality and excellent biocompatibility of anticancer drug nanocarriers, which limits their application. Therefore, to overcome this limitation, we aimed to develop a biocompatible drug delivery system for the treatment of hepatocellular carcinoma (HCC). In this study, we employed poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) as the fundamental framework of the nanocarrier and utilized the emulsion solvent evaporation method to fabricate nanoparticles loaded with paclitaxel (PTX), known as PTX-PHBV NPs. To enhance the tumor-targeting capability, a dopamine self-polymerization strategy was employed to form a pH-sensitive coating on the surface of the nanoparticles. Then, folic acid (FA)-targeting HCC was conjugated to the nanoparticles with a polydopamine (PDA) coating by using the Michael addition reaction, resulting in the formation of HCC-targeted nanoparticles (PTX-PHBV@PDA-FA NPs). The PTX-PHBV@PDA-FA NPs were characterized and analyzed by using dynamic light scattering, scanning electron microscopy, fourier-transform infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. Encouragingly, PTX-PHBV@PDA-FA NPs exhibited remarkable anticancer efficacy in an HCC xenograft mouse model. Furthermore, compared to raw PTX, PTX-PHBV@PDA-FA NPs showed less toxicity in vivo. In conclusion, these results demonstrate the potential of PTX-PHBV@PDA-FA NPs for HCC treatment and biocompatibility.

Effect of 8-week frequency-specific electrical muscle stimulation combined with resistance exercise training on muscle mass, strength, and body composition in men and women: a feasibility and safety study.

In recent years, electrical muscle stimulation (EMS) devices have been developed as a complementary training technique that is novel, attractive, and time-saving for physical fitness and rehabilitation. While it is known that EMS training can improve muscle mass and strength, most studies have focused on the elderly or specific patient populations. The aim of this study was to investigate the effects of frequency-specific EMS combined with resistance exercise training for 8 weeks on muscle mass, strength, power, body composition, and parameters related to exercise fatigue. Additionally, we aimed to evaluate the feasibility and safety of EMS as an exercise aid to improve body composition. We recruited 14 male and 14 female subjects who were randomly assigned to two groups with gender parity (seven male and seven female/group): (1) no EMS group (age: 21.6 ± 1.7; height: 168.8 ± 11.8 cm; weight: 64.2 ± 14.4 kg) and (2) daily EMS group (age: 21.8 ± 2.0; height: 167.8 ± 9.9 cm; weight: 68.5 ± 15.5 kg). The two groups of subjects were very similar with no significant difference. Blood biochemical routine analysis was performed every 4 weeks from pre-intervention to post-intervention, and body composition, muscle strength, and explosive power were evaluated 8 weeks before and after the intervention. We also performed an exercise challenge analysis of fatigue biochemical indicators after 8 weeks of intervention. Our results showed that resistance exercise training combined with daily EMS significantly improved muscle mass (p = 0.002) and strength (left, p = 0.007; right, p = 0.002) and significantly reduced body fat (p < 0.001) than the no EMS group. However, there was no significant advantage for biochemical parameters of fatigue and lower body power. In summary, our study demonstrates that 8 weeks of continuous resistance training combined with daily upper body, lower body, and abdominal EMS training can significantly improve muscle mass and upper body muscle strength performance, as well as significantly reduce body fat percentage in healthy subjects.

An investigation of the influence of reactive oxygen species produced from riboflavin-5'-phosphate by blue or violet light on the inhibition of WiDr colon cancer cells.

Riboflavin-5'-phosphate (FMN), an innocuous product of riboflavin (RF) phosphorylation, is vital for humans. FMN is sensitive to light illumination, as indicated by reactive oxygen species (ROS) formation. This investigation was undertaken to evaluate the influence of blue light illumination (BLI) and violet light illumination (VLI) upon FMN to develop a method to inhibit WiDr colon cancer cells by FMN photolysis. When FMN is subjected to BLI and VLI, it inhibits WiDr colon cancer cells by generating superoxide radical anions (O2•-). The respective reduction rates are 42.6 and 81.9 % in WiDr colon cancer cells for FMN treated with BLI and VLI at 20 W/m2 for 0.5 h. FMN treated with VLI inhibits WiDr colon cancer cells more effectively than BLI. Propidium iodide (PI) is a fluorescent dye that is used to detect abnormal DNA due to cell death by apoptosis or necrosis. The PI-positive count for nuclei increased significantly for the WiDr colon cancer cells that were treated with FMN under VLI at 20 W/m2 for 0.5 h. FMN photolysis achieved using VLI allows efficient photodynamic therapy (PDT) by triggering the cytotoxicity of FMN on WiDr colon cancer cells.

Enrichment of the flavonoid fraction from Eucommia ulmoides leaves by a liquid antisolvent precipitation method and evaluation of antioxidant activities in vitro and in vivo.

Eucommia ulmoides leaves originate from the dry leaves of the Eucommia ulmoides plant. Flavonoids are the main functional components of Eucommia ulmoides leaves. Some flavonoids such as rutin, kaempferol and quercetin are rich in Eucommia ulmoides, and they have outstanding antioxidant efficacy. However, the poor water solubility significantly affects the bioavailability of flavonoids. In this study, we used a liquid antisolvent precipitation (LAP) method to enrich the main flavonoid fractions in Eucommia ulmoides leaves, and prepared nanoparticles by the LAP method to increase flavonoids' solubility and antioxidant properties. The technological parameters were optimized by Box-Behnken Design (BBD) software and were displayed as follows: (1) total flavonoids (TFs) concentration: 83 mg mL-1; (2) antisolvent-solvent ratio: 11; (3) deposition temperature: 27 °C. Under optimal processing conditions, the purity and recovery rate of TFs were 88.32% ± 2.54% and 88.08% ± 2.13%, respectively. In vitro experiments showed that the radical scavenging IC50 values for DPPH, ABTS, hydroxyl radicals and superoxide anions were 16.72 ± 1.07, 10.76 ± 0.13, 227.68 ± 18.23 and 335.86 ± 15.98 µg mL-1, respectively. In vivo studies showed that the obtained purified flavonoid (PF) (100, 200, 400 mg kg-1) treatment is able to improve CCl4-induced liver and kidney damage through adjusting, superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) levels. These results demonstrated that the LAP method is capable of extracting TFs from Eucommia ulmoides leaves with high bioaccessibility.

Regulation of dendritic cell maturation in osimertinib-treated lung adenocarcinoma patients.

Osimertinib (OSI), a third-generation tyrosine kinase inhibitor (TKI), efficiently benefits lung adenocarcinoma (LUAD) patients with epidermal growth factor receptor (EGFR) mutations. However, combined OSI and immune checkpoint inhibitor in EGFR-mutant patients increases the incidence of interstitial lung disease (ILD), although the mechanism is unknown. Here, we investigated the interaction between dendritic cells (DCs), a potential critical player in ILD, and OSI. Seventeen LUAD patients received TKI therapy, and only the OSI therapy group (N = 10) showed a significant increase in CD40 and CD83 on immature DCs (iDCs), and an elevated trend for both markers on mature DCs (mDCs) during short- and long-term OSI therapy. Our results indicated that OSI therapy may potentially activate DC functions, which might increase the potential immune toxicity when combined with onco-immunotherapy.

Curcumin Induces Apoptosis of Chemoresistant Lung Cancer Cells via ROS-Regulated p38 MAPK Phosphorylation.

This study aimed to challenge chemoresistance by curcumin (CUR) with drug-selected human lung cancer A549 sublines that continuously proliferate in the present of docetaxel (DOC) and vincristine (VCR). Their sensitivities to CUR were measured by MTT assay and the particular intracellular reactive oxygen species (ROS) was detected by fluorescence activated cell sorting (FACS) analysis. Apoptosis was analyzed by Annexin V assay of the flow cytometry. Inhibitors and RNA interference were used to examine the signaling pathway regulated by the kinases. The obtained data demonstrated that CUR induces chemoresistant cell apoptosis by generating ROS and application of N-acetylcysteine (NAC) blocks ROS production, resulting in apoptosis suppression. Phosphorylation of extracellular regulated kinase (ERK), p38 MAPK, and eIF-2α were increased but c-Jun N-terminal kinase (JNK) did not increase when chemoresistant cells were treated with CUR. Downregulation of ERK and p38 MAPK phosphorylation by their inhibitors had no effect on CUR-induced apoptosis. Interestingly, the knockdown of p38 MAPK with shRNA significantly reduced CUR-induced apoptosis on the chemoresistant sublines. Phosphorylation of the eIF-2α protein was inhibited when p38 MAPK was knocked down in DOC-resistant A549 cells, but a high level of phosphorylated eIF-2α protein remained on the VCR-resistant A549 cells when p38 MAPK was knocked down. These data confirmed that CUR-augmented ROS potently induced apoptosis via upregulated p38 MAPK phosphorylation. Therefore, activated p38 MAPK is considered a pro-apoptotic signal for CUR-induced apoptosis of chemoresistant human lung cancer cells.

Electrochemical Corrosion Behavior of MIG-Welded 7N01-T4 Aluminum Alloy by ER5356 and ER5087 Welding Wires.

7N01-T4 aluminum alloy plates were welded by the metal inert gas (MIG) welding method, with ER5087 and ER5356 welding wires, respectively. The electrochemical corrosion behavior of the weld zones in the two kinds of welded joints using 3.5 wt.% and 5 wt.% NaCl solutions were investigated by polarization curve, electrochemical impedance spectroscopy (EIS), scanning electron microscope (SEM), and laser confocal scanning microscope (LCSM). The results indicated the better corrosion resistance of the weld zone in the ER5356 welded joint than that in the ER5087 welded joint, which was related to the different contents of Mn and Zn elements and the distribution of precipitates for the weld zones in the two kinds of welded joints. Based on the LSCM of the weld zones, the maximum depth (dmax) of corrosion pits for the weld zone in the ER5356 welded joint was lower than that in the ER5087 welded joint when immersed in the same NaCl concentrations. The dmax of the corrosion pit of the weld zone in the ER5356 welded joint using the 5 wt.% NaCl solution was 78.5 ± 0.96 µm, which was much bigger than that using the 3.5 wt.% NaCl solution. For the weld zone in the ER5087 welded joint with 5 wt.% NaCl solution, more Cl- was adsorbed onto the active surface of weld zones, which accelerated the corrosion, resulting in the corrosion mechanism from pitting to intergranular corrosion.

Efficacy of GMI, a fungal immunomodulatory protein, for head and neck cancer patients with chemotherapy-related oral mucositis: An open-labeled prospective single-arm study.

BACKGROUND: Cancer patients usually suffer from intensive chemotherapy-related oral mucositis (OM), yet limited effective treatment can rapidly alleviate OM severity. METHODS: This prospective study examined the efficacy of Reishimmune-S containing one fungal immunomodulatory protein, GMI on OM in patients with head and neck cancer. Patients with head and neck cancer and the diagnosis of chemotherapy-related OM were enrolled randomizedly to receive standard supportive care with/without Reishimmune-S 500 mg/day orally for consecutive 14 days. Due to intolerance to standard supportive care alone in the control arm, only the experimental arm with Reishimmune-S supplementation was analyzed in our trial. OM grading was evaluated as the primary outcome on day 1, 8, and 15. Secondary outcomes were absolute neutrophil counts and quality of life assessed by the EORTC-QLQ-H&N 35 questionnaire on day 1, 8, and 15. RESULTS: Reishimmune-S supplement significantly reduced OM grading both at day 8 and 15. Trouble with social contact and weight loss conditions were also improved by Reishimmune-S. Reishimmune-S did not significantly affect absolute neutrophil counts during the 15-day follow-up. CONCLUSION: Reishimmune-S supplement potentially alleviates the severity of chemotherapy-mediated OM.

The Trend of TIM3 Expression on T Cells in Patients With Nontuberculous Mycobacterial Lung Disease: From Immune Cell Dysfunction to Clinical Severity.

Background: The incidence of nontuberculous mycobacterial lung disease (NTM-LD) is increasing worldwide. Immune exhaustion has been reported in NTM-LD, but T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), a co-inhibitory receptor on T cells, has been scarcely studied. Methods: Patients with NTM-LD and healthy controls were prospectively recruited from July 2014 to August 2019 at three tertiary referral centers in Taiwan. We examined TIM3 expression on the T cells from the participants using flow cytometry. TIM3 expression was analyzed for different disease statuses and after treatment. The apoptosis and cytokine profiles were analyzed according to the TIM3 expression. Results: Among enrolled subjects (47 patients and 46 controls), TIM3 on CD4+ cells (6.44% vs. 4.12%, p = 0.028) and CD8+ cells (18.47% vs. 9.13%, p = 0.003) were higher in NTM-LD patients than in the controls. The TIM3 level on CD4+ and CD8+ T cells was positively associated with T-cell apoptosis in the NTM-LD patients. In stimulating peripheral blood mononuclear cells using PMA plus ionomycin, a high TIM3 level on T cells correlated with low interleukin-2 and tumor necrosis factor-alpha (TNF-α) on CD4+ cells and interferon-gamma and TNF-α on CD8+ T cells. For clinical manifestation, low body mass index (BMI), positive sputum acid-fast smear, and high radiographic score correlated with high TIM3 expression on T cells. After NTM treatment, TIM3+ decreased significantly on CD4+ and CD8+ T cells. Conclusions: In patients with NTM-LD, TIM3+ expression increased over CD4+ and CD8+ T cells and correlated with cell apoptosis and specific cytokine attenuation. Clinically, TIM3+ T cells increased in patients with low BMI, high disease extent, and high bacilli burden but decreased after treatment.

The Dynamic Change of Immune Checkpoints and CD14+ Monocytes in Latent Tuberculosis Infection.

Controlling latent tuberculosis infection (LTBI) is important for preventing tuberculosis (TB). However, the immune regulation of LTBI remains uncertain. Immune checkpoints and CD14+ monocytes are pivotal for immune defense but have been scarcely studied in LTBI. We prospectively enrolled participants with LTBI and controls from January 2017 to December 2019. We measured their CD14+ monocytes and the expression of immune checkpoints, including programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and T cell immunoglobulin mucin domain-containing-3 (TIM3) on T lymphocytes in peripheral blood mononuclear cells before and after LTBI treatment. A total of 87 subjects were enrolled, including 29 IGRA-negative healthy controls (HC), 58 in the LTBI group (19 without chronic kidney disease (non-CKD), and 39 with end-stage renal disease (ESRD)). All PD-1, CTLA-4, and TIM3 on lymphocytes and monocytes were higher in the LTBI group than that in the HC group. Total CD14+ monocytes were higher and PD-L2+CD14+ over monocytes were lower in patients with LTBI-non-CKD than that in the HC group. After LTBI treatment, CD14+ monocytes, TIM3+ on CD4+ and monocytes, and CTLA-4 on lymphocytes decreased significantly. Multivariable logistic regression indicated that CD14+ monocytes was an independent factor for LTBI-non-CKD from the HC group, whereas PD-L2+CD14+ monocytes and TIM3+ monocytes were significant for LTBI-ESRD from the HC group. In conclusion, LTBI status was associated with increasing CD14+ monocytes plus low PD-L2 expression. By contrast, increased expression of immune checkpoints over all immune cells might be due to Mycobacterium tuberculosis related immune exhaustion, which decreased after treatment.

Ultrasonic Microwave-Assisted Micelle Combined with Fungal Pretreatment of Eucommia ulmoides Leaves Significantly Improved the Extraction Efficiency of Total Flavonoids and Gutta-Percha.

A biological pretreatment of Eucommia ulmoides leaf biomass was carried out. Above all, the total flavonoids were isolated from Eucommia ulmoides leaves by the treatment of alkaline solution of sodium dodecyl benzene sulfonate combined with ultrasonic microwave. The extraction parameters were optimized by central composite design (CCD) software and were displayed as follows: surfactant concentration of 1.5%, microwave power of 700 W, extraction time of 30 min, and liquid-solid ratio of 50 mL/g. The actual yield of total flavonoids was 1.45%. The results of Sudan III color development showed that the cuticle of Eucommia ulmoides leaves was completely removed after dilute alkali pretreatment. Then, Eucommia ulmoides leaves were fermented by Trichoderma viride to remove the holocellulose and obtain gutta-percha. The content of cellulose and hemicellulose in Eucommia ulmoides leaves obviously decreased after Trichoderma viride fermentation. The optimum parameters were listed as follows: solid-liquid ratio of 0.06 g/mL, four extraction times, extraction time of 89.72 min, and extraction temperature of 85 °C. The actual yield of gutta-percha was 4.38%. The amount of extraction solvent per unit weight of gutta-percha from untreated Eucommia ulmoides leaves was 2.91 mL/mg, while that from leaves treated by Trichoderma viride was only 0.96 mL/mg. The amount of extraction solvent was grossly reduced, which is beneficial in terms of environmental protection. The characterizations of gutta-percha were verified by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and proton nuclear magnetic resonance (1H NMR). This study laid a certain theoretical and experimental basis for the multi-stage extraction of Eucommia ulmoides leaves and the utilization of Eucommia ulmoides resources.

DNA methylome and transcriptome landscapes of cancer-associated fibroblasts reveal a smoking-associated malignancy index.

Unlike the better-studied aberrant epigenome in the tumor, the clinicopathologic impact of DNA methylation in the tumor microenvironment (TME), especially the contribution from cancer-associated fibroblasts (CAFs), remains elusive. CAFs exhibit profound patient-to-patient tumorigenic heterogeneity. We asked whether such heterogeneity may be exploited to quantify the level of TME malignancy. We developed a robust and efficient methylome/transcriptome co-analytical system for CAFs and paired normal fibroblasts (NFs) from non-small-cell lung cancer patients. We found 14,781 CpG sites of CAF/NF differential methylation, of which 3,707 sites showed higher methylation changes in ever-smokers than in nonsmokers. Concomitant CAF/NF differential gene expression analysis pointed to a subset of 54 smoking-associated CpG sites with strong methylation-regulated gene expression. A methylation index that summarizes the ß values of these CpGs was built for NF/CAF discrimination (MIND) with high sensitivity and specificity. The potential of MIND in detecting premalignancy across individual patients was shown. MIND succeeded in predicting tumor recurrence in multiple lung cancer cohorts without reliance on patient survival data, suggesting that the malignancy level of TME may be effectively graded by this index. Precision TME grading may provide additional pathological information to guide cancer prognosis and open up more options in personalized medicine.

Exercise training combined with Bifidobacterium longum OLP-01 treatment regulates insulin resistance and physical performance in db/db mice.

Type 2 diabetes mellitus (T2DM) is a prevalent chronic disease characterized by hyperglycemia and insulin resistance. Regular exercise is one of the effective lifestyle interventions for maintaining healthy weight and blood glucose levels in the normal range and lowering risk factors. Probiotics, live microorganisms that are beneficial to health, are involved in the regulation of host metabolism. We thus hypothesize that the combination of exercise training and Bifidobacterium longum OLP-01 (OLP-01) could improve insulin sensitivity, blood glucose control and body composition in db/db mice. Twenty-four C57BL/6 J db/db male mice (20-weeks old) were divided into four groups (n = 6 per group): vehicle, OLP-01 supplementation (OLP-01), exercise training (EX) and exercise training with OLP-01 supplementation (EX + OLP-01). Animals in the EX and EX + OLP-01 groups underwent strength exercise training for 6 weeks, 5 days per week. After the exercise training, we tested forelimb grip strength, exhaustive running, oral glucose tolerance test (OGTT) and serum biomarkers. Results: Combined intervention of EX and OLP-01 prevented elevation of body weight and body fat. Grip strength and exhaustive swimming time were significantly higher in the EX + OLP-01 group than in the other groups. We found that EX OLP-01 reduced glycolipid parameters (fasting blood glucose and hemoglobin A1c), improved insulin sensitivity (oral glucose tolerance test and HOMA-IR), relieved liver injury parameters (aspartate aminotransferase and alanine aminotransferase) and repaired pancreas damage. Based on our findings, we speculate that the positive effects of combining EX with OLP-01 on capacity for physical activity, blood glucose control and body composition suggest an integrative approach to treating type 2 diabetes. Altogether, the combination of EX with OLP-01 treatment might be a good candidate for preventing and treating diabetes.

pH-responsive delivery vehicle based on RGD-modified polydopamine-paclitaxel-loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) nanoparticles for targeted therapy in hepatocellular carcinoma.

A limitation of current anticancer nanocarriers is the contradiction between multiple functions and favorable biocompatibility. Thus, we aimed to develop a compatible drug delivery system loaded with paclitaxel (PTX) for hepatocellular carcinoma (HCC) therapy. A basic backbone, PTX-loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) PHBV nanoparticle (PHBV-PTX-NPs), was prepared by emulsion solvent evaporation. As a gatekeeper, the pH-sensitive coating was formed by self-polymerization of dopamine (PDA). The HCC-targeted arginine-glycine-aspartic acid (RGD)-peptide and PDA-coated nanoparticles (NPs) were combined through the Michael addition. Subsequently, the physicochemical properties of RGD-PDA-PHBV-PTX-NPs were characterized by dynamic light scattering-autosizer, transmission electron microscope, fourier transform infrared spectroscopy, differential scanning calorimetry, thermogravimetry and X-ray spectroscopy. As expected, the RGD-PDA-PHBV-PTX-NPs showed robust anticancer efficacy in a xenograft mouse model. More importantly, they exhibited lower toxicity than PTX to normal hepatocytes and mouse in vitro and in vivo, respectively. Taken together, these results indicate that the RGD-PDA-PHBV-PTX-NPs are potentially beneficial for easing conflict between multifunction and biocompatible characters of nanocarriers.

Olmutinib in T790M-positive non-small cell lung cancer after failure of first-line epidermal growth factor receptor-tyrosine kinase inhibitor therapy: A global, phase 2 study.

BACKGROUND: In this open-label, international phase 2 study, the authors assessed the efficacy and safety of olmutinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had a confirmed T790M mutation and disease progression on previous epidermal growth factor receptor-tyrosine kinase inhibitor therapy. METHODS: Patients aged ≥20 years received once-daily oral olmutinib 800 mg continuously in 21-day cycles. The primary endpoint was the objective response rate (patients who had a confirmed best overall response of a complete or partial response), assessed by central review. Secondary endpoints included the disease control rate, the duration of objective response, progression-free survival, and overall survival. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). RESULTS: Overall, 162 patients (median age, 63 years; women, >60%) were enrolled from 68 sites in 9 countries. At the time of database cutoff, 23.5% of enrolled patients remained on treatment. The median treatment duration was 6.5 months (range, 0.03-21.68 months). Overall, 46.3% of patients (95% CI, 38.4%-54.3%) had a confirmed objective response (all partial responses). The best overall response (the objective response rate regardless of confirmation) was 51.9% (84 patients; 95% CI, 43.9%-59.8%). The confirmed disease control rate for all patients was 86.4% (95% CI, 80.2%-91.3%). The median duration of objective response was 12.7 months (95% CI, 8.3-15.4 months). Estimated median progression-free survival was 9.4 months (95% CI, 6.9-12.3 months), and estimated median overall survival was 19.7 months (95% CI, 15.1 months to not reached). All patients experienced treatment-emergent adverse events, and 71.6% of patients had grade ≥3 treatment-emergent adverse events. CONCLUSIONS: Olmutinib has meaningful clinical activity and a manageable safety profile in patients with T790M-positive non-small cell lung cancer who received previous epidermal growth factor receptor-tyrosine kinase inhibitor therapy.