Pharmacokinetics and pharmacodynamics of sacubitril/valsartan in peritoneal dialysis patients.

BACKGROUND: There is little information on the pharmacokinetics and pharmacodynamics of sacubitril/valsartan (SV) in patients undergoing peritoneal dialysis (PD) complicated with hypertension or heart failure (HF). This study was designed to evaluate the pharmacokinetics and pharmacodynamics of SV in PD patients with complications of hypertension or HF. METHODS: This was an open-label and cross-sectional study investigating PD patients diagnosed with hypertension or New York Heart Association Class II-IV HF. The concentrations of valsartan, sacubitril and sacubitrilat (LBQ657) were measured by ultra-performance liquid chromatography tandem mass spectrometry in plasma, urine and peritoneal dialysate samples. Pharmacodynamics were evaluated by comparing changes in mean sitting systolic blood pressure (msSBP), mean sitting diastolic blood pressure (msDBP), mean sitting heart rate, N-terminal-pro B-type natriuretic peptide (NT-proBNP) and left ventricular ejection fraction (LVEF). RESULTS: Forty patients with PD were enrolled including 27 (67.5%) patients with hypertension, 4 (10%) patients with HF and 9 (22.5%) patients with both hypertension and HF. This study included three treatment cohorts: 50 mg twice daily (BID), 100 mg once daily and 100 mg BID. The plasma maximum drug concentrations in the 100 mg BID group were 1995 ± 1499 ng/mL for valsartan, 171 ± 148 ng/mL for sacubitril and 13 686 ± 7418 ng/mL for LBQ657. The 24-h recovery rate of LBQ657 was 3.77% in urine and 2.23% in peritoneal dialysate. After taking SV, msSBP and msDBP decreased by 19.25 ± 10.32 mmHg and 10.10 ± 8.00 mmHg from baseline, respectively. NT-proBNP decreased by 1436.50 (0.00-18 198.00) from baseline, while LVEF increased by 5.00 (-0.25 to 9.25) from baseline after SV treatment. CONCLUSIONS: PD and residual renal function contributed only to a minor degree to the elimination of LBQ657. Additionally, a dose of 100 mg BID SV is safe and effective in patients with PD with complications of hypertension or HF.

The pharmacokinetics and safety of lidocaine in liver cancer patients undergoing hepatic resection.

PURPOSE: The purpose of this study was to explore the pharmacokinetics (PK) characteristics and safety of continuous lidocaine infusion during hepatectomy in liver cancer patients. METHODS: This study included thirty-five patients undergoing laparoscopic hepatectomy from January 2021 to December 2021. Patients received a short infusion of 1% lidocaine at a dose of 1.5 mg/kg based on ideal body weight, followed by a continuous infusion of 1 mg/kg/h during the operation. The plasma concentrations of lidocaine and its active metabolites were measured using validated ultra-performance liquid chromatography-tandem mass spectrometry. Safety was evaluated by monitoring and recording all adverse events (AEs). RESULTS: The concentrations of lidocaine were within the safe range, except one patient's concentration of lidocaine which reached the toxic range (> 5 µg/mL). The mean half-life (T1/2), the mean time to maximum observed concentration (Tmax), and the mean maximum observed concentration (Cmax) of lidocaine were 3.96 h, 2.85 h, and 2030 ng/mL, respectively; the mean T1/2, Tmax, and Cmax (n = 32) of MEGX were 6.59 h, 5.05 h, and 333.28 ng/mL, respectively; and the mean T1/2, Tmax, and Cmax of GX (n = 18) were 25.98 h, 7.33 h, and 75.81 ng/mL. Although eight subjects with AEs were reported, there were no serious AEs or deaths. No patients had serious postoperative complications. No deaths occurred within 30 days after the operation. CONCLUSIONS: Under the administration regimen of this study, intravenous infusion of lidocaine is safe and tolerable for liver cancer patients with laparoscopic hepatectomy. Fine safety and PK characteristics support the application of lidocaine in such patients and further clinical research. TRIAL REGISTRATION: China Clinical Trial Registration Center (ChiCTR2100042730), Registered 27 January 2021.

Toxicity and antitumor activity of novel agents in elderly patients with cancer included in phase 1 studies.

Introduction The number of cancer cases among the elderly continue to increase as the worldwide population ages. This patient subset is underrepresented in clinical trials, partly because of unresolved uncertainties about age-associated tolerabilities and antitumor activities. We reviewed phase 1 trial data to study tolerance and efficacy of novel agents used for treatment of elderly patients with cancer. Methods Data from 773 consecutive evaluable patients in 85 phase 1 clinical trials (2008-2016) at START Madrid-CIOCC were analyzed according to age, with respect to objective response, survival, and toxicity. Results The mean age was 58.7 (range: 18-87) years; 260 (33.6%) patients were >65 y (elderly group). One hundred thirty-seven (17.8%) patients received immunotherapy drugs, 308 (39.8%) received targeted agents, and 328 (42.4%) received chemotherapy. No statistically significant differences in overall survival, objective response, or severe toxicity rates were found according to treatment type. Similar toxicities and clinical activities were found between the two age subgroups; 18.8% of the elderly and 20.7% of the younger patients experienced severe hematological toxicity (p=0.5), and 30.2% and 32.7%, respectively, experienced severe non-hematological toxicity (p=0.4). Regarding antitumor activity, 12.4% of the elderly and 15% of the younger patients achieved objective responses (p=0.41). There were no significant between-group differences in overall survival (9.7 versus 11.5 months, respectively, p=0.1) or progression-free survival (2.3 versus 2.2 months, respectively, p=0.7). Conclusions This retrospective study found that elderly and younger populations had comparable antitumor activities and toxicity profiles. These results support including elderly patients with cancer in early-phase trials.

A Predictive Score of Antitumour Activity of Novel Agents in Cancer Patients Treated in Early Phase Studies.

INTRODUCTION: Phase I trials aim to determine the maximum-tolerated dose of a particular drug while minimizing the number of patients exposed to either sub-therapeutic doses or severe toxicity. Thus, patient selection for phase I trials is a key component of any clinical trial design. Though several studies have been made to address this issue, patient selection still represents a major clinical challenge that needs further investigation. METHODS: Twenty-nine baseline clinical and analytical characteristics of 773 consecutive patients treated in phase I trials between 2008 and 2016 in START Madrid-CIOCC were analysed and correlated to objective response (OR), progression-free survival, median overall survival, toxicity, and treatment type. The ones associated to OR in the univariate analysis were included in the stepwise logistic regression multivariate and Cox analysis. The statistically significant ones were included in a predictive score (named here as the Madrid score) of antitumour activity. RESULTS: Body mass index (BMI) >25 (p = 0.027), two or less previous lines of treatment (p = 0.007), and normal levels of alkaline phosphatase (ALP) (p = 0.007) were found to positively correlate to radiological response. A Madrid score was generated using these three factors as predictive parameters: compared to a score of 2-3 (where 2 or 3 of these variables are altered), a score of 0-1 is associated with longer survival time (11.6 vs. 8.6 months; p = 0.005) and overall response (17 vs. 7.6%; p = 0.003). CONCLUSION: The predictive Madrid score, based on the BMI, number of prior lines of treatment, and ALP levels, might be helpful to accurately select patients who would benefit from oncology phase I clinical trials.

Ketogenic therapy towards precision medicine for brain diseases.

Precision nutrition and nutrigenomics are emerging in the development of therapies for multiple diseases. The ketogenic diet (KD) is the most widely used clinical diet, providing high fat, low carbohydrate, and adequate protein. KD produces ketones and alters the metabolism of patients. Growing evidence suggests that KD has therapeutic effects in a wide range of neuronal diseases including epilepsy, neurodegeneration, cancer, and metabolic disorders. Although KD is considered to be a low-side-effect diet treatment, its therapeutic mechanism has not yet been fully elucidated. Also, its induced keto-response among different populations has not been elucidated. Understanding the ketone metabolism in health and disease is critical for the development of KD-associated therapeutics and synergistic therapy under any physiological background. Here, we review the current advances and known heterogeneity of the KD response and discuss the prospects for KD therapy from a precision nutrition perspective.

Safety, tolerability, and pharmacokinetic of HY0721 in Chinese healthy subjects: A first-in-human randomized, double-blind, placebo-controlled dose escalation phase I study.

BACKGROUND: HY0721 is a novel inhibitor of sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) for the treatment of acute ischemic stroke. This study aimed to evaluate the safety, tolerability, and pharmacokinetic (PK) profiles of single and multiple intravenous administration of HY0721 in Chinese healthy subjects. METHODS: The study enrolled 48 and 30 healthy volunteers in the single-ascending dose (SAD) cohort (20, 60, 120, 240, and 320 mg) and multiple-ascending dose (MAD) cohort (60, 120, and 160 mg/bid), respectively, to receive the corresponding dosage of HY0721 or placebo. Safety monitoring included but was not limited to recording adverse events (AEs), vital signs, electrocardiograms, and laboratory tests. The blood samples were collected from subjects to determine the concentrations of HY0721 for PK evaluation. RESULTS: The administration of HY0721 showed good safety and tolerability up to 320 mg in the SAD study and up to 160 mg twice daily in the MAD study. The most common AE was injection site reaction, and no AE led to discontinuation of administration or subject dropout. The exposures of HY0721 increased greater than dose proportional manner at the dosages of 20 to 320 mg in the SAD study. A linear PK profile was observed following multiple doses ranging from 60 to 160 mg twice daily, with no evidence of accumulation. Additionally, the human effective dose of HY0721 was estimated to be 120 mg. CONCLUSION: This study demonstrated the intravenous administration of HY0721 is safe and well-tolerated in Chinese healthy subjects and provided 60 to 160 mg b.i.d. as the recommended dosing range for further clinical trials. TRIAL REGISTRATION: ChinaDrugTrials.Org.cn; No. CTR20202604, 18 December 2020.

Safety, Tolerability, Pharmacokinetics, and Immunogenicity of a Novel Recombination Human Nerve Growth Factor in Healthy Chinese Subjects.

BACKGROUND: Nerve growth factor (NGF), the first-discovered member of the neurotrophin family, has long been regarded as a potential drug to combat acute and chronic neurodegenerative processes. However, the pharmacokinetic profile of NGF is poorly described. OBJECTIVES: The aim of this study was to investigate the safety, tolerability, pharmacokinetics, and immunogenicity of a novel recombinant human NGF (rhNGF) in healthy Chinese subjects. METHOD: The study randomized 48 and 36 subjects to receive (i) single-ascending dose (SAD group; 7.5, 15, 30, 45, 60, 75 µg or placebo) and (ii) multiple-ascending dose (MAD group; 15, 30, 45 µg, or placebo) rhNGF intramuscular injections, respectively. In the SAD group, all participants received rhNGF or placebo only once. In the MAD group, participants were randomly assigned to receive multiple doses of rhNGF or placebo once a day for 7 consecutive days. Adverse events (AEs) and anti-drug antibodies (ADAs) were monitored throughout the study. Recombinant human NGF serum concentrations were determined using a highly sensitive enzyme-linked immunosorbent assay. RESULTS: All AEs were mild, except for some injection-site pain and fibromyalgia, which were experienced as moderate AEs. Only one moderate AE was observed in the 15 µg cohort throughout the study and resolved within 24 hours of stopping dosing. Many participants (10% in 30 µg, 50% in 45 µg, and 50% in 60 µg in the SAD group; 10% in 15 µg, 30% in 30 µg, and 30% in 45 µg in the MAD group) experienced moderate fibromyalgia. However, all moderate fibromyalgia were resolved by the end of the subject's participation in the study. No severe AEs or clinically significant abnormalities were reported. All subjects in the 75 µg cohort experienced positive ADA in the SAD group, and one subject in the 30 µg dose and four subjects in the 45 µg dose also experienced positive ADA in the MAD group. Recombinant human nerve growth factor was absorbed (median Tmax, 4.0-5.3 h) and eliminated biexponentially (mean t1/2, 4.53-6.09 h) with a moderate speed. The Cmax and AUC increased in an approximately dose-proportional manner over the dose range of 7.5-45 µg, and at doses higher than 45 µg these parameters increased more than dose proportionally. There was no obvious accumulation after 7 days of daily dosing of rhNGF. CONCLUSION: The favorable safety and tolerability and predictable pharmacokinetic profile of rhNGF in healthy Chinese subjects support its continuing clinical development for the treatment of nerve injury and neurodegenerative diseases. The AEs and immunogenicity of rhNGF will continue to be monitored in future clinical trials. TRIAL REGISTRATION: This study was registered with Chinadrugtrials.org.cn (ChiCTR2100042094) on January 13th, 2021.

The Phytochemical Potential for Brain Disease Therapy and the Possible Nanodelivery Solutions for Brain Access.

Plant-derived phytochemicals have gifted humans with vast therapeutic potentials. Yet, the unique features of the blood-brain barrier significantly limit their accession to the target tissue and thus clinical translation in brain disease treatment. Herein, we explore the medicinal outcomes of both the rare examples of phytochemicals that can easily translocate across the blood-brain barrier and most of the phytochemicals that were reported with brain therapeutic effects, but a bizarre amount of dosage is required due to their chemical nature. Lastly, we offer the nanodelivery platform that is capable of optimizing the targeted delivery and application of the non-permeable phytochemicals as well as utilizing the permeable phytochemicals for boosting novel applications of nanodelivery toward brain therapies.

Pharmacokinetics and Safety of Erenumab after a Single Subcutaneous Injection Dose in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVE: Erenumab is the first-in-class, selective, and competitive human monoclonal antibody antagonist of the calcitonin gene-related peptide (CGRP) receptor that has been shown to be effective and well-tolerated in the preventive therapy of episodic and chronic migraine. The pharmacokinetics of erenumab may be affected by differences in race and ethnicity, which can lead to suboptimal outcomes. The present study was conducted to assess the single-dose pharmacokinetics and safety of erenumab in healthy Chinese subjects. METHODS: This was an open-label, randomized, parallel group, non-confirmatory, single-dose study in healthy Chinese subjects. A total of 24 healthy Chinese subjects of both sexes aged between 14 and 45 years were administered a single subcutaneous injection of erenumab 70 mg or 140 mg. The serum concentration of erenumab was quantified using a validated enzyme-linked immunosorbent assay method and pharmacokinetic parameters were determined using non-compartmental models. Safety was also assessed. RESULTS: A total of 55 subjects were screened for eligibility and 25 subjects were randomized to receive study treatments (12 subjects to the 70-mg erenumab group and 13 subjects to the 140-mg erenumab group). Erenumab was absorbed slowly with maximum serum concentration (Cmax) occurring 3-11 days after administration. The mean Cmax and area under the serum concentration versus time curve from time 0 to infinity with extrapolation of the terminal phase (AUC0-∞) were 9.20 µg/mL and 296 day·µg/mL for the 70 mg dose group, and 15.6 µg/mL and 569 day·µg/mL for the 140 mg dose group, respectively. Serum concentrations of erenumab exhibited low to high variability, with variable coefficients ranging from 17.1 to 72.2% for the 70-mg dose and 32.5 to 88.5% for the 140-mg dose. All adverse events were mild or moderate in intensity, and all resolved without intervention. CONCLUSIONS: Erenumab was safe and well tolerated after a single subcutaneous injection in healthy Chinese subjects. The systemic exposure in Chinese subjects in terms of AUC0-∞ was 70% higher than that in White subjects as previously reported. CHINESE CLINICAL TRIAL REGISTRY NO: ChiCTR2000032435.

Safety, Efficacy, and Pharmacokinetics of HP501 in Healthy Volunteers and Hyperuricemic Patients: A Phase I/IIa Study.

CONTEXT: Uricosuric agents are the typical approach to the control of hyperuricemia; however, their use has been eclipsed by adverse reactions, and a safer uricosuric drug is badly needed. OBJECTIVE: HP501 is a novel renal urate transporter 1 inhibitor for the treatment of hyperuricemia. In this first-in-human study, we investigated the safety, efficacy, and pharmacokinetics of HP501 in healthy volunteers and hyperuricemic patients. METHODS: The placebo-controlled, double-blind, randomized, 3-part, phase I/IIa study consists of a single ascending dose (SAD) part with 32 participants, a multiple ascending dose part with 48 participants, and a drug-drug interaction part with 20 participants. Effects of food in healthy volunteers administered 45 mg HP501 in the fed state were also assessed in the SAD part. RESULTS: A total of 68 healthy volunteers and 32 hyperuricemic patients were enrolled. HP501 appeared to be safe and well tolerated in both groups. In hyperuricemic patients dosed with 45 mg HP501 over 10 days, 2/10 and 3/10 patients had elevated AST (< 2 times upper limit of normal [ULN]) and ALT (< 2.5 times ULN), respectively. No dose-limiting adverse events were observed. Across doses of HP501 from 5 to 60 mg, the concentrations of serum uric acid (sUA) are reduced by a maximum of about 50%. HP501 exhibited predictable pharmacokinetics across different dose levels in healthy volunteers or hyperuricemic patients. HP501 and febuxostat have obvious synergistic sUA-lowering effects with no apparent pharmacokinetics interaction. CONCLUSION: HP501 was effective at reducing sUA in healthy volunteers and hyperuricemic patients with a tolerable safety profile, warranting further development.

An ultra-performance LC-MS/MS method for determination of JRF103 in human plasma: application in first in-patient study.

Background: JRF103, a novel pan-HER inhibitor, has shown potent activity against HER1, HER2, HER4 and EGFR in vitro. To support its first in-patient trial, a sensitive and rapid method was developed and validated using ultra-performance LC-MS/MS. Materials & methods: JRF103 was extracted from plasma using protein precipitation. Extracts were subjected to ultra-performance LC-MS/MS with electrospray ionization. Results: Separation of analyte was achieved using a 1.7-µm C18 column (2.1 × 50-mm internal diameter) with a gradient elution. The developed method was fully validated following the international guides. Conclusion: The developed method was sensitive, specific and suitable for measuring JRF103 concentration in patients with advanced solid tumors in the first in-patient study of JRF103.

First-in-human safety, tolerability, and pharmacokinetics of SY-007, a prolonged action neuroprotective drug for ischemic stroke, in healthy Chinese subjects.

BACKGROUND AND PURPOSE: SY-007 is an interfering peptide designed to disrupt the cell death signaling of phosphatase and tensin homolog deleted on chromosome ten (PTEN) nuclear translocation during ischemic stroke. Preclinical studies indicated that rats treated with 1.5 mg/kg SY-007 in the middle cerebral artery occlusion (MACO) model had significantly reduced stroke lesion size even when administered 6 h after the stroke onset. The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics of ascending doses of SY-007 administered intravenously in healthy Chinese subjects. METHODS: A total of 78 healthy Chinese subjects were enrolled in the single ascending dose study (1-60 mg) and received a 15-min intravenous infusion SY-007 or placebo. Plasma concentrations of SY-007 were measured by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were determined using non-compartmental and compartment analyses. A model based on target-mediated drug disposition was applied. Model evaluation was performed through visual predictive checks and bootstrap analysis. RESULTS: Across doses of 1-60 mg, SY-007 was well tolerated. All adverse events (AEs) were mild or moderate in intensity, and all resolved without intervention. After infusion, SY-007 plasma concentrations decreased quickly with the mean terminal half-life was shorter than 0.78 h. The area under the concentration-time curve increased with a greater than dose-dependent manner from 1 to 30 mg and resulted in a dose-dependent increased from 30 to 60 mg. The nonlinear phenomenon was well described by a simplified target-mediated drug disposition (TMDD) model. CONCLUSIONS: Intravenous dosing of SY-007 appears to be safe up to a dose of 60 mg. Nonlinear pharmacokinetics was observed across the evaluated doses and TMDD might be the primary reason. The effective dose of SY-007 for neuroprotective effect in patients with ischemic stroke is expected to be 10-30 mg and was recommended for the later multiple ascending dose study of SY-007. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT04111523.

Simultaneous determination and pharmacokinetics study of valsartan, sacubitril and its major metabolite in human plasma, urine and peritoneal dialysis fluid in patients with end-stage renal disease by UPLC-MS/MS.

Sacubitril/valsartan was indicated for the treatment of heart failure and hypertension in patients with end-stage renal disease on peritoneal dialysis therapy. Herein, a rapid, sensitive and robust method based on ultra-liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed and validated for the determination of the concentrations of valsartan, sacubitril and its major metabolite LBQ657 in plasma, urine and peritoneal dialysis fluid. Samples were extracted from various biological fluids using protein precipitation. Extracts were subjected to UPLC-MS/MS with electrospray ionization in positive-ion mode. The developed method was fully validated over a concentration range of 8.00-8000 ng/mL for valsartan, 2.00-2000 ng/mL for sacubitril and 30.0-30,000 ng/mL for LBQ657 in plasma, 2.00-1000 ng/mL for valsartan, 1.00-500 ng/mL for sacubitril and 20.0-10000 ng/mL for LBQ657 in urine, and 0.200-100 ng/mL for valsartan, 0.0400-20.0 ng/mL for sacubitril and 2.00-1000 ng/mL for LBQ657 in peritoneal dialysis fluid. The intra- and inter-day precisions for all analytes in various matrices were less than 12.3%, and the intra- and inter-day accuracies results were all between 88.0% and 109.2%. All analytes were stable for at least 8 h at room temperature (25°C), five freeze-thaw cycles, and 37 days at -40°C and -80°C in plasma, urine and peritoneal dialysis fluid. In conclusion, this developed method is reliable, sensitive and specific for determining the concentrations of valsartan, sacubitril and LBQ657 in plasma, urine and peritoneal dialysis fluid. The assay was available to pilot the pharmacokinetics study of sacubitril/valsartan in patients with end-stage renal disease on peritoneal dialysis, and it could provide evidence that peritoneal dialysis had an effect on the clearance of sacubitril/valsartan.

Simultaneous determination of lidocaine and its active metabolites in plasma by UPLC-MS/MS and application to a clinical pharmacokinetic study in liver cancer patients with laparoscopic hepatectomy.

Lidocaine, widely used as a local anesthetic, has anti-inflammatory and inhibitory effects on tumor recurrence and metastasis. To investigate the pharmacokinetics of lidocaine in liver cancer patients undergoing laparoscopic hepatectomy, a fast and sensitive analytical technique was developed. The method was adequately validated with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to simultaneously determine the concentration of lidocaine and its metabolites in plasma. The chromatographic separation was achieved on an Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 µm) by gradient elution with a mobile phase of A (formic acid-water (1:1000, v/v)) and B (formic acid-acetonitrile (1:1000, v/v)). The accuracy and precision were verified within the concentration ranges of 10-5000 ng/mL for lidocaine, 2-1000 ng/mL for monoethylglycinexylidide (MEGX) and 2-500 ng/mL for glycinexylidide (GX). The selectivity, carry-over effect, interference between the analytes and internal standard (IS), precision and accuracy, matrix effect extraction recovery, dilution integrity and stability were satisfactory for the relevant guideline standards. The method was successfully applied to the pharmacokinetic study of lidocaine in liver cancer patients undergoing laparoscopic hepatectomy. After receiving a bolus and continuous infusion, the mean peak concentration of lidocaine was 2097 ng/mL for lidocaine, 336.6 ng/mL for MEGX and 72.66 ng/mL for GX, respectively. The mean peak time was 2.89 h for lidocaine, 5.14 h for MEGX and 9.88 h for GX, respectively. In addition, the mean half-life was 4.19 h for lidocaine and 6.92 h for MEGX. In this study, we found that the metabolism of lidocaine and MEGX might be affected by the hepatic blood flow occlusion or liver injury.

Heme Oxygenase-1 targeting exosomes for temozolomide resistant glioblastoma synergistic therapy.

Glioblastoma (GBM) is a highly fatal and recurrent brain cancer without a complete prevailing remedy. Although the synthetic nanotechnology-based approaches exhibit excellent therapeutic potential, the associated cytotoxic effects and organ clearance failure rest major obstacles from bench to clinics. Here, we explored allogeneic bone marrow mesenchymal stem cells isolated exosomes (BMSCExo) decorated with heme oxygenase-1 (HMOX1) specific short peptide (HSSP) as temozolomide (TMZ) and small interfering RNA (siRNA) nanocarrier for TMZ resistant glioblastoma therapy. The BMSCExo had excellent TMZ and siRNA loading ability and could traverse the blood-brain barrier (BBB) by leveraging its intrinsic brain accumulation property. Notably, with HSSP decoration, the TMZ or siRNA encapsulated BMSCExo exhibited excellent TMZ resistant GBM targeting ability both in vitro and in vivo due to the overexpression of HMOX1 in TMZ resistant GBM cells. Further, the HSSP decorated BMSCExo delivered the STAT3 targeted siRNA to the TMZ resistant glioma and restore the TMZ sensitivity, consequently achieved the synergistically drug resistant GBM treatment with TMZ. Our results showed this biomimetic nanoplatform can serve as a flexible, robust and inert system for GBM treatment, especially emphasizing the drug resistant challenge.

Correlation in gene expression between the aggravation of chronic obstructive pulmonary disease and the occurrence of complications.

Aggravation of the chronic obstructive pulmonary disease (COPD) often leads to a slew of complications, but the correlation between COPD aggravation and the complications on the basis of molecular level remains unclear. In this study, gene expression profiles of COPD in patients at early and aggravation stages were collected and differentially-expressed genes were selected. Meanwhile, gene expression data implicated in COPD complications were analyzed to establish a regulatory network of COPD aggravation and COPD related complications. In addition, the gene enrichment function of DAVID6.7 was utilized to evaluate the similarities between COPD aggravation and COPD complications in term of biological process. By analyzing the genes of COPD aggravation and the COPD complications, we found 18 genes highly related to COPD aggravation, among which haptoglobin (HP) was correlated with 14 complications, followed by ADRB2, LCK and CA1, which were related to 13, 11 and 11 complications, respectively. As far as the complications concerned, obesity was regulated by 17 of the 18 genes, which indicated that there was a close correlation between COPD aggravation and obesity. Meanwhile, lung cancer, diabetes and heart failure were regulated by 15, 15 and 14 genes, respectively, among the 18 selected genes. This study suggested the driver genes of COPD aggravation were capable of extensively regulating COPD complications, which would provide a theoretical basis for development of cures for COPD and its complications.