Association between prior cancer diagnosis and osteoporosis: a matched case-control study.

Epidemiological studies show an inconsistent association between cancer and osteoporosis. In this nationally representative population-based study, we found that a prior cancer diagnosis was not associated with osteoporosis. This finding may primarily apply to cancer survivors seen many years after their cancer diagnosis. BACKGROUND: Epidemiological studies show an inconsistent association between cancer and osteoporosis. We examined the association between a prior cancer diagnosis and osteoporosis in population-based data. METHODS: We performed an age- and sex-matched case-control study (1:2 matching ratio) using the National Health and Nutrition Examination Survey, 2011-2018. Cases were determined by self-reported prior diagnosis of cancer; all controls were free of cancer at the time of bone density measurement with dual-energy x-ray absorptiometry. We defined osteoporosis as a T-score ≤ - 2.5 at femoral neck, total hip, or lumbar spine. Unconditional multivariable logistic regression was used to test the association between a prior cancer diagnosis and osteoporosis. RESULTS: We identified 246 prior cancer cases and 492 controls (mean age: 65.8 years) in females, and 243 prior cancer cases and 486 controls (mean age: 68.0 years) in males. The most common types of cancer in females and males were breast cancer and prostate cancer, respectively. Osteoporosis prevalences were comparable between cases and controls among females (19.1% in cases vs. 18.7% in controls; P = 0.894) and males (5.8% in cases vs. 6.8% in controls; P = 0.594). After adjusting for covariates, a prior cancer diagnosis was not associated with osteoporosis in females (odds ratio [OR]: 0.83; 95% confidence interval [CI]: 0.54-1.29) or males (OR: 1.09; 95% CI: 0.51-2.30). Results were unaffected by cancer severity, cancer type, or time since cancer diagnosis. CONCLUSIONS: A prior cancer diagnosis was not associated with osteoporosis in this nationally representative population.

[Retracted] MiR­132 inhibits cell proliferation, invasion and migration of hepatocellular carcinoma by targeting PIK3R3.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the data shown in Figs. 2C and 3A bore unexpected similarities to data appearing in different form in other articles by different authors. Owing to the fact that some of the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Internatinal Journal of Oncology, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in International Journal of Oncology 47: 1585­1593, 2015; DOI: 10.3892/ijo.2015.3112].

The basic route of nuclear-targeted transport of IGF-1/IGF-1R and potential biological functions in intestinal epithelial cells.

OBJECTIVES: Insulin-like growth factor (IGF-1) plays an important role in many biological processes in the intestinal tract. However, the cellular behaviour and characteristics of IGF-1/IGF-1R in intestinal cells remain unclear. MATERIALS AND METHODS: A series of techniques (such as indirect immunofluorescence, co-localization and Western blot) have been used to systematically study the cellular behaviour of IGF-1/IGF-1R on intestinal cells. RESULTS: We found that IGF-1 can not only internalize into the cytoplasm, but also transport into the cell nuclei. We systematically studied the detailed molecular pathways of IGF-1/IGF-1R's nuclear translocation. We found that IGF-1R underwent clathrin-mediated endocytosis into cells and then entered into Rab-5-positive endosomes. Dynein/dynactin were used as motors to drive Rab-5-positive endosomes carrying IGF-1R (cargo molecule) to Golgi apparatus (transit station) along the surface of the microtubule. IGF-1 and/or IGF-1R entered the cell nuclei through NPC (nuclear pore complex), a process mediated by NUP358. Further study indicated that nuclear localization of IGF-1 and/or IGF-1R promoted cell proliferation and increased the nuclear residence time of signalling molecules activated by IGF-1. Further experiments showed that IGF-1R may regulate the transcription of genes in the cell nuclei, indicating that nuclear-localized IGF-1R plays an important in cell proliferation. CONCLUSIONS: In short, we revealed the molecular mechanism by which IGF-1/IGF-1R transports into the cell nuclei of intestinal cells. More importantly, the current work showed that the nuclear-localized IGF-1R has important biological functions.

Preparation of a Growth Hormone Receptor/Prolactin Receptor Bispecific Antibody Antagonist Which Exhibited Anti-Cancer Activity.

Prolactin receptor (PRLR) and growth hormone receptor (GHR) are closely related to the occurrence and development of breast cancer, and breast cancer cell endogenously express GHR, PRLR and GHR-PRLR heterodimer. In this case, the combined use of PRLR or GHR inhibitors may produce better anti-breast cancer potential than PRLR or GHR inhibitors alone. In this case, it is necessary to develop the dual-function GHR/PRLR antagonists with anti-breast cancer potential. For this, we used hybridoma technology to generate an anti-idiotypic antibody (termed H53). We then used various techniques, including competitive ELISA, competitive receptor binding analysis, and indirect immunofluorescence assay to identify H53, and the results show that H53 behaves as a typical internal image anti-idiotypic antibody (Ab2ß). Further experiments indicate that H53 is a dual-function inhibitor, which not only inhibited PRLR-mediated intracellular signaling, but also blocked GHR-mediated intracellular signaling in a dose-dependent manner. Furthermore, H53 could inhibit PRL/GH-driven cancer cell proliferation in vivo and in vitro. This study indicates that H53 exhibits potential biological activity against breast tumors, which implies that internal image anti-idiotypic antibodies may be a useful strategy for the development of PRLR/GHR dual-function antagonists for breast cancer therapy.

Bone Marrow Mesenchymal Stem Cell-Derived Exosomal miRNA-29c Decreases Cardiac Ischemia/Reperfusion Injury Through Inhibition of Excessive Autophagy via the PTEN/Akt/mTOR Signaling Pathway.

BACKGROUND: Cardiac ischemia/reperfusion (I/R) injury will cause a large amount of cardiomyocyte loss and cascade reactions such as apoptosis, mitochondrial dysfunction, and excessive autophagy. Mesenchymal stem cells (MSCs) are promising therapeutic tools to replace damaged cardiomyocytes, but the underlying mechanism is still unknown.Methods and Results:Exosomes contain many microRNAs and protein, which are believed to have multiple biological functions. This study explored the role of bone marrow MSCs (BMMSCs)-derived exosomes under different oxidation levels in heart protection and miRNA-related mechanisms. Exosomes extracted from BMMSCs contained a high level of miR-29c, and its expression level changed after cells were treated under hypoxia/reoxygenation (H/R) conditions. In vivo I/R experiments also confirmed an expression change of miR-29c, and PTEN-Akt-mTOR is one of the predominant pathways that regulate autophagic change during this process. CONCLUSIONS: This study highlighted the role of miR-29c in regulating autophagy under cardiac I/R injury, which also extended existing mechanisms of a stem cell and its derivative to explore potential therapeutic interventions in ischemic heart diseases.

Associations of C-reactive Protein with 25-hydroxyvitamin D in 24 Specific Diseases: A Cross-sectional Study from NHANES.

Most diseases might be associated with acute or chronic inflammation, and the role of vitamin D in diseases has been extensively explored in recent years. Thus, we examined the associations of one of the best markers for inflammation - C-reactive protein (CRP) with 25-hydroxyvitamin D [25(OH)D] in 24 specific diseases. We performed cross-sectional analyses among 9,809 subjects aged ≥18 years who participated in the U.S. National Health and Nutrition Examination Survey (NHANES) in 2007~2010. The generalized additive model (GAM) was used to explore the associations of CRP with 25(OH)D in different diseases, adjusted for the age, gender, examination period and race. Distributions of CRP were significantly different (P < 0.05) in gender, examination period and race, and distributions of 25(OH)D were different (P < 0.05) in the examination period and race. Generally, CRP was negatively associated with 25(OH)D for majority diseases. 25(OH)D was negatively associated with CRP generally, and the associations were disease-specific and disease category-specific. In respiratory, gastrointestinal and mental diseases, the associations tended to be approximately linear. While in metabolic diseases, the associations were nonlinear, and the slope of the nonlinear curve decreased with 25(OH)D, especially when 25(OH)D < 30 µg/L.

Polypeptide Nanogels With Different Functional Cores Promote Chemotherapy of Lung Carcinoma.

Two kinds of tumor microenvironment-responsive polypeptide nanogels were developed for intracellular delivery of cytotoxics to enhance the antitumor efficacies and reduce the side effects in the chemotherapy of lung carcinoma. The sizes of both doxorubicin (DOX)-loaded nanogels methoxy poly(ethylene glycol)-poly(L-phenylalanine-co-L-cystine) [mPEG-P(LP-co-LC)] and methoxy poly(ethylene glycol)-poly(L-glutamic acid-co-L-cystine) [mPEG-P(LG-co-LC)] (NGP/DOX and NGG/DOX) were less than 100 nm, which was appropriate for the enhanced permeability and retention (EPR) effect. The bigger and smaller scale of nanoparticle could induce the elimination of reticuloendothelial system (RES) and decrease the in vivo circulating half-life, respectively. The loading nanogels were stable in the neutral environment while quickly degraded in the mimic intracellular microenvironment. Furthermore, the DOX-loaded reduction-responsive nanogels showed significantly higher tumor cell uptake than free DOX⋅HCl as time went on from 2 to 6 h. In addition, these DOX-loaded nanogels showed efficient antitumor effects in vivo, which was verified by the obviously increased necrosis areas in the tumor tissues. Furthermore, these DOX-loaded nanogels efficiently reduced the side effects of DOX. In conclusion, these reduction-responsive polypeptides based nanogels are suitable for the efficient therapy of lung carcinoma.

Controlled Drug Delivery by Polylactide Stereocomplex Micelle for Cervical Cancer Chemotherapy.

A stable doxorubicin (DOX)-loaded stereocomplex micelle drug delivery system was developed via the stereocomplex interaction between enantiomeric 4-armed poly(ethylene glycol)-poly(D-lactide) and poly(ethylene glycol)-poly(L-lactide) to realize control drug release and improve tumor cell uptake for efficient cervical carcinoma therapy. All these DOX-loaded micelles including poly(D-lactide)-based micelle (PDM/DOX), poly(L-lactide)-based micelle (PLM/DOX), and stereocomplex micelle (SCM/DOX) exhibited appropriate sizes of ∼100 nm for the enhanced permeability and retention (EPR) effect. In addition, compared to PDM/DOX and PLM/DOX, SCM/DOX exhibited the slowest DOX releaser, highest tumor cell uptake and the most efficient tumor cell suppression in vitro. Moreover, the excellent tumor inhibiting rates of the DOX-loaded micelles, especially SCM/DOX, were verified in the U14 cervical carcinoma mouse model. Increased tumorous apoptosis and necrosis areas were observed in the DOX-loaded micelles treatment groups, especially the SCM/DOX group. In addition, all these DOX-loaded micelles obviously alleviated the systemic toxicity of DOX. As a result, SCM can be a promising drug delivery system for the future therapy of cervical carcinoma.

A sensitive LC-MS/MS-based bioanalytical method for quantification of salviaflaside and rosmarinic acid in rat plasma and its application in a pharmacokinetic study.

A selective and sensitive liquid chromatography tandem mass spectrometry method was developed for the simultaneous determination of salviaflaside and rosmarinic acid in rat plasma. Sample preparation was carried out through liquid-liquid extraction with ethyl acetate using curculigoside as internal standard (IS). The analytes were determined by selected reaction monitoring operated in the positive ESI mode. Chromatographic separation was performed on an Agilent Eclipse Plus C18 column (100 × 4.6 mm, 1.8 µm) with a mobile phase consisting of methanol-water-formic acid (50:50:0.1, v/v/v) at a flow rate of 0.3 mL/min. The run time was 1.9 min per sample and the injection volume was 5 µL. The method had an LLOQ of 1.6 ng/mL for salviaflaside and 0.94 ng/mL for rosmarinic acid in plasma. The linear calibration curves were fitted over the range of 1.6-320 ng/mL for salviaflaside and 0.94-188 ng/mL for rosmarinic acid in plasma with correlation coefficients (r2 ) >0.99. Intra- and inter-day precisions (relative standard deviation) were < 13.5%, and accuracies (relative error) were between -8.6% and 14.5% for all quality control samples. The method was validated and applied to the pharmacokinetics of salviaflaside and rosmarinic acid in plasma after oral administration of Prunella vulgaris extract to rats.

Hyperbaric oxygen treatment for Parkinson's disease with severe depression and anxiety: A case report.

RATIONALE: Patients with Parkinson's disease (PD) frequently suffer from psychiatric disorders, and treating these symptom whereas managing the motor symptoms associated with PD can be a therapeutic challenge. PATIENT CONCERNS: We report a case of PD patient with severe depression and anxiety that refused to be treated with dopaminagonists or SSRIs, the most common treatments for PD patients suffering from psychiatric symptoms. DIAGNOSES: Parkinson's disease with severe depression and anxiety. INTERVENTIONS: This man was treated with hyperbaric oxygen treatment for 30 days. OUTCOMES: Clinical assessment scores for depression and anxiety, including Unified Parkinson's Disease Rating ScaleI (UPDRS I), UPDRS II, Hanmilton Depression Rating Scale, and Hamiliton Anxiety Rating Scale, were improved following the hyperbaric oxygen treatment. LESSONS: Hyperbaric oxygen treatment may be a potential therapeutic method for PD patient suffering from depression and anxiety. Further research is needed to validate this finding and explore a potential mechanism.

Bioequivalence and Pharmacokinetic Profiles of Agomelatine 25-mg Tablets in Healthy Chinese Subjects: A Four-Way Replicate Crossover Study Demonstrating High Intra- and Inter-Individual Variations.

The present study was designed to assess the bioequivalence of two agomelatine formulations (25-mg tablets) in healthy Chinese male subjects. This single-dose, open-label, randomized, four-way replicate study with a 1-week washout period was conducted in 60 healthy Chinese male volunteers under fasting conditions. Blood samples were collected over a 12-h period after a single dose of the 25-mg agomelatine test (T) formulation or a reference (R) formulation, and the drug concentrations were assayed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated using a non-compartmental model. Bioequivalence between the formulations was assessed. Tolerability and safety were monitored by physical examination, electrocardiogram (12-lead ECG), clinical laboratory tests, and adverse events (AEs). A total of 56 out of 60 subjects completed the study. No AEs were observed. The values of maximum plasma concentration (Cmax), maximum concentration (Tmax), area under curve (AUC)0-t and t1/2 were 12.032 ng/mL, 0.658 h, 12.637 ng·h/mL, and 0.813 h, respectively, for the test formulation, and 10.891 ng/mL, 0.709 h, 11.572 ng·h/mL, and 0.96 h, respectively, for the reference formulation. The intra-individual variability of Cmax and AUC0-t were 78.3 and 61.8%, respectively. The inter-individual coefficients of variance (CVs) of Cmax and AUC0-t were approximately 100%. The 90% confidence intervals for the ratio of means for the log-transformed Cmax (97.7-124.9%), AUC0-t (98.2-118%), and AUC0-∞ (97.8-117.2%) were within the guideline range of bioequivalence (80-125%). The test and reference formulations of agomelatine met the regulatory criteria for bioequivalence of the Chinese Food and Drug Administration. Significant intra-individual and inter-individual variations were found.

Quantification of complanatoside A in rat plasma using LC-MS/MS and its application to a pharmacokinetic study.

Complanatoside A is a flavonol glycoside isolated from Astragalus complanatus, and currently it is used as a quality control index for A. complanatus in the 2010 edition of the Chinese Pharmacopoeia. For the first time, a simple and sensitive LC-MS/MS method was developed for the determination of complanatoside A in rat plasma over the range of 2.3-575 ng/mL. Complanatoside A was extracted from plasma by a protein precipitation procedure, separated by LC and detected by MS/MS in positive electrospray ionization mode. The method was validated for selectivity, carryover, sensitivity, linearity, extraction recovery, matrix effect, accuracy, precision and stability studies. The lower limit of quantification was established at 2.3 ng/mL. Intra- and inter-day precisions (LLOQ, low-QC, med-QC and high-QC) were <7.9%, and accuracies were between 94.0 and 105.1%. Matrix effect was acceptable (97.9-103.0%) and extraction recovery was reproducible (88.5-94.4%). Complanatoside A was stable in the investigated conditions. The method was applied to the pharmacokinetics of complanatoside A in rats. Copyright © 2015 John Wiley & Sons, Ltd.

A sensitive and selective LC-MS/MS method for the quantitative determination of segetalin A from the plasma of rats.

A sensitive and selective LC-MS/MS method was developed and validated for the determination and pharmacokinetic investigation of segetalin A in rat plasma. Sample preparation was accomplished through a simple SPE procedure for the removal and preconcentration of the analyte and IS. Plasma samples were separated by HPLC on a Symmetry C18 column using a mobile phase consisting of methanol and 0.1% formic acid in water (70:30, v/v) with isocratic elution. The quantification was performed using multiple reaction monitoring with the transitions m/z 610.3 → 511.2 for segetalin A and m/z 779.4 → 751.4 for IS, respectively. The calibration curve was linear over the range of 8.0-4000 ng/mL with a limit of quantitation (LOQ) of 8.0 ng/mL. This method was applied in a pharmacokinetic study of segetalin A in rats. For intravenous (i.v.) administration, the plasma concentrations of segetalin A decreased quickly (t1/2z, 1.31 ± 0.341 h). For oral administration, the plasma concentrations of segetalin A increased to a peak value at 1.50 ± 0.577 h, followed by a gradual decrease to the LOQ in 12 h. The mean AUC values after i.v. and oral administration were 553 ± 105 and 1482 ± 110 ng h/mL, respectively.

Glutathione-degradable drug-loaded nanogel effectively and securely suppresses hepatoma in mouse model.

The reduction-responsive polymeric nanocarriers have attracted considerable interest because of a significantly higher concentration of intracellular glutathione in comparison with that outside cells. The smart nanovehicles can selectively transport the antitumor drugs into cells to improve efficacies and decrease side effects. In this work, a facilely prepared glutathione-degradable nanogel was employed for targeting intracellular delivery of an antitumor drug (ie, doxorubicin [DOX]). DOX was loaded into nanogel through a sequential dispersion and dialysis approach with a drug loading efficiency of 56.8 wt%, and the laden nanogel (noted as NG/DOX) showed an appropriate hydrodynamic radius of 56.1±3.5 nm. NG/DOX exhibited enhanced or improved maximum tolerated dose on healthy Kunming mice and enhanced intratumoral accumulation and dose-dependent antitumor efficacy toward H22 hepatoma-xenografted mouse model compared with free drug. In addition, the upregulated antitumor efficacy of NG/DOX was further confirmed by the histopathological and immunohistochemical analyses. Furthermore, the excellent in vivo security of NG/DOX was confirmed by the detection of body weight, histopathology, and biochemical indices of corresponding organs and serum. With controllable large-scale preparation and fascinating in vitro and in vivo properties, the reduction-responsive nanogel exhibited a good prospect for clinical chemotherapy.

Analysis of the Molecular Evolution of the Mycobacterium Tuberculosis Drug-Resistant Gene rpoB in Asia Using a Bayesian Evolutionary Method.

BACKGROUND: Tuberculosis (TB) is a serious communicable disease throughout the world. Re-emergence of the TB epidemic is aggravated by the circulation of multidrug-resistant Mycobacterium tuberculosis strains, and more than half of new cases have occurred in Asia. Therefore, it is important to understand the gene mutations underlying the development of rifampicin resistance in Asia. METHODS: In this study, we classified the rifampicin-resistant Mycobacterium tuberculosis (MTB) rpoB data downloaded from Genbank, based on 12 mutation points. The relationship between the mutation sites and regional information was analyzed, after which the mutation dates and mutation trends of the rpoB gene were predicted by the Markov Chain Monte Carlo (MCMC) method. RESULTS: We discovered that the mutation sites of the rpoB gene were disparate in different regions of Asia. The results of this study clearly showed that drug-resistant gene mutations in Asia started to increase in 2000 and peaked in 2006, indicating the relationship between drug resistance and outbreak trends of TB. CONCLUSIONS: From our analysis, it was not difficult to see the relationship between the mutation rates of the rpoB gene and the outbreak of TB. Hence, to some degree, outbreak trends of TB can be predicted through genotyping based on the rpoB gene.

MiR-132 inhibits cell proliferation, invasion and migration of hepatocellular carcinoma by targeting PIK3R3.

MicroRNA-132 (miR­132) has been reported to play a tumor suppressive role in different human malignancies. However, its role and underling mechanism in hepatocellular carcinoma (HCC) remains poorly defined due to lack of target gene information. In the present study, we demonstrated that the mean level of miR­132 in hepatocellular carcinoma (HCC) tissues was significantly lower than that in matched tumor-adjacent tissues, and its expression negatively correlated with tumor differentiation (P<0.01), TNM stage (P<0.01) and lymph node metastasis (P<0.01). Similarly, the expression of miR­132 was obviously reduced in HCC cell lines as compared with a normal hepatic cell line. Ectopic expression of miR­132 inhibited cell proliferation, colony formation, migration and invasion, and induced apoptosis in HepG2 cells. In vivo studies showed that miR­132 inhibited tumor growth of HCC and decreased tumor volume and weight. In addition, phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) was identified as a direct target of miR­132 by a luciferase reporter assay. Western blot and qRT-PCR analysis indicated that PIK3R3 was significantly downregulated by miR­132 in HCC cells. miR­132 expression inversely correlated with PIK3R3 mRNA expression in clinical HCC tissues. Investigations into possible mechanisms revealed that miR­132 inactivated the AKT/mTOR signaling pathway, which may contribute to inhibition of proliferation, migration, and invasion of HCC. These findings suggested that miR­132 may serve as a potential target in the treatment of human HCC.

VKORC1 and CD-14 genetic polymorphisms associate with susceptibility to cardiovascular and cerebrovascular diseases.

OBJECTIVE: To investigate the associations of VKORC1 rs2359612 and rs9923231 and CD-14 rs2569190 with susceptibility to cardiovascular and cerebrovascular diseases (CCVD). METHODS: A case-control study was conducted with 614 cases of CCVD patients selected at our hospital between January 2011 and June 2012 as case group and 590 healthy individuals participating physical examination during the same period as control group. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to detect genotypes of VKORC1 and CD-14 genetic polymorphisms. SHEsis software was used to conduct haplotype analysis and logistic regression analysis was used to identify risk factors for CCVD. RESULTS: The genotype and allele frequencies of VKORC1 rs2359612 and rs9923231 and CD-14 rs2569190 between the case and control groups were statistically different (all P<0.05). Haplotype analysis showed that the frequencies of CAT and TAT haplotypes were significantly higher while the frequencies of TAC and TGC haplotypes were significantly lower in the case group than those in the control group (P = 0.013, 0.029, 0.019 and 0.042, respectively). Logistic regression analysis showed that age, systolic pressure, smoking history and VKORC1 rs2359612 maybe risk factors for CCVD; and body mass index (BMI), diastolic pressure and VKORC1 rs9923231 may be protective factors for CCVD (all P<0.05). CONCLUSION: VKORC1 rs2359612 and rs9923231, and CD-14 rs2569190 might associate with susceptibility to CCVD. CAT and TAT haplotypes may be risk factors while TAC and TGC haplotype may be protective factors for CCVD.