Association between the composite dietary antioxidant index and infertility: the national health and nutrition examination survey 2013-2020.

BACKGROUND: The use of antioxidant-rich foods to treat female infertility has received significant attention in recent years. The aim of this study was to investigate the potential correlation between the composite dietary antioxidant index (CDAI) and female infertility. METHODS: The participants in the cross-sectional data were women between the ages of 20 and 45 who had complete CDAI-related data and infertility information, which were taken from the National Health and Nutrition Examination Survey (NHANES) conducted between 2013 and 2020. The independent association between CDAI and infertility was investigated using multivariate logistic regression analysis. Trends between the two variables were examined using smoothed curve fitting, and subgroup analysis and interaction tests were conducted. RESULTS: The prevalence of infertility was 12.57% of the 3,259 participants included in the study; individuals in higher CDAI quartiles tended to have a lower percentage of infertility. The risk of infertility was 44% lower among individuals in the highest quartile of the CDAI compared to those in the lowest quartile (OR = 0.56, 95%CI: 0.36-0.85, P = 0.0072), and the test for trend was also significant (P for trend = 0.0235). Smoothed curve fitting showed a negative non-linear relationship between CDAI and infertility. Subgroup analysis and interaction tests showed that there was an interaction of BMI in the relationship between CDAI and infertility risk (P for interaction = 0.0497) and that education, PIR, marital status, smoking status, hypertension, diabetes, age at menarche, ever having been treated for pelvic infection, ever having used female hormones, and ever been pregnant had no significant dependence on this negative association (all P for interaction > 0.05). CONCLUSION: There was a negative non-linear correlation between CDAI and infertility among reproductive-aged women in the US. The risk of infertility may be reduced by increasing the intake of antioxidant-rich foods.

Supramolecular self-assembled gold nanoparticle clusters for synergistic photothermal-chemo tumor therapy.

The combination of photothermal therapy and chemotherapy has emerged as a promising strategy to improve cancer therapeutic efficacy. However, developing a versatile nanoplatform that simultaneously possesses commendable photothermal effect and high drug encapsulation efficiency remains a challenging problem yet to be addressed. Herein, we report a facile supramolecular self-assembly strategy to construct gold nanoparticle clusters (AuNCs) for synergistic photothermal-chemo therapy. By utilizing the functional polysaccharide as a targeted ligand, hyaluronic acid-enriched AuNCs were endowed with targeting CD44 receptor overexpressed on the B16 cancer cells. Importantly, these hyaluronic acid modified AuNCs can shelter therapeutic cargo of doxorubicin (DOX) to aggregate larger nanoparticles via a host-guest interaction with the anchored ß-cyclodextrin, as a "nanocluster-bomb" (DOX@AuNCs). The in vitro results revealed that these DOX@AuNCs showed light-triggered drug release behavior and synergistic photothermal-chemo therapy. The improved efficacy of synergistic therapy was further demonstrated by treating a xenografted B16 tumor model in vivo. We envision that our multipronged design of DOX@AuNCs provides a potent theranostic platform for precise cancer therapy and could be further enriched by introducing different imaging probes and therapeutic drugs as appropriate suitable guest molecules.

Estimation of tumor cell total mRNA expression in 15 cancer types predicts disease progression.

Single-cell RNA sequencing studies have suggested that total mRNA content correlates with tumor phenotypes. Technical and analytical challenges, however, have so far impeded at-scale pan-cancer examination of total mRNA content. Here we present a method to quantify tumor-specific total mRNA expression (TmS) from bulk sequencing data, taking into account tumor transcript proportion, purity and ploidy, which are estimated through transcriptomic/genomic deconvolution. We estimate and validate TmS in 6,590 patient tumors across 15 cancer types, identifying significant inter-tumor variability. Across cancers, high TmS is associated with increased risk of disease progression and death. TmS is influenced by cancer-specific patterns of gene alteration and intra-tumor genetic heterogeneity as well as by pan-cancer trends in metabolic dysregulation. Taken together, our results indicate that measuring cell-type-specific total mRNA expression in tumor cells predicts tumor phenotypes and clinical outcomes.

Penetrance Estimates Over Time to First and Second Primary Cancer Diagnosis in Families with Li-Fraumeni Syndrome: A Single Institution Perspective.

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder associated with TP53 germline mutations and an increased lifetime risk of multiple primary cancers (MPC). Penetrance estimation of time to first and second primary cancer within LFS remains challenging because of limited data and the difficulty of characterizing the effects of a primary cancer on the penetrance of a second primary cancer. Using a recurrent events survival modeling approach that incorporates a family-wise likelihood to efficiently integrate the pedigree structure, we estimated the penetrance for both first and second primary cancer diagnosis from a pediatric sarcoma cohort at MD Anderson Cancer Center [MDACC, Houston, TX; number of families = 189; single primary cancer (SPC) = 771; and MPC = 87]. Validation of the risk prediction performance was performed using an independent MDACC clinical cohort of TP53 tested individuals (SPC = 102 and MPC = 58). These findings showed that an individual diagnosed at a later age was more likely to be diagnosed with a second primary cancer. In addition, TP53 mutation carriers had a HR of 1.65 (95% confidence interval, 1.1-2.5) for developing a second primary cancer versus SPC. The area under the ROC (AUC) curve for predicting individual outcomes of MPC versus SPC was 0.77. In summary, we provide the first set of penetrance estimates for first and second primary cancer for TP53 germline mutation carriers and demonstrate its accuracy for cancer risk assessment. SIGNIFICANCE: These findings present an open-source R package LFSPRO that could be used for genetic counseling and health management of individuals with LFS as it estimates the risk of both first and second primary cancer diagnosis.See related article by Shin et al., p. 354.

Penetrance of Different Cancer Types in Families with Li-Fraumeni Syndrome: A Validation Study Using Multicenter Cohorts.

Li-Fraumeni syndrome (LFS) is a rare hereditary cancer syndrome associated with an autosomal-dominant mutation inheritance in the TP53 tumor suppressor gene and a wide spectrum of cancer diagnoses. The previously developed R package, LFSPRO, is capable of estimating the risk of an individual being a TP53 mutation carrier. However, an accurate estimation of the penetrance of different cancer types in LFS is crucial to improve the clinical characterization and management of high-risk individuals. Here, we developed a competing risk-based statistical model that incorporates the pedigree structure efficiently into the penetrance estimation and corrects for ascertainment bias while also increasing the effective sample size of this rare population. This enabled successful estimation of TP53 penetrance for three LFS cancer types: breast (BR), sarcoma (SA), and others (OT), from 186 pediatric sarcoma families collected at MD Anderson Cancer Center (Houston, TX). Penetrance validation was performed on a combined dataset of two clinically ascertained family cohorts with cancer to overcome internal bias in each (total number of families = 668). The age-dependent onset probability distributions of specific cancer types were different. For breast cancer, the TP53 penetrance went up at an earlier age than the reported BRCA1/2 penetrance. The prediction performance of the penetrance estimates was validated by the combined independent cohorts (BR = 85, SA = 540, and OT = 158). Area under the ROC curves (AUC) were 0.92 (BR), 0.75 (SA), and 0.81 (OT). The new penetrance estimates have been incorporated into the current LFSPRO R package to provide risk estimates for the diagnosis of breast cancer, sarcoma, or other cancers. SIGNIFICANCE: These findings provide specific penetrance estimates for LFS-associated cancers, which will likely impact the management of families at high risk of LFS.See related article by Shin et al., p. 347.

Co-responsive smart cyclodextrin-gated mesoporous silica nanoparticles with ligand-receptor engagement for anti-cancer treatment.

Combination of both internal- and external-stimuli responsive strategies in nanoplatforms can maximize therapeutic outcomes by overcoming drug efflux-mediated resistance and prolonging sustained release of therapeutic payloads in controlled and sequential manner. Here, we show a light/redox dual-stimuli responsive ß-cyclodextrin (ß-CD)-gated mesoporous silica nanoparticles (MSN) that can effectively load and seal the chemotherapeutics, doxorubicin (DOX), inside MSN with a dual-capped system. The primary gatekeeper was achieved by capping ß-CD via a disulfide linkage. An azobenzene/galactose-grafted polymer (GAP) was introduced to functionalize the MSN surface through host-guest interaction. GAP not only served as a secondary non-covalent polymer-gatekeeper to further prevent molecules from leaking out, but also presented targeting ligand for engagement of the asialoglycoprotein receptor (ASGPR) on hepatocellular carcinoma (HepG2) cells. The controlled and stimuli release of DOX could be realized via dissociation of azobenzene moieties from ß-CD cage upon UV-irradiation, followed by liberation with the endogenous glutathione. The in vitro studies verified the redox-sensitive DOX release behavior, and the UV irradiation could accelerate this process to trigger DOX burst from MSN-ss-CD/GAP. Notably, the DOX@MSN-ss-CD/GAP could more efficiently deliver DOX into HepG2 cells and demonstrate enhanced cytotoxicity as compared with HeLa and COS7 cells. The smart MSN-ss-CD/GAP delivery system holds the potential for universal therapeutic uses in both biomedical research and clinical settings.

Risk factors for 90-day reoperation and readmission after lumbar surgery for lumbar spinal stenosis

OBJECTIVES: The objective of this study was to evaluate the incidence and risk factors for 90-day readmission and reoperation after elective surgery for lumbar spinal stenosis (LSS). METHODS: The authors performed a retrospective consecutive cohort analysis of patients undergoing posterior lumbar decompression with or without fusion for LSS with claudication from January 2014 through December 2015. RESULTS: Data were collected on 1592 consecutive patients. The mean age at surgery was 67.4 ± 10.1 years and 45% of patients were female. The 90-day reoperation rate was 4.7%, and 69.3% of the reoperations occurred within the first 30 days. The 90-day readmission rate was 7.2%. Multivariable analysis showed that postoperative development of a surgical site infection (SSI; odds ratio [OR] 14.09, 95% confidence interval [CI] 7.86­25.18), acute kidney injury (AKI; OR 6.76, 95% CI 2.39­19.57), and urinary tract infection (UTI; OR 3.96, 95% CI 2.43­6.37), as well as a history of congestive heart failure (CHF; OR 3.03, 95% CI 1.69­5.28), were significant risk factors for readmission within 90 days. Male sex (OR 0.60, 95% CI 0.38­0.92) was associated with decreased odds for readmission. With regards to reoperation, development of SSI (OR 25.06, 95% CI 13.54­46.51), sepsis (OR 7.63, 95% CI 1.52­40.59), UTI (OR 2.54, 95% CI 1.31­4.76), and increased length of stay (LOS; OR 1.25, 95% CI 1.17­1.33) were found to be significant risk factors. A subsequent analysis found that morbid obesity (OR 6.99), history of coronary artery disease (OR 2.263), increased duration of surgery (OR 1.004), and LOS (OR 1.07) were significant risk factors for developing an SSI. CONCLUSIONS: Overall, this study found rates of 4.7% and 7.2% for reoperation and readmission, respectively, within 90 days: 30.7% of the reoperations and 44.7% of the readmissions occurred beyond the first 30 days. A diagnosis of SSI, AKI, UTI, and history of CHF were significant factors for readmission, while male sex was associated with decreased odds for readmission. A diagnosis of SSI, sepsis, UTI, and increased LOS were found to be significant predictors for reoperation. Understanding 90-day complication rates is imperative because there has been increased discussion and healthcare policy extending the global postoperative window to 90 days. Current literature supports a readmission rate of 3%­9% after spine surgery. However, this literature either is limited to a 30-day window or does not stratify between different types of spine surgeries. ABBREVIATIONS: AKI = acute kidney injury; BPH = benign prostate hyperplasia; CAD = coronary artery disease; CHF = congestive heart failure; CI = confidence interval; CMS = Centers for Medicare and Medicaid Services; COPD = chronic obstructive pulmonary disease; DM = diabetes mellitus; EBL = estimated blood loss; LOS = length of stay; LSS = lumbar spinal stenosis; OR = odds ratio; POUR = postoperative urinary retention; SSI = surgical site infection; UTI = urinary tract infection.

Designing heparan sulfate-based biocompatible polymers and their application for intracellular stimuli-sensitive drug delivery.

Heparan sulfate (HS) is a kind of natural polysaccharides with good biocompatibility. And as drug carriers, it has some advantages compared to heparin. However, the preparation of HS is cumbersome and difficult, which limits its application in drug delivery. Here, we use modern separation technique combined with chromatography to establish a new preparation method of HS. The molecular weight and degree of dispersion of HS were (1.03 × 104 ±â€¯107) kDa and 1.106, respectively. HS also showed low anticoagulation activity in comparison with heparin. Subsequently, novel redox-sensitive heparan sulfate-cystamine-vitamin E succinate (HS-SS-VES, HSV) micelles were designed to increase tumor selectivity and improve the therapeutic effect of doxorubicin (DOX). DOX-loaded HSV micelles (DOX/HSV) with spherical morphology had average particle size of 90-120 nm and good redox-triggered release behavior. The cell viabilities of blank micelles were >90% in both human breast cancer (MCF7) cells and African green monkey SV40-transformed kidney fibroblast (COS7) cells. However, the cytotoxicity of DOX/HSV in MCF7 cells was higher than that of COS7 cells. Flow cytometry analyses and confocal laser scanning microscopy observation indicated that DOX/HSV micelles were internalized by endocytosis, and then the drug was released quickly and entered the nuclei of tumor cells. The results demonstrate that high-purity HS can be prepared and has the potential to be further used for drug delivery in antitumor applications.

Dual-Responsive Core Crosslinking Glycopolymer-Drug Conjugates Nanoparticles for Precise Hepatocarcinoma Therapy.

Nanoparticles (NPs) have demonstrated a potential for hepatocarcinoma therapy. However, the effective and safe NP-mediated drug transportation is still challenging due to premature leakage and inaccurate release of the drug. Herein, we designed a series of core cross-linking galactose-based glycopolymer-drug conjugates (GPDs) NPs with both redox-responsive and pH-sensitive characteristics to target and program drug release. Glycopolymer is comprised of galactose-containing units, which gather on the surface of GPD NPs and exhibit specific recognition to hepatocarcinoma cells, which over-express the asialoglycoprotein receptor. GPD NPs are stable in a normal physiological environment and can rapidly release the drug in hepatocarcinoma cells, which are reductive and acidic, by combining disulfide bond cross-linked core, as well as boronate ester-linked hydrophilic glycopolymer chain and the hydrophobic drug.

Fabrication of tough poly(ethylene glycol)/collagen double network hydrogels for tissue engineering.

In this study, a series of poly(ethylene glycol)/collagen (PEG/Col) double network (DN) hydrogel is fabricated from PEG and Col. Results of the compressive strength test indicate that the strength and toughness of these DN hydrogels are significantly enhanced. The fracture strength of PEG/Col DN hydrogels increases by 9- to 12-fold compared with that of PEG single network (SN) hydrogel, and by 36- to 48-fold compared with that of Col SN hydrogel. Taking advantage of both PEG and Col building blocks, the PEG/Col DN hydrogels possess a strengthened skeleton. Moreover, the water-storage capability and favorable biocompatibility of Col are effectively maintained. Given that the DN hydrogels can provide the appropriate environment for the adhesion, growth, and proliferation of MC3T3-E1 cells, PEG/Col DN hydrogels have potential as a load-bearing tissue repair material. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 192-200, 2018.

[Endocytosis pathway and intracellular distribution of heparosan].

In this study, the endocytosis pathway of heparosan and its intracellular distribution were investigated in MCF-7 tumor cells and COS7 normal cells. The endocytosis inhibition and cellular probe location experiments showed that MCF-7 tumor cells took heparosan more efficiently and selectively than COS7 cells. The cellular uptake of heparosan was energy-dependent in both MCF-7 tumor cells and COS7 normal cells. Moreover, the major endocytosis pathway of heparosan into MCF-7 tumor cells was caveolin-mediated endocytosis and macropinocytosis. The internalized heparosan was mainly located in lysosomes of the cells.

Mechanism of the immunostimulatory activity by a polysaccharide from Dictyophora indusiata.

Dictyophora indusiata, an edible mushroom, is widely used not only as health foods but also as traditional Chinese medicine. This study aimed to investigate the molecular mechanism involved in the immunostimulatory activity of a polysaccharide from Dictyophora indusiata (DIP) in RAW264.7 cells. Results indicated that DIP induced the up-regulation of nitric oxide (NO), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumour necrosis factor (TNF-α) production as well as the mRNA expression levels of iNOS, IL-1ß, IL-6 and TNF-α in macrophages. Furthermore, the functional blocking antibodies against TLR4 could markedly suppress DIP-mediated NO, IL-1ß, IL-6 and TNF-α production. Flow cytometry and confocal laser-scanning microscopy analyses confirmed that DIP could bind specifically to target cells, and the binding could be inhibited by anti-TLR4 monoclonal antibodies. The expression of nuclear factor kappa B (NF-κB) p65 was significantly induced by DIP. Therefore, the DIP-induced macrophage activation may be mediated via the TLR4/NF-κB signalling pathway.

One-pot construction of boronate ester based pH-responsive micelle for combined cancer therapy.

In this study, one-pot strategy for the construction of micelles loaded with two types of anticancer drugs (i.e., doxorubicin and methotrexate) together is reported. On the basis of the reaction between boronic acid and 1,2-diol to form boronate ester, the formation of amphiphiles, their self-assembly into micelles and drug encapsulation occurs simultaneously under simple dialysis at the appropriate pH condition. In the one-pot strategy, the micelle yield is high (78.2%) and the drug encapsulation efficiency of the two drugs is improved compared with that of the traditional method. The micelles can selectively increase the drug release ratio at acidic pH, showing the pH-responsive behavior inherited from the property of boronate ester. By combining doxorubicin and methotrexate, the half-maximum inhibition concentrations of the two drugs are obviously reduced, showing synergistic efficacy against cancer cells. This strategy is promising and may be expanded to various applications.

Modulating the SDF-1/CXCL12-induced cancer cell growth and adhesion by sulfated K5 polysaccharides in vitro.

Stromal cell-derived factor-1 (SDF-1)/chemokine (CXC motif) ligand 12 (CXCL12) is involved in the process of tumor progression. Sulfated K5 polysaccharides have shown anti-cancer activity by acting on multiple targets, though it remains unclear whether sulfated K5 polysaccharides would disrupt SDF-1/CXCL12-stimulated cancer biology. This study aimed to investigate the effects of sulfated K5 polysaccharides on cell growth, adhesion in murine B16 melanoma cells and the underlying mechanism by targeting SDF-1/CXCL12. Results indicated that K5-NS,OS inhibited the proliferation of B16 melanoma cells, induced the cell cycle arrest mainly at the G0/G1 phase, and suppressed cancer cell proliferation or adhesion induced by SDF-1/CXCL12. It was possible that K5-NS,OS appeared to interact with CXCL12 and block the subsequent biological functions. This work suggests that the existence of O- and N-sulfate groups is more effective in targeting CXCL12 and exhibiting anti-cancer activity.

Hyaluronic acid and polyethylenimine self-assembled polyion complexes as pH-sensitive drug carrier for cancer therapy.

In this study, a series of polyion complexes (PICs) were prepared via electrostatic interaction between hyaluronic acid-histidine conjugate (HH) and polyethylenimine-histidine conjugate (PH). These PICs with the average size ranging from 410.5 nm to 98.5 nm at different weight ratios of HH/PH were able to encapsulate doxorubicin (DOX) as the model antitumor drug. The PICs at the weight ratio of 4:1 had negative surface charge and were of good dispersity and stability in the solution containing serum. In vitro drug release assay demonstrated that the DOX release rate were higher at acidic pH showing a controllable property. These HA coated PICs could targetedly deliver DOX to B16F10 tumor cells, showing improved antitumor activity.

Preparation of heparan sulfate-like polysaccharide and application in stem cell chondrogenic differentiation.

Heparan sulfate is a component of the extracellular matrix (ECM) that modulates individual development and cell growth through its interaction with growth factors. Structurally, heparan sulfate consists of repeating linear sulfated poly-anionic disaccharide structures. The K5 polysaccharide has the same structure as heparosan, and is the capsular polysaccharide of Escherichia coli K5 strain which serves as a precursor in heparin and heparan sulfate biosynthesis. Here, we prepared sulfated K5 polysaccharides that are structurally similar to heparan sulfate and investigated their biocompatibility and bioactivity in stem cell chondrogenic differentiation. Briefly, sulfation groups were added to -NH- and/or -OH of a precursor heparosan and the modified heparosan was qualitatively analyzed by FT-IR, (1)H NMR, and (13)C NMR techniques. Cell viability was not significantly affected by the sulfated K5 capsular polysaccharide. Relative mRNA expression of the chondrogenic differentiation marker COL2A1 was significantly upregulated in cells treated with the N,O-sulfated K5 polysaccharide confirming that the sulfated K5 capsular polysaccharide is able to stimulate chondrogenic differentiation. The main sulfation pattern for chondrogenic activity is N,6-O sulfation and the activity was not proportional to the sulfation level. This type of mimic was prepared in nearly a gram scale, supporting further structural study and 3 dimension stem cell culture. Together, the results of this study show that sulfated K5 capsular polysaccharides are able to stimulate chondrogenic differentiation without affecting cell viability.

Heparosan based negatively charged nanocarrier for rapid intracellular drug delivery.

In this study, a heparosan-DOX conjugate (HDC) was designed and prepared by covalently linking heparosan with anticancer drug doxorubicin (DOX) via "Schiff" base. Due to the amphiphilic nature, the HDC could self-assemble into nanoparticles in aqueous solution of pH 7.4. In spite of the surface charge of HDC nanoparticles was negative, HDC could achieve intracellular delivery of DOX efficiently. Cellular uptake study revealed the endocytosis pathway of heparosan based nanocarrier includes clathrin-mediated endocytosis and macropinocytosis, and the process of endocytosis is energy dependent. This meant the HDC would reach endosomes and behave pH-sensitive DOX release profile due to the inherent property of "Schiff" base. The cytotoxicity assay and flow cytometry analysis demonstrated the cellular uptake of HDC was faster than that of free DOX, showing improved efficacy within short co-incubation period. Furthermore, the HDC nanoparticles were stable in culture medium containing 10% FBS, indicating promising application for drug delivery.

Construction of serum resistant micelles based on heparosan for targeted cancer therapy.

A novel micelle based on heparosan and deoxycholic acid (DOCA) conjugate (HD) as drug carrier was reported here. As the surface was negatively charged, this micelle could resist serum adsorption, showing favorable stability. Moreover, fluorescence observation confirmed that it was able to deliver model hydrophobic drug doxorubicin (DOX) into HeLa cells efficiently. The DOX-loaded micelles showed sustained release behavior at pH 7.4, and accelerated release behavior at pH 5.0 or in the presence of ß-glucuronidase, which over-expressed in tumor cells. In vitro cytotoxicity assay demonstrated that the half-maximal inhibitory concentration (IC50) of DOX-loaded micelles against HeLa cells was much lower than that of COS7 cells, showing significant therapeutic distinction between tumor cells and normal cells. Combining with the good biocompatibility and biodegradability of heparosan, this micelle may be promising in clinical application for targeted drug delivery.

Fabrication of doxorubicin and heparin co-loaded microcapsules for synergistic cancer therapy.

In this study, a layer-by-layer (LbL) assembly (HEP/CHI)5 microcapsule with doxorubicin hydrochloride (DOX) encapsulating inside was fabricated via alternatively depositing heparin (HEP) and chitosan (CHI) onto DOX-loaded CaCO3 templates. The microcapsules were of stable architecture and had good dispersity in aqueous medium. Fluorescence observation showed that DOX distributed both in the wall and in the cavity of microcapsules, while HEP presented in the capsule wall. The release rate of DOX increased at acidic pH as compared with that at basic pH, suggesting a pH-responsive drug release behavior. The microcapsules with positively charged CHI lying on the outer layer could protect HEP from heparanase degradation and achieve intracellular co-delivery of both DOX and HEP. Thus, the DOX-loaded microcapsules could have improved inhibition activity against A549 cells by combining pharmacological actions of DOX and HEP.