•Tumor-derived exosomes as a novel liquid biopsy biomarker for cancer diagnosis.•MUC-1 is over-expressed on the surface of adenocarcinomas, in particular MCF-7 cells.•MUC-1 is also highly expressed ...on the surface of exosomes secreted by MCF-7 cells.•MUC-1 aptasensor of “on-off”-type specific detection of tumor exosomes in the blood.
Numerous studies have demonstrated tumor-derived exosomes (TEX) as an ideal biomarker for cancer. However, most present exosome detection methods were cumbersome and expensive, simple and specific detection of TEX in the blood still remained a challenging task. To solve the above problem, we found firstly that MUC1 was highly expressed on the surface of exosomes secreted by MCF-7 cells compared to other cells. Here, we designed an “on-off”-type aptasensor based on MUC1 activation on TEX. In the absence of TEX, the aptasensor was “off” state. Once in the presence of TEX, the aptasensor recognized the MUC1 on TEX and then turned “on” state, resulting in emitting a fluorescence signal. We used the aptasensor to detect exosomes derived from MCF-7, MCF-7/ADR, A549, MGC-803 and Hs578Bst cells and blood serum from breast cancer patients and healthy donors. The fluorescence signal value of exosomes from serum in breast cancer patients was markedly higher than healthy donors, which were a significant difference between the two groups (P < 0.05). Consequently, the method based on exosomes with high sensitivity, specificity and small amount sample were very likely to be used for breast cancer diagnosis. More importantly, this method can be universally applicable for other tumor diagnosis by changing the aptamer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Development of a radiosensitivity predictive assay is a central goal of radiation oncology. We reasoned a gene expression model could be developed to predict intrinsic radiosensitivity and treatment ...response in patients.
Radiosensitivity (determined by survival fraction at 2 Gy) was modeled as a function of gene expression, tissue of origin, ras status (mut/wt), and p53 status (mut/wt) in 48 human cancer cell lines. Ten genes were identified and used to build a rank-based linear regression algorithm to predict an intrinsic radiosensitivity index (RSI, high index = radioresistance). This model was applied to three independent cohorts treated with concurrent chemoradiation: head-and-neck cancer (HNC, n = 92); rectal cancer (n = 14); and esophageal cancer (n = 12).
Predicted RSI was significantly different in responders (R) vs. nonresponders (NR) in the rectal (RSI R vs. NR 0.32 vs. 0.46, p = 0.03), esophageal (RSI R vs. NR 0.37 vs. 0.50, p = 0.05) and combined rectal/esophageal (RSI R vs. NR 0.34 vs. 0.48, p = 0.001511) cohorts. Using a threshold RSI of 0.46, the model has a sensitivity of 80%, specificity of 82%, and positive predictive value of 86%. Finally, we evaluated the model as a prognostic marker in HNC. There was an improved 2-year locoregional control (LRC) in the predicted radiosensitive group (2-year LRC 86% vs. 61%, p = 0.05).
We validate a robust multigene expression model of intrinsic tumor radiosensitivity in three independent cohorts totaling 118 patients. To our knowledge, this is the first time that a systems biology-based radiosensitivity model is validated in multiple independent clinical datasets.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Prior observational research identified dyslipidemia as a risk factor for endometriosis (EMS) but the causal relationship remains unestablished due to inherent study limitations.
Genome-wide ...association study data for high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC) from European (EUR) and East Asian (EAS) ancestries were sourced from the Global Lipids Genetics Consortium. Multi-ancestry EMS data came from various datasets. Univariable Mendelian randomization (MR) examined causal links between serum lipids and EMS. Multivariable and mediation MR explored the influence of seven confounding factors and mediators. Drug-target MR investigates the association between lipid-lowering target genes identified in positive results and EMS. The primary method was inverse-variance weighted (IVW), with replication datasets and meta-analyses reinforcing causal associations. Sensitivity analyses included false discovery rate (FDR) correction, causal analysis using summary effect estimates (CAUSE), and colocalization analysis.
IVW analysis in EUR ancestry showed a significant causal association between TG and increased EMS risk (OR = 1.112, 95% CI 1.033-1.198, P = 5.03×10-3, PFDR = 0.03), supported by replication and meta-analyses. CAUSE analysis confirmed unbiased results (P < 0.05). Multivariable and mediation MR revealed that systolic blood pressure (Mediation effect: 7.52%, P = 0.02) and total testosterone (Mediation effect: 10.79%, P = 0.01) partly mediated this relationship. No causal links were found between other lipid traits and EMS (P > 0.05 & PFDR > 0.05). In EAS ancestry, no causal relationships with EMS were detected (P > 0.05 & PFDR > 0.05). Drug-target MR indicated suggestive evidence for the influence of ANGPTL3 on EMS mediated through TG (OR = 0.798, 95% CI 0.670-0.951, P = 0.01, PFDR = 0.04, PP.H4 = 0.85%).
This MR study in EUR ancestry indicated an increased EMS risk with higher serum TG levels.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Spatiotemporal (2001–2017) characterization of sediment metal concentrations were assessed in 31 small craft harbours (SCHs) in Nova Scotia, Canada by analyzing secondary data from government ...sediment assessment reports. Surficial sediment samples (n = 576) were collected prior to routine maintenance or constriction dredging activities. Sediment metal concentration ranges were 0.5–62 (As), 0.05–3.8 (Cd), 1–305 (Cr), 0.5–220 (Cu), 0.003–1.85 (Hg), 0.73–583 (Pb) and 5–2300 (Zn) mg/kg (dw), respectively. Most sediment metal concentrations (>56% of samples) were below low effect level and >96% were below high effect level sediment quality guidelines, suggesting limited ecological impairment to marine biota. Despite wide temporal coverage (16 years), large variation in sediment concentrations across SCHs were likely due to regular dredging activities preventing long-term accumulation of contaminants. Spatial distribution and enrichment factor results revealed that Canso was most impacted by metals, followed by Clarks Harbour.
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•Small craft harbours (SCHs) are crucial to the Canadian fishing industry.•Metal concentrations were assessed in 31 SCHs in Nova Scotia from 2001 to 2017.•Metal concentrations were compared to Canadian and US sediment quality guidelines.•Few SCHs exceeded high effect SQG thresholds indicating limited risk to aquatic biota.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Herein, a pH/ultrasound dual‐responsive gas generator is reported, which is based on mesoporous calcium carbonate (MCC) nanoparticles by loading sonosensitizer (hematoporphyrin monomethyl ether ...(HMME)) and modifying surface hyaluronic acid (HA). After pinpointing tumor regions with prominent targeting efficiency, HMME/MCC‐HA decomposes instantaneously under the cotriggering of tumoral inherent acidic condition and ultrasound (US) irradiation, concurrently accompanying with CO2 generation and HMME release with spatial/temporal resolution. Afterward, the CO2 bubbling and bursting effect under US stimulus results in cavitation‐mediated irreversible cell necrosis, as well as the blood vessel destruction to further occlude the blood supply, providing a “bystander effect.” Meanwhile, reactive oxygen species generated from HMME can target the apoptotic pathways for effective sonodynamic therapy. Thus, the combination of apoptosis/necrosis with multimechanisms consequently results in a remarkable antitumor therapeutic efficacy, simultaneously minimizing the side effects on major organs. Moreover, the echogenic property of CO2 make the nanoplatform as a powerful ultrasound contrast agent to identify cancerous lesions. Based on the above findings, such all‐in‐one drug delivery platform of HMME/MCC‐HA is utilized to provide the US imaging guidance for therapeutic inertial cavitation and sonodynamic therapy simultaneously, which highlights possibilities of advancing cancer theranostics in biomedical fields.
The sonosensitizer loaded mesoporous calcium carbonate nanoparticles decompose instantaneously under the cotriggering of tumoral inherent acidic condition and ultrasound irradiation. The released CO2 and sonosensitizer exploited the merits of synergistic combination of therapeutic inertial cavitation and sonodynamic therapy simultaneously, resulting in antitumor effects with multimechanisms.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract Single-walled carbon nanotubes (SWNTs) are special nano-materials which exhibit interesting physical and chemical properties, presenting new opportunities for biomedical research and ...applications. In this study, we have successfully adopted a novel strategy to chemically functionalize SWNTs with polyethylenimine (PEI) through purification, oxidation, amination and polymerization, which were then bound by DSPE-PEG2000-Maleimide for further conjugation with the tumor targeting NGR (Cys-Asn-Gly-Arg-Cys-) peptide via the maleimide group and sulfhydryl group of cysteine, and finally hTERT siRNA was loaded to obtain a novel tumor targeting siRNA delivery system, designated as SWNT-PEI/siRNA/NGR. The results showed that SWNT-PEI/siRNA/NGR could efficiently cross cell membrane, induced more severe apoptosis and stronger suppression in proliferation of PC-3 cells in vitro. Furthermore, in tumor-bearing mice model the delivery system exhibited higher antitumor activity due to more accumulation in tumor without obvious toxicity in main organs. The combination of RNAi and near-infrared (NIR) photothermal therapy significantly enhanced the therapeutic efficacy. In conclusion, SWNT-PEI/siRNA/NGR is a novel and promising anticancer system by combining gene therapy and photothermal therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Thyroid hormones (THs) significantly affect the cardiovascular system. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a useful biomarker for diagnosing, evaluating, and predicting outcomes ...in heart failure (HF). This comprehensive review and meta-analysis aimed to investigate the effects of thyroid dysfunction (hypothyroidism and hyperthyroidism) on NT-proBNP levels.
Two investigators independently searched PubMed, Embase, Cochrane Library, and Web of Science databases for studies published from inception to July 31, 2022, without any restrictions on language.
21 studies were included. In participants without HF, NT-proBNP levels may be elevated in those with overt hyperthyroidism (standardized mean difference SMD 2.38, 95% confidence interval CI:1.0-3.76). Notably, among patients with preexisting HF, significantly higher NT-proBNP levels were found in patients with overt hyperthyroidism, overt hypothyroidism, or subclinical hypothyroidism than in euthyroid subjects (SMD 95%CI = 0.310.01, 0.62, 0.320.08, 0.56, and 0.330.21, 0.46, respectively). Seven trials compared NT-proBNP levels in patients with thyroid dysfunction before and after therapy, and significant drops in NT-proBNP levels were observed in patients with hyperthyroidism (SMD 95%CI = -1.53-2.50, -0.55) upon achieving a euthyroid state. In contrast, increased NT-proBNP levels were observed in hypothyroid patients after treatment (SMD 95%CI = 1.070.28, 1.85).
Thyroid dysfunction can significantly affect NT-proBNP levels, which may change upon achieving a euthyroid state. Notably, the effect of thyroid dysfunction on cardiac function may depend on the underlying cardiac status. Thus, timely recognition and effective treatment of cardiac symptoms in patients with thyroid dysfunction are mandatory because the prognosis of HF may be improved with appropriate treatment of thyroid dysfunction.
https://www.crd.york.ac.uk/prospero, identifier CRD42022353700.
Gas transport in nano-scale channels has been of high complexity. The extra properties of shale gas reservoirs make it even more complicated. Therefore, accurate modeling of the apparent permeability ...of gas transport in shale gas reservoirs is urgently needed. In this work, we developed apparent permeability models for real gas transport in both nano-capillary tube and nanopores which incorporate different mechanisms including gas adsorption, stress dependence, non-Darcy flow, and surface diffusion. In particular, both monolayer and multi-layer adsorptions were included using a unified equation. The models were verified using the experimental data of gas transport in nano-capillary tube and nanopores. After that, we used the models to study the behaviors of different mechanisms of apparent permeabilities focusing on their contributions to the total apparent permeability and their sensitivity to several important parameters. We investigated the variations of apparent permeabilities with different mechanisms for gas transport under four different cases, which are, in nano-capillary tubes or nanopores, and with monolayer or multi-layer adsorptions, respectively. The results indicated that, under most real shale-gas-reservoir conditions, the corrected permeability due to gas adsorption and the non-Darcy flow permeability are dominant in the apparent permeability, while the surface diffusion permeability caused by adsorbed gas can be largely overlooked. In addition, for the cases with relatively larger sizes of nano-capillary tubes or nanopores, we observe a smaller ratio of non-Darcy flow permeability over the corrected permeability due to gas adsorption and a smaller contribution of surface diffusion as well. However, if we artificially increase the diffusion coefficient, the contribution of surface diffusion to the total apparent permeability can rapidly increase. The findings are crucial for evaluating the contribution of surface diffusion.
•We model apparent permeability for gas transport in capillary tube and nanopores.•The models include all the complex mechanisms of gas flow in nano-scale channels.•Both monolayer and multi-layer adsorptions are included using a unified equation.•The applications of our models are performed after well model verification.•The surface diffusion permeability can be overlooked in real shale gas reservoirs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
This study intends to investigate the correlation between blood pressure variability (BPV) levels and the use of optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) ...to measure retinal microvasculature in hypertensive patients.
All individuals in the study had 24-hour ambulatory blood pressure monitoring and bilateral OCT and OCTA exams, and only data from the right eye were analyzed statistically.
The study included 170 individuals, with 60 in the control group. The experimental group was separated into two groups based on the average real variability (ARV) median, with 55 in the low ARV group and 55 in the high ARV group. The mean thicknesses of the Retinal Nerve Fiber Layer (RNFL), internal limiting membrane-retinal pigment epithelial cell layer (ILM-RPE), vessel density (VD), and perfusion density (PD) in the high-ARV group were substantially lower in the low-ARV and control groups (p＜0.05). Multiple linear regression analysis revealed that disease duration, age, and 24 h diastolic standard deviation all affected RNFL mean thickness (p＜0.05). VD and PD were influenced by disease duration, systolic-ARV, daytime systolic blood pressure, intraocular pressure(IOP), and best-corrected visual acuity (BCVA) (p＜0.05). And the change in VD was connected to best-corrected visual acuity.
Hypertensive retinopathy is related to BPV. In clinical practice, we can assess the degree of BPV and retinopathy in hypertensive patients to track the progression of hypertension-mediated organ damage (HMOD). Correction of BPV may help treat or postpone the progression of HOMD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The discovery of effective biomarkers is a fundamental goal of molecular medicine. Developing a systems-biology understanding of radiosensitivity can enhance our ability of identifying ...radiation-specific biomarkers.
Radiosensitivity, as represented by the survival fraction at 2 Gy was modeled in 48 human cancer cell lines. We applied a linear regression algorithm that integrates gene expression with biological variables, including ras status (mut/wt), tissue of origin and p53 status (mut/wt).
The biomarker discovery platform is a network representation of the top 500 genes identified by linear regression analysis. This network was reduced to a 10-hub network that includes c-Jun, HDAC1, RELA (p65 subunit of NFKB), PKC-beta, SUMO-1, c-Abl, STAT1, AR, CDK1, and IRF1. Nine targets associated with radiosensitization drugs are linked to the network, demonstrating clinical relevance. Furthermore, the model identified four significant radiosensitivity clusters of terms and genes. Ras was a dominant variable in the analysis, as was the tissue of origin, and their interaction with gene expression but not p53. Overrepresented biological pathways differed between clusters but included DNA repair, cell cycle, apoptosis, and metabolism. The c-Jun network hub was validated using a knockdown approach in 8 human cell lines representing lung, colon, and breast cancers.
We have developed a novel radiation-biomarker discovery platform using a systems biology modeling approach. We believe this platform will play a central role in the integration of biology into clinical radiation oncology practice.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
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