The screening and diagnosis of cancer are hallmarks of medicine in the aging population. Recently, microRNAs have shown potential for use as biomarkers, which could advance the field of diagnostics. ...The presence of miRNA-141 in the serum has been well described in several malignancies. However, the invasive approach used for sampling represents the major limitation for its practical application and, hence, its notable absence as a method for screening the general population. In light of this, we aimed to develop a high-sensitivity microRNA (miR) biosensor for application in the diagnosis of all miR-141-associated cancers, such as colorectal cancer (CRC) and breast cancer (BC). The novelty lies in our dual-probe design, which is reliant on the hybridization of the fluorescein isothiocyanate (FITC) targeting probe onto an existing sample of urinary miR-141 in the first step, followed by complementary binding with a biotinylated probe that has been coated on a modified screen-printed carbon electrode (SPCE). The hybridization of the probe and sensor produces signals via the catalytic reduction of H
O
at HRP-modified SPCEs in the presence of H
O, which was measured by either cyclic voltammetry or chronoamperometry (CA) currents. In our study, the detection and expression of miR-141 in a cohort of colorectal cancer (
= 6) and breast cancer (
= 4) samples showed that its levels were significantly higher than in a healthy cohort (
= 9) (
< 0.004). Moreover, our miR sensor demonstrated high stability, reliability, and sensitivity (
< 0.0001). This work hopefully provides new information for the detection and monitoring of de novo and existing cancers.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
We aimed to determine whether cardiovascular (CV) risk in patients with prostate cancer (PCa) differs between those who receive gonadotropin‐releasing hormone (GnRH) agonist (GnRHa) ...therapy and those who receive GnRH antagonist therapy.
Methods
Using the Taiwan National Health Insurance Research Database, we analyzed data by comparing 666 participants receiving GnRH antagonists and 1332 propensity score‐matched participants treated with GnRHa in a 1:2 fashion during the period from May 1, 2015, to September 30, 2018. Cox proportional‐hazards models were used to estimate the treatment effect on CV outcomes. Furthermore, we conducted an in vitro study to investigate the effect of a GnRHa (leuprolide) or a GnRH antagonist (degarelix) on matrix metalloproteinase‐9 (MMP‐9) expression and invasion ability in THP‐1 differentiated macrophages.
Results
GnRH antagonist therapy was associated with a lower risk of composite CV events of myocardial infarction, ischemic stroke, or CV death (hazard ratio HR, 0.48; 95% confidence interval CI, 0.25–0.90) than GnRHa therapy, with a mean follow‐up period of 1.21 years. Significantly lower risks of CV death (HR, 0.21; 95% CI, 0.06–0.70) and all‐cause mortality (HR, 0.77; 95% CI, 0.61–0.97) were observed in the GnRH antagonist group. In the in vitro study, leuprolide, but not degarelix, significantly increased the expression of MMP‐9 activity and the invasive ability of THP‐1 differentiated macrophages through gelatin zymography and the matrix invasion assay, respectively.
Conclusion
GnRH antagonists were associated with reduced risk CV events compared with the GnRHa among patients with PCa, which may be through effects on macrophages.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
•InZnxOy sensing film on flexible PET using a simple sol-gel method for an EGFET pH sensor.•InZnxOy EGFET sensor showed an excellent sensing performance in terms of sensitivity, hysteresis and ...drift.•InZnxOy EGFET flexible biosensor exhibited a high sensitivity of 10.69 mV/log(dopamine) in the range from 1 fM to 1 nM.
With the aim of a simple, label-free, and highly specific dopamine detection, we proposed an indium-zinc oxide (InZnxOy) sensing film on flexible PET using a simple sol-gel method for an extended gate field-effect transistor (EGFET) sensor. In this study, X-ray diffraction, atomic force spectroscopy, and X-ray photoelectron spectroscopy were used to characterize the structural, morphological, and chemical features, respectively. The InZnxOy based EGFET sensor showed a super Nernstian pH response of 61.53 mV/pH with an excellent linearity of 0.995 (in the range of pH 2–12), a low hysteresis voltage of ∼ 3 mV (in the pH loop of 7→4→7→10→7) and a small drift rate of 3.52 mV/h (in the pH 7). Correspondingly, to investigate the impact of mechanical bending on the pH performances of InZnxOy based flexible EGFET sensor, a couple of bending tests, which include different bending radius and bending cycles, were performed. The device showed better mechanical durability up to 1500 bending cycles for pH sensitivity. In order to achieve the label-free detection of dopamine, the InZnxOy on PET-based EGFET was functionalized using a synthetic receptor named 4-carboxylphenylboronic acid, for the covalent binding of dopamine on the sensing surface. The sensitivity of dopamine is 10.69 mV/log(dopamine) with linearity 0.998 within the dopamine concentration range of 1 fM–1 nM and the limit of detection value is 0.523 fM. In addition, this InZnxOy based EGFET biosensor showed excellent selectivity to dopamine over other interfering chemicals. Our proposed InZnxOy EGFET biosensor was successfully applied to detect dopamine level in the real samples like rat blood serum and rat brain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
DNA N6-methyldeoxyadenosine (6mA) is rarely present in mammalian cells and its nuclear role remains elusive.
Here we show that hypoxia induces nuclear 6mA modification through a DNA ...methyltransferase, METTL4, in hypoxia-induced epithelial-mesenchymal transition (EMT) and tumor metastasis. Co-expression of METTL4 and 6mA represents a prognosis marker for upper tract urothelial cancer patients. By RNA sequencing and 6mA chromatin immunoprecipitation-exonuclease digestion followed by sequencing, we identify lncRNA RP11-390F4.3 and one novel HIF-1α co-activator, ZMIZ1, that are co-regulated by hypoxia and METTL4. Other genes involved in hypoxia-mediated phenotypes are also regulated by 6mA modification. Quantitative chromatin isolation by RNA purification assay shows the occupancy of lncRNA RP11-390F4.3 on the promoters of multiple EMT regulators, indicating lncRNA-chromatin interaction. Knockdown of lncRNA RP11-390F4.3 abolishes METTL4-mediated tumor metastasis. We demonstrate that ZMIZ1 is an essential co-activator of HIF-1α.
We show that hypoxia results in enriched 6mA levels in mammalian tumor cells through METTL4. This METTL4-mediated nuclear 6mA deposition induces tumor metastasis through activating multiple metastasis-inducing genes. METTL4 is characterized as a potential therapeutic target in hypoxic tumors.
Urothelial carcinoma in the upper tract is rare and often discussed separately. Many established risk factors were identified for the disease, including genetic and external risk factors. ...Radiographic survey, endoscopic examination and urine cytology remained the most important diagnostic modalities. In localized upper tract urothelial carcinomas, radical nephroureterectomy with bladder cuff excision are the gold standard for large, high‐grade and suspected invasive tumors of the renal pelvis and proximal ureter, whereas kidney‐sparing surgeries should be considered in patients with low‐risk disease. Advances in technology have given endoscopic surgery an important role, not only in diagnosis, but also in treatment. Although platinum‐based combination chemotherapy is efficacious in advanced or metastatic disease, current established chemotherapy regimens are toxic and lack a sustained response. Immune checkpoint inhibitors have led to a new era of treatment for advanced or metastatic urothelial carcinomas. The remarkable results achieved thus far show that immunotherapy will likely be the future treatment paradigm. The combination of immune checkpoint inhibitors and other agents is another inspiring avenue to explore that could benefit even more patients. With respect to the high incidence rate and different clinical appearance of upper tract urothelial carcinomas in Taiwan, a possible correlation exists between exposure to certain external risk factors, such as arsenic in drinking water and aristolochic acid in Chinese herbal medicine. As more gene sequencing differences between upper tract urothelial carcinomas and various disease causes are detailed, this has warranted the era of individualized screening and treatment for the disease.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Sarcomatoid renal cell carcinoma (sRCC) is an aggressive subtype of RCC. In the current study, we investigated whether the POLR2A and RUNX2 genes are involved in RCC-related signaling pathway and ...associated with miR-378.
Thirteen formalin-fixed and paraffin-embedded RCC samples were collected. Three software programs were used to predict the potential gene regulation in RCC by miR-378 and immunohistochemistry analysis was applied to confirm the expression of targeted proteins in FFPE samples. MicroRNA-378 transfection, analysis of mRNA and protein expression via Western Blotting and cell apoptosis analysis via flow cytometry for POLR2A and RUNX2 were further studied in four renal cell carcinoma cell lines.
Both the mRNA and protein expression levels of POLR2A and RUNX2 in sRCC cell lines and were significantly higher than those in other subtypes of RCC, and similar results were obtained in clinical samples (p<0.01). Second, overexpression of miR-378 significantly suppressed the expression of POLR2A and RUNX2 in sRCC cells (p<0.01) and enhanced apoptosis (p<0.05).
miR-378 significantly inhibits the expression of POLR2A and RUNX2 in sRCC and further promotes apoptosis of sRCC cells. We speculated that the apoptosis mechanism in sRCC occurs via regulation of the ERK2 and PI3K/AKT pathways, which might distinguish it from other subtypes of RCC.
In this article, the TaOx/Ta stacked sensing films as sensing membranes were deposited onto n+-type Si substrate by a radio-frequency (RF) magnetron sputtering technique for solid-state extended-gate ...field-effect transistor (EGFET) pH sensors. The effect of rapid thermal annealing (RTA) treatment (300–700 °C) on structural properties of the TaOx/Ta stacked sensing films was investigated in detail. The chemical compositions, element profiles, crystallographic structures, surface morphologies, and film microstructures of the TaOx/Ta stacked sensing films were characterized by X-ray photoelectron spectroscopy, Auger electron spectroscopy, X-ray diffraction, atomic force microscopy, and transmission electron microscopy, respectively. The sensing performance of the TaOx/Ta stacked sensing films is most closely correlated with their relative structural features. Among these RTA temperatures, the best sensing performance including pH sensitivity, hysteresis and drift was achieved at the RTA temperature of 500 °C. The obtained experimental results showed that the TaOx/Ta stacked sensing film is considered a feasible alternative for pH sensor and biosensor applications.
•Impact of RTA treatment on the structural and sensing properties of TaOx sensing films was studied.•TaOx EGFET sensor with the 500 °C exhibited the best sensing performance.•pH response is Super-Nernstian with more than one proton per electron.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
With the rising importance of pH detection in biomedical diagnostic applications and environmental monitoring systems, it is crucial to develop a highly efficient, cost-effective, and stable ...electrochemical pH sensor device. This study reports the effect of silver doping on the structural properties and electrical characteristics of the RuAgxOy films for an EGFET (extended-gate field-effect transistor) sensor. The RuAgxOy sensing film was fabricated by a sol-gel spin coating technique using different silver doping concentrations, i.e. 1, 3 and 5 mol%. These synthesized RuAgxOy films were determined by X-ray diffraction, atomic force microscopy, X-ray photoelectron spectroscopy, and energy-dispersive X-ray spectroscopy with elemental mapping to study their structural properties, surface morphologies, chemical characteristics as well as their compositions and elemental distributions, respectively. The RuAgxOy sensor treated at an Ag doping concentration of 3 mol% showed a pH sensitivity of 61.38 mV/pH over the pH 2–12 range with an outstanding linearity of 0.996. This fabricated sensor exhibited an excellent reversibility associated with a lower hysteresis voltage of 3 mV and a smaller drift rate of 0.23 mV/h. Furthermore, the pH sensing performance of the RuAgxOy EGFET sensor processed with the 3 mol% condition remained constant after 500 repeated bending cycles. These results suggested that the smaller grain size, finer surface, and the presence of the metal Ag0 with larger atomic radius provide free electrons on the surface, resulting in elevated electrical conductivity of the RuAgxOy sensing platform.
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•Impact of silver content on structural properties and sensing performances of RuAgxOy films for EGFET sensors.•RuAgxOy based EGFET sensor processed at 3 mol% Ag concentration showed good sensing performance.•Presence of metallic Ag0 with higher atomic radius offering free electrons on the surface.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Many traditional pharmacopeias include
and related plants, which contain nephrotoxins and mutagens in the form of aristolochic acids and similar compounds (collectively, AA). AA is implicated in ...multiple cancer types, sometimes with very high mutational burdens, especially in upper tract urothelial cancers (UTUCs). AA-associated kidney failure and UTUCs are prevalent in Taiwan, but AA's role in hepatocellular carcinomas (HCCs) there remains unexplored. Therefore, we sequenced the whole exomes of 98 HCCs from two hospitals in Taiwan and found that 78% showed the distinctive mutational signature of AA exposure, accounting for most of the nonsilent mutations in known cancer driver genes. We then searched for the AA signature in 1400 HCCs from diverse geographic regions. Consistent with exposure through known herbal medicines, 47% of Chinese HCCs showed the signature, albeit with lower mutation loads than in Taiwan. In addition, 29% of HCCs from Southeast Asia showed the signature. The AA signature was also detected in 13 and 2.7% of HCCs from Korea and Japan as well as in 4.8 and 1.7% of HCCs from North America and Europe, respectively, excluding one U.S. hospital where 22% of 87 "Asian" HCCs had the signature. Thus, AA exposure is geographically widespread. Asia, especially Taiwan, appears to be much more extensively affected, which is consistent with other evidence of patterns of AA exposure. We propose that additional measures aimed at primary prevention through avoidance of AA exposure and investigation of possible approaches to secondary prevention are warranted.
In this research, we used a polycrystalline silicon nanowire field-effect transistor (poly-Si NWFET) as a biosensor that employs the sidewall spacer technique instead of an expensive electron beam ...lithography method. When compared with commercial semiconductor processes, the sidewall spacer technique has the advantages of simplicity and low cost. In this study, we employed a novel poly-Si NWFET device for real-time, label-free, and ultrahigh-sensitivity detection of prostate-specific antigen (PSA) in human serum. Since serum proteome is very complex containing high levels of salts and other interfering compounds, we hereby developed a standard operating procedure for real-sample pretreatment to keep a proper pH value and ionic strength of the desalted serum and also utilized Tween 20 to serve as the passivation agent by surface modification on the NWFET to reduce nonspecific binding for medical diagnostic applications. We first modified 3-aminopropyltriethoxysilane on the surface of a poly-Si nanowire device followed by glutaraldehyde functionalization, and the PSA antibodies were immobilized on the aldehyde terminal. While PSA was prepared in the buffers to maintain an appropriate pH value and ionic strength, the results indicated that the sensor could detect trace PSA at less than 5 fg/mL in a microfluidic channel. The novel poly-Si NWFET is developed as a diagnostic platform for monitoring prostate cancer and predicting the risk of early biochemical relapse.
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