A 5-Hydroxymethylcytosine-Based Noninvasive Model for Early Detection of Colorectal Carcinomas and Advanced Adenomas: The METHOD-2 Study.

PURPOSE: Detection of colorectal carcinomas at a time when there are more treatment options is associated with better outcomes. This prospective case-control study assessed the 5-hydroxymethylcytosine (5hmC) biomarkers in circulating cell-free DNA (cfDNA) for early detection of colorectal carcinoma and advanced adenomas (AA). EXPERIMENTAL DESIGN: Plasma cfDNA samples from 2,576 study participants from the multicenter METHOD-2 study (NCT03676075) were collected, comprising patients with newly diagnosed colorectal carcinoma (n = 1,074), AA (n = 356), other solid tumors (n = 80), and non-colorectal carcinoma/AA controls (n = 1,066), followed by genome-wide 5hmC profiling using the 5hmC-Seal technique and the next-generation sequencing. A weighted diagnostic model for colorectal carcinoma (stage I-III) and AA was developed using the elastic net regularization in a discovery set and validated in independent samples. RESULTS: Distribution of 5hmC in cfDNA reflected gene regulatory relevance and tissue of origin. Besides being confirmed in internal validation, a 96-gene model achieved an area under the curve (AUC) of 90.7% for distinguishing stage I-III colorectal carcinoma from controls in 321 samples from multiple centers for external validation, regardless of primary location or mutation status. This model also showed cancer-type specificity as well as high capacity for distinguishing AA from controls with an AUC of 78.6%. Functionally, differential 5hmC features associated with colorectal carcinoma and AA demonstrated relevance to colorectal carcinoma biology, including pathways such as calcium and MAPK signaling. CONCLUSIONS: Genome-wide mapping of 5hmC in cfDNA shows promise as a highly sensitive and specific noninvasive blood test to be integrated into screening programs for improving early detection of colorectal carcinoma and high-risk AA.

A Highly Sensitive and Specific Non-Invasive Test through Genome-Wide 5-Hydroxymethylation Mapping for Early Detection of Lung Cancer.

Low-dose computed tomography screening can increase the detection for non-small-cell lung cancer (NSCLC). To improve the diagnostic accuracy of early-stage NSCLC detection, ultrasensitive methods are used to detect cell-free DNA (cfDNA) 5-hydroxymethylcytosine (5hmC) in plasma. Genome-wide 5hmC is profiled in 1990 cfDNA samples collected from patients with non-small cell lung cancer (NSCLC, n = 727), healthy controls (HEA, n = 1,092), as well as patients with small cell lung cancer (SCLC, n = 41), followed by sample randomization, differential analysis, feature selection, and modeling using a machine learning approach. Differentially modified features reflecting tissue origin. A weighted diagnostic model comprised of 105 features is developed to compute a detection score for each individual, which showed an area under the curve (AUC) range of 86.4%-93.1% in the internal and external validation sets for distinguishing lung cancer from HEA controls, significantly outperforming serum biomarkers (p < 0.001). The 5hmC-based model detected high-risk pulmonary nodules (AUC: 82%)and lung cancer of different subtypes with high accuracy as well. A highly sensitive and specific blood-based test is developed for detecting lung cancer. The 5hmC biomarkers in cfDNA offer a promising blood-based test for lung cancer.

PETCH-DB: a Portal for Exploring Tissue-specific and Complex disease-associated 5-Hydroxymethylcytosines.

Epigenetic modifications play critical roles in gene regulation and disease pathobiology. Highly sensitive enabling technologies, including microarray- and sequencing-based approaches have allowed genome-wide profiling of cytosine modifications in DNAs in clinical samples to facilitate discovery of epigenetic biomarkers for disease diagnosis and prognosis. Historically, many previous studies, however, did not distinguish the most investigated 5-methylcytosines (5mC) from other modified cytosines, especially the biochemically stable 5-hydroxymethylcytosines (5hmC), which have been shown to have a distinct genomic distribution and regulatory role from 5mC. Notably, during the past several years, the 5hmC-Seal, a highly sensitive chemical labeling technique, has been demonstrated to be a powerful tool for genome-wide profiling of 5hmC in clinically feasible biospecimens (e.g. a few milliliter of plasma or serum). The 5hmC-Seal technique has been utilized by our team in biomarker discovery for human cancers and other complex diseases using circulating cell-free DNA (cfDNA), as well as the characterization of the first 5hmC Human Tissue Map. Convenient access to the accumulating 5hmC-Seal data will allow the research community to validate and re-use these results, potentially providing novel insights into epigenetic contribution to a range of human diseases. Here we introduce the PETCH-DB, an integrated database that was implemented to provide 5hmC-related results generated using the 5hmC-Seal technique. We aim the PETCH-DB to be a central portal, which will be available to the scientific community with regularly updated 5hmC data in clinical samples to reflect current advances in this field. Database URL http://petch-db.org/.

PETCH-DB: a Portal for Exploring Tissue-specific and Complex disease-associated 5-Hydroxymethylcytosines.

Epigenetic modifications play critical roles in gene regulation and disease pathobiology. Highly sensitive enabling technologies, including microarray- and sequencing-based approaches have allowed genome-wide profiling of cytosine modifications in DNAs in clinical samples to facilitate discovery of epigenetic biomarkers for disease diagnosis and prognosis. Historically, many previous studies, however, did not distinguish the most investigated 5-methylcytosines (5mC) from other modified cytosines, especially the biochemically stable 5-hydroxymethylcytosines (5hmC), which have been shown to have a distinct genomic distribution and regulatory role from 5mC. Notably, during the past several years, the 5hmC-Seal, a highly sensitive chemical labeling technique, has been demonstrated to be a powerful tool for genome-wide profiling of 5hmC in clinically feasible biospecimens (e.g. a few milliliter of plasma or serum). The 5hmC-Seal technique has been utilized by our team in biomarker discovery for human cancers and other complex diseases using circulating cell-free DNA (cfDNA), as well as the characterization of the first 5hmC Human Tissue Map. Convenient access to the accumulating 5hmC-Seal data will allow the research community to validate and re-use these results, potentially providing novel insights into epigenetic contribution to a range of human diseases. Here we introduce the PETCH-DB, an integrated database that was implemented to provide 5hmC-related results generated using the 5hmC-Seal technique. We aim the PETCH-DB to be a central portal, which will be available to the scientific community with regularly updated 5hmC data in clinical samples to reflect current advances in this field. Database URL http://petch-db.org/.

Rapid Gas-Phase Synthesis of the Perovskite-Type BaCe0.7Zr0.1Y0.1Yb0.1O3-δ Proton-Conducting Nanocrystalline Electrolyte for Intermediate-Temperature Solid Oxide Fuel Cells.

Perovskite-type proton-conducting materials, such as BaCe0.7Zr0.1Y0.1Yb0.1O3-δ (BCZYYb), are very attractive for the next-generation equipment of electrochemical energy conversion and storage owing to their excellent conductivity in the intermediate-temperature range (300-750 °C), as well as good thermo-chemical stability, coking resistance, and sulfur tolerance. However, the lack of a reliable and cost-effective synthesis method for such multi-component co-doping oxides limits their large-scale application. In this study, for the first time, we successfully synthesize BCZYYb electrolyte nanopowders by using a rapid, scalable flame-based gas-phase synthesis method with two different barium precursors Ba(NO3)2 and Ba(CH3COO)2, named as BCZYYb (N) and BCZYYb (CA). The as-synthesized nanoparticles exhibit good crystallinity of the pure orthorhombic perovskite BCZYYb phase. BCZYYb (CA) shows more uniform doping with the element ratio of 1:0.74:0.12:0.08:0.1, which is very close to the theoretical value. The shrinkage and surface SEM (scanning electron microscope) results indicate that the flame-made powders have superior sinterability compared to the sol-gel-made powders because of the smaller primary particle size (∼20 nm). Electrochemical impedance spectroscopy tests show that BCZYYb (CA) sintered at 1450 °C has the highest protonic conductivity of 1.31 × 10-2 S cm-1 in wet H2 when operating at 600 °C and still maintains a high-level conductivity of 1.19 × 10-2 S cm-1 even when the sintering temperature is reduced to 1350 °C, which is mainly attributed to uniform doping and good sinterability. The activation energy for the conductivity of BCZYYb (CA) is also significantly lower than that of conventional electrolytes, which suggests much better conductivity in the intermediate (∼600 °C) and even lower operating temperature. The excellent conductivity performance combined with the high-throughput production capability makes the swirling spray flame a promising synthesis method for promoting the BCZYYb electrolytes from lab to industrial-scale solid oxide fuel cells.

Guest-Induced Switchable Breathing Behavior in a Flexible Metal-Organic Framework with Pronounced Negative Gas Pressure.

Flexible metal-organic frameworks (MOFs) have attracted great interest for their dynamically structural transformability in response to external stimuli. Herein, we report a switchable "breathing" or "gate-opening" behavior associated with the phase transformation between a narrow pore (np) and a large pore (lp) in a flexible pillared-layered MOF, denoted as MOF-1 as, which is also confirmed by SCXRD and PXRD. The desolvated phase (MOF-1 des) features a unique stepwise adsorption isotherm for N2 coupled with a pronounced negative gas adsorption pressure. For comparison, however, no appreciable CO2 adsorption and gate-opening phenomenon with stepwise sorption can be observed. Furthermore, the polar micropore walls decorated with thiophene groups in MOF-1 des reveals the selective sorption of toluene over benzene and p-xylene associated with self-structural adjustment in spite of the markedly similar physicochemical properties of these vapor molecules.

Effectiveness of ozonated saline in the treatment of VX2 tumors in rabbits.

Objective To investigate the efficacy, safety, and associated mechanisms of injected ozonated saline in the treatment of VX2 tumors. Methods A total of 90 rabbits bearing VX2 tumors on their left hind legs were randomly divided into three groups. The control group (A) received normal saline, while groups B and C received 20 µg/mL and 40 µg/mL O3/O2 ozonated saline, respectively. Rabbits were anesthetized and 2 mL of blood was drawn directly from the heart to measure serum concentrations of interleukin (IL-6) and tumor necrosis factor (TNF-α). The skin covering the VX2 tumor was cut in each rabbit and the maximum and vertical diameters of the tumors were measured under direct visualization. Several milliliters of saline, saline pre-treated with 20 µg/mL O3/O2, or saline pre-treated with 40 µg/mL O3/O2 were directly injected into the tumors of groups A, B, and C, respectively (injection volume (milliliter) =1/2 volume of the tumor, V = 1/2ab2). On days 4, 8 and 12 following treatment, 10 rabbits were randomly selected from each group for blood sample collection, and serum IL-6 and TNF-α were measured. The tumor growth rate was calculated by measuring the maximum and vertical diameters of the VX2 tumors under direct visualization. All selected rabbits were euthanized and the tumors, livers, and lungs were removed for pathological examination. The tumor necrosis rate was calculated by cutting the tumors into half along the longitudinal axis and measuring the maximum diameters of the intratumoral necrotic regions. Results The average tumor volume in the three groups increased to different degrees at each time point; however, the average tumor growth rates in groups B and C were substantially lower than that in group A, exhibiting a statistically significant difference. The difference in the tumor growth rate between group B and group C was not statistically significant. The serum concentrations of IL-6 and TNF-α increased in the three groups at each time point, with larger increases occurring in groups B and C; however, the greater increases did not reach statistical significance. Although the diameters of the necrotic areas were larger in both groups B and C than that in group A, significant differences in necrotic area diameters were only found when comparing groups A and C on days 4 and 12 following treatment. Conclusion Direct injection of different concentrations of ozonated saline into VX2 tumors significantly increased intratumoral necrosis and reduced the tumor growth rate. The associated mechanism may be partially mediated by IL-6 and TNF-α, as the serum concentrations of these molecules increased after the treatment.

A bifunctional solid oxide electrolysis cell for simultaneous CO2 utilization and synthesis gas production.

We hereby report on a pioneering and inspiring solid oxide cell which, assisted by natural gas, utilizes a bifunctional electrolysis cell configuration to effectively consume CO2 to produce CO at the cathode side and simultaneously synthesize highly valuable syngas (mixture of CO and H2) at the anode side via a one-step green process.

A Zn(II) coordination polymer and its photocycloaddition product: syntheses, structures, selective luminescence sensing of iron(III) ions and selective absorption of dyes.

One coordination polymer [Zn2(L)2(bpe)2(H2O)2] (1) (L = 4,4'-((1,2-phenylenebis(methylene))bis(oxy))dibenzoic acid; bpe = (E)-1,2-di(pyridin-4-yl)ethene) was prepared and structurally determined. Compound 1 has a chain structure in which its pair of bpe ligands is arranged in a head-to-tail manner with their C=C bonds being close enough for a [2 + 2] cycloaddition reaction. Upon exposure to UV light, compound 1 undergoes a single-crystal-to-single-crystal (SCSC) [2 + 2] photodimerization to generate one 2D coordination polymer [Zn(L)(rctt-tpcb)0.5(H2O)] (1a) (rctt (regio cis, trans, trans)-tpcb = tetrakis(4-pyridyl)cyclobutane). The tpcb ligands in the crystals of 1a show an intriguing in situ thermal isomerisation. The nanospheres of 1 can be obtained by recrystallization in DMSO/alcohol. The nanospheres of 1a can also be readily produced from the corresponding nanospheres of 1 by the photocyclodimerization method. Compared with those of 1a, the nanospheres of 1 display highly selective sensing of Fe(3+) ions over mixed metal ions through fluorescence quenching. Moreover, the nanospheres of 1a can rapidly adsorb CR (congo red), MB (methylene blue) or RhB (rhodamine B) over MO (methyl orange) from aqueous solutions. This work offers a new photoinduced post-synthetic method for the synthesis of multifunctional MOFs, which show luminescence sensing of Fe(3+) ions and dye adsorption properties.