Single nucleotide polymorphisms in the mitochondrial displacement loop and outcome of esophageal squamous cell carcinoma

<p>Abstract</p> <p>Backgroud</p> <p>Accumulation of single nucleotide polymorphisms (SNPs) in the displacement loop (D-loop) of mitochondrial DNA (mtDNA) has been described for different types of cancers and might be associated with cancer risk and disease outcome. We used a population-based series of esophageal squamous cell carcinoma (ESCC) patients for investigating the prediction power of SNPs in mitochondrial D-loop.</p> <p>Methods</p> <p>The D-loop region of mtDNA was sequenced for 60 ESCC patients recorded in the Fourth Hospital of Hebei Medical University between 2003 and 2004. The 5 year survival curve were calculated with the Kaplan-Meier method and compared by the log-rank test at each SNP site, a multivariate survival analysis was also performed with the Cox proportional hazards method.</p> <p>Results</p> <p>The SNP sites of nucleotides 16274G/A, 16278C/T and 16399A/G were identified for prediction of post-operational survival by the log-rank test. In an overall multivariate analysis, the 16278 and 16399 alleles were identified as independent predictors of ESCC outcome. The length of survival of patients with the minor allele 16278T genotype was significantly shorter than that of patients with 16278C at the 16278 site (relative risk, 3.001; 95% CI, 1.029 - 8.756; <it>p </it>= 0.044). The length of survival of patients with the minor allele 16399G genotype was significantly shorter than that of patients with the more frequent allele 16399A at the 16399 site in ESCC patients (relative risk, 3.483; 95% CI, 1.068 - 11.359; <it>p </it>= 0.039).</p> <p>Conclusion</p> <p>Genetic polymorphisms in the D-loop are independent prognostic markers for patients with ESCC. Accordingly, the analysis of genetic polymorphisms in the mitochondrial D-loop can help identify patient subgroups at high risk of a poor disease outcome.</p

Clinical biomarkers for thyroid immune-related adverse events in patients with stage III and IV gastrointestinal tumors

BackgroundThyroid immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) treatment appear to correlate with a better prognosis. We aimed to investigate clinical biomarkers associated with thyroid irAEs.MethodsWe retrospectively analyzed data from 129 patients receiving programmed cell death protein 1 (PD-1) inhibitors for stage III and IV gastrointestinal tumors. Patients were divided into two groups: “thyroid irAEs” group and “no thyroid irAEs” group. We compared continuous variables using Mann–Whitney U and Kruskal–Wallis tests and categorical variables using Pearson’s chi–square test. Survival curves were generated using the Kaplan–Meier method, and associations between clinical features and thyroid irAEs were assessed using univariate and multivariate logistic regression models. Associations for thyroid irAEs and outcomes [progression-free survival (PFS), overall survival (OS)] of the patients were performed with a Cox proportional hazard model.ResultsA total of 129 patients, including 66 gastric cancer, 30 esophageal squamous cell carcinoma, and 33 hepatocellular carcinoma (HCC), were involved in this analysis with 47 cases of thyroid irAEs occurrence. The Cox proportional hazard model analysis confirmed the extended PFS [hazard rate (HR) = 0.447, 95% confidence interval (CI): 0.215 to 0.931, p = 0.031] and OS (HR = 0.424, 95% CI: 0.201 to 0.893, p = 0.024) for thyroid irAEs group when compared with those of the no thyroid irAEs group. Association between thyroid irAEs and clinical characteristics at baseline was analyzed subsequently by univariate analysis. Higher body mass index (p = 0.005), increased eosinophil count (p = 0.014), increased lactate dehydrogenase (p = 0.008), higher baseline thyroid stimulating hormone (TSH) (p = 0.001), HCC (p = 0.001) and increased adenosine deaminase (ADA) (p = 0.001) were linked with thyroid irAEs occurrence. The multivariable logistic regression model indicated that ADA [odds rate (OR) = 4.756, 95% CI: 1.147 to 19.729, p = 0.032] was independently associated with thyroid irAEs occurrence.ConclusionsIncreased baseline level of ADA was associated with thyroid irAEs occurrence in patients with advanced gastrointestinal tumors who received ICI treatment. In the case of abnormal ADA, attention should be paid to the risk of thyroid irAEs

Parkin Modulates ERRα/eNOS Signaling Pathway in Endothelial Cells

Background/Aims: Although a number of reports documented the important role of parkin in mitophagy, emerging evidence also indicated additional functions of parkin besides mitophagy. The present study was undertaken to investigate the role of parkin in the regulation of ERRα/eNOS pathway in endothelial cells (ECs). Methods: Mouse aortic endothelial cells (MAECs) and cardiac muscle HL-1 cells were transfected with parkin plasmid or siRNA. ERRα inhibitor XCT-790, autophagy inhibitor 3-MA and Bafilomycin A1, and caspase inhibitor Z-VAD-FMK were used to block autophagy or apoptosis. Western blotting was performed to examine the protein levels. Flow cytometry was applied to determine the cell apoptosis and ROS production. Mitochondrial membrane potential was measured using JC-1 and TMRM. Immunoprecipitation was performed to confirm the parkin effect on ERRα ubiquitination. Results: Overexpression of parkin resulted in a significant reduction of total-eNOS and p-eNOS in parallel with the downregulation of ERRα (a regulator of eNOS) protein and the enhancement of ERRα ubiquitination. To test the role of ERRα in regulating eNOS in this experimental setting, we treated ECs with ERRα inhibitor and found a decrement of total-eNOS and p-eNOS. On the contrary, overexpression of ERRα increased the levels of total-eNOS and p-eNOS. Meanwhile, parkin overexpression induced mitochondrial dysfunction and cell apoptosis in both ECs and HL-1 cells. Finally, we confirmed that the parkin effect on the regulation of eNOS was independent of the autophagy and apoptosis. Conclusion: These findings suggested that parkin overexpression downregulated eNOS possibly through the ubiquitination of ERRα in endothelial cells

Isomeric Effects of Solution Processed Ladderâ Type Nonâ Fullerene Electron Acceptors

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138922/1/solr201700107_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138922/2/solr201700107-sup-0001-SuppData-S1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138922/3/solr201700107.pd

Trapping internal water clusters and hydrogen-bonding networks in photosynthetic oxygen evolution

To summarize the work presented in this thesis, I have investigated the structure and function of the internal hydrogen-bonding network in PSII in three different ways. In the first (Chapter 2), I used an infrared signal from a protonated water cluster in the S2 state of the OEC. When trapped at 190 K, solvent isotope exchange confirmed the spectral assignment to the internal water network. This signal then became a novel and effective probe of the effects of hydrogen bond disruption, calcium depletion and replacement, and pH change on the network. In the second (Chapter 3), I used EPR spectroscopy at 190 K to investigate the effects of these treatments on the EPR signal and decay rate of YZ radical. The radical was trapped in the S2 state and decayed by coupled proton and electron transfer through recombination with QA−. A correlation was discovered between the intensity of the protonated water cluster and conditions that altered YZ radical decay rates. In the third (Chapter 4), I used reaction induced FT-IR spectroscopy to obtain structural information concerning YZ radical and YZ singlet in the S2 state. Calcium depletion and replacement was employed. This third approach provides a new high-resolution method to define the structure of the radical and singlet state in the presence of an intact metal cluster.Ph.D

Calcium, Ammonia, Redox-Active Tyrosine YZ, and Proton-Coupled Electron Transfer in the Photosynthetic Oxygen-Evolving Complex

A redox-active tyrosine, YZ (Y161 in the D1 polypeptide), is essential in photosystem II (PSII), which conducts photosynthetic oxygen evolution. On each step of the light-driven oxygen evolving reaction, YZ radical is formed by a chlorophyll cation radical. YZ radical is then reduced by a Mn₄CaO₅ cluster in a proton coupled electron transfer (PCET) reaction. YZ is hydrogen bonded to His190-D1 and to water molecules in a hydrogen-bonding network, involving calcium. This network is sensitive to disruption with ammonia and to removal and replacement of calcium. Only strontium supports activity. Here, we use electron paramagnetic resonance (EPR) spectroscopy to define the influence of ammonia treatment, calcium removal, and strontium/barium substitution on YZ radical PCET at two pH values. A defined oxidation state of the metal cluster (S₂) was trapped by illumination at 190 K. The net reduction and protonation of YZ radical via PCET were monitored by EPR transients collected after a 532 nm laser flash. At 190 K, YZ radical cannot oxidize the Mn₄CaO₅ cluster and decays on the seconds time scale by recombination with Q_A^–. The overall decay half-time and biexponential fits were used to analyze the results. The reaction rate was independent of pH in control, calcium-reconstituted PSII (Ca-PSII). At pH 7.5, the YZ radical decay rate decreased in calcium-depleted (CD-PSII) and barium/strontium-reconstituted PSII (Ba-PSII, Sr-PSII), relative to Ca-PSII. At pH 6.0, the YZ radical decay rate was not significantly altered in CD-PSII and Sr-PSII but decreased in Ba-PSII. A two-pathway model, involving two competing proton donors with different p<i>K</i>_a values, is proposed to explain these results. Ammonia treatment decreased the YZ decay rate in Ca-PSII, Sr-PSII, and CD-PSII, consistent with a reaction that is mediated by the hydrogen-bonding network. However, ammonia treatment did not alter the rate in Ba-PSII. This result is interpreted in terms of the large ionic radius of barium and the elevated p<i>K</i>_a of barium-bound water, which are expected to disrupt hydrogen bonding. In addition, evidence for a functional interaction between the S₂ protonated water cluster (W_n⁺) and the YZ proton donation pathway is presented. This interaction is proposed to increase the rate of the YZ PCET reaction

Coal-Based Semicoke-Derived Carbon Anode Materials with Tunable Microcrystalline Structure for Fast Lithium-Ion Storage

Fast charging capability is highly desired for new generation lithium-ion batteries used in consumer-grade electronic devices and electric vehicles. However, currently used anodes suffer from sluggish ion kinetics due to limited interlayer distance. Herein, the coal-based semicoke was chosen as precursor to prepare cost-effective carbon anodes with high-rate performance through a facile pyrolytic strategy. The evolution of microstructure and its effect on electrochemical performance are entirely studied. The results show that large number of short-ordered defective structures are generated due to the occurrence of turbostatic-like structures when pyrolyzed at 900 °C, which are propitious to large interlayer distance and developed porous structure. High accessible surface area and large interlayer spacing with short-ordered defective domains endow the sample treated at 900 °C under argon (A900) with accelerated ion dynamics and enhanced ion adsorption dominated surface-induced capacitive processes. As a result, A900 delivers high capacity (331.1 mAh g−1 at 0.1 A g−1) and long life expectancy (94.8% after 1000 cycles at 1 A g−1) as well as good rate capability (153.2 mAh g−1 at 5 A g−1). This work opens a scalable avenue to fabricating cost-effective, high-rate, and long cycling life carbon anodes

Cryogenic Trapping and Isotope Editing Identify a Protonated Water Cluster as an Intermediate in the Photosynthetic Oxygen-Evolving Reaction

Internal water is known to play a catalytic role in several enzymes. In photosystem II (PSII), water is the substrate. To oxidize water, the PSII Mn₄CaO₅ cluster or oxygen evolving center (OEC) cycles through five oxidation states, termed S_<i>n</i> states. As reaction products, molecular oxygen is released, and protons are transferred through a ∼25 Å hydrogen-bonded network from the OEC to the thylakoid lumen. Previously, it was reported that a broad infrared band at 2880 cm^–1 is produced during the S₁-to-S₂ transition and accompanies flash-induced, S state cycling at pH 7.5. Here, we report that when the S₂ state is trapped by continuous illumination under cryogenic conditions (190 K), an analogous 2740/2900 cm^–1 band is observed. The frequency depended on the sodium chloride concentration. This band is unambiguously assigned to a normal mode of water by D₂¹⁶O and H₂¹⁸O solvent exchange. Its large, apparent H₂¹⁸O isotope shift, ammonia sensitivity, frequency, and intensity support assignment to a stretching vibration of a hydronium cation, H₃O⁺, in a small, protonated internal water cluster, <i>n</i>H₂O­(H₃O⁺). Water OH stretching bands, which may be derived from the hydration shell of the hydronium ion, are also identified. Using the 2740 cm^–1 infrared marker, the results of calcium depletion and strontium reconstitution on the protonated water cluster are found to be pH dependent. This change is attributed to protonation of an amino acid side chain and a possible change in <i>n</i>H₂O­(H₃O)⁺ localization in the hydrogen-bonding network. These results are consistent with an internal water cluster functioning as a proton acceptor and an intermediate during the S₁-to-S₂ transition. Our experiments demonstrate the utility of this infrared signal as a novel functional probe in PSII