Nickel/Photoredox-Catalyzed Carbonylative Cross-Electrophile Coupling of Organohalides and Carboxylic Acid Esters with Phenyl Formate.

A photoinduced nickel-catalyzed reductive carbonylative coupling from organohalides and N-(acyloxy)phthalimide esters with phenyl formate as the carbonyl source has been developed. This reaction could perform smoothly under mild conditions, and a series of aryl-alkyl and alkyl-alkyl unsymmetrical ketones were produced without the need of stoichiometric metal reductants. Mechanistic studies indicate that this reaction was initiated from radical capture by Ni(I)-carbonyl species and subsequent rapid carbonyl insertion.

Activation of sigma-1 receptor ameliorates sepsis-induced myocardial injury by mediating the Nrf2/HO1 signaling pathway to attenuate mitochondrial oxidative stress.

BACKGROUND: Sepsis is a condition that triggers the release of large amounts of reactive oxygen species and inflammatory factors in the body, leading to myocardial injury and cardiovascular dysfunction - an important contributor to the high mortality rate associated with sepsis. Although it has been demonstrated that the sigma-1 receptor (S1R) is essential for preventing oxidative stress, its effectiveness in treating sepsis is yet unknown. AIM: This study aimed to investigate the role and mechanisms of S1R activation in sepsis-induced myocardial injury. METHODS: A model of sepsis-induced myocardial injury was constructed by performing cecum ligation and puncture(CLP) surgery on rats. Flv or BD1047 were intraperitoneally injected into rats for one consecutive week before performing CLP, and then intraperitoneally injected into the rats again 1 h after the surgery.The effects of Flv and BD1047 were detected by HE staining, immunofluorescence staining, IHC staining, echocardiography measurements,TUNEL, oxidative stress detection, TEM, flow cytometry and western blot. We further validated the mechanism in vitro using neonatal rat cardiomyocites and H9C2 cells. RESULTS: S1R protein level was reduced in the hearts of septic rats, whereas administration of Flv, an S1R activator, ameliorated myocardial injury, mitochondrial oxidative stress, and pathological manifestations of sepsis. On the other hand, administration of the S1R inhibitor BD1047 exacerbated the mitochondrial oxidative stress, and apoptosis, as well as symptoms and pathological manifestations of sepsis. In addition, we found that up-regulation of S1R activated the Nrf2/HO1 signaling pathway and promoted nuclear translocation of Nrf2, which activated downstream proteins to generate antioxidant factors, such as HO1, in turn alleviating oxidative stress and countering myocardial damage. CONCLUSION: By scavenging ROS accumulation and reducing mitochondrial oxidative stress via the Nrf2/HO1 signaling pathway, activation of S1R improves cardiac function, mitigates death of cardiomyocytes, and attenuates sepsis-induced myocardial injury.

The Tp-e/QT ratio as a predictor of nocturnal premature ventricular contraction events in patients with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is significantly associated with a higher risk of ventricular arrhythmia (VA). QT, the Tp-e/QT ratio, and QT dispersion (QTd) are used to evaluate myocardial repolarization and are highly correlated with VA. The aim was to evaluate the predictive value of the Tp-e/QT ratio and other electrocardiogram (ECG) parameters for nocturnal premature ventricular contractions (PVCs) in patients with OSA. METHODS: We retrospectively analyzed data from patients with OSA and conducted a 1:1 matched cohort study. Patients diagnosed with OSA who met our criteria for the PVC group, and sex- and age-matched patients with OSA who met our criteria for the control group were enrolled in the study. The Tp-e, Tp-e/QT ratio, corrected QT interval (QTc), corrected Tp-e interval (Tp-ec), and QTd were measured, calculated and analyzed. RESULTS: Patients in the PVC group (n = 31) showed a greater Tp-e, Tp-ec, QTc, Tp-e/QT ratio, and QTd than patients in the control group (n = 31). In the univariate binary logistic regression analysis, higher Tp-ec (OR: 1.025; P = 0.042), QTc (OR: 1.014; P = 0.036), Tp-e/QT ratio (OR: 1.675; P < 0.001), and QTd (OR: 1.052; P = 0.012) values were all significantly associated with nocturnal PVCs. In multivariate analysis and receiver operating characteristic analysis, a higher Tp-e/QT ratio (OR: 2.168; 95% CI: 0.762-0.952; P < 0.001) was an independent predictor of nocturnal PVCs. CONCLUSIONS: The QTc, Tp-e/QT ratio, and QTd in patients with OSA with nocturnal PVCs were significantly increased compared with those in patients without nocturnal PVCs. A prolonged Tp-e/QT ratio was an independent predictor of nocturnal PVCs in patients with OSA.

Short sleep duration associated with increased risk for new-onset cardiovascular diseases in individuals with metabolic syndromes: Evidence from the China Health and Retirement Longitudinal Study.

To explore the impact and risk of short sleep duration (sleep duration < 6 h/night) on new-onset cardiovascular and cerebrovascular diseases (CVDs) in people with metabolic syndromes (Mets), this study used the 2011 baseline and 2015 follow-up data from the China Longitudinal Study of Health and Retirement (CHARLS) to conduct a prospective study of people aged ≥ 45 years in China. A total of 5,530 individuals without pre-existing CVDs in baseline were included. Mets were defined according to the harmonized criteria. We applied the Logistic Regression (LR), the Deep Neural Networks (DNN), and the Adaptive Boosting (AdaBoost), to evaluate the association between Mets components, short sleep, and the risk of new-onset CVDs, and the importance of multiple variates for new-onset CVDs. During the 4-year follow-up period, 512 individuals developed CVDs, and short sleep increased the risk of CVD in individuals with Mets. The odds ratio for prevalent CVD in Mets with short sleep group was 3.73 (95%CI 2.95-4.71; P < 0.001) compared to the normal group, and 1.99 (95% CI 1.58-2.51; P < 0.001) compared to the Mets without short sleep group. The DNN method reached the highest precision of 92.24% and f1-score of 95.86%, and the Adaboost method reached the highest recall of 99.92%. Both DNN and Adaboost have better predictive performance than LR and revealed short sleep duration and components of Mets are all the strongest predictors of CVD onset.

Lysine demethylase 3A is a positive regulator of cardiac myofibroblast transdifferentiation that increases Smad3 phosphorylation following transforming growth factor beta1 stimulation.

BACKGROUND: The epigenetic modifier molecule lysine demethylase 3A (KDM3A) has been shown to help ameliorate cardiovascular diseases, but its effect on cardiac fibroblasts (CFs) remains unclear. METHODS AND RESULTS: We designed gain- and loss-of-function experiments to investigate the biological functions of KDM3A in CFs. Moreover, we used SIS3-HCl (a specific inhibitor of p-Smad3) to explore the underlying mechanism. Cell viability and migration were verified by CCK-8 and cell migration experiments, respectively, and the degree of fibrosis was measured by Western blot analysis. Our data revealed that KDM3A enhanced the proliferation and migration of CFs and increased the fibroblast-to-myofibroblast transition while enabling the Smad3 phosphorylation response to transforming growth factor beta1 (TGFß1) stimulation. However, these effects were abolished by SIS3-HCl. Furthermore, KDM3A inhibition obviously protected against cardiac myofibroblast transdifferentiation under TGFß1 stimulation. CONCLUSIONS: KDM3A may act as a novel regulator of cardiac myofibroblast transdifferentiation through its ability to modulate the phosphorylation of Smad3 following TGFß1 stimulation.

MiR-128-3p inhibits vascular smooth muscle cell proliferation and migration by repressing FOXO4/MMP9 signaling pathway.

BACKGROUND: MicroRNAs (miRNAs) have been identified as important participants in the development of atherosclerosis (AS). The present study explored the role of miR-128-3p in the dysfunction of vascular smooth muscle cells (VSMCs) and the underlying mechanism. METHODS: Human VSMCs and ApoE knockout (ApoE-/-) C57BL/6J mice were used to establish AS cell and animal models, respectively. Expression levels of miR-128-3p, forkhead box O4 (FOXO4) and matrix metallopeptidase 9 (MMP9) were detected using qRT-PCR and Western blot, respectively. CCK-8, BrdU, and Transwell assays as well as flow cytometry analysis were performed to detect the proliferation, migration and apoptosis of VSMCs. Levels of inflammatory cytokines and lipids in human VSMCs, mice serum and mice VSMCs were also determined. The binding site between miR-128-3p and 3'UTR of FOXO4 was confirmed using luciferase reporter gene assay. RESULTS: MiR-128-3p was found to be decreased in AS patient serum, ox-LDL-treated VSMCs, AS mice serum and VSMCs of AS mice. Transfection of miR-128-3p mimics suppressed the proliferation and migration of VSMCs, accompanied by the promoted apoptosis and the decreased levels of inflammatory cytokines. Further experiments confirmed the interaction between miR-128-3p and FOXO4. Augmentation of FOXO4 or MMP9 reversed the effects of miR-128-3p. Besides, miR-128-3p inhibited triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) but increased high-density lipoprotein cholesterol (HDL-C) in the serum of AS mice. CONCLUSION: MiR-128-3p repressed the proliferation and migration of VSMCs through inhibiting the expressions of FOXO4 and MMP9.

Copper(II)-catalyzed enantioselective hydrosilylation of halo-substituted alkyl aryl and heteroaryl ketones: asymmetric synthesis of (R)-fluoxetine and (S)-duloxetine.

A set of reaction conditions has been established to facilitate the non-precious copper-catalyzed enantioselective hydrosilylation of a number of structurally diverse ß-, γ- or ε-halo-substituted alkyl aryl ketones and α-, ß- or γ-halo-substituted alkyl heteroaryl ketones under air to afford a broad spectrum of halo alcohols in high yields and good to excellent enantioselectivities (up to 99% ee). The developed procedure has been successfully applied to the asymmetric synthesis of antidepressant drugs (R)-fluoxetine and (S)-duloxetine, which highlighted its synthetic utility.

Copper-dipyridylphosphine-catalyzed hydrosilylation: enantioselective synthesis of aryl- and heteroaryl cycloalkyl alcohols.

The non-precious metal copper-catalyzed enantioselective hydrosilylation of a vast array of aryl cycloalkyl ketones with different ring sizes was studied systematically for the first time (up to 99% enantiomeric excess). The results demonstrated that the steric size of cycloalkyl groups has a significant influence on the reaction outcomes. The first stereoselective formation of a selection of cyclohexyl heteroaryl alcohols of up to 97% enantiopurity was realized as well. Dramatic temperature effects on both the enantiopurity and the absolute configuration of the alcohol products were observed in the reduction of some cyclohexyl pyridyl ketones.

[Value of QT hysteresis during treadmill exercise test for diagnosing coronary heart disease].

OBJECTIVE: To investigate the value of QT hysteresis index during treadmill exercise test (TET) in diagnosing coronary heart disease (CHD). METHODS: One hundred consecutive patients suspected for CHD were referred for TET and selective coronary angiography (CAG). Patients were divided into positive [n = 55, age (56.0 ± 7.9) years] and negative [n = 45, age (53.2 ± 6.7) years] group based on their CAG results. For each TET recording, 50 points were selected for the RR, QTp, and QTe interval measurements. QTp and QTe interval was plotted against corresponding RR interval. QT/RR curve was constructed by connect all point, QT hysteresis index was calculated for each patient. RESULTS: The QTp [(22.4 ± 10.3) ms vs. (6.7 ± 4.6) ms, P < 0.001] and QTe [(27.1 ± 11.1) ms vs. (7.6 ± 4.6) ms, P < 0.001] hysteresis index of patients in positive group were significantly higher than those in negative group. The sensitivity of QTp and QTe hysteresis index for diagnosing CHD was 89.1% (49/55) and 94.5% (52/55), respectively, and the specificity was 82.2% (37/45) and 80.0% (36/45), respectively. If the patient fulfilled both the classical TET and QT hysteresis criteria, the sensitivity for diagnosing CHD increased to 94.3% (33/35, QTp) and 94.6% (35/37, QTe), and the specificity were both 100% (26/26, 26/26). Moreover, QTp (r = -0.399, P < 0.001) and QTe (r = -0.547, P < 0.001) hysteresis index highly correlated to Duke treadmill score. CONCLUSION: QT hysteresis index is useful parameter for CHD diagnosis and which could improve the diagnostic value of TET for CHD in combination with the classical TET criteria for diagnosis of CHD.

Nickel(II)-dipyridylphosphine-catalyzed enantioselective hydrosilylation of ketones in air.

Out of thin air: Catalytic amounts of nickel(II) salt and non-racemic dipyridylphosphine ligand, as well as the stoichiometric hydride source PhSiH(3), formed an effective catalyst system for the Ni(II)-catalyzed asymmetric hydrosilylation of a diverse range of electron-deficient aryl alkyl ketones with enantioselectivities up to 90% ee. The practical potential of the protocol was evinced by its good air-stability.

Cu(II)-catalyzed asymmetric hydrosilylation of diaryl- and aryl heteroaryl ketones: application in the enantioselective synthesis of orphenadrine and neobenodine.

With certain amounts of sodium tert-butoxide and tert-butanol as additives, catalytic amounts of an inexpensive and easy-to-handle copper source Cu(OAc)(2)⋅H(2)O, a commercially available and air-stable non-racemic dipyridylphosphine ligand, as well as the stoichiometric desirable hydride donor polymethylhydrosiloxane (PMHS), formed a versatile in situ catalyst system for the enantioselective reduction of a broad spectrum of prochiral diaryl and aryl heteroarylketones in air, in high yields and with good to excellent enantioselectivities (up to 96 %). In particular, the practical viability of this process was evinced by its successful applications in the asymmetric synthesis of optically enriched potent antihistaminic drugs orphenadrine and neobenodine.

Copper(II)-catalyzed hydrosilylation of ketones using chiral dipyridylphosphane ligands: highly enantioselective synthesis of valuable alcohols.

In the presence of PhSiH(3) as the reductant, the combination of enantiomeric dipyridylphosphane ligands and Cu(OAc)(2)·H(2)O, which is an easy-to-handle and inexpensive copper salt, led to a remarkably practical and versatile chiral catalyst system. The stereoselective formation of a selection of synthetically interesting ß-, γ- or δ-halo alcohols bearing high degrees of enantiopurity (up to 99.9% enantiomeric excess (ee)) was realized with a substrate-to-ligand molar ratio (S/L) of up to 10,000. The present protocol also allowed the hydrosilylation of a diverse spectrum of alkyl aryl ketones with excellent enantioselectivities (up to 98% ee) and exceedingly high turn-over rates (up to 50,000 S/L molar ratio in 50 min reaction time) in air, under very mild conditions, which offers great opportunities for the preparation of various physiologically active targets. The synthetic utility of the chiral products obtained was highlighted by the efficient conversion of optically enriched ß-halo alcohols into the corresponding styrene oxide, ß-amino alcohol, and ß-azido alcohol, respectively.

Cobalt(II)-catalyzed asymmetric hydrosilylation of simple ketones using dipyridylphosphine ligands in air.

In the presence of PhSiH(3) as the hydride donor, catalytic amounts of non-racemic dipyridylphosphine and an easy-to-handle cobalt salt Co(OAc)(2)·4H(2)O formed in situ an effective catalyst system for the asymmetric reduction of a diverse range of aryl alkyl ketones with moderate-to-excellent enantioselectivities (up to 96% ee). This approach tolerated the handling of both catalyst and reactants under air without special precautions.

Image-guided stereotactic body radiotherapy for lung tumors using BodyLoc with tomotherapy: clinical implementation and set-up accuracy.

We investigated the use of a BodyLoc immobilization and stereotactic localization device combined with TomoTherapy megavoltage CT (MVCT) in lung stereotactic body radiotherapy (SBRT) to reduce set-up uncertainty and treatment time. Eight patients treated with 3-5 fractions of SBRT were retrospectively analyzed. A BodyLoc localizer was used in both CT simulation for localization and the initial patient treatment set-up. Patients were immobilized with a vacuum cushion on the back and a thermoplastic body cast on the anterior body. Pretreatment MVCT from the TomoTherapy unit was fused with the planning kilovoltage CT (KVCT) before each fraction of treatment to determine interfractional set-up error. The comparison of two MVCTs during a fraction of treatment resulted in the intrafractional uncertainty of the treatment. A total of 224 target isocenter shifts were analyzed to assess these inter- and intrafractional tumor motions. We found that for interfractional shifts, the mean set-up errors and standard deviations were -1.1 +/- 2.8 mm, -2.5 +/- 8.7 mm, and 4.1 +/- 2.6 mm, for lateral, longitudinal, and vertical variation, respectively; the mean setup rotational variation was -0.3 +/- 0.7 degrees; and the maximum motion was 13.5 mm in the longitudinal direction. For intrafractional shifts, the mean set-up errors and standard deviations were -0.1 +/- 0.7 mm, -0.3 +/- 2.0 mm, and 0.5 +/- 1.1 mm for the lateral, longitudinal, and vertical shifts, respectively; the mean rotational variation was 0.1 +/- 0.2 degrees; and the maximum motion was 3.8 mm in the longitudinal direction. There was no correlation among patient characteristics, set-up uncertainties, and isocenter shifts, and the interfractional set-up uncertainties were larger than the intrafractional isocenter shift. The results of this study suggested that image-guided stereotactic body radiotherapy using the BodyLoc immobilization system with TomoTherapy can improve treatment accuracy.

Analysis of daily setup variation with tomotherapy megavoltage computed tomography.

The purpose of this study was to evaluate different setup uncertainties for various anatomic sites with TomoTherapy pretreatment megavoltage computed tomography (MVCT) and to provide optimal margin guidelines for these anatomic sites. Ninety-two patients with tumors in head and neck (HN), brain, lung, abdominal, or prostate regions were included in the study. MVCT was used to verify patient position and tumor target localization before each treatment. With the anatomy registration tool, MVCT provided real-time tumor shift coordinates relative to the positions where the simulation CT was performed. Thermoplastic facemasks were used for HN and brain treatments. Vac-Lok cushions were used to immobilize the lower extremities up to the thighs for prostate patients. No respiration suppression was administered for lung and abdomen patients. The interfractional setup variations were recorded and corrected before treatment. The mean interfractional setup error was the smallest for HN among the 5 sites analyzed. The average 3D displacement in lateral, longitudinal, and vertical directions for the 5 sites ranged from 2.2-7.7 mm for HN and lung, respectively. The largest movement in the lung was 2.0 cm in the longitudinal direction, with a mean error of 6.0 mm and standard deviation of 4.8 mm. The mean interfractional rotation variation was small and ranged from 0.2-0.5 degrees, with the standard deviation ranging from 0.7-0.9 degrees. Internal organ displacement was also investigated with a posttreatment MVCT scan for HN, lung, abdomen, and prostate patients. The maximum 3D intrafractional displacement across all sites was less than 4.5 mm. The interfractional systematic errors and random errors were analyzed and the suggested margins for HN, brain, prostate, abdomen, and lung in the lateral, longitudinal, and vertical directions were between 4.2 and 8.2 mm, 5.0 mm and 12.0 mm, and 1.5 mm and 6.8 mm, respectively. We suggest that TomoTherapy pretreatment MVCT can be used to improve the accuracy of patient positioning and reduce tumor margin.

Potential of intensity-modulated radiotherapy to escalate doses to head-and-neck cancers: what is the maximal dose?

PURPOSE: To investigate the potential of intensity-modulated radiotherapy (IMRT) to escalate doses to head-and-neck cancer and find the maximal dose that could be prescribed to the target volume with IMRT while doses to critical organs were maintained at their currently acceptable levels. The secondary goal was to search for limits in current IMRT technology. METHODS AND MATERIALS: For a group of 12 head-and-neck cancer patients with different tumor locations and shapes, we performed IMRT planning using a simultaneous integrated boost strategy, that is, the gross tumor volume (GTV), clinical target volume (CTV), and electively treated nodes were treated simultaneously at different dose levels. The critical structures involved in the treatment field that needed to be spared included the brainstem, spinal cord, and parotid glands, depending on the disease site. Nine coplanar 6-MV photon beams were used for planning with the IMRT system developed at our institution, and dose-volume criteria were used for optimization. By varying the optimization parameters, we gradually increased the dose to the GTV while keeping the dose to the critical structures at less than the acceptable tolerance level. The criteria for accepting the plan included the following: (1) the prescription dose to the GTV had to cover 99% of the volume, and the dose homogeneity of the GTV needed to be <10%; (2) the prescription to the CTV (which was set either at 60 Gy or 10 Gy less than that of the GTV) had to cover 95% of the volume, and the same amount of normal tissue outside the CTV received the CTV prescription dose as in the current acceptable plan; (3) the prescription to the electively treated lymph nodes needed to cover 90% of the volume; and (4) the maximal dose to the brainstem and spinal cord had to be <55 Gy and 45 Gy, respectively. For parotid glands, the dose needed to be as low as possible without compromising the target doses. The deliverable plans as determined by the actual multileaf collimator leaf sequences were used for the final evaluation. To verify that the acceptable plans were deliverable, the experimental measurements of planar dose distribution were performed in phantom with film. RESULTS: The maximal dose to the GTV varied from 86 to 176 Gy if the CTV dose increased with the GTV dose. It was reduced to 76-82 Gy if the CTV dose was kept at 60 Gy. The competing criteria usually are the requirements of the tolerance doses to the critical organs and target dose homogeneity, not the target prescription dose. Using more beams only increased the dose marginally. The results could change significantly if a different set of criteria for the plan evaluation were used. Dosimetric measurements confirmed that such a high dose and dose gradient could be delivered accurately with dynamic multileaf collimators. Statistical analyses showed no significant correlations between the maximal doses and the number of GTVs and volume of GTVs and CTVs. CONCLUSION: Doses to head-and-neck cancers with simultaneous integrated boost IMRT can be escalated to a greater level than currently prescribed clinically. The limit of IMRT in head-and-neck cancer has not been reached at the current prescription level of 70 Gy. Such high total and fractionated doses should be carefully evaluated before being prescribed clinically.

Intensity-modulated radiotherapy optimization with gEUD-guided dose-volume objectives.

Currently, most intensity-modulated radiation therapy systems use dose-volume (DV)-based objectives. Although acceptable plans can be generated using these objectives, much trial and error is necessary to plan complex cases with many structures because numerous parameters need to be adjusted. An objective function that makes use of a generalized equivalent uniform dose (gEUD) was developed recently that has the advantage of involving simple formulae and fewer parameters. In addition, not only does the gEUD-based optimization provide the same coverage of the target, it provides significantly better protection of critical structures. However, gEUD-based optimization may not be superior once dose distributions and dose-volume histograms (DVHs) are used to evaluate the plan. Moreover, it is difficult to fine-tune the DVH with gEUD-based optimization. In this paper, we propose a method for combining the gEUD-based and DV-based optimization approaches to overcome these limitations. In this method, the gEUD optimization is performed initially to search for a solution that meets or exceeds most of the treatment objectives. Depending on the requirements, DV-based optimization with a gradient technique is then used to fine-tune the DVHs. The DV constraints are specified according to the gEUD plan, and the initial intensities are obtained from the gEUD plan as well. We demonstrated this technique in two clinical cases: aprostate cancer and ahead and neck cancer case. Compared with the DV-optimized plan, the gEUD plan provided better protection of critical structures and the target coverage was similar. However, homogeneities were slightly poorer. The gEUD plan was then fine-tuned with DV constraints, and the resulting plan was superior to the other plans in terms of the dose distributions. The planning time was significantly reduced as well. This technique is an effective means of optimizing individualized treatment plans.