Nucleophilicity Prediction Using Graph Neural Networks.

The quantitative description between chemical reaction rates and nucleophilicity parameters plays a crucial role in organic chemistry. In this regard, the formula proposed by Mayr et al. and the constructed reactivity database are important representatives. However, the determination of Mayr's nucleophilicity parameter N often requires time-consuming experiments with reference electrophiles in the solvent. Several machine learning (ML)-based models have been proposed to realize the data-driven prediction of N in recent years. However, in addition to DFT-calculated electronic descriptors, most of them also use a set of artificially predefined structural descriptors as input, which may result in a biased representation of the nucleophile's structural information depending on descriptors' definition preference. Compared with traditional ML algorithms, graph neural networks (GNNs) can naturally take the molecule's structural information into account by applying the message passing technique. We herein proposed a SchNet-based GNN model that only takes the molecular conformation and solvent type as input. The model achieves a comparable performance to the previous benchmark study on 10-fold cross-validation of 894 data points (R2 = 0.91, RMSE = 2.25). To enhance the model's ability to capture the molecule's electronic information, some DFT-calculated parameters are then incorporated into the model via graph global features, and substantial improvement is achieved in the prediction precision (R2 = 0.95, RMSE = 1.63). These results demonstrate that both structural and electronic information are important for the prediction of N, and GNN can integrate these two kinds of information more effectively.

A mechanistic study on Cu(i) catalyzed carboxylation of the C-F bond with CO2: a DFT study.

The Cu(i) catalyzed carboxylation of the C-F bond recently reported by Yu and co-workers is an excellent method for the construction of complex fluoroacrylate compounds with high regioselectivity. In the present study, theoretical calculations were carried out to investigate the detailed mechanism of the catalytic cycle and the origin of regioselectivity. The calculation results reveal that the overall catalytic cycle proceeds via the migratory insertion of difluoroalkene on the boryl-Cu(i) species, synß-F elimination, transmetalation, and carboxylation steps. The rate determining step is the carboxylation step, and the migration insertion is the regioselectivity determining step. The regioselectivity for 2,1-insertion is consistent with Yu's experiment, and is determined by both steric and electronic effects.

Micro-Lensed Fiber Laser Desorption Mass Spectrometry Imaging Reveals Subcellular Distribution of Drugs within Single Cells.

The visualization of temporal and spatial changes in the intracellular environment has great significance for chemistry and bioscience research. Mass spectrometry imaging (MSI) plays an important role because of its unique advantages, such as being label-free and high throughput, yet it is a challenge for laser-based techniques due to limited lateral resolution. Here, we develop a simple, reliable, and economic nanoscale MSI approach by introducing desorption laser with a micro-lensed fiber. Using this integrated platform, we achieved 300 nm resolution MSI and successfully visualized the distribution of various small-molecule drugs in subcellular locations. Exhaustive dynamic processes of anticancer drugs, including releasing from nanoparticle carriers entering nucleus of cells, can be readily acquired on an organelle scale. Considering the simplicity and universality of this nanoscale desorption device, it could be easily adapted to most of laser-based mass spectrometry applications.

Endovascular Treatment for Acute Type B Aortic Dissection Involving a Right-sided Aortic Arch and Kommerell's Diverticulum: A Case Report and Review of the Literature.

BACKGROUND: Aortic dissection involving a right-sided aortic arch (RAA) associated with Kommerell's diverticulum is extremely rare and remains a complicated entity for surgical therapy because of its anatomical characteristics. Fewer than 40 cases have been reported in the English language literature to date. METHODS: We reported a case of 69-year-old male patient who presented with acute type B aortic dissection involving an RAA associated with Kommerell's diverticulum, a stent-graft was accurately deployed and embolization of the left subclavian artery. In addition, a review of the literature was performed to examine its clinical presentation and the efficacy of management strategies. RESULTS: One year follow-up showed positive aortic remodeling with exclusion of Kommerell's diverticulum and thrombosis of the false lumen. CONCLUSIONS: An aortic dissection involving an RAA associated with Kommerell's diverticulum is an extremely rare condition. Endovascular therapy is technically feasible when the dissection involves this unusual vascular malformation.

DFT insights into the Ni-catalyzed regioselective hydrocarboxylation of unsaturated alkenes with CO2.

The nickel-catalyzed hydrocarboxylation of alkenes using carbon dioxide has recently become an appealing method to prepare functionalized carboxylic acids with high efficiency and regioselectivity. Herein, density functional theory (DFT) calculations were conducted on the Ni-catalyzed hydrocarboxylation of aryl-/alkyl-substituted alkenes with CO2. The α- and ß-carboxylation of aromatic and aliphatic olefins originate from distinct catalytic cycles: H-transfer-carboxylation and carboxylation-H-transfer pathways. The typical hydrometallation-carboxylation mechanism is unlikely because water/carbonic acid (H-resource) are inferior hydride donors.

Catalytic asymmetric reductive hydroalkylation of enamides and enecarbamates to chiral aliphatic amines.

To increase the reliability and success rate of drug discovery, efforts have been made to increase the C(sp3) fraction and avoid flat molecules. sp3-Rich enantiopure amines are most frequently encountered as chiral auxiliaries, synthetic intermediates for pharmaceutical agents and bioactive natural products. Streamlined construction of chiral aliphatic amines has long been regarded as a paramount challenge. Mainstream approaches, including hydrogenation of enamines and imines, C-H amination, and alkylation of imines, were applied for the synthesis of chiral amines with circumscribed skeleton structures; typically, the chiral carbon centre was adjacent to an auxiliary aryl or ester group. Herein, we report a mild and general nickel-catalysed asymmetric reductive hydroalkylation to effectively convert enamides and enecarbamates into drug-like α-branched chiral amines and derivatives. This reaction involves the regio- and stereoselective hydrometallation of an enamide or enecarbamate to generate a catalytic amount of enantioenriched alkylnickel intermediate, followed by C-C bond formation via alkyl electrophiles.

Surface Modification with Chondroitin Sulfate Targets Nanoparticles to the Neuronal Cell Membrane in the Substantia Nigra.

Localizing nanoparticles on or near cell membranes in vivo remains a big challenge. We present a cell membrane targeting complex based on chondroitin sulfate (CS)-conjugated superparamagnetic iron oxide nanoparticles (CS-SPIONs). After SPIONs were injected into the substantia nigra of rats, the subcellular distributions of SPIONs with and without CS modification have been evaluated by transmission electron microscopy (TEM) analysis. CS-SPIONs exhibited low toxicity and low endocytosis and were highly distributed in the extracellular spaces nearing neuronal cell bodies and synapses. This can be attributed to the nature of CS, one of the main components of perineuronal nets with the tendency to surround neuronal cell bodies, dendrites, and synapses. It is expected that CS-SPIONs have a great potential for therapies requiring targeting of or approach to cell membranes.

Subcellular distributions of iron oxide nanoparticles in rat brains affected by different surface modifications.

The impact of the surface modification on the subcellular distribution of nanoparticles in the brain remains elusive. The nanoparticles prepared by conjugating polyethylene glycol and maleic anhydride-coated superparamagnetic iron oxide nanoparticles (Mal-SPIONs) with bovine serum albumin (BSA/Mal-SPIONs) and with Arg-Gly-Asp peptide (RGD/Mal-SPIONs) were injected into the rat substantia nigra. Observation of transmission electron microscopy (TEM) samples obtained 24 h after perfusion showed that abundant RGD/Mal-SPIONs accumulated in the myelin sheath, dendrites, axon terminals and mitochondria, and on cell membranes in the brain tissue near the injection site. For rats injected with BSA/Mal-SPIONs, a few nanoparticles accumulated in the myelin sheath, axon terminals, endoplasmic reticulum, mitochondria, Golgi, and lysosomes of neurons and glial cells while least SPIONs in rats injected with Mal-SPIONs were found. TEM pictures showed some Mal-SPIONs were expelled out of the brain. RGD/Mal-SPIONs diffused extensively to the thalamus, frontal cortex, temporal lobe, olfactory bulb, and brain stem after injection. Only a few BSA/Mal-SPIONs diffused to the afore-mentioned brain areas. This work reveals different surface modifications on the iron oxide nanoparticles play crucial roles in their distribution and diffusion in the rat brains.

[Comparison of treatment response in primary hepatocellular carcinomas with contrast-enhanced ultrasonography and contrast-enhanced helical CT].

OBJECTIVE: To investigate the value of contrast-enhanced ultra sonography for non-surgical treatment response in hepatocellular carcinomas. METHODS: Non-surgical therapies were performed on 56 patients (64 liver neoplasms) who were diagnosed by ultrasonography-guided biopsy before the therapy. Contrast-enhanced ultrasonography(CEUS) and contrast-enhanced helical CT were performed to assess the treatment response. RESULTS: Forty-six of the 64 lesions were not enhanced with CEUS.Partial enhancement was demonstrated in the other 18 lesions. Forty-eight of the 64 lesions were not enhanced with contrast-enhanced helical CT. Partial enhancement were demonstrated in the other 16 lesions.The sensitivity, specificity, and accuracy were 94.4%, 97.8%, and 96.9% for CEUS and 83.3%, 97.8%, and 93.8% for contrast-enhanced helical CT (P>0.05). CONCLUSION: CEUS is a good method in assessing the non-surgical treatment response in hepatocellular carcinomas and is more sensitive and useful than contrast-enhanced helical CT in assessing the treatment response of transcatheter hepatic arterial chemoembolization.

Glutathione-s-transferase A 4 (GSTA4) suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting AKT pathway.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies of cancers and its prognosis remains dismal due to the paucity of effective therapeutic targets. Up-regulation of glutathione-s-transferase A 4 (GSTA4) is associated with poor prognosis of HCC, but its functional mechanism in HCC remains unclear. In this study, we investigated the roles of GSTA4 in tumor growth and metastasis of HCC and found that GSTA4 was frequently up-regulated in HCC tissues. Through gain- and loss-of-function studies, GSTA4 was demonstrated to significantly regulate cell proliferation, migration, and invasion in vitro. Furthermore, GSTA4 overexpressing significantly promoted the tumorigenicity and metastasis of HCC cells in nude mice models bearing human HCC, whereas silencing endogenous GSTA4 caused an opposite outcome. Moreover, we demonstrated that GSTA4 enhanced HCC aggressiveness by activating protein kinase B (AKT) signaling. In multivariate analysis, our results GSTA4 overexpression promotes the progression of hepatocellular carcinoma and might represent a novel therapeutic target for its treatment.

Two-stage resection of a disseminated mixed endometrial stromal sarcoma and smooth muscle tumor with intravascular and intracardiac extension.

OBJECTIVE: Mixed endometrial stromal and smooth muscle tumor (MESSMT)-a rare mesenchymal uterine tumor of the uterus with atypical clinical symptoms-is susceptible to misdiagnosis and missed diagnosis. We report a case of a disseminated MESSMT with intravenous and intracardiac extensions treated with staging surgery and review previously documented cases of such tumors with intracardiac extension. CASE REPORT: The case involves a 45-year-old woman with disseminated MESSMT that originated in the uterus and progressed through the iliac vein, inferior vena cava, right atrium, and into the right ventricle, which closely resembled intravenous leiomyomatosis (IVL) grossly and microscopically. She presented with a 1-year history of dyspnea on exertion. IVL was highly suspected preoperatively based on computed tomography and magnetic resonance imaging findings. Two-stage surgeries were performed successfully. The postoperative pathology indicated a disseminated MESSMT. CONCLUSION: This case illustrates the important role of pathology and immunohistochemistry in the differential diagnosis of a rare tumor that mimics the characteristics of IVL with intracardiac involvement and demonstrates the therapeutic strategy for this rare entity.

[Laser inducing mucosal fibrosis for preventing recurrence of esophageal varices].

OBJECTIVE: To investigate the prevention of esophageal varices recurrence by laser inducing esophageal mucosal fibrosis. METHODS: Our study included 42 patients after esophageal varices eradicated by endoscopic varices ligation, and they were divided into 2 groups randomly, each group included 21 patients. One group was assigned to received laser treatment, and indocyanine green solution (1 mg/ml) was injected submucosally, a diode laser (power 10 watts) was applied to the surface from the esophagogastric junction to 5 cm above it. Another group was controlling without any treatments. All patient were followed up by endoscopy every 3 months until 12 months. RESULTS: Laser irradiation was performed safely without any major complications. And lower esophageal mucosa produced fibrosis widely after laser irradiated 1 month. After 12 months follow up, the cumulative recurrence rate was significantly lower than the control group, 14% (3/21) vs 43% (9/21) (chi(2) = 4.20, P < 0.05). CONCLUSIONS: Our study indicates that laser inducing mucous fibrosis is safely and can prevent recurrence of esophageal varices.

Association between reversal of multidrug resistance by methyl jasmonate and P-glycoprotein ATPase activity in hepatocellular carcinoma.

OBJECTIVE: To study the effects of methyl jasmonate on multidrug resistance in a mouse model of hepatocellular carcinoma. METHODS: Multidrug resistant H22 (H22/FAP) hepatocellular carcinoma cells were produced in vitro by continuous exposure to increasing doses of doxorubicin, cisplatin and 5-fluorouracil (FAP regimen). Cell toxicity was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolum bromide (MTT) assay. Survival time was calculated for BALB/c mice that received intraperitoneal injections of H22/FAP cells followed by treatment with methyl jasmonate or verapamil in combination with FAP for 7 days. Adenosine triphosphate (ATP) hydrolysis was used to measure the activity of permeability-glycoprotein (P-gp) ATPase activity in plasma membranes. RESULTS: The MTT assay showed that methyl jasmonate significantly enhanced the cytotoxicity of the FAP regimen in multidrug resistant H22/FAP cells. Methyl jasmonate (10 mg/kg and 5 mg/kg) combined with FAP significantly increased survival time in BALB/c mice by 44.25% and 48.01%, respectively, compared with FAP. Methyl jasmonate increased P-gp ATPase activity. CONCLUSION: The combined use of methyl jasmonate and the FAP regimen might be a novel strategy for overcoming the multidrug resistance often observed in hepatocellular carcinoma.

[Therapeutic effect of subtotal gastrectomy and Roux-en-Y gastrojejunostomy on type 2 diabetes mellitus in non-obese patients].

OBJECTIVE: To evaluate the therapeutic effect of Roux-en-Y anastomosis following subtotal gastrectomy on type 2 diabetes mellitus (T2DM) in non-obese patients. METHODS: We performed a retrospective analysis of 16 non-obese patients with T2DM undergoing Roux-en-Y anastomosis following subtotal gastrectomy for stomach cancer and upper gastrointestinal tract ulcer. RESULTS: All the patients were followed up for 6 months after the surgery. Roux-en-Y gastrojejunostomy significantly lowered the levels of fasting plasma glucose (FPG), 2 h postprandial plasma glucose (2hPG), and glycated hemoglobin (HbA1c)(P<0.05). Of these patients, 8 (50%) achieved adequate glycemic control without antidiabetic medication and 5 (31.25%) showed obvious improvement. The total effectiveness rate of the surgery was 81.25%. CONCLUSION: Roux-en-Y gastrectomy can effectively ameliorate the diabetic symptoms and might serve as a new treatment option for T2DM in non-obese patients.

[Risk factors for anastomotic leakage after anterior resection for rectal cancer].

OBJECTIVE: To identify the risk factors associated with anastomotic leakage following an anterior resection for rectal cancer. METHODS: Between June, 1999 and June, 2009, 628 patients underwent anterior resection for rectal cancer. A retrospective study of the cases was performed to identify the risk factors for anastomotic leakage following the resection. RESULTS: The overall incidence rate of anatomic leak was 8.6% (54/628) in these patients. A low albumin level (less than 35 g/L), diabetes, absence of a protective stoma, a distance less than 7 cm from the tumor to the anal edge, and a tumor diameter over 5 cm were identified as the risk factors for anastomotic leakage after anterior resection. CONCLUSION: For patients at a high risk for anastomotic leakage, a protective stoma can significantly decrease the rate of clinical leaks and subsequent reoperation after low anterior resection for rectal cancer.