Clinical significance of overexpressed cyclin-dependent kinase subunits 1 and 2 in esophageal carcinoma.

The mammalian cyclin-dependent kinase subunit (Cks) family has two members, Cks1 and Cks2. Overexpression of Cks1 and Cks2 has been reported to be associated with high aggressiveness and poor prognosis in several malignancies, including prostate and hepatocellular carcinomas. However, whether Cks1 and Cks2 are overexpressed in esophageal carcinoma remains uncharacterized. To investigate whether overexpression of the Cks family is clinically relevant in esophageal carcinoma, and whether expression patterns of Cks1 and Cks2 can serve as biomarkers for esophageal carcinoma. Real-time quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and Western blot analyses were applied to detect the expression of Cks1 and Cks2 at the mRNA and protein levels, respectively. The associations between Cks1 or Cks2 expressions and clinical features and p27(kip1) expressions in esophageal carcinoma were analyzed. Comparing with the adjacent noncancerous tissues, esophageal carcinoma exhibited elevated expression of Cks1 in 58% cases at the mRNA level and 54% cases at the protein level, and elevated expression of Cks2 in 65% cases at the mRNA level and 61% cases at the protein level, respectively. The expressions of both Cks1 and Cks2 were negatively associated with the p27(kip1) protein level in the tumor tissues. Furthermore, overexpression of Cks1 and Cks2 in esophageal carcinoma was closely associated with poor pathological features of esophageal carcinoma, including higher histologic grade of tumor, regional lymph nodes invasion, and neoplastic embolus. Overexpression of Cks1 and Cks2 is associated with the aggressive tumor behaviors of esophageal carcinoma. Further efforts are needed to determine whether overexpression of Cks1 and Cks2 can serve as novel biomarkers for esophageal carcinoma.

Prediction of potential therapeutic drugs against SARS-CoV-2 by using Connectivity Map based on transcriptome data.

OBJECTIVE: Transcriptome data related to severe acute respiratory syndrome-related coronavirus 2 (a novel coronavirus discovered in 2019, SARS-CoV-2) in GEO database were downloaded. Based on the data, influence of SARS-CoV-2 on human cells was analyzed and potential therapeutic compounds against the SARS-CoV-2 were screened. MATERIALS AND METHODS: R package "DESeq2" was used for differential gene analysis on the data of cells infected or non-infected with SARS-CoV-2. The "ClusterProfiler" package was used for GO functional annotation and KEGG pathway enrichment analysis of the differentially expressed genes (DEGs). A protein-protein interaction (PPI) network of the DEGs was constructed through STRING website, and the key subset in the PPI network was identified after visualization by Cytoscape software. Connectivity Map (CMap) database was used to screen known compounds that caused genomic change reverse to that caused by SARS-CoV-2. RESULTS: By intersecting DEGs in two datasets, a total of 145 DEGs were screened out, among which 136 genes were upregulated and 9 genes were downregulated in SARS-CoV-2-infected cells. Functional enrichment analyses revealed that these genes were mainly associated with the pathways involved in viral infection, inflammatory response, and immunity. The CMap research found that there were three compounds with a median_tau_score less than -90, namely triptolide, tivozanib and daunorubicin. CONCLUSIONS: SARS-CoV-2 can cause abnormal changes in a large number of molecules and related signaling pathways in human cells, among which IL-17 and TNF signaling pathways may play a key role in pathogenic process of SARS-CoV-2. Here, three compounds that may be effective for the treatment of SARS-CoV-2 were screened, which would provide new options for improving treatment of patients infected with SARS-CoV-2.

The gene regulatory network in different brain regions of neuropathic pain mouse models.

OBJECTIVE: Neuropathic pain is directly developed from lesions or somatosensory nervous system diseases that are associated with emotion regulation. In general population, the incidence of neuropathic pain ranges from 7% to 10%, but the underlying mechanism remains largely unknown. Neuropathic pain is often associated with structural and functional abnormalities in multiple brain regions, and its regulation has been shown to correspond with the forebrain, including nucleus accumbens (NAc), medial prefrontal cortex (mPFC) and periaqueductal gray (PAG). MATERIALS AND METHODS: To investigate the molecular mechanism of neuropathic pain across different brain regions, we identified the differentially expressed genes (DEGs) between the spared nerve injury model (SNI) mice suffering neuropathic pain and the control Sham mice in NAc, mPFC and PAG three brain regions, and mapped these genes onto a comprehensively functional association network. Thereafter, novel neuropathic pain genes in these three regions were identified using With Random Walk with Restart (RWR) analysis, such as Asic3, Cd200r1 and MT2, besides well-known Capn11 and CYP2E1. RESULTS: Interactions or cross talks among DEGs in NAc, mPFC and PAG three brain regions were discovered. CONCLUSIONS: Our results provide novel insights into neuropathic pain and help to explore therapeutic targets in the treatment.

On the structure selectivity problem in drug design. A comparative study of benzylpyrimidine inhibition of vertebrate and bacterial dihydrofolate reductase via molecular graphics and quantitative structure-activity relationships.

Quantitative structure-activity relationships (QSAR) have been derived for the action of 68 5-(substituted benzyl)-2,4-diaminopyrimidines on dihydrofolate reductase (DHFR) from Lactobacillus casei and chicken liver. The QSAR are analyzed with respect to the stereographics models of the active sites of the enzymes and found to be in good agreement. Using these QSAR equations, we have attempted to design new trimethoprim-type antifolates having higher selectivity for the bacterial enzyme. The general problem of developing selective inhibitors is discussed.

Inhibition of chicken liver dihydrofolate reductase by 5-(substituted benzyl)-2,4-diaminopyrimidines. A quantitative structure-activity relationship and graphics analysis.

The inhibition of chicken liver dihydrofolate reductase by a series of substituted benzylpyrimidines has been investigated. From the inhibition constants a quantitative structure-activity relationship has been formulated. This mathematical model is compared with molecular graphics models constructed from the X-ray crystallographic coordinates of trimethoprim and 5-(3,4-dimethoxy-4-isopropenylbenzyl)-2,4- diaminopyrimidine bound to the enzyme. There is good correspondence between the two types of models.

Oxygen radicals in bronchoconstriction of guinea pigs elicited by isocapnic hyperpnea.

The role of oxygen radicals in isocapnic hyperpnea-induced bronchoconstriction (HIB) of guinea pigs was investigated using scavengers of the radicals. In series 1, 50 young guinea pigs were randomly divided into seven groups: control 1, control 2, chlorisondamine, tetrodotoxin (TTX), acute dimethylthiourea (DMTU), tachykinin depletion, and 5% CO2 in air. Animals of the control 2 group received vehicle (saline) infusion while those of the control 1 group did not. Chlorisondamine was used to block ganglionic transmission, TTX to interrupt nerve conduction, DMTU to scavenge hydroxyl radicals, and chronic capsaicin pretreatment to deplete tachykinins. The animals in the last group were ventilated with dry 5% CO2 in air during hyperpnea. In series 2, 13 additional animals were used to test the effects of intratracheal administration of superoxide dismutase and catalase (SOD + CAT) on HIB. Each animal was anesthetized with pentobarbital sodium, cannulated with a tracheal cannula and venous catheter, paralyzed with gallamine triethiodide, and mechanically ventilated. During the baseline period, each animal was ventilated normally with humidified air. Then it was hyperventilated 15 min with a dry gas mixture of 95% O2-5% CO2, except animals in the last group of series 1. Subsequently, all animals returned to normal ventilation with humidified air for 45 min (recovery period). The maximal expiratory flow and dynamic compliance were obtained periodically during the recovery period. The isocapnic hyperpnea using 95% O2-5% CO2, but not 5% CO2 in air, caused bronchoconstriction that was significantly blocked by acute DMTU, acute SOD + CAT, and tachykinin depletion. In an additional group of six animals, acute DMTU did not significantly alter acetylcholine-induced airway constriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of [3H]dopamine uptake into rat striatal slices by quaternary N-methylated nicotine metabolites.

The effects of quaternary N-methylated nicotine derivatives were examined on in vitro uptake of [3H]dopamine ([3H]DA) in rat striatal slices. Striatal slices were incubated with a 10 microM concentration of the following compounds: N-methylnicotinium, N-methylnornicotinium, N-methylcotininium, N,N'-dimethylnicotinium and N'-methylnicotinium salts. The results clearly indicated that significant (60%) inhibition of [3H]DA uptake occurred with those compounds possessing a N-methylpyridinium group; whereas, compounds that were methylated at the N'-pyrrolidinium position were less effective or exhibited no inhibition of [3H]DA uptake. The results suggest that high concentrations of quaternary N-methylated nicotine metabolites which are structurally related to the neurotoxin MPP+, and which may be formed in the CNS, may protect against Parkinson's Disease and explain the inverse relationship between smoking and Parkinsonism reported in epidemiologic studies.

Noncholinergic airway constriction: role of axon reflex and oxygen radicals.

In the airways and lungs, activated afferent C-fibers release tachykinins, which induce noncholinergic bronchoconstriction. We have, for several years, focused our research on the role of axon reflex and oxygen radicals in noncholinergic airway constriction in guinea pigs. In this species, the noncholinergic bronchial constriction is not affected by administration of a ganglionic blocking agent, chlorisondamine, indicating that only the afferent C-fiber, not a complete reflex arc, is required for this constriction. Accordingly, we investigated the role of axon reflex by using tetrodotoxin (TTX) and bupivacaine to block impulse conduction in the axon. For the role of oxygen radicals, superoxide dismutase (SOD), catalase (CAT), and dimethylthiourea (DMTU) were employed to scavenge superoxide anion, hydrogen peroxide, and hydroxyl radical, respectively. We used capsaicin, resiniferatoxin (RTX), or hyperventilation to activate afferent C-fibers which, in turn, release tachykinins and lead to noncholinergic airway constriction. The constriction was quantified by measuring the maximal expiratory flow rate (Vmax) and dynamic compliance (Crs). Both capsaicin and RTX caused an immediate decrease in Vmax and Crs, indicating severe bronchoconstriction. This constriction decreased gradually with time. Tachykinin depletion abolished neurotoxin-induced airway constriction, suggesting that tachykinins mediate the constriction. Both TTX and bupivacaine significantly attenuated the constriction at 15-20 min after neurotoxin administration. Therefore, these data suggest that the axon reflex plays an important role in noncholinergic bronchial constriction. In other studies, capsaicin- or hyperventilation-induced bronchoconstriction was abolished by tachykinin depletion, as well as significantly ameliorated by the administration of antioxidants. These data indicate that oxygen radicals modulate the tachykinin-mediated noncholinergic airway constriction.

[Use of signal averaging system in the study of ventricular late potentials].

Signal-averaged electrocardiograms (SAECGs) were performed in 93 patients with various heart diseases and 20 dogs with experimental acute myocardial infarction. SA-ECGs were recorded with a high-pass bidirectional digital filter Mode FDS which was made by Shanghai Fudan University and Suzhou Medical College. All the patients and dogs were also examined with ART 1200 EPX recorder. Ventricular late potentials (VLPs) were directly recorded from the epicardium with experimental infarction by using composite electrodes and signal averaging system in late stage of coronary ligation. The results showed: VLPs were detected by body surface SA-ECG only in half of the dogs with VLPs detected by the real time mapping on infarction region, but the abnormal SAECGs did reveal the delayed ventricular activity; the data obtained with FDS or ART SA-ECG were similar.

[The development of computerized cardiac programmable stimulator].

This paper introduces a fully computerized cardiac programmable stimulator. With the visual interface of computer, the configuration and control of stimulation will be realized conveniently. Meanwhile, the current status and the waves during stimulation will be displayed in window real-time, which improved the visualization and availability in medical application. It has been proved that this system is simpler in operation and more functional than traditional cardiac programmable stimulators, and therefore it is valuable in medical applications.

[The development of a 64-channel epicardial potential mapping system].

A 64-channel epicardial potential mapping system was developed in order to study the mechanics of arrhythmia such as atrial fibrillation and ventricular fibrillation, and instruct the procedure of detecting and eliminating abnormal rhythm in experiment or clinic. The system was consist of electrode, amplifier, A/D card, computer and output device. The system's software include signal acquisition module, signal preprocessing module, character-point detecting module, isochrone-map construction module, output display and print module. The system could be used to detect the activation path of atrial fibrillation and ventricular fibrillation.

[Ventricular wave identification in epicardial mapping system using wavelet transform].

A novel method for the identification of ventricular wave based on wavelet transform is presented. First, "Multi-Scale Intersectional Search" is adopted for analysis of wavelet transform coefficients on some different scales, then adaptive detection is used on this basis. The results of practice show that it has a discrimination of 94.5%, and is obviously superior to any routime method.

Factors affecting the concentration of compound A resulting from the degradation of sevoflurane by soda lime and Baralyme in a standard anesthetic circuit.

Carbon dioxide absorbents, such as soda lime and Baralyme brand absorbent, convert sevoflurane to CF2 = C(CF3)OCH2F, a vinyl ether called "Compound A," whose toxicity raises concerns regarding the safety of sevoflurane in rebreathing circuits. Because an increased inflow rate to an anesthetic circuit decreases rebreathing, we assumed that an increased rate would proportionately decrease the concentration of Compound A. In the present report, we measured the Compound A concentration resulting from the action of wet (standard) soda lime and wet (standard) Baralyme on 2% sevoflurane in a model anesthetic circuit, using inflow rates (0.5, 1.0, 2.0, 4.0, and 6.0 L/min), ventilations (5 and 10 L/min), and carbon dioxide production/removal (200 and 400 mL/min) found in clinical practice. An increase in inflow rate decreased Compound A concentration to lower levels as inflow rate approached minute ventilation. At lower inflow rates, increasing duration of sevoflurane inflow increased the concentration of Compound A, a finding consistent with a progressive increase in absorbent temperature from absorption of carbon dioxide and consequently greater sevoflurane degradation. There was no material difference between Baralyme and soda lime in the concentrations of Compound A produced at a particular inflow rate. An increase in ventilation increased the concentration of Compound A, having a much greater effect at high rather than low inflow rates. An increase in amount of carbon dioxide absorbed also increased the concentration of Compound A. We conclude that inflow rate, ventilation, and carbon dioxide production are major determinants of the concentration of Compound A.