Differentiating gastrointestinal stromal tumors from gastric adenocarcinomas and normal mucosae using confocal Raman microspectroscopy.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, and gastric adenocarcinomas are a common cancer worldwide. To differentiate GISTs from adenocarcinomas is important because the surgical processes for both are different; the former excises the tumor with negative margins, while the latter requires radical gastrectomy with lymph node dissection. Endoscopy with biopsy is used to distinguish GISTs from adenocarcinomas; however, it may cause tumor bleeding in GISTs. We reported here the confocal Raman microspectroscopy as an effective tool to differentiate GISTs, adenocarcinomas, and normal mucosae. Of 119 patients enrolled in this study, 102 patients underwent gastrectomy (40 GISTs and 62 adenocarcinomas), and 17 patients with benign lesions were obtained as normal mucosae. Raman signals were integrated for 100 s for each spot on the specimen, and 5 to 10 spots, depending on the sample size, were chosen for each specimen. There were significant differences among those tissues as evidenced by different Raman signal responding to phospholipids and protein structures. The spectral data were further processed and analyzed by using principal component analysis. A two-dimensional plot demonstrated that GISTs, adenocarcinomas, and normal gastric mucosae could be effectively differentiated from each other.

Novel Method for Differentiating Histological Types of Gastric Adenocarcinoma by Using Confocal Raman Microspectroscopy.

Gastric adenocarcinoma, a single heterogeneous disease with multiple epidemiological and histopathological characteristics, accounts for approximately 10% of cancers worldwide. It is categorized into four histological types: papillary adenocarcinoma (PAC), tubular adenocarcinoma (TAC), mucinous adenocarcinoma (MAC), and signet ring cell adenocarcinoma (SRC). Effective differentiation of the four types of adenocarcinoma will greatly improve the treatment of gastric adenocarcinoma to increase its five-year survival rate. We reported here the differentiation of the four histological types of gastric adenocarcinoma from the molecularly structural viewpoint of confocal Raman microspectroscopy. In total, 79 patients underwent laparoscopic or open radical gastrectomy during 2008-2011: 21 for signet ring cell carcinoma, 21 for tubular adenocarcinoma, 14 for papillary adenocarcinoma, 6 for mucinous carcinoma, and 17 for normal gastric mucosas obtained from patients underwent operation for other benign lesions. Clinical data were retrospectively reviewed from medical charts, and Raman data were processed and analyzed by using principal component analysis (PCA) and linear discriminant analysis (LDA). Two-dimensional plots of PCA and LDA clearly demonstrated that the four histological types of gastric adenocarcinoma could be differentiated, and confocal Raman microspectroscopy provides potentially a rapid and effective method for differentiating SRC and MAC from TAC or PAC.

Positive cyclin T expression as a favorable prognostic factor in treating gastric gastrointestinal stromal tumors.

Positive transcriptional elongation factor b (P-TEFb) contains the catalytic subunit cyclin-dependent kinase 9 (Cdk9) and the regulatory subunit cyclin T. Cyclin T1 and Cdk9 are the key factors of the PTEFb pathways and are overexpressed in the human head and neck carcinoma cell line. However, there have been limited studies regarding the role of cyclin T1 and Cdk9 in gastric gastrointestinal stromal tumors (GISTs). The aim of the present study was to assess the association between cyclin T1 and Cdk9 and their clinical significance in gastric GISTs. A total of 30 gastric GIST patients who underwent either laparoscopic or laparotomic partial gastrectomy were enrolled in the study. The surgical tissue slides were stained with Cdk9 and cyclin T1 antibodies, and the immunohistochemistry scores and disease-free survival (DFS) were analyzed. Ten patients were cyclin T1-positive, and 20 were negative. All 11 patients with recurrent tumors or distant metastases were cyclin T1-negative patients. Old age, large tumor size, a high Ki67 IHC staining score, high mitotic count and negative cyclin T1 staining revealed a worse clinical outcome in univariate analysis. By contrast, the Cdk9 score was not associated with clinical parameters. The Kaplan-Meier survival curve illustrated that the DFS rate of the patients with negative cyclin T1 staining was significantly lower than that of the patients with positive cyclin T1 staining. Positive expression of cyclin T1 was a good prognostic factor in patients with gastric GISTs.

Increased cyclin T1 expression as a favorable prognostic factor in treating gastric adenocarcinoma.

The expression of cyclin A, B1, D1 and E in gastric adenocarcinoma is known to be associated with clinical outcome. However, few studies have investigated the role of cyclin T1 and cyclin-dependent kinase 9 (CDK9) in gastric adenocarcinoma. Therefore, this study assessed the clinical significance of cyclin T1 and CDK9 expression in gastric adenocarcinoma. A total of 39 gastric adenocarcinoma patients received either radical total or distal gastrectomy in this study. Surgical tissue slides were stained with CDK9 and cyclin T1 antibodies, and immunohistochemistry scores and disease-free survival (DFS) rates were analyzed. Among the 19 patients with tumor-recurrent or distant metastasis, 16 were recorded as exhibiting low expression of cyclin T1. The remaining three patients exhibited high expression of the antibody. The results of patients with a higher T stage, N stage and tumor grade were less favorable. For patients with adenocarcinoma, the percentage of tissue slides stained with cyclin T1 was significantly higher than for those with normal stomach epithelia. The DFS rates of patients with low expression of cyclin T1 were significantly associated with poorer DFS rates. In conclusion, high expression of cyclin T1 is a favorable prognostic factor in treating patients with stomach adenocarcinoma.

Computational study of cycloaddition reactions of 16-electron d8 ML4 complexes with C60.

The potential energy surfaces of the cycloaddition reactions M(CO)(4) + C(60) → (CO)(4)M(C(60)) (M = Fe, Ru, and Os) have been studied at the B3LYP/LANL2DZ level of theory. It has been found that these reactions have two competing pathways, which can be classified as a [6,5]-attack (path A) and a [6,6]-attack (path B). Our B3LYP results suggest that, given the same reaction conditions, the [6,6]-attack is more favorable than the [6,5]-attack both kinetically and thermodynamically. A qualitative model based on the theory of Pross and Shaik has been used to develop an explanation for the barrier heights. As a consequence, the theoretical findings indicate that the singlet-triplet splitting ΔE(st) (=E(triplet) - E(singlet)) of the 16-electron d(8) M(CO)(4) and C(60) species can be used as a guide to predict their reactivity toward cycloaddition. Our computational results reveal that the reactivity of d(8) M(CO)(4) cycloaddition to C(60) decreases in the order Fe(CO)(4) > Os(CO)(4) > Ru(CO)(4). Accordingly, we demonstrate that both electronic and geometric effects play a crucial role in determining the energy barriers as well as the reaction enthalpy.

A computational study of cycloaddition reactions of d8 metal tetroxide (iron, ruthenium, osmium) complexes with C60.

The potential energy surfaces of the cycloaddition reactions MO(4)(NC(5)H(5))(2) + C(60)→ MO(4)(NC(5)H(5))(2)(C(60)) (M = Fe, Ru, and Os) have been studied at the B3LYP/LANL2DZ level of theory. It has been found that there should be two competing pathways in these reactions, which can be classified as a [6,5]-attack (path A) and a [6,6]-attack (path B). Our theoretical calculations indicate that, given the same reaction conditions, the cycloaddition reaction of C(60)via [6,6]-attack is more favorable than that via [6,5]-attack both kinetically and thermodynamically. This is in good agreement with the available experimental observations. A qualitative model, which is based on the theory of Pross and Shaik, has been used to develop an explanation for the barrier heights. As a result, our theoretical findings suggest that the singlet-triplet splitting ΔE(st) (= E(triplet)- E(singlet)) of the d(8) MO(4)(NC(5)H(5))(2) and C(60) species can be a guide to predict their reactivity towards cycloaddition. Our model results demonstrate that the reactivity of d(8) metal tetroxide cycloaddition to C(60) decreases in the order FeO(4)(NC(5)H(5))(2) > RuO(4)(NC(5)H(5))(2) > OsO(4)(NC(5)H(5))(2). In consequence, we show that both electronic and geometric effects play a decisive role in determining the energy barriers as well as the reaction enthalpy.

Theoretical study of the mechanisms of [3+2] cycloaddition reactions of trimetallaallenes [[double bond splayed left]M=M=M [double bond splayed right]] (M=C, Si, Ge, Sn, and Pb).

The potential energy surfaces for the cycloaddition reactions of 16 valence-electron trimetallaallene species have been studied using density functional theory (B3LYP/LANL2DZ). Seven trimetallaallene species of the form [double bond splayed left]M=M=M[double bond splayed right] with five-membered-rings where M = C, Si, Ge, Sn, and Pb, have been chosen as model reactants in this work. Also, the alkene cycloaddition has been used to study the chemical reactivities of these 16 valence-electron trimetallaallene species. The present theoretical investigations suggest that their relative reactivity increases in the order: C=C=C < Si=Si=Si < Si=Ge=Si < Ge=Si=Ge < Ge=Ge=Ge < Sn=Sn=Sn < Pb=Pb=Pb. That is, less electronegative and heavier main group atoms will lead to a smaller ΔE(st) and, in turn, will facilitate the [3 + 2] cycloaddition reactions to alkenes. Furthermore, the singlet-triplet energy splitting of the 16 valence-electron trimetallaallene species, as described in the configuration mixing model attributed to the work of Pross and Shaik, can be used as a diagnostic tool to predict their reactivities. The results obtained allow a number of predictions to be made.

Reactivity and mechanism of stable heterocyclic silylenes with carbon tetrachloride.

The potential energy surfaces for the reactions of stable silylenes with carbon tetrachloride have been characterized in detail using density functional theory [B3LYP/6-311G(d)], including zero-point corrections. Five stable silylene species (1-5) have been chosen in this work as model reactants. The activation barriers and enthalpies of the reactions are compared to determine the relative reactivity of the stable silylenes on the reaction potential energy surface. Our theoretical findings suggest that stable silylene 5, which has two carbon atoms bonded to the silicon center and does not contain a resonance structure, is relatively unstable with respect to the reaction with haloalkanes, in comparison with the other stable silylenes (1-4). Of the three possible reaction paths, Cl abstraction (path 1), CCl3 abstraction (path 2), and CCl4 insertion (path 3), path 1 is found to be most favorable, with a very low activation energy and a large exothermicity. In short, electronic as well as steric factors play a dominant role in determining the chemical reactivity of the stable silylene species kinetically as well as thermodynamically. Furthermore, a configuration mixing model based on the work of Pross and Shaik is used to rationalize the computational results. The results obtained allow a number of predictions to be made.

Cycloaddition reactions of 16-electron d4 metallocene complexes with C60: a theoretical study.

The potential-energy surfaces of the cycloaddition reaction Cp(2)M+C60-->Cp(2)M(C60) (Cp=eta5-C(5)H(5); M=Cr, Mo, and W) were studied at the B3LYP/LANL2DZ level of theory. Two competing reaction pathways were found, which can be classified as [6,5] attack (path A) and [6,6] attack (path B). Given the same reaction conditions, the [6,6]-attack pathway for cycloaddition to C60 is more favorable than the [6,5]-attack pathway, both kinetically and thermodynamically. A qualitative model, based on the theory of Pross and Shaik, was used to develop an explanation for the reaction barrier heights. Thus, our theoretical findings suggest that the singlet-triplet splitting DeltaE(st) (=E(triplet)-E(singlet)) of the 16-electron d4 Cp(2)M and C60 species are a guide to predicting their reactivity towards cycloaddition. Our model results demonstrate that the propensity for cycloaddition to C60 increases in the order Cp(2)Cr

Theoretical studies of the [2 + 4] Diels-Alder cycloaddition reactions of alkene analogues of the group 13 elements with toluene.

The potential energy surfaces for the cycloaddition reactions of formally double-bonded molecules containing group 13 elements have been studied using density functional theory (B3LYP/LANL2DZ). Five group 13 alkene analogues, ArX=XAr, where X = B, Al, Ga, In, and Tl, have been chosen as model reactants in this work. Our present theoretical work predicts that the smaller the singlet-triplet splitting in ArX=XAr, the lower the activation barrier and, in turn, the more rapid are its [4 + 2] cycloaddition reactions. Moreover, the theoretical investigations suggest that the relative dimeric reactivity decreases in the order B > Al > Ga > In > Tl. That is, the heavier the group 13 atom (X), the more stable is its dimetallene toward chemical reactions. In consequence, our results predict that the dimetallenes containing heavier group 13 elements (in particular, X = Ga, In, and Tl) should be stable and should be readily synthesized and isolated at room temperature. This is in good agreement with available experimental observations. Besides this, the singlet-triplet energy splitting of a dimetallene, as described in the configuration mixing model attributed to the work of Pross and Shaik, can be used as a diagnostic tool to predict its reactivity. The results obtained allow a number of predictions to be made.