[Assessment of the metastatic potential of localized forms of colorectal cancer]. / Otsenka metastaticheskogo potentsiala lokalizovannykh form kolorektal'nogo raka.

OBJECTIVE: To assess the risk of recurrence after surgical treatment is an integral part of the management of patients with colorectal cancer. The AJCC/UICC TNM staging system, in which the risk is identified by grouping the patients on the basis of anatomical elements, is commonly used. Despite the simplicity of implementation, significant heterogeneity remains within each stage group. A better tool for predicting a recurrence is needed in the era of multimodal treatment. SUBJECTS AND METHODS: A total of 1350 archival colorectal cancer cases during 2012 to 2015 were retrospectively analyzed; among which the investigators identified 3 patient groups: 1) 53 patients with non-metastatic colon cancer for at least 5 years; 2) 45 patients with metachronous metastases detected during the same period; and 3) 53 patients with synchronous metastases. Among the estimated 31 parameters, the investigators used a multidimensional analysis to select 6 most significant prognostic factors that were included in the final model based on a logistic regression analysis. The resulting model was applied to assess the risk of metastasis after cytoreductive surgery. It was internally and externally validated in an examination group (n=25). RESULTS: The model has a sensitivity of 97.78% and a specificity of 96.23%, improving the risk stratification for metastatic colon cancer. The factors in the model include extramural venous invasion, the severity of budding, the expression of E-cadherin and ß-catenin, the proportion of cytotoxic CD8+ lymphocytes of the total number of T lymphocytes in the microenvironment, and the ratio of newly formed vessels to tumor stromal microvessel density. CONCLUSION: Using morphopathological factors, the resulting model allows better consideration of tumor specificity in a particular patient, thereby providing a more individual prediction of outcome than that provided by the AJCC/UICC TNM staging system. By identifying patients at both high- and low-risk for metastasis, the model can be useful to plan treatment and to choose clinical management tactics for patients with colorectal cancer.

[Research of chewing efficiency in patients with extensive acquired defects of the upper jaw after resections of nasopharyngeal zone tumors and various terms of orthopedic rehabilitation]. / Zhevatel'naia éffektivnost' u patsientov s obshirnymi priobretennymi defektami verkhnei cheliusti posle ortopedicheskoi reabilitatsii.

The aim of the study was to estimate how the quality and terms of rational dental orthopedic treatment affects masticatory efficiency in patients using obturators after extensive resections of nasopharyngeal area tumors. The analysis of indicators of masticatory efficiency in dynamics with the use of masticatory probe of V.N. Trezubov considering prosthetics terms, functional and age features was conducted in 14 patients. The results of the research show that high-quality substitution of obturating structures positively affects masticatory efficiency dynamics and therefore has positive impact on the general health state and also on the level of physical and psychological comfort of patients.

[Caroli's disease: diagnostic problems and possibilities of treatment].

Caroli's disease is a rare congenital condition characterized by segmental non-obstructive fibrocystic dilation of intrahepatic bile ducts. Dilated ducts may be infected and contain stones. This review of the modern literature describes few known cases of the disease, analyses its clinical features and results of treatment. The principal diagnostic methods include visualization by ultrasound study, CT, MRT, retrograde and transhepatic cholangiography. Surgical intervention is the method of choice for the treatment of the disease including resection of liver, placement of hepatico-jejunal anastomoses and transplantation. The choice depends on the extent of the lesion and anticipated complications. The authors' observation of the patient with Caroli's disease in a 35 year-old woman is presented. It was successfully treated by left-hand bisegmentectomy even though the disease was diagnosed 14 years after the first symptoms. It is recommended that the disease, even if a rare one, should be included in the algorithm of differential diagnostics ofrecurrent abdominal pain with manifestations of cholestasis or fever of an unknown origin.

Differential requirement of CAAX-mediated posttranslational processing for Rheb localization and signaling.

The Rheb1 and Rheb2 small GTPases and their effector mTOR are aberrantly activated in human cancer and are attractive targets for anti-cancer drug discovery. Rheb is targeted to endomembranes via its C-terminal CAAX (C=cysteine, A=aliphatic, X=terminal amino acid) motif, a substrate for posttranslational modification by a farnesyl isoprenoid. After farnesylation, Rheb undergoes two additional CAAX-signaled processing steps, Ras converting enzyme 1 (Rce1)-catalyzed cleavage of the AAX residues and isoprenylcysteine carboxyl methyltransferase (Icmt)-mediated carboxylmethylation of the farnesylated cysteine. However, whether these postprenylation processing steps are required for Rheb signaling through mTOR is not known. We found that Rheb1 and Rheb2 localize primarily to the endoplasmic reticulum and Golgi apparatus. We determined that Icmt and Rce1 processing is required for Rheb localization, but is dispensable for Rheb-induced activation of the mTOR substrate p70 S6 kinase (S6K). Finally, we evaluated whether farnesylthiosalicylic acid (FTS) blocks Rheb localization and function. Surprisingly, FTS prevented S6K activation induced by a constitutively active mTOR mutant, indicating that FTS inhibits mTOR at a level downstream of Rheb. We conclude that inhibitors of Icmt and Rce1 will not block Rheb function, but FTS could be a promising treatment for Rheb- and mTOR-dependent cancers.

Differential effects of Ras signaling through NFkappaB on skeletal myogenesis.

Oncogenic Ras (H-Ras G12V) inhibits skeletal myogenesis through multiple signaling pathways. Previously, we demonstrated that the major downstream effectors of Ras (i.e., MEK/MAPK, RalGDS and Rac/Rho) play a minor, if any, role in the differentiation-defective phenotype of Ras myoblasts. Recently, NFkappaB, another Ras signaling target, has been shown to inhibit myogenesis presumably by stimulating cyclin D1 accumulation and cell cycle progression. In this study, we address the involvement of NFkappaB activation in the Ras-induced inhibition of myogenesis. Using H-Ras G12V and three G12V effector-loop variants, we detect high levels of NFkappaB transcriptional activity in C3H10T1/2-MyoD cells treated with differentiation medium. Myogenesis is blocked by all Ras proteins tested, yet only in the case of H-Ras G12V are cyclin D1 levels increased and cell cycle progression maintained. Expression of IkappaBalpha SR, an inhibitor of NFkappaB, does not reverse the differentiation-defective phenotype of Ras expressing cultures, but does induce differentiation in cultures treated with tumor necrosis factor (TNFalpha) or in cultures expressing the RelA/p65 subunit of NFkappaB. These data confirm that NFkappaB is a target of Ras and suggest that the cellular actions of NFkappaB require additional signals that are discriminated by the Ras effector-loop variants. Results with IkappaBalpha SR convincingly demonstrate that H-Ras G12V does not rely on NFkappaB activity to block myogenesis, an observation that continues to implicate another unidentified signaling pathway(s) in the inhibition of skeletal myogenesis by Ras.

B-ATF functions as a negative regulator of AP-1 mediated transcription and blocks cellular transformation by Ras and Fos.

B-ATF is a nuclear basic leucine zipper protein that belongs to the AP-1/ATF superfamily of transcription factors. Northern blot analysis reveals that the human B-ATF gene is expressed most highly in hematopoietic tissues. Interaction studies in vitro and in vivo show that the leucine zipper of B-ATF mediates dimerization with members of the Jun family of proteins. Chimeric proteins consisting of portions of B-ATF and the DNA binding domain of the yeast activator GAL4 do not stimulate reporter gene expression in mammalian cells, indicating that B-ATF does not contain a conventional transcription activation domain. Jun/B-ATF dimers display similar DNA binding profiles as Jun/Fos dimers, with a bias toward binding TRE (12-O-tetradecanolyphorbol-13-acetate-response element) over CRE (cyclic AMP-response element) DNA sites. B-ATF inhibits transcriptional activation of a reporter gene containing TRE sites in a dose-dependent manner, presumably by competing with Fos for Jun and forming transcriptionally inert Jun/B-ATF heterodimers. Stable expression of B-ATF in C3H10T1/2 cells does not reduce cell viability, but does result in a reduced cellular growth rate when compared to controls. This effect is dominant in the presence of the growth promoting effects of the H-Ras or the v-Fos oncoproteins, since expression of B-ATF restricts the efficiency of focus formation by these transforming agents. These findings demonstrate that B-ATF is a tissue-specific transcription factor with the potential to function as a dominant-negative to AP-1.