Microsatellite instability (MSI) or the deficiency of mismatch repair (MMR) proteins is one of the molecular pathways of colorectal tumorigenesis and may have important clinical implications in predicting the treatment response. We evaluated the relationship between clinicopathological features and MMR proteins [mutL homologue 1 (MLH1), mutS homologue 2 (MSH2), mutS homologue 6 (MSH6), postmeiotic segregation increased 2 (PMS2)], adhesion molecules (E-cadherin, beta-catenin) and caudal-type homeobox 2 (CDX2) in 31 patients with colon adenocarcinoma, using immunohistochemistry. We also aimed to assess the prognostic value of the studied proteins. MLH1 loss was correlated to PMS2 loss (p=0.006) and MSH2 loss (p=0.023); MSH2 loss was significantly associated to MSH6 loss (p=0.011). Tumors with MSH6 loss, together with tumors with PMS2 loss, covered all the patients with MSI status. We found a significant correlation between MSI tumors and mucinous histological type (p=0.03), but no significant associations with other clinicopathological features or with survival rate. There was a significant correlation between E-cadherin expression and differentiation degree (p=0.018) and between beta-catenin expression and lymph node invasion (p=0.046). No significant association between CDX2 loss and any clinical or pathological features was found (p>0.05). No significant differences were identified in overall survival according to E-cadherin, beta-catenin or CDX2 expression (p>0.05). In our study, PMS2 loss was significantly correlated with CDX2 loss (p=0.03). In conclusion, the molecular analysis of biological markers for colon cancer may be important for patient stratification, in order to select the optimal treatment algorithm. Our results suggest that probably the double panel (MSH6 and PMS2) is enough to detect the MSI status, instead of using the quadruple panel.
In recent years, the advances in stem cell research have suggested that the human body may have a higher plasticity than it was originally expected.Until now, four categories of stem cells were isolated and cultured in vivo: embryonic stem cells, fetal stem cells, adult stem cells and induced pluripotent stem cells (hiPSCs).Although multiple studies were published, several issues concerning the stem cells are still debated, such as: the molecular mechanisms of differentiation, the methods to prevent teratoma formation or the ethical and religious issues regarding especially the embryonic stem cell research.The direct differentiation of stem cells into specialized cells: cardiac myocytes, neural cells, pancreatic islets cells, may represent an option in treating incurable diseases such as: neurodegenerative diseases, type I diabetes, hematologic or cardiac diseases.Nevertheless, stem cell-based therapies, based on stem cell transplantation, remain mainly at the experimental stages and their major limitation is the development of teratoma and cancer after transplantation. The induced pluripotent stem cells (hiPSCs) represent a prime candidate for future cell therapy research because of their significant self-renewal and differentiation potential and the lack of ethical issues.This article presents an overview of the biological advances in the study of stem cells and the current progress made in the field of regenerative medicine.
Hepatic stellate cell (HSC), initially analyzed by von Kupffer, in 1876, revealed to be an extraordinary mesenchymal cell, essential for both hepatocellular function and lesions, being the hallmark of hepatic fibrogenesis and carcinogenesis. Apart from their implications in hepatic injury, HSCs play a vital role in liver development and regeneration, xenobiotic response, intermediate metabolism, and regulation of immune response. In this review, we discuss the current state of knowledge regarding HSCs morphology, human HSCs markers and human HSC cell lines. We also summarize the latest findings concerning their roles in normal and liver pathology, focusing on their impact in fibrogenesis, chronic viral hepatitis and liver tumors.
Basal cell carcinoma (BCC) is the most frequent form of skin cancer and is not a tumor with a lethal outcome if diagnosed and treated adequately. The gold standard for treatment is surgical excision with histologically safe margins. Even so, tumors excised with free margins may recur after a period of time. The identification of predictive factors for the recurrence of BCCs besides the localization, size and aggressive histology may be useful for the clinician. The aim of the present study was to identify clinical and pathological factors associated with recurrence in tumors with histologically free margins and assess via immunohistochemical staining, the expression of glioma-associated oncogene homolog 1 (GLI1), yes-associated protein (YAP), connective tissue growth factor (CTGF) and E-cadherin as they are involved in the development of BCCs, in the hope of identifying markers that are predictive for recurrence. In total, 8 recurrent BCCs and 38 non-recurrent tumors were analyzed. A Breslow index >2 (Se 100.0%, Sp 67.5%, P=0.008), Clark level >3 (Se 100.0%, Sp 47.5%, P<0.001), and excision margins both lateral (Se 87.5%, Sp 60.0%, P=0.04) and deep (Se 75.0%, Sp 82.5%, P<0.001) free from tumoral cells ≤1 mm proved to be predictive for recurrence in the present study. Recurrence may appear even after more than 3 years since the initial excision (Se 87.50%, Sp 70.0%, P<0.001). The expression levels of GLI1, YAP and E-cadherin were not different in the recurrent vs. non-recurrent BCCs. However, the low expression of CTGF may indicate a tumor with a higher aggressiveness. In conclusion, close follow-up of patients with excised BCCs at least annually is recommended and re-excision should be taken into consideration for locally advanced tumors especially if they are located in high-risk areas or those with histologically free margins <1 mm.
In inflammatory bowel disease (IBD), experimental models have proven to be important tools for evaluating potential therapeutic agents and for investigating the mechanisms of pathogenesis. Oxidative stress and the immune response have been associated with acetic acid (AA)-induced ulcerative colitis (UC). Our study aimed to evaluate, for the first time, the ability of a spore-based probiotic and an amino acid and immunoglobulin supplement in reducing tissue damage and inflammatory responses in an experimental animal model of UC. Forty-two Wistar rats were divided into six groups, receiving 1% carboxymethylcellulose, 4% AA, MegaSporeBiotic™ (MSB; 1 × 109 colony forming units/day) and MegaMucosa™ (MM; 70 mg/100 g/day). Pretreatment with MSB or MM alone and in combination significantly lowered inflammation and reduced damage to the colonic mucosa. Pretreatment with these agents resulted in levels of proinflammatory cytokines, vascular tight junction proteins, and measures of oxidative stress similar to those reported for methylprednisolone, one of the first-line therapies for moderate to severe activity of UC. The protection was further confirmed by histologic analysis of the colon tissue. In conclusion, pretreatment with probiotic spore-forming Bacillus strains and a supplement of amino acids in combination with immunoglobulins exhibited anti-inflammatory and antioxidant effects in an AA-induced rat model of UC.
The central nervous system (CNS) represents a complex network of different cells, such as neurons, glial cells, and blood vessels. In tumor pathology, glial cells result in the highest number of cancers, and glioblastoma (GB) is considered the most lethal tumor in this region. The development of GB leads to the infiltration of healthy tissue through the interaction between all the elements of the brain network. This results in a GB microenvironment, a complex peritumoral hallo composed of tumor cells and several non-tumor cells (e.g., nervous cells, stem cells, fibroblasts, vascular and immune cells), which might be the principal factor for the ineffective treatment due to the fact that the microenvironment modulates the biologic status of the tumor with the increase in its evasion capacity. Crosstalk between glioma cells and the brain microenvironment finally inhibits the beneficial action of molecular pathways, favoring the development and invasion of the tumor and its increasing resistance to treatment. A deeper understanding of cell–cell interactions in the tumor microenvironment (TME) and with the tumor cells could be the basis for a more efficient therapy.
Background and Objectives: To assess ovarian cysts with texture analysis (TA) in magnetic resonance (MRI) images for establishing a differentiation criterion for endometriomas and functional hemorrhagic cysts (HCs) that could potentially outperform their classic MRI diagnostic features. Materials and Methods: Forty-three patients with known ovarian cysts who underwent MRI were retrospectively included (endometriomas, n = 29; HCs, n = 14). TA was performed using dedicated software based on T2-weighted images, by incorporating the whole lesions in a three-dimensional region of interest. The most discriminative texture features were highlighted by three selection methods (Fisher, probability of classification error and average correlation coefficients, and mutual information). The absolute values of these parameters were compared through univariate, multivariate, and receiver operating characteristic analyses. The ability of the two classic diagnostic signs (“T2 shading” and “T2 dark spots”) to diagnose endometriomas was assessed by quantifying their sensitivity (Se) and specificity (Sp), following their conventional assessment on T1-and T2-weighted images by two radiologists. Results: The diagnostic power of the one texture parameter that was an independent predictor of endometriomas (entropy, 75% Se and 100% Sp) and of the predictive model composed of all parameters that showed statistically significant results at the univariate analysis (100% Se, 100% Sp) outperformed the ones shown by the classic MRI endometrioma features (“T2 shading”, 75.86% Se and 35.71% Sp; “T2 dark spots”, 55.17% Se and 64.29% Sp). Conclusion: Whole-lesion MRI TA has the potential to offer a superior discrimination criterion between endometriomas and HCs compared to the classic evaluation of the two lesions’ MRI signal behaviors.
BackgroundIn spite of the multimodal treatment used today, glioblastoma is still the most aggressive and lethal cerebral tumour. To increase survival in these patients, novel therapeutic targets must be discovered. Signal transducer and activator of transcription 3 (Stat3), a transcription factor that controls normal cell differentiation and survival is also involved in neoplastic celltransformation. In this study we evaluated the immunohistochemical expression of pY705-Stat3 in patients with primary glioblastoma and determined its prognostic role by correlating it with survival.MethodsThis retrospective study included 94 patients diagnosed with glioblastoma. We determined the localization, number of positive cells, and marker intensity for pY705-Stat3 in these patients with the use of immunohistochemistry. The prognostic role was determined by correlating pY705-Stat3 expression on formalin-fixed paraffin-embedded tumour tissues with the patient’s survival in univariate and multivariate COX regressions.ResultsWe found a statistically significant difference in survival between the patients with more than 20% pY705-Stat3 positive cells and those with less than 20% pY705-Stat3 positive cells (8.9 months median survival versus 13.7 months medial survival, p < 0.001). On multivariate analyses with the COX proportional hazards regression model including pY705-Stat3 expression, age and relapse status, pY705-Stat3 status was an independent prognostic factor in glioblastoma (P < 0.001).ConclusionThe results obtained show that the immunohistochemical expression of pY705-Stat3 correlates with survival in glioblastoma. This study identifies Stat3 as a possible target for existing or new developed Stat3 inhibitors.
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