From cell to heart: the impact of the cell organelles dysfunction on heart disease.

: Cellular morphology reflects biologic behavior and activity of the tissue and of the organ also reflects the genetic and molecular biology of the cells themselves. This intermediary position places examination of the cell in a key role to our understanding of the innumerable processes that affect this closely knit chain, from molecules to host. A large volume of the cell is occupied by organelles that come in a variety of shapes and sizes. Organelles are dynamic to maintain homeostasis and adjust to the various functions of the cell. The cardiovascular system is metabolically very active and is therefore particularly vulnerable to defects of the cellular substructures, such as the mitochondrial respiratory chain. Given the functional complexity of the cardiovascular system, it is not surprising that defects in cell organelles produce diverse clinical manifestations. Organelle dysfunction is being recognized as the basis of a wide variety of heart diseases. In this review, the authors discuss the relationship between organelle structure and function in myocardial cells and how these organelles have been linked to the cardiovascular diseases.

Tumor Protein p53 (TP53) Gene and Left Main Coronary Artery Disease.

Patients with left main (LM) coronary artery disease (CAD) are at the highest risk of cardiovascular events. We evaluated possible gene polymorphisms of tumor protein 53 ( TP53, rs1042522, p.Arg72Pro) that can differentiate LM-CAD from patients with more peripheral CAD (MP-CAD) and healthy participants (control group) in 520 individuals (LM-CAD, n = 175; MP-CAD, n = 185; and control group, n = 160). Patients with LM-CAD had the lowest Arg/Arg genotype frequency (36.0%) compared with the MP-CAD (57.3%) and control groups (61.9%), P < .001 for both comparisons. Similarly, the Arg allele was more frequent in the control group than in patients with MP-CAD (78.8% vs 73.2%; P = .007) and LM-CAD (78.8% vs 64.0%; P < .001). The Arg/Pro genotype was more frequent in the LM-CAD group compared with the MP-CAD and control groups (56.0, 31.9, and 33.8, respectively, P < .001 for both comparisons). Furthermore, the frequency of Arg/Arg genotypes was the lowest in the LM-CAD group compared with the MP-CAD and control groups. Knowing that TP53 is an antioncogene protein that acts as a tumor suppressor and regulator of apoptosis, the lowest frequency of Arg/Arg genotype observed in these high-risk patients may indicate lower protection from the atherosclerosis process. Replication studies are needed to evaluate this association.

Immunocytochemical expression of a panel of markers in pleural effusions from patients with primary lung adenocarcinoma.

INTRODUCTION: This study's principal objective was to evaluate the critical role of the application of immunocytochemistry to a novel panel of diagnostic markers for the accurate detection of the source of malignancies in pleural effusions of lung adenocarcinoma. MATERIALS AND METHODS: In 40 effusion smears from lung adenocarcinoma, the expression of the E-cadherin, a-catenin, Thyroid Transcription Factor (TTF-1), Epidermal Growth Factor Receptor (EGFR), p53, caspase 9 and 3, Bax and Bcl-2 was examined by immunocytochemistry. RESULTS: All cases showed positive immunoreactivity of tumour cells to caspase 3 (42,5%), caspase 9 (40%), Bcl-2 (30%), Bax (40%), p53 (55%), E-cadherin (82,5%), a-catenin (80%), TTF-1 (87,5%) and EGFR (62,5%). The Pearson's x2 analysis demonstrated a highly significant correlation to each of the other marker when analysed separately. Caspase 3 expression was correlated significantly with caspase 9 (p<0.0001), Bax (p=0.002), Bcl-2(p=0.014) and p53 (p=0.011). Caspase 9 was correlated with Bax (p=0.005) and p53 (p=0.047), p53 correlated with E-cadherin (p=0.011), a-catenin(p=0.011), EGFR (p<0.0001) and Bax (p=0.032). Correlation was also observed between Bcl-2 and Bax expression (p<0.0001), E-cadherin and a-catenin expression (p<0.0001) and a-catenin and TTF-1 expression (p=0.002). CONCLUSIONS: The use of a panel of biomarkers can be of great value in determining effusion immunoprofile in patients with lung adenocarcinoma for clinical application.

Chest radiograph of an asymptomatic man.

Case report: An asymptomatic man undergoes a chest radiograph http://ow.ly/4nmyfG.

Prognostic value of COX-2, P53, and EZH-2 evaluated by quantitative image analysis in premalignant and malignant breast lesions.

BACKGROUND: Cytological differential diagnosis of atypical hyperplasia and well differentiated breast carcinoma may be challenging, because sometimes there is an overlap between the cytomorphological features of these lesions. The aim of the study was to investigate COX-2, EZH-2, p53 expression in carcinomas and the gray zone of breast cytology categories of atypical hyperplastic lesions with regard to biological behavior of the tumor. METHODS: FNA speciments from 100 patients with breast hyperplastic lesions and cancer were investigated by immunocytochemistry and a quantitative analysis for COX-2, p53, and EZH-2. RESULTS: Extent of staining for COX-2 correlated with percentage of positive for EZH-2 (P < 0.0001) and p53 nuclei (P < 0.001). The intensity of COX-2 was lower in the carcinoma group (118.57 ± 12.43) than in the hyperplastic (127.16 ± 11.71) group (P = 0.006). On the contrary the mean value of staining extent was greater in the adenocarcinoma cases (15.96 ± 13.03) than in hyperplastic (4.04 ± 1.94) cases (P < 0.0001). The percentage of EZH-2 and p53 positive cells correlated with the histological type of the lesions (P = 0.001 and P = 0.011, respectively). There was also a statistically significant relation between tumor size and expression of COX-2 (P = 0.007) and EZH-2 (P = 0.010). CONCLUSION: Our study showed that the expression of COX-2, EZH-2, and p53 as determined by immunocytochemistry at quantitative level may be a predictor for distinguishing cytologically atypical hyperplastic from malignant breast lesions and may be regarded as potential prognostic factor in breast cancer patients.

Novel oral anticoagulants in peripheral arterial and coronary artery disease.

Atherosclerosis comprises of a chronic disease of the vessels which mainly targets the arterial system. The disease's main characteristic is the accumulation of inflammatory cells, lipids, smooth muscle cells and connective tissue within the vascular intima layer. The atherosclerotic lesion can be more accurately defined as a fibro-inflammatory lipid plaque. The pathogenesis of the atherosclerotic plaque is a progressive and additive process that usually occurs over decades. Antiplatelet and anticoagulant agents have been the major elements of large trials since decades, in an attempt to promote the primary and secondary prevention of atherothrombosis. The atherosclerotic plaque rupture and the following thrombosis involve, among others, activation of both platelets and coagulation factors, therefore a potential combination of antiplatelet and anticoagulant therapy, particularly in the setting of secondary prevention has been reconsidered in the light of the newly developed oral anticoagulants.

Significance of cyclooxygenase 2, EZH-2 polycomb group and p53 expression in actinic keratosis and squamous cell carcinomas of the skin.

The development and progression of squamous cell carcinoma (SCC) of the skin is characterized by an accumulation of molecular changes. The aim of this study was to investigate the association of the immunohistochemical expression of cyclooxygenase-2 (COX-2), enhancer of zeste homolog 2 (EZH-2), and p53 in actinic keratosis (AK) and SCC and detect any differences between invasive and preinvasive squamous epidermal lesions. Forty-three cases with AK, 38 with SCC, and 9 with SCC arising on AK (SCC/AK) were studied. For COX-2 immunostaining, weak or no reaction was associated with AK (58.10% of cases), whereas moderate or strong reaction with SCCs (34.2% and 39.5%, respectively). Furthermore, 88.9% of the "mixed" SCC/AK specimens demonstrated moderate reaction (χ2 = 29.924, P < 0.0001). For EZH-2 immunostaining, a weak or no reaction was observed in 62.8% of AK cases, whereas a moderate reaction was observed in 42.1% of SCCs and 77.8% of "mixed" SCC/AK cases (χ2 = 18.91, P = 0.001). Weak immunoreactivity of p53 was associated with AK (58.1%), moderate with SCC (44.7%), and strong with SCC/AK lesions (66.7%) (χ2 = 15.999, P = 0.003). COX-2, p53, but mainly EZH-2 immune expression seems to be strongly associated with the biological potential of squamous epidermal cells and seems to be differentiating SCC by comparison to AK of the skin. The value of the combined expression of these markers is worth being further investigated as an additional tool for diagnostic, prognostic, and possibly, therapeutic use.

Mitochondrial UCP4 and bcl-2 expression in imprints of breast carcinomas: relationship with DNA ploidy and classical prognostic factors.

Mitochondria are the bioenergetic and metabolic centers of cells and play an important role in the regulation of cell death. The mitochondrial apoptosis pathway is controlled by the bcl-2 protein family. Overexpression of mitochondrial uncoupling protein 4 (UCP4) can promote proliferation and inhibit apoptosis and differentiation. Imprint smears obtained from 124 tumors were studied immunocytochemically, and results were correlated with prognostic markers. There were 112 ductal and 12 lobular carcinomas. The positivity of UCP4 was correlated with lymph node metastases (p=0.005), positive ER and PR expression (p<0.0001 for both), as well as positivity for p53 (p<0.0001) and Ki-67 (p<0.0001). Decreased expression of bcl-2 correlated with increased expression of UCP4 (p=0.001). Regarding DNA ploidy, UCP4 positivity was correlated with aneuploid tumors (p=0.002). Negative expression of bcl-2 was correlated with poorly differentiated carcinomas (p<0.0001), as well as with positive expression of p53 (p<0.0001) and Ki-67 (p<0.0001). Logistic regression revealed that ploidy and p53 expression had an impact on UCP4. These findings encourage future investigations regarding the potential role of UCPs not only into mechanisms underlying breast cancer, but also as a novel candidate to the design and development of more effective therapeutic strategies.

The significance of Survivin and Nectin-4 expression in the prognosis of breast carcinoma.

To investigate the prognostic significance of Survivin and Nectin-4 expression in breast carcinomas. Imprint smears were obtained from 140 breast carcinoma specimens and studied immunocytochemically for the expression of Survivin and Nectin-4. The results were correlated with several clinicopathological parameters, including five-year survival. Increased Survivin staining pattern correlated with increased grade (p < 0.0001), increased lymph node invasion (p < 0.0001), increased tumor size and reduced survival (p < 0.0001). Elevated Nectin-4 expression also correlated significantly with increased grade (p < 0.0001), increased tumor size (p < 0.0001) and reduced survival (p < 0.0001). In addition, Survivin and Nectin-4 staining patterns correlated strongly with one another (p < 0.0001). However, on multivariate analysis, neither Survivin nor Nectin-4 expression seemed to have an independent impact on survival in our study cases. The findings of our study suggest that increased expression of Survivin and Nectin-4 may indicate a worse prognosis in breast cancer patients. The exact implications of the expression of these markers in breast cancer prognosis and treatment remain to be clarified.

Enhancer of zeste homologue 2 expression in breast carcinoma smears in relationship with p53, Ki-67 and other prognostic parameters.

BACKGROUND: The polycomb group protein enhancer of zeste homologue 2 (EZH 2) has been reported as a marker of aggressive breast cancer. The aim of this study was to investigate the correlation between the expression of EZH 2 with p53 and Ki-67 expression and other clinicopathological parameters in primary breast carcinomas in order to determine the role of the above marker as a prognosticator of tumor aggressiveness and patient outcome. PATIENTS AND METHODS: One hundred primary operable breast cancer patients were investigated in order to identify the expression of EZH 2, Ki-67 and p53 in imprint smears immunocytochemically. The prevalence of expression of these markers was then correlated with clinicopathological parameters. Follow-up was available for all patients. RESULTS: EZH 2 was expressed in 64% of the cases and correlated with higher levels of p53 (relative risk = 3.00, p < 0.0001) and Ki-67 (relative risk = 3.25, p < 0.0001). Malignant cells showed immunoreactivity for all markers in the nucleus. Univariate analysis revealed a strong association between EZH 2 protein expression and tumor grade and size, lymph node metastasis, and HER-2 and estrogen and progesterone receptor status. Multivariable statistical analysis revealed that lymph node metastasis was the main predictor for EZH 2 expression. Decreased patient survival was also significantly associated with EZH 2 expression (p < 0.0001). CONCLUSIONS: EZH 2 expression may be a marker of poor prognosis in breast carcinoma patients and has been suggested as a candidate for targeted therapy.

Apoptosis-related factors p53, bcl-2 and the defects of force transmission in dilated cardiomyopathy.

The etiology of heart failure in dilated cardiomyopathy involves multiple agents. The purpose of this study was to investigate the presence of apoptosis-related proteins p53, bcl-2, and the defects of force transmission in end-stage dilated cardiomyopathy. We studied myocardial samples from 20 hearts with histologic findings of dilated cardiomyopathy. Myocardial samples obtained from 10 normal hearts were used as controls. An immunohistochemical method was performed with the use of desmin, N-cadherin, p53, and bcl-2 antibodies. The expression of desmin and N-cadherin was much more pronounced in dilated cardiomyopathy, and both of them were arranged disorderly. On the other hand, increased expression of p53 is associated with progressive loss of myocytes by apoptosis in heart failure, and increased expression of bcl-2 represents a possible compensatory antiapoptotic mechanism. The increased amount and the irregular distribution of desmin and N-cadherin in dilated cardiomyopathy may compensate for the loss of cellular stability due to the loss of contractile material. These alterations contribute to the deterioration of contractile function in heart failure. Furthermore, the prevalence of an apoptotic or compensatory antiapoptotic mechanism may influence the evolution of heart failure in dilated cardiomyopathy.

CD24 expression has a prognostic impact in breast carcinoma.

We investigated the prognostic significance of BAG-1 and CD24 in invasive breast carcinomas. Seventy cases of invasive breast carcinoma were studied immunocytochemically for the expression of BAG-1 and CD24. The results were correlated with several prognostic parameters, including 5-year survival. Univariate analysis showed a significant correlation of BAG-1 and CD24 overall positive staining with several adverse prognostic parameters, such as increased stage (p<0.0001), tumor grade 3 (p=0.016 and p=0.02, respectively), positive lymph nodes (p<0.0001), and increased tumor size (p<0.0001). Similar results were found for BAG-1 nuclear staining, as well as for positive cytoplasmic CD24 expression. Both of our markers studied had a significant, negative effect on survival. Multivariate analysis further revealed an independent prognostic impact for CD24 overall staining. The results of our study showed that overall cytoplasmic and especially nuclear BAG-1 expression, as well as overall and cytoplasmic CD24 expression, correlates with adverse prognostic parameters. An independent prognostic value for overall CD24 staining was also demonstrated.

Telomerase RNA expression and DNA ploidy as prognostic markers of prostate carcinomas.

AIMS AND BACKGROUND: The objective of this study was to determine whether there was a correlation between telomerase RNA expression and DNA ploidy status with clinicopathological parameters and biochemical recurrence after radical prostatectomy. STUDY DESIGN: Telomerase RNA expression and DNA ploidy were evaluated in imprint smear samples obtained from 112 prostates after radical prostatectomy. The results were correlated with pathological stage, Gleason score and serum PSA. RESULTS: Positive telomerse RNA expression was detected in 67.8% of prostate carcinomas. The multiple linear regression model showed a statistically significance increase in telomerase RNA expression with increased Gleason score (P < 0.0001) and preoperative serum PSA values (P = 0.0125). DNA ploidy status also varied significantly with Gleason score (P < 0.0001) and preoperative serum PSA values (P = 0.0110). Five patients with diploid tumors and negative telomerase RNA expression developed a recurrence. However, recurrence was associated with DNA aneuploidy (P = 0.001) as well as with high telomerase RNA overexpression (P = 0.001). CONCLUSIONS: We conclude that telomerase RNA expression and DNA ploidy could be additional markers in the field of prognosis of prostate carcinomas.

The prognostic significance of COX-2 and survivin expression in ovarian cancer.

We investigated the prognostic significance of cyclooxygenase-2 (COX-2) and survivin in ovarian carcinoma. Imprint smears were obtained from 100 ovarian carcinoma specimens and were studied immunocytochemically for the expression of COX-2 and survivin. The results were correlated with several clinicopathological parameters, including 5-year survival. Increased COX-2 staining pattern correlated with a non-mucinous histological type (p=0.008), increased stage (p<0.0001), high histological grade (p<0.0001), and reduced survival rates (p<0.00001). Survivin expression was strongly associated with increased stage (p<0.0001), increased histological grade (p<0.0001), and reduced survival (p<0.00001). Elevated survivin expression also correlated significantly with pre-menopausal status (p=0.033). In addition, COX-2 and survivin staining patterns correlated strongly with one another (p<0.0001). However, on multivariate analysis, an independent prognostic value was found only for tumor stage and grade. The findings of our study indicate that the increased expression of COX-2 and survivin in ovarian cancer is associated with one another and with several adverse clinicopathologic parameters, including reduced survival, thus suggesting a role of these molecules in disease progression. Further investigations of the exact prognostic and therapeutic implications of COX-2 and survivin expression are strongly warranted.