Prognostic significance of micropapillary pattern in lung adenocarcinoma and expression of apoptosis-related markers: caspase-3, bcl-2, and p53

We evaluated the clinicopathological characteristics and prognostic significance of lung adenocarcinoma with micropapillary pattern (MPP) and analyzed the expression of apoptosis-related markers: caspase-3, bcl-2, and p53. A series of 166 lung adenocarcinoma that had been surgically resected between 2004 and 2009 were reviewed. Histopathologic patterns, presence of tumor necrosis, mitosis, lymphovascular and perineural invasion, the status of pleura, and tumor differentiation were examined. Of the 166 patients; 71 were stage I, 35 stage II, 51 stage III, and nine stage IV. Histologically they were divided into two groups: MPP-positive (n = 55) and MPP-negative (n = 111). The following items were significantly more frequent in the MPP positive group: female gender (p = 0.03), lymph node metastasis (p = 0.031), and pleural invasion (p = 0.045). Age, smoking status, tumor stage, lymphatic invasion, perineural invasion, mitotic count, and survival rates had no statistically significant difference between groups (p > 0.05). In MPP positive tumors, visceral pleural invasion was identified significantly more frequent than in MPP negative tumors, at stage I. Tumors with MPP showed elevated expressions of caspase-3 (94.5%), p53 (60%), and bcl-2 (54.5%). In MPP positive group, the expression of these three markers had no statistically significant impact on survival. In whole population, bcl-2 expression was correlated with a better outcome. We conclude that MPP is associated with poor prognostic factors both in early and late stages in lung adenocarcinoma. Bcl-2 provides prognostic information independent from the MPP.     

Oncogenic WIP1 phosphatase attenuates the DNA damage response and sensitizes p53 mutant Jurkat cells to apoptosis

Wild-type (wt) p53-induced phosphatase 1 (Wip1), encoded by the protein phosphatase, Mg²⁺/Mn²⁺ dependent 1D (PPM1D) gene, is a serine/threonine phosphatase induced upon genotoxic stress in a p53-dependent manner. Wip1/PPM1D is frequently overexpressed, amplified and mutated in human solid tumors harboring wt p53 and is thus currently recognized as an oncogene. Oncogenic Wip1 dampens cellular stress responses, such as cell cycle checkpoints, apoptosis and senescence, and consequently increases resistance to anticancer therapeutics. Targeting Wip1 has emerged as a therapeutic strategy for tumors harboring wt p53. However, little is known about the efficacy of Wip1-targeted therapies in tumors lacking p53. The present study aimed to investigate the potential role of oncogenic Wip1 in p53 mutant (mt) Jurkat cells. In the present study, it was demonstrated that p53 mt Jurkat cells exhibited PPM1D/Wip1 gene amplification and expressed relatively high levels of Wip1, as confirmed by gene copy number and RNA expression analysis. In addition, Jurkat cells underwent G2 cell cycle arrest, apoptotic cell death and senescence in response to etoposide and doxorubicin, although the phosphorylation levels of DNA damage response (DDR) elements, including ataxia-telangiectasia mutated, ataxia-telangiestasia and Rad3-related, checkpoint kinase (Chk)1 and Chk2 were significantly low. Accordingly, the targeting of Wip1 phosphatase by RNA interference increased the phosphorylation of DDR elements, but decreased the rate of apoptosis in response to etoposide or doxorubicin in Jurkat cells. The induction of senescence or cell cycle arrest was not affected by the knockdown of Wip1. The results suggest that increased Wip1 expression enhances the apoptotic sensitivity of Jurkat cells in response to chemotherapeutic agents by attenuating DDR signaling. The present study highlights the possible pro-apoptotic role of Wip1 in a p53 mt T-cell acute lymphoblastic leukemia cell line. The data suggest the careful consideration of future treatment strategies aiming to manipulate or target Wip1 in human cancers lacking p53.     

The role of ADC measurement in differential diagnosis of focal hepatic lesions

Purpose

To evaluate the utility of apparent diffusion coefficient (ADC) measurement in characterization of focal solid hepatic lesions and determine the role of ADC values in differentiation of solid benign and solid malignant hepatic lesions.

Materials and methods

Between June 2006 and December 2010, a total of 95 focal solid hepatic lesions in 95 consecutive patients were evaluated by abdominal MRI. Diffusion weighted MRI was performed with b 100, b 600 and b 1000 gradients with ADC measurements. Comparison of mean ADC values between solid benign (focal nodular hyperplasia and other solid benign lesions) and solid malignant lesion (hepatocellular carcinoma, metastasis, and cholangiocarcinoma) groups and between each benign and malignant lesion was done. The ROC analyses were performed in order to determine cut-off ADC values for differentiation of benign and malignant lesion groups at 3 different gradients.

Results

Twenty-six of 95 lesions were benign and 69 were malignant. Mean ADC values of solid benign lesions at b 100, b 600 and b 1000 gradients were 2.25 ± 0.54 × 10⁻³, 1.97 ± 0.64 × 10⁻³ and 1.52 ± 0.47 × 10⁻³ mm²/s, respectively. Mean ADC values of solid malignant lesions at b 100, b 600 and b 1000 gradients were 1.84 ± 0.57 × 10⁻³, 1.37 ± 0.38 × 10⁻³ and 1.08 ± 0.22 × 10⁻³ mm²/s, respectively. The ADC values of solid benign lesions were significantly higher than solid malignant lesions at all 3 gradients (P < 0.05). Differentiation of benign and malignant subtype lesions from each other in their groups did not yield as significant findings as comparing results between benign and malignant lesions.

Conclusion

Although ADC measurements were not helpful for differentiating subtypes of solid benign or solid malignant lesions, ADC measurements at 3 different gradients may be useful in differential diagnosis of benign lesions from malignant ones.     

Some Heavy Metals Accumulation in Tissues in <Emphasis Type="Italic">Capoeta umbla</Emphasis> (Heckel, 1843) from Uzuncayir Dam Lake (Tunceli,Turkey)

Concentrations of metals were determined in the gills, liver, kidney, heart and muscle in Capoeta umbla caught from six stations from the Munzur River system. Metal concentrations in the tissues tended to vary significantly among stations (p < 0.05). Liver (Cu, 10.10 ± 0.23–23.03 ± 9.37 ppm; Zn, 14.67 ± 3.01–21.82 ± 2.39 ppm; Cd, 18.04 ± 4.56–52.69 ± 10.65 ppb and Fe, 28.87 ± 6.78–115.11 ± 34.87 ppm) and kidney (Cu, 1.80 ± 0.25–3.70 ± 0.62 ppm; Zn, 20.81 ± 0.37–29.36 ± 0.70 ppm; Cd, 132.06 ± 5.29–639.51 ± 20.14 ppb and Fe, 24.40 ± 1.98–59.39 ± 1.97 ppm) tissues showed higher metal concentrations than other tissues. It seems that metal contamination in the river is too high for the health of fish and the people who eat them. The geographical locations of catch, season, nature of diet, and the size of fish used for analyses might lead to different metal concentration in the same fish species.     

Cortisol levels during an oral glucose tolerance test in lean and obese women

Because of the similarities between Cushing's syndrome and insulin resistance syndrome,cortisol metabolism in obesity has been investigated in numerous studies. Our study investigates serum glucose, insulin, and cortisol response to oral glucose stimulation in a group of obese and lean normotensive, normolipidemic, and glucose-tolerant premenopausal women. Twenty-one obese [body mass index (BMI) 37Z +/- 6.3 kg/m2) and 14 lean (BMI: 21.5 +/- 1.0 kg/m2) age-matched healthy premenopausal women were included in the study. Serum glucose, insulin, and cortisol levels were measured at 30-minute intervals during 120 minutes of oral glucose tolerance testing (OGTT). Mean serum glucose and insulin levels were significantly higher in the obese group compared with lean subjects, and cortisol levels were similar during OGTT. There was not a significant difference for cortisol area under the curve (AUC) during OGTT between the two groups. No correlation between cortisol AUC, insulin AUC, and glucose AUC was noted for both groups. During OGTT, a decrease in cortisol levels was observed in both groups. The decrement occurred at 30 minutes of the OGTT in the obese group and at 60 minutes of the OGTT in the lean group. At 90 and 120 minutes of the OGTT, serum cortisol levels were similar to basal levels in both the obese group and the lean group. Previous studies reported altered hypotalamic-pituitary-adrenal axis activity, altered levels of urinary cortisol excretion, and increased metabolic clearance of cortisol in obesity. In our study in obese women, the only detected difference from lean subjects was a quicker suppression and recovery in serum cortisol levels after glucose administration.     

Coronary atherosclerosis distribution and the effect of blood glucose level on operative mortality/morbidity in diabetic patients undergoing coronary artery bypass grafting surgery: a single center experience.

OBJECTIVE: The study aim was to investigate the effect of blood glucose level on atherosclerotic lesion distribution and the contribution to the operative mortality/morbidity in diabetic patients who underwent coronary artery bypass grafting (CABG). METHODS: Between 1986-2003, a total of 2095 patients with diabetes mellitus underwent CABG. The analysis was carried out retrospectively from the clinical records. The patients were divided into four groups according to the blood glucose levels that were obtained when they first applied to hospital; Group 1 (492 patients with blood glucose < 120 mg/dl), group 2 (1112 patients with blood glucose - 120-200 mg/dl, group 3 (261 patients with blood glucose 201-250 mg/dl) and group 4 (230 patients with blood glucose > 250 mg/dl). One way ANOVA test was used for the statistical analysis of continuous variables and Chi-square test was used for analyzing the categorical variables. RESULTS: Emergent operation rate due to acute ischemia gradually increased from Group 1 to Group 4 and reached 6.6% in Group 4 (p=0.005). Operation time and the duration of cardiopulmonary bypass and cross clamp were significantly longer in patients with high blood glucose levels (p<0.05). Necessity for inotropic drug administration postoperatively (p<0.05) and mechanical support (p<0.05) were significantly higher also. The hospital mortality in group 3 was 9.6% and in group 4 was 11.3% (p=0.09). No statistically significant difference was found in terms of morbidity between the groups (p>0.05). The multi-vessel coronary artery disease was more common in groups with high blood glucose level (p<0.05). As the blood glucose level raised, patients were more frequently (p<0.05) confronted with distal left anterior descending artery, middle circumflex artery and right coronary artery lesions. CONCLUSION: Uncontrolled blood glucose level not only increased the perioperative complications but also the incidence of middle and distal coronary artery lesions. It is necessary to diagnose and aggressively treat the high blood glucose level especially before the CABG.