Tumor Protein 53 Gene Mutations Without 17p13 Deletion Have No Significant Clinical Implications in Chronic Lymphocytic Leukemia. Detection of a New Mutation.

BACKGROUND: The tumor protein p53 (TP53) gene may be inactivated through 17p13 deletion, somatic mutations, or both. In chronic lymphocytic leukemia (CLL) although 17p13 deletion is correlated with poor prognosis, the role of sole TP53 mutations remains controversial. MATERIALS AND METHODS: We carried out a mutation analysis of TP53 gene in 72 patients with CLL. RESULTS: Seventy-one (98.6%) patients carried the polymorphic site c.215C>G, p.Pro72Arg, but its presence was not correlated with overall survival (OS). Moreover, 19 (26.4%) patients carried a mutation of TP53. Among the eight detected mutations, to our knowledge, one (c.587G>A) has never been reported in the past. There was a correlation of the mutation burden with the stage of the disease (p=0.022), but not with OS. None of the detected mutations was individually correlated with OS. CONCLUSION: The clinical significance of TP53 mutations is still a matter of debate and larger studies and meta-analyses are required to reach an unequivocal conclusion.

Development of an animal model of fibrous cholangitis in pigs.

INTRODUCTION: The aim of this study was to develop a model of fibrous cholangitis in the offspring of gravid domestic pigs through the administration of 1,4-phenylene diisothiocyanate (DITC). MATERIAL AND METHODS: Six young domestic pigs and two gravid pigs with their offspring (21 pigs) were used as experimental models and six wild-type animals were used as controls. All pigs were divided into five main groups and five subgroups, according to their developmental stage and time of exposure to DITC. The following histopathological characteristics were quantitatively evaluated on a scale of 0-5: ductal proliferation, periportal fibrosis, inflammatory infiltration, periductal fibrosis and edema, intraluminal fibrosis, duct wall thickening, epithelial apoptosis, and arterial hyperplasia/hypertrophy. RESULTS: Statistically significant differences were observed for most of the histopathological markers between the group of pigs' offspring that received DITC at early gestation and their control group. Moreover, the group of animals that were exposed to the agent at early gestation exhibited significant differences for all histopathological characteristics compared to the animals that were exposed at late gestation. On the other hand, no statistically significant differences were observed between the group of animals that received the agent at late gestation and their healthy controls. CONCLUSIONS: Administration of DITC to domestic pigs in early pregnancy may induce histopathological patterns of fibrous cholangitis to their offspring imitating biliary atresia. This model may provide insight to the pathogenesis of the obstructive cholangitis in pigs.

Hydroxyethyl starch 6% (130/0.4) ameliorates acute lung injury in swine hemorrhagic shock.

BACKGROUND: Traumatic hemorrhage induces acute lung injury. The aim of this study was to assess whether lactated Ringer's solution or 6% hydroxyethyl starch 130/0.4 would have different effects on acute lung injury following hemorrhagic shock. METHODS: Twenty healthy pigs (19 ± 2 kg) were subjected to hemorrhage and were randomly allocated to two groups: Group A (10 pigs) who received lactated Ringer's solution and Group B (10 pigs) who received hydroxyethyl starch 130/0.4. Hemodynamic response and serum lactate were measured at predetermined phases. Four hours after fluid resuscitation animals were euthanized. Lungs were harvested, and tissue samples were collected. Focal thickening of the alveolar membranes, vascular congestion, number of activated neutrophils, alveolar edema, interstitial neutrophil infiltration, intraalveolar infiltration, and alveolar hemorrhage were assessed. Each feature was given a score from 0 to 3 (0 = absence, 3 = severe). The wet/dry ratio was also calculated, and with the use of Evans blue dye extravasation method, capillary permeability was assessed. RESULTS: The total histology score of Group A differed significantly from that of Group B, being significantly lower in Group B animals P = 0.048. The wet/dry weight ratio was significantly higher in the lactated Ringer's group (median [range]) (Group A, 5.1 [0.5]; Group B, 4.9 [0.3]; P = 0.009). The Evans blue dye extravasation method was utilized to study the lung capillary permeability. The animals in Group B showed a marked reduction in microvascular capillary permeability compared with the animals in Group A (Group A, 58.5 [21] mg/g; Group B, 51.5 [14] mg/g; P = 0.017). CONCLUSIONS: Our study indicates that resuscitation after hemorrhagic shock with hydroxyethyl starch 130/0.4 led to less lung edema and less microvascular permeability in this swine model.

Topoisomerase I and IIalpha protein expression in primary colorectal cancer and recurrences following 5-fluorouracil-based adjuvant chemotherapy.

PURPOSE: Human DNA topoisomerases I and II (topo-I and -II) are essential for vital cellular processes such as DNA replication, transcription, translation, recombination, and repair. In the present study, we correlate topo-I and -II expression and outcome after chemotherapy in primary and relapsed colorectal cancer. PATIENTS AND METHODS: Patients with colorectal cancer that had recurred, following surgery and adjuvant chemotherapy and underwent a second operation were included in the present study. All had undergone surgical resection of the primary tumor and received post-operatively 5-FU-based (5FU + Leucovorin, Mayo Clinic regimen) adjuvant chemotherapy. Tumor tissue was collected at the initial operation from the primary tumor and at the time of recurrence (during the second operation following chemotherapy). All tissue samples were analyzed for levels of expression of both topo-I and topo-IIa using standard three-step immunohistochemistry on paraffin sections. RESULTS: Forty patients were included. Levels of expression of topo-I and topo-II were higher in malignant cells from tumor recurrences compared to primary tumors (P = 0.0001 for both). There was a statistically significant positive relationship between patients age and levels of topo-I (P = 0.011) and topo-II (P = 0.011) expression. CONCLUSIONS: The study results reported here underscore the role of topoisomerase expression in colorectal cancer and suggest a potential role in tumor recurrence.

Effects of nimodipine administration on small bowel mucosa under conditions of laparotomy and consequent 48-hour starvation in a rat model.

BACKGROUND/AIMS: The combination of starvation and surgical trauma induces disturbances to the intestinal mucosal structure and function, as well as changes in mucosal barrier function in the rat small bowel. The aim of the present study was to evaluate the effects of nimodipine administration, on intestinal mucosal structural changes and enterocyte apoptosis, following laparotomy and subsequent postsurgical starvation (PSS) in the rat. METHODS: Thirty Wistar rats were divided into two experimental groups: A: Control group (n=15), where the animal models underwent laparotomy and consequent 48-hours PSS and B: Nimodipine group (n=15), where the rats underwent laparotomy, followed by intraperitoneal nimodipine administration and consequent 48-hour (h) PSS. Small bowel mucosal structural changes and enterocyte epithelial apoptosis were determined 48 h following laparotomy. RESULTS: Nimodipine rats (group B) demonstrated a significant decrease in small bowel villous height in jejunum (p=0.016) and ileum (p=0.002). Similarly, crypt depth decreased in jejunum (p<0.001) and ileum (p<0.001). Nimodipine group exhibited significantly higher apoptotic index in ileum compared to control rats (p=0.006). CONCLUSION: Nimodipine did not protect the intestinal mucosa from damage caused by surgery and consequent PSS and had obvious damaging effects on intestinal mucosa with derangements to its structure and subsequent mucosal atrophy.