Rational design of a cytotoxic dinuclear Cu2 complex that binds by molecular recognition at two neighboring phosphates of the DNA backbone.

The mechanism of the cytotoxic function of cisplatin and related anticancer drugs is based on their binding to the nucleobases of DNA. The development of new classes of anticancer drugs requires establishing other binding modes. Therefore, we performed a rational design for complexes that target two neighboring phosphates of the DNA backbone by molecular recognition resulting in a family of dinuclear complexes based on 2,7-disubstituted 1,8-naphthalenediol. This rigid backbone preorganizes the two metal ions for molecular recognition at the distance of two neighboring phosphates in DNA of 6-7 Å. Additionally, bulky chelating pendant arms in the 2,7-position impede nucleobase complexation by steric hindrance. We successfully synthesized the Cu(II)2 complex of the designed family of dinuclear complexes and studied its binding to dsDNA by independent ensemble and single-molecule methods like gel electrophoresis, precipitation, and titration experiments followed by UV-vis spectroscopy, atomic force microscopy (AFM), as well as optical tweezers (OT) and magnetic tweezers (MT) DNA stretching. The observed irreversible binding of our dinuclear Cu(II)2 complex to dsDNA leads to a blocking of DNA synthesis as studied by polymerase chain reactions and cytotoxicity for human cancer cells.

Risk factors for lateral cervical lymph node involvement in follicular thyroid carcinoma.

BACKGROUND: Metastases from follicular thyroid carcinoma (FTC) are usually blood borne and far less to lymph nodes (LN). The present study was designed to evaluate the factors that are associated with LN metastases in patients operated on for FTC. METHODS: A retrospective review of 70 patients (25 men; mean age, 47 (range, 14-92) years) operated on between January 1995 and December 2005 for FTC was undertaken. All patients had histopathology study of the regional LN and postoperative radioiodine scintigraphy. According to LN invasion, they were divided into two groups in which various parameters were compared. RESULTS: The length of follow-up was 52 (range 17-108) months. A total of 375 LN were examined from ipsilateral neck side and 87 LN from the contralateral side. LN metastases were found in five (7%) cases: all ipsilateral. Comparing data from the patients with and without LN metastases, respectively, age was 60 and 47 years (p = 0.12), male/female ratio was 1/4 and 24/41 (p = 0.44), tumor size was 68 and 37 mm (p < 0.01), tumor differentiation (well/moderate) was 3/2 and 25/19 (p = 0.89), distant metastases were detected in 1 and 8 cases (p = 0.72) .The tumor size was >40 mm in 35 (50%) patients. All patients with LN metastases were found in this group (5/35; 14%). CONCLUSIONS: Follicular thyroid carcinoma results in metastases to regional lymph nodes in 7% of cases but only to the ipsilateral neck side. Tumor size is the only factor that impacts it. We do not recommend lymph node dissection in follicular thyroid carcinomas <4 cm.

Influence of preservation solution on human islet isolation outcome.

BACKGROUND: The influence of the preservation solution used for in situ perfusion of the donor and pancreas storage on islet isolation has received little attention. METHODS: In this prospective controlled trial, we compared the outcome of human islet isolation from pancreata perfused with University of Wisconsin (UW) solution or Celsior, an alternative colloid-free extracellular solution. RESULTS: At the 1-year interim analysis, the viability and insulin secretion of islets isolated from donors perfused with UW (n=19) or Celsior (n=5) were identical. However, total islet recovery (IEQ) and isolation yield (IEQ/g) were 1.8-fold and 2.1-fold inferior in the Celsior group (P<0.05 vs. UW). Overall, 13 (68%) of islet preparations were effectively transplanted from the UW group vs. none from the Celsior group (P=0.01). The clinical study was discontinued and the causes of these differences were further explored in the pig (n=14). In contrast to UW, Celsior induced cell swelling and pancreas edema after only four hours of cold storage. These abnormalities were delayed when the donor was perfused with Solution de Conservation d'Organes et de Tissus (SCOT), an extracellular solution containing polyethylene glycol. CONCLUSIONS: Our results suggest that colloid-free preservation solutions might be suboptimal for pancreas perfusion and cold storage prior to islet isolation and transplantation. Because pancreata are now frequently recovered for islet transplantation, preliminary experimental and clinical data about islet isolation should be obtained prior to the routine implementation of new preservation solutions for abdominal perfusion during multiorgan recovery.

The evolution of severe steatosis after bariatric surgery is related to insulin resistance.

BACKGROUND & AIMS: In severely obese patients, factors implicated in the evolution of severe steatosis after bariatric surgery remain unresolved. Our aim was to determine whether insulin resistance (IR) influences the histologic effects induced by bariatric surgery. METHODS: We prospectively included 185 severely obese patients (body mass index >/=35 kg/m(2)) referred for bariatric surgery. The evolution of IR (IR index = 1/quantitative insulin sensitivity check index) and liver injury with consecutive biopsy was concomitantly assessed before and 1 year after surgery. RESULTS: At preoperative biopsy, 27% of severely obese patients disclosed severe steatosis (>/=60%). The alanine aminotransferase (P = .01) and IR indexes (P = .04) were independent predictive factors of severe steatosis at baseline. One year after surgery, surgical treatment induced a decrease in body mass index (9.5 kg/m(2); P < .0001), steatosis score (8.5%; P < .0001), and IR index (0.29; P < .0001). The preoperative IR index (P = .01) and preoperative steatosis (P = .006) were independent predictive factors in the persistence of severe steatosis after surgery. Moderate or severe steatosis was more frequently observed in patients who had conserved a higher IR index after surgery than in patients who had improved their IR index (44% vs 20.2%; P = .04). CONCLUSIONS: IR was independently associated with severe steatosis and predicted its persistence after surgery. The amelioration of IR after surgery is associated with a decrease in the amount of fat. Taken together, the results of this prospective study in severely obese patients demonstrate that severe steatosis and its evolution after surgery are intimately connected with IR.

Intragastric balloon for preoperative weight reduction in candidates for laparoscopic gastric bypass with massive obesity.

BACKGROUND: Laparoscopic bariatric operations can be technically challenging in massively obese patients. The potential of the intragastric balloon for preoperative weight reduction was evaluated in candidates for laparoscopic Roux-en-Y gastric bypass (LRYGBP) with super obesity. METHODS: From January 2004 to March 2005, 10 patients with super obesity who were potential candidates for LRYGBP were included in a prospective observational study. An intragastric balloon was placed endoscopically under general anesthesia. Patients were then followed by a multidisciplinary team until removal of the balloon after 6 months. Weight, BMI, and percent excess weight lost (%EWL) were monitored after 1, 3 and 6 months. RESULTS: The 10 patients were all female with mean +/- SD age of 33+/-11 years (range 17-51). Initial weight was 175+/-25 kg (range 135-223) and initial BMI was 64+/-7 kg/m2 (range 59-78). After completion of 1, 3 and 6 months, weight, BMI, and %EWL reached respectively: 166+/-27 kg*, 165+/-27 kg*, and 169+/-26 kg*; 61.1+/-7.6 kg/m2*, 60.8+/-8.4 kg/m2*, and 61+/-8.2 kg/m2*; 9+/-5%, 10+/-7%, 7+/-6%. (*=P<0.01 vs preop). CONCLUSION: In potential candidates for LRYGBP with super obesity, preoperative placement of an intragastric balloon can reduce the excess weight by 10% within 3 months. Extending this period failed to improve these results further.