A possible mechanism for exonuclease 1-independent eukaryotic mismatch repair

Mismatch repair contributes to genetic stability, and inactivation of the mammalian pathway leads to tumor development. Mismatch correction occurs by an excision-repair mechanism and has been shown to depend on the 5′ to 3′ hydrolytic activity exonuclease 1 (Exo1) in eukaryotic cells. However, genetic and biochemical studies have indicated that one or more Exo1-independent modes of mismatch repair also exist. We have analyzed repair of nicked circular heteroduplex DNA in extracts of Exo1-deficient mouse embryo fibroblast cells. Exo1-independent repair under these conditions is MutLα-dependent and requires functional integrity of the MutLα endonuclease metal-binding motif. In contrast to the Exo1-dependent reaction, we have been unable to detect a gapped excision intermediate in Exo1-deficient extracts when repair DNA synthesis is blocked. A possible explanation for this finding has been provided by analysis of a purified system comprised of MutSα, MutLα, replication factor C, proliferating cell nuclear antigen, replication protein A, and DNA polymerase δ that supports Exo1-independent repair in vitro. Repair in this system depends on MutLα incision of the nicked heteroduplex strand and dNTP-dependent synthesis-driven displacement of a DNA segment spanning the mismatch. Such a mechanism may account, at least in part, for the Exo1-independent repair that occurs in eukaryotic cells, and hence the modest cancer predisposition of Exo1-deficient mammalian cells.     

The Impact of On-pump Coronary Artery Bypass Surgery vs. Off-pump Coronary Artery Bypass Surgery on Sexual Function

IntroductionErectile dysfunction and ischemic heart disease are common health problems that affect elderly individuals. Despite advances in treatment strategies, cardiopulmonary bypass (CPB) has been used for coronary artery bypass grafting (CABG) for over three decades for surgical myocardial revascularization.AimTo discuss the difference between the on pump and the newer alternative—the off-pump CABG (OPCABG) surgery—on the sexual function.MethodsThis prospective study included 100 patients who underwent CABG.Main Outcome MeasuresThe patients were evaluated by an abridged form of International Index of Erectile Function questionnaire (IIEF-5), Pharmaco-Penile Duplex Ultrasound and finally by the European System for Cardiac Operative Risk Evaluation. The patients were underwent either on-pump CABG or OPCABG. Six months after surgery, the erectile function was revaluated according to the same preoperative measures.ResultsPatients included in the study were classified into two matched groups: group I—patients who underwent on-pump CABG (N = 50); and group II—patients who underwent OPCABG (N = 50). The frequency of intercourse was significantly higher in OPCABG (P < 0.05) after surgery. The mean ± standard deviation of the IIEF-5 scores of the on-pump group postoperatively became 12.48 ± 7.19 whereas it became 15.88 ± 6.67 in the off-pump group (P < 0.05). Moreover, the number of patients who reported postoperative improvement of their IIEF-5 score was significantly higher in OPCABG group (N = 23) compared with the conventional on-pump CABG group (N = 13) (P < 0.05). There was no significant change in the duplex ultrasound after surgery between both groups.ConclusionsThe OPCABG has a diminished impact on the sexual function of patients compared with the conventional on-pump CABG. Therefore, the type of operation can be considered a predictive factor of sexual function following CAB surgery. Mohamed OA, Bennett CJ, Farid RM, Helmy T, Mahran A, and Hamed HA. The impact of on-pump coronary artery bypass surgery vs. off-pump coronary artery bypass surgery on sexual function. J Sex Med **;**:**–**.     

Relative bioavailability of griseofulvin lyophilized dry emulsion tablet vs. immediate release tablet: A single-dose, randomized, open-label, six-period, crossover study in healthy adult volunteers in the fasted and fed states

The oral bioavailability of griseofulvin (GF) formulated as a fast disintegrating lyophilized dry emulsion (LDE) tablet was studied and compared to the commercially available immediate release (IR) tablet, as a reference, in both the fasted and fed states in nine healthy volunteers after a single oral dose (125mg) in a crossover design. Furthermore the LDE tablets were ingested with and without water under both the fasted and fed states. In the fasted state, the rate of absorption was found to be significantly faster from LDE tablets, in the presence and absence of water, as shown by a higher C(max) (more than two times higher, p=0.0001) and a shorter t(max) (by more than 3h, p=0.0001) compared to IR tablets. The extent of absorption, expressed as AUC, from LDE tablets in the presence and absence of water was 65% and 77% larger and statistically significantly different relative to the mean AUC from IR tablets (p=0.006). In the fed state, C(max) from LDE tablets ingested with and without water was found to be about 30% and 50% higher, respectively, than the immediate release tablets. A shorter t(max) was also shown whether LDE tablets were ingested with or without water in the fed state as compared to immediate release tablets. The mean AUC from LDE tablets under fed conditions in the presence of water was about 21% larger and was not statistically significantly different from AUC from immediate release tablets (p=0.517). When ingested without water, AUC from LDE tablets was about 43% larger and statistically significantly different relative to AUC from IR tablets (p=0.033). The mean AUC from the LDE tablet ingested with water under fed conditions relative to AUC from LDE tablet ingested without water was not statistically significantly different (p=0.454). Results show that the food effect of the high fat meal is very pronounced in case of the immediate release tablets, Fulvin, than in case of LDE tablets whether given with or without water.     

A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia

The chemo- and radioresponse of tumor cells can be determined by genetic factors (e.g., those that modify cell cycle arrest, DNA damage repair or cell death) and microenvironmental factors, such as hypoxia. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that rapidly recognizes and binds to DNA breaks to facilitate DNA strand break repair. Pre-clinical data suggest that PARP inhibitors (PARPi) may potentiate the effects of radiotherapy and chemotherapy. However, it is unclear as to whether PARPi are effective against hypoxic cells. We therefore tested the role for a novel PARPi, ABT-888, as a radiosensitizing agent under hypoxic conditions. Using human prostate (DU-145, 22RV1) and non-small cell lung (H1299) cancer cell lines, we observed that ABT-888 inhibited both recombinant PARP activity and intracellular PARP activity (86% to 92% decrease in all 3 cells lines following 2.5muM treatment). ABT-888 was toxic to both oxic and hypoxic cells. When ABT-888 was combined with ionizing radiation (IR), clonogenic radiation survival was decreased by 40-50% under oxic conditions. Under acute hypoxia, ABT-888 radiosensitized malignant cells to a level similar to oxic radiosensitivity. To our knowledge, this is the first study to demonstrate that inhibition of PARP activity can sensitize hypoxic cancer cells and the combination of IR-PARPi has the potential to improve the therapeutic ratio of radiotherapy.     

Comparison of hypoxic cell radiosensitizers,KIN-804, KIN-844, KIN-806 and TX-1877, on brain and liver metabolizing capacities in mice bearing Ehrlich ascites carcinoma

The biochemical effects of the 2-nitroimidazole hypoxic cell radiosensitizers KIN-804, KIN-806, and their analogues KIN-844 and TX-1877 on brain acetylcholinesterase (AChE) and hepatic free radical scavenging systems, such as reduced glutathione (GSH) and glucose-6-phosphate dehydrogenase (G-6-PDH) levels, and hepatic antioxidants, such as superoxide dismutase (SOD) and catalase, were evaluated in Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. The assay of brain AChE revealed nonsignificant changes with all drugs examined. To evaluate the hepatic metabolic capacity, groups of mice were divided into control, EAC-inoculated, 10-Gy local gamma-irradiated, and KIN-804, KIN-844, KIN-806, or TX-1877 (50 mg/kg body weight, i.p.) groups, and gamma-irradiation was combined with each drug. EAC inoculation markedly suppressed GSH, G-6-PDH, SOD, and catalase levels. On the other hand, treatment with gamma-irradiation significantly enhanced them. The treatment of EAC-bearing mice with each drug alone in the absence of gamma-irradiation revealed that KIN-806 and its derivative TX-1877 showed antitumor activity through their significant recovery of GSH and SOD levels, respectively, in the EAC-bearing mice group. Similarly, the combined treatment of EAC-bearing mice with gamma-irradiation with each of the drugs tested showed that KIN-806 and TX-1877 significantly increased GSH and SOD, and to a lesser extent G-6-PDH and catalase levels. On the other hand, KIN-804 and KIN-844 had only a nonsignificant effect on all parameters examined. In conclusion, these data reveal that the administration of KIN-806 and TX-1877 with or without subsequent gamma-irradiation, resulted in significant recovery of GSH and SOD activities that were inhibited by EAC inoculation.     

Spontaneous sternoclavicular joint infections

Spontaneous sternoclavicular (SC) joint infections are uncommon. Most cases of contained SC joint infections respond well to conservative treatment measures such as intravenous antibiotics and local drainage. However, some cases are more extensive, extending beyond the boundaries of the joint capsule, occasionally involving the anterior chest wall and mediastinum. We report our experience with 3 patients with spontaneous advanced SC joint infections. Radical surgical treatment seemed to provide the best control of this infection.     

Goiter prevalence,urinary iodine excretion,thyroid function and anti-thyroid function and anti-thyroid antibodies after 12 years of salt iodization in Shahriar,Iran

OBJECTIVE: In a previous study in 1983, goiter was found to be endemic in Shahriar, Iran. Iodized salt has been distributed in the region for the past 12 years, and the present study was performed to examine the effect of iodide supplementation on indicators of iodine deficiency (IDD) and thyroid antibodies. DESIGN & METHODS: A total of 3164 people, 58% women and 42% men, were selected by random sampling from the Shahriar area. Goiter was staged according to World Health Organization guidelines. Urinary iodine was measured by a digestion method, and thyroid hormone measurements were done by radioimmunoassay. The results were compared with those of 1983. RESULTS: Goiter prevalence before and after iodine supplementation was 50 and 40% in men, 70 and 51% in women, and 60 and 47% in the whole community, respectively (p < 0.001). A decrease in the prevalence of goiter was observed especially in younger individuals. The mean urinary iodine excretion was 7.6 and 18.5 micrograms/dL, before and after iodine supplementation. In 1983, the urinary iodine in 47.5% of the population studied was between 2 to 5 micrograms/dL, while in 1995, 65% of the population studied had urinary iodine between 10 to 25 micrograms/dL, 12 years after iodine supplementation. Mean serum T4, T3, and thyroid-stimulating hormone (TSH) were normal before and after intervention. There was no significant change in occurrence of positive antibodies, or of hypo- and hyperthyroidism, following iodine supplementation. CONCLUSION: The result of this study shows that the use of iodized salt causes an increase in excreted urinary iodine and a decrease in the prevalence of thyroid goiter, especially in younger age groups. Consumption of iodized salt with 40 parts per million (ppm) iodine has not caused increased prevalence of thyroid dysfunction in this area.     

Combination chemotherapy without cisplatin in the treatment of advanced non-small cell lung cancer

Cisplatin-based combinations are standard regimens in the treatment of advanced non-small cell lung cancer. Survival improvement has been achieved using this therapy. However, the high toxicity induced by cisplatin-based doublets urges the research of alternate treatments. Newest cytotoxic compounds yield a better efficacy-toxicity ratio. Platinum-free doublet regimens based on new drugs are expected to offer the patient an improved survival without decreasing his quality of life. Treatment-allocated time and period with high grade toxicity could be considered as wasted from the patient point of view. QUALY methods based on time without symptoms and toxicity allow the accurate evaluation of this end-point. This brief state-of-the-art deals with methodological statements highlighted by the first publications of randomized studies comparing non-platinum-based doublets with either single-drug chemotherapy or standard cisplatin-based doublets.