OBJECTIVE: Test the safety and efficacy of sequentially blocking angiogenesis by adding oral cyclophosphamide to bevacizumab following cancer progression on bevacizumab in patients with recurrent ovarian cancer. METHODS: Eligibility included≤2 lines of treatment for recurrence and measurable cancer by RECIST 1.0. Patients received bevacizumab (15mg/kg every 3weeks IV) and upon RECIST progression, oral cyclophosphamide (50mg orally daily) was added. Objectives included safety, toxicities, 3- and 6-month PFS rates, response rate, PFS, and OS. RESULTS: 20 patients were enrolled. Overall response rate was 10%, and 65% of patients had confirmed stable disease (SD). Thirteen of 20 patients received oral cyclophosphamide added to bevacizumab upon bevacizumab progression. Of these 13 patients, 1 patient subsequently achieved a PR (this patient had SD as best response during bevacizumab) and 3 patients had a confirmed SD. For all patients, median PFS was 8.41months, 6month PFS rate was 65%, duration of response (DOR) 7.3months, and median OS was 22.72months. Median DOR for patients receiving both bevacizumab and cyclophosphamide was 8.4months. Most toxicities were grade 1 and 2 and manageable. Grade 3 and grade 4 toxicities included 1 myocardial infarction, 1 gastrointestinal perforation (GIP), and 12/20 patients (60%) developed grade 3 HTN. CONCLUSIONS: Addition of oral cyclophosphamide to bevacizumab at the time of cancer progression on bevacizumab appears to have continued anti-cancer effects in a subgroup of patients and appears to be safe. Randomized trials testing combination versus sequential anti-angiogenic therapy for recurrent ovarian cancer are warranted.

Objective: To investigate the lag structure effects from exposure to atmospheric pollution in acute outbursts in hospital admissions of paediatric rheumatic diseases (PRDs). Methods: Morbidity data were obtained from the Brazilian Hospital Information System in seven consecutive years, including admissions due to seven PRDs (juvenile idiopathic arthritis, systemic lupus erythematosus, dermatomyositis, Henoch-Schönlein purpura, polyarteritis nodosa, systemic sclerosis and ankylosing spondylitis). Cases with secondary diagnosis of respiratory diseases were excluded. Daily concentrations of inhaled particulate matter (PM(10)), sulphur dioxide (SO(2)) nitrogen dioxide (NO(2)), ozone (O(3)) and carbon monoxide (CO) were evaluated. Generalized linear Poisson regression models controlling for short-term trend, seasonality, holidays, temperature and humidity were used. Lag structures and magnitude of air pollutants' effects were adopted to estimate restricted polynomial distributed lag models. Results: The total number of admissions due to acute outbursts PRD was 1,821. The SO(2) interquartile range (7.79 µg/m(3)) was associated with an increase of 1.98%(confidence interval 0.25-3.69) in the number of hospital admissions due to outcome studied after 14 days of exposure. This effect was maintained until day 17. Of note, the other pollutants, with the exception of O(3), showed an increase in the number of hospital admissions from the second week. Conclusion: This study is the first to demonstrate a delayed association between SO(2) and PRD outburst, suggesting that oxidative stress reaction could trigger the inflammation of these diseases.

Autophagy is a highly conserved cellular process occurring during periods of stress to ensure a cell's survival by recycling cytosolic constituents and making products that can be used in energy generation and other essential processes. Three major forms of autophagy exist according to the specific mechanism through which cytoplasmic material is transported to a lysosome. Chaperone-mediated autophagy is a highly selective form of autophagy that delivers specific proteins for lysosomal degradation. Microautophagy is a less selective form of autophagy that occurs through lysosomal membrane invaginations, forming tubes and directly engulfing cytoplasm. Finally, macroautophagy involves formation of new membrane bilayers (autophagosomes) that engulf cytosolic material and deliver it to lysosomes. This review provides new insights on the crosstalks between different forms of autophagy and the significance of bilayer-forming phospholipid synthesis in autophagosomal membrane formation.

Polymorphisms in the TP53 gene codon 72 (Arg72Pro) influence apoptosis induction and DNA damage repair. We evaluated how variants of protein p53 (p53Arg and p53Pro) affect cell death and DNA damage repair by analyzing the frequencies of karyorrhexis and micronuclei. There were significant differences in the frequency of karyorrhexis between the three p53 genotypes (Arg/Arg, Arg/Pro, and Pro/Pro), between samples taken before and after radiotherapy, and between patients and controls. The frequency of micronucleated cells increased significantly after radiotherapy. There were no significant differences in the micronucleus frequency in healthy tissues of these patients compared to controls, or in the comparisons between the three genotypes. We conclude that Arg72Pro polymorphism influences cell apoptotic capacity. This is the first study investigating karyorrhexis and micronuclei, as indicators of apoptosis after radiotherapy, and how these indicators are influenced by the TP53 polymorphism Arg72Pro.

Aim: The present report describes and discusses root canal variations in the internal morphology of maxillary molars. Background: Dental internal anatomy is directly related to all the technical stages of the endodontic treatment. Even though, in some situations a typical anatomical characteristics can be faced, and the professional should be able to identify them. Case descriptions: This clinical report describes five cases with different pulpar and periapical diagnostics where the endodontic treatment was performed, in which during the treatment the unusual occurrence of two or three canals in the palatal root 'or even two distinct palatal roots' of first and second maxillary molars, were described and important details for achieving treatment success were discussed. Conclusion: The knowledge of tooth internal anatomy must be considered during clinical and radiographic examinations. This should be valued not only to find atypical canals but also to enable calcified canals cleaning and shaping, once they are frequently omitted during endodontic therapy. Clinical significance: Anatomic variations can occur in any tooth, and palatal roots of maxillary first and second molars are no exception. The complexity of the root canal system and the importance of identifying its internal anatomy for planning endodontic treatment increase the chances of success. Keywords: Unusual canal configuration, Anatomy, Maxillary molar, Palatal root, Endodontics. How to cite this article: Scarparo RK, Pereira L, Moro D, Grundling G, Gomes M, Grecca FS. Morphologic Variations of Maxillary Molars Palatal Root and the Importance of Its Knowledge for Endodontic Practice: A Case Series. J Contemp Dent Pract 2011;12(2):138-142. Source of support: Nil Conflict of interest: None declared.

Abstract Objective: To determine the prevalence of abnormal karyotype results in women undergoing chorionic villus sampling (CVS) for abnormal first trimester screening compared to CVS for historical indications (advanced maternal age (AMA) or prior aneuploidy). Methods: Retrospective cohort of all patients undergoing CVS at Oregon Health & Science University from January 2006- June 2010. Patients were separated based on CVS indication: 1) positive ultrasound (U/S) or serum screening; or 2) AMA or prior aneuploidy with normal or no screening. Prevalence of abnormal karyotype results were compared between groups. Results: Fetal karyotyping was successful in 500 of 506 CVS procedures performed. 203 CVS were performed for positive screening with 69 abnormal karyotypes (34.0%). 264 CVS were performed for historical indications with 11 abnormal karyotypes (4.2%). This difference was statistically significant (χ2 71.9, p < 0.001; OR 11.8 [95%CI 5.8, 24.6]). There were 2 age-related aneuplodies in AMA women without positive screening. 42 out of 44 AMA women diagnosed with aneuploidy (95.5%) had abnormal U/S and/or serum screening (35 U/S, 4 serum, 3 U/S and serum). Conclusions: Combined ultrasound and serum screening should be recommended to all women, including AMA women, prior to undergoing invasive testing to improve risk-based counseling and minimize morbidity.

Epac is a guanine nucleotide exchange protein that is directly activated by cAMP, but whose cardiac cellular functions remain unclear. It is important to understand cardiac Epac signaling, because it is activated in parallel to classical cAMP-dependent signaling via protein kinase A. In addition to activating contraction, Ca(2+) is a key cardiac transcription regulator (excitation-transcription coupling). It is unknown how myocyte Ca(2+) signals are decoded in cardiac myocytes to control nuclear transcription. We examine Epac actions on cytosolic ([Ca(2+)](i)) and intranuclear ([Ca(2+)](n)) Ca(2+) homeostasis, focusing on whether Epac alters [Ca(2+)](n) and activates a prohypertrophic program in cardiomyocytes. Adult rat cardiomyocytes, loaded with fluo-3 were viewed by confocal microscopy during electrical field stimulation at 1Hz. Acute Epac activation by 8-pCPT increased Ca(2+) sparks and diastolic [Ca(2+)](i), but decreased systolic [Ca(2+)](i). The effects on diastolic [Ca(2+)](i) and Ca(2+) spark frequency were dependent on phospholipase C (PLC), inositol 1,4,5 triphosphate receptor (IP(3)R) and CaMKII activation. Interestingly, Epac preferentially increased [Ca(2+)](n) during both diastole and systole, correlating with the perinuclear expression pattern of Epac. Moreover, Epac activation induced histone deacetylase 5 (HDAC5) nuclear export, with consequent activation of the prohypertrophic transcription factor MEF2. These data provide the first evidence that the cAMP-binding protein Epac modulates cardiac nuclear Ca(2+) signaling by increasing [Ca(2+)](n) through PLC, IP(3)R and CaMKII activation, and initiates a prohypertrophic program via HDAC5 nuclear export and subsequent activation of the transcription factor MEF2.

Environmental lead contamination in Uruguay became a matter of public concern in 2001, when cases of children with blood lead levels (BLL) higher than 20 μg/dl appeared in some low-income neighborhoods of Montevideo, being 10 μg/dl the intervention reference BLL. The aim of this paper is to show the results of multidisciplinary actions taken by decisions makers in social, environmental and healthcare aspects, to minimize lead exposure risks. We evaluated changes in blood lead levels of different children and non-exposed adult populations before and after the actions were taken, from 2001 on. For children populations and non-exposed adults, we found a significant decrease of almost 50% in BLL compared with studies done before the actions were taken. The main action to consider was the phasing out process of leaded gasoline in our country among other. We conclude that the integration of inter and multidisciplinary actions promoted was of high impact on the population, bringing about a public sensitization and growing awareness of the lead environmental risks.

Autophagy, the process involved in the breakdown of intracellular proteins and organelles, has become an area of great importance in both cell survival and cell death. Despite the abundance of information on this topic, persisting issues remain about the origin and mechanism of formation of the autophagosomal membrane. The endoplasmic reticulum (ER) plays a critical role in the initiation of autophagy, especially in the formation of early lipid particles, termed the phagophores or the isolation membranes. The bulk, if not all of the lipid biosynthetic pathways cease at the level of the ER where the main synthesizing enzymes are resident proteins. We postulate that if the initial isolation membrane is formed from the locally synthesized lipids at the level of the ER, than an increase in the biosynthesis of the bilayer-forming phospholipids (phosphatidylcholine-PC, phosphatidylethanolamine-PE, and phosphatidylserine-PS) would occur simultaneously with induction of autophagy. As part of the isolation membranes, PE conjugates the cytosolic microtubule-associated protein 1 light chain 3 (LC3-I), to form LC3-II, the selective autophagosomal protein. Phosphatidylinositol-3-kinase (PI3K) action on the ER phosphatidylinositol occurs with phospholipid biogenesis, and together they act to contribute to the elongation and assembly of the autophagosomal particle.

BACKGROUND: Eribulin mesylate is a tubulin inhibitor with activity superior to paclitaxel in NIH:OVCAR-3 human epithelial ovarian cancer xenograft models. In this study, the authors assessed the efficacy of eribulin in platinum-resistant and platinum-sensitive recurrent ovarian cancer. METHODS: Patients with recurrent, measurable epithelial ovarian cancer who had received ≤2 prior cytotoxic regimens and who had adequate organ function were enrolled into 2 separate cohorts: 1) platinum-resistant patients (who had a progression-free interval <6 months after their last platinum-based therapy) and 2) platinum-sensitive patients (who had a progression-free interval ≥6 months after their last platinum-based therapy). Eribulin 1.4 mg/m(2) was administered over 15 minutes intravenously on days 1 and 8 every 21 days. Efficacy was determined by objective response on computed tomography studies. RESULTS: In the platinum-resistant cohort, 37 patients enrolled, and 36 patients were evaluable for response and toxicity. Two patients achieved a partial response (5.5%), and 16 patients (44%) had stable disease as their best response. The median progression-free survival was 1.8 months (95% confidence interval, 1.4-2.8 months). In the platinum-sensitive cohort, 37 patients enrolled, and all were evaluable for response. Seven patients achieved a partial response (19%). The median progression-free survival was 4.1 months (95% confidence interval, 2.8-5.8 months). The major toxicity was grade 3 or 4 neutropenia (42% of platinum-resistant patients; 54% of platinum-sensitive patients). CONCLUSIONS: Eribulin produced an objective response in 5.5% of women with platinum-resistant, recurrent ovarian cancer and in 19% of women with platinum-sensitive disease. The median progression-free survival was 1.8 months in the platinum-resistant group and 4.1 months in the platinum-sensitive group. Cancer 2011. © 2011 American Cancer Society.