Wanna Get Away? Maintenance Treatments and Chemotherapy Holidays in Gynecologic Cancers.

Epithelial ovarian cancer has a very high rate of relapse after primary therapy; historically approximately 70% of patients with a complete clinical response to surgery and adjuvant chemotherapy will relapse and die of the disease. Although this number has slowly improved, cure rates remain less than 50%. As such, maintenance therapy with the aim of preventing or delaying disease relapse and the goal of improving overall survival has been the subject of intense study. Numerous earlier studies with agents ranging from radioactive phosphorus to extended frontline therapy or to monthly taxol administration demonstrated encouraging improvements in progression-free survival (PFS) only to find, disappointingly, no benefit in overall survival. In addition, the PFS advantage of maintenance therapy was associated with disconcerting side effects such that maintenance therapy was not adapted as standard of care. Studies with bevacizumab and PARP inhibitors have demonstrated a PFS advantage with a manageable side-effect profile. However, an overall survival advantage remains unclear, and the use of these approaches thus remains controversial. Furthermore, in recurrent disease, the length of chemotherapy and benefits of extended chemotherapy is unclear. Thus, additional trials assessing maintenance strategies in ovarian and other gynecologic malignancies are needed

Global gene expression of Prochlorococcus ecotypes in response to changes in nitrogen availability

Nitrogen (N) often limits biological productivity in the oceanic gyres where Prochlorococcus is the most abundant photosynthetic organism. The Prochlorococcus community is composed of strains, such as MED4 and MIT9313, that have different N utilization capabilities and that belong to ecotypes with different depth distributions. An interstrain comparison of how Prochlorococcus responds to changes in ambient nitrogen is thus central to understanding its ecology. We quantified changes in MED4 and MIT9313 global mRNA expression, chlorophyll fluorescence, and photosystem II photochemical efficiency (F(v)/F(m)) along a time series of increasing N starvation. In addition, the global expression of both strains growing in ammonium-replete medium was compared to expression during growth on alternative N sources. There were interstrain similarities in N regulation such as the activation of a putative NtcA regulon during N stress. There were also important differences between the strains such as in the expression patterns of carbon metabolism genes, suggesting that the two strains integrate N and C metabolism in fundamentally different ways

Potential conservation of circadian clock proteins in the phylum Nematoda as revealed by bioinformatic searches

Although several circadian rhythms have been described in C. elegans, its molecular clock remains elusive. In this work we employed a novel bioinformatic approach, applying probabilistic methodologies, to search for circadian clock proteins of several of the best studied circadian model organisms of different taxa (Mus musculus, Drosophila melanogaster, Neurospora crassa, Arabidopsis thaliana and Synechoccocus elongatus) in the proteomes of C. elegans and other members of the phylum Nematoda. With this approach we found that the Nematoda contain proteins most related to the core and accessory proteins of the insect and mammalian clocks, which provide new insights into the nematode clock and the evolution of the circadian system.Fil: Romanowski, Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; ArgentinaFil: Garavaglia, Matías Javier. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Ing.genética y Biolog.molecular y Celular. Area Virus de Insectos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Goya, María Eugenia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ghiringhelli, Pablo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Ing.genética y Biolog.molecular y Celular. Area Virus de Insectos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Golombek, Diego Andres. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Cytoglobin is upregulated by tumour hypoxia and silenced by promoter hypermethylation in head and neck cancer

Background: Cytoglobin (Cygb) was first described in 2002 as an intracellular globin of unknown function. We have previously shown the downregulation of cytoglobin as a key event in a familial cancer syndrome of the upper aerodigestive tract. Methods: Cytoglobin expression and promoter methylation were investigated in sporadic head and neck squamous cell carcinoma (HNSCC) using a cross-section of clinical samples. Additionally, the putative mechanisms of Cygb expression in cancer were explored by subjecting HNSCC cell lines to hypoxic culture conditions and 5-aza-2-deoxycitidine treatment. Results: In clinically derived HNSCC samples, CYGB mRNA expression showed a striking correlation with tumour hypoxia (measured by HIF1A mRNA expression P=0.013) and consistent associations with histopathological measures of tumour aggression. CYGB expression also showed a marked negative correlation with promoter methylation (P=0.018). In the HNSCC cell lines cultured under hypoxic conditions, a trend of increasing expression of both CYGB and HIF1A with progressive hypoxia was observed. Treatment with 5-aza-2-deoxycitidine dramatically increased CYGB expression in those cell lines with greater baseline promoter methylation. Conclusion: We conclude that the CYGB gene is regulated by both promoter methylation and tumour hypoxia in HNSCC and that increased expression of this gene correlates with clincopathological measures of a tumour's biological aggression.</p

First Neutrino Observations from the Sudbury Neutrino Observatory

The first neutrino observations from the Sudbury Neutrino Observatory are presented from preliminary analyses. Based on energy, direction and location, the data in the region of interest appear to be dominated by 8B solar neutrinos, detected by the charged current reaction on deuterium and elastic scattering from electrons, with very little background. Measurements of radioactive backgrounds indicate that the measurement of all active neutrino types via the neutral current reaction on deuterium will be possible with small systematic uncertainties. Quantitative results for the fluxes observed with these reactions will be provided when further calibrations have been completed.Comment: Latex, 7 pages, 10 figures, Invited paper at Neutrino 2000 Conference, Sudbury, Canada, June 16-21, 2000 to be published in the Proceeding

Functional diversification of the nematode mbd2/3 gene between Pristionchus pacificus and Caenorhabditis elegans

Abstract Background Several members of the Methyl-Binding Domain protein family link DNA methylation with chromatin remodeling complexes in vertebrates. Amongst the four classes of MBD proteins, MBD2/3 is the most highly conserved and widespread in metazoans. We have previously reported that an mbd2/3 like gene (mbd-2) is encoded in the genomes of the nematodes Pristionchus pacificus, Caenorhabditis elegans and Caenorhabditis briggsae. RNAi knock-down of mbd-2 in the two Caenorhabditis species results in varying percentages of lethality. Results Here, we report that a general feature of nematode MBD2/3 proteins seems to be the lack of a bona fide methyl-binding domain. We isolated a null allele of mbd-2 in P. pacificus and show that Ppa-mbd-2 mutants are viable, fertile and display a fully penetrant egg laying defect. This egg laying defect is partially rescued by treatment with acetylcholine or nicotine suggesting a specific function of this protein in vulval neurons. Using Yeast-two-hybrid screens, Ppa-MBD-2 was found to associate with microtubule interacting and vesicle transfer proteins. Conclusion These results imply that MBD2/3 proteins in nematodes are more variable than their relatives in insects and vertebrates both in structure and function. Moreover, nematode MBD2/3 proteins assume functions independent of DNA methylation ranging from the indispensable to the non-essential.</p

NO Dioxygenase Activity in Hemoglobins Is Ubiquitous In Vitro, but Limited by Reduction In Vivo

Genomics has produced hundreds of new hemoglobin sequences with examples in nearly every living organism. Structural and biochemical characterizations of many recombinant proteins reveal reactions, like oxygen binding and NO dioxygenation, that appear general to the hemoglobin superfamily regardless of whether they are related to physiological function. Despite considerable attention to “hexacoordinate” hemoglobins, which are found in nearly every plant and animal, no clear physiological role(s) has been assigned to them in any species. One popular and relevant hypothesis for their function is protection against NO. Here we have tested a comprehensive representation of hexacoordinate hemoglobins from plants (rice hemoglobin), animals (neuroglobin and cytoglobin), and bacteria (Synechocystis hemoglobin) for their abilities to scavenge NO compared to myoglobin. Our experiments include in vitro comparisons of NO dioxygenation, ferric NO binding, NO-induced reduction, NO scavenging with an artificial reduction system, and the ability to substitute for a known NO scavenger (flavohemoglobin) in E. coli. We conclude that none of these tests reveal any distinguishing predisposition toward a role in NO scavenging for the hxHbs, but that any hemoglobin could likely serve this role in the presence of a mechanism for heme iron re-reduction. Hence, future research to test the role of Hbs in NO scavenging would benefit more from the identification of cognate reductases than from in vitro analysis of NO and O2 binding

Swedish high school students' knowledge and attitudes regarding fertility and family building

<p>Abstract</p> <p>Background</p> <p>Infertility is a serious problem for those who suffer. Some of the risks for infertility are preventable and the individual should therefore have knowledge of them. The purposes of this study were to investigate high-school students' knowledge about fertility, plans for family building and to compare views and knowledge between female and male students.</p> <p>Methods</p> <p>A questionnaire containing 34 items was answered by 274 students. Answers from male and female students were compared using student's <it>t</it>-test for normally distributed variables and Mann-Whitney <it>U</it>-test for non-normal distributions. The chi-square test was used to compare proportions of male and female students who answered questions on nominal and ordinal scales. Differences were considered as statistically significant at a <it>p</it>-value of 0.05.</p> <p>Results</p> <p>Analyses showed that 234 (85%) intended to have children. Female students felt parenthood to be significantly more important than male students: <it>p </it>= <it><</it>0.01. The mean age at which the respondents thought they would like to start to build their family was 26 (± 2.9) years. Men believed that women's fertility declined significantly later than women did: <it>p </it>= <it><</it>0.01. Women answered that 30.7% couples were involuntarily infertile and men answered 22.5%: <it>p </it>= <it><</it>0.01. Females thought it significantly more likely that they would consider IVF or adoption than men, <it>p = </it>0.01. Men felt they were more likely to abstain from having children than women: <it>p = <</it>0.01. Women believed that body weight influenced fertility significantly more often than men: <it>p = <</it>0.01 and men believed significantly more often that smoking influenced fertility: <it>p </it>= 0.03. Both female and male students answered that they would like to have more knowledge about the area of fertility.</p> <p>Conclusions</p> <p>Young people plan to start their families when the woman's fertility is already in decline. Improving young people's knowledge about these issues would give them more opportunity to take responsibility for their sexual health and to take an active role in shaping political change to improve conditions for earlier parenthood.</p

Epidemiological Surveillance of Birth Defects Compatible with Thalidomide Embryopathy in Brazil

The thalidomide tragedy of the 1960s resulted in thousands of children being born with severe limb reduction defects (LRD), among other malformations. In Brazil, there are still babies born with thalidomide embryopathy (TE) because of leprosy prevalence, availability of thalidomide, and deficiencies in the control of drug dispensation. Our objective was to implement a system of proactive surveillance to identify birth defects compatible with TE. Along one year, newborns with LRD were assessed in the Brazilian hospitals participating in the Latin-American Collaborative Study of Congenital Malformations (ECLAMC). A phenotype of LRD called thalidomide embryopathy phenotype (TEP) was established for surveillance. Children with TEP born between the years 2000–2008 were monitored, and during the 2007–2008 period we clinically investigated in greater detail all cases with TEP (proactive period). The period from 1982 to 1999 was defined as the baseline period for the cumulative sum statistics. The frequency of TEP during the surveillance period, at 3.10/10,000 births (CI 95%: 2.50–3.70), was significantly higher than that observed in the baseline period (1.92/10,000 births; CI 95%: 1.60–2.20), and not uniformly distributed across different Brazilian regions. During the proactive surveillance (2007–2008), two cases of suspected TE were identified, although the two mothers had denied the use of the drug during pregnancy. Our results suggest that TEP has probably increased in recent years, which coincides with the period of greater thalidomide availability. Our proactive surveillance identified two newborns with suspected TE, proving to be a sensitive tool to detect TE. The high frequency of leprosy and the large use of thalidomide reinforce the need for a continuous monitoring of TEP across Brazil

Bilobalide modulates serotonin-controlled behaviors in the nematode Caenorhabditis elegans

<p>Abstract</p> <p>Background</p> <p>Dysfunctions in the serotonergic system have been implicated in several neurological disorders such as depression. Elderly individuals who have been diagnosed with clinical depression show elevated cases of neurodegenerative diseases. This has led to suggestions that modulating the serotonin (5-HT) system could provide an alternative method to current therapies for alleviating these pathologies. The neuroprotective effects of bilobalide <it>in vitro </it>have been documented. We aim to determine whether bilobalide affects the 5-HT system in the nematode <it>C. elegans</it>. The wild type worms, as well as well-characterized 5-HT mutants, were fed with bilobalide in a range of concentrations, and several 5-HT controlled behaviors were tested.</p> <p>Results</p> <p>We observed that bilobalide significantly inhibited 5-HT-controlled egg-laying behavior in a dose-dependent manner, which was blocked in the 5-HT receptor mutants (<it>ser-4, mod-1</it>), but not in the 5-HT transporter (<it>mod-5</it>) or synthesis (<it>tph-1</it>) mutants. Bilobalide also potentiated a 5-HT-controlled, experience-dependent locomotory behavior, termed the enhanced slowing response in the wild type animals. However, this effect was fully blocked in 5-HT receptor <it>mod-1 </it>and dopamine defective <it>cat-2 </it>mutants, but only partially blocked in <it>ser-4 </it>mutants. We also demonstrated that acetylcholine transmission was inhibited in a transgenic <it>C. elegans </it>strain that constitutively expresses Aβ, and bilobalide did not significantly affect this inhibition.</p> <p>Conclusion</p> <p>These results suggest that bilobalide may modulate specific 5-HT receptor subtypes, which involves interplay with dopamine transmission. Additional studies for the function of bilobalide in neurotransmitter systems could aid in our understanding of its neuroprotective properties.</p