Genotype-matched treatment for patients with advanced type I epithelial ovarian cancer (EOC).

BACKGROUND: Genomic alterations that activate the MAPK signaling pathway frequently occur in Type I Epithelial Ovarian Cancers (EOCs). We evaluated therapeutic response outcomes in patients with type I EOC treated with genotype-matched therapy on clinical trials enrolled in a prospective molecular profiling program. MATERIAL AND METHODS: Formalin fixed paraffin embedded tumor tissues were prospectively screened for genomic alterations using MALDI-ToF mass-spectrometry platform or targeted sequencing using the Illumina MiSeq TruSeq Amplicon Cancer Panel. Treatment outcomes on genotype-matched trials were retrospectively reviewed using RECIST version 1.1 and Gynecological Cancer Intergroup CA125 related-response criteria RESULTS: 55 patients with type I EOC underwent molecular profiling, 41 (75%) low grade serous (LGS), 9 (16%) clear cell (CC), and 5 (9%) mucinous (MC) histologies. Thirty-five patients (64%) were found to have ≥1 somatic mutations: 23 KRAS, 6 NRAS, 5 PIK3CA, 2 PTEN, 1 BRAF, 1 AKT, 1 TP53, and 1 CTNNB1. Fifteen patients were subsequently enrolled in genotype-matched phase I or II trials, including 14 patients with KRAS/NRAS mutations treated with MEK inhibitor targeted combinations. Among 14 RECIST evaluable patients, there were 7 partial responses (PR), 7 stable disease (SD) and 1 disease progression (PD). CA125 responses were observed in 10/10 evaluable KRAS/NRAS mutant patients treated with MEK inhibitor combinations CONCLUSIONS: Genotyping and targeted sequencing of Type I EOCs frequently identifies actionable mutations. Matched treatment with MEK-based combination therapy in KRAS and/or NRAS mutant type I EOC patients is an active therapeutic strategy.

Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study.

BACKGROUND: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. METHODS: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. RESULTS: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94). CONCLUSIONS: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.

Particle separation options for emergency water treatment.

Emergencies can result from the effects of unpredictable natural forces or from the cruelty of conflicts. The affected population is often left vulnerable to increased health risks. The victims' exposure to these risks can be reduced by timely public health interventions. Often, one of the first basic mitigations is the provision of water for essential needs. The quickest option, and generally more polluted, is of surface waters. We have reviewed particle separation options for emergency water treatment of surface waters. These vary from granular filtration package treatment facilities to ceramic candle filters and have therefore been broadly classified in three categories: modular, mobile and point-of-use (or household). The operational requirements and process limitations that can influence the choice of each option are discussed alongside with their underlying particle separation mechanisms and performance data.

The role of preoperative biopsy in pancreatic cancer.

BACKGROUND: Cyto-histological diagnosis of pancreatic pathology in the management of suspected pancreatic malignancy is re-evaluated in the light of evolving trends in management and tissue sampling. METHODS: The literature on cyto-histological diagnosis of pancreatic pathology was reviewed over the period 1977-2003. RESULTS AND CONCLUSION: Endoluminal techniques of tissue sampling carry less risk of tumour seeding and are the sampling methods of choice for potentially resectable lesions if a tissue diagnosis will alter therapy. Endosonar-guided biopsy in expert hands appears to be the most reliable tissue sampling technique. Transcoelomic sampling methods should be reserved for those with un-resectable disease. All methods of cyto-histological diagnosis have high specificity but have a low negative predictive value. Therefore, potentially resectable lesions that are highly suspicious for malignancy should be explored even if pre-operative histology or cytology is negative.

Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways.

Skeletal muscle is composed of multinucleated fibres, formed after the differentiation and fusion of myoblast precursors. Skeletal muscle atrophy and hypertrophy refer to changes in the diameter of these pre-existing muscle fibres. The prevention of atrophy would provide an obvious clinical benefit; insulin-like growth factor 1 (IGF-1) is a promising anti-atrophy agent because of its ability to promote hypertrophy. However, the signalling pathways by which IGF-1 promotes hypertrophy remain unclear, with roles suggested for both the calcineurin/NFAT (nuclear factor of activated T cells) pathway and the PtdIns-3-OH kinase (PI(3)K)/Akt pathway. Here we employ a battery of approaches to examine these pathways during the hypertrophic response of cultured myotubes to IGF-1. We report that Akt promotes hypertrophy by activating downstream signalling pathways previously implicated in activating protein synthesis: the pathways downstream of mammalian target of rapamycin (mTOR) and the pathway activated by phosphorylating and thereby inhibiting glycogen synthase kinase 3 (GSK3). In contrast, in addition to demonstrating that calcineurin does not mediate IGF-1-induced hypertrophy, we show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy.

Identification of ubiquitin ligases required for skeletal muscle atrophy.

Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 (MuRF1), and a gene we designate Muscle Atrophy F-box (MAFbx), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.

Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt.

Extracellular signals often result in simultaneous activation of both the Raf-MEK-ERK and PI3K-Akt pathways (where ERK is extracellular-regulated kinase, MEK is mitogen-activated protein kinase or ERK kinase, and PI3K is phosphatidylinositol 3-kinase). However, these two signaling pathways were shown to exert opposing effects on muscle cell hypertrophy. Furthermore, the PI3K-Akt pathway was shown to inhibit the Raf-MEK-ERK pathway; this cross-regulation depended on the differentiation state of the cell: Akt activation inhibited the Raf-MEK-ERK pathway in differentiated myotubes, but not in their myoblast precursors. The stage-specific inhibitory action of Akt correlated with its stage-specific ability to form a complex with Raf, suggesting the existence of differentially expressed mediators of an inhibitory Akt-Raf complex.

Reflective practice in nursing: issues and implications for nurse education.

Reflective practice is a frequently used but inadequately defined concept in nursing. Part of the reason for this may be the inadequate conceptualisation of the process of reflection. This paper argues that now is an appropriate time to critically examine the notion of reflective practice and maintains that there is a need for more debate and research into the nature of reflection in nursing. This paper reviews recent nursing ideologies and explores the concept of reflective practice in relation to different forms of practical knowledge. It discusses and critically analyses the attraction of reflective practice to different interest groups and concludes by examining the implication of reflective practice models of nursing for nurse educators.

Nursing role supplementation for adolescent parents: prescriptive nursing practice.

Role supplementation interventions were developed to support role taking in parenting and health decision-making for adolescent parents. The prescriptive nursing interventions provided during prenatal, well child, and home visits during the first 2 years of the child's life are based on role supplementation theory. Strategies derived from role theory are integrated with assessment and intervention activities. Adolescents receive role supplementation from a primary nurse who continues to see them and their infants over the 2-year period. The role supplementation intervention is currently being tested in a longitudinal research project.

Social support and adaptation to the parent role in first-time adolescent mothers.

The relationship between social support and adaptation to parenthood for first-time adolescent mothers was investigated in this descriptive correlational study. The outcomes of adaptation were defined as the synchrony of parent-infant interaction and the level of stress related to parenting. A nonprobability sample of 18 adolescent, first-time mothers who had an uncomplicated perinatal experiences and delivered healthy, term newborns were selected. Data were collected during a home interview at one month postpartum. The measure of social support was significantly related to parent-infant reciprocity. Total functional support scores were inversely, but not significantly, correlated with total scores of stress related to parenting (r = -.31). Finally, the measure of reciprocity and the measure of stress related to parenting were inversely but not significantly related.

Evolutionary relationship of three southern African maize streak virus isolates.

The aligned restriction endonuclease maps of three sequenced maize streak virus isolates, three restriction-mapped southern African maize streak virus isolates, and two other sequenced geminiviruses were used as a means of calculating the sequence divergence between these viruses. The degree of divergence was used to construct a phylogenetic tree for the viruses; this tree agrees well with predictions from sequence comparisons, and so the method can be used to study the relationship of geminivirus isolates without the labor and expense of sequencing each one.

Characterization of southern African isolates of maize streak virus: typing of three isolates by restriction mapping.

The genomic replicative form DNAs (RF-DNA) of three maize streak virus isolates (MSV-CT, MSV-PE, and MSV-SW) from widely separated locations in southern Africa were characterized by restriction endonuclease mapping in order to assess the feasibility of using the technique to determine genetic variability between isolates. The viruses were transmitted to and propagated in laboratory-grown maize by the leafhopper vector Cicadulina mbila (Naudé). MSV-PE produced more severe symptoms than MSV-CT and MSV-SW; the isolates were serologically identical in 'western' immunoblot tests, but distinct in 'sandwich' enzyme-linked immunosorbent assays. RF-DNA of all three isolates was prepared from infected maize; the RF-DNA of MSV-CT and MSV-PE was cloned in a plasmid vector in Escherichia coli. Restriction maps were generated from this cloned DNA and from the RF-DNA of MSV-SWA. The maps were similar in regions expected to be conserved, but there were also important differences between all isolates. The implications of these results, and of relationships amongst these and other sequenced isolates of MSV, are discussed.

Improving adolescent parenting through participant modeling and self-evaluation.

This article describes how nurses can promote adolescent parenting by providing opportunities for young mothers to view and practice appropriate behavior to foster their infants' development. The importance of utilizing such an intervention in the context of an ongoing caring environment is stressed as a key element. The program was developed with consideration of the adolescent's developmental stage and parenting characteristics. Participant modeling and self-evaluation were utilized as effective means of fostering behavioral change. Content for the films was drawn from the findings of the Harvard Preschool Study, the work of Badger, the research of Wachs, Uzgiris, and Hunt, and the nursing child assessment training materials developed by Barnard at the University of Washington. Timing and sites for class sessions have been suggested. The reader is encouraged to study the literature on phases of transition, organization, reorganization, and adaptation when considering the timing for developmental intervention. The goal of this program is to foster competent, curious children and competent, supportive parents who will assume full responsibility for the health care decisions relating to their child. As young parents develop their decision-making skills, the health provider role should move from a protective/collaborative stance to one of a resource for health care maintenance and problems.

Suppression of rat liver fatty acid synthesis by eicosa-5,8,11,14-tetraynoic acid without a reduction in lipogenic enzymes.

In meal-fed rats supplementation of safflower oil (5 g per 100 g diet) to a fat-free basal diet resulted in the characteristic suppression of liver fatty acid synthetase and acetyl-CoA carboxylase activities, which was accompanied by a 60% decrease in the rate of hepatic fatty acid synthesis. The decline in activity of these lipogenic enzymes was completely prevented by adding 0.05% eicosa-5,8,11,14-tetraynoic acid (TYA) to the safflower oil diet. Fatty acid analysis of the livers indicated that TYA significantly impaired the conversion of linoleate to arachidonate. Apparently the selective suppression of lipogenic enzymes by dietary linoleate is not caused by linoleate per se but requires its conversion to longer-chain fatty acids and/or protaglandins. In spite of high activities of fatty acid synthetase and acetyl-CoA carboxylase, liver fatty acid synthesis continued to be inhibited by the safflower oil + TYA dietary regimen. This continued inhibition of lipogenesis was due to the TYA, because addition of TYA to the fat-free diet precipitated a significant decline in liver fatty acid synthesis without a drop in lipogenic enzymes. Inhibition of fatty acid synthesis by TYA could not be attributed to a decrease in liver glucose utilization based on hepatic glycogen concentration, nor was it due to a reduction in the fraction of catalytically active polymeric acetyl-CoA carboxylase based on sensitivity of the enzyme activity to avidin.