INOVATYON/ ENGOT-ov5 study: Randomized phase III international study comparing trabectedin/pegylated liposomal doxorubicin (PLD) followed by platinum at progression vs carboplatin/PLD in patients with recurrent ovarian cancer progressing within 6-12 months after last platinum line.

BACKGROUND: This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian cancer (OC). METHODS: Patients with OC (up to two previous platinum-based lines), with a TFIp of 6-12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75). RESULTS: The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94-1.35; p = 0.197). Grade 3-5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP). CONCLUSIONS: This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6-12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT01379989.

A prognostic regulatory pathway in stage I epithelial ovarian cancer: new hints for the poor prognosis assessment.

BACKGROUND: Clinical and pathological parameters of patients with epithelial ovarian cancer (EOC) do not thoroughly predict patients' outcome. Despite the good outcome of stage I EOC compared with that of stages III and IV, the risk assessment and treatments are almost the same. However, only 20% of stage I EOC cases relapse and die, meaning that only a proportion of patients need intensive treatment and closer follow-up. Thus, the identification of cell mechanisms that could improve outcome prediction and rationalize therapeutic options is an urgent need in the clinical practice. PATIENTS AND METHODS: We have gathered together 203 patients with stage I EOC diagnosis, from whom snap-frozen tumor biopsies were available at the time of primary surgery before any treatment. Patients, with a median follow-up of 7 years, were stratified into a training set and a validation set. RESULTS AND CONCLUSIONS: Integrated analysis of miRNA and gene expression profiles allowed to identify a prognostic cell pathway, composed of 16 miRNAs and 10 genes, wiring the cell cycle, 'Activins/Inhibins' and 'Hedgehog' signaling pathways. Once validated by an independent technique, all the elements of the circuit resulted associated with overall survival (OS) and progression-free survival (PFS), in both univariate and multivariate models. For each patient, the circuit expressions have been translated into an activation state index (integrated signature classifier, ISC), used to stratify patients into classes of risk. This prediction reaches the 89.7% of sensitivity and 96.6% of specificity for the detection of PFS events. The prognostic value was then confirmed in the external independent validation set in which the PFS events are predicted with 75% sensitivity and 94.7% specificity. Moreover, the ISC shows higher classification performance than conventional clinical classifiers. Thus, the identified circuit enhances the understanding of the molecular mechanisms lagging behind stage I EOC and the ISC improves our capabilities to assess, at the time of diagnosis, the patient risk of relapse.

Body composition by dual-energy X-ray spectrometry and bioelectrical impedance spectroscopy in a healthy population at age 75 and 80.

OBJECTIVE: Bioelectrical impedance spectroscopy (BIS) is a versatile field tool to obtain information about body composition (BC), if prediction equations are available that are valid for the group under consideration. We aimed to validate prediction equations for total body skeletal muscle mass (TBSMM) developed in healthy 75-year olds from the Gothenburg area (Sweden) in a similar sample examined at age 80. We give new prediction equations for fat mass (FM), fat-free mass (FFM), and TBSMM that are based on the entire group of elderly subjects, using values from Dual-energy X-ray spectrometry (DXA) as reference standard. Finally, we describe the longitudinal change in BC in the subset of subjects, who participated at both age 75 and 80. SUBJECTS AND METHODS: Body composition was measured by DXA and multiple-frequency BIS at age 75 (n = 111) and 80 (n = 91) years. Ordinary and mixed linear regression was used to examine previous and new prediction equations. Longitudinal change was assessed by paired sample t-test. RESULTS: The prediction equations for TBSMM developed in 75-year old subjects showed good validity when applied to the sample of 80 year olds. The results were independent of the presence of a metal prosthesis in hip or knee. New, sex-specific prediction equations for FM, FFM, and TBSMM were derived for 75 - 80 year-old subjects that further improved the accuracy of prediction. Using DXA-derived BC at ages 75 and 80, we observed a decline in TBSMM in both sexes, which was mainly due to muscle loss in the legs. In men, the decrease in trunk FFM was accompanied by an increase in FM, leaving no overall weight change in the trunk. When the 5-year change in TBSMM was based on longitudinal BIS measurements, the results from DXA were reproduced only when the prediction was based on BIS-values at 50 kHz. CONCLUSIONS: Good cross-sectional validity of BIS equations for TBSMM was found in a population sample of 80-year olds. The presence of a metal prosthesis did not influence the quality of prediction. New prediction equations for FM, FFM, and TBSMM need to be evaluated in an independent sample.

Adherence to a Mediterranean-like dietary pattern in children from eight European countries. The IDEFICS study.

BACKGROUND: Despite documented benefits of a Mediterranean-like dietary pattern, there is a lack of knowledge about how children from different European countries compare with each other in relation to the adherence to this pattern. In response to this need, we calculated the Mediterranean diet score (MDS) in 2-9-year-old children from the Identification and prevention of dietary- and lifestyle-induced health effects in children and infants (IDEFICS) eight-country study. SUBJECTS AND METHODS: Using 24 h dietary recall data obtained during the IDEFICS study (n=7940), an MDS score was calculated based on the age- and sex-specific population median intakes of six food groups (vegetables and legumes, fruit and nuts, cereal grains and potatoes, meat products and dairy products) and the ratio of unsaturated to saturated fats. For fish and seafood, which was consumed by 10% of the population, one point was given to consumers. The percentages of children with high MDS levels (>3) were calculated and stratified by sex, age and by having at least one migrant parent or both native parents. Demographic (sex and age) and socioeconomic characteristics (parental education and income) of children showing high (>3) vs low (⩽3) MDS levels were examined. RESULTS: The highest prevalence of children with MDS>3 was found among the Italian pre-school boys (55.9%) and the lowest among the Spanish school-aged girls (26.0%). Higher adherence to a Mediterranean-like dietary pattern was not associated with living in a Mediterranean country or in a highly educated or high-income family, although with some exceptions. Differences in adherence between boys and girls or age groups varied between countries without any general pattern. CONCLUSIONS: With the exception of Italian pre-schoolers, similar adherence levels to a Mediterranean-like dietary pattern have been observed among European children.

Associations between energy intake, daily food intake and energy density of foods and BMI z-score in 2-9-year-old European children.

PURPOSE: The aim of this study was to investigate the associations between proxy-reported energy intake, daily food intake and energy density of foods and body mass index (BMI) z-score in 2-9-year-old European children. METHODS: From 16,225 children who participated in the identification and prevention of dietary- and lifestyle-induced health effects in children and infants (IDEFICS) baseline examination, 9,782 children with 24-h proxy dietary information and complete covariate information were included in the analysis. Participating children were classified according to adapted Goldberg cutoffs: underreports, plausible energy reports and overreports. Energy intake, daily food intake and energy density of foods excluding noncaloric beverages were calculated for all eating occasions. Effect of energy intake, daily food intake and energy density of foods on BMI z-score was investigated using multilevel regression models in the full sample and subsample of plausible energy reports. Exposure variables were included separately; daily food intake and energy intake were addressed in a combined model to check for interactions. RESULTS: In the group of plausible energy reports (N = 8,544), energy intake and daily food intake were significantly positively associated with BMI z-score. Energy density of foods was not associated with BMI z-score. In the model including energy intake, food intake and an interaction term, only energy intake showed a significantly positive effect on BMI z-score. In the full sample (N = 9,782), only energy intake was significantly but negatively associated with BMI z-score. CONCLUSION: Proxy-reporters are subject to misreporting, especially for children in the higher BMI levels. Energy intake is a more important predictor of unhealthy weight development in children than daily food intake.

Mediterranean diet, overweight and body composition in children from eight European countries: cross-sectional and prospective results from the IDEFICS study.

BACKGROUND & AIMS: A Mediterranean-like dietary pattern has been shown to be inversely associated with many diseases, but its role in early obesity prevention is not clear. We aimed to determine if this pattern is common among European children and whether it is associated with overweight and obesity. METHODS AND RESULTS: The IDEFICS study recruited 16,220 children aged 2-9 years from study centers in eight European countries. Weight, height, waist circumference, and skinfolds were measured at baseline and in 9114 children of the original cohort after two years. Diet was evaluated by a parental questionnaire reporting children's usual consumption of 43 food items. Adherence to a Mediterranean-like diet was calculated by a food frequency-based Mediterranean Diet Score (fMDS). The highest fMDS levels were observed in Sweden, the lowest in Cyprus. High scores were inversely associated with overweight including obesity (OR = 0.85, 95% CI: 0.77; 0.94) and percent fat mass (ß = -0.22, 95% CI: -0.43; -0.01) independently of age, sex, socioeconomic status, study center and physical activity. High fMDS at baseline protected against increases in BMI (OR = 0.87, 95% CI: 0.78; 0.98), waist circumference (OR = 0.87, 95% CI: 0.77; 0.98) and waist-to-height ratio (OR = 0.88, 95% CI: 0.78; 0.99) with a similar trend observed for percent fat mass (p = 0.06). CONCLUSIONS: Although a Mediterranean dietary pattern is inversely associated with childhood obesity, it is not common in children living in the Mediterranean region and should therefore be advocated as part of EU obesity prevention strategies.

The association between plasma homocysteine and coronary heart disease is modified by the MTHFR 677C>T polymorphism.

OBJECTIVE: An elevated level of total plasma homocysteine (tHcy) has been associated with risk of coronary heart disease (CHD). The level of tHcy is affected by lifestyle, in addition to genetic predisposition. The methylene tetrahydrofolate reductase (MTHFR) 677C>T polymorphism (rs1801133) is among the strongest genetic predictors of tHcy. We examined whether the association between tHcy and CHD is modified by the MTHFR 677C>T polymorphism. DESIGN AND SETTING: Data from two case-control studies of first-time myocardial infarction (MI), Stockholm Heart Epidemiology Programme (SHEEP), and for MI and unstable angina, INTERGENE, were analysed in parallel. PATIENTS: THcy was determined in a total of 1150 cases and 1753 controls. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The outcome comprised first-time MI and unstable angina, subsumed as CHD. Logistic regression was used to investigate the association between tHcy and CHD, and its modification by genotype. RESULTS: High tHcy was confirmed to be a risk factor for CHD in both studies. In SHEEP, the association between tHcy and MI was observed in MTHFR 677 C-homozygotes (OR=1.4, 95% CI 1.2 to 1.6, for a difference by 1 SD of log tHcy) and in heterozygotes (OR=1.3, 95% CI 1.1 to 1.6) but not in T-homozygotes, independent of smoking, physical activity and obesity. An effect modification of similar magnitude was observed but not statistically significant in the smaller INTERGENE study, and confirmed in a meta-analysis of both studies. CONCLUSIONS: Two Swedish case-control studies showed that the association between elevated tHcy and CHD was confined to carriers of the MTHFR 677 C-allele, which could have implications for the efficiency of tHcy-lowering treatment.

Estaquia de Ipomoea cairica (L. ) Sweet / Stem cutting of Ipomoea cairica (L. ) Sweet

A Ipomoea cairica (L.) Sweet é uma trepadeira herbácea nativa, amplamente utilizada na medicina popular brasileira e inexistem informações sobre a propagação vegetativa. Em vista disso, objetivou-se avaliar a presença de folhas nas estacas, o substrato e a dose de reguladores vegetais mais adequados para a propagação por estaquia. Foram conduzidos dois experimentos, no primeiro, foram avaliados dois tipos de estacas (com e sem folhas) e quatro substratos (areia, casca de arroz carbonizada, latossolo vermelho distrófico + matéria orgânica - 1:1, latossolo vermelho distrófico + matéria orgânica + areia - 1:1:2), enquanto no segundo foram testadas cinco concentrações diferentes de AIB (0, 250, 500, 750 e 1000 mg L-1). Após 20 dias, obteve-se 86,2% de estacas enraizadas no substrato areia e, no segundo experimento, observou-se que o AIB não influenciou a porcentagem de enraizamento (94% em média). Conclui-se que a presença de folhas melhora a qualidade do enraizamento, que os substratos indicados para a propagação são areia e casca de arroz carbonizada devido ao maior enraizamento, fácil disponibilidade e baixo custo, e que a utilização de AIB na concentração 250 mg L-1 é a mais adequada para propagação por estaquia de I. cairica.

Ipomoea cairica (L.) Sweet is an herbaceous climbing plant widely used in Brazilian folk medicine and there is no information regarding its vegetative propagation. In view of this, the aim of this study was to evaluate the presence of leaves on stem cuttings and the most adequate substrate and level of plant growth regulators for propagation by stem cuttings of this morning glory. Two experiments were conducted, in the first, two types of stem cuttings (with and without leaves) and four substrates (sand; carbonized rice hull; Haplortox + organic matter - 1:1; Haplortox + organic matter + sand - 1:1:2) were evaluated, and in the second experiment five different concentrations of IBA (0, 250, 500, 750 and 1000 mg L-1) were tested. After 20 days, we obtained 86.2% of cuttings rooted in sand substrate and in the second experiment IBA did not affect the rooting percentage (94% on average). We can conclude that the presence of leaves improved the quality of rooting, the substrates indicated for propagation are sand and carbonized rice hull due to greater rooting, easy availability and low cost, and the use of IBA at 250 mg L-1 is more appropriate to propagation by stem cuttings of I. cairica.

Intake of total, animal and plant protein and subsequent changes in weight or waist circumference in European men and women: the Diogenes project.

BACKGROUND: As protein is considered to increase thermogenesis and satiety more than other macronutrients, it may have beneficial effects on prevention of weight gain and weight maintenance. OBJECTIVE: The objective of this study is to assess the association between the amount and type of dietary protein, and subsequent changes in weight and waist circumference (WC). METHODS: 89,432 men and women from five countries participating in European Prospective Investigation into Cancer and Nutrition (EPIC) were followed for a mean of 6.5 years. Associations between the intake of protein or subgroups of protein (from animal and plant sources) and changes in weight (g per year) or WC (cm per year) were investigated using gender and centre-specific multiple regression analyses. Adjustments were made for other baseline dietary factors, baseline anthropometrics, demographic and lifestyle factors and follow-up time. We used random effect meta-analyses to obtain pooled estimates across centres. RESULTS: Higher intake of total protein, and protein from animal sources was associated with subsequent weight gain for both genders, strongest among women, and the association was mainly attributable to protein from red and processed meat and poultry rather than from fish and dairy sources. There was no overall association between intake of plant protein and subsequent changes in weight. No clear overall associations between intakes of total protein or any of the subgroups and changes in WC were present. The associations showed some heterogeneity between centres, but pooling of estimates was still considered justified. CONCLUSION: A high intake of protein was not found associated with lower weight or waist gain in this observational study. In contrast, protein from food items of animal origin, especially meat and poultry, seemed to be positively associated with long-term weight gain. There were no clear associations for waist changes.

Mechanisms involved in the photosensitized inactivation of Acanthamoeba palestinensis trophozoites.

AIMS: To advance our understanding of the mechanisms involved in the RLP068 phthalocyanine-photosensitized inactivation of Acanthamoeba palestinensis trophozoites through a precise identification of the targets of the photoprocess in both the cytosolic and mitochondrial compartments. METHODS AND RESULTS: We followed the activities of selected marker enzymes as well as we performed fluorescence and transmission electron microscopy investigations of the alterations induced by the photoprocess in the fine structure of subcellular compartments. RLP068 is preferentially located in the contractile vacuole: the fluorescence in that site is particularly evident in the unirradiated cells and becomes more diffused after irradiation. Electron microscopic analysis of photosensitized A. palestinensis cells clearly shows that the swelling of trophozoites and the appearance of vacuoles spread throughout the cytoplasm after phototreatment. The activity of a typical cytoplasmic enzyme, such as lactate dehydrogenase, underwent a 35% decrease as a consequence of the photoprocess, reflecting the photodamage induced by migrating phthalocyanine molecules in their micro-environment. CONCLUSIONS: The presence of multiple targets for the phthalocyanine-photosensitized process is of utmost importance because this pattern of cell damage makes it unlikely that photoresistant A. palestinensis strains are gradually selected or mutagenic phenomena are developed as a consequence of the photoinduced damage. SIGNIFICANCE AND IMPACT OF THE STUDY: Photosensitization via phthalocyanines appears to represent an efficient and safe approach for achieving a close control of the population of a potentially pathogenic protozoan such as A. palestinensis, opening new perspectives for the disinfection of microbiologically polluted waters.

Aluminum-triggered structural modifications and aggregation of beta-amyloids.

We investigated the structural effects induced by Al3+ on different beta-amyloid (Abeta) fragments at pH 7.4 and T=25 degrees C, with particular attention given to the sequences 1-40 and 1-42. Al3+ caused peptide enrichment in beta sheet structure and formation of solvent-exposed hydrophobic clusters. These intermediates evolved to polymeric aggregates which organized in fibrillar forms in the case of the Al3+-Abeta(1-42) complex. Comparative studies showed that Zn2+ and Cu2+ were much less efficient than Al3+ in stimulating the spontaneous aggregation/fibrillogenesis of Abetas. Studies with liposomes as membrane models showed dramatic changes in the structural properties of the lipid bilayer in the presence of Al3+-Abeta complexes, suggesting a major role of Al3+ in Abeta-induced cell dysfunction. Al3+ effects were abolished by desferrioxamine mesylate (DFO) only in solution. We concluded that, in vivo, DFO may act as a protective agent by preventing or reverting Abeta aggregation in the extracellular spaces.

Effect of Aplidin in acute lymphoblastic leukaemia cells.

The cytotoxic effect of Aplidin was investigated on fresh leukaemia cells derived from children with B-cell-precursor (BCP) acute lymphoblastic leukaemia (ALL) by using stromal-layer culture system and on four cell lines, ALL-PO, Reh, ALL/MIK and TOM-1, derived from patients with ALL with different molecular genetic abnormalities. In ALL cell lines Aplidin was cytotoxic at nanomolar concentrations. In the ALL cell lines the drug-induced cell death was clearly related to the induction of apoptosis and appeared to be p53-independent. Only in ALL-PO 20 nM Aplidin treatment caused a block of vascular endothelial growth factor (VEGF) secretion and downregulation of VEGF-mRNA, but Aplidin cytotoxicity does not seem to be related to VEGF inhibition since the sensitivity of ALL-PO cells to Aplidin is comparable to that observed for the other cells used. Aplidin induced a G(1) and a G(2) M block in ALL cell lines. In patient-derived leukaemia cells, Aplidin induced a strong cytotoxicity evidenced in a stroma-supported immunocytometric assay. Cells from children with genetic abnormalities such as t(9;22) and t(4;11) translocations, associated with an inferior treatment outcome, were sensitive to Aplidin to the same extent as that observed in other BCP-ALL cases. Aplidin exerted a strong cell killing effect (>88%) against primary culture cells from five relapsed ALL cases, at concentrations much lower than those reported to be achieved in plasma of patients receiving Aplidin at recommended doses. Taken together these data suggest that Aplidin could be a new anticancer drug to be investigated in ALL patients resistant to available therapy.

Poly(ADP-ribose) polymerase cleavage during apoptosis: when and where?

Poly(ADP-ribose) polymerase-1 (PARP-1) plays the active role of "nick sensor" during DNA repair and apoptosis, when it synthesizes ADP-ribose from NAD(+) in the presence of DNA strand breaks. Moreover, PARP-1 becomes a target of apoptotic caspases, which originate two proteolytic fragments of 89 and 24 kDa. The precise relationship between PARP-1 activation and degradation during apoptosis is still a matter of debate. In human Hep-2 cells driven to apoptosis by actinomycin D, we have monitored PARP-1 activity by the mAb 10H, which is specific for the ADP-ribose polymers, and we have observed that poly(ADP-ribose) synthesis is a very early response to the apoptotic stimulus. The analysis of the presence and fate of the p89 proteolytic fragment revealed that PARP-1 proteolysis by caspases is concomitant with poly(ADP-ribose) synthesis and that p89 migrates from the nucleus into the cytoplasm in late apoptotic cells with advanced nuclear fragmentation.

Aluminum as an inducer of the mitochondrial permeability transition.

Treatment of rat liver mitochondria with aluminum in the presence of Ca2+ results in large amplitude swelling accompanied by loss of endogenous Mg2+ and K+ and oxidation of endogenous pyridine nucleotides. The presence of cyclosporin A, ADP, bongkrekic acid, N-ethylmaleimide and dithioerythritol prevent these effects, indicating that binding of aluminum to the inner mitochondrial membrane, most likely at the level of adenine nucleotide translocase, correlates with the induction of the membrane permeability transition (MPT). Indeed, aluminum binding promotes such a perturbation at the level of ubiquinol-cytochrome c reductase, which favors the production of reactive oxygen species. These metabolites generate an oxidative stress involving two previously defined sites in equilibrium with the glutathione and pyridine nucleotides pools, the levels of which correlate with the increase in MPT induction. Although the above-described phenomena are typical of MPT, they are not paralleled by other events normally observed in response to treatment with inducers of MPT (e.g., phosphate), such as the collapse of the electrochemical gradient and the release of accumulated Ca2+ and oxidized pyridine nucleotides. Biochemical and ultrastructural observations demonstrate that aluminum induces a pore opening having a conformation intermediate between fully open and closed in a subpopulation of mitochondria. While inorganic phosphate enhances the MPT induced by ruthenium red plus a deenergizing agent, aluminum instead inhibits this phenomenon. This finding suggests the presence of a distinct binding site for aluminum differing from that involved in MPT induction.

The Helicobacter pylori neutrophil-activating protein is an iron-binding protein with dodecameric structure.

The neutrophil-activating protein (HP-NAP) of Helicobacter pylori is a major 17 kDa antigen of the immune response of infected individuals. Amino acid sequence comparison indicated a high similarity between HP-NAP and both bacterial DNA-protecting proteins (Dps) and ferritins. The structure prediction and spectroscopic analysis presented here indicate a close similarity between HP-NAP and Dps. Electron microscopy revealed that HP-NAP forms hexagonal rings of 9-10 nm diameter with a hollow central core as seen in Dps proteins, clearly different from the 12 nm icositetrameric (24 subunits) ferritins. However, HP-NAP is resistant to thermal and chemical denaturation similar to the ferritin family of proteins. In addition, HP-NAP binds up to 40 atoms of iron per monomer and does not bind DNA. We therefore conclude that HP-NAP is an unusual, small, ferritin that folds into a four-helix bundle that oligomerizes into dodecamers with a central hole capable of binding up to 500 iron atoms per oligomer.

A two-exposure technique for ice-embedded samples successfully reconstructs the chlorocruorin pigment of Sabella spallanzanii at 2. 1 Nm resolution.

A technique for reconstructing ice-embedded macromolecules from electron micrographs taken at two specimen tilts (+/-23 degrees ) has been used to determine the structure of chlorocruorin isolated from the Polychaete annelid Sabella spallanzanii. Images of individual molecules were extracted in couples from two micrographs of the same field of view so each couple consists of two projections of the same molecule. One couple was used as a fixed reference for alignment. Different references yielded reconstructions with different orientations. These were merged to give a model against which the orientation of 1624 first-exposure images was refined to give a final reconstruction at 2.1 nm resolution. The structure of this hematic pigment, essentially the same as that for Lumbricus terrestris, is a bilayer structure with overall symmetry D6, containing six hollow groups per layer. A hollow group is formed by six globular masses and has approximate threefold symmetry. Other structural elements connect the two layers and the hollow groups in a layer. This non-globin material occupies about 15% of the total molecular volume. The results show that the double-exposure strategy, previously described by some of the authors and tested in computer simulations, performs well in real experiments and could be used to obtain preliminary reconstructions in a semiautomatic way.

Well-differentiated papillary mesothelioma of the peritoneum: a separate entity.

Three female patients with a diffuse well-differentiated papillary mesothelioma of the peritoneum are presented. They did not have a history of exposure to asbestos. The peritoneal biopsies were studied extensively, including electron microscopy, nuclear morphometry and DNA ploidy analysis. The results from these more sophisticated investigations confirmed the mesothelial origin and further characterised these lesions. One of the 3 patients has continuing elevated serum CA-125 levels, which increased transiently during and after pregnancy. All 3 patients have done well without therapy, 2 patients being alive and non-symptomatic 6 and 7 years after the initial diagnosis. It is important to distinguish this disorder from the malignant diseases of the peritoneum and the ovary. In view of the indolent course of this subtype of mesothelioma, avoidance of treatment is justified unless there is evidence of progressive disease.

Three-dimensional structure of the higher-plant photosystem II reaction centre and evidence for its dimeric organization in vivo.

The three-dimensional structure of photosystem II (PSII) has been determined by conventional transmission electron microscopy and computerized three-dimensional reconstruction. Both the complete system and that lacking the oxygen-evolving complex have been analyzed. The PSII complex has a four-lobed structure with twofold symmetry. An estimate of the molecular mass and the results of Deriphat/PAGE analysis suggest that a reaction centre is present in each half of the structure resolved by electron microscopy. Stepwise removal of components of the complex showed that the removal of CP47 (a 47-kDa chlorophyll-protein complex) induces monomerization of PSII, which indicates the importance of this subunit for the dimeric structure.

The effect of chemotherapy on the different components of advanced carcinosarcomas (malignant mixed mesodermal tumors) of the female genital tract.

The effect of chemotherapy on the different components of uterine and ovarian carcinosarcoma is largely unknown. This report describes six patients with advanced carcinosarcoma, five of whom received 4 cycles of doxorubicin and ifosfamide (AI) directed at the sarcomatous component of the tumor. Responses in these five patients at second-look laparotomy were: one complete response, two partial responses (persistence of only the carcinomatous component), one stable disease, and one progressive disease (both components still present in both cases). Thereafter 4 cycles of a cisplatin-based regimen were scheduled. Response to the cisplatin-containing regimen was only evaluated clinically. The sixth patient (with no macroscopic disease left after initial surgery) received 6 cycles of a cisplatin-based chemotherapy from the onset and was found to be in complete response at relaparotomy. Median progression-free survival for all patients was 15 months and median survival 21 months. A literature survey showed that carcinosarcoma differs from adult soft tissue sarcomas with respect to responsiveness to chemotherapy. Cisplatin and ifosfamide are active as single agents, whereas the response to single-agent doxorubicin seems to be lower. The data suggest, however, that superior response rates and increased survival times are achieved with cisplatin/doxorubicin-based chemotherapy. The sensitivity of carcinosarcoma to cisplatin supports the recent view that carcinosarcoma of the female genital tract is possibly a high grade carcinoma with metaplastic sarcomatous elements.