Inhibition of the phosphoinositide 3-kinase pathway for the treatment of patients with metastatic metaplastic breast cancer.

BACKGROUND: Mesenchymal/metaplastic breast cancers (MpBCs) are often triple-negative (TNBC), and chemo-refractory, and can harbor phosphoinositide 3-kinase (PI3kinase) alterations; thus, therapy with mTor inhibitors may demonstrate activity. PATIENTS AND METHODS: Patients with mesenchymal/MpBC treated with temsirolimus-based regimens were evaluated. Mutational analyses [polymerase chain reaction (PCR)-based DNA sequencing method, mass spectrometric detection (Sequenom MassARRAY), or next-generation sequencing] as well as loss of phosphatase and tensin homolog (PTEN) (immunohistochemistry) were performed (archived tissue when available). RESULTS: Twenty-three patients (one of whom was on two separate trials) were treated using temsirolimus-containing regimens: temsirolimus alone (n = 1 patient) or combined with the following: liposomal doxorubicin and bevacizumab (DAT, n = 18); liposomal doxorubicin (DT, n = 1); paclitaxel and bevacizumab (TAT, n = 2); paclitaxel (TT, n = 1); carboplatin and bevacizumab (CAT, n = 1). Response rate [complete response (CR) + partial response (PR)] was 25% across all regimens; 32% in the anthracycline-based regimens [DAT and DT (CR = 2, PR = 4; N = 19)]. An additional two patients achieved stable disease (SD) ≥6 months [total SD ≥6 months/CR/PR = 8 (33%)]. Molecular aberrations in the PI3K pathway were common: PIK3CA mutation = 6/15 (40%), PTEN mutation = 3/11 (27%), and PTEN loss = 2/11 (18%). A point mutation in the NF2 gene (K159fs*16; NF2 alterations can activate mTor) was found in one patient who attained CR (3+ years). Of the eight patients who achieved SD ≥6 months/CR/PR, all 4 patients with available tissue had a molecular aberration that activate the PIK3CA/Akt/mTOR axis: PIK3CA mutation = 2; PTEN loss = 1; NF2 aberration = 1. CONCLUSIONS: DAT has activity in MpBCs including complete CRs. Molecular aberrations that can activate the PI3 K/Akt/mTOR axis are common in MpBC.

Bioaugmentation of pilot-scale slow sand filters can achieve compliant levels for the micropollutant metaldehyde in a real water matrix.

Metaldehyde is a polar, mobile, low molecular weight pesticide that is challenging to remove from drinking water with current adsorption-based micropollutant treatment technologies. Alternative strategies to remove this and compounds with similar properties are necessary to ensure an adequate supply of safe and regulation-compliant drinking water. Biological removal of metaldehyde below the 0.1 µg•L-1 regulatory concentration was attained in pilot-scale slow sand filters (SSFs) subject to bioaugmentation with metaldehyde-degrading bacteria. To achieve this, a library of degraders was first screened in bench-scale assays for removal at micropollutant concentrations in progressively more challenging conditions, including a mixed microbial community with multiple carbon sources. The best performing strains, A. calcoaceticus E1 and Sphingobium CMET-H, showed removal rates of 0.0012 µg•h-1•107 cells-1 and 0.019 µg•h-1•107 cells-1 at this scale. These candidates were then used as inocula for bioaugmentation of pilot-scale SSFs. Here, removal of metaldehyde by A. calcoaceticus E1, was insufficient to achieve compliant water regardless testing increasing cell concentrations. Quantification of metaldehyde-degrading genes indicated that aggregation and inadequate distribution of the inoculum in the filters were the likely causes of this outcome. Conversely, bioaugmentation with Sphingobium CMET-H enabled sufficient metaldehyde removal to achieve compliance, with undetectable levels in treated water for at least 14 d (volumetric removal: 0.57 µg•L-1•h-1). Bioaugmentation did not affect the background SSF microbial community, and filter function was maintained throughout the trial. Here it has been shown for the first time that bioaugmentation is an efficient strategy to remove the adsorption-resistant pesticide metaldehyde from a real water matrix in upscaled systems. Swift contaminant removal after inoculum addition and persistent activity are two remarkable attributes of this approach that would allow it to effectively manage peaks in metaldehyde concentrations (due to precipitation or increased application) in incoming raw water by matching them with high enough degrading populations. This study provides an example of how stepwise screening of a diverse collection of degraders can lead to successful bioaugmentation and can be used as a template for other problematic adsorption-resistant compounds in drinking water purification.

Differentiated vascular myocytes: are they involved in neointimal formation?

The role of differentiated vascular myocytes are neointimal formation in canine carotid artery was investigated. Using antibodies and cDNA probes, cells were characterized in situ and after isolation. In situ characterization indicated the majority of medial cells expressed both smooth muscle myosin and alpha actin but many cells were negative to these markers. All adventitial cells were negative for these proteins. The muscle protein-positive cells were designated differentiated, vascular myocytes (VSMC). The others were designated type 2 cells. Sequential enzyme digestion from lumenal surface yielded VSMC ( > 90%) while digestions from the adventitial surface yielded type 2 cells ( > 90%). VSMC were viable in culture but did not spread, proliferate, or alter expression of muscle proteins. Type 2 cells proliferated and increased their expression of muscle actin but did not express muscle myosin. Characterization of neointimal cells from injured carotid arteries indicated they were morphologically and immunologically identical to cultured type 2 cells. We concluded that: (a) canine carotid artery media consists of a heterogeneous cell population: (b) serum does not stimulate isolated VSMC to undergo phenotypic modulation or proliferate: and (c) type 2 cells may be responsible for neointimal formation because they proliferate and acquire a phenotype identical to in situ neointimal cells.

A feasibility study of neoadjuvant talazoparib for operable breast cancer patients with a germline BRCA mutation demonstrates marked activity.

This study was undertaken to determine the feasibility of enrolling breast cancer patients on a single-agent-targeted therapy trial before neoadjuvant chemotherapy. Specifically, we evaluated talazoparib in patients harboring a deleterious BRCA mutation (BRCA+). Patients with a germline BRCA mutation and ≥1 cm, HER2-negative primary tumors were eligible. Study participants underwent a pretreatment biopsy, 2 months of talazoparib, off-study core biopsy, anthracycline, and taxane-based chemotherapy ± carboplatin, followed by surgery. Volumetric changes in tumor size were determined by ultrasound at 1 and 2 months of therapy. Success was defined as 20 patients accrued within 2 years and <33% experienced a grade 4 toxicity. The study was stopped early after 13 patients (BRCA1 + n = 10; BRCA2 + n = 3) were accrued within 8 months with no grade 4 toxicities and only one patient requiring dose reduction due to grade 3 neutropenia. The median age was 40 years (range 25-55) and clinical stage included I (n = 2), II (n = 9), and III (n = 2). Most tumors (n = 9) were hormone receptor-negative, and one of these was metaplastic. Decreases in tumor volume occurred in all patients following 2 months of talazoparib; the median was 88% (range 30-98%). Common toxicities were neutropenia, anemia, thrombocytopenia, nausea, dizziness, and fatigue. Single-agent-targeted therapy trials are feasible in BRCA+ patients. Given the rapid rate of accrual, profound response and favorable toxicity profile, the feasibility study was modified into a phase II study to determine pathologic complete response rates after 4-6 months of single-agent talazoparib.

A linkage study of distal chromosome 5q and bipolar disorder.

There are well-established abnormalities of hypothalamic-pituitary-adrenal (HPA) axis and beta 2 adrenergic receptor function in affective disorders. The genes for the glucocorticoid receptor (GRL) and the beta 2 adrenergic receptor (ADRB2) have been cloned and mapped to distal chromosome 5q. In this study, we have examined polymorphisms of these two candidate genes and other nearby markers for linkage to bipolar disorder in Amish pedigree 110 and three large Icelandic pedigrees. These loci were tested for linkage in two-point and multipoint analyses using a model of autosomal dominant transmission with age-dependent reduced penetrance. Two-point analyses revealed a maximum LOD score of 1.14 at theta = 0.20 from GRL. Linkage could be excluded to ADRB2, as well as to three nearby anonymous markers, D5S207, D5S70, and D5S119. Analyses of another anonymous marker, D5S36, were inconclusive. Multipoint analyses excluded linkage to a 55 cM region including the interval between D5S207 and D5S36 and flanking regions, with the exception of a 7 cM interval between GRL and ADRB2. Despite the intriguing positive LOD score obtained with GRL, linkage to bipolar disorder could not be demonstrated in the region examined.

A genetic linkage study of bipolar disorder and 13 markers on chromosome 11 including the D2 dopamine receptor.

Chromosome 11 is a region of great interest in the search for genes for bipolar disorder. Although an initial report of linkage to 11p15 was not replicated in numerous subsequent studies, the remainder of the chromosome contains a variety of interesting candidate genes and regions. These include the D2 dopamine receptor and the site of a chromosomal translocation that has been reported to be associated with bipolar disorder. As part of a systematic survey of the genome for markers linked to bipolar disorder, we have examined 13 markers on chromosome 11 in three large Icelandic families and Amish pedigree 110. No clear evidence of linkage was obtained. The highest lod score was found at D11S29 (lod = 1.63 at theta = 0.1), which is in the general region of the reported translocation breakpoints. However, this lod is not statistically significant, and its meaning is further mitigated by strongly negative lods in two nearby flanking markers. Linkage to the D2 dopamine receptor locus was strongly excluded (lod = -4.02 at theta = 0.0). In two-point analyses, linkage to bipolar disorder could be excluded to eight of the 13 markers. Multipoint analyses, similarly, failed to reveal any evidence of linkage.

Genetic linkage study of bipolar disorder and the serotonin transporter.

The serotonin transporter (HTT) is an important candidate gene for the genetic transmission of bipolar disorder. It is the site of action of many antidepressants, and plays a key role in the regulation of serotonin neurotransmission. Many studies of affectively ill patients have found abnormalities in serotonin metabolism, and dysregulation of the transporter itself. The human serotonin transporter has been recently cloned and mapped to chromosome 17. We have identified a PstI RFLP at the HTT locus, and here report our examination of this polymorphism for possible linkage to bipolar disorder. Eighteen families were examined from three populations: the Old Order Amish, Iceland, and the general North American population. In addition to HTT, three other microsatellite markers were examined, which span an interval known to contain HTT. Linkage analyses were conducted under both dominant and recessive models, as well as both narrow (bipolar only) and broad (bipolar + recurrent unipolar) diagnostic models. Linkage could be excluded to HTT under all models examined. Linkage to the interval spanned by the microsatellites was similarly excluded under the dominant models. In two individual families, maximum lod scores of 1.02 and 0.84 were obtained at D17S798 and HTT, respectively. However, these data overall do not support the presence of a susceptibility locus for bipolar disorder near the serotonin transporter.

No evidence of linkage between schizophrenia and D3 dopamine receptor gene locus in Icelandic pedigrees.

The D3 dopamine receptor gene is an important candidate gene for schizophrenia, since--because of its almost exclusive expression in the limbic system--it combines the dopamine receptor hypothesis with the limbic system hypothesis of schizophrenia. Pairwise linkage analyses were carried out between the D3 dopamine receptor gene locus (DRD3) and schizophrenia (including major depression among its pleiotropic manifestations). On the basis of these analyses, which assumed a penetrance of 0.71 and a dominant mode of inheritance, we were able to exclude the DRD3 locus with a lod score of -2.50 in four Icelandic pedigrees. The area of exclusion (lod score < -2.00) extended 1.2 centimorgans. We conclude that the genetic predisposition to schizophrenia in these pedigrees is not due to a mutation in the DRD3 locus. However, these results cannot exclude the possibility that a defect in other genes regulating the expression of the D3 dopamine receptor gene could be involved in the pathogenesis of schizophrenia or that linkage analyses in other families or population-based association studies might show a positive result.

Distance of foetal movement measured using the analytical signal derived from non-directional Doppler sound.

Foetal heart rate (FHR) monitoring using the Doppler shift resulting from the movements of the foetal heart is a standard examination in most obstetrical wards. Other movements also give rise to a low frequency Doppler shift. These signals are incompletely understood. Their characteristics may offer a way for diagnostic exploitation through complementing or replacing time consuming ultrasound observation of foetal movements. It is shown that a wealth of information is contained in these signals which can easily be extracted on line by a standard PC computer using straightforward methods of signal processing. In its amplitude an ultrasonic Doppler signal contains information concerning the size of the reflector in movement and speed as frequency. The displacement of the reflector can also be derived from the phase evolution of a complex Doppler signal. Examples of signals generated by various types of foetal activity are shown and analyzed.

Effect of surfactant surface coverage on formation of solid lipid nanoparticles (SLN).

The effect of surfactant surface coverage on formation and stability of Tween 20 stabilized tripalmitin solid lipid nanoparticles (SLN) was investigated. A lipid phase (10% w/w tripalmitin) and an aqueous phase (2% w/w Tween 20, 10 mM phosphate buffer, pH 7) were heated to 75 degrees C and then homogenized using a microfluidizer. The resulting oil-in-water emulsion was kept at a temperature (37 degrees C) above the crystallization temperature of the tripalmitin to prevent solidification of emulsion droplets, and additional surfactant at various concentrations (0-5% w/w Tween 20) was added. Droplets were then cooled to 5 degrees C to initiate crystallization and stored at 20 degrees C for 24 h. Particle size and/or aggregation were examined visually and by light scattering, and crystallization behavior was examined by differential scanning calorimetry (DSC). Excess Tween 20 concentration remaining in the aqueous phase was measured by surface tensiometry. Emulsion droplets after homogenization had a mean particle diameter of 134.1+/-2.0 nm and a polydispersity index of 0.08+/-0.01. After cooling to 5 degrees C at low Tween 20 concentrations, SLN dispersions rapidly gelled due to aggregation of particles driven by hydrophobic attraction between insufficiently covered lipid crystal surfaces. Upon addition of 1-5% w/w Tween 20, SLN dispersions became increasingly stable. At low added Tween 20 concentration (<1% w/w) the SLN formed gels but only increased slightly at higher surfactant concentrations (>1% w/w). The Tween 20 concentration in the aqueous phase decreased after tripalmitin crystallization suggesting additional surfactant adsorption onto solid surfaces. At higher Tween 20 concentrations, SLN had increasingly complex crystal structures as evidenced by the appearance of additional thermal transition peaks in the DSC. The results suggest that surfactant coverage at the interface may influence crystal structure and stability of solid lipid nanoparticles via surface-mediated crystal growth.

Epidemiological research needs access to data.

Data protection laws and their implementation have led to serious restrictions on access to personal data for research purposes. This seriously affects the development of social medicine and public health by making effective prevention of illness, and rational planning of health services, and their evaluation impossible in many instances. The conflict between people's need for knowledge about prevention and cure of illness and the control over personal data must be solved. Therefore, it is necessary to change the laws and ensure access to data for research use in accordance with the guidelines laid down by the European Science Foundation.

[Psychiatric epidemiological research in Iceland].

Epidemiological studies of mental disorders in Iceland have a long tradition. The first study was carried out 150 years ago. The results of some of these studies are reviewed to illustrate the uses of epidemiolgy. According to the results of the first study in 1839-1841 mental disorders seemed to be more prevalent in Iceland than in Denmark. The explanation was methodological, it was easier to identify cases in the small population of Iceland. Later studies have shown that the frequency of mental disorders is similar to that in other countries. The frequency of mental disorders have not changed during this century except for alcoholism, which has increased during the last 50-60 years. The prevalence of mental disorders among people aged 5-60 years is about 20%, but increases after the age of 70 years due to organic mental disorders. The incidence of first consultations with psychiatrists has been just under one per cent per year. The disease expectancy until the age of 61 years has been estimated to be 34%, but is probably higher due to increase in alcoholism and the fact that mild anxiety disorders have not been accounted for. The need for service is far from being met. It can be estimated that 40-50 thousand Icelanders suffer from some mental disorder at any time. Psychiatrists see only about eight thousand patients each year. Approximately seven thousand patients receive prescriptions for psychotropic medications, other than hypnotics, each month. Most of these medications are prescribed by general practitioners, which is their main treatment for mental disorders. About 1,600 persons are treated as inpatients each year for alcoholism and other drug abuse. Preventive work could be made more effective by attending to risk groups which have been defined through epidemiological work. It is imperative that the Icelandic Medical Association defends the freedom of research and encourages further epidemiolgical research in all fields of medicine. Such research in Iceland can contribute to the general knowledge about prevention and treatment of medical disorders.

[Who are admitted to an adolescent psychiatric ward and why?].

The University Hospital's adolescent psychiatric ward is the first health service in Iceland exclusively intended for adolescents. The service was opened in order to meet the needs for a better treatment for adolescents with psychiatric disorders. The service was primarily intended for the most severely disordered who had to be admitted for hospital treatment. The paper shows the use of the unit during its first five years by studying the first 100 patients admitted. Slightly more girls than boys were admitted in the age range 11-19 years, the majority being 14-16 years of age, one half of the patients being 15 years or more. That group comprised a greater proportion with shorter stay, less than nine weeks. Almost one half of the group had conspicuous behaviour disorders at admission, and almost one third had shown suicidal behaviour or expressed having suicidal thoughts. Two thirds of the patients had been under a marked psychosocial stress according to a psychosocial stressor scale. The school and social situation of the majority was bad. One third of the patients were diagnosed as having mood or neurotic disorders according to ICD-10 and almost one half had behaviour or personality disorders. Adolescents with primarily behaviour or social problems, who needed longterm teaching and pedagogical support took up too much of the units resources. Therefore it was not possible to admit a number of patients with other disorders who needed treatment. This might be changed by more and improved outpatient service.

Behaviour and social characteristics of young associal alcohol abusers.

In the present study all available young social alcohol abusers in the capital of Iceland are compared with a control group matched for age and intellectual level. Certain behaviour and social characteristics were found to occur more often during childhood among the abusers. Boys showing these characteristics should be regarded as being at high risk of developing asocial alcohol abuse. In order to prevent this they and their families should be offered social, psychiatric and medical help.

Aortic stiffness in insulin-dependent diabetics: an echocardiographic study.

To assess the aortic stiffness (AS) in young (15-35 year old) insulin-dependent diabetics without manifestations of atherosclerotic disease or hypertension, M-mode echocardiography was used to measure relative changes in aortic diameter expressed as Aortic strain = Diameter change/Diastolic diameter-100% Aortic stiffness can be calculated from the formula AS = Pulse pressure/Aortic strain. Fifty-seven diabetics were investigated, 31 men (aged 23.6 +/- 5.6 years, mean +/- SD) and 26 women (aged 25.7 +/- 6.4 years). There were 26 healthy controls with similar blood pressure, 14 men (aged 25.0 +/- 5.5 years) and 12 women (aged 24.6 +/- 7.1). The AS in diabetic men was 14 +/- 8.0 (mean +/- SD) compared to 3.6 +/- 0.7 in controls (p less than 0.001). In diabetic women the AS was 5.8 +/- 3.1 compared to 4.3 +/- 1.3 in controls (p less than 0.05). Diabetic men also had much stiffer aortas than diabetic women (p less than 0.001). There was a linear correlation between AS and duration of diabetes in men (R = 0.70; (p less than 0.001). For females no such correlation was found, the AS frequently being within the range of the controls in spite of long duration of the disease. In males there was a significant correlation between AS and retinopathy (R = 0.49; p less than 0.01) and an inverse correlation with HDL-cholesterol/total cholesterol ratio (R = 0.51; p less than 0.01). In diabetic females AS was significantly greater in smokers (7.0 +/- 3.7) than in non-smokers (4.2 +/- 2.2; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)