The molecular landscape and associated clinical experience in infant medulloblastoma: prognostic significance of second-generation subtypes.

AIMS: Biomarker-driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub-classify iMB, and proffer strategies for personalized, risk-adapted therapies. METHODS: We characterized the iMB molecular landscape, including second-generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387). RESULTS: iMBGrp3 (42%) and iMBSHH (40%) subgroups predominated. iMBGrp3 harboured second-generation subtypes II/III/IV. Subtype II strongly associated with large-cell/anaplastic pathology (LCA; 23%) and MYC amplification (19%), defining a very-high-risk group (0% 10yr overall survival (OS)), which progressed rapidly on all therapies; novel approaches are urgently required. Subtype VII (predominant within iMBGrp4 ) and subtype IV tumours were standard risk (80% OS) using upfront CSI-based therapies; randomized-controlled trials of upfront radiation-sparing and/or second-line radiotherapy should be considered. Seventy-five per cent of iMBSHH showed DN/MBEN histopathology in discovery and validation cohorts (P < 0.0001); central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non-DN/MBEN pathology was associated significantly with worse outcomes within iMBSHH . iMBSHH harboured two distinct subtypes (iMBSHH-I/II ). Within the discriminated favourable-risk iMBSHH DN/MBEN patient group, iMBSHH-II had significantly better progression-free survival than iMBSHH-I , offering opportunities for risk-adapted stratification of upfront therapies. Both iMBSHH-I and iMBSHH-II showed notable rescue rates (56% combined post-relapse survival), further supporting delay of irradiation. Survival models and risk factors described were reproducible in independent cohorts, strongly supporting their further investigation and development. CONCLUSIONS: Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup-dependent survival models highlight opportunities for biomarker-directed therapies.

Opportunistic CT screening predicts individuals at risk of major osteoporotic fracture.

Millions of CT scans are performed annually and could be also used to opportunistically assess musculoskeletal health; however, it is unknown how well this secondary assessment relates to osteoporotic fracture. This study demonstrates that opportunistic CT screening is a promising tool to predict individuals with previous osteoporotic fracture. INTRODUCTION: Opportunistic computed tomography (oCT) screening for osteoporosis and fracture risk determination complements current dual X-ray absorptiometry (DXA) diagnosis. This study determined major osteoporotic fracture prediction by oCT at the spine and hip from abdominal CT scans. METHODS: Initial 1158 clinical abdominal CT scans were identified from administrative databases and were the basis to generate a cohort of 490 men and women with suitable abdominal CT scans. Participant CT scans met the following criteria: over 50 years of age, the scan had no image artifacts, and the field-of-view included the L4 vertebra and proximal femur. A total of 123 participants were identified as having previously suffered a fracture within 5 years of CT scan date. Fracture cause was identified from clinical data and used to create a low-energy fracture sub-cohort. At each skeletal site, bone mineral density (BMD) and finite element (FE)-estimated bone strength were determined. Logistic regression predicted fracture and receiver-operator characteristic curves analyzed prediction capabilities. RESULTS: In participants with a fracture, low-energy fractures occurred in 88% of women and 79% of men. Fracture prediction by combining both BMD and FE-estimated bone strength was not statistically different than using either BMD or FE-estimated bone strength alone. Predicting low-energy fractures in women determined the greatest AUC of 0.710 by using both BMD and FE-estimated bone strength. CONCLUSIONS: oCT screening using abdominal CT scans is effective at predicting individuals with previous fracture at major osteoporotic sites and offers a promising screening tool for skeletal health assessment.

[An analytical study of the patterns of the survival curves of experimental objects in model experiments on Daphnia magna.]

The phenomenon of multiphase survival curves found in drosophila is confirmed in experiments on daphnia. Mathematical modeling showed that the multiphase nature of the daphnia survival curves reflects abrupt changes in the intensity of death of crustaceans during the transition from phase to phase. In intact daphnia there is no phase of a sharp increase in mortality observed at an early age in drosophila. It arises as a reaction to weak negative influences, which leads to a sharp decrease in the survival of young individuals. A logical conclusion was made about the readiness for reaction of each experimental individual. The effect was observed in a series of experiments posed in different years. It is proved that in daphnia, the predisposition to reaction persists for an indefinitely large number of generations. It is postulated that this reaction has an epigenetic nature. Previous experimental materials suggest that a reaction of this type is widespread in natural surroundings.

Self-Assembly of Triblock Copolymers from Cyclic Esters as a Tool for Tuning Their Particle Morphology.

This paper presents the effect of end groups, chain structure, and stereocomplexation on the microparticle and nanoparticle morphology and thermal properties of the supramolecular triblock copolyesters. Therefore, the series of the triblock copolymers composed of l,l- and d,d-lactide, trimethylene carbonate (TMC), and ε-caprolactone (CL) with isopropyl ( iPr) or 2-ureido-4-[1 H]-pyrimidinone (UPy) end groups at both chain ends were synthesized. In addition, these copolymers were intermoleculary stereocomplexed by polylactide (PLA) blocks with an opposite configuration of repeating units to promote their self-assembly in various organic solvents. The combination of two noncovalent interactions of the end groups and PLA enantiomeric chains leads to stronger interactions between macromolecules and allows for alteration of their segmental mobility. The simple tuning of the copolymer microstructure and functionality induced the self-assembly of macromolecules at liquid/liquid interfaces, which consequently leads to their phase separation in the form of particles with diameters ranging from 0.1 µm to 10 µm. This control is essential for their potential applications in the biomedical field, where biocompatible and well-defined microparticles and nanoparticles are highly desirable.

Maternal periconceptional exposure to drinking water disinfection by-products and neural tube defects in offspring.

BACKGROUND: Associations between maternal periconceptional exposure to disinfection by-products (DBPs) in drinking water and neural tube defects (NTDs) in offspring are inconclusive, limited in part by exposure misclassification. METHODS: Maternal interview reports of drinking water sources and consumption from the National Birth Defects Prevention Study were linked with DBP concentrations in public water system monitoring data for case children with an NTD and control children delivered during 2000-2005. DBPs analyzed were total trihalomethanes, the five most common haloacetic acids combined, and individual species. Associations were estimated for all NTDs combined and selected subtypes (spina bifida, anencephaly) with maternal periconceptional exposure to DBPs in public water systems and with average daily periconceptional ingestion of DBPs accounting for individual-level consumption and filtration information. Mixed effects logistic regression models with maternal race/ethnicity and educational attainment at delivery as fixed effects and study site as a random intercept were applied. RESULTS: Overall, 111 case and 649 control children were eligible for analyses. Adjusted odds ratios for maternal exposure to DBPs in public water systems ranged from 0.8-1.5 for all NTDs combined, 0.6-2.0 for spina bifida, and 0.7-1.9 for anencephaly; respective ranges for average daily maternal ingestion of DBPs were 0.7-1.1, 0.5-1.5, and 0.6-1.8. Several positive estimates (≥1.2) were observed, but all confidence intervals included the null. CONCLUSIONS: Using community- and individual-level data from a large, US, population-based, case-control study, we observed statistically nonsignificant associations between maternal periconceptional exposure to total and individual DBP species in drinking water and NTDs and subtypes.

Near-field investigation of THz surface-wave emission from optically excited graphite flakes.

THz emission from an unbiased graphite flake after optical sub-ps pulse inter-band excitation is measured using a novel micro-machined photoconductive probe-tip. Oscillatory behavior of the measured THz near-field emission is shown to originate from electromagnetic eigenmode resonances of the laterally limited graphite flake. The excitation efficiency of the lowest order eigenmode resonances strongly dependents on optical pump location. From this data a radial symmetric charge carrier translocation at the pump location is revealed as the dominating THz surface-wave emission effect. Measurements show good agreement with numerical field simulations of the eigenmode center frequencies and the spectral response expected for THz emission through basal plane oriented radial current surge excitation.

The effect of immunomodulating drugs on the percentage of apoptotic and necrotic lymphocytes in inflammatory infiltrations in the muscle tissue of mice infected with Trichinella spiralis.

In order to determine the effect of apoptosis and necrosis on the intensity of the muscular phase of infection by Trichinella spiralis, male CFW mice were orally infected with T. spiralis larvae and treated with some immunomodulating drugs: calf thymus extract (TFX), lipopolysaccharide from Escherichia coli (LPS), and dexametasone (DEX). Treatment with TFX increased the proportion of apoptotic lymphocytes and decreased the proportion of necrotic lymphocytes from 14 to 60 days after infection in mice infected with T. spiralis. Treatment with LPS increased proportions of both apoptotic and necrotic lymphocytes from 21 to 60 days after infection, especially at 28 days after infection. Treatment with DEX increased the proportion of apoptotic lymphocytes only at 28 days after infection, and significantly increased the proportion of necrotic lymphocytes at 21 days after infection. Parasite load in the affected muscle tissue was significantly lower than the control in mice treated with TFX, not significantly different from the control in mice treated with LPS, and significantly higher than the control in mice treated with DEX. The results of the study suggest that the parasite made an effort to reduce the effectivity of the host immune response in order to ensure its own survival.

Trichinella spiralis: Effect of thymus factor X on apoptosis and necrosis in mice.

The aim of the study was to determine the effect of thymus factor X (TFX-Jelfa) on the percentage of apoptotic and necrotic lymphocytes in the spleen, mesenteric lymph nodes, and muscle tissue of mice infected with 200 larvae of Trichinella spiralis. TFX was administered subcutaneously at a dose of 15mg/kg. On days 7, 14, 21, 28, 35, 42, and 60 after infection, apoptotic and necrotic cells were detected by flow cytometry after staining with the Annexin V-Fluos Staining Kit. TFX increased the percentage of apoptotic lymphocytes in the spleen, mesenteric lymph nodes, and muscle tissue of mice infected with T. spiralis. The effect of TFX on the percentage of necrotic lymphocytes was weaker and less clear. Parasite load was lower in infected mice treated with TFX than in the untreated control mice. The effect of TFX on the host immune response and the survival of parasite larvae was therefore probably affected by the extent of inflammatory infiltrates, and not by the percentage of lymphocytes undergoing apoptosis.

Isolation of chromosome-specific DNA sequences from an Alu polymerase chain reaction library to define the breakpoint in a patient with a constitutional translocation t(1;13) (q22;q12) and ganglioneuroblastoma.

We describe the cytogenetic and molecular characterization of a t(1;13)(q22;q12) constitutional rearrangement occurring in a patient with a relatively benign form of neuroblastoma, called ganglioneuroblastoma. Somatic cell hybrids were generated between mouse 3T3 cells and a lymphoblastoid cell line from this patient, D.G. One isolated subclone, DGF27C11, contained the derivative chromosome, 1pter-q22::13q12-qter, but no other material from either chromosome 1 or 13. Using available DNA probes the 13 breakpoint was assigned proximal to all reported markers. In order to generate flanking markers to define this translocation further, an Alu polymerase chain reaction library was constructed from a somatic cell hybrid containing only the proximal, 13pter-13q14, region of chromosome 13. Seven unique sequences have been isolated from the library, three of which lie below and four of which lie above the 13q12 breakpoint. More precise mapping of the distal markers was achieved using a panel of somatic cell hybrids with overlapping deletions of chromosome 13. The paucity of probes in the 1q22 region has made a precise assignment of this breakpoint difficult, however it has been shown to lie distal to c-SKI and proximal to APOA2. This refined characterization of the breakpoint is a prerequisite for its cloning, which may yield genes important in the pathogenesis of ganglioneuroblastoma.

Gorlin syndrome: the PTCH gene links ocular developmental defects and tumour formation.

AIM: To identify a gene linking microphthalmia with cyst with early onset medulloblastoma. METHODS: Mutation analysis of the PTCH gene. RESULTS: A mutation in exon 10 of the PTCH gene was identified, confirming a diagnosis of Gorlin syndrome. CONCLUSIONS: This is the first genetically identified mutation giving rise to microphthalmia with cyst and provides a valuable link in the eye developmental gene pathway.

Effect of cross-linking degree on selected properties of retrograded starch adipate.

The aim of this study was to determine the effects of the concentration of paste used to produce retrograded starch, and esterification degree, on selected properties of the resultant distarch adipate. Starch paste was prepared from native potato starch (1, 4, 10, 18 or 30 g/100g), frozen, defrosted and dried. Thus produced preparations of retrograded starch were cross-linked with various doses of a cross-linking agent (0.125, 0.25, 0.5, 1.0 or 2.0 ml per 100g of starch). Properties of the produced adipates depended on both the concentration of paste used to produce retrograded starch and the degree of substitution with adipic acid residues. Solubility in water and swelling power of the cross-linked preparations of retrograded starch, as well as pasting temperature and viscosity of produced pastes, all decreased along with the increasing degree of substitution with adipic acid residues.

A microfluidic device for real-time monitoring of Bacillus subtilis bacterial spores during germination based on non-specific physicochemical interactions on the nanoscale level.

A microfluidic device for studies on the germination of bacterial spores (e.g. Bacillus subtilis) based on non-specific interactions on the nanoscale is presented. A decrease in the population of spores during germination followed by the appearance of transition forms and an increase in the number of vegetative cells can be registered directly and simultaneously by using the microfluidic device, which is equipped with a conductive polymer layer (polyaniline) in the form of a nano-network. The lab-on-a-chip-type device, operating in a continuous flow regime, allows monitoring of germination of bacterial spores and analysis of the process in detail. The procedure is fast and accurate enough for quantitative real-time monitoring of the main steps of germination, including final transformation of the spores into vegetative cells. All of this is done without the use of biomarkers or any bio-specific materials, such as enzymes, antibodies and aptamers, and is simply based on an analysis of physicochemical interactions on the nanoscale level.

Ageing and survival after different doses of heat shock: the results of analysis of data from stress experiments with the nematode worm Caenorhabditis elegans.

Stress experiments performed on a population of sterilised nematode worms (Caenorhabditis elegans) show a clear hormesis effect after short exposure and clear debilitation effects after long exposure to heat shock. An intermediate duration of exposure results in a mixture of these two effects. In this latter case the survival curves for populations in the stress and control groups intersect. In this paper we develop an adaptation model of stress and apply it to the analysis of survival data from three such stress experiments. We show that the model can be used to explain empirical age-patterns of mortality and survival observed in these experiments. We discuss possible biological mechanisms involved in stress response and directions for further research.

Combination chemotherapy with vincristine, epirubicin and cyclophosphamide in small cell lung carcinoma. Polish Lung Cancer Cooperative Group.

The aim of this prospective study was to assess the activity of a combination of vincristine, epirubicin and cyclosphosphamide (VEC) in previously untreated patients with limited small cell lung carcinoma (SCLC) and to delineate the feasibility of dose escalation for epirubicin in this regimen. The chemotherapy schedule included cyclophosphamide, 1000 mg/m2, vincristine, 1 mg/m2 and escalating doses of epirubicin: 50 mg/m2, 70 mg/m2 and 90 mg/m2; respectively in three consecutive groups of patients. Drug cycles were repeated every 3 weeks. 118 patients from eight institutions were enrolled in this study between February 1986 and March 1989. Objective tumour response was observed in 81 of 116 evaluable patients (70%) including 25 patients (22%) who achieved a complete remission. Responding patients received thoracic radiation after the fourth cycle of chemotherapy. The median duration of response was 30 weeks and the median duration of survival was 52 weeks. There were no significant differences in treatment results between the consecutive groups of patients. The regimen was well tolerated for all doses of epirubicin. The main toxicities included alopecia (96%), nausea and vomiting (81%) and leukopenia (44%). Grade 4 haematological toxicity was observed in 3 patients (2.6%). No significant epirubicin dose-dependent side effects, except for mucositis were observed.

The effect of accomplishment and failure on P300 potentials evoked by neutral stimuli.

The effects of emotional states of 'being successful' vs. 'being unsuccessful' were studied by measuring the P300 component of event-related potentials (ERPs). Nine subjects were instructed to reduce their P300 amplitude using feedback. Feedback was random but the relative probability of different signals created the situations of 'being successful' or 'being unsuccessful'. The probability of 'small' feedback was 0.7 in 'successful' and 0.15 in 'unsuccessful' trials. ERPs recorded without the feedback were used as a reference. Potentials, evoked by light stimuli in a standard 'odd-ball' procedure, were recorded from Fz, Cz and Pz scalp sites. The amplitudes of P300 components were reduced in 'unsuccessful' trials whereas in 'successful' trials they did not differ significantly from responses recorded without the feedback. There were no significant differences in peak latencies. These findings indicate that tonic emotional states affect the processing of neutral stimuli and that late components of ERPs can be useful indices in the analysis of these alterations. The results also indicate that the effects of positive and negative emotional states are not always reciprocal. Manipulated feedback is suggested as an useful model in the studies of emotions. Data can also facilitate the interpretation of the real feedback effects.

The ocular following reflex in cats deprived of pattern vision from birth.

An investigation of vertical ocular following reflexes evoked from retinal sites of different horizontal eccentricity was carried out on visually deprived cats. The recording was performed in pretrigeminal preparations where horizontal eye movements are absent. A light slit or a black stick (1 degrees X 4 degrees) were moved with 10 degrees/sec speed for 2 sec along the vertical meridian or parallelly up to 40 degrees in the nasal or temporal hemifield. As in previously described normally reared cats, the following reflexes were evoked from the whole area, but the pursuit movements had longer latency and lower velocity at the periphery than in the center of the retina. However, irrespectively of the place of stimulation, the latency of the pursuit movements was longer, their velocity lower and the course less regular than in normally reared cats. It therefore follows that in visually deprived cats the ocular following reflex is impaired.

Surveillance neuroimaging in childhood intracranial ependymoma: how effective, how often, and for how long?

OBJECT: The authors examined images obtained in 52 children with intracranial ependymomas to determine risk factors for tumor recurrence and to assess the impact of surveillance imaging on patient outcome. METHODS: Data obtained in all children with intracranial ependymomas were prospectively entered into a database from January 1987 to June 2000. The imaging and clinical details in all patients were reviewed. Fifty-two children with histologically proven intracranial ependymomas were treated at the authors' institution; recurrences developed in 28 (54%) of them, with a median time from surgery to first recurrence of 14.5 months (range 3-65 months). Of these tumor recurrences, 43% were asymptomatic and were noted on surveillance imaging. Seventeen children died, all of whom had recurrences. Incomplete excision of the primary tumor was significantly associated with reduced time to recurrence (p = 0.0144) and time to death (p = 0.0472). The age of the patient, location of the primary tumor, histological findings, and the presence or absence of spinal metastases on preoperative imaging were not significantly associated with outcome. The risk of death at any given time was 12-fold greater in patients in whom a recurrence was identified due to symptoms rather than on surveillance images (p = 0.016). CONCLUSIONS: Recurrent childhood ependymoma has a poor prognosis. The extent of the initial local tumor resection is the factor most closely associated with outcome. Surveillance imaging reveals a substantial number of asymptomatic recurrences, and survival appears to be improved in these patients compared with those identified by symptoms. The improvement in survival is thought to be greater than that expected just from earlier diagnosis.

Primitive neuroectodermal tumours: anatomic location, extent of surgery, and outcome.

BACKGROUND/PURPOSE: Primitive neuroectodermal tumours (PNET) are rare tumours sharing similar histology, immunohistochemistry, and cytogenetics to Ewing's sarcomas. The aim of the study was to document the effect of site of origin and the completeness of surgical excision on the outcome in infants and children with PNET. METHODS: All patients (n = 26) with PNET treated in our hospital during the last 6 years were included in the study. The diagnosis was based on the histopathologic findings and a positive MIC2 antibody test. The tumours were classified according to the Intergroup Rhabdomyosarcoma Study III, and were treated according to the UKEESG protocol for Ewing's Sarcoma. RESULTS: Complete remission (CR) was achieved in 52% of the patients completing their chemotherapy. Overall, survival was 42% (11 of 26). Tumours from the paraspinal and scapula areas responded relatively well (CR, 83%), whereas abdominal PNET did not respond to treatment. Tumours arising from the head, neck, or chest had an intermediate prognosis (37% survival). Three of the 10 patients who had a complete excision of the tumour died of progressive disease. CONCLUSIONS: Complete surgical excision reduced the risk of local recurrence but did not prevent metastatic spread. These data indicate that PNET have a worse prognosis and different favourable sites than other sarcomas. New treatment strategies are necessary for these rare tumours.

Expectation of an important event affects responses to irrelevant stimuli of different modalities.

Periodic alterations of event-related potentials (ERPs) were studied during "oddball" tasks. Sequences of randomly intermixed frequent (non-target) and rare (target) stimuli were presented. In visual experiments, these were flashes of light of two different colors. In auditory tests there were two tones of different frequencies. The instruction was to keep a mental count of each target stimulus. To study the alterations of the "state of the brain" produced by target detection, responses to non-targets immediately following targets were compared with responses to an eighth subsequent non-target stimulus. To evaluate the effect of such "brain states" on responses to stimuli of a different modality, additional visual stimuli (probes) were delivered after both auditory and visual "oddball" stimuli. It was found that responses to the eighth presentation of non-target stimulus were preceded by significant negative shift of recorded potential. This shift was smaller before the responses to non-targets immediately following the presentation of target stimuli. The difference was significant both in auditory and visual tests. Responses to "oddball" stimuli were little affected: only the reduction of P200 peaks in "after target" responses was significant in visual tests. Responses to probes showed stronger effects: when visual probes followed visual "oddball" stimuli, all three components measured (N100, P130 and P200) were shifted positively in responses to eighth presentations of non-targets. When visual probes were presented in auditory tests, only the amplitude of the N100 component was significantly affected.