Low expression of ANT1 confers oncogenic properties to rhabdomyosarcoma tumor cells by modulating metabolism and death pathways.

Rhabdomyosarcoma (RMS) is the most frequent form of pediatric soft-tissue sarcoma. It is divided into two main subtypes: ERMS (embryonal) and ARMS (alveolar). Current treatments are based on chemotherapy, surgery, and radiotherapy. The 5-year survival rate has plateaued at 70% since 2000, despite several clinical trials. RMS cells are thought to derive from the muscle lineage. During development, myogenesis includes the expansion of muscle precursors, the elimination of those in excess by cell death and the differentiation of the remaining ones into myofibers. The notion that these processes may be hijacked by tumor cells to sustain their oncogenic transformation has emerged, with RMS being considered as the dark side of myogenesis. Thus, dissecting myogenic developmental programs could improve our understanding of RMS molecular etiology. We focused herein on ANT1, which is involved in myogenesis and is responsible for genetic disorders associated with muscle degeneration. ANT1 is a mitochondrial protein, which has a dual functionality, as it is involved both in metabolism via the regulation of ATP/ADP release from mitochondria and in regulated cell death as part of the mitochondrial permeability transition pore. Bioinformatics analyses of transcriptomic datasets revealed that ANT1 is expressed at low levels in RMS. Using the CRISPR-Cas9 technology, we showed that reduced ANT1 expression confers selective advantages to RMS cells in terms of proliferation and resistance to stress-induced death. These effects arise notably from an abnormal metabolic switch induced by ANT1 downregulation. Restoration of ANT1 expression using a Tet-On system is sufficient to prime tumor cells to death and to increase their sensitivity to chemotherapy. Based on our results, modulation of ANT1 expression and/or activity appears as an appealing therapeutic approach in RMS management.

Prototyping Trastuzumab Docetaxel Immunoliposomes with a New FCM-Based Method to Quantify Optimal Antibody Density on Nanoparticles.

Developing targeted nanoparticles is a rising strategy to improve drug delivery in oncology. Antibodies are the most commonly used targeting agents. However, determination of their optimal number at the surface remains a challenging issue, mainly due to the difficulties in measuring precisely surface coating levels when prototyping nanoparticles. We developed an original quantitative assay to measure the exact number of coated antibodies per nanoparticle. Using flow cytometry optimized for submicron particle analysis and beads covered with known amounts of human IgG-kappa mimicking various amounts of antibodies, this new method was tested as part of the prototyping of docetaxel liposomes coated with trastuzumab against Her2+ breast cancer. This quantification method allowed to discriminate various batches of immunoliposomes depending on their trastuzumab density on nanoparticle surface (i.e., 330 (Immunoliposome-1), 480 (Immunoliposome-2) and 690 (Immunoliposome-3), p = 0.004, One-way ANOVA). Here we showed that optimal number of grafted antibodies on nanoparticles should be finely tuned and highest density of targeting agent is not necessarily associated with highest efficacy. Overall, this new method should help to better prototype third generation nanoparticles.

Optic neuritis revealing Kikuchi-Fujimoto disease.

Kikuchi-Fujimoto disease is a rare systemic disease with uncommon neurological involvement. We report the case of a 30-year-old Asian woman who presented a rapidly progressive loss of vision. Magnetic resonance imaging (MRI) of the optic nerve revealed an inflammation of the left optic nerve with chiasmatic involvement, without any encephalic or medullar lesion. Thoracic computed tomography scan showed bilateral axillary lymphadenopathy. Analysis of a biopsy of the axillary lymph node showed typical histological findings of Kikuchi-Fujimoto disease. There was no clinical or biological sign of associated systemic lupus erythematosus. The patient spontaneously recovered normal visual acuity in 4 weeks, with resolution of MRI abnormalities. No optic neuritis relapse or neurological event occurred in a 3-year follow-up. To our knowledge this is the first case of optic neuritis associated with Kikuchi-Fujimoto disease.

Kapellasite: a kagome quantum spin liquid with competing interactions.

Magnetic susceptibility, NMR, muon spin relaxation, and inelastic neutron scattering measurements show that kapellasite, Cu3Zn(OH)6Cl2, a geometrically frustrated spin-1/2 kagome antiferromagnet polymorphic with herbertsmithite, is a gapless spin liquid showing unusual dynamic short-range correlations of noncoplanar cuboc2 type which persist down to 20 mK. The Hamiltonian is determined from a fit of a high-temperature series expansion to bulk susceptibility data and possesses competing exchange interactions. The magnetic specific heat calculated from these exchange couplings is in good agreement with experiment. The temperature dependence of the magnetic structure factor and the muon relaxation rate are calculated in a Schwinger-boson approach and compared to experimental results.

Miyoshi-like distal myopathy with mutations in anoctamin 5 gene.

Miyoshi myopathy is the most common form of recessive distal myopathy. Recessive mutations in the ANO5 gene have been recently identified in Northern Europe as a cause of non dysferlin-linked distal myopathy and limb girdle muscular dystrophy. We report here the first French cases of anoctamin 5 myopathy in 2 brothers presenting with a Miyoshi-like pattern. Comparing these patients with 12 other cases from the literature shows that all cases share a homogeneous clinical pattern, characterized by initial calf muscles involvement. Asymmetric muscle atrophy often precedes weakness. In this setting, high CK level and normal expression of dysferlin in muscle should lead to consider the diagnosis, which will be confirmed by ANO5 gene testing. The c.191dupA mutation, already reported as a founder mutation in Caucasian patients with anoctamin myopathies, was found in our family in a heterozygous state.

Specific heat of single crystal MgB2: a two-band superconductor with two different anisotropies.

Heat-capacity measurements of a 39 microg MgB2 single crystal in fields up to 14 T and below 3 K allow the determination of the low-temperature linear term of the specific heat, its field dependence, and its anisotropy. Our results are compatible with two-band superconductivity, the band carrying the smaller gap being isotropic, that carrying the larger gap having an anisotropy of approximately 5. Three different upper critical fields are thus needed to describe the superconducting state of MgB2.

Specific heat of Mg11B2: evidence for a second energy gap.

Measurements of the specific heat of Mg11B2 from 1 to 50 K, in magnetic fields to 9 T, give the Debye temperature, Theta = 1050 K, the coefficient of the normal-state electron contribution, gamma(n) = 2.6 mJ mol(-1) K-2, and a discontinuity in the zero-field specific heat of 133 mJ mol(-1) K-1 at T(c) = 38.7 K. The estimated value of the electron-phonon coupling parameter, lambda = 0.62, could account for the observed T(c) only if the important phonon frequencies are unusually high relative to Theta. At low T, there is a strongly field-dependent feature that suggests the existence of a second energy gap, about 4 times smaller than the major gap.

An unusual phase transition to a second liquid vortex phase in the superconductor YBa2Cu3O7.

A magnetic field penetrates a superconductor through an array of 'vortices', each of which carries one quantum of flux that is surrounded by a circulating supercurrent. In this vortex state, the resistivity is determined by the dynamical properties of the vortex 'matter'. For the high-temperature copper oxide superconductors (see ref.1 for a theoretical review), the vortex phase can be a 'solid', in which the vortices are pinned, but the solid can 'melt' into a 'liquid' phase, in which their mobility gives rise to a finite resistance. (This melting phenomenon is also believed to occur in conventional superconductors, but in an experimentally inaccessible part of the phase diagram.) For the case of YBa2Cu3O7, there are indications of the existence of a critical point, at which the character of the melting changes. But neither the thermodynamic nature of the melting, nor the phase diagram in the vicinity of the critical point, has been well established. Here we report measurements of specific heat and magnetization that determine the phase diagram in this material to 26 T, well above the critical point. Our results reveal the presence of a reversible second-order transition above the critical point. An unusual feature of this transition-namely, that the high-temperature phase is the less symmetric in the sense of the Landau theory-is in accord with theoretical predictions of a transition to a second vortex-liquid phase.

[Ethical evaluation of biomedical research]. / La valutazione etica della ricerca biomedica.

Every human behaviour, therefore also biomedical research, implies a reference, either implicit or explicit, to ethic values. The expression "biomedical research" attains to the domain of two distinct fields, the scientific and the technical one and this distinction is important for its ethic implications. In fact, it was the great progress in the biotechnologies that in the early 70's stimulated the birth of a new discipline known as bioethics, that from its very start was meant to be the meeting point between culturers of the biological sciences and those of human sciences. Among the paradigms adopted by bioethics, those of Beauchamp and Childress, which refer to the principles of "beneficence" (well doing), "non maleficence" (not wrong doing), autonomy and justice, are still of great importance. Bioethics proposed to establish an inequivocal and shared language and to develop adequate and rigorous procedures of analysis. So, at various levels, international, national and local, those interesting tools of the trade, which are the ethics committees, have arose. In order for an ethic committee to function, one must guarantee from the start, the conditions of autonomy and representativeness of different knowledges and cultural options that characterize our complex society. It is also necessary that an ethics committee, rather than assuming a prescriptive role, should promote attention and reflection on the ethical aspects of biomedical research.

Endozepine stupor in children.

Recurring episodes of stupor in adults have been shown to be related to increased levels of endozepines, which are endogenous ligands for the GABAA receptors. We report here two children presenting with recurrent episodes of stupor associated with fast EEG activity who had increased levels of endozepine-4 in plasma. Mass spectroscopy did not reveal commercially available benzodiazepines. Interictal endozepine-4 levels were normal. In one of the patients, administration of flumazenil (0.25 mg i.v.), a benzodiazepine inverse agonist, induced improvement of consciousness and attenuation of EEG fast activity. In conclusion, children presenting with recurrent episodes of stupor and EEG fast activity should be evaluated for endozepine levels and can be effectively treated with i.v. flumazenil.

Use of the fractal dimension for the analysis of electroencephalographic time series.

Electroencephalogram (EEG) traces corresponding to different physiopathological conditions can be characterized by their fractal dimension, which is a measure of the signal complexity. Generally this dimension is evaluated in the phase space by means of the attractor dimension or other correlated parameters. Nevertheless, to obtain reliable values, long duration intervals are needed and consequently only long-term events can be analysed; also much calculation time is required. To analyse events of brief duration in real-time mode and to apply the results obtained directly in the time domain, thus providing an easier interpretation of fractal dimension behaviour, in this work we optimize and propose a new method for evaluating the fractal dimension. Moreover, we study the robustness of this evaluation in the presence of white or line noises and compare the results with those obtained with conventional spectral methods. The non-linear analysis carried out allows us to investigate relevant EEG events shorter than those detectable by means of other linear and non-linear techniques, thus achieving a better temporal resolution. An interesting link between the spectral distribution and the fractal dimension value is also pointed out.

Coeliac disease, epilepsy, and cerebral calcifications. The Italian Working Group on Coeliac Disease and Epilepsy.

There have been anecdotal reports of an association between coeliac disease and epilepsy with cerebral calcifications that resemble those of the Sturge-Weber syndrome. A series of patients who had epilepsy with calcifications, in whom coeliac disease (CD) was incidentally observed, prompted us to study this association. 43 patients (15 male, age range 4.6-30.7 years) were selected from two series. 31 patients with cerebral calcifications of unexplained origin and epilepsy (series A) underwent intestinal biopsy. 12 patients with CD and epilepsy (series B) underwent computed tomography. Antibodies to gluten, folic acid serum concentrations, were measured, and HLA typing was done in most patients. 24 of the series A patients were identified as having CD on the basis of a flat intestinal mucosa (15/22 with a high concentration of serum antigluten), and 5 series B patients showed cerebral calcifications, giving a total of 29 cases with the combination of CD, epilepsy, and cerebral calcifications (CEC). In 27 of these CEC patients, calcifications were located in the parieto-occipital regions. Only 2 of the series A patients had gastrointestinal symptoms at the time of intestinal biopsy; most patients had recurrent diarrhoea, anaemia, and other symptoms suggestive of CD in the first 3 years of life. The epilepsy in CEC patients was poorly responsive to antiepileptic drugs. Gluten-free diet beneficially affected the course of epilepsy only when started soon after epilepsy onset. Cases of "atypical Sturge-Weber syndrome" (characterised by serpiginous cerebral calcifications and epilepsy without facial port-wine naevus) should be reviewed, and CD should be ruled out in all cases of epilepsy and cerebral calcifications of unexplained origin.

Coeliac disease, folic acid deficiency and epilepsy with cerebral calcifications.

Two cases of focal occipital epilepsy with cerebral calcifications poorly responsive to antiepileptic treatment are described. In both cases coeliac disease was diagnosed and folic acid deficiency documented. A gluten-free diet and a brief supplementation with folic acid lead to a complete EEG and clinical normalization in one case and to a significant improvement of EEG and seizure control in the other.

[Recurrent iatrogenic benign intracranial hypertension in a case of congenital adrenogenital syndrome with loss of salts]. / Ipertensione endocranica benigna iatrogena ricorrente in un caso di sindrome surreno genitale congenita con perdita di sali.

Pseudotumor cerebri is a condition that produces symptoms and signs of brain tumor; the increased intracranial pressure is caused by diffuse cerebral edema. The authors describe a case of 12 years boy, with adrenal hyperplasia, treated by DOCA, presenting recurrent episodes of hyponatremia, headache, nausea and papilledema, cured definitively after correction of natremia and after institution 9-alpha-fluorohydrocortisone therapy.