Hidden intra-mandibular carcinoma cuniculatum appearing in a patient with metastatic prostate cancer: a case report.

BACKGROUND: Whereas the incidence of cancers increases, overall survival of cancerous patients improves. Preventing the onset of second primary cancer is a new public health challenge and requires a special attention from organ specialists. We report a rare case of carcinoma cuniculatum in a context of metastatic prostate cancer. No case was previously described. Diagnosis delay of carcinoma cuniculatum is frequent and particularly in case of endophytic intra-osseous topography. The aim of this case report is to remind that persistent pain requires medical evaluation to rule out any possibility of second primary cancer. CASE PRESENTATION: A 78-year-old patient followed for a metastatic prostate cancer had been describing neuralgic dental pain in the lower posterior left quadrant for several months. Healing delay of tooth #37 (second left mandibular molar) extraction socket in the painful region led to an intra-alveolar incisional biopsy, which showed a tumor widely invading the mandibular body. Radiologic, histopathologic and clinical elements finally concluded to an intra-osseous carcinoma cuniculatum. Duration of total treatment (oral biopsy to hemimandibulectomy) and follow up were about five months and one year respectively. Patient died before reconstruction. CONCLUSION: This case recalls that any persistent tooth pain affecting cancer patients requires a thorough review to exclude any secondary primary cancers or any metastasis of the oral cavity and more specifically in jawbones.

Type I ROP16 regulates retinal inflammatory responses during ocular toxoplasmosis.

Ocular toxoplasmosis (OT), mostly retinochorioditis, is a major feature of infection with the protozoan parasite Toxoplasma gondii. The pathophysiology of this infection is still largely elusive; especially mouse models are not yet well developed. In contrast, numerous in vitro studies showed the highly Toxoplasma strain dependent nature of the host-parasite interactions. Some distinct polymorphic virulence factors were characterized, notably the rhoptry protein ROP16. Here, we studied the strain-dependent pathophysiology in our OT mouse model. Besides of two wild type strains of the canonical I (RH, virulent) and II (PRU, avirulent) types, we used genetically engineered parasites, RHΔROP16 and PRU ROP16-I, expressing the type I allele of this virulence factor. We analyzed retinal integrity, parasite proliferation and retinal expression of cytokines. PRU parasites behaved much more virulently in the presence of a type I ROP16. In contrast, knockout of ROP16 in the RH strain led to a decrease of intraocular proliferation, but no difference in retinal pathology. Cytokine quantification in aqueous humor showed strong production of Th1 and inflammatory markers following infection with the two strains containing the ROP16-I allele. In strong contrast, immunofluorescence images showed that actual expression of most cytokines in retinal cells is rapidly suppressed by type I strain infection, with or without the involvement of its homologous ROP16 allele. This demonstrates the particular immune privileged situation of the retina, which is also revealed by the fact that parasite proliferation is nearly exclusively observed outside the retina. In summary, we further developed a promising OT mouse model and demonstrated the specific pathology in retinal tissues.

Overexpression of Fkbp11, a feature of lupus B cells, leads to B cell tolerance breakdown and initiates plasma cell differentiation.

Systemic Lupus Erythematosus (SLE) is a severe systemic autoimmune disease, characterized by multi-organ damages, triggered by an autoantibody-mediated inflammation, and with a complex genetic influence. It is today accepted that adult SLE arises from the building up of many subtle gene variations, each one adding a new brick on the SLE susceptibility and contributing to a phenotypic trait to the disease. One of the ways to find these gene variations consists in comprehensive analysis of gene expression variation in a precise cell type, which can constitute a good complementary strategy to genome wide association studies. Using this strategy, and considering the central role of B cells in SLE, we analyzed the B cell transcriptome of quiescent SLE patients, and identified an overexpression of FKBP11, coding for a cytoplasmic putative peptidyl-prolyl cis/trans isomerase and chaperone enzyme. To understand the consequences of FKBP11 overexpression on B cell function and on autoimmunity's development, we created lentiviral transgenic mice reproducing this gene expression variation. We showed that high expression of Fkbp11 reproduces by itself two phenotypic traits of SLE in mice: breakdown of B cell tolerance against DNA and initiation of plasma cell differentiation by acting upstream of Pax5 master regulator gene.

Myxoid liposarcoma with heterologous components: dedifferentiation or metaplasia? A FISH-documented and CGH-documented case report.

Heterologous differentiation in myxoid liposarcoma is a rare phenomenon. Few cases have been reported thus far, often without molecular assays, and the concept of "dedifferentiated" myxoid liposarcoma remains controversial. We describe a primary myxoid liposarcoma with chondroid and osseous components affecting the right thigh of a 27-year-old woman. We wondered whether these areas represented dedifferentiated components or simply metaplasia, and performed fluorescent in situ hybridization and array comparative genomic hybridization assays in the myxoid liposarcoma component and chondroid component. Fluorescent in situ hybridization analysis demonstrated a DDIT3 gene rearrangement in both components; array comparative genomic hybridization analysis did not detect any gain or loss of DNA regions in both components. Our results, demonstrating that both components have the same molecular alterations, suggest that heterologous components seen in some myxoid liposarcomas reflect a metaplastic phenomenon and not a real dedifferentiation phenomenon, challenging the concept of "dedifferentiated" myxoid liposarcoma.

Interleukin-6-driven inflammatory response induces retinal pathology in a model of ocular toxoplasmosis reactivation.

Ocular inflammation is one of the consequences of infection with the protozoan parasite Toxoplasma gondii. Even if lesions are self-healing in immunocompetent persons, they pose a lifetime risk of reactivation and are a serious threat to vision. As there are virtually no immunological data on reactivating ocular toxoplasmosis, we established a model of direct intravitreal injection of parasites in previously infected mice with a homologous type II strain. Two different mouse strains with variable ability to control retinal infection were studied in order to describe protective and deleterious reaction patterns. In Swiss-Webster mice, which are already relatively resistant to primary infection, no peak of parasite load was observed upon reinfection. In contrast, the susceptible inbred strain C57BL/6 showed high parasite loads after 7 days, as well as marked deterioration of retinal architecture. Both parameters were back to normal on day 21. C57BL/6 mice also reacted with a strong local production of inflammatory and Th1-type cytokines, like interleukin-6 (IL-6), IL-17A, and gamma interferon (IFN-γ), while Swiss-Webster mice showed only moderate expression of the Th2 cytokine IL-31. Interestingly, rapid intraocular production of anti-Toxoplasma antibodies was observed in Swiss-Webster but not in C57BL/6 mice. We then localized the cellular source of different immune mediators within the retina by immunofluorescence. Finally, neutralization experiments of IFN-γ or IL-6 demonstrated the respective protective and deleterious roles of these cytokines for parasite control and retinal integrity during reinfection. In conclusion, we developed and immunologically characterized a promising mouse model of reactivating ocular toxoplasmosis.

Neural tube defects: the experience of the registry of congenital malformations of Alsace, France, 1995-2009.

CONTEXT AND OBJECTIVE: Considering the lack of accurate and up-to-date information available about neural tube defects (NTDs) in France, the purpose of this study was to review clinical and epidemiological data of NTDs and to evaluate the current efficiency of prenatal diagnosis in Alsace (northeastern France). METHODS: A population-based retrospective study was performed from data of the Registry of Congenital Malformations of Alsace between 1995 and 2009. Data were analyzed as a whole and according to the anatomical type of the malformation (anencephaly, cephalocele and spina bifida). Statistical analyses were carried out using the Statistical Package for the Social Sciences. RESULTS: 272 NTDs were recorded divided in 113 cases of anencephaly (42%), 35 cases of cephalocele (13%) and 124 cases of spina bifida (45%). The total prevalence at birth of 14/10,000 (95% CI 13-16) was stable throughout the reporting period. A chromosome abnormality was identified in 27 cases (12% of all karyotyped cases). NTDs were prenatally diagnosed by ultrasound in 88% of the cases. The mean age upon prenatal diagnosis slightly declined during the 15-year period, significantly for spina bifida only. The global rate of terminations of pregnancy following prenatal diagnosis was 97% (230/238). CONCLUSION: This work constitutes a unique population-based study providing accurate and specific up-to-date data from a unique center over a longer period (1995-2009). The most important information concerns the high and stable prevalence, which calls into question the efficiency of the primary prevention by folic acid supplementation and the efficiency of prenatal diagnosis.

Müller cell activation and photoreceptor depletion in a mice model of congenital ocular toxoplasmosis.

Müller glial cells are critically involved in retinal inflammatory processes. Here, we investigate the activation of Müller cells in a model of congenital ocular toxoplasmosis (OT). Four weeks after infection, retinal sections were studied immunohistochemically using the markers glial fibrillary acidic protein (GFAP) and vimentin. Müller cells showed strong up-regulation of both markers, as well as a deteriorated morphology in all infected retinas. Moreover, cell density and color intensity of the outer nuclear layer (ONL) of photoreceptors were decreased. Our results indicate that the severe retinal damage and loss of vision observed in human OT may be not only directly caused by infection but rather mediated by infection induced reactive gliosis.

Next-generation sequencing (NGS) as a fast molecular diagnosis tool for left ventricular noncompaction in an infant with compound mutations in the MYBPC3 gene.

Left ventricular noncompaction (LVNC) is a clinically heterogeneous disorder characterized by a trabecular meshwork and deep intertrabecular myocardial recesses that communicate with the left ventricular cavity. LVNC is classified as a rare genetic cardiomyopathy. Molecular diagnosis is a challenge for the medical community as the condition shares morphologic features of hypertrophic and dilated cardiomyopathies. Several genetic causes of LVNC have been reported, with variable modes of inheritance, including autosomal dominant and X-linked inheritance, but relatively few responsible genes have been identified. In this report, we describe a case of a severe form of LVNC leading to death at 6 months of life. NGS sequencing using a custom design for hypertrophic cardiomyopathy panel allowed us to identify compound heterozygosity in the MYBPC3 gene (p.Lys505del, p.Pro955fs) in 3 days, confirming NGS sequencing as a fast molecular diagnosis tool. Other studies have reported neonatal presentation of cardiomyopathies associated with compound heterozygous or homozygous MYBPC3 mutations. In this family and in families in which parental truncating MYBPC3 mutations are identified, preimplantation or prenatal genetic screening should be considered as these genotypes leads to neonatal mortality and morbidity.

Candida albicans arteritis transmitted by preservation fluid after liver transplantation.

BACKGROUND: Fungal infections remain among the main causes of mortality in the chronically immunosuppressed liver transplant (LT) patient. Bacterial and fungal contamination of preservation fluid (PF), in which grafts are stored, represents a potential source of infection for recipients. CASE REPORT: A 54-year-old patient underwent LT for chronic alcoholic cirrhosis. Mycological culture of the liver PF was positive for Candida albicans. The patient received antimycotic prophylaxis for 4 weeks in absence of clinical and serological signs of infection. He was urgently readmitted 4 months later with hemobilia caused by an arterial pseudoaneurysm that was fistulized in the biliary anastomosis. After an unsuccessful embolization, arterial resection and reconstruction and a biliodigestive anastomosis were performed, with an uneventful postoperative course. Pathology found a mycotic arteritis of the graft artery. Mycotic culture of the arterial segment confirmed the presence of the same Candida albicans genotype previously isolated in the PF. CONCLUSIONS: Mycotic arteritis is one of the possible complications of yeast contamination of PF. Surgeons and physicians involved in the care of LT patients should be aware of this potentially lethal complication and adopt all the available means for early detection.

Role of Topoisomerases in Pediatric High Grade Osteosarcomas: TOP2A Gene Is One of the Unique Molecular Biomarkers of Chemoresponse.

Currently, the treatment of pediatric high-grade osteosarcomas systematically includes one topoisomerase IIα inhibitor. This chemotherapy is usually adapted to the response to the neo-adjuvant therapy after surgery. The current and unique marker of chemoresponsiveness is the percentage of viable residual cells in the surgical resection. This late patient management marker has to be evaluated earlier in the therapeutic history of the patients on initial biopsy. Therefore, new biomarkers, especially those involved in the topoisomerase IIα inhibitor response might be good candidates. Therefore, our study was designed to target TOP1, TOP2A and TOP2B genes in 105 fresh-frozen diagnostic biopsies by allelotyping and real-time quantitative PCR. Our analyses in those pediatric osteosarcomas, homogeneously treated, highlighted the frequent involvement of topo-isomerase genes. The main and most important observation was the statistical link between the presence of TOP2A amplification and the good response to neo-adjuvant chemotherapy. Compared to adult cancers, the 17q21 amplicon, including TOP2A and ERBB2 genes, seems to be differentially implicated in the osteosarcoma chemoresponsiveness. Surprisingly, there is no ERBB2 gene co-amplification and the patients harboring TOP2A amplification tend to show a worse survival, so TOP2A analyses remain a preliminary, but a good molecular approach for the evaluation at diagnosis of pediatric osteosarcoma chemoresponsiveness.

Carabin deficiency in B cells increases BCR-TLR9 costimulation-induced autoimmunity.

The mechanisms behind flares of human autoimmune diseases in general, and of systemic lupus in particular, are poorly understood. The present scenario proposes that predisposing gene defects favour clinical flares under the influence of external stimuli. Here, we show that Carabin is low in B cells of (NZB × NZW) F1 mice (murine SLE model) long before the disease onset, and is low in B cells of lupus patients during the inactive phases of the disease. Using knock-out and B-cell-conditional knock-out murine models, we identify Carabin as a new negative regulator of B-cell function, whose deficiency in B cells speeds up early B-cell responses and makes the mice more susceptible to anti-dsDNA production and renal lupus flare after stimulation with a Toll-like Receptor 9 agonist, CpG-DNA. Finally, in vitro analysis of NFκB activation and Erk phosphorylation in TLR9- and B-cell receptor (BCR)-stimulated Carabin-deficient B cells strongly suggests how the internal defect synergizes with the external stimulus and proposes Carabin as a natural inhibitor of the potentially dangerous crosstalk between BCR and TLR9 pathways in self-reactive B cells.

Comparison of the dosimetries of 3-dimensions Radiotherapy (3D-RT) with linear accelerator and intensity modulated radiotherapy (IMRT) with helical tomotherapy in children irradiated for neuroblastoma.

BACKGROUND: Intensity modulated radiotherapy is an efficient radiotherapy technique to increase dose in target volumes and decrease irradiation dose in organs at risk. This last objective is mainly relevant in children. However, previous results suggested that IMRT could increase low dose, factor of risk for secondary radiation induced cancer. This study was performed to compare dose distributions with 3D-radiotherapy (3D-RT) and IMRT with tomotherapy (HT) in children with neuroblastoma. Seven children with neuroblastoma were irradiated. Treatment plans were calculated for 3D-RT, and for HT. For the volume of interest, the PTV-V95% and conformity index were calculated. Dose constraints of all the organs at risk and integral dose were compared. RESULTS: The conformity index was statistically better for HT than for 3D-RT. PTV-V95% constraint was reached in 6 cases with HT compared to 2 cases with 3D-RT. For the ipsilateral kidney of the tumor, the V12 Gy constraint was reached for 3 patients with both methods. The values were lower with HT than with 3D-RT in two cases and higher in one case. The threshold was not reached for one patient with either technique, but the value was lower with HT than with 3D-RT. For the contralateral kidney of the tumors, the V12 Gy constraint was reached for all patients with both methods. The values were lower with HT than with 3D-RT in 5 of 7 children, equal in one patient and higher in one patient. The organ-at-risk volumes receiving low doses were significantly lower with 3D-RT but larger for the highest doses, compared to those irradiated with HT. The integral doses were not different. CONCLUSIONS: IMRT with HT allows a better conformity treatment, a more frequently acceptable PTV-V95% than 3D-RT and, concomitantly, a better shielding of the kidneys. The integral doses are comparable between both techniques but consideration of differences in dose distribution between the two techniques, for the organs at risk, has to be taken in account when validating treatment.

Efficacy of intravitreal administrations of linezolid in an experimental model of S. aureus-related endophthalmitis.

PURPOSE: To evaluate the efficacy of intravitreal administration of linezolid (LZD) in a rabbit model of Staphylococcus aureus endophthalmitis. METHODS: Of 40 rabbits studied, 36 of them received 10(2) colony-forming units (CFU) of S. aureus in their right eye before being randomly assigned to the following groups: four groups of 8 animals received 24 hours after the bacterial inoculation, 1, 10, 30 mg of LZD (LZD 1, LZD 10, and LZD 30) or 1 mg of vancomycin (V1), respectively. Four other animals had a sham injection in their infected eye. The 4 remaining animals were used as negative controls. Clinical, bacterial, and histologic assessments were conducted at different endpoints. Animals were euthanized at day 8. The safety profile of intravitreal LZD was assessed by electroretinography in 5 more animals by comparing the recordings in eyes injected with 30 mg of LZD and contralateral control eyes injected with a solution of sterile saline water. RESULTS: At day 5, the mean inflammatory clinical scores of Nussenblatt were 7.0 ± 1.0, 3.6 ± 0.7, and 3.1 ± 0.8, in the LZD 1, LZD 10, and LZD 30 groups and 3.4 ± 1.7 and 7.5 ± 0 in the V1 and BSS+ groups, respectively (P < 0.05, ANOVA). The corresponding mean bacterial counts in the vitreous (log 10 CFU/mL) were 6.2 ± 6.5, 3.5 ± 3.8, 0, 3.8 ± 4.2, and 7.8 ± 4.9, respectively (P < 0.05, ANOVA). A 30 mg dose of LZD sterilized all the eyes at day 5 and displayed the lowest (best) histologic score (1.5 ± 0.6). Residual LZD concentrations 24 hours after the administration were between 0.1 and 7.2 mg/L LZD 30 group. The half-time of linezolid in the vitreous was 2 hours. There were no differences in the electroretinogram recordings between control eyes and eyes injected with 30 mg of linezolid at days 1 and 14 after the intravitreal injection. CONCLUSIONS: This is the first evidence of the effectiveness of linezolid for the treatment of experimental staphylococcal endophthalmitis. High ocular concentrations of LZD were needed to obtain a satisfactory bactericidal effect. Linezolid displayed a concentration-dependent killing activity in the eye. Such doses of intravitreal linezolid appeared to be safe for the retinal function.

Prenatal diagnosis of a 12q22q23.2 interstitial deletion by array CGH in a malformed fetus.

We report the prenatal diagnosis of a 12q22q23.2 de novo interstitial deletion performed by array based comparative genomic hybridization (array CGH) in a fetus with cystic hygroma colli, intrauterine growth retardation, microcephaly and micrognathism. Haploinsufficiency for insuline-like growth factor 1 gene (IGF1), which is mapped in the deleted region, is suggested because of its implication in prenatal and postnatal growth and in neuronal maturation. This case demonstrates the contribution of array CGH in prenatal diagnosis for detecting small unbalanced chromosomal abnormalities in malformed fetuses and, subsequently, for genetic counselling.

Daptomycin versus vancomycin in a methicillin-resistant Staphylococcus aureus endophthalmitis rabbit model: bactericidal effect, safety, and ocular pharmacokinetics.

Staphylococcus aureus is a frequent cause of acute endophthalmitis, and infection with this virulent bacterium is often associated with a poor visual outcome. In this study, we investigated the bactericidal efficacy and the safety of intravitreal daptomycin (DAP), a lipopeptide antibiotic with broad-spectrum activity against Gram-positive bacteria, compared with those of intravitreal vancomycin (VAN) in a methicillin-resistant S. aureus endophthalmitis rabbit model. The pharmacokinetics and pharmacodynamics of daptomycin in the infected eyes were also studied. Rabbits were randomly divided into three treatment groups (n = 8) and one untreated group (n = 4), to compare the effect of single intravitreal injections of 0.2 mg and 1 mg of daptomycin (DAP 0.2 and DAP 1 groups, respectively) with that of 1 mg of intravitreal vancomycin (VAN 1 group). Vitreal aspirates were regularly collected and grading of ocular inflammation was regularly performed until euthanasia on day 7. In the DAP 0.2 group, 62.5% of the eyes were sterilized and the mean bacterial count presented a reduction of 1 log unit. In the DAP 1 and VAN 1 groups, the infection was eradicated (100% and 87.5% of eyes sterilized, respectively), with a 4-log-unit reduction of the mean bacterial count. The bactericidal efficacy in the DAP 1 group was not inferior to that in the VAN 1 group and was superior to that of the other regimens in limiting the ocular inflammation and preserving the architecture of the ocular structures (P < 0.05). The elimination half-life (t(1/2ß)) of daptomycin was independent of the administered dose (38.8 ± 16.5 h and 40.9 ± 6.7 h, respectively, for the DAP 0.2 and DAP 1 groups) and was significantly longer than the t(1/2ß) of vancomycin (20.5 ± 2.0 h for the VAN 1 group) (P < 0.05). This antibiotic could therefore be considered for the treatment of intraocular infections caused by Gram-positive bacteria.

Heavy chain-only antibodies and tetravalent bispecific antibody neutralizing Staphylococcus aureus leukotoxins.

Panton-Valentine leukocidin (PVL) is a pore-forming toxin associated with current outbreaks of community-associated methicillin-resistant strains and implicated directly in the pathophysiology of Staphylococcus aureus-related diseases. Humanized heavy chain-only antibodies (HCAb) were generated against S. aureus PVL from immunized transgenic mice to neutralize toxin activity. The active form of PVL consists of the two components, LukS-PV and LukF-PV, which induce osmotic lysis following pore formation in host defense cells. One anti-LukS-PV HCAb, three anti-LukF-PV HCAbs with affinities in the nanomolar range, and one engineered tetravalent bispecific HCAb were tested in vitro and in vivo, and all prevented toxin binding and pore formation. Anti-LukS-PV HCAb also binds to γ-hemolysin C (HlgC) and inhibits HlgC/HlgB pore formation. Experiments in vivo in a toxin-induced rabbit endophthalmitis model showed that these HCAbs inhibit inflammatory reactions and tissue destruction, with the tetravalent bispecific HCAb performing best. Our findings show the therapeutic potential of HCAbs, and in particular, bispecific antibodies.

Murine neonatal infection provides an efficient model for congenital ocular toxoplasmosis.

Congenital infection is one of the most serious settings of infection with the apicomplexan parasite Toxoplasma gondii. Ocular diseases, such as retinochoroiditis, are the most common sequels of such infection in utero. However, while numerous studies have investigated the physiopathology of acquired toxoplasmosis, congenital infection has been largely neglected so far. Here, we establish a mouse model of congenital ocular toxoplasmosis. Parasite load and ocular pathology have been followed for the first 4 weeks of life. Ocular infection developed slowly compared to cerebral infection. Even after 4 weeks, not all eyes were infected and ocular parasite load was low. Therefore, we evaluated a scheme of neonatal infection to overcome problems associated with congenital infection. Development of infection and physiopathology was similar, but at a higher, more reliable rate. In summary, we have established a valuable model of neonatal ocular toxoplasmosis, which facilitates the research of the underlying physiopathological mechanisms and new diagnostic approaches of this pathology.

Constitutive overexpression of muscarinic receptors leads to vagal hyperreactivity.

BACKGROUND: Alterations in muscarinic receptor expression and acetylcholinesterase (AchE) activity have been observed in tissues from Sudden Infant Death Syndrome (SIDS). Vagal overactivity has been proposed as a possible cause of SIDS as well as of vasovagal syncopes. The aim of the present study was to seek whether muscarinic receptor overexpression may be the underlying mechanism of vagal hyperreactivity. Rabbits with marked vagal pauses following injection of phenylephrine were selected and crossed to obtain a vagal hyperreactive strain. The density of cardiac muscarinic receptors and acetylcholinesterase (AchE) gene expression were assessed. Blood markers of the observed cardiac abnormalities were also sought. METHODOLOGY/PRINCIPAL FINDINGS: Cardiac muscarinic M(2) and M(3) receptors were overexpressed in hyperreactive rabbits compared to control animals (2.3-fold and 2.5-fold, respectively) and the severity of the phenylephrine-induced bradycardia was correlated with their densities. A similar overexpression of M(2) receptors was observed in peripheral mononuclear white blood cells, suggesting that cardiac M(2) receptor expression can be inferred with high confidence from measurements in blood cells. Sequencing of the coding fragment of the M(2) receptor gene revealed a single nucleotide mutation in 83% of hyperreactive animals, possibly contributing for the transcript overexpression. Significant increases in AchE expression and activity were also assessed (AchE mRNA amplification ratio of 3.6 versus normal rabbits). This phenomenon might represent a compensatory consequence of muscarinic receptors overexpression. Alterations in M(2) receptor and AchE expression occurred between the 5th and the 7th week of age, a critical period also characterized by a higher mortality rate of hyperreactive rabbits (52% in H rabbits versus 13% in normal rabbits) and preceeded the appearance of functional disorders. CONCLUSIONS/SIGNIFICANCE: The results suggest that cardiac muscarinic receptor overexpression plays a critical role in the development of vagal hyperreactivity, whereas AchE hyperactivity appears as a compensatory consequence of it. Since similar vagal disorders were observed recently by us in SIDS, muscarinic receptor overexpression could become a marker of risk of vasovagal syncopes and SIDS.

Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer.

Hepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/beta-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. beta-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy.