Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial.

BACKGROUND: In EMBRACA, talazoparib prolonged progression-free survival versus chemotherapy (hazard ratio [HR] 0.542 [95% confidence interval (CI) 0.413-0.711]; P < 0.0001) and improved patient-reported outcomes (PRO) in germline BRCA1/2 (gBRCA1/2)-mutated advanced breast cancer (ABC). We report final overall survival (OS). PATIENTS AND METHODS: This randomized phase III trial enrolled patients with gBRCA1/2-mutated HER2-negative ABC. Patients received talazoparib or physician's choice of chemotherapy. OS was analyzed using stratified HR and log-rank test and prespecified rank-preserving structural failure time model to account for subsequent treatments. RESULTS: A total of 431 patients were entered in a randomized study (287 talazoparib/144 chemotherapy) with 412 patients treated (286 talazoparib/126 chemotherapy). By 30 September 2019, 216 deaths (75.3%) occurred for talazoparib and 108 (75.0%) chemotherapy; median follow-up was 44.9 and 36.8 months, respectively. HR for OS with talazoparib versus chemotherapy was 0.848 (95% CI 0.670-1.073; P = 0.17); median (95% CI) 19.3 months (16.6-22.5 months) versus 19.5 months (17.4-22.4 months). Kaplan-Meier survival percentages (95% CI) for talazoparib versus chemotherapy: month 12, 71% (66% to 76%)/74% (66% to 81%); month 24, 42% (36% to 47%)/38% (30% to 47%); month 36, 27% (22% to 33%)/21% (14% to 29%). Most patients received subsequent treatments: for talazoparib and chemotherapy, 46.3%/41.7% received platinum and 4.5%/32.6% received a poly(ADP-ribose) polymerase (PARP) inhibitor, respectively. Adjusting for subsequent PARP and/or platinum use, HR for OS was 0.756 (95% bootstrap CI 0.503-1.029). Grade 3-4 adverse events occurred in 69.6% (talazoparib) and 64.3% (chemotherapy) patients, consistent with previous reports. Extended follow-up showed significant overall improvement and delay in time to definitive clinically meaningful deterioration in global health status/quality of life and breast symptoms favoring talazoparib versus chemotherapy (P < 0.01 for all), consistent with initial analyses. CONCLUSIONS: In gBRCA1/2-mutated HER2-negative ABC, talazoparib did not significantly improve OS over chemotherapy; subsequent treatments may have impacted analysis. Safety was consistent with previous observations. PRO continued to favor talazoparib.

A novel mouse model of rhabdomyosarcoma underscores the dichotomy of MDM2-ALT1 function in vivo.

Alternative splicing of the oncogene murine double minute 2 (MDM2) is induced in response to genotoxic stress. MDM2-ALT1, the major splice variant generated, is known to activate the p53 pathway and impede full-length MDM2's negative regulation of p53. Despite this perceptible tumor-suppressive role, MDM2-ALT1 is also associated with several cancers. Furthermore, expression of MDM2-ALT1 has been observed in aggressive metastatic disease in pediatric rhabdomyosarcoma (RMS), irrespective of histological subtype. Therefore, we generated a transgenic MDM2-ALT1 mouse model that would allow us to investigate the effects of this splice variant on the progression of tumorigenesis. Here we show that when MDM2-ALT1 is ubiquitously expressed in p53 null mice it leads to increased incidence of spindle cell sarcomas, including RMS. Our data provide evidence that constitutive MDM2-ALT1 expression is itself an oncogenic lesion that aggravates the tumorigenesis induced by p53 loss. On the contrary, when MDM2-ALT1 is expressed solely in B-cells in the presence of homozygous wild-type p53 it leads to significantly increased lymphomagenesis (56%) when compared with control mice (27%). However, this phenotype is observable only at later stages in life (⩾18 months). Moreover, flow cytometric analyses for B-cell markers revealed an MDM2-ALT1-associated decrease in the B-cell population of the spleens of these animals. Our data suggest that the B-cell loss is p53 dependent and is a response mounted to persistent MDM2-ALT1 expression in a wild-type p53 background. Overall, our findings highlight the importance of an MDM2 splice variant as a critical modifier of both p53-dependent and -independent tumorigenesis, underscoring the complexity of MDM2 posttranscriptional regulation in cancer. Furthermore, MDM2-ALT1-expressing p53 null mice represent a novel mouse model of fusion-negative RMS.

A review of craniofacial and dental findings of the RASopathies.

OBJECTIVES: The RASopathies are a group of syndromes that have in common germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway and have been a focus of study to understand the role of this pathway in development and disease. These syndromes include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML or LEOPARD syndrome), neurofibromatosis type 1 (NF1), Costello syndrome (CS), cardio-facio-cutaneous (CFC) syndrome, neurofibromatosis type 1-like syndrome (NFLS or Legius syndrome) and capillary malformation-arteriovenous malformation syndrome (CM-AVM). These disorders affect multiple systems, including the craniofacial complex. Although the craniofacial features have been well described and can aid in clinical diagnosis, the dental phenotypes have not been analysed in detail for each of the RASopathies. In this review, we summarize the clinical features of the RASopathies, highlighting the reported craniofacial and dental findings. METHODS: Review of the literature. RESULTS: Each of the RASopathies reviewed, caused by mutations in genes that encode different proteins in the Ras pathway, have unique and overlapping craniofacial and dental characteristics. CONCLUSIONS: Careful description of craniofacial and dental features of the RASopathies can provide information for dental clinicians treating these individuals and can also give insight into the role of Ras signalling in craniofacial development.

Toxic effects of prenatal exposure to alcohol, tobacco and other drugs.

Tobacco, alcohol, cannabis and cocaine are the most consumed psychoactive drugs throughout the population. Prenatal exposure to these drugs could alter normal foetal development and could threaten future welfare. The main changes observed in prenatal exposure to tobacco are caused by nicotine and carbon monoxide, which can impede nutrient and oxygen exchange between mother and foetus, restricting foetal growth. Memory, learning processes, hearing and behaviour can also be affected. Alcohol may cause physical and cognitive alterations in prenatally exposed infants, fundamentally caused by altered NMDAR and GABAR activity. Tetrahydrocannabinol, the psychoactive compound of cannabis, is capable of activating CB1R, inducing connectivity deficits during the foetal brain development. This fact could be linked to behavioural and cognitive deficits. Many of the effects from prenatal cocaine exposure are caused by altered cell proliferation, migration, differentiation and dendritic growth processes. Cocaine causes long term behavioural and cognitive alterations and also affects the uteroplacental unit.

Fecal detection of enterotoxigenic Bacteroides fragilis.

Bacteroides fragilis is a common colonic symbiote of which one subtype, enterotoxigenic Bacteroides fragilis (ETBF), causes inflammatory diarrhea. However, asymptomatic ETBF colonization is common. Through its primary virulence factor, B. fragilis toxin (BFT), ETBF causes asymptomatic, chronic colitis in C57BL/6 mice and increased colon tumorigenesis in multiple intestinal neoplasia mice. Human studies suggest an association between ETBF infection, inflammatory bowel disease, and colon cancer. Additional studies on ETBF epidemiology are, therefore, crucial. The goal of this study is to develop a reliable fecal diagnostic for ETBF. To develop a sensitive assay for ETBF, we tested multiple protocols on mouse stools spiked with serially diluted ETBF. Each assay was based on either touchdown or quantitative polymerase chain reaction (qPCR) and used primers targeted to bft to detect ETBF. Using touchdown PCR or qPCR, the mean ETBF detection limit was 1.55 × 10(6) colony-forming units (CFU)/g stool and 1.33 × 10(4) CFU/g stool, respectively. Augmentation of Bacteroides spp. growth in fecal samples using PYGB (Peptone Yeast Glucose with Bile) broth enhanced ETBF detection to 2.93 × 10(2) CFU/g stool using the touchdown PCR method and 2.63 × 10(2) CFU/g stool using the qPCR method. Fecal testing using combined culture-based amplification and bft touchdown PCR is a sensitive assay for the detection of ETBF colonization and should be useful in studying the role of ETBF colonization in intestinal diseases, such as inflammatory bowel disease and colon cancer. We conclude that touchdown PCR with culture-based amplification may be the optimal ETBF detection strategy, as it performs as well as qPCR with culture-based amplification, but is a less expensive technique.

Tumor oncogene (KRAS) status and risk of venous thrombosis in patients with metastatic colorectal cancer.

BACKGROUND: Patients with metastatic colon cancer (mCRC) are at increased risk of venous thromboembolism (VTE). Limited preclinical data suggest that the oncogene (KRAS) mutational status of the tumor represents a plausible clinical link to systemic hypercoagulability in cancer patients. OBJECTIVES: To determine if a tumor genetic characteristic, KRAS mutational status, is associated with an increased risk of VTE in patients with mCRC. PATIENTS/METHODS: A retrospective cohort study of patients with mCRC and KRAS test results was conducted at multiple practice sites across New England in the United States. The primary outcome was a VTE event, defined as deep venous thrombosis (DVT) and/or pulmonary embolism (PE), either 6 months before or at any time after the diagnosis of mCRC. KRAS status (mutated vs. wild type) and other relevant predictors of thrombosis were collected. RESULTS: Of 172 histologically confirmed patients with mCRC, 40 developed a VTE (23.3%). Sixty-five patients (37.8%) had a mutant KRAS status. The incidence of VTE and DVT among patients with mutated KRAS was 32.3 and 23.1%, respectively. The corresponding incidence among patients with wild-type KRAS was 17.8 and 9.4%. Odd ratios for the association were 2.21 (95% CI, 1.08-4.53) for VTE and 2.62 (95% CI, 1.12-6.12) for DVT, and remained significant despite adjustment for Khorana score and bevacizumab use. CONCLUSION: Tumor mutant KRAS status is associated with an increased risk of VTE in patients with mCRC. The tumor genetic profile may represent a novel and important risk factor for thrombosis in patients with cancer.

A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma.

We report four previously undescribed families with germline BRCA1-associated protein-1 gene (BAP1) mutations and expand the clinical phenotype of this tumor syndrome. The tumor spectrum in these families is predominantly uveal malignant melanoma (UMM), cutaneous malignant melanoma (CMM) and mesothelioma, as previously reported for germline BAP1 mutations. However, mutation carriers from three new families, and one previously reported family, developed basal cell carcinoma (BCC), thus suggesting inclusion of BCC in the phenotypic spectrum of the BAP1 tumor syndrome. This notion is supported by the finding of loss of BAP1 protein expression by immunochemistry in two BCCs from individuals with germline BAP1 mutations and no loss of BAP1 staining in 53 of sporadic BCCs consistent with somatic mutations and loss of heterozygosity of the gene in the BCCs occurring in mutation carriers. Lastly, we identify the first reported recurrent mutation in BAP1 (p.R60X), which occurred in three families from two different continents. In two of the families, the mutation was inherited from a common founder but it arose independently in the third family.

Multimodality imaging to assess immediate response to irreversible electroporation in a rat liver tumor model.

PURPOSE: To compare changes on ultrasonographic (US), computed tomographic (CT), and magnetic resonance (MR) images after irreversible electroporation (IRE) ablation of liver and tumor tissues in a rodent hepatoma model. MATERIALS AND METHODS: Studies received approval from the institutional animal care and use committee. Forty-eight rats were used, and N1-S1 tumors were implanted in 24. Rats were divided into groups and allocated for studies with each modality. Imaging was performed in normal liver tissues and tumors before and after IRE. MR imaging was performed in one group before and after IRE after hepatic vessel ligation. US images were graded to determine echogenicity changes, CT attenuation was measured (in Hounsfield units), and MR imaging signal-to-noise ratio (SNR) was measured before and after IRE. Student t test was used to compare attenuation and SNR measurements before and after IRE (P < .05 indicated a significant difference). RESULTS: IRE ablation produced greater alterations to echogenicity in normal tissues than in tumors. Attenuation in ablated liver tissues was reduced compared with that in control tissues (P < .001), while small attenuation differences between ablated (42.11 HU ± 2.11) and control (45.14 HU ± 2.64) tumors trended toward significance (P = .052). SNR in ablated normal tissues was significantly altered after IRE (T1-weighted images: pre-IRE, 145.95 ± 24.32; post-IRE, 97.80 ± 18.03; P = .004; T2-weighted images, pre-IRE, 47.37 ± 18.31; post-IRE, 90.88 ± 37.15; P = .023). In tumors, SNR differences before and after IRE were not significant. No post-IRE signal changes were observed after hepatic vessel ligation. CONCLUSION: IRE induces rapid changes on gray-scale US, unenhanced CT, and MR images. These changes are readily visible and may assist a performing physician to delineate ablation zones from the unablated surrounding parenchyma.

Clinical and dermoscopic characteristics of new naevi in adults: results from a cohort study.

BACKGROUND: Naevogenesis is a process known to occur throughout life. To date, investigators have made conclusions about new naevi in adults based on results of cross-sectional studies. OBJECTIVES: To determine the incidence of new naevus development in adults and to describe the dermoscopic morphology of new naevi. METHODS: A cohort of 182 patients seen at the outpatient dermatology clinic at Memorial Sloan-Kettering Cancer Center between 2000 and 2009 was evaluated with baseline total body photographs. The patients were aged 17 years or older and had presented for routine follow-up surveillance examination at least 3 months after baseline total body photographs. The number of new naevi and the dermoscopic morphology of these naevi were recorded. RESULTS: Of the 182 patients evaluated, 50 (27%) developed at least one new naevus during follow-up. The incidence of new naevi was 202 per 1000 person-years of follow-up. The most common types of naevi were reticular (47·1%), followed by the homogeneous (22·1%) and complex (reticuloglobular) patterns (15·4%). CONCLUSIONS: Our results provide support for the theory that there are two distinct pathways of naevogenesis, a dynamic process occurring throughout life. This study demonstrates that the predominant dermoscopic morphology of newly acquired naevi in adults is reticular.

Craniofacial and dental development in cardio-facio-cutaneous syndrome: the importance of Ras signaling homeostasis.

Cardio-facio-cutaneous syndrome (CFC) is a RASopathy that is characterized by craniofacial, dermatologic, gastrointestinal, ocular, cardiac, and neurologic anomalies. CFC is caused by activating mutations in the Ras/mitogen-activated protein kinase (MAPK) signaling pathway that is downstream of receptor tyrosine kinase (RTK) signaling. RTK signaling is known to play a central role in craniofacial and dental development, but to date, no studies have systematically examined individuals with CFC to define key craniofacial and dental features. To fill this critical gap in our knowledge, we evaluated the craniofacial and dental phenotype of a large cohort (n = 32) of CFC individuals who attended the 2009 and 2011 CFC International Family Conferences. We quantified common craniofacial features in CFC which include macrocephaly, bitemporal narrowing, convex facial profile, and hypoplastic supraorbital ridges. In addition, there is a characteristic dental phenotype in CFC syndrome that includes malocclusion with open bite, posterior crossbite, and a high-arched palate. This thorough evaluation of the craniofacial and dental phenotype in CFC individuals provides a step forward in our understanding of the role of RTK/MAPK signaling in human craniofacial development and will aid clinicians who treat patients with CFC.

Characteristics of children enrolled in treatment trials for NF1-related plexiform neurofibromas.

OBJECTIVE: To describe the characteristics of children enrolled in treatment trials for neurofibromatosis type 1 (NF1)-related plexiform neurofibroma (PN), PN tumor burden, PN-related complications, and treatment outcomes and to highlight the differences between characteristics of children with NF1 vs children with cancers entered on early phase drug trials. METHODS: Pre-enrollment characteristics and complications of PN were retrospectively analyzed in a cohort of 59 children with NF1-related PN treated on 1 of 7 clinical trials at the NIH between 1996 and 2007. Outcome was analyzed in a subset of 19 patients enrolled in phase I trials. Comparisons to children with cancer were made from a similar analysis performed recently. RESULTS: The median age at enrollment was 8 years. The median PN volume was 555 mL. Most patients had no prior chemotherapy or radiation, but nearly half had previous surgery for PN. PN-associated complications and NF1 manifestations were common, including pain (53%), other tumors (18%), and hypertension (8%). Investigational drug therapy was well tolerated. A median of 10 treatment cycles was administered. Patients with NF1-related PN were younger, had better performance score, had less prior therapy, and remained on study longer than cancer patients. CONCLUSIONS: Children with NF1-related plexiform neurofibroma (PN) enrolled in clinical trials had large tumors with substantial morbidity. Clinical trials in these children provide information about drug tolerance, cumulative toxicity, and pharmacokinetics in a younger population than early phase pediatric cancer trials. This report may aid in the evaluation of the applicability of traditional pediatric cancer trial designs and endpoints for NF1-related PN.

A study of functional outcomes following implantation of a total distal radioulnar joint prosthesis.

This paper reports a long-term follow-up measuring pain, range of motion and weight-bearing ability, following implantation of a total distal radioulnar joint prosthesis. This prosthesis differs from excision arthroplasties and ulnar head replacements by replacing all three components of the distal radioulnar joint, viz. the sigmoid notch, the ulnar head and the triangular fibrocartilage. The design allows longitudinal migration of the radius throughout pronation and supination, as well as load bearing of the wrist. Thirty-one patients receiving the prosthesis returned or were interviewed by telephone at a mean of 5.9 (range 4-9) years. Pronation increased from a mean of 65.5 degrees (range 5-90 degrees ) to 74 degrees (range 20-90 degrees ) and supination from 53 degrees (range 5-90 degrees ) to 70 degrees (range 20-90 degrees ) while greatly diminishing and/or eliminating pain. Grip increased from a mean of 10 kg (22 lbs) to 24 kg (52 lbs). Weight bearing was restored or increased in 29 of 31 patients.

Allogeneic bone marrow transplant for refractory mediastinal germ cell tumour: possible evidence of graft-versus-tumour effect.

Mediastinal germ cell tumours (GCT) carry a poor prognosis, particularly after relapse. We have reviewed the published reports of current treatments and describe a case with a cure after an allogeneic bone marrow transplant, which is not reported in the current published data. We believe that GCT may be susceptible to a graft-versus-tumour effect and suggest that patients with relapsed GCT be considered for allogeneic transplantation.

Detection of the herpesviral hematopoietic necrosis disease agent (Cyprinid herpesvirus 2) in moribund and healthy goldfish: validation of a quantitative PCR diagnostic method.

Cyprinid herpesvirus 2 (CyHV-2) is a pathogen of goldfish Carassius auratus auratus L. that causes herpesviral hematopoietic necrosis (HVHN) disease. The disease is associated with necrosis of hematopoietic tissues and anemia with high mortality. We have developed a real time 5'-nuclease PCR method (Taqman) that quantitatively detects CyHV-2 with a linear response over 8 logs of target concentration. The coefficient of variability on replicate samples tested on different days was 13% and the calculated sensitivity approached 1 target molecule per reaction. The assay does not cross-react with other similar fish herpesviruses, including CyHV-1 (carp pox) and CyHV-3 (koi herpesvirus), but reliably detects known CyHV-2 positive fish. The assay detects CyHV-2 not just in clinical cases of HVHN but also in apparently healthy 1 yr old goldfish fingerlings and even in 3 to 5 yr old broodfish.

Secondhand smoke, dietary fruit intake, road traffic exposures, and the prevalence of asthma: a cross-sectional study in young children.

The authors have investigated the independent effects of exposure to secondhand smoke, road vehicle traffic, and dietary fruit intake in a cross-sectional study of asthma in young children. They surveyed all children aged 4-6 years in 235 schools in the East Midlands and East of England regions of the United Kingdom in 2003. Data on respiratory symptoms, diagnoses and treatment, smoking in the home, and dietary fruit intake were collected by parental questionnaire. A geographic information system was used to map postcodes and determine the distance of the home from the nearest main road. Responses were obtained from 11,562 children. Wheeze in the past year and physician-diagnosed asthma were reported by 14.1% and 18.2%, respectively. Both of these outcomes were more common in children who lived with a smoker, and the prevalence of asthma increased with the number of smokers in the home. Asthma prevalence was not associated with proximity of the home to a main road or with dietary fruit intake. The authors conclude that, of the potential risk factors considered in this study, preventing secondhand smoke exposure may be the most effective way of preventing asthma.

Fish-tail plasty: a safe technique to improve cosmesis at the lateral end of mastectomy scars.

BACKGROUND AND AIMS: Redundant skin at the lateral end of a mastectomy scar can be unsightly and uncomfortable, especially in elderly obese patients. The aim of this study is to evaluate a technique of mastectomy wound closure designed to maximise cosmesis at the lateral end. PATIENTS AND METHODS: Thirty lateral skin flap advancements were performed in 28 patients. The procedure was performed primarily in 27 cases. In three cases a delayed scar revision was performed. Following anterior advancement of the skin overlying the latissimus dorsi muscle, two areas of redundant skin were excised and the wound closed in the shape of Y-plasty. RESULTS: The patients' mean age was 70.6 years (range 51-93) and the mean body mass index (BMI) 30.4 kg/m2 (range 21-35). The mean weight of the excised breast tissue was 1015 g (range 356-2003). The mean lengths of the two limbs of the Y-plasty were 5.3c m (range 3-10). The mean length of the base of the flap was 8.3 cm (range 4-14). One patient developed a small area of skin necrosis at the apex of the Y-plasty. Two further patients developed superficial wound infections. CONCLUSION: Fish-tail plasty is a safe and easy technique and may be recommended following mastectomy in obese patients to improve cosmesis and avoid discomfort caused by redundant skin.

Iliac vein compression in an asymptomatic patient population.

OBJECTIVE: May-Thurner syndrome is a well-recognized anatomic variant that is associated with the development of symptomatic acute venous thrombosis of the left iliac vein. However, the natural frequency of compression of the left iliac vein and its clinical significance in asymptomatic disease has not been established. Therefore the purpose of this descriptive anatomic study was to determine the incidence of left common iliac vein compression in an asymptomatic population. METHODS: A retrospective analysis of medical records and helical abdominal computed tomography scans was conducted in 50 consecutive patients evaluated in the emergency department because of abdominal pain. Medical records were reviewed for symptoms and risk factors for deep venous thrombosis, and data were collected and reported according to the Joint Society Reporting Standards for acute lower extremity venous thrombosis. All computed tomography was performed with intravenous contrast medium, and 2-mm to 5-mm axial images were obtained. The minor diameter of the common iliac arteries and veins was measured. The technique of transverse image measurement was validated with multiplanar reconstructions and orthogonal diameter measurements in a subset of subjects. Statistical analysis was performed with the Student t test or Spearman rank correlation. RESULTS: Mean age of subjects without symptoms was 40 years (range, 19-85 years), and 60% (n = 30) were female patients. The mean acute lower extremity venous thrombosis risk factor score was 1.16 +/- 0.23 (range, 0-6; maximum possible score, 28). It was surprising that 24% (n = 12) of patients had greater than 50% compression and 66% (n = 33) had greater than 25% compression. Mean compression of the left common iliac vein was 35.5% (range, -5.6%-74.8%). The structure most often compressing the left common iliac vein against the vertebral body was the right common iliac artery (84%). There was no strong correlation between patient age or common iliac artery size and compression of the left common iliac vein. However, women had greater mean compression of the left common iliac vein (women, 41.2% +/- 3.1%; men, 27.0% +/- 3.0%; P =.003). CONCLUSION: Hemodynamically significant left common iliac vein compression is a frequent anatomic variant in asymptomatic individuals. Therefore compression of the left iliac vein may represent a normal anatomic pattern that has thus far been thought of as a pathologic condition.

A new bacilliform fathead minnow rhabdovirus that produces syncytia in tissue culture.

A pathogenic bacilliform virus 130-180 nm in length and 31-47 nm in diameter was isolated from moribund fathead minnows (Pimephales promelas) exhibiting hemorrhages in their eyes and skin. A cytopathic effect of multifocal syncytia was observed in the epithelioma papulosum cyprini cell line after a 48 h incubation at 20 degrees C. A similar cytopathic effect was also observed in other cell lines tested, but not in bluegill fry, koi fin, or Chinook salmon embryo cells. The filterable agent was inactivated by exposure to 50 degrees C for 10 min, 20% ether, 2 and 50% chloroform, pH 3, and pH 10, was unaffected by 5'-iodo-2 deoxyuridine, and appeared bacilliform and occasionally bullet-shaped by electron microscopy. These results are consistent with those of rhabdoviruses. Immunodot blots performed with antisera against selected fish rhabdoviruses, an aquareovirus, and a birnavirus were all negative. River's postulates were fulfilled in fathead minnows, but the agent did not replicate or cause disease in other cyprinids or salmonids during challenge experiments. Hepatic, splenic, and renal lesions were observed during histological analysis of diseased fish from viral challenges and from the original case. Structural proteins resolved via SDS-PAGE had molecular weights similar to those reported in lyssaviruses of the family Rhabdoviridae; however, syncytia formation is not a typical cytopathic effect of rhabdoviruses. This virus, has tentatively been named the fathead minnow rhabdovirus (FHMRV) and is most similar to the members of the family Rhabdoviridae, but atypical properties like syncytia formation may justify the assignment to a novel taxon.

Wnt signaling in the vasculature.

The Wnt signaling pathway regulates normal development as well as a variety of pathologies. Studies of the Wnt pathway have focused largely on very early development and on tumorigenesis. Recent observations point to a role for Wnt signaling in vessel development and pathology. Although not yet investigated systematically, several Wnt ligands have been demonstrated to be expressed in the cells of blood vessels in vivo and in vitro, including Wnt-2, -5a, -7a and -10b. Mice deficient for Wnt-2 display vascular abnormalities including defective placental vasculature. Wnt receptors, called frizzled (Fz), are also expressed by vascular cells in culture and in situ. Of the 10 murine Fz identified to date, Fz-1, -2, -3, and -5 have been demonstrated in endothelial and vascular smooth muscle cells; mice deficient for Fz-5 display vascular abnormalities and are embryonic lethal. Two soluble, naturally occurring Wnt antagonists, frizzled-related proteins (FRP)-1 and -3, are also expressed by vascular cells. Stabilization of the downstream signaling component beta-catenin in blood vessels has been demonstrated in several developmental and pathologic states, further supporting the idea that Wnt signaling plays an important regulatory role in the vasculature.