Atypical Spindle Cell Lipomatous Lesion Resected From Patient With History of CLL.

Atypical spindle cell lipomatous neoplasm, also known as well-differentiated spindle cell liposarcoma, represents a newly discovered entity of adipocytic tumors. Recent research has shown this tumor variant to be more related to spindle cell lipoma, rather than the originally hypothesized atypical lipomatous tumor spectrum. Here we present a case of a 58-year-old man with a history of chronic lymphocytic leukemia with an enlarging mass on the posterior left shoulder, initially hypothesized to be a benign lipoma. However, magnetic resonance imaging showed a large, multiseptated, heterogeneous mass concerning for soft tissue sarcoma. After resection, pathologic analysis showed cells closely resembling spindle cell lipoma, with additional cellular and fascicular zones containing lipoblasts and mitotic figures. Molecular analysis showed no MDM2 amplification. This lack of amplification indicates this tumor is distinctly different from an atypical lipomatous tumor, which characteristically displays MDM2 amplification. However, tumor expression of RB1 was normal. The majority of atypical spindle cell lipomatous neoplasms are associated with RB1 deletions. We conclude that we have a unique example of an atypical spindle cell lipomatous tumor.

Pur-alpha regulates cytoplasmic stress granule dynamics and ameliorates FUS toxicity.

Amyotrophic lateral sclerosis is characterized by progressive loss of motor neurons in the brain and spinal cord. Mutations in several genes, including FUS, TDP43, Matrin 3, hnRNPA2 and other RNA-binding proteins, have been linked to ALS pathology. Recently, Pur-alpha, a DNA/RNA-binding protein was found to bind to C9orf72 repeat expansions and could possibly play a role in the pathogenesis of ALS. When overexpressed, Pur-alpha mitigates toxicities associated with Fragile X tumor ataxia syndrome (FXTAS) and C9orf72 repeat expansion diseases in Drosophila and mammalian cell culture models. However, the function of Pur-alpha in regulating ALS pathogenesis has not been fully understood. We identified Pur-alpha as a novel component of cytoplasmic stress granules (SGs) in ALS patient cells carrying disease-causing mutations in FUS. When cells were challenged with stress, we observed that Pur-alpha co-localized with mutant FUS in ALS patient cells and became trapped in constitutive SGs. We also found that FUS physically interacted with Pur-alpha in mammalian neuronal cells. Interestingly, shRNA-mediated knock down of endogenous Pur-alpha significantly reduced formation of cytoplasmic stress granules in mammalian cells suggesting that Pur-alpha is essential for the formation of SGs. Furthermore, ectopic expression of Pur-alpha blocked cytoplasmic mislocalization of mutant FUS and strongly suppressed toxicity associated with mutant FUS expression in primary motor neurons. Our data emphasizes the importance of stress granules in ALS pathogenesis and identifies Pur-alpha as a novel regulator of SG dynamics.

Characteristics affecting survival after locally advanced colorectal cancer in Quebec.

BACKGROUND: We estimated the relations of sociodemographic, organizational, disease, and treatment variables with the risk of death from colorectal cancer (crc) in a Quebec population-based sample of patients with locally advanced crc (lacrc) who underwent tumour resection with curative intent. METHODS: Information from medical records and administrative databases was obtained for a random sample of 633 patients surgically treated for stages ii-iii rectal and stage iii colon cancer and declared to the Quebec cancer registry in 1998 and 2003. We measured personal, disease, and clinical management characteristics, relative survival, and through multivariate modelling, relative excess rate (rer) of death. RESULTS: The relative 5- and 10-year survivals in this cohort were 67.7% [95% confidence interval (ci): 65.8% to 69.6%] and 61.2% (95% ci: 58.3% to 64.0%) respectively. Stage T4, stage N2, and emergency rather than elective surgery affected 18%, 24% and 10% of patients respectively. Those disease progression characteristics each independently increased the rer of death by factors of 2 to almost 5. Grade, vascular invasion, and tumour location were also significantly associated with the rer for death. Receiving guideline-adherent treatment was associated with a 60% reduction in the rer for death (0.41; 95% ci: 0.28 to 0.61), an effect that was consistent across age groups. Clear margins (proximal-distal, radial) and clinical trial enrolment were each associated with a nonsignificant 50% reduction in the rer. Of patients less than 70 years of age and 70 years of age and older, 81.3% and 42.0% respectively received guideline-adherent treatment. CONCLUSIONS: This study is the first Quebec population-based examination of patients with lacrc and their management, outcomes, and outcome determinants. The results can help in planning crc control strategies at a population level.

The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson's models.

Neurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between impaired IGF-1/insulin-like signaling (IIS) and lifespan extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using data sets of established DAF-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-associated genetic modifiers of α-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson's disease. An outcome of this strategy was the identification of GPI-1/GPI, an enzyme in glucose metabolism, as a daf-2-regulated modifier that acts independent of the downstream cytoprotective transcription factor DAF-16/FOXO to modulate neuroprotection. Subsequent mechanistic analyses using Drosophila and mouse primary neuron cultures further validated the conserved nature of GPI neuroprotection from α-synuclein proteotoxicity. Collectively, these results support glucose metabolism as a conserved functional node at the intersection of proteostasis and neurodegeneration.

RNA-binding ability of FUS regulates neurodegeneration, cytoplasmic mislocalization and incorporation into stress granules associated with FUS carrying ALS-linked mutations.

Amyotrophic lateral sclerosis (ALS) is an uncommon neurodegenerative disease caused by degeneration of upper and lower motor neurons. Several genes, including SOD1, TDP-43, FUS, Ubiquilin 2, C9orf72 and Profilin 1, have been linked with the sporadic and familiar forms of ALS. FUS is a DNA/RNA-binding protein (RBP) that forms cytoplasmic inclusions in ALS and frontotemporal lobular degeneration (FTLD) patients' brains and spinal cords. However, it is unknown whether the RNA-binding ability of FUS is required for causing ALS pathogenesis. Here, we exploited a Drosophila model of ALS and neuronal cell lines to elucidate the role of the RNA-binding ability of FUS in regulating FUS-mediated toxicity, cytoplasmic mislocalization and incorporation into stress granules (SGs). To determine the role of the RNA-binding ability of FUS in ALS, we mutated FUS RNA-binding sites (F305L, F341L, F359L, F368L) and generated RNA-binding-incompetent FUS mutants with and without ALS-causing mutations (R518K or R521C). We found that mutating the aforementioned four phenylalanine (F) amino acids to leucines (L) (4F-L) eliminates FUS RNA binding. We observed that these RNA-binding mutations block neurodegenerative phenotypes seen in the fly brains, eyes and motor neurons compared with the expression of RNA-binding-competent FUS carrying ALS-causing mutations. Interestingly, RNA-binding-deficient FUS strongly localized to the nucleus of Drosophila motor neurons and mammalian neuronal cells, whereas FUS carrying ALS-linked mutations was distributed to the nucleus and cytoplasm. Importantly, we determined that incorporation of mutant FUS into the SG compartment is dependent on the RNA-binding ability of FUS. In summary, we demonstrate that the RNA-binding ability of FUS is essential for the neurodegenerative phenotype in vivo of mutant FUS (either through direct contact with RNA or through interactions with other RBPs).

The role of tumor necrosis factor signaling pathways in the response of murine brain to irradiation.

Late effects after radiotherapy for brain tumors can be severe and tend to limit the efficacy of this treatment modality. The mechanisms governing the development of late radiation-induced lesions in the brain are not clear, but they are preceded by cycles of molecular and cellular events including production of cytokines, one of which is tumor necrosis factor (TNF)-alpha. There is literature to support possible roles for TNF-alpha as a contributor to edema, gliosis, and demyelination in the brain, all of which are histopathologically associated with radiation-induced brain damage. We have examined the role of TNF-alpha signaling in the response to brain irradiation using TNFRp55- or TNFRp75-deficient and control mice. Mice lacking TNFRp75 exhibited increased early radiation-induced apoptosis in putative stem cell regions of the brain. At 1 month, they had decreased proliferative responses in the same regions, and by 3 months they were demonstrating dose-dependent seizures and other severe neurological abnormalities that were not seen in control or TNFRp55-/- mice. Seizure activity correlated with the onset of extensive demyelination, and by 6 months, levels of myelin basic protein in irradiated TNFRp75-/- mice were approximately 40% of those seen in the other two strains; the animals were moribund and had to be euthanized. These observations indicate that radiation-induced TNF-alpha, acting through TNFRp75, protects against the development of late complications of brain irradiation.

Draining tracts and nodules in dogs and cats.

Draining tracts and nodules in the dog and cat can present a diagnostic challenge to the veterinarian. A systematic approach and a complete list of differential diagnoses are needed to define the underlying disease, so that appropriate therapeutic management can be instituted and prognosis can be discussed with the owner. The purpose of this article is to review a complete list of differential diagnoses for draining tracts and nodules in the dog and cat, and discuss the appropriate diagnostic steps including cytology, biopsy and histopathology, culture and sensitivity, serology, and diagnostic imaging that are an important part of the work-up for draining tracts and nodules.

The possible role of contact current in cancer risk associated with residential magnetic fields.

Residential electrical wiring safety practices in the US result in the possibility of a small voltage (up to a few tenths of a volt) on appliance surfaces with respect to water pipes or other grounded surfaces. This "open circuit voltage" (V(OC)) will cause "contact current" to flow in a person who touches the appliance and completes an electrical circuit to ground. This paper presents data suggesting that contact current due to V(OC) is an exposure that may explain the reported associations of residential magnetic fields with childhood leukemia. Our analysis is based on a computer model of a 40 house (single-unit, detached dwelling) neighborhood with electrical service that is representative of US grounding practices. The analysis was motivated by recent research suggesting that the physical location of power lines in the backyard, in contrast to the street, may be relevant to a relationship of power lines with childhood leukemia. In the model, the highest magnetic field levels and V(OC)s were both associated with backyard lines, and the highest V(OC)s were also associated with long ground paths in the residence. Across the entire neighborhood, magnetic field exposure was highly correlated with V(OC) (r = 0.93). Dosimetric modeling indicates that, compared to a very high residential level of a uniform horizontal magnetic field (10 mu T) or a vertical electric field (100 V/m), a modest level of contact current (approximately 18 mu A) leads to considerably greater induced electric fields (> 1 mV/m) averaged across tissue, such as bone marrow and heart. The correlation of V(OC) with magnetic fields in the model, combined with the dose estimates, lead us to conclude that V(OC) is a potentially important exposure with respect to childhood leukemia risks associated with residential magnetic fields. These findings, nonetheless, may not apply to residential service used in several European countries or to the Scandinavian studies concerned with populations exposed to magnetic fields from overhead transmission lines.

Androstenediol antagonizes herpes simplex virus type 1-induced encephalitis through the augmentation of type I IFN production.

Dehydroepiandrosterone and androstenediol (AED) have previously been found to protect mice from viral-induced encephalitis resulting in an increased survival rate of the animals. These hormones have been shown to antagonize corticosteroids, which have immunosuppressive effects in vivo and in vitro, suggesting the antiviral effect of DHEA and AED may be linked to the anticorticosteroid action. The present study was undertaken to address the immune response to herpes simplex virus type 1 (HSV-1) during the acute ocular infection with and without AED treatment focusing on the early immune events in the eye and trigeminal ganglion. AED treatment was found to significantly improve the survival of HSV-1-infected mice in a dose-dependent fashion. While AED did not antagonize the elevated serum corticosterone levels following acute infection, AED enhanced the expression of IFN-alpha mRNA and decreased the expression of HSV-1-infected cell polypeptide 27 mRNA in the trigeminal ganglion during the acute (day 6 postinfection) infection of mice, as determined by reverse transcription-PCR. However, there was no change in the viral load from the eye or trigeminal ganglion when comparing the AED-treated with the vehicle-treated mice. Neutralization Abs to IFN-alpha, -beta, or -alpha/beta, but not control Ab, blocked the protective effect following AED exposure, confirming the involvement of type I IFN in the enhancement of survival in AED-treated mice. Collectively, these results identify innate immunity as a key component in augmenting the survival of HSV-1-infected mice following AED treatment.

Major limb replantation in children.

This retrospective study evaluated patients under 18 years of age who underwent major limb replantation between 1976 and 1989 at Louisville Hand Surgery. The age of the 15 patients followed for between 1 and 8.5 years (mean 4.2 years) ranged from 2 to 17 years (mean 9.8). Of amputations, 40% were guillotine, 40% were limited crush-avulsions, 7% were extended crushing, and eight were of an upper extremity and seven of a lower extremity. Average warm/total ischemia times were 4.8/14.8 hr in failures and 1.1/7.5 hours in successful replantation. Overall limb survival was 87%. Among the patients, 93% felt that their replanted limb functioned and looked better than a prosthesis; 87% of patients had a sensory recovery of more than S2+ in the lower extremity or S3 in the upper extremity; and 38% of upper extremity replantation patients had two-point discrimination of less than 15 mm.

Immunomodulation of experimental murine herpes simplex keratitis: I. UV-HSV protection.

A/J mice were immunized subcutaneously with ultraviolet light (UV) inactivated herpes simplex virus type-1, MP strain (HSV-MP). Control A/J mice were immunized subcutaneously either with media (unimmunized controls) or with live HSV-MP (immunized controls). Immunized and control mice were challenged ocularly with either MP or mP strain HSV-1 after corneal scarification and were followed for 3 weeks post corneal challenge. The mice were observed during this time period for signs of herpes simplex keratitis (HSK), lid lesions and encephalitis. At the time of sacrifice, the ipsilateral trigeminal ganglia were removed and assayed for latent HSV-1 using cocultivation on Vero cell monolayers. The results of these studies demonstrated that immunization with UV inactivated HSV (UV-HSV) gave the same protection against keratitis and encephalitis as immunization with live virus. Furthermore, the cocultivation assays indicated that immunization with either live HSV-1 or UV inactivated HSV-1 protected against the establishment of latency.