Ex vivo introduction of an immunomodulatory transgene into a face or hand allograft may improve the risk-to-benefit ratio of vascularized composite allografts. Abrogation of the immunogenicity of the ...skin component of a face or hand allograft may decrease alloreactivity and permit the induction of immunologic tolerance. Proof-of-principle demonstrations of transduction of composite tissue have been established using adenoviral vectors, producing transient gene expression. The authors hypothesized that transduction, integration, and long-term expression of transgenes in a vascularized composite allograft could be achieved using lentiviral vectors.
Ex vivo transduction of heterogeneous primary rat cell lines representative of a composite tissue flap's cellular architecture was performed using a luc-enhanced green fluorescent protein (eGFP) human immunodeficiency virus-1-based lentiviral vector. Ex vivo injections of rat superficial inferior epigastric artery flaps with the viral vector were performed intraarterially, intramuscularly, and intradermally.
Quantifiable reporter expression by flow cytometry (fluorescence-activated cell sorting) analysis and in vitro bioluminescence was observed. The luc-eGFP vector exhibited broad tropism and allowed transgene expression in relevant cell lines and throughout the flaps. Ex vivo intradermal transfection resulted in genomic integration and long-term constitutive gene expression (>150 days). Similarly, efficient intradermal transfection of face and hand flaps in a rat model corroborated this approach. Ex vivo intravascular perfusion of the vector proved inferior to intradermal injection.
Intradermal delivery of the transgenes proved superior to intravascular perfusion. Optimization of this gene-delivery approach may allow long-term, constitutive expression of immunomodulatory proteins in face and hand allografts. Future goals include replacement of the luciferase and eGFP reporter genes with key immunomodulatory proteins.
Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and ...treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.
Display omitted
•Generation of a foundational genomic resource in multiple system atrophy•GWAS identifies novel risk loci at GAB1, lnc-LRRC49-3, TENM2, and RABGEF1•Functional genomics implicates USP38-DT, KCTD7, and lnc-KCTD7-2 within these loci•Gene-burden analysis identifies nominal enrichment of rare missense mutations in KCTD7
Chia et al. comprehensively analyzed genome sequence data from patients with multiple system atrophy (MSA) and controls. The study identified four novel risk loci associated with MSA and prioritized significantly associated genes (USP38-DT, KCTD7, and lnc-KCTD7-2) within these loci. This initiative's data constitute a valuable resource for the research community.
To determine the incidence and the prognostic factors of objectively diagnosed deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with epithelial ovarian malignancy.
We reviewed the ...records of all patients with epithelial ovarian cancer who were diagnosed, treated, and followed-up at our institution between 1990 and 2001. Data were collected regarding age, body mass index, previous DVT and PE, menopause status, FIGO stage, grade, histology, type of surgery, residual disease, first line chemotherapy, and relapse status.
Of the 253 cases, the overall incidence of symptomatic venous thromboembolic events (VTE) was 16.6% (42 patients): 1.6% (4) with PE and 15% (38) with DVT. 8 events (3.2%) were detected before tumor diagnosis, 6 (2.4%) in the postoperative period, 16 (6.4%) during first line chemotherapy and 12 (4.8%) throughout the follow-up period. Risk factors associated with occurrence of VTE were: at diagnosis, history of deep vein thrombosis (
P = 0.001); during chemotherapy, older age (
P = 0.017), larger body mass index (
P = 0.019), FIGO stage 2c–4 (
P = 0.004), no surgery (
P = 0.003), and presence of residual tumor (
P = 0.026). None of the considered risk factors were found to be predictors of VTE postoperatively. The multivariate regression analysis found that residual tumor, age, and body mass index were independent prognostic factors.
The incidence of VTE throughout the entire history of ovarian malignancy is high. Prognostic factors could be used to establish prophylaxis protocols based on risk stratification.
The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of desmoplastic small round cell tumor, breast, and gastrointestinal stromal tumor specifically ...related to peritoneal surface malignancy. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.
Ultrashort pulsed laser ablation in vacuum of different targets was performed in order to investigate the possibility of producing nanoparticles with controlled size and shape. A systematic ...morphology characterization of deposited products was performed for nickel and silicon as a function of laser pulse intensity and wavelength, at a fixed pulse repetition rate. The nanoparticles were investigated by atomic force microscopy, and clear trends for their size and shape anisotropy were evidenced. The best conditions to obtain nanosized particles of oblate ellipsoidal shape, with the minor axis below 10
nm, were determined in the case of nickel targets. Our results show that ultrashort pulse laser deposition can be considered as an interesting technique for the tailoring of nanogranular films with the desired particles dimension and shape, according to the peculiar properties required in specific applications. Moreover, the preliminary features are very promising from the point of view of the production of magnetoresistive films with specific anisotropy.
Small fiber pathology has been demonstrated in Parkinson Disease (PD). To verify if it is among the early non-motor features of PD, unrelated to Levodopa therapy, we assessed function and morphology ...of cutaneous sensory and autonomic nerves in 32 consecutive drug-naive PD patients (M/F = 16/16; age 57.3 ± 11.1 years) and 64 age and sex matched controls. Fifty-micron-thick sections of skin samples from thigh, leg and fingertip were processed by indirect immunofluorescence techniques. Digital images were acquired using a non-laser confocal microscope. Density of intrapapillar myelinated endings (IME), Meissner’s corpuscles (MC) and epidermal nerve fibers (ENFs) was calculated. Sudomotor, pilomotor and vasomotor nerves were assessed semi-quantitatively. Further evaluation included sural nerve conduction study, sympathetic skin response, quantitative sensory testing and dynamic sweat test. Nerve conduction was normal in all patients. Morphological analysis showed: a significant loss ( p < 0.01) of ENF compared to controls in all sites, a significant loss ( p < 0.01) of MC and IME in glabrous skin, a reduction of autonomic nerves involving noradrenergic and cholinergic populations. Functional assessment revealed an increase of sensory thresholds ( p < 0.01) and a reduction of sweat output ( p < 0.01). Our findings demonstrated that cutaneous denervation underlying sensory and autonomic dysfunction is an early feature in PD unrelated to Levodopa treatment.
PDF
