Project description:Localized nodular pulmonary amyloidosis can form pulmonary nodules associated with cystic air spaces, but due to its rarity, it cannot be included in the differential diagnosis without appropriate knowledge. Among the differential diagnoses of nodules with cysts in the lungs is primary lung cancer, however, diagnosis based solely on imaging findings is challenging. A 59-year-old Japanese female was referred to our hospital for an abnormality noted on the chest radiograph of an annual health check. She had no history of smoking or medical issues. Chest computed tomography revealed a 1.2 cm pulmonary nodule with surrounding multilocular cystic air spaces in the superior lingular segment. We suspected it was a nodule of primary lung cancer arising in the pulmonary cyst and performed video-assisted thoracic surgery. As the intraoperative frozen examination after a wedge resection revealed fibrotic tissue without malignancy, we did not do any further resection. The histopathological examination of the permanent section revealed unstructured eosinophilic deposits positive for direct fast scarlet staining, which were consistent with amyloidosis. The surrounding pulmonary cysts contained the check valve made by amyloid deposition. Localized nodular pulmonary amyloidosis can give rise to pulmonary cysts and mimic primary lung cancer associated with cystic air spaces. It should be raised as a potential differential diagnosis for pulmonary nodules with cystic air space formation, particularly in patients without a smoking history.
Project description:Localized amyloidosis has not been documented in the epididymis; we report this phenomenon for the first time.The first aim of this work is to report three cases of localized epididymal amyloidosis. Two cases were clinically detected as epididymal nodules, and a third after reviewing 120 epididymides obtained with neighbouring pathological processes. Amyloid deposits showed Congo red positivity, with yellow-green birefringence, and immunohistochemical expression for light chains kappa and lambda, transthyretin, amyloid P and cytokeratin AE1 AE3. No immunoreactivity for amyloid A was seen. Amyloid deposit location was intraluminal, with partial or total loss of the epididymal epithelium and subsequent passage to the interstitium, forming large masses. No amyloid deposits were observed around blood vessels. A secondary objective was to explore in normal epididymis the amyloid tested in epididymal amyloidosis. In normal epididymides, expression of amyloid P and transthyretin was detected in the apical surface of epithelial cells. Amyloid P also showed strong expression in spermatozoa.We contribute the existence of localized epididymal amyloidosis, which presents a distinctive, initial intratubular location, where there is a unique proteome and where functional amyloids act during sperm maturation.
Project description:Transthyretin amyloidosis (ATTR) is a progressive and fatal disease caused by transthyretin (TTR) amyloid fibril accumulation in tissues, which disrupts organ function. As the TTR protein is primarily synthesized by the liver, liver transplantation can cure familial ATTR but is not an option for the predominant age-related wild-type ATTR. Approved treatment approaches include TTR stabilizers and an RNA-interference therapeutic, but these require regular re-administration. Gene editing could represent an effective one-time treatment. We evaluated adeno-associated virus (AAV) vector-delivered, gene-editing meganucleases to reduce TTR levels. We used engineered meganucleases targeting two different sites within the TTR gene. AAV vectors expressing TTR meganuclease transgenes were first tested in immunodeficient mice expressing the human TTR sequence delivered using an AAV vector and then against the endogenous TTR gene in rhesus macaques. Following a dose of 3 × 1013 genome copies per kilogram, we detected on-target editing efficiency of up to 45% insertions and deletions (indels) in the TTR genomic DNA locus and >80% indels in TTR RNA, with a concomitant decrease in serum TTR levels of >95% in macaques. The significant reduction in serum TTR levels following TTR gene editing indicates that this approach could be an effective treatment for ATTR.
Project description:To investigate the role of viral and host factors in HDV-related HCC we analyzed the serum, tissue specimens and laser microdissected hepatocytes obtained at the time of liver transplantation from five patients with HDV-HCC. Livers of seven patients with HDV-cirrhosis without HCC were also analyzed. We carried out an integrated clinicopathological analysis and gene expression profiling,
Project description:To investigate the role of viral and host factors in HDV-associated HCC we carried out an integrated clinicopathological and gene expression study of tissue specimens and laser microdissected hepatocytes obtained at the time of liver transplantation from livers with HDV-HCC, HDV-cirrhosis without HCC, HCV-HCC and HBV-HCC. References to GSM series of HDV and HBV livers, already deposited in GEO, are included in this series. Part of data of HCV livers are a re-analysis of GSE series GSE69715 and GSE78737, the re-analyzed GSM is indicated in the 'description' column and with a link at the bottom of the page.
Project description:Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal-dominant disorder associated with chronic skin itching and deposition of epidermal keratin filament-associated amyloid material in the dermis. FPLCA has been mapped to 5p13.1-q11.2, and by candidate gene analysis, we identified missense mutations in the OSMR gene, encoding oncostatin M-specific receptor beta (OSMRbeta), in three families. OSMRbeta is a component of the oncostatin M (OSM) type II receptor and the interleukin (IL)-31 receptor, and cultured FPLCA keratinocytes showed reduced activation of Jak/STAT, MAPK, and PI3K/Akt pathways after OSM or IL-31 cytokine stimulation. The pathogenic amino acid substitutions are located within the extracellular fibronectin type III-like (FNIII) domains, regions critical for receptor dimerization and function. OSM and IL-31 signaling have been implicated in keratinocyte cell proliferation, differentiation, apoptosis, and inflammation, but our OSMR data in individuals with FPLCA represent the first human germline mutations in this cytokine receptor complex and provide new insight into mechanisms of skin itching.
Project description:Expansion of viral variants associated with immune escape and impaired virion secretion in patients with HBV reactivation from resolved infection