Analysis of TFEB function in Ksp-Cadherin16 CRE mouse lines to model a particular type of renal cell carcinoma

TFE-fusion renal cell carcinomas (TFE-fusion RCCs) are caused by chromosomal translocations that lead to the overexpression of the TFE3 and TFEB genes Kauffman et al, 2014). The mechanisms causing kidney tumour development starting from TFE3/TFEB gene overexpression, remain largely uncharacterized and effective targeted therapies are yet to be identified, hence the need to model these diseases in an experimental animal system (Kauffman et al, 2014). Here we show that kidney-specific TFEB overexpression, in both constitutive and inducible conditional transgenic mouse lines, resulted in a phenotype characterized by renal clear cells, multi-layered basement membranes, severe cystic pathology, and ultimately papillary carcinomas with hepatic metastases. These features closely recapitulate the phenotype observed in both TFEB- and TFE3-mediated human kidney tumors. Analysis of kidney samples from these mice revealed both transcriptional induction of genes belonging to the WNT pathway and enhanced WNT βcatenin signalling. The use of specific WNT signalling inhibitors normalized the proliferation rate of primary kidney cells derived from transgenic mice and significantly rescued the disease phenotype in the mouse model. These data shed new light on the mechanisms underlying TFE-fusion RCCs and suggest a possible therapeutic strategy based on the inhibition of the WNT pathway

Excessive dietary lipid intake provokes an acquired form of lysosomal lipid storage disease in the kidney

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Is 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography useful to discriminate metachronous lung cancer from metastasis in patients with oncological history?

BACKGROUND: Solitary pulmonary nodules detected during follow-up in patients with previous cancer history have a high probability of malignancy being either a metachronous lung cancer or a metastasis. This distinction represents a crucial issue in the perspective of "personalized medicine", implying different treatments and prognosis. Aim - to evaluate the role of 18F-Fluorodeoxyglucose (18F-FDG) Positron Emission Tomography/Computed Tomography (PET/CT) in distinguishing whether solitary pulmonary nodules are metachronous cancers or metastases and the relationship between the nodule's characteristics and their nature. METHODS: From a single-institution database, we retrospectively selected all patients with a previous cancer history who performed 18F-FDG PET/CT to evaluate pulmonary nodules detected during follow-up, ranging from 5mm to 40mm, and histologically diagnosed as malignant. RESULTS: Between September 2009 and August 2017, 127 patients (80 males; mean age=70.2\ub18.5years) with 127 malignant nodules were included: 103/127 (81%) metachronous cancers, 24/127 (19%) metastases. In both groups, PET/CT provided good and equivalent detection rate of malignancy (81% vs 83%). No differences between metachronous cancers and metastases were found in: patient's age (70.3\ub18.1years vs 69.5\ub19.7years), gender (males=63.1% vs 62.5%), interval between previous cancer diagnosis and nodules' detection (median time=4years vs 4.5years), location (right-lung=55% vs 54%; upper-lobes=64% vs 67%; central-site=31% vs 25%), size (median size=17mm vs 19.5mm), 18F-FDG standardized uptake value (median SUVmax=5.2 vs 5.9). CONCLUSIONS: In oncological patients, despite its high detection rate, 18F-FDG PET/CT, as well as any other clinico-anatomical features, cannot distinguish whether a malignant solitary pulmonary nodule is a metachronous lung cancer or a metastasis, supporting the need of histological differential diagnosis

Double-outlet left ventricle: single-center experience and literature review

Double-outlet left ventricle (DOLV) is an abnormal ventriculo-arterial connection characterized by origin of both great arteries, or more than 50% of each arterial root, from the morphological left ventricle. The aim of our paper is to describe the anatomic, echocardiographic, and multi-modality imaging characteristics of DOLV and associated malformations, and to assess its surgical outcomes. Methods: From 2011 to 2022, we retrospectively reviewed case records, intra-operatory reports and follow-up data of patients diagnosed with DOLV at Bambino Gesu Children’s Hospital. A systematic search was developed in MEDLINE, EMBASE and Web of Science databases, to identify original reports between January 1, 1975 and May 30, 2022, assessing the morphology and surgical outcomes of DOLV. Retrospective cohort studies, cross-sectional and case series were included in the analysis. Single case reports and reviews were excluded. Results: At our center, four cases of DOLV were identified. Patient 1 was diagnosed with (S,D,D) DOLV and hypoplastic right ventricle. The aorta overrode a large, doubly-committed VSD with absence of infundibular septum. A tenuous mitro-aortic discontinuity and a well-developed subpulmonary conus were present. Associated abnormalities included crossed pulmonary arteries and two adjacent, side-by-side coronary ostia, located in the anterior facing sinus, which gave origin to the left anterior descending (LAD) and the right coronary artery (RCA). Left circumflex artery (LCx) had a retro-aortic course and originated from the RCA. After pulmonary artery banding, Damus-Kaye-Stansel and Glenn intervention were proposed as first-stage of univentricular palliation. Patient 2 and 3 were diagnosed with (S,D,D) DOLV, subaortic VSD and pulmonary stenosis. Patient 2 underwent Rastelli operation and no anatomic detail were available. Patient 3 showed absence of the infundibular septum and mitro-pulmonary continuity, whereas subaortic conus was well developed. Anomalous origin of the LCx, originating from the posterior facing sinus with retro-aortic course was present. Rastelli procedure was performed to reconstruct right ventricular outflow tract. LCA and RCA were respectively caudal to subvalvular and supravalvular segments of the RV-to-PA conduit. After a 6-years follow-up, severe stenosis of the RV-to-PA conduit was present, nevertheless percutaneous conduit dilatation was contraindicated, due to coronary abnormality, and an aortic homograft was implanted Patient 4 was diagnosed with (S,D,L) DOLV with subaortic VSD and mitro-pulmonary fibrous continuity. A large subaortic conus was present. Reparation à l’etage ventriculaire was performed to reconstruct RVOT. Follow-up MRI at 8 years showed severe pulmonary artery regurgitation with mild RV dilatation (indexed volume 99mL/m2) and normal RV ejection fraction (54 %) Systematic review:Through our systematic research strategy we scrutinized 96 records for inclusion criteria (Figure 4). After systematic evaluation, a total of 9 reports fulfilled eligibility criteria and were included in our study. Morphological findings and surgical outcomes are summarized in Table 1. Among 191 cases of DOLV included, the most common subtypes of VSD were subaortic (128/191), subpulmonary (23/191) or doubly committed (14/191) (Figure 5). d-transposition of the aorta was present in 117/191 (61%) cases, whereas l-transposition was reported in 63/191 (32%) (Figure 6

TFEB regulates murine liver cell fate during development and regeneration.

It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes. However, the signaling pathways implicated in the differentiation of LPCs are still incompletely understood. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is known to be involved in osteoblast and myeloid differentiation, but its role in lineage commitment in the liver has not been investigated. Here we show that during development and upon regeneration TFEB drives the differentiation status of murine LPCs into the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation. Genetic interaction studies show that Sox9, a marker of precursor and biliary cells, is a direct transcriptional target of TFEB and a primary mediator of its effects on liver cell fate. In summary, our findings identify an unexplored pathway that controls liver cell lineage commitment and whose dysregulation may play a role in biliary cancer

Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation

: Batten disease, one of the most devastating types of neurodegenerative lysosomal storage disorders, is caused by mutations in CLN3. Here, we show that CLN3 is a vesicular trafficking hub connecting the Golgi and lysosome compartments. Proteomic analysis reveals that CLN3 interacts with several endo-lysosomal trafficking proteins, including the cation-independent mannose 6 phosphate receptor (CI-M6PR), which coordinates the targeting of lysosomal enzymes to lysosomes. CLN3 depletion results in mis-trafficking of CI-M6PR, mis-sorting of lysosomal enzymes, and defective autophagic lysosomal reformation. Conversely, CLN3 overexpression promotes the formation of multiple lysosomal tubules, which are autophagy and CI-M6PR-dependent, generating newly formed proto-lysosomes. Together, our findings reveal that CLN3 functions as a link between the M6P-dependent trafficking of lysosomal enzymes and lysosomal reformation pathway, explaining the global impairment of lysosomal function in Batten disease

Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth

The mechanistic target of rapamycin complex 1 (mTORC1) is recruited to the lysosome by Rag guanosine triphosphatases (GTPases) and regulates anabolic pathways in response to nutrients. We found that MiT/TFE transcription factors-master regulators of lysosomal and melanosomal biogenesis and autophagy-control mTORC1 lysosomal recruitment and activity by directly regulating the expression of RagD. In mice, this mechanism mediated adaptation to food availability after starvation and physical exercise and played an important role in cancer growth. Up-regulation of MiT/TFE genes in cells and tissues from patients and murine models of renal cell carcinoma, pancreatic ductal adenocarcinoma, and melanoma triggered RagD-mediated mTORC1 induction, resulting in cell hyperproliferation and cancer growth. Thus, this transcriptional regulatory mechanism enables cellular adaptation to nutrient availability and supports the energy-demanding metabolism of cancer cells

“I Didn\u27t Know I Could Turn Colors”: Health Problems and Health Care Experiences of Women Strangled by an Intimate Partner

Strangulation is a unique and particularly pernicious form of intimate partner violence. To increase the relatively little that is known about strangulation survivors, focus groups and interviews were conducted as part of a practice–research engagement with a domestic violence shelter. All of the participants had been strangled and, among them, almost all were strangled multiple times. The loss of consciousness was common. Participants associated “choking” with use of body parts and “strangling” with use of objects. Although some minimized the assault, most considered strangulation to be serious and reported a variety of medical conditions following the assault. Few sought medical care. Of those who did, few disclosed the assault, or were asked about strangulation, which commonly resulted in misdirected treatment. Implications for improving detection and treatment are discussed