Tuberous sclerosis complex (TSC) is a rare disease caused by mutations in TSC1 and TSC2, resulting in activation of mechanistic target of rapamycin complex 1 (mTORC1). Neurological manifestations in TSC patients include epilepsy, autism and intellectual disability. Two types of brain lesions, cortical tubers and subependymal giant cell astrocytomas (SEGAs), cause the majority of neurological manifestations in TSC. We have limited understanding of the molecular changes that occur in tubers and SEGAs and how these contribute to disease pathogenesis. To investigate this, we performed proteomic and phosphoproteomic analysis of TSC patient tuber and SEGA tissue. Tubers showed evidence of alterations in mitochondrial respiration, cytoskeleton organisation and neuronal function. However, we were unable to detect mTORC1 activation in tubers, likely due to the small number of cells with complete inactivation of TSC1 or TSC2. By contrast, SEGAs showed evidence of strong mTORC1 activation and large-scale changes in the proteome and phosphoproteome. SEGAs exhibited increased expression of ribosomal proteins and activation of a neuroinflammatory response. Phosphoproteomics identified 6060 phosphosites within 2154 proteins increased in SEGAs. Phosphorylation of multiple proteins involved in RNA-metabolism, including mRNA splicing, was increased in SEGAs. Consistent with this, we found evidence of extensive alterations in mRNA transcript splicing in SEGA tissue that is shared with a wide range of cancers. These data greatly expand the repertoire of known mTORC1 target proteins in the human brain and reveal that large-scale mis-regulation of mRNA splicing may promote the formation of SEGAs in TSC.
Perinatal mental health conditions (PMHCs) are common, impactful, and frequently left untreated, affecting roughly one in five individuals during pregnancy and the first year postpartum. Despite their far-reaching consequences for parents, infants, and broader social outcomes, nearly 75
Addressing developmental-contextual understandings of Latino/a adolescents' language brokering, we estimated language brokering changes from early to middle adolescence and their variation by neighborhood ethnic-racial compositional characteristics (e.g., % Latino/a residents). Data were collected among 485 Latino/a adolescents (Wave 1: Mage = 13.33 years; 57% girls; 88.7% U.S.-born) from immigrant families in suburban Atlanta, Georgia. Two-level growth models across 10 timepoints (6-month intervals) showed that, on average, language brokering remained stable for everyday and school situations but increased for official situations. Adolescents living in neighborhoods with stronger Latino/a presence and lower out-group exposure, however, showed higher language brokering during early adolescence and increases in everyday and official brokering over time. Findings underscore the context-dependent nature of language brokering development, suggesting gaps in dual-language infrastructure for some families in emerging immigrant areas.
Due to its heterogeneous morphology and its rarity, anaplastic lymphoma kinase gene-rearranged renal cell carcinoma (ALK RCC) is a diagnostically challenging entity, often leading to labelling these tumors as RCC, not otherwise classified. This may have clinical and managerial implications, given that patients with ALK oncogene rearrangement may benefit from ALK-inhibitors. Therefore, we attempted to elucidate the clinicopathologic and immunophenotypical characteristics of ALK RCC in a large international cohort. Sixteen multi-institutional tumors were included in the study. Clinical, macroscopic, microscopic, immunohistochemical (IHC), molecular (DNA and RNA sequencing, FISH) and follow-up data were evaluated. There were 9 male and 7 female patients with tumor size ranging from 2 to 12.2 cm (mean=7.1 cm). All tumors had solid, tan-white with focal cystic changes and gelatinous appearance. Cystic changes and necrosis were seen in 7 and 6 tumors, respectively. Microscopically, a heterogeneous growth pattern was observed including solid (12), tubular (7), papillary (5), tubulocystic (2), pleomorphic epithelioid cells (6), sarcomatoid (2), rhabdoid (4), and intranuclear pseudoinclusions. All tumors were ALK-positive, coexpressing PAX8, KRT7, SDH, FH, and variably CD10, Vimentin, and AMACR. Molecular analysis through next-generation sequencing (NGS) was performed on 14/16 tumors. EML4::ALK (n=5) was the most common gene fusion observed; others included TPM1::ALK(n=4), TPM3::ALK(n=2), SLIT1::ALK(n=2)and VCL::ALK(n=1). Despite focal TFE3 immunoreactivity in 4/13 cases, the absence of TFE3 gene rearrangement by molecular analysis excludes TFE3- rearranged RCC as a differential diagnosis. Our study further expands the clinicopathologic, morphologic, and molecular genetic spectrum of ALK-RCC. ALK-RCC can be morphologically heterogeneous and mimic other well-established entities posing a misdiagnosis if appropriate IHC and/or molecular studies are not performed. Accurate diagnosis is of clinical significance as patients with this neoplasm may potentially benefit from ALK-inhibitors, particularly in a metastatic setting. As TFE3 immunoreactivity is not uncommon in ALK-RCC, documentation of ALK gene rearrangement is critical, either by surrogate IHC staining or cytogenetic/molecular analysis is essential.
Delayed bleeding following endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) remains a recognized adverse event. Despite observational studies suggesting lower delayed bleeding rates with the use of self-assembling peptide (SAP), randomized data have yielded inconsistent results, precluding routine prophylactic application. We aimed to evaluate the effectiveness of SAP in preventing delayed bleeding after ESD and EMR. We systematically searched PubMed, Embase, and the Cochrane Library through October 2025 for prospective or retrospective cohorts reporting delayed bleeding following ESD or EMR in direct association with adjunctive SAP application, with or without a comparator group. Random-effects meta-analyses estimated pooled delayed bleeding rates and, where applicable, risk ratios (RR), with prespecified subgroup analyses by resection technique. Eleven studies comprising 928 patients were included. Comparative analyses (five studies), SAP in conjunction with standard therapy was not associated with a reduction in delayed bleeding compared with standard care (RR 1.34, 95
