Objective: Trinucleotide GGC repeat expansion in the 5’UTR of the NOTCH2NLC gene has been recognized as the pathogenesis of neuronal intranuclear inclusion disease (NIID). Previous studies have described that some NIID patients showed clinical and pathological similarities with multiple system atrophy (MSA). This study aimed to address the possibility that GGC repeat expansion in NOTCH2NLC might be associated with some cases diagnosed as MSA.Methods: A total of 189 patients with probable or possible MSA were recruited to screen for GGC repeat expansion in NOTCH2NLC by repeat‐primed PCR (RP‐PCR). In addition, long‐read sequencing (LRS) was performed for all patients with RP‐PCR‐positive expansion, five patients with RP‐PCR‐negative expansion, and five controls on the Nanopore platform. Skin biopsies were performed on two patients with GGC expansion.Results: Five of 189 patients (2.6%) were found to have GGC expansion in NOTCH2NLC. LRS results identified that the five patients had GGC expansion between 101 and 266, but five patients with RP‐PCR‐negative expansion and five controls had GGC expansion between 8 and 29. Besides the typical symptoms and signs of MSA, patients with GGC expansion might have longer disease duration, severe urinary retention, and prominent cognitive impairment. In the skin samples from the patients with GGC expansion, typical p62‐postive but alpha‐synuclein‐negative intranuclear inclusions were found in fibroblasts, adipocyte and ductal epithelial cells of sweat glands.Conclusion: Trinucleotide GGC repeat expansion in NOTCH2NLC could be observed in patients with clinically diagnosed MSA. Adult‐onset NIID should be considered as a differential diagnosis of MSA.

Endoscopic endonasal approach for craniopharyngioma (CP) resection provides a wide view and direct observation of hypothalamus and origin of tumor. Under endoscopy, 92 CPs were classified into 2 types: Peripheral and Central, according to its relation to pituitary stalk. Peripheral type was further divided into 3 subtypes: Hypothalamic stalk, Suprasellar stalk and Intrasellar stalk CP, according to the different origin site along hypothalamus-pituitary axis. Peripheral type arisen from the stalk but expanded and grown laterally in an exophytic pattern, accounting for 71.7% of all CPs, preservation rate of stalk was higher (76.0%). Central type grew within and along pituitary stalk and located strictly in the midline. The pituitary stalk was hardly preserved (only15.4%). Hypothalamic stalk CPs (n = 36, 54.6%) developed from the junction of hypothalamus and stalk, hypothalamus damage was found in all of this subtype after surgery. Suprasellar stalk CPs (n = 14, 21.2%) originated from the lower portion of stalk and displaced hypothalamus upward rather than infiltrated it. Intrasellar stalk CPs (n = 16, 24.2%) arose from the subdiaphragma portion of the stalk, with less hypothalamus damage. Recoginzing the origin of CP is helpful to understand its growth pattern and relation to hypothalamus, which is critical in planning the most appropriate surgical approach and degree of excision.

The proliferation of pulmonary artery smooth muscle cells (PASMCs) is an important cause of pulmonary vascular remodelling in hypoxia‐induced pulmonary hypertension (HPH). However, its underlying mechanism has not been well elucidated. Connexin 43 (Cx43) plays crucial roles in vascular smooth muscle cell proliferation in various cardiovascular diseases. Here, the male Sprague‐Dawley (SD) rats were exposed to hypoxia (10% O₂) for 21 days to induce rat HPH model. PASMCs were treated with CoCl₂ (200 µM) for 24 h to establish the HPH cell model. It was found that hypoxia up‐regulated the expression of Cx43 and phosphorylation of Cx43 at Ser 368 in rat pulmonary arteries and PASMCs, and stimulated the proliferation and migration of PASMCs. HIF‐1α inhibitor echinomycin attenuated the CoCl₂‐induced Cx43 expression and phosphorylation of Cx43 at Ser 368 in PASMCs. The interaction between HIF‐1α and Cx43 promotor was also identified using chromatin immunoprecipitation assay. Moreover, Cx43 specific blocker (^37,43Gap27) or knockdown of Cx43 efficiently alleviated the proliferation and migration of PASMCs under chemically induced hypoxia. Therefore, the results above suggest that HIF‐1α, as an upstream regulator, promotes the expression of Cx43, and the HIF‐1α/Cx43 axis regulates the proliferation and migration of PASMCs in HPH.

Pancreatic cancer (PC) is among the deadliest malignancies, with an extremely poor diagnosis and prognosis. Gemcitabine (GEM) remains the first-line drug for treating PC; however, only a small percentage of patients benefit from current immunotherapies or targeted therapies. Resistance to GEM is prevalent and affects long-term survival. We found that ubiquitin-protein ligase E3 module N-recognition 5 (UBR5) is a therapeutic target against GEM resistance. UBR5 was markedly upregulated in clinical GEM-resistant PC samples and GEM-resistant PC cells. UBR5 knockdown markedly increased GEM sensitivity in GEM-resistant PC cell lines. UBR5-mediated GEM resistance was accompanied by activation of epithelial-mesenchymal transition (EMT) and could be mitigated by inhibiting EMT. Further analysis revealed that UBR5 promoted GEM resistance in PC cells by enhancing O-GlcNAcylation-mediated EMT. In addition, UBR5 knockdown resulted in increased O-GlcNAase (OGA) levels, an essential negatively regulated enzyme in the O-GlcNAcylation process. We identified a negative association between OGA and UBR5 levels, which further supported the hypothesis that O-GlcNAcylation-mediated GEM resistance induced by UBR5 is OGA-dependent in PC cells. Mechanistic studies revealed that UBR5 acts as an E3 ubiquitin ligase of OGA and regulates O-GlcNAcylation by binding and modulating OGA, facilitating its degradation and ubiquitination. Additionally, high-throughput compound library screening using three-dimensional protein structure analysis and drug screening identified a Food and Drug Administration drug, Y-39983 dihydrochloride, as a potent GEM sensitiser and UBR5 inhibitor. The combination of Y-39983 dihydrochloride and GEM attenuated tumour growth in a mouse xenograft tumour model. Collectively, these data demonstrated that UBR5 plays a pivotal role in the sensitisation of PC to GEM and provides a potential therapeutic strategy to overcome GEM resistance.

Surgery for pituitary adenomas (PAs) with cavernous sinus (CS) invasion in Knosp grade 4 is a great challenge and whether to adopt a conservative or aggressive surgical strategy is controversial. The aim of this study is to provide the outcomes and complications of an aggressive resection strategy for Knosp grade 4 PAs with transsphenoidal endoscopic surgery. Outcomes and complications were retrospectively analyzed in 102 patients with Knosp grade 4 PAs. Among them, primary PAs were seen in 60 patients and recurrent PAs were seen in 42 cases. Gross total resection (GTR) of the entire tumor was achieved in 72 cases (70.6%), subtotal tumor resection (STR) in 18 cases (17.6%), and partial tumor resection (PTR) in 12 cases (11.8%). Additionally, GTR of the tumor within the CS was achieved in 82 patients (80.4%), STR in 17 patients (16.7%), and PTR in 3 patients (2.9%). Statistical analyses showed that both recurrent tumors and firm consistency tumors were adverse factors for complete resection (P<0.05). Patients with GTR of the entire tumor were more likely to have favorable endocrine and visual outcomes than those with incomplete resection (P<0.05). Overall, the most common surgical complication was new cranial nerve palsy (n=7, 6.8%). The incidence of internal carotid artery (ICA) injury and postoperative cerebrospinal fluid (CSF) leakage was 2.0% (n=2) and 5.9% (n=6), respectively. Six patients (5.9%) experienced tumor recurrence postoperatively. For experienced neuroendoscopists, an aggressive tumor resection strategy via transsphenoidal endoscopic surgery may be an effective and safe option for Knosp grade 4 PAs.