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Background: Nowadays, the characteristics and treatment of combined small-cell lung carcinoma (CSCLC) remain controversial. This study aimed to analyze the features of clinical demographics, survival outcomes and treatment modalities among IV CSCLC, IV SCLC and IV NSCLC, to provide more evidence for the study of IV CSCLC. Methods: All CSCLC, SCLC and NSCLC patient data were obtained from the SEER database (2010–2020). Pearson's χ2 test was used to compare the differences in clinical characteristics. Propensity score matching (PSM) was utilized to balance the bias of the variables between patients. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify prognostic factors. KM analysis was used to calculate survival. Adjusted analyses for the primary outcome of different treatment modalities of IV CSCLC, IV SCLC and IV NSCLC were performed using Cox regression models. Results: A total of 493 patients with IV CSCLC, 35503 patients with SCLC, 122807 patients with IV NSCLC were included in this study. The demographic characteristics and tumor characteristics of the three groups were different. Before PSM, there were significant differences in OS and CSS among IV CSCLC, IV SCLC and IV NSCLC, After PSM, there was a significant difference in OS and CSS between the IV CSCLC and IV NSCLC. Risk/protective factors for OS and CSS were different in three groups. Chemotherapy, radiotherapy, and surgery can improve IV CSCLC's survival time. The combination of surgery and chemoradiotherapy treatment group for patients with IV CSCLC demonstrated best OS compared to control treatment groups, and the surgery combined chemotherapy treatment group exhibited the best CSS. Additionally, for select patients with stage IV CSCLC who have missed the window for surgical intervention at the time of initial diagnosis, chemoradiotherapy presents a viable and effective treatment option. Conclusions: The clinical characteristics IV CSCLC, IV SCLC and IV NSCLC were significantly different. The prognosis for IV CSCLC is notably poorer than IV NSCLC, similar to IV SCLC. Surgery combined therapy emerged as the preferred treatment modalities and chemoradiotherapy was a good choice for patients who have lost the indication of surgery for patients diagnosed with IV CSCLC. [ABSTRACT FROM AUTHOR]

Coxsackievirus B3 (CVB3) belongs to the genus Enterovirus of the family Picornaviridae and can cause acute acinar pancreatitis in adults. However, the molecular mechanisms of pathogenesis underlying CVB3-induced acute pancreatitis have remained unclear. In this study, we discovered that CVB3 capsid protein VP1 inhibited pancreatic cell proliferation and exerted strong cytopathic effects on HPAC cells. Through yeast two-hybrid, co-immunoprecipitation, and confocal microscopy, we show that Menage a trois 1 (MAT1), a subunit of the Cdk-Activating Kinase (CAK) complex involved in cell proliferation and transcription, is a novel interaction protein with CVB3 VP1. Moreover, CVB3 VP1 inhibited MAT1 accumulation and localization, thus interfering with its interaction with CDK7. Furthermore, CVB3 VP1 could suppress CAK complex enzymic phosphorylation activity towards RNA Pol II and CDK4/6, direct substrates of CAK. VP1 also suppresses phosphorylation of retinoblastoma protein (pRb), an indirect CAK substrate, especially at phospho-pRb Ser780 and phospho-pRb Ser807/811 residues, which are associated with cell proliferation. Finally, we present evidence using deletion mutants that the C-terminal domain (VP1-D8, 768-859aa) is the minimal VP1 region required for its interaction with MAT1, and furthermore, VP1-D8 alone was sufficient to arrest cells in G1/S phase as observed during CVB3 infection. Taken together, we demonstrate that CVB3 VP1 can inhibit CAK complex assembly and activity through direct interaction with MAT1, to block MAT1-mediated CAK-CDK4/6-Rb signaling, and ultimately suppress cell proliferation in pancreatic cells. These findings substantially extend our basic understanding of CVB3-mediated pancreatitis, providing strong candidates for strategic therapeutic targeting. Author summary: Coxsackievirus B3 (CVB3) is one of the pathogens causing acute acinar pancreatitis. We show that CVB3 VP1 could lead to inhibit cell proliferation and exert strong cytopathic effects on pancreatic cells. Our further studies indicate that VP1 through interacting with MAT1 disrupts the assembly and reduces the activity of Cdk-Activating Kinase (CAK) complex, which is involved in cellular proliferation and transcription. The interaction not only decreases the amount of MAT1, but interferes with MAT1 binding to CDK7. In addition, VP1 impairs the functions of a series of proteins associated with cellular proliferation, including RNA Pol II, CDK4/6, and retinoblastoma protein (pRb). The C-terminal domain of VP1 (VP1 D8, 768-859aa) is identified as the minimal VP1 region that can cause the same effect as the full length of VP1. Consequently, we propose that the interaction between CVB3 capsid protein VP1 and MAT1 induces apparently cytopathic effect, blocks MAT1-mediated CAK-CDK4/6-Rb signaling pathway, and thereby inhibits cell proliferation ultimately during CVB3 infection in pancreatic cells. It provides us a new insight for understanding CVB3-mediated pancreatitis and new candidates for therapeutic strategy. [ABSTRACT FROM AUTHOR]

Using a complete set of RING domains from Drosophila melanogaster, all the solved RING domains and cocrystal structures of RING-containing ubiquitin-ligases (RING-E3) and ubiquitin-conjugating enzyme (E2) pairs, we analyzed RING domains structures from their primary to quarternary structures. The results showed that: i) putative orthologs of RING domains between Drosophila melanogaster and the human largely occur (118/139, 84.9%); ii) of the 118 orthologous pairs from Drosophila melanogaster and the human, 117 pairs (117/118, 99.2%) were found to retain entirely uniform domain architectures, only Iap2/Diap2 experienced evolutionary expansion of domain architecture; iii) 4 evolutionary structurally conserved regions (SCRs) are responsible for homologous folding of RING domains at the superfamily level; iv) besides the conserved Cys/His chelating zinc ions, 6 equivalent residues (4 hydrophobic and 2 polar residues) in the SCRs possess good-consensus and conservation- these 4 SCRs function in the structural positioning of 6 equivalent residues as determinants for RING-E3 catalysis; v) members of these RING proteins located nucleus, multiple subcellular compartments, membrane protein and mitochondrion are respectively 42 (42/139, 30.2%), 71 (71/139, 51.1%), 22 (22/139, 15.8%) and 4 (4/139, 2.9%); vi) CG15104 (Topors) and CG1134 (Mul1) in C3HC4, and CG3929 (Deltex) in C3H2C3 seem to display broader E2s binding profiles than other RING-E3s; vii) analyzing intermolecular interfaces of E2/RING-E3 complexes indicate that residues directly interacting with E2s are all from the SCRs in RING domains. Of the 6 residues, 2 hydrophobic ones contribute to constructing the conserved hydrophobic core, while the 2 hydrophobic and 2 polar residues directly participate in E2/RING-E3 interactions. Based on sequence and structural data, SCRs, conserved equivalent residues and features of intermolecular interfaces were extracted, highlighting the presence of a nucleus for RING domain fold and formation of catalytic core in which related residues and regions exhibit preferential evolutionary conservation.