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Background: Mood swings have been observed in patients with intracranial aneurysm (IA), but it is still unknown whether mood swings can affect IA. Aim: To explore the causal association between mood swings or experiencing mood swings and IA through a two‐sample Mendelian randomization (MR) study. Methods: Summary‐level statistics of mood swings, experiencing mood swings, IA, aneurysm‐associated subarachnoid hemorrhage (aSAH), and non‐ruptured IA (uIA) were collected from the genome‐wide association study. Two‐sample MR and various sensitivity analyses were employed to explore the causal association between mood swings or experiencing mood swings and IA, or aSAH, or uIA. The inverse‐variance weighted method was used as the primary method. Results: Genetically determined mood swings (odds ratio [OR] = 5.23, 95% confidence interval (95%CI): 1.65–16.64, p =.005) and experiencing mood swings (OR = 2.50, 95%CI: 1.37–4.57, p =.003) were causally associated with an increased risk of IA. Mood swings (OR = 5.67, 95%CI: 1.40–23.04, p =.015) and experiencing mood swings were causally associated with the risk of aSAH (OR = 2.91, 95%CI: 1.47–5.75, p =.002). Neither mood swings (OR = 1.95, 95%CI:.31–12.29, p =.478) nor experiencing mood swings (OR = 1.20, 95%CI:.48–3.03, p =.693) were associated with uIA. Conclusions: Mood swings and experiencing mood swings increased the risk of IA and aSAH incidence. These results suggest that alleviating mood swings may reduce IA rupture incidence and aSAH incidence. [ABSTRACT FROM AUTHOR]

Aim This study was designed to determine the risk factors of lymph node metastasis in non-small cell lung cancer (NSCLC) patients with tumors ≤ 2 cm, using the Shanghai Chest Hospital Lung Cancer Database. Methods Five hundred and eighteen patients with NSCLC ≤ 2 cm were included in this study, and were classified into lymph node-positive and lymph node-negative groups. Univariate and multivariate logistic regression analyses were performed to select the independent risk factors for lymph node metastasis in NSCLC patients. Results No evidence of metastasis was found in tumors ≤ 1 cm, all positive results were in tumors sized 1-2 cm. Imaging characteristics, including solid and part-solid nodules, were strongly associated with lymph node metastasis (odds ratio [ OR] 24.959, 95% confidence interval [ CI] 5.999-103.835, P < 0.001; OR 12.559, 95% CI 3.564-44.259, P < 0.001) and subgroup logistic analysis ( OR 21.384, 95% CI 5.058-90.407, P < 0.001; OR 11.632, 95% CI 3.290-41.126, P < 0.001). Greater lymph node metastasis was observed in non-adeno non-squamous carcinoma. The presence of pleural invasion and carcinoembryonic antigen levels indicated lymph node dissection. Similar results were revealed in subgroup analysis in tumors ≤ 2 to > 1 cm. Conclusion Size had a great impact on lymph node metastasis, especially tumors of 1-2 cm. Preoperative imaging, non-adeno non-squamous carcinoma, pleural invasion, and carcinoembryonic antigen all indicated lymph node dissection. There was no discrepancy between N1 and N2 positive lymph nodes. [ABSTRACT FROM AUTHOR]

The epidermal growth factor receptor 2 (HER2) has been established as an important target of HER2-positive lung cancer, but somatic mutations in HER2 kinase domain are frequently observed that may cause drug resistance and sensitivity for tyrosine kinase inhibitors (TKIs). In this study, the response profile of 14 small-molecule TKIs upon 11 clinical HER2 mutations was investigated systematically using a synthetic strategy that integrated in silico analysis and in vitro assay to explore the structural basis, energetic property and biological implication underlying the intermolecular interactions of TKIs with wild-type and variant HER2. It is found that most clinical mutations are far away from HER2 active site and thus can only address modest or moderate effect on inhibitor binding. However, few single-point substations such as D769H and D769Y as well as the gatekeeper mutation T798 M were predicted to cause strong resistance for an array of TKIs by reshaping the geometric feature and physiochemical property of the active site. Furthermore, inhibitor response to the most common insertion mutation in HER2 exion 20 (HER2YVMA) was examined in detail; the response can be grouped into three classes: sensitization, resistance and insusceptibility. The Bcr-Abl inhibitor bosutinib and EGFR inhibitor gefitinib were selected as the representatives of, respectively, sensitization and insusceptibility to perform kinase assay against the GST-tagged, recombinant kinase domains of wild-type HER2WT and HER2YVMA variant. As expected, the biological activity of bosutinib was improved by ∼160-fold due to the insertion, while gefitinib exhibited low inhibitory potency on both HER2WT and HER2YVMA (IC50>100 μM). Structural analysis revealed an intensive network of hydrogen bonds and hydrophobic interactions in HER2YVMAbosutinib complex, whereas only few nonspecific van der Waals contacts were observed at the complex interface of HER2YVMA with gefitinib. [ABSTRACT FROM AUTHOR]

Summary Although oxidative stress is a key aspect of innate immunity, little is known about how host-restricted pathogens successfully repair DNA damage. Base excision repair is responsible for correcting nucleobases damaged by oxidative stress, and is essential for bloodstream infection caused by the human pathogen, Neisseria meningitidis. We have characterized meningococcal base excision repair enzymes involved in the recognition and removal of damaged nucleobases, and incision of the DNA backbone. We demonstrate that the bi-functional glycosylase/lyases Nth and MutM share several overlapping activities and functional redundancy. However, MutM and other members of the GO system, which deal with 8-oxoG, a common lesion of oxidative damage, are not required for survival of N. meningitidis under oxidative stress. Instead, the mismatch repair pathway provides back-up for the GO system, while the lyase activity of Nth can substitute for the meningococcal AP endonuclease, NApe. Our genetic and biochemical evidence shows that DNA repair is achieved through a robust network of enzymes that provides a flexible system of DNA repair. This network is likely to reflect successful adaptation to the human nasopharynx, and might provide a paradigm for DNA repair in other prokaryotes. [ABSTRACT FROM AUTHOR]