Helicobacter pylori persistently colonizes the human stomach, with mixed roles in human health. The CagA protein, a key host-interaction factor, is translocated by a type IV secretion system into host epithelial cells, where its EPIYA tyrosine phosphorylation motifs (TPMs) are recognized by host cell kinases, leading to multiple host cell signaling cascades. The CagA TPMs have been described as type A, B, C or D, each with a specific conserved amino acid sequence surrounding EPIYA. Database searching revealed strong non-random distribution of the B-motifs (including EPIYA and EPIYT) in Western H. pylori isolates. In silico analysis of Western H. pylori CagA sequences provided evidence that the EPIYT B-TPMs are significantly less associated with gastric cancer than the EPIYA B-TPMs. By generating and using a phosphorylated CagA B-TPM-specific antibody, we demonstrated the phosphorylated state of the CagA B-TPM EPIYT during H. pylori co-culture with host cells. We also showed that within host cells, CagA interaction with phosphoinositol 3-kinase (PI3-kinase) was B-TPM tyrosine-phosphorylation-dependent, and the recombinant CagA with EPIYT B-TPM had higher affinity to PI3-kinase and enhanced induction of AKT than the isogenic CagA with EPIYA B-TPM. Structural modeling of the CagA B-TPM motif bound to PI3-kinase indicated that the threonine residue at the pY+1 position forms a side-chain hydrogen bond to N-417 of PI3-kinase, which cannot be formed by alanine. During co-culture with AGS cells, an H. pylori strain with a CagA EPIYT B-TPM had significantly attenuated induction of interleukin-8 and hummingbird phenotype, compared to the isogenic strain with B-TPM EPIYA. These results suggest that the A/T polymorphisms could regulate CagA activity through interfering with host signaling pathways related to carcinogenesis, thus influencing cancer risk.

Background: Lung cancers with air lucency are poorly understood, often recognized only after substantial progression.Methods: From a systematic review (PubMed and EMBASE, 2000-2022, terms related to cystic, cavitary, bulla, pseudocavitary, bubble-like, date 10-30-2022) 49 studies were selected using broad inclusion criteria (case series of ≥10 cases up to trials and reviews). There was no source of funding. Primary evidence relevant to clinical management issues was assembled. Because data was available only from heterogeneous retrospective case series, meta-analysis and formal risk-of-bias assessment was omitted. A framework was developed to guide clinical management based on the available data.Results: Demographic, smoking and histologic differences suggest that cystic, cavitary and bullous lung cancers with air lucency may be distinct entities; insufficient data leaves it unclear whether this also applies to pseudocavitary (solid) or bubble-like (ground glass) cancers. Annual observation of irregular thinwalled cysts is warranted; a surgical diagnosis (and resection) is justified once a solid component appears because subsequent progression is often rapid with markedly worse outcomes. Bubble-like ground glass lesions should be managed similarly. Cavitary lesions must be distinguished from infection or vasculitis, but generally require needle or surgical biopsy. Pseudocavitary lesions are less well studied; positron emission tomography may be useful in this setting to differentiate scar from malignancy. Further research is needed because these conclusions are based on interpretation of retrospective case series. Conclusions:The aggregate of available evidence suggests a framework for management of suspected lung cancers with air lucency. Greater awareness, earlier detection, and aggressive management once a solid component appears are needed. This review and framework should facilitate further research; questions include whether the suggested entities and proposed management are borne out and should involve clearly defined terms and outcomes related to progression and treatment. In summary, a conceptual understanding is emerging from interpretation of available data about a previously poorly understood topic; this should improve patient outcomes.

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