ObjectivePeritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC’s development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets.DesignWe performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs.ResultsWe identified distinct alterations in PC versus primary GACs, such as more frequent CDH1 and TAF1 mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C, higher level of ‘clock-like’ mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: ‘mesenchymal-like’ and ‘epithelial-like’ with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive ‘mesenchymal-like’ subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-β as potential therapeutic immune targets.ConclusionsWe have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.
Of 238 patients, 192 had attempted surgery after preoperative therapy. Of these, 13 patients (6.8%) had GPC and one had liver metastases, thus surgery was aborted. We followed 164 patients who had an R0 resection. The median follow-up duration was 3.4 (range, 0.6-18) years. The rate of PC was 13.4%, (22/164 patients) and the median time to PC was 15.6 months. Female gender was associated with PC on multivariate analysis. The 5-year OS rate for patients without subsequent PC was 75%. Conclusion Even with baseline -Cyt, ∼25% of patients develop PC following multimodality therapy. Patients who do not develop PC have an excellent OS rate. Further research is warranted to detect PC at baseline by the use of biomarkers.
Actinia tenebrosa Farqu, is viviparous and the juvenile anemones are ejected
from the gastrovascular cavity ready for immediate attachment to the first solid substrate
they contact. It is several days after the initial attachment before the juveniles have the
potential to move, and then it is at a rate approaching that of the adults. This may be
at least 2.5 cm/hr for 8 hr and often more. When these animals are in the preferred
zone in the intertidal region movement is much less.
The movement of Actinia may be resolved into three categories: firstly, movement
in the vertical plane, where prolonged submergence initiates negative geotaxis and
prolonged emergence initiates positive geotaxis; secondly, slight inherent activity which
continues even in the absence of environmental gradients; thirdly, directed lateral
movements in response to stimuli other than submergence, emergence, or gravity.
In the tidal tank, both adult and juvenile Actinia could be induced to form a
zone in the intertidal region which corresponded to that formed in the natural environment.
The distributions formed by adults and juveniles under identical conditions were
significantly different although the range of the distributions was very similar. The high
mortality of juveniles observed in the laboratory is attributed to the effects of dehydration
during emergence, and it is suggested that at this stage of development Actinia is very
susceptible to comparatively low relative humidities. The response of juvenile Actinia
to a humidity gradient is examined.
The zonation of Actinia tenebrosa is discussed with reference to coelenterate
behaviour patterns and to the zonation of intertidal molluscs.
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