The gene-reduction effect of chromosomal losses detected in gastric cancers

<p>Abstract</p> <p>Background</p> <p>The level of loss of heterozygosity (LOH) that reduces a gene dose and exerts a cell-adverse effect is known to be a parameter for the genetic staging of gastric cancers. This study investigated if the cell-adverse effect induced with the gene reduction was a rate-limiting factor for the LOH events in two distinct histologic types of gastric cancers, the diffuse- and intestinal-types.</p> <p>Methods</p> <p>The pathologic specimens obtained from 145 gastric cancer patients were examined for the level of LOH using 40 microsatellite markers on eight cancer-associated chromosomes (3p, 4p, 5q, 8p, 9p, 13q, 17p and 18q).</p> <p>Results</p> <p>Most of the cancer-associated chromosomes were found to belong to the gene-poor chromosomes and to contain a few stomach-specific genes that were highly expressed. A baseline-level LOH involving one or no chromosome was frequent in diffuse-type gastric cancers. The chromosome 17 containing a relatively high density of genes was commonly lost in intestinal-type cancers but not in diffuse-type cancers. A high-level LOH involving four or more chromosomes tended to be frequent in the gastric cancers with intestinal and mixed differentiation. Disease relapse was common for gastric cancers with high-level LOH through both the hematogenous (38%) and non-hematogenous (36%) routes, and for the baseline-level LOH cases through the non-hematogenous route (67%).</p> <p>Conclusions</p> <p>The cell-adverse effect of gene reduction is more tolerated in intestinal-type gastric cancers than in diffuse-type cancers, and the loss of high-dose genes is associated with hematogenous metastasis.</p

Improved survival of gastric cancer with tumour Epstein–Barr virus positivity: an international pooled analysis

About 9% of gastric carcinomas have Epstein–Barr virus (EBV) in the tumour cells, but it is unclear whether viral presence influences clinical progression. We therefore examined a large multicentre case series for the association of tumour EBV status with survival after gastric cancer diagnosis, accounting for surgical stage and other prognostic factors

Mucin expression in gastric- and gastro-oesophageal signet-ring cell cancer: results from a comprehensive literature review and a large cohort study of Caucasian and Asian gastric cancer

Background: The literature on the prognostic relevance of signet-ring cell (SRC) histology in gastric cancer (GC) is controversial which is most likely related to inconsistent SRC classification based on haematoxylin–eosin staining. We hypothesised that mucin stains can consistently identify SRC-GC and predict GC patient outcome. Methods: We performed a comprehensive literature review on mucin stains in SRC-GC and characterised the mucin expression in 851 Caucasian GC and 410 Asian GC using Alcian Blue (AB)-Periodic Acid-Schiff (PAS), MUC2 (intestinal-type mucin), and MUC5AC (gastric-type mucin). The relationship between mucin expression and histological phenotype [poorly cohesive (PC) including proportion of SRCs, non-poorly cohesive (non-PC), or mucinous (MC)], clinicopathological variables, and patient outcome was analysed. Results: Depending on mucin expression and cut-offs, the positivity rates of SRC-GC reported in the literature varied from 6 to 100%. Patients with MUC2 positive SRC-GC or SRC-GC with (gastro)intestinal phenotype had poorest outcome. In our cohort study, PC with ≥ 10% SRCs expressed more frequently MUC2, MUC5AC, and ABPAS (p < 0.001, p = 0.004 and p < 0.001, respectively). Caucasians with AB positive GC or combined ABPAS-MUC2 positive and MUC5AC negative had poorest outcome (all p = 0.002). This association was not seen in Asian patients. Conclusions: This is the first study to suggest that mucin stains do not help to differentiate between SRC-GC and non-SRC-GC. However, mucin stains appear to be able to identify GC patients with different outcome. To our surprise, the relationship between outcome and mucin expression seems to differ between Caucasian and Asian GC patients which warrants further investigations

Integration of a Multi-Camera Vision System and Admittance Control for Robotic Industrial Depalletizing

This work addresses the task of robot depalletizing by means of a mobile manipulator, taking into account the problem of localizing the boxes to be removed from the pallet and a manipulation strategy that allows to pull the boxes without lifting them with the robot arm. The depalletizing task is of particular interest in the industrial scenario in order to increase efficiency, flexibility and economic affordability of automatic warehouses.The proposed solution makes use of a multi-sensor vision system and a force-controlled collaborative robot in order to detect the boxes on the pallet and to control the robot interaction with the boxes to be removed. The vision system comprises a fixed 3D Time-of-flight camera and an eye-in-hand 2D camera. Preliminary experimental results performed on a laboratory setup with a fixed-based robotic manipulator are reported to show the effectiveness of the perception and control system

Integration of a Multi-Camera Vision System and Admittance Control for Robotic Industrial Depalletizing

This work addresses the task of robot depalletizing by means of a mobile manipulator, taking into account the problem of localizing the boxes to be removed from the pallet and a manipulation strategy that allows to pull the boxes without lifting them with the robot arm. The depalletizing task is of particular interest in the industrial scenario in order to increase efficiency, flexibility and economic affordability of automatic warehouses.The proposed solution makes use of a multi-sensor vision system and a force-controlled collaborative robot in order to detect the boxes on the pallet and to control the robot interaction with the boxes to be removed. The vision system comprises a fixed 3D Time-of-flight camera and an eye-in-hand 2D camera. Preliminary experimental results performed on a laboratory setup with a fixed-based robotic manipulator are reported to show the effectiveness of the perception and control system

NEMO specifically recognizes K63-linked poly-ubiquitin chains through a new bipartite ubiquitin-binding domain

An important property of NEMO, the core element of the IKK complex involved in NF-κB activation, resides in its ability to specifically recognize poly-ubiquitin chains. A small domain called NOA/UBAN has been suggested to be responsible for this property. We recently demonstrated that the C-terminal Zinc Finger (ZF) of NEMO is also able to bind ubiquitin. We show here by ZF swapping and mutagenesis that this represents its only function. While neither NOA nor ZF shows any preference for K63-linked chains, we demonstrate that together they form a bipartite high-affinity K63-specific ubiquitin-binding domain. A similar domain can be found in two other proteins, Optineurin and ABIN2, and can be freely exchanged with that of NEMO without interfering with its activity. This suggests that the main function of the C-terminal half of NEMO is to specifically bind K63-linked poly-ubiquitin chains. We also demonstrate that the recently described binding of NEMO to linear poly-ubiquitin chains is dependent on the NOA alone and does not require the presence of the ZF

Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers

Gastric cancer (GC) is a deadly disease with limited treatment options. Recent studies with PD-1 inhibition have shown promising results in GC, but key questions remain regarding which GC subclass may respond best. In other cancers, expression of the PD-1 ligand PD-L1 has been shown to identify cancers with greater likelihood of response to PD-1 blockade. We here show with immunohistochemistry that Epstein-Barr Virus (EBV)+ GCs (n = 32) have robust PD-L1 expression not seen in other GCs. In EBV+ GC, we observed PD-L1 staining in tumor cells in 50% (16/32) and immune cells in 94% (30/32) of cases. Among EBV-negative GCs, PD-L1 expression within tumors cells was observed only in cases with microsatellite instability (MSI), although 35% of EBV-/MSS GCs possessed PD-L1 expression of inflammatory cells. Moreover, distinct classes of GC showed different patterns of PD-L1+ immune cell infiltrations. In both EBV+ and MSI tumors, PD-L1+ inflammatory cells were observed to infiltrate the tumor. By contrast, such cells remained at the tumor border of EBV-/MSS GCs. Consistent with these findings, we utilized gene expression profiling of GCs from The Cancer Genome Atlas study to demonstrate that an interferon-γ driven gene signature, an additional proposed marker of sensitivity to PD-1 therapy, were enriched in EBV+ and MSI GC. These data suggest that patients with EBV+ and MSI GC may have greater likelihood of response to PD-1 blockade and that EBV and MSI status should be evaluated as variables in clinical trials of these emerging inhibitors