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Background
We assessed the novel MACC1 gene to further stratify stage II colon cancer
patients with proficient mismatch repair (pMMR).
Patients and methods
Four cohorts with 596 patients were analyzed: Charité 1 discovery cohort
was assayed for MACC1 mRNA expression and MMR in cryo-preserved
tumors. Charité 2 comparison cohort was used to translate MACC1 qRT-
PCR analyses to FFPE samples. In the BIOGRID 1 training cohort MACC1
mRNA levels were related to MACC1 protein levels from
immunohistochemistry in FFPE sections; also analyzed for MMR.
Chemotherapy-naïve pMMR patients were stratified by MACC1 mRNA and
protein expression to establish risk groups based on recurrence-free
survival (RFS). Risk stratification from BIOGRID 1 was confirmed in the
BIOGRID 2 validation cohort. Pooled BIOGRID datasets produced a best
effect-size estimate.
Results
In BIOGRID 1, using qRT-PCR and immunohistochemistry for MACC1
detection, pMMR/MACC1-low patients had a lower recurrence probability
versus pMMR/MACC1-high patients (5-year RFS of 92% and 67% versus
100% and 68%, respectively). In BIOGRID 2, longer RFS was confirmed
for pMMR/MACC1-low versus pMMR/MACC1-high patients (5-year RFS of
100% versus 90%, respectively). In the pooled dataset, 6.5% of patients
were pMMR/MACC1-low with no disease recurrence, resulting in a 17%
higher 5-year RFS (95% CI (12.6-21.3%)) versus pMMR/MACC1-high
patients (P=0.037). Outcomes were similar for pMMR/MACC1-low and
deficient MMR (dMMR) patients (5-year RFS of 100% and 96%,
respectively).
Conclusions
MACC1 expression stratifies colon cancer patients with unfavorable pMMR
status. Stage II colon cancer patients with pMMR/MACC1-low tumors have
a similar favorable prognosis to those with dMMR with potential
implications for the role of adjuvant therapy.
The role of titanium surface nanotopography on preosteoblast morphology, adhesion and migration
(2017)
Surface structuring of titanium-based implants with appropriate nanotopographies can significantly modulate their impact on the biological behavior of cells populating these implants. Implant assisted bone tissue repair and regeneration require functional adhesion and expansion of bone progenitors. The surface nanotopography of implant materials used to support bone healing and its effect on cell behavior, in particular cell adhesion, spreading, expansion, and motility, is still not clearly understood. The aim of this study is to investigate preosteoblast proliferation, adhesion, morphology, and migration on different titanium materials with similar surface chemistry, but distinct nanotopographical features. Sonochemical treatment and anodic oxidation were employed to fabricate disordered – mesoporous titania (TMS), and ordered – titania nanotubular (TNT) topographies respectively. The morphological evaluation revealed a surface dependent shape, thickness, and spreading of cells owing to different adherence behavior. Cells were polygonal-shaped and well-spread on glass and TMS, but displayed an elongated fibroblast-like morphology on TNT surfaces. The cells on glass however, were much flatter than on nanostructured surfaces. Both nanostructured surfaces impaired cell adhesion, but TMS was more favorable for cell growth due to its support of cell attachment and spreading in contrast to TNT. Quantitative wound healing assay in combination with live-cell imaging revealed that cells seeded on TMS surfaces migrated in close proximity to neighboring cells and less directed when compared to the migratory behavior on other surfaces. The results indicate distinctly different cell adhesion and migration on ordered and disordered titania nanotopographies, providing important information that could be used in optimizing titanium-based scaffold design to foster bone tissue growth and repair.