Mortality prediction model from combined serial lactate, procalcitonin and calprotectin levels in critically ill patients with sepsis: A retrospective study according to Sepsis-3 definition.

OBJECTIVE: 1) To evaluate the ability of baseline and on 24 h serum calprotectin, in comparison to canonical biomarkers (lactate and procalcitonin), for prognosis of 28-day mortality in critically ill septic patients; and 2) To develop a predictive model combining the three biomarkers. DESIGN: A single-center, retrospective study. SETTING: Intensive Care Unit of a university hospital. PATIENTS OR PARTICIPANTS: One hundred and seventy three septic pacientes were included. INTERVENTIONS: Measurement of baseline lactate, procalcitonin and calprotectin level and procalcitonin and calprotectin levels on 24 h. MAIN VARIABLES OF INTEREST: Demographics and comorbidities, SOFA score on ICU admission, baseline lactate, procalcitonin and calprotectin on admission and on 24 h and 28-day mortality. RESULTS: 1) On ICU admission, lactate was the only biomarker achieving a significant accuracy (AUC: 0.698); 2) On 24 h, no differences were found on procalcitonin and calprotectin levels. Procalcitonin and calprotectin clearances were significantly lower in non-survivors and both achieved a moderate performance (AUCs: 0.668 and 0.664, respectively); 3) A biomarker based-model achieved a significant accuracy (AUC: 0.766), trending to increase (AUC: 0.829) to SOFA score alone; y 4) Baseline lactate levels and procalcitonin and calprotectin clearance were independent predictors for the outcome. CONCLUSIONS: 1) Baseline and on 24 h calprotectina and procalcitonin levels lacked ability in predicting 28-day mortality; 2) Accuracy of clearance of both biomarkers was moderate; and 3) Combination of SOFA score and the predictive biomarker based-model showed a high prognostic accuracy.

Monastrol suppresses invasion and metastasis in human colorectal cancer cells by targeting fascin independent of kinesin-Eg5 pathway.

Rearrangement of the actin cytoskeleton is a prerequisite for carcinoma cells to develop cellular protrusions, which are required for migration, invasion, and metastasis. Fascin is a key protein involved in actin bundling and is expressed in aggressive and invasive carcinomas. Additionally, fascin appears to be involved in tubulin-binding and microtubule rearrangement. Pharmacophoric-based in silico screening was performed to identify compounds with better fascin inhibitory properties than migrastatin, a gold-standard fascin inhibitor. We hypothesized that monastrol displays anti-migratory and anti-invasive properties via fascin blocking in colorectal cancer cell lines. Biophysical (thermofluor and ligand titration followed by fluorescence spectroscopy), biochemical (NMR), and cellular assays (MTT, invasion of human tissue), as well as animal model studies (zebrafish invasion) were performed to characterize the inhibitory effect of monastrol on fascin activity. In silico analysis revealed that monastrol is a potential fascin-binding compound. Biophysical and biochemical assays demonstrated that monastrol binds to fascin and interferes with its actin-bundling activity. Cell culture studies, including a 3D human myoma disc model, showed that monastrol inhibited fascin-driven cytoplasmic protrusions as well as invasion. In silico, confocal microscopy, and immunoprecipitation assays demonstrated that monastrol disrupted fascin-tubulin interactions. These anti-invasive effects were confirmed in vivo. In silico confocal microscopy and immunoprecipitation assays were carried out to test whether monastrol disrupted the fascin-tubulin interaction. This study reports, for the first time, the in vitro and in vivo anti-invasive properties of monastrol in colorectal tumor cells. The number and types of interactions suggest potential binding of monastrol across actin and tubulin sites on fascin, which could be valuable for the development of antitumor therapies.

Epithelial aPKC deficiency leads to stem cell loss preceding metaplasia in colorectal cancer initiation.

The early mechanisms of spontaneous tumor initiation that precede malignancy are largely unknown. We show that reduced aPKC levels correlate with stem cell loss and the induction of revival and metaplastic programs in serrated- and conventional-initiated premalignant lesions, which is perpetuated in colorectal cancers (CRCs). Acute inactivation of PKCλ/ι in vivo and in mouse organoids is sufficient to stimulate JNK in non-transformed intestinal epithelial cells (IECs), which promotes cell death and the rapid loss of the intestinal stem cells (ISCs), including those that are LGR5+. This is followed by the accumulation of revival stem cells (RSCs) at the bottom of the crypt and fetal-metaplastic cells (FMCs) at the top, creating two spatiotemporally distinct cell populations that depend on JNK-induced AP-1 and YAP. These cell lineage changes are maintained during cancer initiation and progression and determine the aggressive phenotype of human CRC, irrespective of their serrated or conventional origin.