Tolerability and Safety of a Nutritional Supplement with Potential as Adjuvant in Colorectal Cancer Therapy: A Randomized Trial in Healthy Volunteers.

Bioactive supplements display relevant therapeutic properties when properly applied according to validated molecular effects. Our previous research efforts established the basis to develop a dietary supplement based on a Rosmarinus officinalis supercritical extract. This was enriched in phenolic diterpenes (RE) with proven properties against signaling pathways involved in colon tumorigenesis, and shark liver oil rich in alkylglycerols (AKG) as a bioactive lipid vehicle to improve RE bioavailability and synergize with the potential therapeutic action of the extract. Herein, we have investigated the tolerability and safety of the supplement and the biological and molecular effects from an immuno-nutritional perspective. Sixty healthy volunteers participated in a six week, double-blind, randomized parallel pilot study with two study arms: RE-AKG capsules (CR) and control capsules (CC). Mean age (±SD) of volunteers was 28.32 (±11.39) and 27.5 (±9.04) for the control and the study groups, respectively. Safety of the CR product consumption was confirmed by analyzing liver profile, vital constants, and oxidation markers (LDLox in blood and isoprostanes and thromboxanes in urine). The following were monitored: (1) the phenotyping of plasmatic leukocytes and the ex vivo response of lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs); (2) expression of genes associated with immune-modulation, inflammation, oxidative stress, lipid metabolism, and tumorigenesis; and (3) the correlation of selected genetic variants (SNPs) with the differential responses among individuals. The lack of adverse effects on liver profile and oxidation markers, together with adequate tolerability and safe immunological adaptations, provide high-quality information for the potential use of CR as co-adjuvant of therapeutic strategies against colorectal cancer.

A significant response to sorafenib in a woman with advanced lung adenocarcinoma and a BRAF non-V600 mutation.

Lung adenocarcinoma includes recurrent activating oncogenic mutations (EGFR, EML4-ALK, ROS1) that have been associated with response to EGFR and ALK inhibitors. Platinum-based chemotherapy is the standard therapy for non-oncodrivers population. Sorafenib is a small molecule that blocks the activation of C-RAF, B-RAF, c-KIT, FLT-3, RET, VEGFR-2, VEGFR-3 and PDGFR approved for advanced renal cell and hepatocellular carcinoma (b, c). Many studies have evaluated sorafenib in advanced non-small-cell lung cancer (NSCLC), with different results. We present a case report of a patient with NSCLC and the BRAF G469R mutation who showed a dramatic response to sorafenib.

Upregulation of trefoil factor 3 (TFF3) after rectal cancer chemoradiotherapy is an adverse prognostic factor and a potential therapeutic target.

PURPOSE: Management of locally advanced rectal cancer (RC) consists of neoadjuvant chemoradiotherapy (CRT) with fluoropyrimidines, followed by total mesorectal excision. We sought to evaluate the expression of selected genes, some of which were derived from a previous undirected SAGE (serial analysis of gene expression)-based approach, before and after CRT, to identify mechanisms of resistance. METHODS: This retrospective cohort study included 129 consecutive patients. Quantitative polymerase chain reaction of 53 candidate genes was performed on the biopsy specimen before treatment and on the surgical specimen after CRT. A paired-samples t test was performed to determine genes that were significantly changed after CRT. The result was correlated with patients' disease-free survival. RESULTS: Twenty-two genes were significantly upregulated, and two were significantly downregulated. Several of the upregulated genes have roles in cell cycle control; these include CCNB1IP1, RCC1, EEF2, CDKN1, TFF3, and BCL2. The upregulation of TFF3 was associated with worse disease-free survival on multivariate analyses (hazard ratio, 2.64; P=.027). Patients whose surgical specimens immunohistochemically showed secretion of TFF3 into the lumen of the tumoral microglands had a higher risk of relapse (hazard ratio, 2.51; P=.014). In vitro experiments showed that DLD-1 cells stably transfected with TFF3 were significantly less sensitive to 5-fluorouracil and showed upregulation of genes involved in the transcriptional machinery and in resistance to apoptosis. CONCLUSION: Upregulation of TFF3 after CRT for RC is associated with a higher risk of relapse. The physiological role of TFF3 in restoring the mucosa during CRT could be interfering with treatment efficacy. Our results could reveal not only a novel RC prognostic marker but also a therapeutic target.

Effect of a high dose of glucosamine on systemic and tissue inflammation in an experimental model of atherosclerosis aggravated by chronic arthritis.

Glucosamine sulfate (GS) is a glycosaminoglycan with anti-inflammatory and immunoregulatory properties. Here we set out to explore the effect of GS administration on markers of systemic and local inflammation in rabbits with atherosclerosis aggravated by chronic arthritis. Atherosclerosis was induced in rabbits by maintaining them on a hyperlipidemic diet after producing an endothelial lesion in the femoral arteries. Simultaneously, chronic arthritis was induced in these animals by repeated intra-articular injections of ovalbumin in previously immunized rabbits. A group of these rabbits was treated prophylactically with oral GS (500 mg.kg(-1).day(-1)), and, when the animals were killed, serum was extracted and peripheral blood mononuclear cells (PBMC) were isolated. Furthermore, the femoral arteries, thoracic aorta, and synovial membranes were examined in gene expression studies and histologically. GS administration reduced circulating levels of the C-reactive protein and of interleukin-6. GS also lowered nuclear factor-kappaB activation in PBMC, and it downregulated the expression of both the CCL2 (monocyte chemoattractant protein) and cyclooxygenase-2 genes in these cells. Lesions at the femoral wall were milder after GS treatment, as reflected by the intimal-to-media thickened ratio and the absence of aortic lesions. Indeed, GS also attenuated the histological lesions in synovial tissue. In a combined rabbit model of chronic arthritis and atherosclerosis, orally administered GS reduced the markers of inflammation in peripheral blood, as well as the femoral and synovial membrane lesions. GS also prevented the development of inflammation-associated aortic lesions. These results suggest an atheroprotective effect of GS.