Polyhydroxybutyrate-co-hydroxyvalerate (PHBV) with Phenolic Acids for Active Food Packaging.

PHBV films incorporating 3, 6 and 9% ferulic acid (FA) or p-coumaric acid (PCA) were obtained by melt blending and compression moulding. The films' microstructures and thermal behaviours were analysed as well as their mechanical, optical and barrier properties. The overall and specific migration of the materials in different food simulants was also characterised. FA was homogeneously mixed with the polymer, whereas PCA was mainly dispersed as fine particles in the PHBV matrices due to its higher melting point. These structural features promoted differences in the physical properties of the films depending on the compound concentration. As the concentration of both compounds rose, the barrier capacity of the films to oxygen, and to a lesser extent water vapour, was enhanced. While FA promoted the extensibility of the films, 9% PCA enhanced their brittleness. Both compounds affected the crystallisation pattern of the polymer, promoting smaller crystalline formations and a slight decrease in crystallinity. Although the overall migration of every film formulation was lower than the overall migration limit (OML), the release of active compounds was dependent on the food simulant; almost total release was noted in ethanol containing simulants but was more limited in aqueous systems. Therefore, these films could be used as food contact materials, contributing to extending the food's shelf life.

Upregulated Heat Shock Proteins After Hyperthermic Chemotherapy Point to Induced Cell Survival Mechanisms in Affected Tumor Cells From Peritoneal Carcinomatosis.

In patients with peritoneal carcinomatosis cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) represents a promising treatment strategy. Here, we studied the role of hyperthermic chemotherapy on heat shock protein (HSP) expression and induction of tumor cell death and survival. HSP27, HSP70, and HSP90 combined with effects on tumor cell proliferation and chemosensitivity were analyzed in human colon cancer. Hyperthermic chemotherapy resulted in significant HSP27/HSP70 and HSP90 gene/protein overexpression in analyzed HT-29/SW480/SW620 colon cancer cells and peritoneal metastases from patients displaying amplified expression of proliferation markers, proliferating cell nuclear antigen and antiapoptotic protein Bcl-xL. Moreover, functionally increased chemoresistance against 5-fluorouracil/mitomycin C and oxaliplatin after hyperthermic chemotherapy points to induced survival mechanisms in cancer cells. In conclusion, the results indicate that intracellular HSP-associated antiapoptotic and proliferative effects after hyperthermic chemotherapy negatively influence beneficial effects of hyperthermic chemotherapy-induced cell death. Therefore, blocking HSPs could be a promising strategy to further improve the rate of tumor cell death and outcome of patients undergoing HIPEC therapy.

Exclusive inhibition of PI3K/Akt/mTOR signaling is not sufficient to prevent PDGF-mediated effects on glycolysis and proliferation in colorectal cancer.

Platelet-derived growth factor (PDGF) and signaling via its receptors plays a crucial role in tumor cell proliferation and thus may represent an attractive target besides VEGF/EGFR-based antibody therapies. In this study we analyzed the influence of PDGF in colorectal cancer. PDGF was expressed intensively in early and even more intensively in late stage primary CRCs. Like VEGF, PDGF enhanced human colon cancer proliferation, and increased oxidative glycolytic activity, and activated HIF1α and c-Myc in vitro. PDGF activated the PI3K/Akt/mTOR pathway while leaving MAPK signaling untouched. Further dissection showed that inhibition of Akt strongly impeded cancer cell growth while inhibition of PI3K did not. MAPK analysis suggested an inhibitory crosstalk between both pathways, thus explaining the different effects of the Akt and PI3K inhibitors on cancer cell proliferation. PDGF stimulates colon cancer cell proliferation, and prevents inhibitor induced apoptosis, resulting in tumor growth. Therefore inhibition of PDGF signaling seems to be a promising target in colorectal cancer therapy. However, due to the multifaceted nature of the intracellular PDGF signaling, careful intervention strategies are needed when looking into specific signaling pathways like PI3K/Akt/mTOR and MAPK.

TLR7 and TLR8 expression increases tumor cell proliferation and promotes chemoresistance in human pancreatic cancer.

Chronic inflammation as an important epigenetic and environmental factor for putative tumorigenesis and tumor progression may be associated with specific activation of Toll-like receptors (TLR). Recently, carcinogenesis has been suggested to be dependent on TLR7 signaling. In the present study, we determined the role of both TLR7 and TLR8 expression and signaling in tumor cell proliferation and chemoresistance in pancreatic cancer. Expression of TLR7/TLR8 in UICC stage I-IV pancreatic cancer, chronic pancreatitis, normal pancreatic tissue and human pancreatic (PANC1) cancer cell line was examined. For in vitro/in vivo studies TLR7/TLR8 overexpressing PANC1 cell lines were generated and analyzed for effects of (un-)stimulated TLR expression on tumor cell proliferation and chemoresistance. TLR expression was increased in pancreatic cancer, with stage-dependent upregulation in advanced tumors, compared to earlier stages and chronic pancreatitis. Stimulation of TLR7/TLR8 overexpressing PANC1 cells resulted in elevated NF-κB and COX-2 expression, increased cancer cell proliferation and reduced chemosensitivity. More importantly, TLR7/TLR8 expression increased tumor growth in vivo. Our data demonstrate a stage-dependent upregulation of both TLR7 and TLR8 expression in pancreatic cancer. Functional analysis in human pancreatic cancer cells point to a significant role of both TLRs in chronic inflammation-mediated TLR7/TLR8 signaling leading to tumor cell proliferation and chemoresistance.

Hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis: role of heat shock proteins and dissecting effects of hyperthermia.

BACKGROUND: In patients with isolated peritoneal carcinomatosis (PC) of gastrointestinal cancer, hyperthermic intraperitoneal chemotherapy (HIPEC) represents a promising treatment option integrated into multimodal concepts. Heat shock proteins (HSP) seem to play a major role in cellular stress during HIPEC therapy. We analyzed differentially hyperthermic conditions and HSPs responsible for cell stress-mediated repair mechanisms in tumor tissues from patients who underwent HIPEC therapy and in an in vitro hyperthermic model. METHODS: Tumor tissues from our patient cohort with isolated PC were selected for further analysis when representative material was available before and after HIPEC therapy. To further dissect the role of HSPs under conditions of hyperthermia, gene and protein expression was additionally determined, together with cellular apoptosis and proliferation in human HT-29 colon cancer cells. RESULTS: Differently up-regulated HSP70/72 and HSP90 gene and protein expression was found in all investigated patient tumors. In vitro studies confirmed observations from clinical tumor analysis as underlying HSP-mediated cell stress mechanisms. Moreover, results from proliferation and apoptosis assays combined with differentiated HSP expression analysis demonstrated the relevance of preselecting specific target temperatures to achieve optimal toxic effects on remaining tumor cells in vivo. CONCLUSIONS: Therapeutic approaches like HIPEC to achieve antiproliferative and apoptosis-inducing cellular effects in patients with PC are negatively influenced by highly conserved HSP mechanisms in tumor cells. This study shows for the first time that specific hyperthermic conditions are necessary to be established to achieve optimal toxic effects on tumor cells during HIPEC therapy, a finding that opens potentially new therapeutic strategies.

A comparison of the MARA and the AdvanSync functional appliances in the treatment of Class II malocclusion.

OBJECTIVES: To determine the skeletal and dentoalveolar effects produced by the MARA and the AdvanSync functional appliances in the treatment of growing patients with Class II malocclusion. MATERIALS AND METHODS: A retrospective study was conducted using lateral cephalograms of patients consecutively treated with MARA (n  =  40) and AdvanSync (n  =  30) during their skeletal growth spurt as evaluated by the improved cervical vertebral maturation method. A comparison was made with 24 untreated Class II control subjects obtained from the University of Michigan growth study and matched with the experimental groups for skeletal age, sex, and craniofacial morphology. Cephalograms were taken at three time points: (T1) pretreatment, (T2) postfunctional appliance treatment, and (T3) fixed orthodontic treatment completion. Treatment changes were evaluated between the time points using 35 variables. Data were analyzed using one-way analysis of variance and Scheffe's post hoc test. RESULTS: At the postfunctional appliances' phase (T2-T1), both appliances showed significant increases in total mandibular length, ramus height, and anterior/posterior facial height. The AdvanSync resulted in significant restriction of maxillary growth, 1° more than MARA. This effect continued during the fixed orthodontic treatment stage (T3-T2). The net changes (T3-T1) revealed significant mandibular growth enhancement with MARA (+2.7mm) and significant headgear effect with AdvanSync. Both appliances caused 5° flaring in mandibular incisors as well as significant decreases in overjet and overbite. The treatment time for AdvanSync was 1 year less than MARA. CONCLUSION: The MARA and the AdvanSync resulted in normalization of the Class II malocclusion. The AdvanSync showed more headgear effect but less mandibular length enhancement than MARA did. Both appliances showed similar dentoalveolar changes.