Original article: Immuno-chemotherapy of advanced colorectal cancer with alpha-2a interferon and 5-Fluorouracil immunopharmacological studies

Summary: Twelve patients with metastatic colorectal cancer received alternating cycles of low immunomodulat-ing doses of alpha-IFN + 5-Fluorouracil (5-FU) or 5-FU alone. Hematological, biochemical and physical evaluation showed that both treatment cycles were well tolerated. However, transient fever and moderate flu-like symptoms were observed following alpha-IFN administration. Treatment with 5-FU alone produced long-lasting inhibition of CD8+ T lymphocytes, but did not depress NK activity (NKA). Combined treatment with alpha-IFN produced a short-term increase of NKA and antagonized the effect of 5-FU on CD8+ cells on day 5 of the cycle. Parallel studies on in vitro models showed antiproliferative effects of 5-FU on PHA-stimulated MNC and confirmed the preferential inhibition of CD8+ cells. Pretreatment with alpha-IFN did not reverse the effect of 5-FU on CD8+ lymphocytes, but partially protected MNC from the toxic effects of the drug. This was presumably due to the cytostatic effects induced by alpha-IFN on MNC before exposure to the cycle-specific antineoplastic agent. This investigation suggests that alpha-IFN could play a positive role in immuno-chemotherapy of colorectal cancer through multiple mechanisms not entirely related to direct antitumor effects of the agent. © 1991 Kluwer Academic Publishers

Effect of the combined treatment with 5-fluorouracil, γ-interferon or folinic acid on carcinoembryonic antigen expression in colon cancer cells

5-Fluorouracil (5-FU) and human recombinant γ-interferon (γ-IFN) were found to increase the expression of carcinoembryonic antigen (CEA) in human cancer cells in vitro. In the present study, the antimetabolite was associated with γ-IFN or folinic acid (FA), a biochemical modulator of cellular metabolism of 5.FU, able to increase its antineoplastic activity. Treatment of two human colon cancer cell lines (HT-29 and WiDr) with 5-FU + γ-IFN resulted in an increase of CEA expression higher than that obtainable with both agents alone, although no synergistic effects were obtained. This was demonstrated in terms of: (a) mRNA transcripts (HT-29); (b) cytoplasm and membrane CEA protein levels detected by Western blot analysis (HT-29); and (c) plasma membrane reactivity determined by flow cytometry analysis (HT-29 and WiDr). Moreover, 5-FU + γ-IFN increased HLA class I molecules in the HT- 29 cell membrane over that obtainable with γ-IFN alone. In contrast, both agents did not induce the expression of the costimulatory molecule B7-1. Treatment with FA enhanced the antitumor effect of 5-FU but not its ability to augment CEA expression. This suggests that the FA-sensitive biochemical mechanism of action of 5-FU is not involved in its effect on CEA expression. In vivo studies showed, for the first time, that 5-FU, alone or combined with γ-IFN, increases the amount of CEA protein over controls, either in cancer cells or in peripheral blood of nude mice bearing HT-29 cells. These results could be of potential diagnostic and/or therapeutic value when CEA protein is the target of humoral or cell-mediated immunity

Differential effects of the phosphodiesterase inhibition in chronic heart failure depending on the echocardiographic phenotype (HFREF or HFpEF): A meta-analysis

INTRODUCTION: According to 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension (PH), no specific drug is currently indicated for PH related to left heart disease (PH-LDH), i.e., the one secondary to left chronic heart failure (CHF), which coincides with the group 2 of the PH classification endorsed by the above-mentioned guidelines. Indeed, adoption of therapies that specifically apply for so-called pulmonary arterial hypertension (group 1 of the PH classification) has been regarded as substantially contraindicated in patients with PH-LHD, according to current ESC/ERS guidelines. Nevertheless, based on some previous studies, phosphodiesterase 5 inhibitors (PDE5i) would seem to exert a beneficial effect in CHF patients, although the comparison between these studies shows quite inconsistent or heterogeneous findings. Thus, in order to better evaluate the effect of PDE5i therapy in CHF patients, we performed a meta-analysis of randomized controlled trials (RCTs). EVIDENCE ACQUISITION: PubMed and EMBASE databases were searched for RCTs that compared PDE5i with placebo in CHF with reduced (HFREF) or preserved (HFpEF) left ventricular ejection fraction. The endpoints of interest were: A composite of all-cause death or hospitalization, adverse events, peak VO2, Six-Minute Walk Test (6MWT), left ventricular ejection fraction (LVEF), E/e' ratio, mean pulmonary arterial pressure (mPAP), pulmonary arterial systolic pressure (PASP) and pulmonary vascular resistance (PVR). EVIDENCE SYNTHESIS: Fourteen studies, enrolling a total of 928 patients, were comprised in the meta-analysis. Among these, 13 were RCTs and one was a subgroup analysis. Among patients with HFREF (N.=555), a significant benefit was conferred by PDE5i against the risk of the composite endpoint of death and hospitalization (OR=0.28; 95% CI: 0.10 to 0.74; P=0.03). Furthermore, among HFREF patients, therapy with PDE5i improved peak VO2 (difference in means [MD] 3.76 mL/min/kg; 95% CI: 3.27 to 4.25), as well as the 6MWT (MD=22.7 m; 95% CI: 8.19 to 37.21) and LVEF (MD=4.30%; 95% CI: 2.18% to 6.42%). For patients with HFREF, PDE5i therapy yielded a nonsignificant decrease in mPAP, while PASP was significantly reduced (MD=-11.52 mmHg; 95% CI: -15.56 to -7.49; P<0.001). By contrast, in the RCTs of patients with HFpEF (N.=373), no benefit ensued from PDE5i use regarding all of the investigated clinical, ergospirometric or hemodynamic endpoints. CONCLUSIONS: Therapy with PDE5i caused a statistically significant improvement of clinical outcomes, exercise capacity and pulmonary hemodynamics in patients with HFREF, but not in HFpEF. However, in view of the relatively small sample size of the HFpEF population recruited so far in the RCTs that investigated the effects of PDE5i treatment, further research in this field is required to clarify whether PDE5i are beneficial even in this subset

Redemption

This chapter analyzes the extent to which films may be said to provide 'redemption' in ways that are analogous to how religions (especially Christianity) claim to do so. Although filmic redemptions usually transpose religious notions to a secular context, this does not erase the similarities between them, and it may also point to the religious necessity of secularizing redemption - placing it in the world we know and live in. Even escapist films may provide images of transforming hope that are akin to those offered by religions, and for this reason it is essential that the dialogue between religious and filmic representations of ideas continues

Image-clustering analysis of the wave-structure interaction processes under breaking and non-breaking waves

This contribution presents the effectiveness and the potentialities of a consolidated technique—the video-cluster analysis—to the study of turbulent flow and breaking waves, in order to demonstrate its suitability as a low-cost, non-intrusive method to derive quantitative key parameters describing the wave-structure interaction processes at coastal defense structures. For this purpose, a new methodology, consisting of a series of pre- and post-processing techniques developed to optimize the automatic detection of clusters in video imagery, was designed to process the video-records of experiments of wave run-up and wave overtopping at sea-dikes subjected to irregular waves. The results of the cluster analysis were elaborated to reconstruct the instantaneous profiles of the free-surface elevations across the structure crest and derive simultaneous information on overtopping volumes, discharges, depths, and velocities and to get spatial-time maps of the concentration of the air entrapped in the liquid phase. The accuracy of the methodology is demonstrated by comparing the quantities derived from the cluster analysis to laboratory measurements performed with resistive gauges and acoustic Doppler profilers. The novelty of the work is either represented by the results of the application of the cluster-analysis and by the procedures of optimizations, whose ensemble may establish a best practice and represent a guideline for other applications