Prognostic and predictive significance of nuclear HIF1α expression in locally advanced HNSCC patients treated with chemoradiation with or without nimotuzumab

Background Anti-EGFR-based therapies have limited success in HNSCC patients. Predictive biomarkers are greatly needed to identify the patients likely to be benefited from these targeted therapies. Here, we present the prognostic and predictive association of biomarkers in HPV-negative locally advanced (LA) HNSCC patients.Methods Treatment-naive tumour tissue samples of 404 patients, a subset of randomised Phase 3 trial comparing cisplatin radiation (CRT) versus nimotuzumab plus cisplatin radiation (NCRT) were analysed to evaluate the expression of HIF1α, EGFR and pEGFR by immunohistochemistry and EGFR gene copy change by FISH. Progression-free survival (PFS), locoregional control (LRC) and overall survival (OS) were estimated by Kaplan–Meier method. Hazard ratios were estimated by Cox proportional hazard models.Results Baseline characteristics of the patients were balanced between two treatment groups (CRT vs NCRT) and were representative of the trial cohort. The median follow-up was of 39.13 months. Low HIF1α was associated with better PFS [HR (95% CI) = 0.62 (0.42–0.93)], LRC [HR (95% CI) = 0.56 (0.37–0.86)] and OS [HR (95% CI) = 0.63 (0.43–0.93)] in the CRT group. Multivariable analysis revealed HIF1α as an independent negative prognostic biomarker. For patients with high HIF1α, NCRT significantly improved the outcomes [PFS:HR (95% CI) = 0.55 (0.37–0.82), LRC:HR (95% CI) = 0.55 (0.36–0.85) and OS:HR (95% CI) = 0.54 (0.36–0.81)] compared to CRT. While in patients with low HIF1α, no difference in the clinical outcomes was observed between treatments. Interaction test suggested a predictive value of HIF1α for OS (P = 0.008).Conclusions High HIF1α expression is a predictor of poor clinical response to CRT in HPV-negative LA-HNSCC patients. These patients with high HIF1α significantly benefited with the addition of nimotuzumab to CRT.Clinical trial registration Registered with the Clinical Trial Registry of India (Trial registration identifier—CTRI/2014/09/004980).Subject terms: Tumour biomarkers, Head and neck cancer, Tumour biomarkers, Head and neck cancer, Predictive markers     

Mechanism of multidrug resistance in relation to passive membrane permeation.

Passive uptake of drugs into cells is described in terms of the following steps: (1) massive immediate binding of the drugs to the outer leaflet of the plasma membrane resulting in practical equilibrium between extremely high drug concentrations at the cell surface compared to the drug concentration in the medium. (2) Due to their amphipathic nature, anticancer drugs are practically excluded from the lipid core of the membrane. They cross the lipid core by distinct flip-flop events that occur in the case of doxorubicin and daunorubicin after an average period of 0.7 and 0.15 min, respectively. (3) The drug reaching the inner leaflet of the plasma membrane is in practical equilibrium with the drug present in the cytoplasm. (4) Almost all the amounts of anticancer drugs present in the cells are bound by molecular sinks, such as DNA or cytoskeleton elements. The resistance afforded to multidrug resistant (MDR) cells by extrusion pumps, such as P-glycoprotein, is negatively correlated with the affinity of the drugs to the membranes and with their flip-flop rates across membranes. Binding rates of the drugs to membranes and intracellular sinks have no effect on drug concentration in the cytoplasm once equilibrium is reached between the passive uptake of drugs and their active extrusion.     

Influence of sugars on the activity of cellulase system from two basidiomycetes cultures

Influence of some sugars was studied on activity of purified cellulase enzymes produced by two white-rot basidiomycetes cultures in submerged fermentation. Exo- and endo-glucanases were found to be stimulated by glucose, sucrose and xylose, but β-glucosidase was inhibited by all sugars tested except sucrose being neutral. Cellobiose severely inhibited all three cellulase activities at all three concentrations taken in reaction mixture.     

Alterations in free radical scavenger system profile of type I diabetic rat brain

The activities of the enzymes related to glutathione synthesis, degradation, and functions as well as reactive oxygen scavenging enzymes were analyzed in different brain regions, such as cerebral hemisphere, cerebellum, brainstem, thalamus, and hypothalamus after 1 and 3 mo of streptozotocin-induced diabetes in rats. Parallel studies were also made in age-matched control rats and insulin-treated diabetic rats. The content of glutathione (GSH) and its synthesizing enzyme γ-glutamylcystein synthetase and also superoxide dismutase (SOD) and catalase activities (reactive oxygen scavenging enzymes) were significantly decreased from almost all the brain regions studied. However, glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), γ-glutamyl transpeptidase (γ-GTP), and glutamine synthetase (GS) activities were increased in the diabetic rat brain. Insulin treatment to the diabetic rats resulted in partial to full recovery in these enzymes activities. The present results emphasize the potentially serious alterations of brain free radical scavenger system in uncontrolled Type I diabetes.     

Antiviral activity of natural and recombinant human leukocyte interferons in tobacco protoplasts

Several purified species of human leukocyte interferon, including recombinant interferons, inhibit the multiplication of tobacco mosaic virus (TMV) in tobacco protoplasts derived from various cultivars. Viral RNA accumulation was determined by dot-blot hybridization to specific cDNA probes, and virus antigen was determined serologically. Interferon apparently inhibited both TMV-RNA replication and its expression into coat protein. However, these effects were of limited duration. Maximum effect was obtained when interferon was applied to the cells either prior to inoculation or within the first hour after inoculation. Antibodies to interferon abolished its antiviral activity in protoplasts. Tobacco protoplasts were about 1000 times more responsive to interferon than the reference animal viral-cell system and showed an "antiviral state" at a ratio of 1 molecule of interferon per cell.     

Hepatic capillariasis

The clinico-pathologic features of Capillaria hepatica infection in a 27-year-old Nigerian woman are discussed. This animal parasite has been encountered only rarely in humans. Less than 30 cases of human infection, mostly in children, having been recorded as far as the present authors are aware. This is the first case of hepatic capillariasis reported in West Africa. The pathologic features of this patient is marked by severe hepatic fibrosis, and this is correlated with disordered liver function. The possibility of histopathologic confusion with schistosomiasis mansoni is discussed.     

GTR with three different types of membranes in the treatment of intrabony periodontal defects: three-year results in sixty consecutive cases

The aim of the present study was to evaluate the clinical results at 3 years following treating intrabony periodontal defects with different nonresorbable and bioabsorbable membrane barriers. Sixty intrabony periodontal defects were treated according to the principles of guided tissue regeneration (GTR). Twenty pockets were treated with Gore Resolut, a bioabsorbable membrane; 20 were treated with Gore-Tex, a titanium-reinforced membrane; and 20 with nonresorbable Gore-Tex membrane (all manufactured by Gore Regenerative Technologies, Flagstaff, AZ). The therapeutic results were evaluated by assessing probing pocket depth (PPD), recession of the gingival margin (GR), and clinical attachment level (CAL) at baseline, at 1 and at 3 years after therapy. The postoperative phase was uneventful in all cases. At 1 year after surgery, the results showed a mean PPD reduction from 9.42 mm to 3.35 mm (p < 0.0001) with Resolut; from 10.30 mm to 4.00 with titanium-reinforced Gore-Tex (p < 0.0001); and from 8.40 mm to 3.73 mm (p < 0.0001) with Gore-Tex membranes. The mean GR increased from 1.92 mm to 3.70 mm (p < 0.001) with Resolut; from 0.47 mm to 2.85 mm (p < 0.0001) with titanium-reinforced Gore-Tex; and from 0.73 mm to 2.15 mm (p < 0.0001) with Gore-Tex membranes. The mean CAL changed from 11.35 mm to 6.92 mm (p < 0.001) with Resolut; from 10.78 mm to 6.85 mm (p < 0.0001) with titanium-reinforced Gore-Tex; and from 9.13 mm to 5.87 mm (p < 0.0001) with Gore-Tex membranes. The clinical results at 3 years were not significantly different when compared with the 1-year results (p > 0.05). No significant differences existed between the mean changes in PPD, GR, and CAL in the three different test groups. Furthermore, one tooth scheduled for extraction for periodontal and prosthodontic reasons was treated with Resolut. Histological analysis 6 months after treatment demonstrated the neoformation of a connective tissue attachment and of new alveolar bone. This additional evidence thus proved that treatment with bioabsorbable membranes according to GTR principles delivers not only clinical improvement, but also histological periodontal regeneration.     

Synthesis and Neuromuscular Blocking Activity of 16β-Piperidino Epiandrosterone Derivatives

This study reports the synthesis of steroidal quaternary ammonium compounds 11 and 12, with quaternary nitrogen at position 3 and 16 of the steroid nucleus in 5α-epiandrosterone series; along with their neuromuscular blocking activity using chick biventer cervicis muscle preparation. The compound 12 was found to be five times more potent than 11 in reducing twitch response to nerve stimulations, indicating the importance of extended interonium distances and 17-acetoxy function for potent antagonist activity.