Synergism Between Immunotherapy and Radiotherapy in Esophageal Cancer: An Overview of Current Knowledge and Future Perspectives

Background: Esophageal cancer (EC) is an aggressive neoplasm of the gastrointestinal tract that is usually treated with a combination of chemotherapy, radiotherapy (RT), and/or surgery, according to disease status. Despite the availability of multimodal therapeutic strategies, local recurrence is frequently observed. Immunotherapy is a promising therapeutic approach that is currently highly investigated in association to standard therapies, including RT, with the aim to improve patients' outcomes. Materials and Methods: A PubMed search was performed with the following keywords in all fields: "esophageal cancer" and "radiotherapy" and "radiation" and "immunotherapy" and "PD-1" and "PD L1." For an overview of ongoing trials, an additional search on ClinicalTrials.gov website was performed using the keywords "esophageal cancer" and "immunotherapy" and "PD-L1" and "CTLA-4" and "radiation" and "radiotherapy." Emerging data from preclinical and clinical studies are suggesting a synergistic effect between immunotherapy and RT. With the aim to update the knowledge of this synergistic immune-mediated antitumor activity and discuss current challenges, the authors summarize published data concerning the basic mechanisms and the effectiveness and tolerance of the combination between immunotherapy and RT for patients with EC, followed by an overview of ongoing clinical trial. Conclusions: Published results encourage the use of personalized therapeutic approaches for EC patients in the future; results from ongoing studies will help to identify the optimal strategies for patient selection and treatment response evaluation

Muscle activity as a key indicator of welfare in farmed European sea bass (Dicentrarchus labrax L. 1758)

Groups of adult sea bass were reared at either low (10 kg m−3) or high (50 kg m−3) stocking densities respectively for 84 and 116 days. To monitor the red muscle activity, about 20 fish from both densities were surgically implanted with EMG (Electromyograms) radio transmitters, after EMG calibration during exhaustive swimming exercise (Ucrit test). Blood samples and morphometric measurements were also taken. EMG showed that the muscle activity of fish reared at 50 kg m−3 was on average twofold higher than fish kept at lower density. Cortisol was significantly more elevated at higher density and haemoglobin, haematocrit and RBCC (red blood cells count) showed the same trend, while lysozyme decreased. Patterns for glucose and lactate were less clear. The results showed that the contemporary use of functional (EMG) and physiological (haematological and biochemical) profiles could give a more comprehensive view of the fish status validating the diagnosis of fish stress induced by culture practices

Molecular determinants for the activating/blocking actions of the 2H-1,4-benzoxazine derivatives, a class of potassium channel modulators targeting the skeletal muscle KATP channels

The 2H-1,4-benzoxazine derivatives are modulators of the skeletal muscle ATP-sensitive-K+ channels (KATP), activating it in the presence of ATP but inhibiting it in the absence of nucleotide. To investigate the molecular determinants for the activating/blocking actions of these compounds, novel molecules with different alkyl or aryl-alkyl substitutes at position 2 of the 1,4-benzoxazine ring were prepared. The effects of the lengthening of the alkyl chain and of branched substitutes, as well as of the introduction of aliphatic/aromatic rings on the activity of the molecules, were investigated on the skeletal muscle KATP channels of the rat, in excised-patch experiments, in the presence or absence of internal ATP (10 -4 M). In the presence of ATP, the 2-n-hexyl analog was the most potent activator (DE50 = 1.08 × 10-10 M), whereas the 2-phenylethyl was not effective. The rank order of efficacy of the openers was 2-n-hexyl ≥2-cyclohexylmethyl >2-isopropyl = 2-n-butyl = 2-phenyl ≥ 2-benzyl = 2-isobutyl analogs. In the absence of ATP, the 2-phenyl analog was the most potent inhibitor (IC50 = 2.5 × 10-11 M); the rank order of efficacy of the blockers was 2-phenyl ≥ 2-n-hexyl > 2-n-butyl > 2-cyclohexylmethyl, whereas the 2-phenylethyl, 2-benzyl, and 2-isobutyl 1,4-benzoxazine analogs were not effective; the 2-isopropyl analog activated the KATP channel even in the absence of nucleotide. Therefore, distinct molecular determinants for the activating or blocking actions for these compounds can be found. For example, the replacement of the linear with the branched alkyl substitutes at the position 2 of the 1,4-benzoxazine nucleus determines the molecular switch from blockers to openers. These compounds were 100-fold more potent and effective as openers than other KCO against the muscle KATP channels. Copyright © 2008 The American Society for Pharmacology and Experimental Therapeutics

Antibacterial activities of peptides from the water-soluble extracts of Italian cheese varieties.

Water-soluble extracts of 9 Italian cheese varieties that differed mainly for type of cheese milk, starter, technology, and time of ripening were fractionated by reversed-phase fast protein liquid chromatography, and the antimicrobial activity of each fraction was first assayed toward Lactobacillus sakei A15 by well-diffusion assay. Active fractions were further analyzed by HPLC coupled to electrospray ionization-ion trap mass spectrometry, and peptide sequences were identified by comparison with a proteomic database. Parmigiano Reggiano, Fossa, and Gorgonzola water-soluble extracts did not show antibacterial peptides. Fractions of Pecorino Romano, Canestrato Pugliese, Crescenza, and Caprino del Piemonte contained a mixture of peptides with a high degree of homology. Pasta filata cheeses (Caciocavallo and Mozzarella) also had antibacterial peptides. Peptides showed high levels of homology with N-terminal, C-terminal, or whole fragments of well known antimicrobial or multifunctional peptides reported in the literature: alphaS1-casokinin (e.g., sheep alphaS1-casein (CN) f22-30 of Pecorino Romano and cow alphaS1-CN f24-33 of Canestrato Pugliese); isracidin (e.g., sheep alphaS1-CN f10-21 of Pecorino Romano); kappacin and casoplatelin (e.g., cow kappa-CN f106-115 of Canestrato Pugliese and Crescenza); and beta-casomorphin-11 (e.g., goat beta-CN f60-68 of Caprino del Piemonte). As shown by the broth microdilution technique, most of the water-soluble fractions had a large spectrum of inhibition (minimal inhibitory concentration of 20 to 200 microg/mL) toward gram-positive and gram-negative bacterial species, including potentially pathogenic bacteria of clinical interest. Cheeses manufactured from different types of cheese milk (cow, sheep, and goat) have the potential to generate similar peptides with antimicrobial activity

Impact of Previous ART and of ART Initiation on Outcome of HIV-Associated Tuberculosis

Background. Combination antiretroviral therapy (cART) has progressively decreased mortality of HIV-associated tuberculosis .To date, however, limited data on tuberculosis treatment outcomes among coinfected patients who are not ART-naive at the time of tuberculosis diagnosis are available. Methods. A multicenter, observational study enrolled 246 HIV-infected patients diagnosed with tuberculosis, in 96 Italian infectious diseases hospital units, who started tuberculosis treatment. A polytomous logistic regression model was used to identify baseline factors associated with the outcome. A Poisson regression model was used to explain the effect of ART during tuberculosis treatment on mortality, as a time-varying covariate, adjusting for baseline characteristics. Results. Outcomes of tuberculosis treatment were as follows: 130 (52.8%) were successfully treated, 36 (14.6%) patients died in a median time of 2 months (range: 0–16), and 80 (32.6%) had an unsuccessful outcome. Being foreign born or injecting drug users was associated with unsuccessful outcomes. In multivariable Poisson regression, cART during tuberculosis treatment decreased the risk of death, while this risk increased for those who were not ART-naive at tuberculosis diagnosis. Conclusions. ART during tuberculosis treatment is associated with a substantial reduction of death rate among HIV-infected patients. However, patients who are not ART-naive when they develop tuberculosis remain at elevated risk of death

Structural nucleotide analogs are potent activators/inhibitors of pancreatic beta-cell KATP channels: an emerging mechanism supporting their use as anti-diabetic drugs.

The 2H-1,4-benzoxazine derivatives are novel drugs structurally similar to nucleotides; however, their actions on the pancreatic beta-cell ATP-sensitive-K(+)(KATP) channel and on glucose disposal are unknown. Therefore, the effects of the linear/branched alkyl substituents and the aliphatic/aromatic rings at position 2 of the 2H-1,4-benzoxazine nucleus on the activity of these molecules against the pancreatic beta-cell KATP channel and the Kir6.2C36 subunit were investigated using a patch-clamp technique. The effects of these compounds on glucose disposal that followed glucose loading by i.p. GTT and on fasted glycemia were investigated in normal mice. The 2-n-hexyl analog blocked the KATP(IC50=10.1x10(-9)M) and Kir6.2C36(IC50=9.6x10(-9)M) channels which induced depolarization. In contrast, the 2-phenyl analog was a potent opener(DE50=0.04x10(-9)M), which induced hyperpolarization. The ranked order of the potency/efficacy of the analog openers was 2-phenyl>2-benzyl>2-cyclohexylmethyl. The 2-phenylethyl and 2-isopropyl analogs were not effective as blockers/openers. The 2-n-hexyl (2-10 mg kg(-1)) and 2-phenyl analogs (2-30 mg kg(-1)) reduced and enhanced the glucose AUC curves, respectively, following the glucose loading in mice. These compounds did not affect the fasted glycemia as is observed with glibenclamide. The linear alkyl chain and the aromatic ring at position 2 of the 1,4-benzoxazine nucleus are the determinants, which respectively confer the KATP channel blocking action with glucose lowering effects and the opening action with increased glucose levels. The opening/blocking actions of these compounds mimic those that were observed with ATP and ADP. The results support the use of these compounds as novel anti-diabetic drugs

Surgical implantation of electronic tags does not induce medium-term effect: insights from growth and stress physiological profile in two marine fish species

Abstract Background Telemetry applied to aquatic organisms has recently developed greatly. Physiological sensors have been increasingly used as tools for fish welfare monitoring. However, for the technology to be used as a reliable welfare indicator, it is important that the tagging procedure does not disrupt fish physiology, behaviour and performance. In this communication, we share our medium-term data on stress physiological profile and growth performance after surgical tag implantation in two important marine fish species for European aquaculture, the sea bream (Sparus aurata) and the European sea bass (Dicentrarchus labrax). Results Blood samples after surgical tag implantation (46 days for the sea bream and 95 days for the sea bass) revealed no differences between tagged and untagged fish in cortisol, glucose and lactate levels, suggesting that the tag implantation does not induce prolonged stress in these species. Moreover, the specific growth rates were similar in the tagged and untagged fish of both species. Conclusion Surgical tag implantation does not have medium-term consequences for the stress physiology and growth performance of these two marine fish species in a controlled environment. These observations support the use of accelerometer tags as valuable tools for welfare monitoring in aquaculture conditions. This study also shows that tagged fish can be sampled during experiments and considered a representative portion of the population, as they display growth and physiological parameters comparable to those of untagged fish

Inhibition of voltage-gated sodium channels by sumatriptan bioisosteres

Voltage-gated sodium channels are known to play a pivotal role in perception and transmission of pain sensations. Gain-of-function mutations in the genes encoding the peripheral neuronal sodium channels, hNav1.7-1.9, cause human painful diseases. Thus while treatment of chronic pain remains an unmet clinical need, sodium channel blockers are considered as promising druggable targets. In a previous study, we evaluated the analgesic activity of sumatriptan, an agonist of serotonin 5HT1B/D receptors, and some new chiral bioisosteres, using the hot plate test in the mouse. Interestingly, we observed that the analgesic effectiveness was not necessarily correlated to serotonin agonism. In this study, we evaluated whether sumatriptan and its congeners may inhibit heterologously expressed hNav1.7 sodium channels using the patch-clamp method. We show that sumatriptan blocks hNav1.7 channels only at very high, supratherapeutic concentrations. In contrast, its three analogs, namely 20b, (R)-31b, and (S)-22b, exert a dose and use-dependent sodium channel block. At 0.1 and 10 Hz stimulation frequencies, the most potent compound, (S)-22b, was 4.4 and 1.7 fold more potent than the well-known sodium channel blocker mexiletine. The compound induces a negative shift of voltage dependence of fast inactivation, suggesting higher affinity to the inactivated channel. Accordingly, we show that (S)-22b likely binds the conserved local anesthetic receptor within voltage-gated sodium channels. Combining these results with the previous ones, we hypothesize that use-dependent sodium channel blockade contributes to the analgesic activity of (R)-31b and (S)-22b. These later compounds represent promising lead compounds for the development of efficient analgesics, the mechanism of action of which may include a dual action on sodium channels and 5HT1D receptors

Calibrating accelerometer data, as a promising tool for health and welfare monitoring in aquaculture: Case study in European sea bass (Dicentrarchus labrax) in conventional or organic aquaculture

Both the conventional and organic aquaculture sectors have grown rapidly over the past few years. Moreover, welfare has attracted increased attention on the part of both consumers and governments. However, fish welfare assessment is complex and thus needs to adapt measurements that are easily applicable to aquaculture conditions. In this study, in addition to classical welfare indicator measurements (physiological stress indicators and growth performance), we recorded the swimming activity data using acoustic transmitters to evaluate the welfare of European sea bass (Dicentrarchus labrax) fed a conventional vs. an organic diet. Prior feeding trial, the swimming activity recorded by tag has been calibrated with water speed during critical swimming speed (Ucrit) tests. This calibration allowed us to increase the power of the recorded data, providing information on swimming activity with respect to the Ucrit value and on the metabolic cost of swimming. After a four-month experimental period, physiological stress indicators and growth performance did not differ significantly between the two diet groups. However, we observed a subtle difference in swimming activity: the fish in the organic diet group were more active during the feeding period in the morning. All indicators considered, our results suggest that an organic diet does not incur higher metabolic costs and does not affect the welfare of the European sea bass. Moreover, this study shows that the use of acoustic transmitters previously calibrated with physiological indicators, such as Ucrit, is a promising tool for welfare monitoring in aquaculture conditions