p65BTK Is a Novel Biomarker and Therapeutic Target in Solid Tumors.

Bruton's tyrosine kinase (BTK) is a non-receptor intracellular kinase playing a key role in the proliferation and survival of normal and malignant B-lymphocytes. Its targeting by Ibrutinib, the first specific inhibitor, represented a turning point for the therapy of certain types of B-cell leukemias/lymphomas and several more BTK inhibitors are today in the clinic or advanced clinical trials. BTK expression was successively found to occur also outside of the hematopoietic compartment.

BTK inhibitors synergise with 5-FU to treat drug-resistant TP53-null colon cancers.

Colorectal cancer (CRC) is the fourth cause of death from cancer worldwide mainly due to the high incidence of drug-resistance. During a screen for new actionable targets in drug-resistant tumours we recently identified p65BTK - a novel oncogenic isoform of Bruton's tyrosine kinase. Studying three different cohorts of patients here we show that p65BTK expression correlates with histotype and cancer progression.

p65BTK is a novel potential actionable target in KRAS-mutated/EGFR-wild type lung adenocarcinoma.

Background: Lung cancer is still the main cause of cancer death worldwide despite the availability of targeted therapies and immune-checkpoint inhibitors combined with chemotherapy. Cancer cell heterogeneity and primary or acquired resistance mechanisms cause the elusive behaviour of this cancer and new biomarkers and active drugs are urgently needed to overcome these limitations. p65BTK, a novel isoform of the Bruton Tyrosine Kinase may represent a new actionable target in non-small cell lung cancer (NSCLC).

Metronomic combination of Vinorelbine and 5Fluorouracil is able to inhibit triple-negative breast cancer cells. Results from the proof-of-concept VICTOR-0 study.

Triple Negative Breast Cancer (TNBC) is an aggressive neoplasia with median Overall Survival (OS) less than two years. Despite the availability of new drugs, the chance of survival of these patients did not increase. The combination of low doses of drugs in a metronomic schedule showed efficacy in clinical trials, exhibiting an anti-proliferative and anti-tumour activity.

GSK3A is redundant with GSK3B in modulating drug resistance and chemotherapy-induced necroptosis.

Glycogen Synthase Kinase-3 alpha (GSK3A) and beta (GSK3B) isoforms are encoded by distinct genes, are 98% identical within their kinase domain and perform similar functions in several settings; however, they are not completely redundant and, depending on the cell type and differentiative status, they also play unique roles. We recently identified a role for GSK3B in drug resistance by demonstrating that its inhibition enables necroptosis in response to chemotherapy in p53-null drug-resistant colon carcinoma cells. We report here that, similarly to GSK3B, also GSK3A silencing/inhibition does not affect cell proliferation or cell cycle but only abolishes growth after treatment with DNA-damaging chemotherapy.

Severely obese adolescents and adults exhibit a different association of circulating levels of adipokines and leukocyte expression of the related receptors with insulin resistance.

Obese adults frequently exhibit a low-grade inflammation and insulin resistance, which have been hypothesized to be established early in childhood. Aim of this study was to evaluate the age-dependent relationships between inflammatory state and insulin resistance in obese adolescents and adults. Clinical and metabolic parameters, circulating adipokines (TNF- α , adiponectin, and leptin), ghrelin, their leukocyte receptors (TNFR1, ADIPOR2, OBRL and GHSR1a), and acute phase reactants (CRP and white blood cells) were assessed in lean and obese adolescents compared with the adult counterparts.

Effect of a somatostatin infusion on circulating levels of adipokines in obese women.

Objective: Changes in circulating levels of many adipocyte-derived peptides, including adipokines such as adiponectin, leptin and tumor necrosis factor alpha (TNF-α), have been reported in obesity (OB). Somatostatin (SRIF) inhibits circulating levels of adiponectin and leptin in lean (LN) subjects, but the effect of a SRIF infusion on these adipokines, including TNF-α, in OB is to date unknown.

Methods: Ten young women (5 OB and 5 LN) were studied.

Effect of somatostatin infusion on peptide YY secretion: studies in the acute and recovery phase of anorexia nervosa and in obesity.

Objective: Changes in many gastrointestinal peptides, including the anorexigenic peptide YY (PYY), which is produced by L cells, occur in both anorexia nervosa (AN) and obesity (OB). High PYY levels are present in AN, whereas in morbid OB fasting and postprandial PYY secretion is blunted. Somatostatin (somatotropin release-inhibiting factor (SRIF)) reportedly inhibits plasma PYY concentrations in animals and healthy humans, but the effect of a SRIF infusion on spontaneous PYY secretion in AN and OB is unknown.

Asymmetric dimethylarginine (ADMA) induces vascular endothelium impairment and aggravates post-ischemic ventricular dysfunction in rats.

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) inhibitor recognized as an independent risk factor for endothelial dysfunction and coronary heart diseases. This study investigated whether ADMA (10 mg/kg day for 14 days) affected endothelial function and aggravated post-ischemic ventricular dysfunction in the perfused rat heart. Systolic blood pressure and heart rate, plasma levels of ADMA and nitrite/nitrate were measured in vehicle- and ADMA-treated rats.

Testosterone inhibition of growth hormone release stimulated by a growth hormone secretagogue: studies in the rat and dog.

Anabolic steroids are frequently taken by athletes and bodybuilders together with recombinant human GH (rhGH), though there is some scientific evidence that the use of anabolic steroids reverses the rhGH-induced effects. Recently, we have shown that treatment with rhGH (0.2 IU/kg s.

Early tolerance to the hypophagic effect of the cannabinoid receptor antagonist SR141716 does not impede blockade of an orexigenic stimulus.

The cannabinoid CB1 receptor antagonist SR141716 (Rimonabant) is known to reduce food intake by central and peripheral mechanisms. Recently, SR141716 has been reported to block the orexigenic effect of ghrelin, a potent orexigenic peptide produced by the stomach. This study investigated whether in rats, made tolerant to the hypophagic effect of SR141716, the drug was still capable to block the orexigenic activity of another non-natural (hypothalamic) peptide, i.

Orexigenic effects of a growth hormone secretagogue and nitric oxide in aged rats and dogs: correlation with the hypothalamic expression of some neuropeptidergic/receptorial effectors mediating food intake.

Hypothalamic neurochemical alterations in mammals underlie disturbances of food intake. There is scarce information on these topics in elderly persons; therefore, the aims of the present study were: (i) to evaluate the orexigenic effects of a growth hormone secretagogue, administered to young and old rats and dogs, alone or in combination with molsidomine, a donor of nitric oxide and (ii) to evaluate by reverse transcription-polymerase chain reaction in the whole hypothalamus of young and old rats messenger RNA levels of a wide number of anabolic and catabolic peptides, receptors, and enzymes involved in the control of feeding behavior, relating the detected titers, whenever possible, to the feeding responses to growth hormone secretagogue. In all, the results obtained strengthen the proposition that, in the hypothalamus of old rats, anti-anorexigenic compensatory mechanisms are operative, aimed at maintaining a "normal" feeding pattern.

Angiotensin II type 1 receptor antagonism improves endothelial vasodilator function in L-NAME-induced hypertensive rats by a kinin-dependent mechanism.

Objective: This study was designed to investigate the ability of a chronic blockade of angiotensin II type 1 receptors with losartan to reverse the endothelial dysfunction present in N-nitro-L-arginine methyl ester (L-NAME)-treated hypertensive rats and the possible dependence of this effect on bradykinin B2-receptor activation.

Methods: Rats treated with L-NAME alone (60 mg/kg per day for 8 weeks) or with L-NAME + losartan, L-NAME + icatibant (a bradykinin B2-receptor antagonist) and L-NAME + losartan + icatibant were studied. Losartan, icatibant or losartan + icatibant were co-administered with L-NAME during the last 4 weeks of the experiment.

Angiotensin-converting enzyme inhibition and angiotensin AT1-receptor antagonism equally improve endothelial vasodilator function in L-NAME-induced hypertensive rats.

Male Sprague-Dawley rats given N(omega)-nitro-L-arginine methyl ester (L-NAME) in drinking water for 8 weeks showed: (1) a clear-cut increase in systolic blood pressure; (2) a consistent decrease of endothelial-cell nitric oxide synthase (eNOS) gene expression in aortic tissue; (3) a marked reduction of plasma nitrite/nitrate concentrations; (4) a reduction of the relaxant activity of acetylcholine (ACh, from 10(-10) to 10(-4) M) on norepinephrine-precontracted aortic rings (reduction by 48+/-5%); (5) a marked decrease (-58%) of the basal release of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) from aortic rings. In L-NAME-treated rats, administration in the last 4 weeks of either the angiotensin-converting enzyme (ACE) inhibitor enalapril (10 mg/kg/day in tap water) or the angiotensin AT(1)-receptor antagonist losartan (10 mg/kg/day in tap water) decreased systolic blood pressure levels, completely restored eNOS mRNA levels in aortic tissue and plasma nitrite/nitrate levels, and allowed a consistent recovery of both the relaxant activity of acetylcholine and the generation of 6-keto-PGF1alpha. Coadministration of icatibant, a bradykinin B(2)-receptor antagonist (200 microg/kg/day), with enalapril blunted the stimulatory effect of the ACE inhibitor on eNOS mRNA expression, circulating levels of nitrite/nitrate, the relaxant activity of ACh and the release of 6-keto-PGF1alpha in L-NAME-treated rats.

Molsidomine antagonizes L-NAME-induced acquisition deficits in a recognition memory task in the rat.

The present study was designed to investigate the role of nitric oxide (NO) on the acquisition of a recognition memory task in the rat. For this purpose, the effects on memory exerted by pre-training administration of the NO synthase inhibitor L-NAME (N(omega)-nitro-L-arginine methyl ester) and the NO donor molsidomine (N-[ethoxycarbonyl]-3-[4-morpholinosydnomine]) were assessed by using the object recognition task, a working memory paradigm based on the differential exploration of a new and familiar object. In a first dose-response study, it was found that L-NAME (10, 30, and 60 mg kg(-1), i.

Enalapril and quinapril improve endothelial vasodilator function and aortic eNOS gene expression in L-NAME-treated rats.

Endothelial dysfunction ensuing inhibition of nitric oxide synthase (NOS) was investigated in male Sprague-Dawley rats given N(omega)-nitro-L-arginine methyl ester (L-NAME) in drinking water for 8 weeks. Age-matched rats served as controls. L-NAME-treated rats, as compared to control animals, showed: (1) a clear-cut increase in systolic blood pressure; (2) a consistent decrease of endothelial-cell NOS (eNOS) gene expression in aortic tissue; (3) a reduction of the relaxant activity of acetylcholine (ACh, from 10(-10) to 10(-4) M) on norepinephrine-precontracted aortic rings (reduction by 52+/-5%); (4) a marked decrease (-50%) of the basal release of 6-keto-prostaglandin F(1 alpha) (6-keto-PGF(1 alpha)) from aortic rings.