Metabolic cell communication within tumour microenvironment: models, methods and perspectives.

Environmental cues are essential in defining tumour malignancy, by promoting tumour initiation, progression and metastatic spreading. Stromal cells may metabolically cooperate or compete with cancer cells, playing a mandatory role in defining cancer metabolic plasticity, potentially dictating the final tumour outcome. Assessing shared nutrients between different tumoural or stromal compartments is essential to understand the impact of environmental nutrients on the metabolic plasticity of tumours. Here, we review analytical and computational approaches for studying the tumour metabolic microenvironment, the destiny of nutrients shared among tumour and stromal populations, as well as the molecular modules of these metabolic relationships.

Lactate modulates CD4+ T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis.

Leukocyte infiltration plays an active role in controlling tumor development. In the early stages of carcinogenesis, T cells counteract tumor growth. However, in advanced stages, cancer cells and infiltrating stromal components interfere with the immune control and instruct immune cells to support, rather than counteract, tumor malignancy, via cell-cell contact or soluble mediators. In particular, metabolites are emerging as active players in driving immunosuppression. Here we demonstrate that in a prostate cancer model lactate released by glycolytic cancer-associated fibroblasts (CAFs) acts on CD4+ T cells, shaping T-cell polarization. In particular, CAFs exposure (i) reduces the percentage of the antitumoral Th1 subset, inducing a lactate-dependent, SIRT1-mediated deacetylation/degradation of T-bet transcription factor; (ii) increases Treg cells, driving naive T cells polarization, through a lactate-based NF-kB activation and FoxP3 expression. In turn, this metabolic-based CAF-immunomodulated environment exerts a pro-invasive effect on prostate cancer cells, by activating a previously unexplored miR21/TLR8 axis that sustains cancer malignancy.

The effect of hyperglycaemia on haemostasis testing--a volunteer study.

We investigated whether the contamination of samples with glucose subsequently tested for haemostasis affected the results, including prothrombin time, activated partial thromboplastin time and fibrinogen concentration. Venous blood was collected from 12 healthy subjects and divided into four aliquots, which were subjected to different degrees of contamination with standard glucose solution (0%, 5%, 10%, 20%). With increasing glucose contamination, prothrombin time increased from mean (SD) 11.0 (0.7) s to 11.2 (0.7) s, 11.5 (0.7) s and 12.2 (0.8) s, all p < 0.001. Activated partial thromboplastin time decreased from 32.3 (0.9) s to 30.9 (0.8) s, 30.8 (0.8) s, and 29.7 (0.7) s, all p < 0.001. Fibrinogen concentration decreased from 3.8 (0.7) g.l(-1) to 3.7 (0.6) g.l(-1), 3.6 (0.6) g.l(-1), and 3.4 (0.6) g.l(-1), all p < 0.001. Bias was clinically meaningful from 5% contamination for activated partial thromboplastin time, 10% contamination for prothrombin time and 20% contamination for fibrinogen concentration. We conclude that if glucose contamination of haemostasis samples is suspected or has occurred, the specimens should not be analysed.

Spectrum of F8 gene mutations in haemophilia A patients from a region of Italy: identification of 23 new mutations.

SUMMARY: Haemophilia A (HA) is an X-linked recessive bleeding disorder caused by a lack or decrease of coagulation factor VIII activity. The molecular diagnosis of HA is challenging and a variety of different mutations have been identified throughout the F8 gene. Our aim was to detect the causative mutation in 266 HA patients from Emilia-Romagna region (Italy) and in all suspected carriers. Molecular analysis of F8 in 201 HA patients (152 index cases) was performed with a combination of several indirect and direct molecular approaches, such as long distance polymerase chain reaction, multiplex ligation-dependent probe amplification, denaturing high performance liquid chromatography and direct sequencing. The analysis revealed 78 different mutations, 23 of which were novel, not having been reported in national or international databases. The detection rate was 100%, 86% and 89% in patients with severe, moderate and mild HA, respectively. The information provided by this registry will be helpful for monitoring the treatment of HA patients in Emilia-Romagna and also for reliable genetic counselling of affected families in the future.

Regional cerebral blood flow and comorbid diagnosis in abstinent opioid addicts.

Studies using single photon emission computed tomography (SPECT) have found low cerebral blood flow (CBF) in frontal and parietal cortices in patients with chronic opiate dependence. In the present study, SPECT with 99mTc-HMPAO as tracer was used to compare 27 detoxified opiate addicts with nine healthy control subjects. All the subjects were evaluated with clinical psychiatric (DSM-IV), psychometric and neuropsychological measures. Compared with normal control subjects, the addicts showed a non-significant reduction of whole brain perfusion values. Significant hypoperfusion in the right frontal and left temporal lobes was found in addicts with comorbid depression, and a significant decrease in CBF in the right frontal lobe was observed in those with antisocial tendencies. A significant negative correlation emerged between Depression subscale scores on the Minnesota Multiphasic Personality Inventory and left temporal CBF in the patients. No significant correlations were found, however, between measures of cognition and CBF in opiate addicts. The asymmetrical findings in CBF that characterized the addicts relative to normal control subjects may be more closely related to mood and behavioral traits than to substance abuse, per se.

[Comparison of HbA1c, fructosamine and the main metabolic parameters in a non-insulin-dependent diabetic population]. / Confronto tra HbA1c, fruttosamina e principali parametri metabolici in una popolazione di diabetici N.I.D.

Our objective was the checking of clinical data obtainable from the assay of some parameters in NID diabetic individuals. To this end, we studied 133 patients--57 males and 76 females, average age 74.36 +/- 1.01 years, 72.6% of which were above 65 years of age. The control population was subdivided as follows: 50 subjects, 26 F and 24 M; average age 71.25 +/- 1.32 years, with normal glucidic tolerance as assessed by OGTT. Current glycemia, average glycemia, fructosamine, glycosylated hemoglobin, triglycerides, LDL-cholesterol and apolipoprotein B were obviously much higher than normal in the individuals admitted to the study. A statistically significant correlation was found between average glycemia, glycosylated hemoglobin, LDL-cholesterol and blood triglycerides (p less than 0.05). No correlation was found between current glycemia, fructosamine and glycosylated hemoglobin. Similarly, serum fructosamine was unrelated to the parameters studied. In our study, fructosamine, glycosylated hemoglobin and current glycemia offered unrelatable data. Hence, in our opinion it is necessary to assay these three parameters contemporaneously for a reliable assessment of metabolic compensation.

[Diabetes insipidus after selective pituitary adenomectomy. A case with late appearance]. / Diabete insipido post-adenomectomia selettiva ipofisaria. Un caso ad insorgenza tardiva.

Diabetes insipidus is a well-known complication of hypophyseal surgery. The case is described of a women presenting with evident polyuropolydipsic syndrome arising 9 years after transphenoidal hypophyseal adenectomy. The diagnosis insipidus diabetes was secondary to intrasellar scars revealed by a hypophyseal CAT scan. The unusually long interval between surgery and the onset of the syndrome is emphasised.

Muscarinic cholinergic and histaminergic H1 and H2 receptors are not involved in the LH response to naloxone in man.

The role of muscarinic-cholinergic and H1-, H2-histaminergic receptors as possible mediators of the LH response to the opioid antagonist naloxone was evaluated in 18 normal men. Subjects were divided in 3 groups of 6 men; the increment of LH in the plasma elicited by naloxone was evaluated after giving naloxone alone or together with dexchlorpheniramine, cimetidine or pirenzepine (respectively H1-, H2-histaminergic and muscarinic-cholinergic receptor antagonists). LH release was significantly stimulated by naloxone in all subjects; this response was not altered by histaminergic or cholinergic blockade. These results confirm the stimulatory effect of naloxone on LH release in man, without evidence of the involvement of H1-, H2-histaminergic or muscarinic-cholinergic pathways.