Anthropometric and reproductive factors and risk of esophageal and gastric cancer by subtype and subsite: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Obesity has been associated with upper gastrointestinal cancers; however, there are limited prospective data on associations by subtype/subsite. Obesity can impact hormonal factors, which have been hypothesized to play a role in these cancers. We investigated anthropometric and reproductive factors in relation to esophageal and gastric cancer by subtype and subsite for 476,160 participants from the European Prospective Investigation into Cancer and Nutrition cohort. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models. During a mean follow-up of 14 years, 220 esophageal adenocarcinomas (EA), 195 esophageal squamous cell carcinomas, 243 gastric cardia (GC) and 373 gastric noncardia (GNC) cancers were diagnosed. Body mass index (BMI) was associated with EA in men (BMI ≥30 vs. 18.5–25 kg/m²: HR = 1.94, 95% CI: 1.25–3.03) and women (HR = 2.66, 95% CI: 1.15–6.19); however, adjustment for waist-to-hip ratio (WHR) attenuated these associations. After mutual adjustment for BMI and HC, respectively, WHR and waist circumference (WC) were associated with EA in men (HR = 3.47, 95% CI: 1.99–6.06 for WHR >0.96 vs. <0.91; HR = 2.67, 95% CI: 1.52–4.72 for WC >98 vs. <90 cm) and women (HR = 4.40, 95% CI: 1.35–14.33 for WHR >0.82 vs. <0.76; HR = 5.67, 95% CI: 1.76–18.26 for WC >84 vs. <74 cm). WHR was also positively associated with GC in women, and WC was positively associated with GC in men. Inverse associations were observed between parity and EA (HR = 0.38, 95% CI: 0.14–0.99; >2 vs. 0) and age at first pregnancy and GNC (HR = 0.54, 95% CI: 0.32–0.91; >26 vs. <22 years); whereas bilateral ovariectomy was positively associated with GNC (HR = 1.87, 95% CI: 1.04–3.36). These findings support a role for hormonal pathways in upper gastrointestinal cancers.     

Pharmacological modulation of neuropeptides in peripheral mononuclear cells.

The concentrations of beta-endorphin and cholecystokinin were measured in fresh resting peripheral mononuclear cells obtained from rats and human subjects in basal conditions and after different pharmacological treatments. Both in the human and the rat, beta-endorphin concentrations in mononuclear cells, increased after treatment with serotoninergic agonists, decreased after dopaminergic or GABAergic drugs, while the respective antagonists exerted the opposite effect. In vitro, serotoninergic and GABAergic compounds confirmed their roles in the modulation of beta-endorphin in mononuclear cells. Cholecystokinin was never affected by the pharmacological treatments.     

Amisulpride in the short-term treatment of depressive and physical symptoms in cancer patients during chemotherapies

Introduction Amisulpride is a substituted benzamide that, at low doses, selectively blocks D2 and D3 presynaptic dopamine receptors, enhancing dopaminergic transmission in frontal cortex and limbic areas. Many clinical studies versus placebo, tricyclic antidepressants and selective serotonin reuptake inhibitors showed amisulpride antidepressant effect, supporting its safety and rapid onset of action. In oncological population, depression is quite frequent and difficult to treat because of the particular sensitivity of cancer patients to the antidepressants’ side effects. Goals of work The aims of this study were to evaluate efficacy, safety and tolerability of low doses of amisulpride (50 mg) in oncological, depressed patients during chemotheraphy. Materials and methods One hundred six consecutive cancer outpatients with depressive symptoms were treated in a prospective, intention to treat, 4-week study, and were evaluated in single-blind with Montgomery Asberg rating scale for depression (MADRS), clinical global impression (CGI) and dosage record treatment emergent symptom scale (DOTES) to assess side effects of treatment. Main results After 4 weeks of treatment, scores of MADRS and CGI significantly improved (p < 0.002; p < 0.001, respectively), with a reduction of depressive symptoms concerning both emotional (such as apparent sadness, reported sadness, inner tension, etc.) and physical cluster (such as lack of appetite, reduction in weight, tiredness and insomnia) with good tolerability (only two patients dropped out). Conclusions This study is the first trial on the use of amisulpride in a cohort of oncological, depressed patients during chemotherapy. Amisulpride demonstrated high efficacy and safety. Controlled studies are needed to confirm these preliminary data.     

Characterization of T-cell subsets infiltrating post-burn hypertrophic scar tissues

In this study, skin-infiltrating cells were characterized in both the active and remission phases of post-burn hypertrophic scar biopstes. Immunohistochemistry examination of active phase samples showed an abundant presence of Langerhans cells, T cells, macrophages, a low presence of natural killer cells and the lack of B lymphocytes. In active hypertrophic scars T lymphocytes infiltrate deep into the superficial dermis and are also observed in the epidermis: CD3⁺ cells were present at about 222±107 per 0.25 mm². In particular the analysis of lymphocyte subpopulations showed that CD4⁺ T cells predominate in the dermis as well as in the epidermis of active hypertrophic scars whereas CD8⁺ cells were less well represented (CD4/CD8 ratio is 2.06). This distribution was also shown in remission phase samples and in normotrophic scar specimens, although the lymphocyte number was significantly lower. Approximately 70 per cent of T lymphocytes present in the tissue involved in active phase hypertrophic scar samples were activated (positive with anti-HLA-DR and IL-2 receptor antibodies) which is significantly higher than remission phase hypertrophic and normotrophic scars, in which positivity was 40 and 38 per cent, respectively. Upon activation, the lesional lymphocytes release several cytokines, locally and transiently, that interact with specific receptors in response to different stimulation. Central to the immune hypothesis of hypertrophic scars is that some of the T-cell lymphokines act on keratinocytes, fibroblasts and other cell types to induce changes characteristic of these scars. The presence and close proximity of activated T lymphocytes and antigen-presenting cells of various phenotypes in both the epidermis and dermis of hypertrophic tissues provides strong circumstantial evidence of a local immune response. However, the manner in which T cells achieve and maintain their activated state in hypertrophic tissues in not yet known, and both antigen-dependent and independent mechanisms may contribute.     

A role for serotonin and beta-endorphin in the analgesia induced by some tricyclic antidepressant drugs

The analgesic effect of acute or chronic nortriptyline, amitriptyline and their effects on morphine induced analgesia were evaluated in the rat. Clomipramine and amitriptyline, but not Nortriptyline, induce analgesia, while all potentiate the effect of morphine when administered acutely. The analgesic effect of clomipramine is blunted by both the serotonin antagonist metergoline and the opiate receptor blocker naloxone, thus indicating an involvement of both the serotoninergic and endogenous opioid system. The involvement of the serotoninergic system is confirmed by the similar results obtained with the serotonin precursor 5-hydroxytryptophan administered alone or together with morphine. A relation between the serotoninergic and the endogenous opioid systems is also shown by the increase in hypothalamic beta-endorphin concentrations elicited by all the drugs used after acute or chronic treatment, with the only exception of nortriptyline, that has been shown to exert its effects mainly through the noradrenergic system. In conclusion, the analgesic effect of clomipramine and amitriptyline and their potentiation of morphine induced analgesia seems to be related to an activation of the endogenous opioid system mediated by serotonin.     

Effect of chronic morphine on plasma and brain beta endorphin and methionine enkephalin in pregnant rats and in their fetuses or newborn

Normal or pregnant rats were treated orally for 21 days or throughout pregnancy with water or increasing doses of morphine and killed on days 7, 14, and 21 of pregnancy and 1 day post partum. At these time intervals, plasma, pituitary, and hypothalamic concentrations of beta-endorphin and methionine enkephalin were measured in normal and pregnant rats. Moreover, pituitary and hypothalamic concentrations of the two peptides were also measured in fetuses and newborn. Plasma beta-endorphin and methionine enkephalin increased significantly during pregnancy without any specific effect of morphine. Pituitary concentrations of beta-endorphin were not modified either by pregnancy or morphine treatment, while methionine enkephalin concentrations increased on days 7 and 11 of pregnancy, in both water- and morphine-treated rats. The pattern of the two peptides in the hypothalamus is completely superimposable to the one present in the pituitary with the exception of an increase of beta-endorphin on day 21 of pregnancy, which is more evident in control animals. Consistently with our observations in human newborn and the neurological dysfunctions we observed in them, the concentrations of both the peptides are significantly increased in the hypothalamus of fetuses and newborn of morphine-treated mothers, while in the pituitary only beta-endorphin concentrations are increased.     

Immunology: Mitogen-induced lymphocyte proliferation and peripheral blood mononuclear cell {beta}-endorphin concentrations in primary dysmenorrhoea

Dysmenorrhoea is a recurrent painful disease which causes physicaland psychological stress. The purpose of the present study wasto investigate whether there was a measurable derangement ofimmune cells and immune responses in women with severe primarydysmenorrhoea. On day 26 of one cycle and on days 1 and 3 ofthe following cycle we measured polyclonal, mitogen-inducedlymphocyte proliferation and -endorphin concentration in peripheralblood mononuclear cells obtained from 16 infertile women withnormal pelvis, of whom eight had and eight did not have thedisorder. In women with dysmenorrhoea, polyclonal mitogen-inducedlymphocyte proliferation was lower than in controls on all 3days considered, but the difference was statistically significantonly on day 26 (43 605 ± 9876 µg/ml versus 67 305± 15 249 µg/ml; P < 0.01). Monocyte -endorphinconcentrations in the patients with dysmenorrhoea were significantlyelevated on day 3 compared to controls (67.8 ± 24.3 pg/10⁶cells versus 29.7 ± 6.9 pg/10⁶ cells; P < 0.05). Ourresults demonstrate that immune responses are modified in patientswith primary dysmenorrhoea. These effects are independent ofcirculating hormone concentrations and are consistent with therole of dysmenorrhoea as a stressful event.     

Trans-Epithelial Transport,Metabolism, and Biological Activity Assessment of the Multi-Target Lupin Peptide LILPKHSDAD (P5) and Its Metabolite LPKHSDAD (P5-Met)

P5 (LILPKHSDAD) is a hypocholesterolemic peptide from lupin protein with a multi-target activity, since it inhibits both 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) and proprotein convertase subtilisin/kexin type-9 (PCSK9). This work shows that, during epithelial transport experiments, the metabolic transformation mediated by intestinal peptidases produces two main detected peptides, ILPKHSDAD (P5-frag) and LPKHSDAD (P5-met), and that both P5 and P5-met are linearly absorbed by differentiated human intestinal Caco-2 cells. Extensive comparative structural, biochemical, and cellular characterizations of P5-met and the parent peptide P5 demonstrate that both peptides have unique characteristics and share the same mechanisms of action. In fact, they exert an intrinsically multi-target behavior being able to regulate cholesterol metabolism by modulating different pathways. The results of this study also highlight the dynamic nature of bioactive peptides that may be modulated by the biological systems they get in contact with.     

Dietary folate and risk of prostate cancer in Italy.

Folate status may affect cancer risk through its role in both methylation and nucleotide synthesis of DNA. A low dietary intake of folate has been linked to risk of several cancers, but epidemiologic studies with reference to prostate cancer are scanty. We therefore analyzed data from a case-control study of prostate cancer conducted between 1991 and 2002 in various areas of Italy. Cases were 1,294 patients with incident, histologically confirmed prostate cancer and controls were 1,451 patients admitted to the same network of hospitals of cases for acute, nonneoplastic conditions. All subjects were < 75 years old. Intake of folate and other nutrients was computed from a validated food frequency questionnaire. We adjusted for energy intake using the residual method, and calculated multivariate odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression. The OR of prostate cancer was 0.66 (95% CI, 0.51-0.85) for the highest versus the lowest quintile of folate intake. The relation between dietary folate and prostate cancer was consistent across strata of age, methionine, vitamin B6, and alcohol intake, and did not vary substantially according to Gleason score of prostate cancer. The combined OR for high-folate and low-alcohol intake versus low-folate and high-alcohol intake was 0.46 (95% CI, 0.29-0.75). Therefore, this study supports a favorable role of dietary folate on prostate cancer risk.