Non-adherence to Mediterranean diet and synergy with lifestyle habits in the occurrence of breast cancer: a case-control study in Italy.

OBJECTIVE: The aim of this study was to assess the synergistic effect of non-adherence to the Mediterranean Diet (MD) and lifestyle habits on the occurrence of breast cancer (BC). PATIENTS AND METHODS: A case-control study was carried out from September 2018 to February 2019 at the Teaching Hospital "Umberto I" in Rome. A Food Frequency Questionnaire was used for assessing the level of adherence to MD, the IPAQ Questionnaire to measure physical activity, and AUDIT-C to estimate alcohol consumption. The possible interaction between risk factors was tested using the synergism index. RESULTS: A total of 94 cases and 88 controls were enrolled (median age 55.8 for cases and 57.9 for controls). The MD Score over 6 was associated with low odds of having breast cancer (OR = 0.29; 95% CI: 0.12-0.69). There is a clear indication for the additivity and synergism between non-adherence to MD and many risk factors on the occurrence of BC: current smoker (S = 2.02; 95% CI 0.62-8.07), physical inactivity (S = 2.14; 95% CI 0.71 2-8.28) and alcohol consumption (S = 3.02; 95% CI 0.91-12.95). CONCLUSIONS: Primary prevention of BC can benefit from intervention targeting nutritional and lifestyle factors that act synergistically.

Pre-operative micronutrient deficiencies in patients with severe obesity candidates for bariatric surgery.

PURPOSE: In patients with obesity, micronutrient deficiencies have been reported both before and after bariatric surgery (BS). Obesity is a chronic pro-inflammatory status, and inflammation increases the risk of micronutrient malnutrition. Our objective was to assess in pre-BS patients the prevalence of micronutrient deficiencies and their correlation with blood values of C-reactive protein (CRP). METHODS: Anthropometric data, instrumental examinations, and blood variables were centrally measured in the first 200 patients undergoing a pre-BS evaluation at the "Città della Salute e della Scienza" Hospital of Torino, starting from January 2018. RESULTS: At least one micronutrient deficiency was present in 85.5% of pre-BS patients. Vitamin D deficiency was the most prevalent (74.5%), followed by folate (33.5%), iron (32%), calcium (13%), vitamin B12 (10%), and albumin (5.5%) deficiency. CRP values were high (> 5 mg/L) in 65% of the patients. These individuals showed increased rate of iron, folate, vitamin B12 deficiency, and a higher number of micronutrient deficiencies. In a multiple logistic regression model, increased CRP levels were significantly associated with deficiencies of vitamin B12 (OR = 5.84; 95% CI 1.25-27.2; p = 0.024), folate (OR = 4.02; 1.87-8.66; p < 0.001), and with the presence of ≥ 2 micronutrient deficiencies (OR = 2.31; 1.21-4.42; p = 0.01). CONCLUSIONS: Micronutrient deficiencies are common in patients with severe obesity undergoing BS, especially when inflammation is present. In the presence of increased CRP values before surgery, it might be advisable to search for possible multiple micronutrient deficiencies.

Returning to work after breast cancer: A systematic review of reviews.

BACKGROUND: Due to improvements in breast cancer diagnosis and treatment, the healthcare system faces a growing number of cancer survivors. Breast cancer survivors experience many difficulties when returning to work, including discrimination at work and lack of support by employers and colleagues. OBJECTIVE: To point out the knowledge in literature up to date about return to work (RTW) after breast cancer, the factors influencing it and the interventions to facilitate it. METHODS: A literature search was conducted in January 2017 using the databases Medline (PubMed) and Scopus. Studies were included if they analyzed the problem of RTW in women treated for breast cancer. RESULTS: Twenty-six articles met the inclusion criteria. The studies were divided into four themes: factors facilitating or impeding RTW; interventions to enhance RTW; lived experiences of RTW; economic aspects related to cancer survivors and RTW. CONCLUSIONS: The heterogeneity of the interventions suggests the need for a better definition of the concept of RTW. To compare interventions, studies should use a rigorous approach and better outcome measures should be identified to evaluate RTW.

Counseling interventions delivered in women with breast cancer to improve health-related quality of life: a systematic review.

BACKGROUND: Higher survival rates for breast cancer patients have led to concerns in dealing with short- and long-term side effects. The most common complications are impairment of shoulder functions, pain, lymphedema, and dysesthesia of the injured arm; psychological consequences concern: emotional distress, anxiety, and depression, thereby, deeply impacting/affecting daily living activity, and health-related quality of life. OBJECTIVE: To perform a systematic review for assessing the efficacy or effectiveness of interventions aiming at improving health-related quality of life, return to daily activity, and correct lifestyles among breast cancer patients. METHODS: A literature search was conducted in December 2016 using the databases PubMed and Scopus. Search terms included: (counseling) AND (breast cancer) AND (quality of life). Articles on counseling interventions to improve quality of life, physical and psychological outcomes were included. RESULTS: Thirty-five articles met the inclusion criteria. The interventions were grouped in five main areas: concerning lifestyle counseling interventions, related to combined interventions (physical activity and nutritional counseling), physical therapy, peer counseling, multidisciplinary approach, included psychological, psycho-educational interventions, and cognitive-behavior therapy (CBT). Exercise counseling as well as physical therapy are effective to improve shoulder mobility, healing wounds, and limb strength. Psychological therapies such as psychoeducation and CBT may help to realize a social and psychological rehabilitation. CONCLUSION: A multidisciplinary approach can help in sustaining and restoring impaired physical, psychosocial, and occupational outcomes of breast cancer patients.

Translation factors and ribosomal proteins control tumor onset and progression: how?

Gene expression is shaped by translational control. The modalities and the extent by which translation factors modify gene expression have revealed therapeutic scenarios. For instance, eukaryotic initiation factor (eIF)4E activity is controlled by the signaling cascade of growth factors, and drives tumorigenesis by favoring the translation of specific mRNAs. Highly specific drugs target the activity of eIF4E. Indeed, the antitumor action of mTOR complex 1 (mTORc1) blockers like rapamycin relies on their capability to inhibit eIF4E assembly into functional eIF4F complexes. eIF4E biology, from its inception to recent pharmacological targeting, is proof-of-principle that translational control is druggable. The case for eIF4E is not isolated. The translational machinery is involved in the biology of cancer through many other mechanisms. First, untranslated sequences on mRNAs as well as noncoding RNAs regulate the translational efficiency of mRNAs that are central for tumor progression. Second, other initiation factors like eIF6 show a tumorigenic potential by acting downstream of oncogenic pathways. Third, genetic alterations in components of the translational apparatus underlie an entire class of inherited syndromes known as 'ribosomopathies' that are associated with increased cancer risk. Taken together, data suggest that in spite of their evolutionary conservation and ubiquitous nature, variations in the activity and levels of ribosomal proteins and translation factors generate highly specific effects. Beside, as the structures and biochemical activities of several noncoding RNAs and initiation factors are known, these factors may be amenable to rational pharmacological targeting. The future is to design highly specific drugs targeting the translational apparatus.

Estrogens stimulate the proliferation of human cholangiocarcinoma by inducing the expression and secretion of vascular endothelial growth factor.

BACKGROUND: Estrogens may induce the proliferation of neoplastic cells by activating neo-angiogenesis. AIM: To evaluate the effect of estrogens on the expression of vascular endothelial growth factor (VEGF) and related receptors (VEGF-R) in human cholangiocarcinoma and the role played by VEGF in mediating the proliferative effects of estrogens. METHODS: Seven biopsies of intra-hepatic cholangiocarcinoma and the HuH-28 cell lines were investigated. Cell proliferation was measured by both PCNA Western blot and MTS proliferation assay. RESULTS: By immunohistochemistry, biopsies of human cholangiocarcinoma stained positively for VEGF-A and VEGF-C and related receptors. HuH-28 cells expressed VEGF-A, -C, and VEGFR-1, -2, -3 and, their protein level was enhanced by 17beta-estradiol in association with the stimulation of cell proliferation. 17beta-Estradiol-stimulated proliferation of HuH-28 cells was blocked by 70% by VEGF-TRAP, a receptor-based VEGF inhibitor. 17beta-Estradiol induced the secretion of VEGF in the supernatant of HuH-28 cells. The stimulatory effect of 17beta-estradiol on the protein expression of VEGF-A, VEGF-C and VEGFR-1, -2, -3 was blocked by antagonists of ER (Ici182,780) or insulin-like growth factor 1-receptor (alphaIR3). CONCLUSIONS: With the limitations of experiments performed in a cell line, our study indicates that VEGF plays a major role in mediating the proliferative effects of estrogens on human cholangiocarcinoma.

Bile salts regulate proliferation and apoptosis of liver cells by modulating the IGF1 system.

BACKGROUND: In different cell types, the insulin-like growth factor 1 and its receptor modulate growth, apoptosis and damage repair in cooperation with estrogen receptors. AIM: To evaluate the involvement of the insulin-like growth factor 1 system and estrogen receptors in bile salts modulation of apoptosis/proliferation of hepatocytes and cholangiocytes. Primary cultures of rat hepatocytes and cholangiocytes were exposed to glycochenodeoxycholate or tauro-CDC in the presence or absence of insulin-like growth factor 1 receptor blocking antibody (alphaIR3), small interfering RNA for insulin-like growth factor 1, 17beta-estradiol or estrogen receptor antagonist (ICI 182,780). Proliferation was evaluated by proliferating cell nuclear antigen Western blot and apoptosis by measuring caspase-3 activity or annexin-V. RESULTS: In hepatocytes, the insulin-like growth factor 1 receptor blocker enhanced glycochenodeoxycholate-induced apoptosis and caused tauro-CDC to promote apoptosis. 17Beta-estradiol or the estrogen receptor antagonist (ICI 182,780) did not influence the apoptotic effect of glycochenodeoxycholate. In cholangiocytes, both glycochenodeoxycholate and tauro-CDC induced proliferation at 100microM, while they induced apoptosis at 1mM with a more pronounced effect of glycochenodeoxycholate. Apoptosis induced by 1mM glycochenodeoxycholate or tauro-CDC in cholangiocytes was enhanced by blocking insulin-like growth factor 1 receptor or by silencing insulin-like growth factor 1. 17Beta-estradiol counteracts glycochenodeoxycholate-induced cholangiocyte apoptosis by enhancing insulin-like growth factor 1 secretion and activating the insulin-like growth factor 1 system. CONCLUSIONS: Modulation of the IGF1 system could represent a potential strategy for the management of bile salts-induced liver injury.

Development of leiomyosarcoma of the uterus in MMTV-CR-1 transgenic mice.

Overexpression of Cripto-1 (CR-1) in FVB/N mice using the MMTV-LTR promoter results in increased mammary tumourigenesis in these female transgenic mice (MMTV-CR-1). Here, we characterize uterine tumours that developed in 15/76 (19.7%) of MMTV-CR-1 female nulliparous or multiparous mice during 24 months of observation compared with 0/33 (0%) of FVB/N normal control mice observed during the same time period (p < 0.01). The uterine tumours collected from the MMTV-CR-1 mice were classified as leiomyosarcomas and found to express the CR-1 transgene by polymerase chain reaction analysis and immunohistochemistry. Detection by western blot analysis showed higher levels of phosphorylated (P) forms of c-src, Akt, GSK-3beta, and dephosphorylated (DP)-beta-catenin in lysates from MMTV-CR-1 uterine leiomyosarcomas in comparison with lysates from normal control FVB/N uteri. Immunostaining showed increased nuclear localization of beta-catenin in the MMTV-CR-1 uterine leiomyosarcomas. Increased immunostaining for CR-1 was detected in 9/13 (69.2%) cases of human leiomyosarcoma compared with staining in 3/15 (20%) human leiomyoma sections. Stronger immunostaining for P-src, P-Akt, P-GSK-3beta and increased nuclear localization of beta-catenin was also seen in human leiomyosarcomas in comparison with leiomyomas. Normal human uterine smooth muscle (UtSM) cells treated with exogenous soluble rhCR-1 showed increased levels of P-src, P-Akt, P-GSK-3beta and dephosphorylated (DP)-beta-catenin and increased proliferation (p < 0.05) and migration (p < 0.01) in comparison with untreated control UtSM cells. Inhibitors against c-src, Akt or beta-catenin, individually or in combination, significantly reduced CR-1-induced migration. These results suggest a role for CR-1 during uterine tumourigenesis either directly by activating c-src and Akt and/or via cross-talk with the canonical Wnt signalling pathway, as suggested by the increased expression of P-GSK-3beta, DP-beta-catenin, and increased nuclear localization of beta-catenin in human and MMTV-CR-1 mice leiomyosarcomas.

Gefitinib inhibits the ability of human bone marrow stromal cells to induce osteoclast differentiation: implications for the pathogenesis and treatment of bone metastasis.

Significant relief of bone pain in patients with bone metastases was observed in a clinical trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in breast cancer. Osteoclast activation and differentiation are regulated by bone marrow stromal cells (BMSC), a heterogeneous cell compartment that comprehends undifferentiated mesenchymal stem cells (MSC) and their specialized progeny. In this regard, we found that human primary BMSCs express immunoreactive EGFR. Expression of EGFR mRNA and protein was also demonstrated in two human, continuous MSC-like cell lines, HDS-1 and HDS-2 cells. Treatment of HDS cells with EGF produced a significant increase in the levels of activated EGFR which was not observed in the presence of gefitinib. A significant reduction in the basal levels of activation of the EGFR and of Akt was observed in HDS cells following treatment with gefitinib. Treatment of HDS cells with gefitinib produced a significant reduction in the levels of secreted macrophage colony-stimulating factor (M-CSF) and cell-associated receptor activator of NF-kappaB ligand (RANKL) in both cell lines, as assessed by using specific ELISA and Western blotting techniques. Finally, the ability to sustain the differentiation of pre-osteoclasts of conditioned medium from gefitinib-treated HDS cells was reduced by approximately 45% as compared with untreated HDS cells. These data have demonstrated for the first time that the EGFR regulates the ability of BMSCs to induce osteoclast differentiation and strongly support clinical trials of gefitinib in breast cancer patients with bone disease.

The ErbB receptors and their ligands in cancer: an overview.

This review article provides an overview on the most recent advances on the role of ErbB receptors and growth factors of the epidermal growth factor (EGF)-family of peptides in cancer pathogenesis and progression. The ErbB tyrosine kinases and the EGF-like peptides form a complex system. In fact, the interactions occurring between receptors and ligands of these families affect the type and the duration of the intracellular signals that derive from receptor activation. Interestingly, activation of ErbB receptors is also driven by different classes of membrane receptor, suggesting that ErbB kinases can amplify growth promoting signals carried by different pathways. The importance of ErbB receptors and EGF-like peptides in development of organs and tissues has been demonstrated by using different mouse models. In vitro and in vivo studies have also shown that ErbB receptors and their ligands can act as transforming genes. However, evidence suggests that cooperation of different receptors and ligands is necessary to induce a fully transformed phenotype. Indeed, co-expression of different ErbB receptors and EGF-like growth factors is a common phenomenon in human primary carcinomas. This observation suggests that the growth and the survival of carcinoma cells is sustained by a network of receptors/ligands of the ErbB family. In this respect, the contemporary expression of different ErbB tyrosine kinases and/or EGF-like growth factors in human carcinomas might also affect tumor response to target based agents directed against the ErbB receptor/ligand system.

Small molecule epidermal growth factor receptor tyrosine kinase inhibitors: an overview.

The epidermal growth factor receptor (EGFR) has been identified as a relevant target for treatment of solid tumors, as it is involved in regulating cellular functions important in the proliferation and survival of cancer cells, is commonly expressed in a range of tumors, and high expression is often related to poor prognosis. Some of the most advanced target based agents in clinical development are the EGFR tyrosine kinase inhibitors (EGFR-TKIs). This brief review summarizes the results of phase II monotherapy trials of EGFR TKIs in cancer patients. The molecular mechanisms involved in regulating the sensitivity/resistance of tumor cells to EGFR-TKIs are also discussed.

Incidence and characterisation of Aeromonas spp. in environmental and human samples in southern Italy.

The incidence and characterisation of Aeromonas species in human and environmental samples in southern Italy were investigated. The results emphasize that 12.3% of the 210 examined patients carried Aeromonas spp. in their faeces. These results underline the need to include Aeromonas spp. in the list of routinely analysed enteropathogens in all diarrhoeal stool samples, especially in children below 10 years of age, elderly persons and immunocompromised patients.

Comparing outcomes of routine care for depression: the dilemma of case-mix adjustment.

The purpose of this study was to formulate and test two case-mix models for depression treatment that permit comparisons of patient outcomes across diverse clinical settings. It assessed demographics; eight, diagnostic-specific, case-mix variables; and clinical status at baseline and follow-up for 187 patients. Regressions were performed to test two models for four dependent variables including depression severity and diagnosis. Individual treatment settings were then ranked based on a comparison of actual versus predicted outcomes using regression coefficients and predictor variables. A model inclusive of baseline physical health status and depression severity predicted depression severity, mental health, and physical health functioning at follow-up. A simpler model performed well in predicting depression remission. This study identifies variables to be included in case-mix adjustment models and demonstrates statistical methods to control for differences across settings when comparing depression outcomes.

Immunotherapy with an alum-adsorbed Parietaria-pollen allergoid: a 2-year, double-blind, placebo-controlled study.

A double-blind, placebo-controlled study was performed in order to confirm the safety, suitability, and efficacy of an alum-adsorbed Parietaria judaica-pollen allergoid, Allergovit, for allergen-specific immunotherapy. Parietaria pollen is an important cause of pollinosis, particularly in the Mediterranean zone, where it may be encountered for up to 8-9 months of the year. It is an aggressive allergen, and the doses tolerated during immunotherapy are less than those achieved with grass pollen. This factor increases the desirability of using therapeutic preparations with minimal IgE-binding activity, such as allergoids, in order to reduce the risk of side-effects and enable patients to tolerate a higher dose of allergen, thereby increasing the chances of successful specific immunotherapy. Forty patients with rhinitis and/or asthma were allocated at random to active- or placebo-treatment groups at the beginning of the study. All patients received the active preparation during the second year of the study. Immunotherapy was well tolerated by all patients and the incidence of side-effects was low. Treatment resulted in significant reductions in specific cutaneous reactivity and increases in nasal tolerance. A progressive improvement in nasal inspiratory peak flow in association with the immunotherapy indicated a reduction in nasal inflammation. These objective assessments of efficacy endorsed the results from the patients' diary cards, which indicated significant improvements in symptoms and reductions in the use of medication. The immunologic activity of the therapeutic preparation was demonstrated by the induction of a significant specific-IgG antibody response, with increases in IgG4 during the second year of treatment. We conclude that the safety and efficacy of immunotherapy with the Parietaria allergoid make it suitable for consideration in the treatment of patients with Parietaria-pollen-induced rhinitis or asthma.

Identification of the motor vehicle accident victim who abuses alcohol: an opportunity to reduce trauma.

OBJECTIVE: We hypothesized that a poor driving history and alcohol abuse, evident in a large number of people injured in automobile accidents, contribute to repeated injury, and that treatment for alcohol abuse may reduce vehicular trauma. METHOD: Patients (N = 150) admitted to the emergency surgical service because of injury sustained in a motor vehicle accident (MVA) were tested for their blood alcohol concentrations, and they responded to a questionnaire concerning their prior driving and medical histories. RESULTS: Contrary to the assumption that motor vehicle injuries are isolated episodes, 68% of MVA patients had experienced a prior accident, and 43% had been injured in an MVA before the present event. Prior MVAs were associated with having been previously arrested for driving while intoxicated (DWI), with illegal drug use and with prior hospitalization. Of the MVA patients, 37% were intoxicated (blood alcohol concentration [BAC] > or = 100 mg/dl). Elevated BAC was associated with having been stopped for drinking, having a restricted license, having a DWI arrest, using illegal drugs and having a previous admission to a hospital. Prior MVAs, prior DWIs, elevated BAC and male gender formed the Louisville Alcohol Abuse Predictor Checklist and were independent predictors of alcohol abuse diagnosis, based on the patient's self-report of problems with alcohol. Forty-two percent of MVA patients were diagnosed as alcohol abusers. The alcohol abuser had a significantly higher rate of recurrent MVAs, DWIs and injuries than did nonabusers. CONCLUSIONS: Surgical service may present an opportunity for assessment of alcohol abuse among MVA victims, and treatment for alcoholism might reduce vehicular trauma.

Psychosensorial and related phenomena in panic disorder and in temporal lobe epilepsy.

Since Cullen coined the term "neurosis" in the 18th century, medical investigators have searched the neural substrates of conditions we now classify as anxiety disorders. Harper and Roth in 1962 hypothesized that the temporal lobes might represent one such substrate for phobic-anxious patients with depersonalization-derealization (DD); the association between the presumed temporal lobe feature and phobic anxiety was so compelling that Roth (in 1959) described the condition as "phobic-anxiety-depersonalization" syndrome. Introduced into our current nosology as panic disorder-agoraphobia (PDA), this seemingly neuropsychiatric condition is nonetheless distinct from complex partial epilepsy (CPE), from which it is conventionally differentiated through clinical and anamnestic evaluation. Yet increasingly there are clinical-and laboratory-hints of certain overlap between manifestations of the two disorders, hitherto based largely on evaluation of psychosensorial phenomena in PDA or affective phenomena in CPE. We located only one systematic study that monitored 24-hour electroencephalogram (EEG) abnormalities in PDA. Finally, recent epidemiologic data suggest a significantly greater than chance association between PDA and a history of seizures. To further explore these intriguing links, the present study directly compared a group of 91 PDA outpatients with a group of 41 CPE outpatients with respect to DD and other psychosensorial symptoms. The broad similarities discovered between psychosensorial and related phenomena provide further support for the hypothesis that there may be a common neurophysiological substrate linking CPE phenomena with PDA.