Impact of migration on diabetes burden: audit in the metropolitan area of Bologna, Italy.

PURPOSE: To investigate the impact of diabetes in immigrants on the Italian healthcare system, as well as their compliance with standard protocols of control and treatment. METHODS: The prevalence of immigrants with diabetes living in the metropolitan area of Bologna (about 1 million inhabitants) in 2019 was investigated using a database containing all subjects in active follow-up for diabetes, based on antidiabetic drug use, disease-specific copayment exemption, ICD-9 codes, continuous care in diabetes units. Country of origin was derived from fiscal code. RESULTS: The overall prevalence of diabetes (n = 53,941; 51.8% males, median age 64) was 6.1% in both Italy-born and immigrant cohorts. Immigrant prevalence was 12.4%, moderately higher than that observed in the total population (12.2%). Diabetes risk was increased in the whole immigrant cohort (odds ratio (OR) 1.74; 95% Confidence Interval (CI) 1.69-1.79). Among cases with incident diabetes, the proportion of immigrants (median age, 49 vs. 65 in Italy-born individuals) increased progressively from 11.7% to 26.5% from 2011 to 2019 (males, 8.9-21.0%; females, 14.9-32.8%) in all age groups, particularly in young adults, but also in older subjects. Metabolic control was lower in immigrants, as was adherence to shared diagnostic and therapeutic protocols, without systematic differences in antidiabetic drug use, but much lower use of drugs for comorbid conditions. CONCLUSIONS: The population with diabetes in the metropolitan area of Bologna is rapidly changing. Quality improvement initiatives are needed to reduce the burden for the universalistic Italian health care system generated by the rapidly-growing high-risk immigrant population.

Remote psychophysical evaluation of olfactory and gustatory functions in early-stage coronavirus disease 2019 patients: the Bologna experience of 300 cases.

BACKGROUND: An objective evaluation of coronavirus disease 2019 in the first days of infection is almost impossible, as affected individuals are generally in home quarantine, and there is limited accessibility for the operator who should perform the test. To overcome this limitation, a recently validated psychophysical self-administered test was used, which can be performed remotely in the assessment of early-stage coronavirus disease 2019 patients. METHODS: Olfactory and gustatory functions were objectively assessed in 300 patients in the first 7 days from coronavirus disease 2019 symptom onset. RESULTS: Seventy per cent of the patients presented olfactory and/or gustatory disorders. The dysfunctions detected were mainly complete anosmia (47 per cent) or ageusia (38 per cent). A significant correlation was found between taste dysfunction and female gender (odds ratio = 1.936, p = 0.014) and fever (odds ratio = 2.132, p = 0.003). CONCLUSION: The psychophysical evaluation protocol proposed is an effective tool for the fast and objective evaluation of patients in the early stages of coronavirus disease 2019. Chemosensitive disorders have been confirmed to be frequent and early symptoms of the coronavirus infection, and, in a significant number of cases, they are the first or only manifestation of coronavirus disease 2019.

Somatic human ZBTB7A zinc finger mutations promote cancer progression.

We recently reported that ZBTB7A is a bona fide transcription repressor of key glycolytic genes and its downregulation in human cancer contributes to tumor metabolism. As reduced expression of ZBTB7A is found only in a subset of human cancers, we explored alternative mechanisms of its inactivation by mining human cancer genome databases. We discovered recurrent somatic mutations of ZBTB7A in multiple types of human cancers with a marked enrichment of mutations within the zinc finger domain. Functional characterization of the mutants demonstrated that mutations within the zinc finger region of ZBTB7A invariably resulted in loss of function. As a consequence, the glycolytic genes were markedly upregulated in cancer cells harboring ZBTB7A zinc finger mutation, leading to increased glycolysis and proliferation. Our study uncovers the loss-of-function mutation in ZBTB7A as a novel mechanism causing elevated glycolysis in human cancer, which carries important therapeutic implication.

TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFß signaling activation.

REST/NRSF is a transcriptional repressor of neuronal genes that has been implicated in development and cancer. In epithelial tissues, REST acts as a tumor suppressor and in breast cancer, loss of REST is associated with disease recurrence and poor prognosis. Here, we identify TSPYL2 (also known as CDA1 and DENTT) as a novel component of the REST protein complex. We show that REST and TSPYL2 are regulators of TGFß signaling and that cell-cycle arrest induced by TGFß requires both REST and TSPYL2. Importantly, knockdown of REST or TSPYL2 resulted in transformation of human mammary epithelial cells. Mechanistically, we demonstrate that the TSPYL2/REST complex promotes TGFß signaling by repressing the expression of genes, such as the proto-oncogene neurotrophic tyrosine kinase receptor C (TrkC). These data provide insight into the role of REST as a tumor suppressor in epithelial tissues through the regulation of the TGFß pathway.

PTEN induces apoptosis and cavitation via HIF-2-dependent Bnip3 upregulation during epithelial lumen formation.

The tumor suppressor phosphatase and tensin homolog (PTEN) dephosphorylates PIP3 and antagonizes the prosurvival PI3K-Akt pathway. Targeted deletion of PTEN in mice led to early embryonic lethality. To elucidate its role in embryonic epithelial morphogenesis and the underlying mechanisms, we used embryonic stem cell-derived embryoid body (EB), an epithelial cyst structurally similar to the periimplantation embryo. PTEN is upregulated during EB morphogenesis in parallel with apoptosis of core cells, which mediates EB cavitation. Genetic ablation of PTEN causes Akt overactivation, apoptosis resistance and cavitation blockade. However, rescue experiments using mutant PTEN and pharmacological inhibition of Akt suggest that the phosphatase activity of PTEN and Akt are not involved in apoptosis-mediated cavitation. Instead, hypoxia-induced upregulation of Bnip3, a proapoptotic BH3-only protein, mediates PTEN-dependent apoptosis and cavitation. PTEN inactivation inhibits hypoxia- and reactive oxygen species-induced Bnip3 elevation. Overexpression of Bnip3 in PTEN-null EBs rescues apoptosis of the core cells. Mechanistically, suppression of Bnip3 following PTEN loss is likely due to reduction of hypoxia-inducible factor-2α (HIF-2α) because forced expression of an oxygen-stable HIF-2α mutant rescues Bnip3 expression and apoptosis. Lastly, we show that HIF-2α is upregulated by PTEN at both transcriptional and posttranscriptional levels. Ablation of prolyl hydroxylase domain-containing protein 2 (PHD2) in normal EBs or inhibition of PHD activities in PTEN-null EBs stabilizes HIF-2α and induces Bnip3 and caspase-3 activation. Altogether, these results suggest that PTEN is required for apoptosis-mediated cavitation during epithelial morphogenesis by regulating the expression of HIF-2α and Bnip3.

BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the t(9;22) translocation coding for the chimeric protein p210 BCR-ABL. The tumor suppressor phosphatase and tensin homolog (PTEN) has recently been shown to have a critical role in the pathogenesis of CML. Nuclear localization and proper nuclear-cytoplasmic shuttling are crucial for PTEN's tumor suppressive function. In this study, we show that BCR-ABL enhances HAUSP-induced de-ubiquitination of PTEN in turn favoring its nuclear exclusion. We further demonstrate that BCR-ABL physically interacts with and phosphorylates HAUSP on tyrosine residues to trigger its activity. Importantly, we also find that PTEN delocalization induced by BCR-ABL does not occur in the leukemic stem cell compartment due to high levels of PML, a potent inhibitor of HAUSP activity toward PTEN. We therefore identify a new proto-oncogenic mechanism whereby BCR-ABL antagonizes the nuclear function of the PTEN tumor suppressor, with important therapeutic implications for the eradication of CML minimal residual disease.

A comparison of risk factors as predictors of cardiovascular and non-cardiovascular mortality in the elderly people--relevance of N-terminal pro-B-type natriuretic peptide and low systolic blood pressure.

BACKGROUND: Many risk factors are known to predict ischaemic events and mortality in the elderly people, but their ranking of importance remains uncertain. This study was designed to identify and compare the main predictors of total mortality (TM), cardiovascular mortality (CVM) and non-cardiovascular mortality (NCVM) in older adults. METHODS: Nine hundred and seventy-nine community resident adults aged ≥ 65 years, free of previous heart failure and cardiovascular events, participated in the study. The univariate and multivariate (Cox regression) relationships of baseline cardiovascular risk factors, treatments and laboratory data with TM, CVM and NCVM were assessed after a median follow up of 6.7 years. RESULTS: Overall, there were 104 deaths (30 because of CVM and 74 to NCVM). In multivariate analysis, the following factors remained independently associated with mortality: NT pro-B-type natriuretic peptide (NT-proBNP) upper quintile (≥ 237 pg/ml for men, ≥ 280 pg/ml for women): hazard ratio (HR) vs. the rest of the population (95% confidence interval) 2.34 (1.52-3.60), p < 0.001 for TM; HR 5.41 (2.32-12.65), p < 0.001 for CVM; systolic blood pressure lower quintile (≤ 130 mmHg): HR 3.06 (1.80-5.21), p < 0.001 for NCVM; diabetes: HR 2.46 (1.29-4.72), p = 0.007 for NCVM; erythrocyte sedimentation rate (ESR) upper decile (≥ 41 mm/h): HR 2.33 (1.16-4.69), p = 0.02 for NCVM; platelet count lower quintile (≤ 177 × 10(9) /l): HR 2.09 (1.20-3.64), p = 0.009 for NCVM; ever-smoker status: HR 2.08 (1.23-3.52), p = 0.007 for NCVM. CONCLUSIONS: In elderly community dwellers, NT-proBNP was the strongest predictor of TM and CVM, while especially low systolic blood pressure, together with diabetes, ESR, reduced platelet count and ever-smoker status, were the main predictors of NCVM.

ATM kinase enables the functional axis of YAP, PML and p53 to ameliorate loss of Werner protein-mediated oncogenic senescence.

Werner syndrome (WS) results from dysfunction of the WRN protein, and is associated with premature aging and early death. Here we report that loss of WRN function elicits accumulation of the Yes-associated protein (YAP protein), a major effector of the Hippo tumor suppressor pathway, both experimentally and in WS-derived fibroblasts. YAP upregulation correlates with slower cell proliferation and accelerated senescence, which are partially mediated by the formation of a complex between YAP and the PML protein, whose activity promotes p53 activation. The ATM kinase is necessary for YAP and PML accumulation in WRN-depleted cells. Notably, the depletion of either YAP or PML partially impairs the induction of senescence following WRN loss. Altogether, our findings reveal that loss of WRN activity triggers the activation of an ATM-YAP-PML-p53 axis, thereby accelerating cellular senescence. The latter has features of SASP (senescence-associated secretory phenotype), whose protumorigenic properties are potentiated by YAP, PML and p53 depletion.

Identification of PTEN at the ER and MAMs and its regulation of Ca(2+) signaling and apoptosis in a protein phosphatase-dependent manner.

The tumor suppressor activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10) is thought to be largely attributable to its lipid phosphatase activity. PTEN dephosphorylates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate to directly antagonize the phosphoinositide 3-kinase-Akt pathway and prevent the activating phosphorylation of Akt. PTEN has also other proposed mechanisms of action, including a poorly characterized protein phosphatase activity, protein-protein interactions, as well as emerging functions in different compartment of the cells such as nucleus and mitochondria. We show here that a fraction of PTEN protein localizes to the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs), signaling domains involved in calcium ((2+)) transfer from the ER to mitochondria and apoptosis induction. We demonstrate that PTEN silencing impairs ER Ca(2+) release, lowers cytosolic and mitochondrial Ca(2+) transients and decreases cellular sensitivity to Ca(2+)-mediated apoptotic stimulation. Specific targeting of PTEN to the ER is sufficient to enhance ER-to-mitochondria Ca(2+) transfer and sensitivity to apoptosis. PTEN localization at the ER is further increased during Ca(2+)-dependent apoptosis induction. Importantly, PTEN interacts with the inositol 1,4,5-trisphosphate receptors (IP3Rs) and this correlates with the reduction in their phosphorylation and increased Ca(2+) release. We propose that ER-localized PTEN regulates Ca(2+) release from the ER in a protein phosphatase-dependent manner that counteracts Akt-mediated reduction in Ca(2+) release via IP3Rs. These findings provide new insights into the mechanisms and the extent of PTEN tumor-suppressive functions, highlighting new potential strategies for therapeutic intervention.

Nucleophosmin/B26 regulates PTEN through interaction with HAUSP in acute myeloid leukemia.

PTEN (phosphatase and tensin homolog deleted in chromosome 10) is a bona fide dual lipid and protein phosphatase with cytoplasmic (Cy) and nuclear localization. PTEN nuclear exclusion has been associated with tumorigenesis. Nucleophosmin (NPM1) is frequently mutated in acute myeloid leukemia (AML) and displays Cy localization in mutated nucleophosmin (NPMc+) AML. Here we show that NPM1 directly interacts with herpes virus-associated ubiquitin specific protease (HAUSP), which is known as a PTEN deubiquitinating enzyme. Strikingly, PTEN is aberrantly localized in AML carrying NPMc+. Mechanistically, NPM1 in the nucleus opposes HAUSP-mediated deubiquitination and this promotes the shuttle of PTEN to the cytoplasm. In the cytoplasm, NPMc+ prevents HAUSP from deubiquitinating PTEN, causing the latter to stay in the cytoplasm where it is polyubiquitinated and degraded. Our findings delineate a new NPM1-HAUSP molecular interaction controlling PTEN deubiquitination and trafficking.

[Improving air quality in urban centers: the Bologna experience]. / Migliorare la qualità dell'aria nei centri urbani: l'esperienza di Bologna.

Among the themes addressed in public health, environmental hygiene represents a good example of how certain questions can be resolved through the construction of strongly integrated operative networks. In particular when one speaks of air quality in urban centers there must be an awareness that there should be coordination of all actors involved. In this way the Department of Prevention can transform itself into the essential part of the hub thanks to its specific skills and expertise. In this discussion, some experiences of the Local Health Agency of Bologna where the Department of Prevention could become the hub of the system will be presented.

[Mortality in a cohort of railway rolling stock construction and repair workers in Bologna]. / Mortalità in una coorte di addetti alla costruzione e riparazione di carrozze ferroviarie in un'azienda di Bologna.

BACKGROUND: A private company in Bologna worked for the Italian State Railways (FS) from 1919 to 1998; since the early '60s it used asbestos for new carriage insulation and renovation of carriages already circulating which were entirely spray-coated with asbestos. OBJECTIVES: The study aimed to investigate all causes mortality, in particular mortality from asbestos-related neoplasms in blue-collar workers. METHODS: The cohort consisted of 1,849 people, active in 1960 or hired in 1960-86: 1,704 (92.2%) blue-collar workers and 145 (7.8%) white-collar workers. The end date of the follow up was established as 31/12/2008. Regional reference mortality rates were used. RESULTS: Mortality from all causes (SMR = 1.16; 95% CI 1.08-1.25) and from malignant neoplasms (SMR = 1.20; 95% CI 1.06-1.35) significantly exceeded expected rates. In particular, a statistically significant increase was observed for pleural malignant cancer (SMR = 24.43; 95% CI 17.37-34.37), lung cancer (SMR = 1.24; 95% CI 1.00-1.53), peritoneal cancer (SMR = 6.35; 95% CI 2.64-15.25) and bladder cancer (SMR = 1.71; 95% CI 1.03-2.84). The excess lung cancer SMR was highly significant after 20 years of exposure and with a latency longer than 40 years. An association between pleural malignant cancer and duration of exposure and latency (trend test p value < 0,0001) was observed CONCLUSION: This study on a cohort of asbestos-exposed workers showed an increase in lung cancer SMRs by risk that was statistically significant in workers exposed for at least 20 years and after 40 years of latency. The neoplasm of pleura was strongly associated with both duration of exposure and latency.

(+)α-Tocopheryl succinate inhibits the mitochondrial respiratory chain complex I and is as effective as arsenic trioxide or ATRA against acute promyelocytic leukemia in vivo.

The vitamin E derivative (+)α-tocopheryl succinate (α-TOS) exerts pro-apoptotic effects in a wide range of tumors and is well tolerated by normal tissues. Previous studies point to a mitochondrial involvement in the action mechanism; however, the early steps have not been fully elucidated. In a model of acute promyelocytic leukemia (APL) derived from hCG-PML-RARα transgenic mice, we demonstrated that α-TOS is as effective as arsenic trioxide or all-trans retinoic acid, the current gold standards of therapy. We also demonstrated that α-TOS induces an early dissipation of the mitochondrial membrane potential in APL cells and studies with isolated mitochondria revealed that this action may result from the inhibition of mitochondrial respiratory chain complex I. Moreover, α-TOS promoted accumulation of reactive oxygen species hours before mitochondrial cytochrome c release and caspases activation. Therefore, an in vivo antileukemic action and a novel mitochondrial target were revealed for α-TOS, as well as mitochondrial respiratory complex I was highlighted as potential target for anticancer therapy.

The role of PML in the control of apoptotic cell fate: a new key player at ER-mitochondria sites.

The development of malignant tumors results from deregulated proliferation or an inability of cells to undergo apoptotic cell death. Experimental works of the past decade have highlighted the importance of calcium (Ca(2+)) in the regulation of apoptosis. Several studies indicate that the Ca(2+) content of the endoplasmic reticulum (ER) determines the cell's sensitivity to apoptotic stress and perturbation of ER Ca(2+) homeostasis appears to be a key component in the development of several pathological situations. Sensitivity to apoptosis depends on the ability of cells to transfer Ca(2+) from the ER to the mitochondria. The physical platform for the interplay between the ER and mitochondria is a domain of the ER called the mitochondria-associated membranes (MAMs). The disruption of these contact sites has profound consequences for cellular function, such as imbalances of intracellular Ca(2+) signaling, cellular stress, and disrupted apoptosis progression. The promyelocytic leukemia (PML) protein has been previously recognized as a critical and essential regulator of multiple apoptotic response. Nevertheless, how PML would exert such broad and fundamental role in apoptosis remained for long time a mystery. In this review, we will discuss how recent results demonstrate that the elusive mechanism whereby the PML tumor suppressor exerts its essential role in apoptosis triggered by Ca(2+)-dependent stimuli can be attributed to its unexpected and fundamental role at MAMs in the control of the functional cross-talk between ER and mitochondria.

Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy.

Glucocorticoids are fundamental drugs used in the treatment of lymphoid malignancies with apoptotic cell death as the hitherto proposed mechanism of action. Recent studies, however, showed that an alternative mode of cell death, autophagy, is involved in the response to anticancer drugs. The specific role of autophagy and its relationship to apoptosis remains, nevertheless, controversial: it can either lead to cell survival or can function in cell death. We show that dexamethasone induced autophagy upstream of apoptosis in acute lymphoblastic leukemia cells. Inhibition of autophagy by siRNA-mediated repression of Beclin 1 expression inhibited apoptosis showing an important role of autophagy in dexamethasone-induced cell death. Dexamethasone treatment caused an upregulation of promyelocytic leukemia protein, PML, its complex formation with protein kinase B or Akt and a PML-dependent Akt dephosphorylation. Initiation of autophagy and the onset of apoptosis were both dependent on these events. PML knockout thymocytes were resistant to dexamethasone-induced death and upregulation of PML correlated with the ability of dexamethasone to kill primary leukemic cells. Our data reveal key mechanisms of dexamethasone-induced cell death that may inform the development of improved treatment protocols for lymphoid malignancies.

[Survey on sports practice and physical activity of primary school children living in the area of Bologna Local Health Unit in relation with some individual and environmental variables]. / Indagine sulla pratica sportiva e le abitudini motorie dei bambini della scuola primaria del territorio dell'Azienda USL di bologna in relazione ad alcune variabili individuali e ambientali.

A randomized stratified sample of 522 children attending the third class of primary schools within the area of Bologna Local Health Unit was analysed for physical activity and sports practice. Information about the children's habits and availability of facilities for physical and sports activities were collected by means of structured questionnaires completed by children (507 respondents), parents (491), reference teachers for physical education (26) and class teachers (46) during the school year 2006-07. At the same time, the children's heights and weights were measured in order to calculate BMI values. Regular sports activity is practised by 80.1% of children (males: 82.4%, females: 77.6%), with significant diferences between genders only in children with at least one non-Italian parent (M>F, p < 0.05); the practice of sports is influenced by the area of residence (metropolitan > plain and hills, p < 0.05) and nationality (Italians > non-Italians, p < 0.01). Children with at least one actively sports practising parent are involved more frequently in sports activities (p < 0.001). In free time, sedentary activities are prevalent for both sports-practising children and not. However children not involved in regular sports activities tend to practise outdoor physical activities with a frequency significantly higher than children involved in sports (17.3% vs 10.4% of respondents). The percentage of completely sedentary children, who stated that they practise neither sports nor physical activity in their free time, is 7.3% (metropolitan area: 4.5%, hills: 8.7%, plain: 10.6%). The prevalence of overweight is 24.4%, of obesity 9.7%, with a better distribution of BMI values in the metropolitan area where there is the highest occurrence of positive conditions and behaviours: availability of sports facilities, the highest prevalence of sports practice, and the lowest prevalence of completely sedentary children.

Regulation of apoptosis by PML and the PML-NBs.

The promyelocytic leukemia protein (PML) is a tumor suppressor identified in acute PML and implicated in the pathogenesis of a variety of tumors. PML is essential for the proper assembly of a nuclear macromolecular structure called the PML nuclear body (PML-NB). PML and PML-NBs are functionally promiscuous and have been associated with the regulation of several cellular functions. Above all these is the control of apoptosis, a function of PML whose physiological relevance is emphasized by in vivo studies that demonstrate that mice and cells lacking Pml are resistant to a vast variety of apoptotic stimuli. The function of PML in regulating apoptosis is not confined to a linear pathway; rather, PML works within a regulatory network that finely tunes various apoptotic pathways, depending on the cellular context and the apoptotic stimulus. Here, we will summarize earlier and recent advances on the molecular mechanisms by which PML regulates apoptosis and the implication of these findings for cancer pathogenesis.

The association of socioeconomic disadvantage with postoperative complications after major elective cardiovascular surgery.

BACKGROUND: Understanding the mechanism by which both patient- and hospital level factors act in generating disparities has important implications for clinicians and policy-makers. OBJECTIVE: To measure the association between socioeconomic position (SEP) and postoperative complications after major elective cardiovascular procedures. DESIGN: Multicity hospital-based study. SUBJECTS: Using Hospital Discharge Registries (ICD-9-CM codes), 19 310 patients were identified undergoing five cardiovascular operations (coronary artery bypass grafting (CABG), valve replacement, carotid endarterectomy, major vascular bypass, repair of unruptured abdominal aorta aneurysm (AAA repair)) in four Italian cities, 1997-2000. MEASURES: For each patient, a five-level median income index by census block of residence was calculated. In-hospital 30-day mortality, cardiovascular complications (CCs) and non-cardiovascular complications (NCCs) were the outcomes. Odds ratios (ORs) were estimated with multilevel logistic regression adjusting for city of residence, gender, age and comorbidities taking into account hospital and individual dependencies. MAIN RESULTS: In-hospital 30-day mortality varied by type of surgery (CABG 3.7%, valve replacement 5.7%, carotid endarterectomy 0.9%, major vascular bypass 8.8%, AAA repair 4.0%). Disadvantaged people were more likely to die after CABG (lowest vs highest income OR 1.93, p trend 0.023). For other surgeries, the relationship between SEP and mortality was less clear. For cardiac surgery, SEP differences in mortality were higher for publicly funded patients in low-volume hospitals (lowest vs highest income OR 3.90, p trend 0.039) than for privately funded patients (OR 1.46, p trend 0.444); however, the difference in the SEP gradients was not statistically significant. CONCLUSIONS: Disadvantaged people seem particularly vulnerable to mortality after cardiovascular surgery. Efforts are needed to identify structural factors that may enlarge SEP disparities within hospitals.