Insulin signaling in insulin resistance states and cancer: A modeling analysis

Insulin resistance is the common denominator of several diseases including type 2 diabetes and cancer, and investigating the mechanisms responsible for insulin signaling impairment is of primary importance. A mathematical model of the insulin signaling network (ISN) is proposed and used to investigate the dose-response curves of components of this network. Experimental data of C2C12 myoblasts with phosphatase and tensin homologue (PTEN) suppressed and data of L6 myotubes with induced insulin resistance have been analyzed by the model. We focused particularly on single and double Akt phosphorylation and pointed out insulin signaling changes related to insulin resistance. Moreover, a new characterization of the upstream signaling of the mammalian target of rapamycin complex 2 (mTORC2) is presented. As it is widely recognized that ISN proteins have a crucial role also in cell proliferation and death, the ISN model was linked to a cell population model and applied to data of a cell line of acute myeloid leukemia treated with a mammalian target of rapamycin inhibitor with antitumor activity. The analysis revealed simple relationships among the concentrations of ISN proteins and the parameters of the cell population model that characterize cell cycle progression and cell death

Cognitive behavioral group therapy versus psychoeducational intervention in Parkinson's disease

Objective: The aim of the current study was to evaluate whether cognitive behavioral group therapy has a positive impact on psychiatric, and motor and non-motor symptoms in Parkinson’s disease (PD). Methods: We assigned 20 PD patients with a diagnosis of psychiatric disorder to either a 12-week cognitive behavioral therapy (CBT) group or a psychoeducational protocol. For the neurological examination, we administered the Unified Parkinson’s Disease Rating Scale and the non-motor symptoms scale. The severity of psychiatric symptoms was assessed by means of the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, the Brief Psychiatric Rating Scale, and the Clinical Global Impressions. Results: Cognitive behavioral group therapy was effective in treating depression and anxiety symptoms as well as reducing the severity of non-motor symptoms in PD patients; whereas, no changes were observed in PD patients treated with the psychoeducational protocol. Conclusion: CBT offered in a group format should be considered in addition to standard drug therapy in PD patient

Effect of high level of bladder filling on spinal nociception and motoneuronal excitability

To verify whether high level of bladder distension may counteract the inhibitory effect of descending pathways on sacral spinal cord neurons and to investigate which spinal circuitries are possibly involved in such a viscero-somatic interaction. Nociceptive withdrawal reflex (NWR), cutaneous silent period (CSP), and H-reflex were recorded in both lower and upper limbs of twenty-eight healthy subjects. Subjects were examined during baseline (empty bladder, no voiding desire), high level of bladder filling (urgency desire), and control (empty bladder, no voiding desire) sessions. Results showed that the NWR and its related pain perception were reduced in the upper limbs, while only a pain perception reduction in males was observed in the lower limbs. The H-reflex was inhibited in both limbs. No effects were found on the CSP duration. The decrease in both the NWR and its related pain perception in the upper limbs confirms the presence of a bladder distension-induced descending inhibitory modulation on nociception at spinal level. The lack of a similar inhibitory effect in the lower limbs suggests that excitatory nociceptive inputs from bladder afferents counterbalance the inhibitory effect on sacral spinal cord. The lack of the descending inhibitory effect may be a mechanism aimed at forcing the micturition phase to avoid bladder damage caused by bladder sovradistension

Dataset on gait patterns in degenerative neurological diseases

We collected the gait parameters and lower limb joint kinematics of patients with three different types of primary degenerative neurological diseases: (i) cerebellar ataxia (19 patients), (ii) hereditary spastic paraparesis (26 patients), and (iii) Parkinson's disease (32 patients). Sixty-five gender-age matched healthy subjects were enrolled as control group. An optoelectronic motion analysis system was used to measure time-distance parameters and lower limb joint kinematics during gait in both patients and healthy controls

Rationalist architecture in rural villages: petro-morphological characterization of natural asbestos fibers in decorative plasters used for artificial stones

At the beginning of the twentieth century, artificial stones became commonly used as structural building materials, masonry materials, and architectural decorative elements. The main purpose of this work was to characterize the building materials used in a historical building in Codigoro, a small town near Ferrara, northeastern Italy. This building was constructed according to the Italian rationalist rules for monumental architecture and is an example of the rationalist architecture found in rural villages, which uses innovative materials and decorations including artificial stone. The samples analyzed in this work were imitation natural stone, such as “fake travertine” and “fake Ceppo di Grè”, composed of reinforced concrete slabs coated with white mortar. Asbestos minerals have been observed in the fillers in these materials. Petrographic, mineralogical, and chemical characterization of samples of artificial stones and concrete was performed with optical transmitted light microscopy, scanning electron microscopy–energy dispersive spectroscopy, and X-ray diffraction analyses. The results revealed chemical and biological degradation in almost all the artificial stones examined and enabled identification of the presence of calcite, iron oxychloride complexes, and asbestos lizardites used as fillers in two of the analyzed samples. This study aimed to describe a general investigation methodology used to examine the artificial stone façades of the Ex Casa del Fascio of Codigoro, whose architecture is particularly representative of the rationalist architecture in rural villages. The results highlight the relevance of compatible and suitable conservation measures that should be monitored during all restoration interventions to minimize post-degradation fracturing and transformation into elements harmful to human health and the environment

Chemical ear peeling: a simple technique for the treatment of chronic external otitis: how we do it

[NFew conditions encountered by otolaryngologists are as frustrating as chronic otitis externa and recurrent exacerbation presents a special challenge for the attending physician. The disease may be extremely therapy-resistant: a great many patients report chronic suffering from otitis externa with inadequate and inefficacious treatment attempts.1 Current medical treatment is based on topical application of steroids, antibiotics and external auditory canal cleansing.2 Moreover, there are no long-term outcome data on medical management.3 In this study we present, showing the short- and longterm clinical outcomes, a new, safe and simple therapeutic technique for the management of chronic otitis externa: chemical ear peeling (CEP).o abstract available

CADASIL or MS? Consider “Red Flags” but Avoid a Misdiagnosis: Case Series of a Concomitant Diagnosis

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic autosome-dominant disease with chronic clinical course. Rarely, CADASIL may present with atypical relapsing-remitting manifestations, cerebral and spinal white matter lesions, mimicking inflammatory CNS disease as multiple sclerosis (MS). The rarely co-occurrence of MS and CADASIL may represent a hard challenging diagnosis even for an expert neurologist. Here, we present a case series of two patients with CADASIL showing MRI pattern overlapping MS. They were the only case of co-occurrence of CADASIL and MS in their own family. Both patients were treated with anti-inflammatory and anti-platelet drugs, mostly with good response. Pathogenic hypothesis highlights that genetic events, related to monogenic disease, may expose CNS antigens with a consequent self-immune attack. In CADASIL, the function of Notch3 receptor showed a consistent interplay with immune system activity. Indeed, certain mutations of Notch3 receptor show abnormal upregulation of specific pro-inflammatory patterns. However, even if it is not possible to determinate if the proinflammatory activity may be promoted by pathogenic mutations in Notch3, the "apparent" difference between MS and “inflammatory CADASIL” could be considered more semantic than etiologic

Multiscale Entropy Algorithms to Analyze Complexity and Variability of Trunk Accelerations Time Series in Subjects with Parkinson’s Disease

The aim of this study was to assess the ability of multiscale sample entropy (MSE), refined composite multiscale entropy (RCMSE), and complexity index (CI) to characterize gait complexity through trunk acceleration patterns in subjects with Parkinson's disease (swPD) and healthy subjects, regardless of age or gait speed. The trunk acceleration patterns of 51 swPD and 50 healthy subjects (HS) were acquired using a lumbar-mounted magneto-inertial measurement unit during their walking. MSE, RCMSE, and CI were calculated on 2000 data points, using scale factors (t) 1-6. Differences between swPD and HS were calculated at each t, and the area under the receiver operating characteristics, optimal cutoff points, post-test probabilities, and diagnostic odds ratios were calculated. MSE, RCMSE, and CIs showed to differentiate swPD from HS. MSE in the anteroposterior direction at t4 and t5, and MSE in the ML direction at t4 showed to characterize the gait disorders of swPD with the best trade-off between positive and negative posttest probabilities and correlated with the motor disability, pelvic kinematics, and stance phase. Using a time series of 2000 data points, a scale factor of 4 or 5 in the MSE procedure can yield the best trade-off in terms of post-test probabilities when compared to other scale factors for detecting gait variability and complexity in swPD

CBX2 shapes chromatin accessibility promoting AML via p38 MAPK signaling pathway

Abstract Background: The dynamic epigenome and proteins specialized in the interpretation of epigenetic marks critically contribute to leukemic pathogenesis but also offer alternative therapeutic avenues. Targeting newly discovered chromatin readers involved in leukemogenesis may thus provide new anticancer strategies. Accumulating evidence suggests that the PRC1 complex member CBX2 is overexpressed in solid tumors and promotes cancer cell survival. However, its role in leukemia is still unclear. Methods: We exploited reverse genetic approaches to investigate the role of CBX2 in human leukemic cell lines and ex vivo samples. We also analyzed phenotypic effects following CBX2 silencing using cellular and molecular assays and related functional mechanisms by ATAC-seq and RNA-seq. We then performed bioinformatic analysis of ChIPseq data to explore the influence of histone modifications in CBX2-mediated open chromatin sites. Lastly, we used molecular assays to determine the contribution of CBX2-regulated pathways to leukemic phenotype. Results: We found CBX2 overexpressed in leukemia both in vitro and ex vivo samples compared to CD34+ cells. Decreased CBX2 RNA levels prompted a robust reduction in cell proliferation and induction of apoptosis. Similarly, sensitivity to CBX2 silencing was observed in primary acute myeloid leukemia samples. CBX2 suppression increased genome-wide chromatin accessibility followed by alteration of leukemic cell transcriptional programs, resulting in enrichment of cell death pathways and downregulation of survival genes. Intriguingly, CBX2 silencing induced epigenetic reprogramming at p38 MAPK-associated regulatory sites with consequent deregulation of gene expression. Conclusions: Our results identify CBX2 as a crucial player in leukemia progression and highlight a potential druggable CBX2-p38 MAPK network in AML

Nuclear lipid microdomains regulate daunorubicin resistance in hepatoma cells

Daunorubicin is an anticancer drug, and cholesterol is involved in cancer progression, but their relationship has not been defined. In this study, we developed a novel experimental model that utilizes daunorubicin, cholesterol, and daunorubicin plus cholesterol in the same cells (H35) to search for the role of nuclear lipid microdomains, rich in cholesterol and sphingomyelin, in drug resistance. We find that the daunorubicin induces perturbation of nuclear lipid microdomains, localized in the inner nuclear membrane, where active chromatin is anchored. As changes of sphingomyelin species in nuclear lipid microdomains depend on neutral sphingomyelinase activity, we extended our studies to investigate whether the enzyme is modulated by daunorubicin. Indeed the drug stimulated the sphingomyelinase activity that induced reduction of saturated long chain fatty acid sphingomyelin species in nuclear lipid microdomains. Incubation of untreated-drug cells with high levels of cholesterol resulted in the inhibition of sphingomyelinase activity with increased saturated fatty acid sphingomyelin species. In daunodubicin-treated cells, incubation with cholesterol reversed the action of the drug by acting via neutral sphingomyelinase. In conclusion, we suggest that cholesterol and sphingomyelin-forming nuclear lipid microdomains are involved in the drug resistance