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

Duodenal-Jejunal Bypass and Jejunectomy Improve Insulin Sensitivity in Goto-Kakizaki Diabetic Rats Without Changes in Incretins or Insulin Secretion

Gastric bypass surgery can dramatically improve type 2 diabetes. It has been hypothesized that by excluding duodenum and jejunum from nutrient transit, this procedure may reduce putative signals from the proximal intestine that negatively influence insulin sensitivity (SI). To test this hypothesis, resection or bypass of different intestinal segments were performed in diabetic Goto-Kakizaki and Wistar rats. Rats were randomly assigned to five groups: duodenal-jejunal bypass (DJB), jejunal resection (jejunectomy), ileal resection (ileectomy), pair-fed sham-operated, and nonoperated controls. Oral glucose tolerance test was performed within 2 weeks after surgery. Baseline and poststimulation levels of glucose, insulin, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were measured. Minimal model analysis was used to assess SI. SI improved after DJB (SI = 1.14 ± 0.32 × 10−4 min−1 ⋅ pM−1) and jejunectomy (SI = 0.80 ± 0.14 × 10−4 min−1 ⋅ pM−1), but not after ileectomy or sham operation/pair feeding in diabetic rats. Both DJB and jejunal resection normalized SI in diabetic rats as shown by SI levels equivalent to those of Wistar rats (SI = 1.01 ± 0.06 × 10−4 min−1 ⋅ pM−1; P = NS). Glucose effectiveness did not change after operations in any group. While ileectomy increased plasma GIP levels, no changes in GIP or GLP-1 were observed after DJB and jejunectomy. These findings support the hypothesis that anatomic alterations of the proximal small bowel may reduce factors associated with negative influence on SI, therefore contributing to the control of diabetes after gastric bypass surgery

Recyclable GO-Arginine Hybrids for CO2 Fixation into Cyclic Carbonates

New covalently modified GO-guanidine materials are realized on a gram-scale synthesis and purified via an innovative microfiltration. The use of these composites in the fixation of CO2into cyclic carbonates is demonstrated. Mild operating conditions, high yields (up to 85%), wide scope (15 examples) and recoverability/reusability (up to 5 cycle) of the material account for the efficiency of the protocol. Dedicated control experiments contributed to shed light on the activation modes exerted by the GO-Arg (Arg: arginine) during the ring-opening/closing synthetic sequence

Synthesis of Indenes via Graphene Oxide Mediated Manipulation of Morita-Baylis-Hillman Alcohols

A new metal-free synthetic approach to functionalized indenes is documented. The use of commercially available graphene oxide (GO) allowed the direct access to indenyl cores (yield up to 80%) via intramolecular Friedel-Crafts-type allylic alkylations with readily available Morita-Baylis-Hillman alcohols. Combined experimental and spectroscopic investigations contributed to shed light on the reaction mechanism dealing with a nanostructured carbon material-based C-C bond forming reaction

Direct Synthesis of α-Aryl-α-Trifluoromethyl Alcohols via Nickel Catalyzed Cross-Electrophile Coupling

A nickel-catalyzed reductive cross-electrophile coupling between the redox-active N-trifluoroeth-oxyphthalimide and iodoarenes is documented. The protocol reproduces a formal arylation of trifluoroacetaldehyde under mild conditions in high yields (up to 88 %) and with large functional group tolerance (30 examples). A combined computational and experimental investigation revealed a pivotal solvent assisted 1,2-Hydrogen Atom Transfer (HAT) process to generate a nucleophilic α-hydroxy-α-trifluoromethyl C-centered radical for theC sp2Csp3 bond forming process

TOX Expression in Mycosis Fungoides and Sezary Syndrome.

Mycosis fungoides (MF) and Sezary syndrome (SS) are the two most common type of cutaneous T-cell lymphoma (CTCL). Currently, no markers can be clearly related to prognosis or to differential diagnosis between early stages and inflammatory benign diseases (IBD). The thymocyte selection-associated high mobility group box factor (TOX), has been proposed as a possible marker in differential diagnosis between early CTCL stages and IBD. Recently TOX has been related to prognosis. We aimed to investigate whether TOX may be a diagnostic or prognostic marker. MF and SS biopsies between 2010 and 2020 were retrieved. New tissues slides were stained with an anti-TOX antibody, (Clone NAN448B). On each slide, 5 fields were examined at high magnification (400×), to evaluate the percentage of marker-positivity in a quantitative way. Thirty-six patients (12 females and 24 males) and 48 biopsies were collected. Nine patients had multiple biopsies. TOX expression in MF/SS cases showed an increase from early to advanced phases. TOX was not regarded as a prognostic marker due to the absence of significant changes by comparing early MF cases with reactive conditions. TOX statistical significance increased in patients alive with disease and in those dead of disease (p = 0.013 and = 0.0005, respectively) as compared with patients in complete remission. Our results show that TOX should be regarded more as a prognostic than a diagnostic marker.This research received no external fundingS

BRAF V600E-positive monomorphic epitheliotropic intestinal T-cell lymphoma complicating the course of hairy cell leukemia

Hairy cell leukemia (HCL) is an uncommon B-cell chronic lymphoproliferative disorder whose pathogenesis and recurrence are strictly dependent on the presence of the BRAF V600E mutant. A 65-year-old male presented a monomorphic epitheliotropic intestinal T-cell lymphoma (formerly enteropathy-associated T-cell lymphoma, type II) with HCL not responding to first-line induction with cladribine. The intestinal lymphoma bears the BRAF V600E mutant, which is the molecular hallmark of HCL, being implicated in its pathogenesis. The case is of interest, as it provides the first description of a BRAF V600E-positive intestinal T-cell lymphoma, along with immunohistochemical and molecular demonstration, occurring in concomitance with HCL. A novel digital PCR-base method for HCL disease assessment is also suggested

Graphene-Oxide Mediated Chemodivergent Ring-Opening of Cyclobutanols

The chemodivergent ring-opening of cyclobutanols is described under the carbocatalytic assistance of graphene oxide (GO). The protocol enables the synthesis of diversely functionalized dienes or indenes (26 examples) based on the amount of GO employed. Spectroscopic (XPS and ssNMR) as well as experimental investigations revealed a direct involvement of the π-domains of GO in tuning the stability of carbocationic intermediates during the reaction