The rat tyrosine phosphatase eta increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue

The expression of the receptor protein tyrosine phosphatase r-PTPeta is drastically reduced in rat and human malignant thyroid cells, whereas its restoration reverts the neoplastic phenotype of retrovirally transformed rat thyroid cells. Moreover, reduced levels and loss of heterozygosity of DEP-1, the human homolog of r-PTPeta, have been found in many human neoplasias. Here, we report that the r-PTPeta protein binds to c-Src in living cells and dephosphorylates the c-Src inhibitory tyrosine phosphorylation site (Tyr 529), thereby increasing c-Src tyrosine kinase activity in malignant rat thyroid cells stably transfected with r-PTPeta. Tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin was enhanced in r-PTPeta-expressing cells. This was associated with increased adhesion of malignant r-PTPeta-transfected thyroid cells vs both untransfected cells and cells stably transfected with an inactive r-PTPeta mutant. Treatment of rat thyroid cells with the c-Src inhibitor PP2 decreased cell adhesion to a higher extent in r-PTPeta-transfected cells than in mock-transfected or stably transfected cells with the inactive r-PTPeta mutant, indicating that r-PTPeta regulates cell-substratum adhesion by activating c-Src. Interestingly, the extent of both c-Src dephosphorylation at Tyr 529, FAK and paxillin phosphorylation, and the increased cell adhesion were associated with the degree of r-PTPeta expression.     

Bloodstream infections and invasive mycoses in children undergoing acute leukaemia treatment: a 13-year experience at a single Italian institution

The incidence rate (IR) of bloodstream infections (BI) and invasive mycoses (IM) during chemotherapy for paediatric acute lymphoblastic (ALL) or non-lymphoblastic leukaemias (AnLL) was evaluated for 153 BI and 22 IM diagnosed during 143,668 patient-days at risk from January 1988 to December 2000. IR, the number of episodes/100 days at risk, was 0.315 for AnLL and 0.092 for ALL (P < 0.001) with significant changes reflecting the intensity of anti-ALL chemotherapy. IR was 0.097 for first-line less intensive, 0.136 during first-line intensive, 0.261 during second-line therapy (P < 0.001), and 0.021 during maintenance. During intensive chemotherapy, the IR for BI was 0.134 in ALL with 0.087 for first-line less intensive therapy, 0.110 for first-line intensive, 0.230 for second-line intensive therapy (P < 0.001) and 0.274 in AnLL (P = 0.001). IR was 0.021 in ALL and 0.048 in AnLL (P = 0.034) for IM. In conclusion, there is a correlation between intensity of chemotherapy and rate of infections in paediatric acute leukaemias.     

Consolidation and maintenance immunotherapy with rituximab improve clinical outcome in patients with B-cell chronic lymphocytic leukemia

BACKGROUND: Rituximab in sequential combination with fludarabine (Flu) allowed patients with B-cell chronic lymphocytic leukemia (B-CLL) to achieve higher remission rates and longer response duration. Based on their recent experience in indolent non-Hodgkin lymphomas, in this study, the authors attempted to demonstrate whether consolidation/maintenance therapy with rituximab could prolong the response duration in this patient population. METHODS: This Phase II study was based on a consolidation/maintenance therapy with rituximab for patients in complete remission (CR) or partial remission (PR) who were positive for minimal residual disease (MRD), as determined by flow cytometry. Seventy-five symptomatic, untreated patients with B-CLL received 6 monthly cycles of Flu (25 mg/m(2) for 5 days) followed by 4 weekly doses of rituximab (375 mg/m(2)). Then, 28 patients who were positive for MRD were consolidated with 4 monthly cycles of rituximab (375 mg/m(2)) followed by 12 monthly low doses of rituximab (150 mg/m(2)). RESULTS: Based on National Cancer Institute criteria, 61 of 75 patients (81%) achieved a CR, 10 of 75 patients (13%) had a PR, and 4 of 75 patients (5%) had either no response or disease progression. MRD-positive patients in CR or PR who received consolidation therapy (n = 28 patients) had a significantly longer response duration (87% vs 32% at 5 years; P = .001) compared with a subset of patients who did not receive consolidation therapy (n = 18 patients). All patients experienced a long progression-free survival from the end of induction treatment (73% at 5 years). It was noteworthy that, within the subset of ZAP-70-positive patients, MRD-positive, consolidated patients (n = 12 patients) had a significantly longer response duration (69% vs 0% at 2.6 years; P = .007) compared with MRD-positive, unconsolidated patients (n = 11 patients). CONCLUSIONS: The addition of a consolidation and maintenance therapy with rituximab prolonged response duration significantly in patients with MRD-positive B-CLL.     

Neuroactive steroids and peripheral myelin proteins

The present review summarizes observations obtained in our laboratories which underline the importance of neuroactive steroids (i.e., progesterone (PROG), dihydroprogesterone (5α-DH PROG), tetrahydroprogesterone (3α, 5α-TH PROG), testosterone (T), dihydrotestosterone (DHT) and 5α-androstan-3α,17β-diol (3α-diol)) in the control of the gene expression of myelin proteins (i.e. glycoprotein Po (Po) and the peripheral myelin protein 22 (PMP22)) in the peripheral nervous system. Utilizing different in vivo (aged and adult male rats) and in vitro (Schwann cell cultures) experimental models, we have observed that neuroactive steroids are able to stimulate the mRNA levels of Po and PMP22. The effects of these neuroactive steroids, which are able to interact with classical (progesterone receptor, PR, and androgen receptor, AR) and non-classical (GABA_A receptor) steroid receptors is further supported by our demonstration in sciatic nerve and/or Schwann cells of the presence of these receptors. On the basis of the observations obtained in the Schwann cells cultures, we suggest that the stimulatory effect of neuroactive steroids on Po is acting through PR, while that on PMP22 needs the GABA_A receptor. The present findings might be of importance for the utilization of specific receptor ligands as new therapeutical approaches for the rebuilding of the peripheral myelin, particularly in those situations in which the synthesis of Po and PMP22 is altered (i.e. demyelinating diseases like Charcot–Marie–Tooth type 1A and type 1B, hereditary neuropathy with liability to pressure palsies and the Déjérine–Sottas syndrome, aging, and after peripheral injury).     

Atopy in childhood idiopathic nephrotic syndrome

AIM: Aim of the study was to evaluate the immunoallergic pattern and their modulating serum cytokines in children with primary manifestation of nephrotic syndrome, in order to analyse the correlation with disease activity and the outcome of childhood NS. MATERIALS AND METHODS: We have evaluated 72 children: 58 steroid-sensitive and 14 steroid-resistant; 42 subjects were the healthy controls. In all were measured serum: T cell-subset, cytokines by Th-1, Th-2, total IgE levels and specific IgE antibodies. RESULTS: Of the 72 children investigated, 35 (48.6%) had either a history of atopy and/or elevated serum IgE; 14 of these children (40%) had clinical sign of an atopic disease (asthma, rhinitis, dermatitis) and 21 (60%) had elevated sIgE. The atopy was more frequent among SS than SRNS patients (52% versus 36%, p<0.05). The CD19 were significantly increased in nephrotic patients compared with controls. IL-4 levels were not different from those in normal control both in SS and SRNS patients, either in relapse than in remission. There was no correlation between the sIgE and IL-4 levels. Therefore, IL-5 and Il-13 levels were significantly higher in SSNS compared to controls, in both pre than posttreatment, and higher in atopic patients. Interestingly, IL-6 and IL-10 levels were significantly increased in SRNS pretreatment compared to posttreatment and controls and, only for IL-10, significantly higher in atopic patients. CONCLUSION: In our study, only 40% of atopic children had a positive allergic history and 51.4% of the nephrotic children had normal sIgE levels, both pre and posttreatment, indicating different aetiologies, as immune mechanisms, in the pathogenesis of NS. Therefore, specific IgE antibodies were not related to disease activity, suggesting that IgE production might be co-incident in childhood NS. However, the increased production of IL-5 and IL-13 in atopic SSNS may indicate that these cytokines are involved in the enhanced production of sIgE while IL-4 have a role as controlling cytokine.     

Keratinocyte growth factor receptors

Modulation of the number of functional growth factor receptors on the epithelial cell surface that is exposed to the action of cognate ligands represents a key strategy in cellular physiology to regulate the proliferation rate and the differentiation process. The keratinocyte growth factor receptor (KGFR) and the epidermal growth factor receptor (EGFR), among the growth factor receptors expressed on keratinocytes, are believed to play a unique crucial role in controlling epithelial proliferation. KGFR and EGFR appear to also contribute to the cell differentiation process. Modulation of KGFR and EGFR on the proliferation rate and differentiation process has been reported either in in vivo or in vitro conditions. This article reviews the architecture, the ligand binding activated-signaling pathways, and the biologic effects of KGFR and EGFR on keratinocytes.     

Helicobacter pylori as cause of gastrointestinal disease in children with hemato-oncologic diseases

After documentation of a case of life threatening Helicobacter pylori (H. pylori) gastric ulcer in an adolescent girl on treatment for acute lymphoblastic leukaemia, we started to systematically look for gastro-intestinal symptoms due to H. pylori infection in our cancer patients at G. Gaslini Children's Hospital. During a period of 46 months, we observed 13 further cases of severe dyspepsia syndrome or gastro intestinal bleeding associated with presence of H. pylori faecal antigen. All patients recovered with appropriate therapy. H. pylori may represent a cause of severe gastrointestinal complications in children with cancer or following bone marrow transplant.     

Efficacy and safety of glucose-lowering agents in patients with type 2 diabetes: A network meta-analysis of randomized,active comparator-controlled trials

AimAim of the present network meta-analysis (NMA) is the comparison across glucose-lowering drugs (GLA) concerning their effects on glucose control, body weight, hypoglycemia, gastrointestinal adverse events, and quality of life.Data synthesisThis NMA includes randomized clinical trials comparing different head-to-head comparison trials with EMA-approved GLA in type 2 diabetes, with a duration of ≥52 weeks. All drugs have to be administered at the maximal approved dose. Primary endpoints were HbA1c at 12, 52, and 104+ weeks. Secondary endpoints were body weight, quality of life, hypoglycemia, and gastrointestinal disorders. Indirect comparisons of different GLA were performed by NMA choosing metformin as reference. The standardized difference in means (SDM) and Mantel-Haenzel Odds Ratio [MH–OR] (using random-effect models) with 95% Confidence Intervals were calculated for categorical and continuous variables, respectively.We included 68 trials fulfilling all inclusion criteria. At 12 weeks, when considering indirect comparisons, insulin secretagogues (IS) were associated with a significantly greater reduction in comparison with metformin (SDM, ?0.3 [-0.4;-0.2]%); a significantly lower efficacy was observed for pioglitazone. At 52 weeks, IS were no longer associated with a greater reduction of HbA1c; whereas a significant decrease in HbA1c was observed for GLP-1 RA (SDM, ?0.2 [-0.1;-0.3]%). At 104+ weeks, only SGLT-2 inhibitors showed a significantly greater HbA1c reduction (SDM, ?0.2 [-0.1;-0.3]%), whereas sulfonylureas and insulin showed a significantly lower efficacy (SDM, 0.1 [0.0; 0.2]%), and 0.4 [0.3; 0.5]%, respectively).ConclusionsThe results of this meta-analysis should be considered together with evidence on long-term outcomes for selecting the most appropriate drugs for individual patients.