Antithrombotic medications and the etiology of intracerebral hemorrhage: MUCH-Italy.

Objective: To test the hypothesis that the effect of antithrombotic medications on the risk of intracerebral hemorrhage (ICH) varies according to the location of the hematoma.

Methods: Consecutive patients with ICH were enrolled as part of the Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy). Multivariable logistic regression models served to examine whether risk factors for ICH and location of the hematoma (deep vs lobar) predict treatment-specific ICH subgroups (antiplatelets-related ICH and oral anticoagulants [OACs]-related ICH).

Kinase-inhibitor-insensitive cancer stem cells in chronic myeloid leukemia.

Introduction: Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the translocation t(9;22), coding for the chimeric protein BCR-ABL. The development of BCR-ABL tyrosine kinase inhibitors (TKIs) has dramatically revolutionized and improved CML therapy. However, TKI-based therapy faces a major challenge: the insensitivity of CML leukemic stem cells (LSCs) to TKIs.

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.

DOK2 inhibits EGFR-mutated lung adenocarcinoma.

Somatic mutations in the EGFR proto-oncogene occur in ~15% of human lung adenocarcinomas and the importance of EGFR mutations for the initiation and maintenance of lung cancer is well established from mouse models and cancer therapy trials in human lung cancer patients. Recently, we identified DOK2 as a lung adenocarcinoma tumor suppressor gene. Here we show that genomic loss of DOK2 is associated with EGFR mutations in human lung adenocarcinoma, and we hypothesized that loss of DOK2 might therefore cooperate with EGFR mutations to promote lung tumorigenesis.

Complications of acute stroke and the occurrence of early seizures.

Background: Seizures are common neurological consequences of stroke. Although a number of factors including stroke severity on admission, cortical involvement, and stroke subtype have been consistently associated with post-stroke seizures, the effect that medical and neurological complications of stroke, occurring in the very acute phase, might have on such a risk has never been adequately explored. In the present study we aimed at determining the extent to which complications within the first week of stroke influence the risk of early seizures (ES).

Obesity and the risk of intracerebral hemorrhage: the multicenter study on cerebral hemorrhage in Italy.

Background And Purpose: The effect of obesity on the risk of intracerebral hemorrhage (ICH) may depend on the pathophysiology of vessel damage. To further address this issue, we investigated and quantified the correlations between obesity and obesity-related conditions in the causal pathways leading to ICH.

Methods: A total of 777 ICH cases ≥ 55 years of age (287 lobar ICH and 490 deep ICH) were consecutively enrolled as part of the Multicenter Study on Cerebral Hemorrhage in Italy and compared with 2083 control subjects by a multivariate path analysis model.

Bilateral optic perineuritis as the presenting feature of giant cell arteritis.

Optic perineuritis (OPN) is an uncommon inflammatory disorder of the optic nerve sheath. Most cases are idiopathic, though OPN can rarely occur as a manifestation of vasculitic diseases. We describe the case of a 74-year-old Caucasian man presenting with diplopia and bilateral visual loss.

A key role for ATF3 in regulating mast cell survival and mediator release.

Activating transcription factor 3 (ATF3) is a basic leucine zipper transcription factor that plays a regulatory role in inflammation, cell division, and apoptosis. Mast cells (MCs) initiate many inflammatory responses and have a central role in allergy and allergic diseases. We report here that ATF3 has a central role in MC development and function.

Identification of DOK genes as lung tumor suppressors.

Genome-wide analyses of human lung adenocarcinoma have identified regions of consistent copy-number gain or loss, but in many cases the oncogenes and tumor suppressors presumed to reside in these loci remain to be determined. Here we identify the downstream of tyrosine kinase (Dok) family members Dok1, Dok2 and Dok3 as lung tumor suppressors. Single, double or triple compound loss of these genes in mice results in lung cancer, with penetrance and latency dependent on the number of lost Dok alleles.

HHV8-positive, HIV-negative multicentric Castleman's disease: early and sustained complete remission with rituximab therapy without reactivation of Kaposi sarcoma.

Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder with systemic symptoms and poor prognosis and is characterized by an abnormal proliferation of polyclonal plasmablasts in the mantle zone of B-cell follicles. The disease is found primarily in chronic HIV carriers and is usually strictly associated with human herpes virus type 8 (HHV-8) coinfection, which is believed to play a key role in the pathogenesis of MCD. The disease is also diagnosed in HIV-negative patients, who are usually elderly or immunosuppressed; however, in about half of these cases, no evidence of HHV8 infection is found.

DNA methylation biomarkers of prostate cancer: confirmation of candidates and evidence urine is the most sensitive body fluid for non-invasive detection.

Background: A prostate cancer (PCa) biomarker with improved specificity relative to PSA is a public health priority. Hypermethylated DNA can be detected in body fluids from PCa patients and may be a useful biomarker, although clinical performance varies between studies. We investigated the performance of candidate PCa DNA methylation biomarkers identified through a genome-wide search.

PML targeting eradicates quiescent leukaemia-initiating cells.

The existence of a small population of 'cancer-initiating cells' responsible for tumour maintenance has been firmly demonstrated in leukaemia. This concept is currently being tested in solid tumours. Leukaemia-initiating cells, particularly those that are in a quiescent state, are thought to be resistant to chemotherapy and targeted therapies, resulting in disease relapse.

Increase sensitivity to chemotherapeutical agents and cytoplasmatic interaction between NPM leukemic mutant and NF-kappaB in AML carrying NPM1 mutations.

Mutations in nucleophosmin (NPM) exon 12 and the resulting delocalization of NPM into the cytoplasm are the most specific and frequent cellular events in acute myeloid leukemia patients (AML) with normal karyotype. Cytoplasmatic NPM (NPMc+) is associated with responsiveness to chemotherapy and better prognosis. The activation of nuclear factor-kappaB (NF-kappaB) has been demonstrated to occur in a subset of AML patients and is thought to induce resistance to many chemotherapeutical agents.

Bortezomib-mediated proteasome inhibition as a potential strategy for the treatment of rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood, divided into two major histological subtypes, embryonal (ERMS) and alveolar (ARMS). To explore the possibility that the proteasome could be a target of therapeutic value in rhabdomyosarcoma, we treated several RMS cell lines with the proteasome inhibitor bortezomib (Velcade or PS-341) at a concentration of 13-26 nM. RMS cells showed high sensitivity to the drug, whereas no toxic effect was observed in primary human myoblasts.

NF-kB inhibition as a strategy to enhance etoposide-induced apoptosis in K562 cell line.

NF-kB is a transcription factor that mediates antiapoptotic signals in several cancer cell lines. Here we have demonstrated that the cytotoxic drug, Etoposide, activates NF-kB in K562, a chronic myeloid leukemia blast crisis cell line. Treatment with the NF-kB inhibitors MG-132, Bay11-7082, and Resveratrol impedes Etoposide-induced NF-kB activation, rendering K562 sensitive to Etoposide-induced apoptosis.

Quantitative assessment of WT1 expression in diagnosis of childhood acute leukemia.

The purpose of this study was to investigate WT1 expression levels in childhood acute leukemia. Bone marrow from 14 children with acute leukemia at diagnosis and from 7 children with solid tumors without bone marrow involvement (control group) was studied. Five of the 14 patients (35.

Valproate enhances imatinib-induced growth arrest and apoptosis in chronic myeloid leukemia cells.

Background: The objective of this study was to evaluate the ability of the clinically available histone deacetylase (HDAC) inhibitor valproate to enhance the cytotoxicity of the Bcr-Abl inhibitor imatinib in imatinib-resistant cell lines.

Methods: Interactions between imatinib, and valproate have been examined in imatinib-sensitive and -resistant chronic myeloid leukemia (CML)cell lines (K562, KCL-22, CML-T1) and in bone marrow mononuclear cells (MNCs) derived from imatinib-resistant CML patients.

Results: In imatinib-sensitive cell lines, cotreatment with imatinib 0.

The NF-kappaB pathway blockade by the IKK inhibitor PS1145 can overcome imatinib resistance.

Imatinib represents at present the most attractive therapy for BCR-ABL positive leukemias, even though a percentage of CML patients develop resistance to this compound. For these resistant patients a therapeutic approach based on a combination of drugs is more likely to be effective. In the last years, constitutive NF-kappaB/Rel activity has been demonstrated in several hematological malignancies.

Increase in platelet count in older, poor-risk patients with acute myeloid leukemia or myelodysplastic syndrome treated with valproic acid and all-trans retinoic acid.

Background: The authors investigated the efficacy and safety of the histone deacetylase inhibitors valproic acid (VPA) and all-trans retinoic acid (ATRA) as differentiation agents in a cohort of older, poor-risk patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

Methods: Twenty older patients with recurrent or refractory AML or MDS were treated in a Phase II protocol with sequential VPA and ATRA therapy. VPA was started at a dose of 10 mg/kg per day and then escalated to achieve the serum concentration of 45-100 microg/mL.

RNAi technology and lentiviral delivery as a powerful tool to suppress Tpr-Met-mediated tumorigenesis.

Tpr-Met, the oncogenic counterpart of the Met receptor, has been detected in gastric cancers, as well as in precursor lesions and in the adjacent normal gastric mucosa. This has prompted the suggestion that Tpr-Met may predispose to the development of gastric tumors. Given the sequence specificity of RNA interference, oncogenes activated by point mutation or rearrangements can be targeted while spearing the product of the wild-type allele.

Rational approaches to the design of therapeutics targeting molecular markers: the case of chronic myelogenous leukemia.

Progress in understanding the molecular basis of signal transmission and transduction has contributed substantially to clarifying the mechanisms of leukemogenesis and of leukemia progression and has led to the identification of a number of specific molecular targets for treatment. Chronic myeloid leukemia (CML) has provided one of the best models, as the identification of a leukemia-specific hybrid tyrosine kinase (BCR-ABL, p210, p190) has led to the identification and the successful therapeutic application of a powerful tyrosine kinase inhibitor, imatinib. The BCR-ABL fusion gene is the result of a reciprocal translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11), which characterizes more than 95% of the cases of CML.

Sensitivity to imatinib therapy may be predicted by testing Wilms tumor gene expression and colony growth after a short in vitro incubation.

Background: The objective of the current study was to verify the ability to predict response to imatinib therapy using in vitro assays to evaluate the inhibition of Wilms tumor gene (WT1) expression and colony growth after samples obtained from patients with chronic myelogenous leukemia (CML) before the start of treatment were subjected to short-term incubation with imatinib.

Methods: WT1 transcript levels and colony growth in bone marrow (BM) samples from 23 patients with CML that was later identified as being responsive to imatinib and from 13 patients with CML that was later identified as not being responsive to imatinib were evaluated after incubation of these samples with imatinib at a concentration of 1 microM for 18 hours. In addition, real-time quantitative polymerase chain reaction (RQ-PCR) analysis of WT1 expression was performed during follow-up, and the results were analyzed for associations with cytogenetic response and with BCR/ABL transcript levels as determined using RQ-PCR analysis.