PAK1 promotes intestinal tumor initiation.

p21-activated kinase 1 (PAK1) is a serine/threonine kinase that is overexpressed in colorectal cancer. PAK1 is a target of mesalamine [5-aminosylicylic acid (5-ASA)], a common drug for the treatment of ulcerative colitis with prospective chemopreventive properties. Here, we investigated whether PAK1 deletion impedes tumorigenesis in murine intestinal cancer models. Ten-week-old APC(min) or APC(min)/PAK1(-/-) mice were monitored for 8 weeks, euthanized, and assessed for tumor number and size. Six- to 8-week-old PAK1(-/-) and wild-type (WT) mice received one 10 mg/kg intraperitoneal injection of azoxymethane (AOM) and four cycles of 1.7% dextran sodium sulfate (DSS) for 4 days followed by 14 days of regular water. Mice also received 5-ASA via diet. Tumor incidence and size was assessed via colonoscopy and pathology. Molecular targets of PAK1 and 5-ASA were evaluated via immunohistochemistry (IHC) in both models. PAK1 deletion reduced tumor multiplicity and tumor burden but did not alter average tumor size in APC(min) mice. IHC revealed that PAK1 deletion reduced p-AKT, ß-catenin, and c-Myc expression in APC(min) adenomas. Colonoscopy and pathologic analysis revealed that PAK1 deletion reduced tumor multiplicity without affecting tumor size in AOM/DSS-treated mice. 5-ASA treatment and PAK1 deletion impeded tumor multiplicity and dysplastic lesions in AOM/DSS mice. IHC further revealed that 5-ASA blocked ß-catenin signaling via inhibition of PAK1/p-AKT. These data indicate that PAK1 contributes to initiation of intestinal carcinogenesis.

[A modified approach to the diagnosis and therapy of epileptic seizures in the third stage of life]. / Modificirani pristup dijagnostici i tretmanu epileptickih napada u trecem zivotnom dobu.

UNLABELLED: Incidence of seizures in the elderly is nowadays greater than the one characteristic for children up to 10 years of age. Epileptic seizures are the third most common serious neurological disorder in this age group, after stroke and dementia. Optimal care for those patients, regarding to the seizures, demands some modification in diagnostic and treatment approach. Aim of this report was to point out problems in diagnostics, treatment and most common mistakes in practice. Fifty one patients were assessed, aged 65-83 years, (30 female and 21 male), with diagnosis of epilepsy and established antiepileptic treatment. All patients were re-examined, and following procedures were utilised: auto and heteroanamnesis (especially data provided by eyewitnesses), clinical examination, biochemical status, complete cardiological examination, EEG registration, serum concentrations of antiepileptic drugs, CT and MRI scan. Out of 51 patients 11 were misdiagnosed (syncope, provoked seizures, TIA). The most common form of seizures were partial seizures with or without secondary generalization (31 cases). Etiologic factors: stroke (25 cases), arteriosclerosis (7 cases), tumours (3 cases), trauma (2 cases), unknown (3 cases) cardiovascular diseases (29 casec) diabetes mellitus (20 cases), respiratory disturbance (12 cases) renal disturbances (8 cases). TREATMENT: Only 30 patients had monotherapy from the beginning, with either carbamazepine or valproate. Rest were treated from the beginning with 2 antiepileptic drugs (phenobarbital + carbamazepine or pheytoin + phenobarbital). Adverse effects were recorded in 21 patients. I. It is crucial to distingiush unprovoked and provoked seizures during diagnostic procedures, as well as epileptic and non-epileptic attacks; 2. Principle of monotherapy is conditio sine qua non, and in treatment attention should be paid to co-morbidity, multitherapy, drug interactions, intoxication, diminished detoxication and elimination of drugs, as well as increased susceptibility for antiepiletic drugs and other medicaments.