Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

Tumours of the central nervous system are intrinsically more dangerous than tumours at other sites, and in particular, brain tumours are responsible for 3% of cancer deaths in the UK. Despite this, research into new therapies only receives 1% of national cancer research spend. The most common chemotherapies are temozolomide, procarbazine, carmustine, lomustine and vincristine, but because of the rapid development of chemoresistance, these drugs alone simply aren’t sufficient for long-term treatment. Such poor prognosis of brain tumour patients prompted us to research new treatments for malignant glioma, and in doing so, it became apparent that aromatic heterocycles play an important part, especially the indole, carbazole and indolocarbazole scaffolds. This review highlights compounds in development for the treatment of tumours of the central nervous system which are structurally based on the indole, carbazole and indolocarbazole scaffolds, under the expectation that it will highlight new avenues for research for the development of new compounds to treat these devastating neoplasms

Infantile epileptic encephalopathy with hypsarrhythmia (infantile spasms/west syndrome) and immunity

West syndrome is a severe epilepsy, occurring in infancy, that comprises epileptic seizures known as spasms, in clusters, and a unique EEG pattern, hypsarrhythmia, with psychomotor regression. Maturation of the brain is a crucial component. The onset is within the first year of life, before 12 months of age. Patients are classified as cryptogenic (10 to 20%), when there are no known or diagnosed previous cerebral insults, and symptomatic (80 to 90%), when associated with pre-existing cerebral damages. The time interval from a brain insult to infantile spasms onset ranged from 6 weeks to 11 months. West syndrome has a time-limited natural evolutive course, usually disappearing by 3 or 4 years of age. In 62% of patients, there are transitions to another age-related epileptic encephalopathies, the Lennox-Gastaut Syndrome and severe epilepsy with multiple independent foci. Spontaneous remission and remission after viral infections may occur. Therapy with ACTH and corticosteroids are the most effective. Reports about intravenous immunoglobulins action deserve attention. There is also immune dysfunction, characterized mainly by anergy, impaired cell-mediated immunity, presence of immature thymocytes in peripheral blood, functional impairment of T lymphocytes induced by plasma inhibitory factors, and altered levels of immunoglobulins. Changes in B lymphocytes frequencies and increased levels of activated B cells have been reported. Sensitized lymphocytes to brain extract were also described. Infectious diseases are frequent and may, sometimes, cause fatal outcomes. Increase of pro-inflamatory cytokines in serum and cerebrospinal fluid of epileptic patients were reported. Association with specific HLA antigens was described by several authors (HLA-DR7, HLA-A7, HLA-DRw52, and HLA-DR5). Auto-antibodies to brain antigens, of several natures (N-methyl-d-aspartate glutamate receptor, gangliosides, brain tissue extract, synaptic membrane, and others), were described in epileptic patients and in epileptic syndromes. Experimental epilepsy studies with anti-brain antibodies demonstrated that epileptiform discharges can be obtained, producing hyperexcitability leading to epilepsy. We speculate that in genetically prone individuals, previous cerebral lesions may sensitize immune system and trigger an autoimmune disease. Antibody to brain antigens may be responsible for impairment of T cell function, due to plasma inhibitory effect and also cause epilepsy in immature brains. © 2008 Bentham Science Publishers Ltd

Alterações cognitivas em escolares de classe socio-econômica desfavorecida: resultados de intervenção psicopedagógica

O objetivo deste estudo é analisar o resultado de intervenções psicopedagógicas no desempenho intelectual e em algumas funções cognitivas específicas em crianças provenientes de famílias de baixa renda, expostas a fatores pessoais e sociais adversos, como desnutrição, stress familiar, ambientes doméstico e de estimulação empobrecidos. Foram examinadas 63 crianças, alunas de escola, gratuita e em regime de semi-internato, que recebe crianças consideradas sob risco pessoal e social. Quarenta e três crianças receberam atividades que objetivam ativação cognitiva, durante período mínimo de 1 ano. Vinte crianças eram recém-admitidas. As técnicas da ativação escolhidas foram: método de aprendizagem ativa, com base em Piaget e método de ativação cognitiva para, através de exercícios psicomotores, desenvolver os pré-requisitos para aprendizagem e prevenção de dificuldades escolares, segundo Lambert. A avaliação das funções cognitivas mostrou: nível intelectual insatisfatório em 30% e médio ou superior em 70% e deficiências cognitivas específicas (noção do esquema corporal, percepção viso-motora, percepção de forma e perseveração) em 74%. Maior prevalência de crianças com inteligência superior (p < 0,05) associou-se a dois fatores: 1º: maior tempo de freqüência à escola (de 1 a 3 anos) e 2º: programas de ativação cognitiva. Não foram observadas diferenças entre os 2 grupos em relação à prevalência de alterações das funções cognitivas específicas examinadas. Os resultados demonstram que a recuperação de crianças com as dificuldades descritas é difícil. Exige investigação sistemática sobre os métodos psicopedagógicas selecionados e possivelmente, grande tempo de permanência da criança na escola, além de admissão mais precoce.Sixty-three school-age children of low socioeconomic status and exposed to adverse environmental factors (malnutrition, familiar distress and low familiar incomes) were submitted to neuropsychological tests to investigate possible cognitive impairments. Classical neuropsychological test battery was employed (Raven test, Bender Gestalt copy of complex figures, draw-a-man Goodenough test). Low intellectual level was found on 30% and 74% showed higher cognitive disorders (visuoperceptual skills and/or perseverations and/or global shapes perception and/or draw-a-man disturbances). These children attended to a school with semi-boarding regimen which receives children under personnel and social adverse factors. School program was enriched with learning activity program based on Piaget and psychomotor exercises based on Lambert for at least one year. They also had some other activities, as painting, singing, computer training, English and Spanish classes. Twenty children were newly accepted and 43 attended at school for one, two or three years. We found significant correlations (pchi0.05) between superior intellectual performances, bigger periods of attendance at school and methods for cognitive development. There was no association between other brain cognitive functions examined, the attendance to the teaching programs and the years of permanence at school

Genetic and modifying factors that determine the risk of brain tumors

Some modifying factors may determine the risk of brain tumors. Until now, it could not be attempted to identify people at risk and also to improve significantly disease progression. Current therapy consists of surgical resection, followed by radiation therapy and chemotherapy. Despite of these treatments, the prognosis for patients is poor. In this review, we highlight general aspects concerning genetic alterations in brain tumors, namely astrocytomas, glioblastomas, oligodendrogliomas, medulloblastomas and ependymomas. The influence of these genetic alterations in patients' prognosis is discussed. Mutagen sensivity is associated with cancer risk. The convincing studies that linked DNA damages and DNA repair alterations with brain tumors are also described. Another important modifying factor is immunity. General immune response against cancer, tumor microenvironment and immune response, mechanisms of tumor escape, CNS tumor immunology, immune defects that impair anti-tumor systemic immunity in brain tumor patients and local immunosuppressive factors within CNS are also reviewed. New hope to treatment perspectives, as dendritic-cell-based vaccines is summarized too. Concluding, it seems well established that there is association between brain tumor risk and mutagen sensivity, which is highly heritable. Primary brain tumors cause depression in systemic host immunity; local immunosuppressive factors and immunological characteristics of tumor cells may explain the poor prognosis and DNA damages responses can alert immune system. However, it is necessary to clarify if individuals with both constitutional defects in immune functions and genetic instability have higher risk of developing brain tumors. Cytogenetic prospective studies and gene copy number variations analysis also must be performed in peripheral lymphocytes from brain tumor patients. © 2011 Bentham Science Publishers Ltd