Inactivation of PNKP by mutant ATXN3 triggers apoptosis by activating the DNA damage-response pathway in SCA3.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an untreatable autosomal dominant neurodegenerative disease, and the most common such inherited ataxia worldwide. The mutation in SCA3 is the expansion of a polymorphic CAG tri-nucleotide repeat sequence in the C-terminal coding region of the ATXN3 gene at chromosomal locus 14q32.1. The mutant ATXN3 protein encoding expanded glutamine (polyQ) sequences interacts with multiple proteins in vivo, and is deposited as aggregates in the SCA3 brain. A large body of literature suggests that the loss of function of the native ATNX3-interacting proteins that are deposited in the polyQ aggregates contributes to cellular toxicity, systemic neurodegeneration and the pathogenic mechanism in SCA3. Nonetheless, a significant understanding of the disease etiology of SCA3, the molecular mechanism by which the polyQ expansions in the mutant ATXN3 induce neurodegeneration in SCA3 has remained elusive. In the present study, we show that the essential DNA strand break repair enzyme PNKP (polynucleotide kinase 3'-phosphatase) interacts with, and is inactivated by, the mutant ATXN3, resulting in inefficient DNA repair, persistent accumulation of DNA damage/strand breaks, and subsequent chronic activation of the DNA damage-response ataxia telangiectasia-mutated (ATM) signaling pathway in SCA3. We report that persistent accumulation of DNA damage/strand breaks and chronic activation of the serine/threonine kinase ATM and the downstream p53 and protein kinase C-d pro-apoptotic pathways trigger neuronal dysfunction and eventually neuronal death in SCA3. Either PNKP overexpression or pharmacological inhibition of ATM dramatically blocked mutant ATXN3-mediated cell death. Discovery of the mechanism by which mutant ATXN3 induces DNA damage and amplifies the pro-death signaling pathways provides a molecular basis for neurodegeneration due to PNKP inactivation in SCA3, and for the first time offers a possible approach to treatment.

Biomimetic superhydrophobic surfaces patterned with wettable spots as implantable chips for in vivo high-content 3D biomaterials response assessment

"Tissue engineering: part A", vol. 21, suppl. 1 (2015)

Assessing treatment response to prophylactic lithium use in patients with bipolar disorder

ABSTRACT Objetive To identify potential clinical and epidemiological predictors of long-term response to lithium treatment. Methods A total of 40 adult outpatients followed in an university hospital, with confirmed diagnosis of bipolar disorder and with history of lithium use for at least a six months period, had their response to this medication assessed through the use of a standardized instrument. The ALDA scale is based on retrospective clinical data, in our study assessed through a thoroughly reviewed of the medical charts, and is used to evaluate the clinical improvement with the treatment (Criterion A), corrected by the acknowledgement of possible confounding factors, such as duration of the treatment, compliance and concomitant use of additional medications (Criterion B), in order to estimate the response that can be specifically attributable to lithium. Results Our study found an inverse relation between the number of mood episodes with psychotic symptoms and lithium treatment outcome. Conclusion The results reinforce the hypothesis that lithium seems to be less efficacious in patients with bipolar disorder who present psychotic symptoms.

HOXA9 as a key regulator in glioma initiation, aggressiveness and response to therapy

Tese de Doutoramento em Ciências da Saúde

Development of multifunctional coatings deposited on polymers based sensors for biomedical applications

Tese de Doutoramento (Programa Doutoral em Engenharia de Materiais)

Ventricular evoked response in patients with hypertrophic obstructive cardiomyopathy treated with DDD pacing

OBJECTIVE: To assess the changes in ventricular evoked responses (VER) produced by the decrease in left ventricular outflow tract gradient (LVOTG) in patients with hypertrophic obstructive cardiomyopathy (HOCM) treated with dual-chamber (DDD) pacing. METHODS: A pulse generator Physios CTM (Biotronik, Germany) was implanted in 9 patients with severe drug-refractory HOCM. After implantation, the following conditions were assessed: 1) Baseline evaluation: different AV delay (ranging from 150ms to 50 ms) were sequentially programmed during 5 to 10 minutes, and the LVOTG (as determined by Doppler echocardiography) and VER recorded; 2) standard evaluation, when the best AV delay (resulting in the lowest LVOTG) programmed at the initial evaluation was maintained so that its effect on VER and LVOTG could be assessed during each chronic pacing evaluation. RESULTS: LVOTG decreased after DDD pacing, with a mean value of 59 ± 24 mmHg after dual chamber pacemaker, which was significantly less than the gradient before pacing (98 + 22mmHg). An AV delay >100ms produced a significantly lower decrease in VER depolarization duration (VER DD) when compared to an AV delay <=100ms. Linear regression analyses showed a significant correlation between the LVOTG values and the magnitude of VER (r=0.69; p<0.05) in the 9 studied patients. CONCLUSION: The telemetry obtained intramyocardial electrogram is a sensitive means to assess left ventricular dynamics in patients with HOCM treated with DDD pacing.

Response of blood pressure to maximum exercise in hypertensive patients under different therapeutic programs

OBJECTIVE: To evaluate the behavior of blood pressure during exercise in patients with hypertension controlled by frontline antihypertension drugs. METHODS: From 979ergometric tests we retrospectively selected 49 hipertensive patients (19 males). The age was 53±12 years old and normal range rest arterial pressure (<=140/90 mmHg) all on pharmacological monotherapy. There were 12 on beta blockers; 14 on calcium antagonists, 13 on diuretics and 10 on angiotensin converting enzyme inhibitor. Abnormal exercise behhavior of blood pressure was diagnosed if anyone of the following criteria was detected: peak systolic pressure above 220 mmHg, raising of systolic pressure > or = 10 mmHg/MET; or increase of diastolic pressure greater than 15 mmHg. RESULTS: Physiologic response of arterial blood pressure occurred in 50% of patients on beta blockers, the best one (p<0.05), in 36% and 31% on calcium antagonists and on diuretics, respectively, and in 20% on angiotensin converting enzyme inhibitor, the later the leastr one (p<0.05). CONCLUSION: Beta-blockers were more effective than calcium antagonists, diuretics and angiotensin-converting enzyme inhibitors in controlling blood pressure during exercise, and angiotensin converting enzyme inhibitors the least effective drugs.