Efeito da curcumina na angiogênese em modelo experimental de câncer de mama

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Melatonin decreases breast cancer metastasis by modulating Rho-associated kinase protein-1 expression

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Neuroimaging during Trance State: A Contribution to the Study of Dissociation

Despite increasing interest in pathological and non-pathological dissociation, few researchers have focused on the spiritual experiences involving dissociative states such as mediumship, in which an individual (the medium) claims to be in communication with, or under the control of, the mind of a deceased person. Our preliminary study investigated psychography - in which allegedly "the spirit writes through the medium's hand" - for potential associations with specific alterations in cerebral activity. We examined ten healthy psychographers - five less expert mediums and five with substantial experience, ranging from 15 to 47 years of automatic writing and 2 to 18 psychographies per month - using single photon emission computed tomography to scan activity as subjects were writing, in both dissociative trance and non-trance states. The complexity of the original written content they produced was analyzed for each individual and for the sample as a whole. The experienced psychographers showed lower levels of activity in the left culmen, left hippocampus, left inferior occipital gyrus, left anterior cingulate, right superior temporal gyrus and right precentral gyrus during psychography compared to their normal (non-trance) writing. The average complexity scores for psychographed content were higher than those for control writing, for both the whole sample and for experienced mediums. The fact that subjects produced complex content in a trance dissociative state suggests they were not merely relaxed, and relaxation seems an unlikely explanation for the underactivation of brain areas specifically related to the cognitive processing being carried out. This finding deserves further investigation both in terms of replication and explanatory hypotheses.

Late-onset social anxiety disorder following traumatic brain injury

Background: Neuropsychiatric sequelae are the predominant long-term disability after traumatic brain injury (TBI). This study reports a case of late-onset social anxiety disorder (SAD) following TBI. Case report: A patient that was spontaneous and extroverted up to 18-years-old started to exhibit significant social anxiety symptoms. These symptoms became progressively worse and he sought treatment at age 21. He had a previous history of traumatic brain injury (TBI) at age 17. Neuroimaging investigations (CT, SPECT and MRI) showed a bony protuberance on the left frontal bone, with mass effect on the left frontal lobe. He had no neurological signs or symptoms. The patient underwent neurosurgery with gross total resection of the lesion and the pathological examination was compatible with intradiploic haematoma. Conclusions: Psychiatric symptoms may be the only findings in the initial manifestation of slowly growing extra-axial space-occupying lesions that compress the frontal lobe from the outside. Focal neurological symptoms may occur only when the lesion becomes large. This case report underscores the need for careful exclusion of general medical conditions and TBI history in cases of late-onset SAD and may also contribute to the elucidation of the neurobiology of this disorder.

Performance of rest myocardial perfusion imaging in the management of acute chest pain in the emergency room in developing nations (PREMIER trial)

Background. Rest myocardial perfusion imaging (MPI) is effective in managing patients with acute chest pain in developed countries. We aimed to define the role and feasibility of rest MPI in low-to-middle income countries. Methods and Results. Low-to-intermediate risk patients (n = 356) presenting with chest pain to ten centers in eight developing countries were injected with a Tc-99m-based tracer, and standard imaging was performed. The primary outcome was a composite of death, non-fatal myocardial infarction (MI), recurrent angina, and coronary revascularization at 30 days. Sixty-nine patients had a positive MPI (19.4%), and 52 patients (14.6%) had a primary outcome event. An abnormal rest-MPI result was the only variable which independently predicted the primary outcome [adjusted odds ratio (OR) 8.19, 95% confidence interval 4.10-16.40, P = .0001]. The association of MPI result and the primary outcome was stronger (adjusted OR 17.35) when only the patients injected during pain were considered. Rest-MPI had a negative predictive value of 92.7% for the primary outcome, improving to 99.3% for the hard event composite of death or MI. Conclusions. Our study demonstrates that rest-MPI is a reliable test for ruling out MI when applied to patients in developing countries. (J Nucl Cardiol 2012;19:1146-53.)

Quantitative coronary arterial stenosis assessment by multidetector CT and invasive coronary angiography for identifying patients with myocardial perfusion abnormalities

Semi-quantitative stenosis assessment by coronary CT angiography only modestly predicts stress-induced myocardial perfusion abnormalities. The performance of quantitative CT angiography (QCTA) for identifying patients with myocardial perfusion defects remains unclear. CorE-64 is a multicenter, international study to assess the accuracy of 64-slice QCTA for detecting a parts per thousand yen50% coronary arterial stenoses by quantitative coronary angiography (QCA). Patients referred for cardiac catheterization with suspected or known coronary artery disease were enrolled. Area under the receiver-operating-characteristic curve (AUC) was used to evaluate the diagnostic accuracy of the most severe coronary artery stenosis in a subset of 63 patients assessed by QCTA and QCA for detecting myocardial perfusion abnormalities on exercise or pharmacologic stress SPECT. Diagnostic accuracy of QCTA for identifying patients with myocardial perfusion abnormalities by SPECT revealed an AUC of 0.71, compared to 0.72 by QCA (P = .75). AUC did not improve after excluding studies with fixed myocardial perfusion abnormalities and total coronary arterial occlusions. Optimal stenosis threshold for QCTA was 43% yielding a sensitivity of 0.81 and specificity of 0.50, respectively, compared to 0.75 and 0.69 by QCA at a threshold of 59%. Sensitivity and specificity of QCTA to identify patients with both obstructive lesions and myocardial perfusion defects were 0.94 and 0.77, respectively. Coronary artery stenosis assessment by QCTA or QCA only modestly predicts the presence and the absence of myocardial perfusion abnormalities by SPECT. Confounding variables affecting the relationship between coronary anatomy and myocardial perfusion likely account for some of the observed discrepancies between coronary angiography and SPECT results.

Regional lung perfusion estimated by electrical impedance tomography in a piglet model of lung collapse

Borges JB, Suarez-Sipmann F, Bohm SH, Tusman G, Melo A, Maripuu E, Sandstrom M, Park M, Costa EL, Hedenstierna G, Amato M. Regional lung perfusion estimated by electrical impedance tomography in a piglet model of lung collapse. J Appl Physiol 112: 225-236, 2012. First published September 29, 2011; doi: 10.1152/japplphysiol.01090.2010.-The assessment of the regional match between alveolar ventilation and perfusion in critically ill patients requires simultaneous measurements of both parameters. Ideally, assessment of lung perfusion should be performed in real-time with an imaging technology that provides, through fast acquisition of sequential images, information about the regional dynamics or regional kinetics of an appropriate tracer. We present a novel electrical impedance tomography (EIT)-based method that quantitatively estimates regional lung perfusion based on first-pass kinetics of a bolus of hypertonic saline contrast. Pulmonary blood flow was measured in six piglets during control and unilateral or bilateral lung collapse conditions. The first-pass kinetics method showed good agreement with the estimates obtained by single-photon-emission computerized tomography (SPECT). The mean difference (SPECT minus EIT) between fractional blood flow to lung areas suffering atelectasis was -0.6%, with a SD of 2.9%. This method outperformed the estimates of lung perfusion based on impedance pulsatility. In conclusion, we describe a novel method based on EIT for estimating regional lung perfusion at the bedside. In both healthy and injured lung conditions, the distribution of pulmonary blood flow as assessed by EIT agreed well with the one obtained by SPECT. The method proposed in this study has the potential to contribute to a better understanding of the behavior of regional perfusion under different lung and therapeutic conditions.

Neuroimaging in specific phobia disorder: a systematic review of the literature

OBJECTIVE: Specific phobia (SP) is characterized by irrational fear associated with avoidance of specific stimuli. In recent years, neuroimaging techniques have been used in an attempt to better understand the neurobiology of anxiety disorders. The objective of this study was to perform a systematic review of articles that used neuroimaging techniques to study SP. METHOD:A literature search was conducted through electronic databases, using the keywords: imaging, neuroimaging, PET, spectroscopy, functional magnetic resonance, structural magnetic resonance, SPECT, MRI, DTI, and tractography, combined with simple phobia and specific phobia. One-hundred fifteen articles were found, of which 38 were selected for the present review. From these, 24 used fMRI, 11 used PET, 1 used SPECT, 2 used structural MRI, and none used spectroscopy. RESULT: The search showed that studies in this area were published recently and that the neuroanatomic substrate of SP has not yet been consolidated. CONCLUSION: In spite of methodological differences among studies, results converge to a greater activation in the insula, anterior cingulate cortex, amygdala, and prefrontal and orbitofrontal cortex of patients exposed to phobia-related situations compared to controls. These findings support the hypotheses of the hyperactivation of a neuroanatomic structural network involved in SP.

Polymeric micelles and molecular modeling applied to the development of radiopharmaceuticals

Micelles composed of amphiphilic copolymers linked to a radioactive element are used in nuclear medicine predominantly as a diagnostic application. A relevant advantage of polymeric micelles in aqueous solution is their resulting particle size, which can vary from 10 to 100 nm in diameter. In this review, polymeric micelles labeled with radioisotopes including technetium (99mTc) and indium (111In), and their clinical applications for several diagnostic techniques, such as single photon emission computed tomography (SPECT), gamma-scintigraphy, and nuclear magnetic resonance (NMR), were discussed. Also, micelle use primarily for the diagnosis of lymphatic ducts and sentinel lymph nodes received special attention. Notably, the employment of these diagnostic techniques can be considered a significant tool for functionally exploring body systems as well as investigating molecular pathways involved in the disease process. The use of molecular modeling methodologies and computer-aided drug design strategies can also yield valuable information for the rational design and development of novel radiopharmaceuticals.

Base racional e plano de estudo prospectivo para avaliar o efeito de terapêutica antiplaquetária e vasodilatadora microcirculatória em pacientes com cardiopatia chagásica crônica e distúrbios microvasculares coronários

INTRODUÇÃO: Há evidência, embasada por estudos em modelos experimentais de infecção pelo Trypanosoma cruzi, e também por investigações histopatológicas em humanos com a doença de Chagas, de que distúrbios de natureza isquêmica participem da patogênese de lesões miocárdicas na fase crônica da moléstia. Esses distúrbios isquêmicos derivam de desregulação microcirculatória. Dor precordial atípica é sintoma comum em pacientes na fase crônica da doença de Chagas. Em substancial proporção desses pacientes, apesar da inexistência de obstruções coronárias angiograficamente detectáveis, documenta-se com cintilografia miocárdica a ocorrência de distúrbios perfusionais durante o estresse, que são reversíveis após repouso. MÉTODOS: Estudo unicêntrico, prospectivo, de coorte única, com intervenção terapêutica seguida de reavaliação quantitativa, após 90 dias, da área ventricular apresentando alterações perfusionais isquêmicas inicialmente detectadas em pacientes cardiopatas chagásicos com coronárias angiograficamente normais. A cintilografia miocárdica de perfusão será executada com o método SPECT, antes e após 90 dias da intervenção terapêutica, tendo o sestamibi-Tc99m como radiotraçador e o esforço físico ou o estímulo vasodilatador com dipiridamol como estressores. A intervenção terapêutica consistirá de ácido acetilsalicílico (dose de 100 mg diária) associado a verapamil (dose diária de 160 mg, em duas tomadas de 80 mg). O desfecho primário do estudo será redução > 50% da área ventricular de isquemia miocárdica reversível calculada pelo mapa polar da cintilografia miocárdica de perfusão. CONCLUSÕES: Este é o primeiro estudo de intervenção terapêutica para atenuar ou reverter alterações miocárdicas isquêmicas de origem microvascular em pacientes com cardiopatia chagásica crônica.

Monte Carlo Simulations of Novel Scintillator Detectors and Dosimetry Calculations

Monte Carlo (MC) simulation techniques are becoming very common in the Medical Physicists community. MC can be used for modeling Single Photon Emission Computed Tomography (SPECT) and for dosimetry calculations. 188Re, is a promising candidate for radiotherapeutic production and understanding the mechanisms of the radioresponse of tumor cells "in vitro" is of crucial importance as a first step before "in vivo" studies. The dosimetry of 188Re, used to target different lines of cancer cells, has been evaluated by the MC code GEANT4. The simulations estimate the average energy deposition/per event in the biological samples. The development of prototypes for medical imaging, based on LaBr3:Ce scintillation crystals coupled with a position sensitive photomultiplier, have been studied using GEANT4 simulations. Having tested, in the simulation, surface treatments different from the one applied to the crystal used in our experimental measurements, we found out that the Energy Resolution (ER) and the Spatial Resolution (SR) could be improved, in principle, by machining in a different way the lateral surfaces of the crystal. We have then studied a system able to acquire both echographic and scintigraphic images to let the medical operator obtain the complete anatomic and functional information for tumor diagnosis. The scintigraphic part of the detector is simulated by GEANT4 and first attempts to reconstruct tomographic images have been made using as method of reconstruction a back-projection standard algorithm. The proposed camera is based on slant collimators and LaBr3:Ce crystals. Within the Field of View (FOV) of the camera, it possible to distinguish point sources located in air at a distance of about 2 cm from each other. In particular conditions of uptake, tumor depth and dimension, the preliminary results show that the Signal to Noise Ratio (SNR) values obtained are higher than the standard detection limit.

Sintesi e ricopertura organica di maghemiti per intrappolamento in polimeri biocompatibili. Applicazioni in nanomedicina.

Il seguente lavoro è stato condotto con lo scopo di sviluppare una nano-piattaforma per imaging multimodale MRI/SPECT e MRI/PET. Nanoparticelle magnetiche sono state intrappolate in un polimero biocompatibile, e la superficie delle nanostrutture risultanti è stata funzionalizzata con un agente chelante per radioisotopi.

Synthese, Radioiodierung und Evaluierung von neuen MGMT-Inhibitoren und ihren Glucose-Konjugaten

Eine häufige Art der Chemotherapie ist die Behandlung von Tumoren mit alkylierenden oder chloralkylierenden Zytostatika, die eine Alkylierung von Guanin in der DNA verursachen. Daraus resultieren eine Blockierung der DNA-Synthese und ein Rückgang im Tumorwachstum. Das Enzym O6-Methylguanin-DNA-methyltransferase (MGMT) ist in der Lage, solche Schäden zu reparieren. Da MGMT auch in verschiedenen Tumorarten exprimiert wird, eine Tatsache, die therapeutische Effekte verringern könnte, wird zur Zeit die Gabe von Inhibitoren der MGMT, wie O6-Benzylguanin, vor der eigentlichen Chemotherapie untersucht. Um möglicher Weise die Selektivität dieser Verbindungen für Tumor- vs. gesundem Gewebe und auch die in vivo-Eigenschaften zu verbessern, wurden glycosylierte Inhibitoren vorgeschlagen. Für eine Entwicklung neuer MGMT-Inhibitoren wäre es hilfreich, die in vivo Bioverteilung in Tier und Mensch durch eine Markierung mit geeigneten Isotopen verfolgen zu können. Im Moment existiert keine Möglichkeit, den MGMT-Status eines Tumors nicht-invasiv zu visualisieren. Diese Information kann sehr wichtig für die Planung einer Chemotherapie mit alkylierenden oder chloralkylierenden Zytostatika sein. Mit Methoden wie der Positronen-Emissions-Tomographie (PET) oder der Einzel-Photonen-Emissions-Tomographie (SPECT) ist eine nicht-invasive Quantifizierung von biochemischen Prozessen prinzipiell möglich. Hierfür wurden verschiedenen MGMT-Inhibitoren bereits mit Isotopen wie Fluor-18, Kohlenstoff-11 un Iod-131 markiert, aber sie waren aus unterschiedlichen Gründen nicht geeignet. Das Ziel dieser Arbeit war die Entwicklung von neuen O6-derivatisierten Guaninen, die über einen C8-Spacer an der N9-Position des Guanins mit einer Glucose-Einheit konjugiert werden sollten, geeigneten Markierungsvorläufern und Radioiodierungs-Methoden. Durch Wahl eines geeigneten Radioiodisotops für die Markierung des Restes an der O6-Position des Guanins kann die ex vivo-Bioverteilung dieser Verbindungen in tumortragenden Nacktmäusen (Iod-131) und die Untersuchung der in vivo-Verteilung (Iod-123) durchgeführt werden. Daher wurden O6-(5-Iodothenyl)- (ITG) und O6-(3-Iodbenzyl)guanin-Derivate (IBG) sowie ihre Glucose-Konjugate ITGG und IBGG synthetisiert. Von diesen inaktiven Standard-Verbindungen wurden die IC50-Werte zur MGMT bestimmt. Da sie alle im nM-Bereich lagen, schienen die Verbindungen für weitere Untersuchungen geeignet zu sein. Die Radiomarkierung der Inhibitoren mit Iod-131 bzw. Iod-123 wurde durch Umsetzung der Trialkyl-stannylierten Markierungsvorläufer mit der Chloramin T-Methode in mittleren (Iod-123) bis hohen (Iod-131) radiochemischen Ausbeuten und mit hohen radiochemischen Reinheiten durchgeführt. Mit den 131I-iodierten Verbindungen wurde die spezifische Bindung zur MGMT nachgewiesen, eine Eigenschaft, die essentiell für eine weitere Verwendung dieser Derivate ist. Sie wurden auch zur Bestimmung der ex vivo-Tumor- und Organverteilung in tumortragenden Nacktmäusen (MEX(+), MEX(-), Glioblastom) verwendet. In allen Fällen war die Tumoraufnahme der nicht-konjugierten Guanin-Derivate höher als die der entsprechenden Glucose-Konjugate. Das Tumor-Blut-Verhältnis, das sehr wichtig für einen potentiellen Einsatz der Verbindungen als Tracer des MGMT-Status eines Tumors ist, variierte abhängig von der Kinetik. Zu allen Zeitpunkten war die in vivo-Deiodierung der Glucose-Konjugate deutlich geringer als die von ITG oder IBG. Unter Verwendung von [131I]IBG und [131I]IBGG wurde die Biodistribution nach Inhibition der Natrium-abhängigen Glucose-Transporter, die zumindests teilweise für die Aufnahme der MGMT-Inhibitoren in Zellen verantwortlich sind, durch Phloretin untersucht. Einen Unterschied in der Tumoraufnahme zwischen den mit Phloretin behandelten und den unbehandelten Mäusen konnte nicht beobachtet werden, wahrscheinlich weil die Akkumulation im Tumor generell niedrig war. Mit den 123I-iodierten Verbindungen [123I]IBG und [123I]IBGG wurden in vivo-Scans an tumortragenden Nacktmäusen (MEX(+), MEX(-)) mit einer Kleintier-SPECT-Kamera durchgeführt. In beiden Fällen wurde eine geringe Akkumulation in den Tumoren im Vergleich zu anderen Organen beobachtet, was die ex vivo-Biodistributionsdaten bestätigte.

Radiochemical aspects of production and processing of radiometals for preparation of metalloradiopharmaceuticals

Radiometals play an important role in nuclear medicine as involved in diagnostic or therapeutic agents. In the present work the radiochemical aspects of production and processing of very promising radiometals of the third group of the periodic table, namely radiogallium and radiolanthanides are investigated. The 68Ge/68Ga generator (68Ge, T½ = 270.8 d) provides a cyclotron-independent source of positron-emitting 68Ga (T½ = 68 min), which can be used for coordinative labelling. However, for labelling of biomolecules via bifunctional chelators, particularly if legal aspects of production of radiopharmaceuticals are considered, 68Ga(III) as eluted initially needs to be pre-concentrated and purified. The first experimental chapter describes a system for simple and efficient handling of the 68Ge/68Ga generator eluates with a cation-exchange micro-chromatography column as the main component. Chemical purification and volume concentration of 68Ga(III) are carried out in hydrochloric acid – acetone media. Finally, generator produced 68Ga(III) is obtained with an excellent radiochemical and chemical purity in a minimised volume in a form applicable directly for the synthesis of 68Ga-labelled radiopharmaceuticals. For labelling with 68Ga(III), somatostatin analogue DOTA-octreotides (DOTATOC, DOTANOC) are used. 68Ga-DOTATOC and 68Ga-DOTANOC were successfully used to diagnose human somatostatin receptor-expressing tumours with PET/CT. Additionally, the proposed method was adapted for purification and medical utilisation of the cyclotron produced SPECT gallium radionuclide 67Ga(III). Second experimental chapter discusses a diagnostic radiolanthanide 140Nd, produced by irradiation of macro amounts of natural CeO2 and Pr2O3 in natCe(3He,xn)140Nd and 141Pr(p,2n)140Nd nuclear reactions, respectively. With this produced and processed 140Nd an efficient 140Nd/140Pr radionuclide generator system has been developed and evaluated. The principle of radiochemical separation of the mother and daughter radiolanthanides is based on physical-chemical transitions (hot-atom effects) of 140Pr following the electron capture process of 140Nd. The mother radionuclide 140Nd(III) is quantitatively absorbed on a solid phase matrix in the chemical form of 140Nd-DOTA-conjugated complexes, while daughter nuclide 140Pr is generated in an ionic species. With a very high elution yield and satisfactory chemical and radiolytical stability the system could able to provide the short-lived positron-emitting radiolanthanide 140Pr for PET investigations. In the third experimental chapter, analogously to physical-chemical transitions after the radioactive decay of 140Nd in 140Pr-DOTA, the rapture of the chemical bond between a radiolanthanide and the DOTA ligand, after the thermal neutron capture reaction (Szilard-Chalmers effect) was evaluated for production of the relevant radiolanthanides with high specific activity at TRIGA II Mainz nuclear reactor. The physical-chemical model was developed and first quantitative data are presented. As an example, 166Ho could be produced with a specific activity higher than its limiting value for TRIGA II Mainz, namely about 2 GBq/mg versus 0.9 GBq/mg. While free 166Ho(III) is produced in situ, it is not forming a 166Ho-DOTA complex and therefore can be separated from the inactive 165Ho-DOTA material. The analysis of the experimental data shows that radionuclides with half-life T½ < 64 h can be produced on TRIGA II Mainz nuclear reactor, with specific activity higher than any available at irradiation of simple targets e.g. oxides.