Molecular imaging of hypoxia with radiolabelled agents

Tissue hypoxia results from an inadequate supply of oxygen (O2) that compromises biological functions. Structural and functional abnormalities of the tumour vasculature together with altered diffusion conditions inside the tumour seem to be the main causes of tumour hypoxia. Evidence from experimental and clinical studies points to a role for tumour hypoxia in tumour propagation, resistance to therapy and malignant progression. This has led to the development of assays for the detection of hypoxia in patients in order to predict outcome and identify patients with a worse prognosis and/or patients that would benefit from appropriate treatments. A variety of invasive and non-invasive approaches have been developed to measure tumour oxygenation including oxygen-sensitive electrodes and hypoxia marker techniques using various labels that can be detected by different methods such as positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), autoradiography and immunohistochemistry. This review aims to give a detailed overview of non-invasive molecular imaging modalities with radiolabelled PET and SPECT tracers that are available to measure tumour hypoxia

Evaluation of gross energy concentration of neutral detergent fiber contained in feed and fecal samples

Starch and NDF are usually assumed to contain the same concentration of gross energy (GE), but NDF is more variable in chemical composition and varies more in the extent of digestion. The variable chemical composition of NDF may have direct implications on dairy nutrition models that predict dietary GE and use this estimate for also predicting digestible energy. For example, when NDF is enriched in lignin and protein, the concentration of GE would increase, whereas NDF enriched in ash would have the opposite effect. Current nutritional models, such as the NASEM (2021) and CNCPS (6.55), assume a GE coefficient of 4.20 Mcal/kg for NDF. This study aimed to determine the heat of combustion of NDF and to consider if it is a contributing factor to the variance in digestible energy. To do so, NDF residues were isolated from 9 feed and 8 fecal samples and then combusted. Approximately 0.20 g of NDF residues from 16 feeds (corn silage, n = 2; grass hay, n = 2; alfalfa hay, n = 2; wheat straw, n = 1; cottonseed hulls, n = 1; soyhulls, n = 1; distillers dried grains with solubles, n = 1; and total mixed ration, n = 6) and 34 fecal samples were collected. A bomb calorimeter (Parr 6400 Calorimeter, Parr Instrument Company) was used to determine concentration of GE in each NDF residue sample. The GE concentration of feed NDF was observed to be 4.03 ± 0.245 Mcal/kg, which was similar to that of fecal NDF (3.94 ± 0.245 Mcal/kg). The lack of difference between feed and fecal NDF GE implies that digested NDF is of a similar GE concentration as total feed NDF and that current nutritional models are validated in their current approach in predicting digestible energy from NDF. However, our observed estimate of GE in NDF is lower than what is assumed and across feed types varied from 3.85 to 4.19 Mcal/kg

Scintigraphic imaging of focal hypoxic tissue: development and clinical applications of 123I-IAZA

Affected tissues in a number of diseases, including cancer, stroke, cardiac infarction and diabetes, develop focal tissue hypoxia during their progression. The presence of hypoxic tissue may make the disease refractory to therapy, as in the case of solid tumor therapy using low LET ionizing radiation. In other pathologies, the detection of viable but hypoxic tissues may serve as a prodromal indicator of developing disease (e.g. diabetes),or as a prognostic indicator for management of the disease (e.g. stroke). Over the past two decades, a number of hypoxia radioimaging agents have been developed and tested clinically. Of these, 18F-Fmiso and 123I-IAZA are the most widely used radiotracers for PET and SPECT/planar imaging, respectively. IAZA and Fmiso are a 2-nitroimidazoles that chemically bind to subcellular components of viable hypoxic tissues. They sensitize hypoxic tumour to the killing effects of ionizing radiation via mechanisms that mimic the radiosensitizing effects of oxygen, and are therefore called oxygen mimetics. The oxygen mimetic effect is attributable in large part to the covalent binding of reductively-activated nitroimidazole intermediates to critical cellular macromolecules. Nitroimidazoles labelled with gamma-emitting radionuclides (e.g. 18F-Fmiso and 123I-IAZA) have been used as scintigraphic markers of tumour hypoxia, based on the need to identify radioresistant hypoxic tumour cells as part of the radiotherapy planning process. Broader interest in non-invasive, imaging-based identification of focal hypoxia in a number of diseases has extended hypoxia studies to include peripheral vascular disease associated with diabetes, rheumatoid arthritis, stroke, myocardial ischaemia, brain trauma and oxidative stress. In this review, the current status of hypoxia-selective studies with 123I-IAZA , an experimental diagnostic radiopharmaceutical, is reviewed with respect to its pre-clinical development and clinical applications.<br>Os tecidos afetados em inúmeras doenças, incluíndo câncer, acidentes vasculares cerebrais, infarto agudo do miocárdio e diabetes, desenvolvem hipoxia focal tecidual durante a evolução da doença. A presença de tecido hipóxico pode tornar a doença refratária à terapia., como no caso do tratamento de tumores sólidos usando baixa radiação ionizante (LET). Em outras doenças, a detecção de tecidos viáveis mais hipóxicos pode servir como indicador prodômico do desenvolvimento da doença (como por exemplo, diabetes), ou um indicador prognóstico do controle da doença (como no acidente vascular cerebral). Nas últimas duas décadas, vários substâncias utilizadas em radioimagem para avaliar a hipóxia foram desenvolvidas e testadas clinicamente. Destas, 18F-Fmiso e 123I-IAZA são os radiotraçadores mais usualmente utilizados para imagens planares de PET e SPECT, respectivamente. IAZA e Fmiso são 2-nitroimidazóis que quimicamente se ligam a componentes subcelulares de tecidos hipóxicos viáveis. Eles sensibilizam tumores hipóxicos aos efeitos letais da radia��ão ionizante via mecanismos que mimetizam os efeitos radiosensíveis do oxigênio, e são consequentemente denominados de oxigênio-miméticos. O efeito oxigênio-mimético é atribuído em grande parte à ligação covalente dos intermediários nitroimidazóis redutivamente ativados paara macromoléculas celulares críticas. Nitroimidazóis marcados com radionuclídeos emissores de radiação gama (por exemplo, 18 F-Fmiso e 123I-IAZA) tem sido usado como marcadores cintigráficos da hipóxia tumoral, baseado na necessidade de identificar células tumorais hipóxicas radioresistentes como parte do processo de planejamento da radioterapia. Um interesse mais amplo em identificação não-invasiva baseada em imagem de hipóxia focal de várias doenças tem estendido os estudos de hipóxia para incluir doenças vasculares periféricas associadas com diabetes, artrite reumatóide, acidentes vasculares cerebrais, isquemia miocárdica, traumatismo encefálico e estresse oxidativo. Nesta revisão, o estado atual dos estudos de hipoxia seletiva com 123I-IAZA, um radiofarmáco para o diagnóstico experimental é revisto em relação ao desenvolvimento de aplicações clinicas e pré-clinicas