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1.
Cancer Immunol Immunother ; 73(2): 27, 2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38280019

RESUMO

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, often presenting comorbidities like osteoporosis and requiring, in a relevant proportion of cases, treatment with bisphosphonates (BPs). This class of drugs was shown in preclinical investigations to also possess anticancer properties. We started an in vitro study of the effects of BPs on CLL B cells activated by microenvironment-mimicking stimuli and observed that, depending on drug concentration, hormetic effects were induced on the leukemic cells. Higher doses induced cytotoxicity whereas at lower concentrations, more likely occurring in vivo, the drugs generated a protective effect from spontaneous and chemotherapy-induced apoptosis, and augmented CLL B cell activation/proliferation. This CLL-activation effect promoted by the BPs was associated with markers of poor CLL prognosis and required the presence of bystander stromal cells. Functional experiments suggested that this phenomenon involves the release of soluble factors and is increased by cellular contact between stroma and CLL B cells. Since CLL patients often present comorbidities such as osteoporosis and considering the diverse outcomes in both CLL disease progression and CLL response to treatment among patients, illustrating this phenomenon holds potential significance in driving additional investigations.


Assuntos
Leucemia Linfocítica Crônica de Células B , Osteoporose , Humanos , Idoso , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Linfócitos B , Apoptose , Osteoporose/tratamento farmacológico , Microambiente Tumoral
2.
J Transl Med ; 21(1): 3, 2023 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-36600265

RESUMO

BACKGROUND: Positron Emission Tomography (PET) imaging with Prostate-Specific Membrane Antigen (PSMA) and Fluorodeoxyglucose (FDG) represent promising biomarkers for risk-stratification of Prostate Cancer (PCa). We verified whether the expression of genes encoding for PSMA and enzymes regulating FDG cellular uptake are independent and additive prognosticators in PCa. METHODS: mRNA expression of genes involved in glucose metabolism and PSMA regulation obtained from primary PCa specimens were retrieved from open-source databases and analyzed using an integrative bioinformatics approach. Machine Learning (ML) techniques were used to create predictive Progression-Free Survival (PFS) models. Cellular models of primary PCa with different aggressiveness were used to compare [18F]F-PSMA-1007 and [18F]F-FDG uptake kinetics in vitro. Confocal microscopy, immunofluorescence staining, and quantification analyses were performed to assess the intracellular and cellular membrane PSMA expression. RESULTS: ML analyses identified a predictive functional network involving four glucose metabolism-related genes: ALDOB, CTH, PARP2, and SLC2A4. By contrast, FOLH1 expression (encoding for PSMA) did not provide any additive predictive value to the model. At a cellular level, the increase in proliferation rate and migratory potential by primary PCa cells was associated with enhanced FDG uptake and decreased PSMA retention (paralleled by the preferential intracellular localization). CONCLUSIONS: The overexpression of a functional network involving four glucose metabolism-related genes identifies a higher risk of disease progression since the earliest phases of PCa, in agreement with the acknowledged prognostic value of FDG PET imaging. By contrast, the prognostic value of PSMA PET imaging is independent of the expression of its encoding gene FOLH1. Instead, it is influenced by the protein docking to the cell membrane, regulating its accessibility to tracer binding.


Assuntos
Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons , Neoplasias da Próstata , Humanos , Masculino , Glucose/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Próstata/diagnóstico por imagem , Próstata/metabolismo , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Aprendizado de Máquina
3.
Eur J Clin Invest ; 53(9): e14011, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37099603

RESUMO

BACKGROUND: This study aimed to estimate if the altered sphygmic wave transmission may affect the left ventricular (LV) contractile function in patients undergoing endovascular aortic repair (EVAR). METHODS: A prospective single-centre study was carried out on consecutive patients undergoing EVAR for abdominal aortic aneurysm. A preoperative and 6-month single photon emission computed tomography (SPECT) with arterial stiffness measurement were performed to evaluate variations in pressure wave curve and myocardial perfusion parameters. RESULTS: From 2018 to 2020 a total of 16 patients were included in the study. Among the parameters evaluated, we found a measurable reduction of the reflected wave transit time from pre- to postoperative period, for both stress (115.13 ± 7.2 ms-111.1 ± 7.0 ms, p = .08) and rest SPECT acquisitions (115.3 ± 6.2 ms-112.2 ± 5.6 ms, p = .1). Unidirectional increase of both LV end-systolic volume (34 ± 9 mL-39 ± 8 mL, p = .02) and end-diastolic volume (85 ± 34 mL-89 ± 29 mL, p = .6) was also observed. Lastly, the ratio between the end-systolic pressure and the end-systolic volume (maximal systolic myocardial stiffness) decreased from 3.6 ± 1.5 mmHg/mL to 2.66 ± .74 mmHg/mL (p = .03). CONCLUSIONS: Our data showed that EVAR induced an altered transmission of the sphygmic wave associated with an early LV contractile impairment.


Assuntos
Aneurisma da Aorta Abdominal , Disfunção Ventricular Esquerda , Humanos , Estudos Prospectivos , Correção Endovascular de Aneurisma , Função Ventricular Esquerda , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/cirurgia
4.
Mol Cell Biochem ; 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38082185

RESUMO

Anthracyclines' cardiotoxicity involves an accelerated generation of reactive oxygen species. This oxidative damage has been found to accelerate the expression of hexose-6P-dehydrogenase (H6PD), that channels glucose-6-phosphate (G6P) through the pentose phosphate pathway (PPP) confined within the endoplasmic/sarcoplasmic reticulum (SR). To verify the role of SR-PPP in the defense mechanisms activated by doxorubicin (DXR) in cardiomyocytes, we tested the effect of this drug in H6PD knockout mice (H6PD-/-). Twenty-eight wildtype (WT) and 32 H6PD-/- mice were divided into four groups to be treated with intraperitoneal administration of saline (untreated) or DXR (8 mg/Kg once a week for 3 weeks). One week thereafter, survivors underwent imaging of 18F-deoxyglucose (FDG) uptake and were sacrificed to evaluate the levels of H6PD, glucose-6P-dehydrogenase (G6PD), G6P transporter (G6PT), and malondialdehyde. The mRNA levels of SR Ca2+-ATPase 2 (Serca2) and ryanodine receptors 2 (RyR2) were evaluated and complemented with Hematoxylin/Eosin staining and transmission electron microscopy. During the treatment period, 1/14 DXR-WT and 12/18 DXR-H6PD-/- died. At microPET, DXR-H6PD-/- survivors displayed an increase in left ventricular size (p < 0.001) coupled with a decreased urinary output, suggesting a severe hemodynamic impairment. At ex vivo analysis, H6PD-/- condition was associated with an oxidative damage independent of treatment type. DXR increased H6PD expression only in WT mice, while G6PT abundance increased in both groups, mismatching a generalized decrease of G6PD levels. Switching-off SR-PPP impaired reticular accumulation of Ca2+ decelerating Serca2 expression and upregulating RyR2 mRNA level. It thus altered mitochondrial ultrastructure eventually resulting in a cardiomyocyte loss. The recognized vulnerability of SR to the anthracycline oxidative damage is counterbalanced by an acceleration of G6P flux through a PPP confined within the reticular lumen. The interplay of SR-PPP with the intracellular Ca2+ exchanges regulators in cardiomyocytes configure the reticular PPP as a potential new target for strategies aimed to decrease anthracycline toxicity.

5.
Eur Radiol ; 33(5): 3343-3353, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36892650

RESUMO

OBJECTIVES: Increased detection of prostate cancer (PCa) recurrences using [68Ga]Ga-PSMA-11 PET/CT has been reported by adding forced diuresis or late-phase imaging to the standard protocol. However, the combination of these procedures in the clinical setting is still not standardized. METHODS: One hundred prospectively recruited biochemical recurrent PCa patients were restaged with dual-phase [68Ga]Ga-PSMA-11 PET/CT from September 2020 to October 2021. All patients received a standard scan (60 min), followed by diuretics (140 min) and a late-phase abdominopelvic scan (180 min). PET readers with low (n = 2), intermediate (n = 2), or high (n = 2) experience rated (i) standard and (ii) standard + forced diuresis late-phase images in a stepwise fashion according to E-PSMA guidelines, scoring their level of confidence. Study endpoints were (i) accuracy against a composite reference standard, (ii) reader's confidence level, and (iii) interobserver agreement. RESULTS: Forced diuresis late-phase imaging increased the reader's confidence category for local and nodal restaging (both p < 0.0001), and the interobserver agreement in identifying nodal recurrences (from moderate to substantial, p < 0.01). However, it significantly increased diagnostic accuracy exclusively for local uptakes rated by low-experienced readers (from 76.5 to 84%, p = 0.05) and for nodal uptakes rated as uncertain at standard imaging (from 68.1 to 78.5%, p < 0.05). In this framework, SUVmax kinetics resulted in an independent predictor of PCa recurrence compared to standard metrics, potentially guiding the dual-phase PET/CT interpretation. CONCLUSIONS: The present results do not support the systematic combination of forced diuresis and late-phase imaging in the clinical setting, but allow the identification of patients-, lesions-, and reader-based scenarios that might benefit from it. KEY POINTS: • Increased detection of prostate cancer recurrences has been reported by adding diuretics administration or an additional late abdominopelvic scan to the standard [68Ga]Ga-PSMA-11 PET/CT procedure. • We verified the added value of combined forced diuresis and delayed imaging, showing that this protocol only slightly increases the diagnostic accuracy of [68Ga]Ga-PSMA-11 PET/CT, thus not justifying its systematic use in clinics. • However, it can be helpful in specific clinical scenarios, e.g., when PET/CT is reported by low-experienced readers. Moreover, it increased the reader's confidence and the agreement among observers.


Assuntos
Radioisótopos de Gálio , Neoplasias da Próstata , Masculino , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Recidiva Local de Neoplasia/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico por imagem , Diurese , Diuréticos , Ácido Edético
6.
Int J Mol Sci ; 24(4)2023 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-36834900

RESUMO

The abscisic acid (ABA)/LANC-like protein 1/2 (LANCL1/2) hormone/receptor system regulates glucose uptake and oxidation, mitochondrial respiration, and proton gradient dissipation in myocytes. Oral ABA increases glucose uptake and the transcription of adipocyte browning-related genes in rodent brown adipose tissue (BAT). The aim of this study was to investigate the role of the ABA/LANCL system in human white and brown adipocyte thermogenesis. Immortalized human white and brown preadipocytes, virally infected to overexpress or silence LANCL1/2, were differentiated in vitro with or without ABA, and transcriptional and metabolic targets critical for thermogenesis were explored. The overexpression of LANCL1/2 increases, and their combined silencing conversely reduces mitochondrial number, basal, and maximal respiration rates; proton gradient dissipation; and the transcription of uncoupling genes and of receptors for thyroid and adrenergic hormones, both in brown and in white adipocytes. The transcriptional enhancement of receptors for browning hormones also occurs in BAT from ABA-treated mice, lacking LANCL2 but overexpressing LANCL1. The signaling pathway downstream of the ABA/LANCL system includes AMPK, PGC-1α, Sirt1, and the transcription factor ERRα. The ABA/LANCL system controls human brown and "beige" adipocyte thermogenesis, acting upstream of a key signaling pathway regulating energy metabolism, mitochondrial function, and thermogenesis.


Assuntos
Ácido Abscísico , Prótons , Animais , Humanos , Camundongos , Ácido Abscísico/metabolismo , Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Metabolismo Energético/genética , Glucose/metabolismo , Hormônios/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Termogênese/genética , Proteína Desacopladora 1/metabolismo
7.
Haematologica ; 106(10): 2598-2612, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32855274

RESUMO

Bone skeletal alterations are no longer considered a rare event in chronic lymphocytic leukemia (CLL), especially at more advanced stages of the disease. This study is aimed at elucidating the mechanisms underlying this phenomenon. Bone marrow stromal cells, induced to differentiate toward osteoblasts in osteogenic medium, appeared unable to complete their maturation upon co-culture with CLL cells, CLL-cell-derived conditioned media (CLL-cm) or CLL-sera (CLL-sr). Inhibition of osteoblast differentiation was documented by decreased levels of RUNX2 and osteocalcin mRNA expression, by increased osteopontin and DKK-1 mRNA levels, and by a marked reduction of mineralized matrix deposition. The addition of neutralizing TNFα, IL-11 or anti-IL-6R monoclonal antibodies to these cocultures resulted in restoration of bone mineralization, indicating the involvement of these cytokines. These findings were further supported by silencing TNFα, IL-11 and IL-6 in leukemic cells. We also demonstrated that the addition of CLL-cm to monocytes, previously stimulated with MCSF and RANKL, significantly amplified the formation of large, mature osteoclasts as well as their bone resorption activity. Moreover, enhanced osteoclastogenesis, induced by CLL-cm, was significantly reduced by treating cultures with the anti-TNFα monoclonal antibody infliximab. An analogous effect was observed with the use of the BTK inhibitor, ibrutinib. Interestingly, CLL cells co-cultured with mature osteoclasts were protected from apoptosis and upregulated Ki-67. These experimental results parallel the direct correlation between amounts of TNFα in CLL-sr and the degree of compact bone erosion that we previously described, further strengthening the indication of a reciprocal influence between leukemic cell expansion and bone structure derangement.


Assuntos
Interleucina-11 , Interleucina-6 , Leucemia Linfocítica Crônica de Células B , Osteogênese , Fator de Necrose Tumoral alfa , Diferenciação Celular , Células Cultivadas , Citocinas , Humanos , Interleucina-11/genética , Interleucina-6/genética , Osteoblastos , Osteoclastos , Fator de Necrose Tumoral alfa/genética
8.
J Nucl Cardiol ; 27(6): 2183-2194, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-30737636

RESUMO

BACKGROUND: Oxidative stress and its interference on myocardial metabolism play a major role in Doxorubicin (DXR) cardiotoxic cascade. METHODS: Mice models of neuroblastoma (NB) were treated with 5 mg DXR/kg, either free (Free-DXR) or encapsulated in untargeted (SL[DXR]) or in NB-targeting Stealth Liposomes (pep-SL[DXR] and TP-pep-SL[DXR]). Control mice received saline. FDG-PET was performed at baseline (PET1) and 7 days after therapy (PET2). At PET2 Troponin-I and NT-proBNP were assessed. Explanted hearts underwent biochemical, histological, and immunohistochemical analyses. Finally, FDG uptake and glucose consumption were simultaneously measured in cultured H9c2 in the presence/absence of Free-DXR (1 µM). RESULTS: Free-DXR significantly enhanced the myocardial oxidative stress. Myocardial-SUV remained relatively stable in controls and mice treated with liposomal formulations, while it significantly increased at PET2 with respect to baseline in Free-DXR. At this timepoint, myocardial-SUV was directly correlated with both myocardial redox stress and hexose-6-phosphate-dehydrogenase (H6PD) enzymatic activity, which selectively sustain cellular anti-oxidant mechanisms. Intriguingly, in vitro, Free-DXR selectively increased FDG extraction fraction without altering the corresponding value for glucose. CONCLUSION: The direct correlation between cardiac FDG uptake and oxidative stress indexes supports the potential role of FDG-PET as an early biomarker of DXR oxidative damage.


Assuntos
Doxorrubicina/química , Fluordesoxiglucose F18/farmacocinética , Coração/efeitos dos fármacos , Miocárdio/patologia , Estresse Oxidativo , Animais , Antioxidantes , Biomarcadores/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Glucose/química , Glucose/farmacocinética , Humanos , Imuno-Histoquímica , Cinética , Camundongos , Camundongos Nus , Neuroblastoma/tratamento farmacológico , Oxirredução , Tomografia por Emissão de Pósitrons
9.
Int J Mol Sci ; 21(21)2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33142766

RESUMO

In cognitively normal patients, mild hyperglycemia selectively decreases 18F-Fluorodeoxyglucose (FDG) uptake in the posterior brain, reproducing Alzheimer disease pattern, hampering the diagnostic accuracy of this widely used tool. This phenomenon might involve either a heterogeneous response of glucose metabolism or a different sensitivity to hyperglycemia-related redox stress. Indeed, previous studies reported a close link between FDG uptake and activation of a specific pentose phosphate pathway (PPP), triggered by hexose-6P-dehydrogenase (H6PD) and contributing to fuel NADPH-dependent antioxidant responses in the endoplasmic reticulum (ER). To clarify this issue, dynamic positron emission tomography was performed in 40 BALB/c mice four weeks after administration of saline (n = 17) or 150 mg/kg streptozotocin (n = 23, STZ). Imaging data were compared with biochemical and histological indexes of glucose metabolism and redox balance. Cortical FDG uptake was homogeneous in controls, while it was selectively decreased in the posterior brain of STZ mice. This difference was independent of the activity of enzymes regulating glycolysis and cytosolic PPP, while it was paralleled by a decreased H6PD catalytic function and enhanced indexes of oxidative damage. Thus, the relative decrease in FDG uptake of the posterior brain reflects a lower activation of ER-PPP in response to hyperglycemia-related redox stress in these areas.


Assuntos
Encéfalo/patologia , Diabetes Mellitus Experimental/fisiopatologia , Retículo Endoplasmático/patologia , Fluordesoxiglucose F18/metabolismo , Glicólise , Hiperglicemia/complicações , Tomografia por Emissão de Pósitrons/métodos , Animais , Transporte Biológico , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Retículo Endoplasmático/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oxirredução , Via de Pentose Fosfato , Compostos Radiofarmacêuticos/metabolismo
10.
Int J Obes (Lond) ; 43(1): 189-201, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30082752

RESUMO

BACKGROUND: Lipocalin-2 (LCN2) is widely expressed in the organism with pleiotropic roles. In particular, its overexpression correlates with tissue stress conditions including inflammation, metabolic disorders, chronic diseases and cancer. OBJECTIVES: To assess the effects of systemic LCN2 overexpression on adipose tissue and glucose metabolism. SUBJECTS: Eighteen-month-old transgenic mice with systemic LCN2 overexpression (LCN2-Tg) and age/sex-matched wild-type mice. METHODS: Metabolic cages; histology and real-time PCR analysis; glucose and insulin tolerance tests; ELISA; flow cytometry; microPET and serum analysis. RESULTS: LCN2-Tg mice were smaller compared to controls but they ate (P = 0.0156) and drank (P = 0.0057) more and displayed a higher amount of visceral adipose tissue. Furthermore, LCN2-Tg mice with body weight ≥20 g showed adipocytes with a higher cell area (P < 0.0001) and altered expression of genes involved in adipocyte differentiation and inflammation. In particular, mRNA levels of adipocyte-derived Pparg (P ≤ 0.0001), Srebf1 (P < 0.0001), Fabp4 (P = 0.056), Tnfa (P = 0.0391), Il6 (P = 0.0198), and Lep (P = 0.0003) were all increased. Furthermore, LCN2-Tg mice displayed a decreased amount of basal serum insulin (P = 0.0122) and a statistically significant impaired glucose tolerance and insulin sensitivity consistent with Slc2a2 mRNA (P ≤ 0.0001) downregulated expression. On the other hand, Insr mRNA (P ≤ 0.0001) was upregulated and correlated with microPET analysis that demonstrated a trend in reduced whole-body glucose consumption and MRGlu in the muscles and a significantly reduced MRGlu in brown adipose tissue (P = 0.0247). Nevertheless, an almost nine-fold acceleration of hexokinase activity was observed in the LCN2-Tg mice liver compared to controls (P = 0.0027). Moreover, AST and ALT were increased (P = 0.0421 and P = 0.0403, respectively), which indicated liver involvement also demonstrated by histological staining. CONCLUSIONS: We show that LCN2 profoundly impacts adipose tissue size and function and glucose metabolism, suggesting that LCN2 should be considered as a risk factor in ageing for metabolic disorders leading to obesity.


Assuntos
Tecido Adiposo/metabolismo , Envelhecimento/metabolismo , Glucose/metabolismo , Lipocalina-2/metabolismo , Tecido Adiposo/patologia , Envelhecimento/fisiologia , Animais , Antropometria , Biomarcadores/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos
11.
Eur J Nucl Med Mol Imaging ; 46(5): 1184-1196, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30617965

RESUMO

PURPOSE: The endoplasmic reticulum (ER) contains hexose-6P-dehydrogenase (H6PD). This enzyme competes with glucose-6P-phosphatase for processing a variety of phosphorylated hexoses including 2DG-6P. The present study aimed to verify whether this ER glucose-processing machinery contributes to brain FDG uptake. METHODS: Effect of the H6PD inhibitor metformin on brain 18F-FDG accumulation was studied, in vivo, by microPET imaging. These data were complemented with the in vitro estimation of the lumped constant (LC). Finally, reticular accumulation of the fluorescent 2DG analogue 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2NBDG) and its response to metformin was studied by confocal microscopy in cultured neurons and astrocytes. RESULTS: Metformin halved brain 18F-FDG accumulation without altering whole body tracer clearance. Ex vivo, this same response faced the doubling of both glucose consumption and lactate release. The consequent fall in LC was not explained by any change in expression or activity of its theoretical determinants (GLUTs, hexokinases, glucose-6P-phosphatase), while it agreed with the drug-induced inhibition of H6PD function. In vitro, 2NBDG accumulation selectively involved the ER lumen and correlated with H6PD activity being higher in neurons than in astrocytes, despite a lower glucose consumption. CONCLUSIONS: The activity of the reticular enzyme H6PD profoundly contributes to brain 18F-FDG uptake. These data challenge the current dogma linking 2DG/FDG uptake to the glycolytic rate and introduce a new model to explain the link between 18-FDG uptake and neuronal activity.


Assuntos
Encéfalo/citologia , Encéfalo/metabolismo , Retículo Endoplasmático/metabolismo , Fluordesoxiglucose F18/metabolismo , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Transporte Biológico/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Desidrogenases de Carboidrato/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxirredução/efeitos dos fármacos , Tomografia por Emissão de Pósitrons
12.
Brain ; 141(8): 2272-2279, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30730551

RESUMO

We recently reported the potential of Hough transform in delineating spinal cord metabolism by 18F-fluorodeoxyglucose PET/CT scanning in amyotrophic lateral sclerosis. The present study aimed to verify the relationship between spinal cord and brain metabolism in 44 prospectively recruited patients affected by amyotrophic lateral sclerosis submitted to 18F-fluorodeoxyglucose brain and whole-body PET/CT. Patients were studied to highlight the presence of brain hypo- or hypermetabolism with respect to healthy controls, and multiple regression analysis was performed to evaluate the correlation between spinal cord and brain metabolism. Our results confirmed higher 18F-fluorodeoxyglucose uptake in both cervical and dorsal spinal cord in patients with amyotrophic lateral sclerosis with respect to controls. This finding was paralleled by the opposite pattern in the brain cortex that showed a generalized reduction in tracer uptake. This hypometabolism was particularly evident in wide regions of the frontal-dorsolateral cortex while it did not involve the midbrain. Bulbar and spinal disease onset was associated with similar degree of metabolic activation in the spinal cord. However, among spinal onset patients, upper limb presentation was associated with a more pronounced metabolic activation of cervical segment. Obtained data suggest a differential neuro-pathological state or temporal sequence in disease progression.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Córtex Cerebral/metabolismo , Medula Espinal/metabolismo , Adulto , Esclerose Lateral Amiotrófica/fisiopatologia , Encéfalo/patologia , Córtex Cerebral/patologia , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neuromusculares/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Medula Espinal/patologia , Coluna Vertebral/patologia
13.
Small ; 14(45): e1802886, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30294852

RESUMO

Targeted delivery of anticancer drugs with nanocarriers can reduce side effects and ameliorate therapeutic efficacy. However, poorly perfused and dysfunctional tumor vessels limit the transport of the payload into solid tumors. The use of tumor-penetrating nanocarriers might enhance tumor uptake and antitumor effects. A peptide containing a tissue-penetrating (TP) consensus motif, capable of recognizing neuropilin-1, is here fused to a neuroblastoma-targeting peptide (pep) previously developed. Neuroblastoma cell lines and cells derived from both xenografts and high-risk neuroblastoma patients show overexpression of neuropilin-1. In vitro studies reveal that TP-pep binds cell lines and cells derived from neuroblastoma patients more efficiently than pep. TP-pep, after coupling to doxorubicin-containing stealth liposomes (TP-pep-SL[doxorubicin]), enhances their uptake by cells and cytotoxic effects in vitro, while increasing tumor-binding capability and homing in vivo. TP-pep-SL[doxorubicin] treatment enhances the Evans Blue dye accumulation in tumors but not in nontumor tissues, pointing to selective increase of vascular permeability in tumor tissues. Compared to pep-SL[doxorubicin], TP-pep-SL[doxorubicin] shows an increased antineuroblastoma activity in three neuroblastoma animal models mimicking the growth of neuroblastoma in humans. The enhancement of drug penetration in tumors by TP-pep-targeted nanoparticles may represent an innovative strategy for neuroblastoma.


Assuntos
Antineoplásicos/uso terapêutico , Nanopartículas/química , Neuroblastoma/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Neuroblastoma/metabolismo , Neuropilina-1/metabolismo , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Transl Med ; 16(1): 295, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30359253

RESUMO

BACKGROUND: Doxorubicin (DOX)-based chemotherapy for Hodgkin lymphoma (HL) yields excellent disease-free survival, but poses a substantial risk of subsequent left ventricular (LV) dysfunction and heart failure, typically with delayed onset. At the cellular level, this cardiotoxicity includes deranged cardiac glucose metabolism. METHODS: By reviewing the hospital records from January 2008 through December 2016, we selected HL patients meeting the following criteria: ≥ 18 year-old; first-line DOX-containing chemotherapy; no diabetes and apparent cardiovascular disease; 18-fluoro-deoxyglucose positron emission tomography (18FDG-PET) scans before treatment (PETSTAGING), after 2 cycles (PETINTERIM) and at the end of treatment (PETEOT); at least one echocardiography ≥ 6 months after chemotherapy completion (ECHOPOST). We then evaluated the changes in LV 18FDG standardized uptake values (SUV) during the course of DOX therapy, and the relationship between LV-SUV and LV ejection fraction (LVEF), as calculated from the LV diameters in the echocardiography reports with the Teicholz formula. RESULTS: Forty-three patients (35 ± 13 year-old, 58% males) were included in the study, with 26 (60%) also having a baseline echocardiography available (ECHOPRE). LV-SUV gradually increased from PETSTAGING (log-transformed mean 0.20 ± 0.27) to PETINTERIM (0.27 ± 0.35) to PETEOT (0.30 ± 0.41; P for trend < 0.001). ECHOPOST was performed 22 ± 17 months after DOX chemotherapy. Mean LVEF was normal (68.8 ± 10.3%) and only three subjects (7%) faced a drop below the upper normal limit of 53%. However, when patients were categorized by median LV-SUV, LVEF at ECHOPOST resulted significantly lower in those with LV-SUV above than below the median value at both PETINTERIM (65.5 ± 11.8% vs. 71.9 ± 7.8%, P = 0.04) and PETEOT (65.6 ± 12.2% vs. 72.2 ± 7.0%, P = 0.04). This was also the case when only patients with ECHOPRE and ECHOPOST were considered (LVEF at ECHOPOST 64.7 ± 8.9% vs. 73.4 ± 7.6%, P = 0.01 and 64.6 ± 9.3% vs. 73.5 ± 7.0%, P = 0.01 for those with LV-SUV above vs. below the median at PETINTERIM and PETEOT, respectively). Furthermore, the difference between LVEF at ECHOPRE and ECHOPOST was inversely correlated with LV-SUV at PETEOT (P < 0.01, R2 = - 0.30). CONCLUSIONS: DOX-containing chemotherapy causes an increase in cardiac 18FDG uptake, which is associated with a decline in LVEF. Future studies are warranted to understand the molecular basis and the potential clinical implications of this observation.


Assuntos
Antraciclinas/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/fisiopatologia , Miocárdio/metabolismo , Volume Sistólico , Adulto , Antraciclinas/farmacologia , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Fluordesoxiglucose F18/metabolismo , Seguimentos , Doença de Hodgkin/diagnóstico por imagem , Humanos , Masculino , Músculos/efeitos dos fármacos , Músculos/metabolismo , Tomografia por Emissão de Pósitrons
15.
Nat Mater ; 16(6): 681-689, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28250420

RESUMO

The degeneration of photoreceptors in the retina is one of the major causes of adult blindness in humans. Unfortunately, no effective clinical treatments exist for the majority of retinal degenerative disorders. Here we report on the fabrication and functional validation of a fully organic prosthesis for long-term in vivo subretinal implantation in the eye of Royal College of Surgeons rats, a widely recognized model of retinitis pigmentosa. Electrophysiological and behavioural analyses reveal a prosthesis-dependent recovery of light sensitivity and visual acuity that persists up to 6-10 months after surgery. The rescue of the visual function is accompanied by an increase in the basal metabolic activity of the primary visual cortex, as demonstrated by positron emission tomography imaging. Our results highlight the possibility of developing a new generation of fully organic, highly biocompatible and functionally autonomous photovoltaic prostheses for subretinal implants to treat degenerative blindness.


Assuntos
Cegueira/fisiopatologia , Cegueira/terapia , Compostos Orgânicos , Recuperação de Função Fisiológica , Visão Ocular , Próteses Visuais , Animais , Modelos Animais de Doenças , Ratos
16.
Int J Hyperthermia ; 34(4): 469-478, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28705098

RESUMO

RATIONALE: Hyperthermic isolated lung Perfusion (ILuP) is used to deliver high-dose chemotherapy to pulmonary metastases while sparing systemic toxicity. Accurate leakage monitoring is however necessary. This study aimed to verify the accuracy of radionuclide leakage monitoring in patients undergoing ILuP, by comparing this method with serial blood sampling. METHODS: A total of 15 consecutive ILuP procedures were performed on eleven patients affected by lung metastases from soft tissue sarcoma. After establishing isolated perfusion, erythrocytes of systemic blood (SB) were labelled with 0.2 MBq/kg of 99mTc. The baseline SB counting rate (CR) was assessed using a γ-probe. Subsequently, erythrocytes of the circuit blood (CB) were labelled with 2 Mbq/kg of 99mTc. Radioactivity leakage factor (RLF) was continuously measured using a formula, accounting for CR, systemic/circuit activity ratio and total/systemic volume ratio. The TNF-α concentration in SB and CB was measured by enzymelinked immunosorbent assay (ELISA) throughout the procedure. RESULTS: RLF averaged 2.3 ± 1.5%, while the systemic/circuit TNF-α ratio was 0.05 ± 0.12%. These two indices were strictly correlated in all of the procedures (average Rvalue 0.88 ± 0.07). RLF exceeded 5% during three of 15 procedures, prompting the application of compensatory manoeuvres. ELISA confirmed a marked increase in systemic TNF-α levels in these patients (2.6 ± 3.5 ng/ml). Conversely, patients whose RLF did not exceed the 5% threshold presented a mean TNF-α of 0.02 ± 0.005 ng/ml (p < 0.01). CONCLUSIONS: In patients submitted to ILuP, RLF monitoring is feasible and accurate. Moreover, it grants immediate results, permitting for the adoption of corrective manoeuvres for leakage, thus minimising toxicity.


Assuntos
Quimioterapia do Câncer por Perfusão Regional , Hipertermia Induzida , Neoplasias Pulmonares/terapia , Radioisótopos/sangue , Compostos Radiofarmacêuticos/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
17.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1862(2): 131-144, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27871880

RESUMO

Abscisic acid (ABA) is a plant hormone also present in animals, where it is involved in the regulation of innate immune cell function and of glucose disposal, through its receptor LANCL2. ABA stimulates glucose uptake by myocytes and pre-adipocytes in vitro and oral ABA improves glycemic control in rats and in healthy subjects. Here we investigated the role of the ABA/LANCL2 system in the regulation of glucose uptake and metabolism in adipocytes. Silencing of LANCL2 abrogated both the ABA- and insulin-induced increase of glucose transporter-4 expression and of glucose uptake in differentiated 3T3-L1 murine adipocytes; conversely, overexpression of LANCL2 enhanced basal, ABA- and insulin-stimulated glucose uptake. As compared with insulin, ABA treatment of adipocytes induced lower triglyceride accumulation, CO2 production and glucose-derived fatty acid synthesis. ABA per se did not induce pre-adipocyte differentiation in vitro, but stimulated adipocyte remodeling in terminally differentiated cells, with a reduction in cell size, increased mitochondrial content, enhanced O2 consumption, increased transcription of adiponectin and of brown adipose tissue (BAT) genes. A single dose of oral ABA (1µg/kg body weight) increased BAT glucose uptake 2-fold in treated rats compared with untreated controls. One-month-long ABA treatment at the same daily dose significantly upregulated expression of BAT markers in the WAT and in WAT-derived preadipocytes from treated mice compared with untreated controls. These results indicate a hitherto unknown role of LANCL2 in adipocyte sensitivity to insulin-stimulated glucose uptake and suggest a role for ABA in the induction and maintenance of BAT activity.


Assuntos
Ácido Abscísico/farmacologia , Adipócitos/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Glucose/metabolismo , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Biomarcadores/metabolismo , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Transportador de Glucose Tipo 4/metabolismo , Humanos , Insulina/metabolismo , Masculino , Camundongos , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Ratos , Ratos Wistar , Transcrição Gênica/efeitos dos fármacos
18.
Blood ; 125(26): 4095-102, 2015 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-25957389

RESUMO

Mechanisms of hematopoietic reconstitution after bone marrow (BM) transplantation remain largely unknown. We applied a computational quantification software application to hybrid 18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) images to assess activity and distribution of the hematopoietic system throughout the whole skeleton of recently transplanted patients. Thirty-four patients underwent PET/CT 30 days after either adult stem cell transplantation (allogeneic cell transplantation [ACT]; n = 18) or cord blood transplantation (CBT; n = 16). Our software automatically recognized compact bone volume and trabecular bone volume (IBV) in CT slices. Within IBV, coregistered PET data were extracted to identify the active BM (ABM) from the inactive tissue. Patients were compared with 34 matched controls chosen among a published normalcy database. Whole body ABM increased in ACT and CBT when compared with controls (12.4 ± 3 and 12.8 ± 6.8 vs 8.1 ± 2.6 mL/kg of ideal body weight [IBW], P < .001). In long bones, ABM increased three- and sixfold in CBT and ACT, respectively, compared with controls (0.9 ± 0.9 and 1.7 ± 2.5 vs 0.3 ± 0.3 mL/kg IBW, P < .01). These data document an unexpected distribution of transplanted BM into previously abandoned BM sites.


Assuntos
Células-Tronco Adultas/transplante , Transplante de Medula Óssea , Medula Óssea/diagnóstico por imagem , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Idoso , Aloenxertos , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X/métodos , Adulto Jovem
19.
J Nucl Cardiol ; 24(5): 1712-1721, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-27151303

RESUMO

BACKGROUND: Recent technical advances in multi-detector computed tomography (MDCT) allow for assessment of coronary flow reserve (CFR). We compared regional CFR by dynamic SPECT and by dynamic MDCT in patients with suspected or known coronary artery disease (CAD). METHODS: Thirty-five patients, (29 males, mean age 69 years) with greater than average Framingham risk of CAD, underwent dipyridamole vasodilator stress imaging. CFR was estimated using dynamic SPECT and dynamic MDCT imaging in the same patients. Myocardial perfusion findings were correlated with obstructive CAD (≥50% luminal narrowing) on CT coronary angiography (CA). RESULTS: Mean CFR estimated by SPECT and MDCT in 595 myocardial segments was not different (1.51 ± 0.46 vs. 1.50 ± 0.37, p = NS). Correlation of segmental CFR by SPECT and MDCT was fair (r 2 = 0.39, p < 0.001). Bland-Altman analysis revealed that MDCT in comparison to SPECT systematically underestimated CFR in higher CFR ranges. By CTCA, 12 patients had normal CA, 11 had non-obstructive, and 12 had obstructive CAD. CFR by both techniques was significantly higher in territories of normal CA than in territories subtended by non-obstructive or obstructive CAD. SPECT CFR was also significantly different in territories subtended by non-obstructive and obstructive CAD, whereas MDCT CFR was not. CONCLUSION: Despite relative underestimation of high CFR values, MDCT CFR shows promise for assessing the pathophysiological significance of anatomic CAD.


Assuntos
Angiografia por Tomografia Computadorizada , Doença da Artéria Coronariana/diagnóstico por imagem , Reserva Fracionada de Fluxo Miocárdico , Imagem de Perfusão do Miocárdio , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X , Idoso , Angiografia Coronária , Doença da Artéria Coronariana/fisiopatologia , Circulação Coronária/fisiologia , Dipiridamol , Feminino , Humanos , Masculino , Risco
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