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Melanoma is the most aggressive skin carcinoma and nanotechnology can bring new options for its pharmacological treatment. Nanostructured lipid carriers (NLC) are ideal drug-delivery carriers for hydrophobic drugs, such as the antineoplastic docetaxel (DTX), and hybrid (NLC-in-hydrogel) systems are suitable for topical application. This work describes a formulation of NLCDTX in xanthan-chitosan hydrogel containing lidocaine (LDC) with anticancer and analgesia effects. The optimized nanoparticles encapsulated 96% DTX and rheological analysis revealed inherent viscoelastic properties of the hydrogel. In vitro assays over murine fibroblasts (NIH/3T3) and melanoma cells (B16-F10), human keratinocytes (HaCaT) and melanoma cells (SK-MEL-103) showed reduction of docetaxel cytotoxicity after encapsulation in NLCDTX and HGel-NLCDTX. Addition of LDC to the hybrid system (HGel-NLCDTX-LDC) increased cell death in tumor and normal cells. In vivo tests on C57BL/6J mice with B16-F10-induced melanoma indicated that LDC, NLCDTX, HGel-NLCDTX-LDC and NLCDTX + HGel-LDC significantly inhibited tumor growth while microPET/SPECT/CT data suggest better prognosis with the hybrid treatment. No adverse effects were observed in cell survival, weight/feed-consumption or serum biochemical markers (ALT, AST, creatinine, urea) of animals treated with NLCDTX or the hybrid system. These results confirm the adjuvant antitumor effect of lidocaine and endorse HGel-NLCDTX-LDC as a promising formulation for the topical treatment of melanoma.

Background The consumption of large amounts of dietary fats can trigger an inflammatory response in the hypothalamus and contribute to the dysfunctional control of caloric intake and energy expenditure commonly present in obesity. The objective of this study was to identify chemokine-related transcripts that could be involved in the early stages of diet-induced hypothalamic inflammation. Methods We used immunoblot, PCR array, real-time PCR, immunofluorescence staining, glucose and insulin tolerance tests, and determination of general metabolic parameters to evaluate markers of inflammation, body mass variation, and glucose tolerance in mice fed a high-fat diet. Results Using a real-time PCR array, we identified leukemia inhibitory factor as a chemokine/cytokine undergoing a rapid increase in the hypothalamus of obesity-resistant and a rapid decrease in the hypothalamus of obesity-prone mice fed a high-fat diet for 1 day. We hypothesized that the increased hypothalamic expression of leukemia inhibitory factor could contribute to the protective phenotype of obesity-resistant mice. To test this hypothesis, we immunoneutralized hypothalamic leukemia inhibitory factor and evaluated inflammatory and metabolic parameters. The immunoneutralization of leukemia inhibitory factor in the hypothalamus of obesity-resistant mice resulted in increased body mass gain and increased adiposity. Body mass gain was mostly due to increased caloric intake and reduced spontaneous physical activity. This modification in the phenotype was accompanied by increased expression of inflammatory cytokines in the hypothalamus. In addition, the inhibition of hypothalamic leukemia inhibitory factor was accompanied by glucose intolerance and insulin resistance. Conclusion Hypothalamic expression of leukemia inhibitory factor may protect mice from the development of diet-induced obesity; the inhibition of this protein in the hypothalamus transforms obesity-resistant into obesity-prone mice.

ObjectiveIntriguingly, hyperinsulinemia, and hyperglycemia can predispose insulin resistance, obesity, and type 2 diabetes, leading to metabolic disturbances. Conversely, physical exercise stimulates skeletal muscle glucose uptake, improving whole-body glucose homeostasis. Therefore, we investigated the impact of short-term physical activity in a mouse model (Slc2a4+/−) that spontaneously develops hyperinsulinemia and hyperglycemia even when fed on a chow diet.MethodsSlc2a4+/− mice were used, that performed 5 days of endurance or strength exercise training. Further analysis included physiological tests (GTT and ITT), skeletal muscle glucose uptake, skeletal muscle RNA-sequencing, mitochondrial function, and experiments with C2C12 cell line.ResultsWhen Slc2a4+/− mice were submitted to the endurance or strength training protocol, improvements were observed in the skeletal muscle glucose uptake and glucose metabolism, associated with broad transcriptomic modulation, that was, in part, related to mitochondrial adaptations. The endurance training, but not the strength protocol, was effective in improving skeletal muscle mitochondrial activity and unfolded protein response markers (UPRmt). Moreover, experiments with C2C12 cells indicated that insulin or glucose levels could contribute to these mitochondrial adaptations in skeletal muscle.ConclusionsBoth short-term exercise protocols were efficient in whole-body glucose homeostasis and insulin resistance. While endurance exercise plays an important role in transcriptome and mitochondrial activity, strength exercise mostly affects post-translational mechanisms and protein synthesis in skeletal muscle. Thus, the performance of both types of physical exercise proved to be a very effective way to mitigate the impacts of hyperglycemia and hyperinsulinemia in the Slc2a4+/− mouse model.

Many efforts have been made to standardize the interpretation of 18 F-FDG PET/CT in multiple myeloma (MM) with qualitative visual analysis or with quantitative metabolic parameters using various methods for lesion segmentation of PET images. The aim of this study was to propose a quantitative method for bone and bone marrow evaluation of 18 F-FDG PET/CT considering the extent and intensity of bone 18 F-FDG uptake: Intensity of Bone Involvement (IBI). Whole body 18 F-FDG PET/CT of 59 consecutive MM patients were evaluated. Compact bone tissue was segmented in PET images using a global threshold for HU of the registered CT image. A whole skeleton mask was created and the percentage of its volume with 18 F-FDG uptake above hepatic uptake was calculated (Percentage of Bone Involvement - PBI). IBI was defined by multiplying PBI by mean SUV above hepatic uptake. IBI was compared with visual analysis performed by two experienced nuclear medicine physicians. IBI calculation was feasible in all images (range:0.00–1.35). Visual analysis categorized PET exams into three groups (negative/mild, moderate and marked bone involvement), that had different ranges of IBI (multi comparison analysis, p < 0.0001). There was an inverse correlation between the patients’ hemoglobin values and IBI (r = −0.248;p = 0.02). IBI score is an objective measure of bone and bone marrow involvement in MM, allowing the categorization of patients in different degrees of aggressiveness of the bone disease. The next step is to validate IBI in a larger group of patients, before and after treatment and in a multicentre setting.

PurposeThe aim of this study was to compare [18F]FDG and [68Ga]Ga-PSMA-11 PET/CT image findings in patients with multiple myeloma (MM).MethodsTwenty consecutive patients with symptomatic biopsy-proven MM were submitted to whole body [18F]FDG and [68Ga]Ga-PSMA-11 PET/CT with a time interval of 1–8 days between procedures. All lesions were counted and had their maximum SUV (SUVmax) measured. Intra-class correlation (ICC) was used to assess the agreement between [18F]FDG and [68Ga]Ga-PSMA-11 PET/CT findings.ResultsA total of 266 lesions were detected in 19/20 patients. [18F]FDG detected 223/266 (84%) lesions in 17 patients and [68Ga]Ga-PSMA-11 190/266 (71%) lesions in 19 patients. Both procedures did not identify any active lesion in 1 patient. Forty-three (16%) lesions were detected only by [68Ga]Ga-PSMA-11 and 76 (29%) only by [18F]FDG. Both tracers identified 147 (55%) lesions. Intralesional mismatch of FDG-PSMA uptake was identified in 25 of these 147 lesions, found in 8 different patients. Different lesions with uptake of only [18F]FDG or [68Ga]Ga-PSMA-11 in the same patient were found in 4 patients. The highest SUVmax of [18F]FDG and [68Ga]Ga-PSMA-11 had a median (min–max) SUVmax of 6.5 (2.0–37.8) and 5.5 (1.7–51.3), respectively. [18F]FDG and [68Ga]Ga-PSMA-11 respectively identified 18 and 19 soft tissue lesions. False-positive [18F]FDG findings had minimal or no uptake of [68Ga]Ga-PSMA-11. Good reliability (ICC ≥ 0.75) was found for number of lesions, number of soft tissue lesions and highest SUVmax in each patient.Conclusion[18F]FDG or [68Ga]Ga-PSMA-11 alone can detect most MM lesions. Almost half of the lesions take up only one of the tracers, reflecting increased glycolysis or angiogenesis in specific lesions, and suggesting their possible complementary role in MM. The marked [68Ga]Ga-PSMA-11 uptake in some cases raises the possibility of a theranostic approach in selected patients.

Filtered back-projection (FBP) is the most commonly used reconstruction method for PET images, which are usually noisy. The iterative reconstruction segmented attenuation correction (IRSAC) algorithm improves image quality without reducing image resolution. The standardized uptake value (SUV) is the most clinically utilized quantitative parameter of [fluorine-18]fluoro-2-deoxy-D-glucose (FDG) accumulation. The objective of this study was to obtain a table of SUVs for several normal anatomical structures from both routinely used FBP and IRSAC reconstructed images and to compare the data obtained with both methods. Twenty whole-body PET scans performed in consecutive patients with proven or suspected non-small cell lung cancer were retrospectively analyzed. Images were processed using both IRSAC and FBP algorithms. Nonquantitative or gaussian filters were used to smooth the transmission scan when using FBP or IRSAC algorithms, respectively. A phantom study was performed to evaluate the effect of different filters on SUV. Maximum and average SUVs (SUVmax and SUVavg) were calculated in 28 normal anatomical structures and in one pathological site. The phantom study showed that the use of a nonquantitative smoothing filter in the transmission scan results in a less accurate quantification and in a 20% underestimation of the actual measurement. Most anatomical structures were identified in all patients using the IRSAC images. On average, SUVavg and SUVmax measured on IRSAC images using a gaussian filter in the transmission scan were respectively 20% and 8% higher than the SUVs calculated from conventional FBP images. Scatterplots of the data values showed an overall strong relationship between IRSAC and FBP SUVs. Individual scatterplots of each site demonstrated a weaker relationship for lower SUVs and for SUVmax than for higher SUVs and SUVavg. A set of reference values was obtained for SUVmax and SUVavg of normal anatomical structures, calculated with both IRSAC and FBP image reconstruction algorithms. The use of IRSAC and a gaussian filter for the transmission scan seems to give more accurate SUVs than are obtained from conventional FBP images using a nonquantitative filter for the transmission scan.

Cisplatin (CDDP) combined with radiotherapy (RT) is employed in head and neck squamous cell carcinoma (HNSCC) with variable toxicities and clinical response. Glutathione S-transferases (GSTs) participate in CDDP excretion from cells, and genes encoding GSTs, GSTM1 , GSTT1 and GSTP1 , are polymorphic in humans. This prospective study aimed to evaluate the roles of GSTM1 , GSTT1 , and GSTP1 Ile105Val polymorphisms in outcomes of HNSCC patients treated with CDDP chemoradiation. Ninety patients were genotyped by multiplex PCR. Urinary CDDP measurements were performed by HPLC. Treatment side effects and response were analysed by conventional criteria. Patients with GSTT1 genes showed 7.23- and 5.37-fold higher likelihood of presenting vomiting and ototoxicity, lower glomerular filtration rate (GFR), and lower elimination of CDDP in urine relative to patients with deleted genes. Patients harbouring the GSTP1 IleVal or ValVal genotypes showed 4.28-fold higher likelihood of presenting grade 2 or 3 vomiting and lower GFR with treatment than those harbouring the IleIle genotype. In multivariate Cox analysis, patients with the GSTP1 105ValVal genotype had 3.87 more chance of presenting disease progression than those with the IleIle or IleVal genotype ( p  < 0.01). Our findings provide preliminary evidence that inherited abnormalities in CDDP metabolism, related to GSTT1 and GSTP1 Ile105Val polymorphisms, alter outcomes of HNSCC patients treated with CDDP and RT.

BACKGROUND Hypertension is the most prevalent and significant modifiable risk factor for coronary heart disease. A portion of patients with uncontrolled hypertension are considered to have resistant hypertension (RHTN). Myocardial ischemia incidence increases along with blood pressure (BP) levels. However, the prevalence of myocardial ischemia in patients with RHTN, as well as the factors associated with it, is unknown. METHODS We enrolled 129 patients with true RHTN regularly followed in our specialty hypertension clinic and evaluated then by resting and dipyridamole pharmacological stress myocardial perfusion scintigraphy. Patients were then divided into 2 groups: those with (I-RHTN; n = 36) and those without (NI-RHTN; n = 93) myocardial ischemia. Echocardiography, 24-hour ambulatory BP monitoring (ABPM), and flow mediated dilation (FMD) were also evaluated. RESULTS Thirty six (28%) patients had myocardial ischemia. There was no difference between groups regarding age, sex, biochemical parameters, office, and 24-hour ABPM levels. Patients in the I-RHTN group were more likely diabetic (31% vs. 11%; P < 0.05) and obese (75% vs. 40%; P < 0.001). Adjusting for age and body mass index, multiple logistic regression showed that diabetes (odds ratio (OR) = 6.5; 95% confidence interval (CI) = 1.06–40.14; P = 0.04), FMD (OR = 0.18; 95% CI = 0.07–0.41; P < 0.001), heart rate (OR = 1.23; 95% CI = 1.11–1.36; P < 0.001), left ventricular mass index (OR = 1.02; 95% CI = 1.01–1.04; P = 0.04), and microalbuminuria (OR = 1.02; 95% CI = 1.01–1.04; P = 0.002) were independent predictors of ischemia. CONCLUSIONS In conclusion, there is a high prevalence of myocardial ischemia in patients with RHTN. Increased microalbuminuria, heart rate, endothelial dysfunction, and left ventricular mass can be useful to guide the investigation for myocardial ischemia in these high risk patients.

Children with an uncomplicated femoral fracture, treated with superimposition of fragments and intentional shortening, usually develop overgrowth of the fractured femur and the ipsilateral tibia which may compensate for the initial shortening and enable the limb in question to reach a length similar to that on the normal side. The overgrowth is evaluated clinically and by scanography. The increased metabolic activity of the growth plates that support this overgrowth has not been documented by any laboratory method. In order to evaluate the metabolic activity of the growth plates, 18 patients (11 males, seven females; mean age 6.1 years) with fractures of the femur were studied at three different time intervals (2-5 months, 6-12 months and 18-24 months). Three-phase bone scintigraphy was performed in all patients. Ten children (five males, five females; mean age 7.5 years) who had had bone imaging for other reasons were used as the control group. Visual analysis of the flow and equilibrium phases was performed for the distal femoral and proximal tibial growth plates. Visual and semi-quantitative analyses of the delayed images were performed for the distal femoral and proximal and distal tibial growth plates. Semi-quantitative analyses yielded the following activity ratios: (a) the distal femoral growth plate of the fractured femur to the contralateral one (FR); (b) the proximal growth plate of the tibia on the side of the fractured femur to the contralateral one (TpR); (c) the distal growth plate of the tibia on the side of the fractured femur to the contralateral one (TdR); and (d) in the control group, the distal growth plates of both femora (FCG) and the proximal (TCGp) and distal (TCGd) growth plates of the tibiae. Visual analysis of the blood flow, equilibrium and delayed images showed increased activity in the distal femoral growth plates during the first and second time intervals, but not during the third. No significant activity changes were found in the proximal and distal tibial growth plates during any of the phases analysed. The mean and standard deviation for FR in the three time intervals were: FRI=1.22+/-0.27, FRII=1.17+/-0.16 and FRIII=1.09+/-0.20. FR values were significantly higher than in the control group (FCG=0.99+/-0.03) (P=0.033). The mean and standard deviation for TpR in the three time intervals were: TpRI=1.08+/-0.18, TpRII=0.94+/-0.09 and TpRIII=0.96+/-0.20. TpR values were not significantly different from those in the control group (TCGp=1.00+/-0.05). However, TpRI was significantly higher than TpRII (P=0.043). The mean and standard deviation for TdR in the three time intervals were: TdRI=1.10+/-0.41, TdRII=1.05+/-0.15 and TdRIII=1.13+/-0.36. TdR values were not significantly higher than in the control group (TCGd=1.00+/-0.04) (P=0.777). These results support the concept that three-phase bone imaging is able to quantify and determine that activation occurs in the distal femoral and proximal tibial growth plates of fractured femora. This phenomenon may explain the overgrowth observed in this injured bone structure.

Many efforts have been made to standardize the interpretation of F-FDG PET/CT in multiple myeloma (MM) with qualitative visual analysis or with quantitative metabolic parameters using various methods for lesion segmentation of PET images. The aim of this study was to propose a quantitative method for bone and bone marrow evaluation of F-FDG PET/CT considering the extent and intensity of bone F-FDG uptake: Intensity of Bone Involvement (IBI). Whole body F-FDG PET/CT of 59 consecutive MM patients were evaluated. Compact bone tissue was segmented in PET images using a global threshold for HU of the registered CT image. A whole skeleton mask was created and the percentage of its volume with F-FDG uptake above hepatic uptake was calculated (Percentage of Bone Involvement - PBI). IBI was defined by multiplying PBI by mean SUV above hepatic uptake. IBI was compared with visual analysis performed by two experienced nuclear medicine physicians. IBI calculation was feasible in all images (range:0.00-1.35). Visual analysis categorized PET exams into three groups (negative/mild, moderate and marked bone involvement), that had different ranges of IBI (multi comparison analysis, p < 0.0001). There was an inverse correlation between the patients' hemoglobin values and IBI (r = -0.248;p = 0.02). IBI score is an objective measure of bone and bone marrow involvement in MM, allowing the categorization of patients in different degrees of aggressiveness of the bone disease. The next step is to validate IBI in a larger group of patients, before and after treatment and in a multicentre setting.