The superior diagnostic accuracy of 68GaGa-prostate-specific membrane antigen-11 (PSMA) (68GaGa-PSMA-11) compared to 18FF-Fluorocholine Positron Emission Tomography/Computed Tomography (PET/CT) in ...Prostate Cancer (PCa) is established. However, it is currently unclear if the added diagnostic accuracy actually translates into improved clinical outcomes in oligometastatic PCa patients treated with 68GaGa-PSMA-11 PET-guided metastasis-directed therapy (MDT). The present study aimed to assess the impact of these two imaging techniques on Progression-Free Survival (PFS) in a real-world sample of oligometastatic PCa patients submitted to PET-guided MDT. Thirty-seven oligometastatic PCa patients treated with PET-guided MDT were retrospectively enrolled. MDT was guided by 18FF-Fluorocholine PET/CT in eleven patients and by 68GaGa-PSMA-11 PET/CT in twenty-six. Progression was defined as biochemical recurrence (BR), radiological progression at subsequent PET/CT imaging, clinical progression, androgen deprivation therapy initiation, or death. Clinical and imaging parameters were assessed as predictors of PFS. 18FF-Fluorocholine PET-guided MDT was associated with significantly lower PFS compared to the 68GaGa-PSMA-11 group (median PFS, mPFS 15.47 months, 95% CI: 4.13−38.00 vs. 40.93 months, 95% CI: 40.93−40.93, respectively; p < 0.05). Coherently, the radiotracer used for PET-guided MDT resulted in predictive PFS at the univariate analysis, as well as the castration-resistant status at the time of MDT and the PSA nadir after MDT. However, in the multivariate analysis, castration resistance and PSA nadir after MDT remained the sole independent predictors of PFS. In conclusion, in the present proof-of-concept study, 68GaGa-PSMA-11 provided higher PFS rates than 18FF-Fluorocholine imaging in oligometastatic PCa patients receiving PET-guided MDT. Although preliminary, this finding suggests that enlarging the “tip of the iceberg”, by detecting a major proportion of the submerged disease thanks to next-generation imaging may favourably impact the oncological outcome of oligometastatic PCa treated with MDT.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Effective and selective targeting of the αVβ3 integrin subtype is of high relevance in cancer research for the development of therapeutic systems with improved efficacy and of diagnostic imaging ...probes. We report here a new class of highly selective, αVβ3‐targeted gold nanoparticles (AuNPs), which carry cyclic 4‐aminoproline‐RGD semipeptides (cAmpRGD) as the targeting moiety immobilized at low surface density on the poly(ethylene glycol) (PEG)‐based nanoparticle coating. We show that these nanoparticles are potent inhibitors of the integrin‐mediated melanoma tumor cell adhesion to vitronectin and are selectively internalized via receptor‐mediated endocytosis. Furthermore, we have developed bifunctional cAmpRGD‐functionalized AuNPs by conjugation of a fluorophore (FAM or TAMRA) to a separate set of reactive groups on the PEG‐based coating. These bifunctional AuNPs not only recapitulate the binding properties of cAmpRGD‐AuNPs but also can be visualized via confocal laser microscopy, allowing direct observation of nanoparticle internalization. The peculiar molecular design of these nanoparticles and their precisely defined architecture at the molecular level accounts for their selective integrin binding with very low nonspecific background.
Na na na nano nano! Gold nanoparticle (AuNP) design is essential for superior αVβ3 integrin targeting. Cyclic cAmpRGD semipeptides are used as selective targeting units at low surface density on top of a compact alkylPEG coating. cAmpRGD‐AuNPs inhibit integrin‐mediated cell adhesion to vitronectin with an IC50≈1 nm indicating a high multivalent enhancement factor (≈200). At 24 h, these AuNPs are internalized 6–7 times more efficiently than non‐targeted nanoparticles, only by cells expressing the αVβ3 integrin subtype.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Spoligotyping and exact tandem repeat (ETR) analysis of Mycobacterium bovis and M. caprae isolated strains has been routinely carried out in Italy since 2000 to obtain a database of genetic profiles ...and support traditional epidemiological investigations. In this study, we characterized 1,503 M. bovis and 57 M. caprae isolates obtained from 2000 to 2006 in 747 cattle herds mainly located in northern Italy. We identified 81 spoligotypes and 113 ETR profiles, while the combination of spoligotyping/ETR analysis differentiated 228 genotypes, with genotypic diversity indices of 0.70 (spoligotyping), 0.94 (ETR-A to -E typing), and 0.97 (spoligotyping/ETR-A to -E typing), respectively. Despite the high degree of resolution obtained, the spoligotyping/ETR methods were not discriminative enough in the case of genotypes characterized by the combination of SB0120, the predominant spoligotype in Italy, with the most common ETR profiles. To obtain a more informative subset of typing loci, 24 mycobacterial interspersed repetitive unit-variable-number tandem repeat (MIRU-VNTR) markers were evaluated by analyzing a panel of 100 epidemiologically unrelated SB0120 isolates. The panel was differentiated into 89 profiles with an overall genotypic diversity of 0.987 that could be also achieved by using a minimal group of 13 loci: ETR-A, -B, and -E; MIRU 26 and 40; and VNTR 2163a, 2163b, 3155, 1612, 4052, 1895, 3232, and 3336. The allelic diversity index and the stability of single loci was evaluated to provide the most discriminative genotyping method for locally prevalent strains.
The authenticity of fish products has become an imperative issue for authorities involved in the protection of consumers against fraudulent practices and market stabilization. The present study aimed ...to provide a method for authentication of European sea bass (Dicentrarchus labrax) according to the requirements for seafood labels (Regulation 1379/2013/EU). Data on biometric traits, fatty acid profile, elemental composition, and isotopic abundance of wild and reared (intensively, semi-intensively, and extensively) specimens from 18 southern European sources (n = 160) were collected, clustered in six sets of parameters, and then subjected to multivariate analysis. Correct allocations of subjects according to their production method, origin, and stocking density were demonstrated with good approximation rates (94, 92, and 92%, respectively) using fatty acid profiles. Less satisfying results were obtained using isotopic abundance, biometric traits, and elemental composition. The multivariate analysis also revealed that extensively reared subjects cannot be analytically discriminated from wild subjects.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Molecular superposition models guided the design of novel melatonin receptor ligands characterized by a 2-acylaminomethyltetrahydroquinoline scaffold. Starting from the structure of ...N-anilinoethylamide ligands, the flexible chain was conformationally constrained to reproduce the bioactive conformation of melatonin. Structure–activity relationships were investigated, focusing on the substituent at the nitrogen atom, the position of the methoxy group, and the replacement of the amide side chain by urea and thiourea groups. The compounds were tested for binding affinity and intrinsic activity at human MT1 and MT2 receptors. Structural optimization resulted in N-(1-benzyl-1,2,3,4-tetrahydro-5-methoxyquinolin-2-yl)methylpropionamide (UCM1014), with picomolar MT2 binding affinity (K i = 0.001 nM), more than 10000-fold selectivity over the MT1 receptor, and a full agonist profile (GTPγS test), being the most potent MT2-selective full agonist reported to date. Molecular dynamics simulations provided a rationale for high binding affinity, stereoselectivity, and agonist behavior of these novel melatonin receptor ligands based on superposition models and conformational preference.
Glutamine (Gln) addiction has been recently described as a typical metabolic feature of MM by our group. In order to sustain high Gln demand, MM cells upregulate the expression of the Gln ...transporters ASCT2, SNAT1 and LAT1 and are characterized by fast Gln uptake. Currently, 2-deoxy-2-18Ffluoro-D-glucose (18FFDG) is the standard tracer for the positron emission tomography/computed tomography (PET/CT) scan to detect both medullary and extramedullary disease in MM patients. However, FDG-PET has some limitations, since there is a portion of MM patients who are false-negative. For these reasons, the aim of our study is to characterize Gln metabolism in vivo in different MM mouse models and investigate the possible use of Gln as a PET tracer in MM.
To this purpose, we have firstly synthesized enantiopure (2 S,4 R)-4-fluoroglutamine (4-FGln) and validated it in human MM cell lines (RPMI8226 and JJN3) comparing its uptake with that of 3H-labelled Gln. Both Gln and 4-FGln were actively accumulated by MM cells. Inhibition analysis revealed that ASCT2 was the major entry route of both compounds.
We then carried out the radiosynthesis of 18F4-FGln and tested its uptake for MM detection by PET in comparison with 18FFDG. Firstly, we characterized 18F4-FGln kinetics using immunodeficient NOD/SCID mice subcutaneously injected with JJN3. In this xenograft model, 18FFDG- and 18F4-FGln-PET were performed after plasmacytomas became palpable. In tumor, 18F4-FGln uptake peaked at 25 min slowly declining thereafter. The Logan plot confirmed linearity starting at 15 min from injection, consistent with largely reversible tracer exchange.
Thereafter, 18FFDG and 18F4-FGln distribution were assessed in both syngeneic (murine Vk12598 cells) and xenograft ( human JJN3 cells) MM models.
C57BL/6 mice were injected intravenously with Vk12598 cells obtained from transgenic Vk*MYC mice. Mice were monitored weekly for M-spike and MM progression by retro-orbital bleeding. At weeks 3, 4 and 5, mice underwent PET with 18FFDG and 18F4-FGln on consecutive days. The expression of ASCT2, checked in the femur of Vk12598 MM bearing mice, increased along with MM progression. Uptake of both tracers was measurable in the spleen of MM mice by week 3, reached a peak at week 4 and declined thereafter. In JJN3 model, all the tumors were positive for 18FFDG and displayed 18F4-FGln uptake (18F4-FGln: tumor to muscle ratios (T/M): 1.6 ± 0.1; 18FFDG: T/M: 3.5 ± 1.1). Tumor volume (896.8 ±349.00 mm3), 18F4-FGln uptake and 18FFDG uptake (T/M: 2.3 ± 0.3 and 7.1 ± 2.6, respectively) increased after 1 week (18F4-FGln p = 0.0156; 18FFDG p = 0.0167).
Thereafter, the effect of bortezomib (BOR) was investigated to evaluate the potential use of 18F4-FGln to monitor anti-MM treatment. JJN3-bearing mice were treated with BOR (1mg/kg) by intravenous injections twice weekly. Before and after treatment, animals performed the PET acquisitions with 18FFDG and 18F4-FGln on consecutive days and were sacrificed for post-mortem analysis on day 7. As expected, bortezomib treatment reduced tumor size compared with vehicles (172.0 ± 86.6 vs 687.9 ± 286.5 mm3; p = 0.0006).
PET analysis performed after BOR treatment showed that BOR significantly reduced the uptake of both radiopharmaceuticals in comparison with vehicles (p< 0.05). BOR-treated mice were classified as responders and non responders according to the adapted RECIST score. Interestingly, responder mice showed a reduction of 18F4-FGln T/M ratio and 18F4-FGln-related tumor volume. On the contrary, all mice displayed increased 18FFDG parameters independently from the response. Lastly, tracer overlap analysis showed that the area of relative exclusive uptake of 18F4-FGln decreased in responders compared to non responders (9% versus 32%, respectively, p=0.04), while that of 18FFDG increased in responders compared to non responders (82% versus 23%, respectively, p=0.04).
Our data indicate that 18F(2 S,4 R)-4-FGln is a new PET tracer in pre-clinical MM models, providing the rationale to design studies in MM patients.
Giuliani: Celgene: Membership on an entity's Board of Directors or advisory committees, Other: congress, Research Funding; Millenium Pharmaceutical: Other: clincial studies; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical studies, congress, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Other: clinical studies; Bristol Mayers Squibb: Other: congress.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Bacillus thuringiensis (Bt) can be effective in controlling insect pests either in spray products or by their toxins expressed in transgenic crops. The discovery of Bt as endophytic in citrus opened ...new perspectives for the control of Diaphorina citri Kuwayama, the vector of the bacteria Candidatus Liberibacter spp. associated with Huanglongbing. In this study, the endophytic translocation of Bt in citrus seedlings (small and large plants) and in different scion-rootstock combinations were investigated. We also assessed the lethal concentration of D. citri nymphs caused by systemic Bt in citrus and, moreover, the binding of Cry toxins with the Asian citrus psyllid (ACP) gut receptors. Endophytic translocation of Bt in citrus seedlings and nursery trees was confirmed by colony isolation, PCR detection, and Btk-GFP microscopy analyses, which demonstrated that, after Bt inoculation into the substrate, the bacteria enter through lateral root emergence sites and are localized in stem xylem vessel elements. Mean lethal concentrations for D. citri third instar nymphs were 4.92 × 104 and 2.19 × 104 spores mL−1 for S1450 and S1302 strains, respectively. Nymphal mortality induced by the bacteria was higher in citrus seedlings than in citrus nursery trees. All Cry-toxins tested were able to bind to D. citri brush border membrane vesicles, suggesting the potential pathogenicity of Bt strains against psyllid. This study clearly demonstrates the penetration and Bt translocation in the xylem of small and large citrus plants and the potential of the bacteria to cause ACP nymphs mortality that fed on shoots from Bt-treated citrus.
Bacillus thuringiensis (Bt) as endophytic in citrus plants has a potential to control the Asian citrus psyllid (ACP), Diaphorina citri Kuwayama. In this study, the endophytic translocation and pathogenicity of Bt against ACP nymphs feeding on citrus under different citrus scion-rootstock combinations were assessed, and Bt-toxins binding with D. citri gut receptors, were investigated. Our results clearly demonstrated the penetration and endophytic Bt translocation in the citrus vessels and the potential of the Bt to control psyllid nymphs that fed on shoots from citrus Bt-treated. Display omitted
•Bacillus thuringiensis strains endophytically translocate in the xylem vessel elements of citrus seedlings and citrus nursery trees grafted on different scion-rootstocks combinations.•Cry toxins bind to brush border membrane vesicles obtained from D. citri nymphs.•Bt systemic product could be an alternative tool for the D. citri management programs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Inflammatory components (PCA) differentiate patients vs controls.•Elastic net results prompted IL-13 as new marker of suicide in major depression.•A positive history of suicide attempts is ...associated to higher level of IL-13.
Every 40 seconds one person dies from suicide worldwide, half of which are related to depression. Neuroinflammation has been reported in neuropsychiatric conditions, including major depressive disorder (MDD). Preliminary findings suggested a link between inflammation and suicidal behavior. Nevertheless, to the best of our knowledge, no previous study explored how a wide range of cytokines may differentiate lifetime suicidal behaviors (i.e. positive history of suicide attempts) in patients affected by MDD.
In 28 healthy controls (HC), 28 MDD patients with a positive history of attempting suicide (SA), and 28 MDD patients with a negative history (nSA), we determined concentrations of immune analytes using an ultra-sensitive Pro Human Cytokine Group 27-Plex Panel and Chemokine immunoassay panels (Bioplex). To deal with the 27 highly correlated cytokines we applied two different statistical approaches that reduce the dimensionality of data: Principal Component Analysis, exploring if suicidality may be related to a comprehensive derived inflammatory state, and elastic-net penalized regression that allows considering as predictor every single cytokine.
Five inflammatory components were identified: none predicted suicidal behavior. Elastic net results prompted IL-13 as a new candidate marker of suicide in patients with MDD.
The retrospective design of the study and the small sample size preclude the possible causal interpretation and generalizability of reported results.
Exploring a wide range of cytokines may provide a new inflammatory signature of suicide useful for understanding pathophysiological underpinnings, developing new therapeutic targets, and allowing the identification of at-risk factors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Although a number of studies have suggested that the use of Telemonitoring (TM) in patients with Chronic Obstructive Pulmonary Disease (COPD) can be useful and efficacious, its real utility in ...detecting Acute Exacerbation (AE) signaling the need for prompt treatment is not entirely clear. The current study aimed to investigate the benefits of a TM system in managing AE in advanced-stage COPD patients to improve their Health-Related Quality of Life (HRQL) and to reduce utilization of healthcare services.
A 12-month Randomised Controlled Trial (RCT) was conducted in the Veneto region (Italy). Adult patients diagnosed with Class III-IV COPD in accordance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification were recruited and provided a TM system to alert the clinical staff via a trained operator whenever variations in respiratory parameters fell beyond the individual's normal range. The study's primary endpoint was HRQL, measured by the Italian version of the two Short Form 36-item Health Survey (SF36v2). Its secondary endpoints were: scores on the Hospital Anxiety and Depression Scale (HADS); the number and duration of hospitalizations; the number of readmissions; the number of appointments with a pulmonary specialist; the number of visits to the emergency department; and the number of deaths.
Three hundred thirty-four patients were enrolled and randomized into two groups for a 1 year period. At its conclusion, changes in the SF36 Physical and Mental Component Summary scores did not significantly differ between the TM and control groups (-2.07 (8.98) vs -1.91 (7.75); p = 0.889 and -1.08 (11.30) vs -1.92 (10.92); p = 0.5754, respectively. Variations in HADS were not significantly different between the two groups 0.85 (3.68) vs 0.62 (3.6); p = 0.65 and 0.50 (4.3) vs 0.72 (4.5); p = 0.71. The hospitalization rate for AECOPD and/or for any cause was not significantly different in the two groups IRR = 0.89 (95% CI 0.79-1,04); p = 0.16 and IRR = 0.91 (95% CI 0,75 - 1.04); p = 0.16, respectively. The readmission rate for AECOPD and/or any cause was, however, significantly lower in the TM group with respect to the control one IRR = 0.43 (95% CI 0.19-0.98); p = 0.01 and 0.46 (95% CI 0.24-0.89); p = 0.01, respectively.
Study results showed that in areas where medical services are well established, TM does not significantly improve HRQL in patients with COPD who develop AE. Although not effective in reducing hospitalizations, TM can nevertheless facilitate continuity of care during hospital-to-home transition by reducing the need for early readmission.
Retrospectively registered on January 2012, ClinicalTrials.gov Identifier: NCT01513980 .
Pneumothorax (PNX) and pneumomediastinum (PNM) are potential complications of COVID-19, but their influence on patients’ outcomes remains unclear. The aim of the study was to assess incidence, risk ...factors, and outcomes of severe COVID-19 complicated with PNX/PNM. Methods: A retrospective multicenter case-control analysis was conducted in COVID-19 patients admitted for respiratory failure in intermediate care units of the Treviso area, Italy, from March 2020 to April 2021. Clinical characteristics and outcomes of patients with and without PNX/PNM were compared. Results: Among 1213 patients, PNX and/or PNM incidence was 4.5%. Among these, 42% had PNX and PNM, 33.5% only PNX, and 24.5% only PNM. COVID-19 patients with PNX/PNM showed higher in-hospital (p = 0.02) and 90-days mortality (p = 0.048), and longer hospitalization length (p = 0.002) than COVID-19 patients without PNX/PNM. At PNX/PNM occurrence, one-third of subjects was not mechanically ventilated, and the respiratory support was similar to the control group. PNX/PNM occurrence was associated with longer symptom length before hospital admission (p = 0.005) and lower levels of blood lymphocytes (p = 0.017). Conclusion: PNX/PNM are complications of COVID-19 associated with a worse prognosis in terms of mortality and length of hospitalization. Although they are more frequent in ventilated patients, they can occur in non-ventilated, suggesting that mechanisms other than barotrauma might contribute to their presentation.
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