Raised pro-inflammatory immune/inflammatory setpoints, leading to an increased production of peripheral cytokines, have been associated with Major Depressive Disorder (MDD) and with failure to ...respond to first-line antidepressant drugs. However, the usefulness of these biomarkers in clinical psychopharmacology has been questioned because single findings did not translate into the clinical practice, where patients are prescribed treatments upon clinical need.
We studied a panel of 27 inflammatory biomarkers in a sample of 108 inpatients with MDD, treated with antidepressant monotherapy for 4 weeks upon clinical need in a specialized hospital setting, and assessed the predictive effect of baseline peripheral measures of inflammation on antidepressing efficacy (response rates and time-lagged pattern of decrease of depression severity) using a machine-learning approach with elastic net penalized regression, and multivariate analyses in the context of the general linear model.
When considering both categorical and continuous measures of response, baseline levels of IL-1β predicted non-response to antidepressants, with the predicted probability to respond being highly dispersed at low levels of IL-1β, and stratifying toward non-response when IL-1β is high. Significant negative effects were also detected for TNF-α, while IL-12 weakly predicted response.
These findings support the usefulness of inflammatory biomarkers in the clinical psychopharmacology of depression, and add to ongoing research efforts aiming at defining reliable cutoff values to identify depressed patients in clinical settings with high inflammation, and low probability to respond.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lymph node (LN) metastasis in canine mast cell tumor (MCT) can affect prognosis and postsurgical treatment recommendations; however, routine histological single-section examination may underestimate ...the incidence of metastases. This prospective study aimed at determining whether longitudinal step-sectioning of the entire LN allows for a more reliable detection of metastases. Dogs with MCT undergoing resection of the primary tumor and regional lymphadenectomy were enrolled. Formalin-fixed LNs were bisected longitudinally, both halves were embedded in paraffin and histological sections prepared at 200 μm steps. The nodal mast cells were classified according to the Weishaar classification. First-section evaluation (FSE; ie, examination of the first section obtained from the blocks) and whole LN step-section evaluation (SSE) were compared. Fifty-eight LNs were included. The median number of sections per LN was 6 (range, 3–28). FSE with toluidine blue (TB) revealed 27 (47%) nonmetastatic (HN0), 14 (24%) premetastatic (HN1), 9 (15%) early metastatic (HN2), and 8 (14%) overtly metastatic (HN3) LNs. SSE with TB resulted in upgrading the LN status in 2 cases (HN2 to HN3; HN0 to HN1). Evaluation of the first section plus an additional step-section resulted in 100% accuracy. Compared with SSE with TB, the accuracy of FSE with HE was 98% for HN3 LNs and 74% for HN2 LNs. FSE appears to reliably allow for the detection of LN metastasis in MCT, although examination of a further parallel section at a 200 μm step may increase the accuracy. A metachromatic stain is recommended for the identification of early metastases.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Drug resistance and off-organ toxicity remain unsolved issues in chemotherapy of advanced-stage melanoma patients. Thus, the creation of new molecular conjugates able to combine a selective ...accumulation, high ability of internalization and signaling pathway inhibition, are highly requested. Recently, we reported a new class of molecular conjugates, compounds 1–3, where the anti-αVβ3 integrin peptidomimetic c(AmpRGD), which is a selective ligand for αVβ3 integrin, was covalently bound to the tyrosine kinase inhibitor sunitinib. Here, we report that these c(AmpRGD)-sunitinib conjugates and, in particular, compound 3, are selectively internalized by human melanoma cells through αVβ3 receptor-mediated endocytosis. Compound 3 is more effective than sunitinib in reducing in vitro melanoma cells proliferation, cloning efficiency, migration, and invasion. More interestingly, compound 3 is able to significantly reduce the growth of xenografted melanoma tumor developed in immune-compromised mice, more efficiently than an equimolar dose of sunitinib. Indeed, its targeting ability was demonstrated by the selective localization at the tumor level with respect to healthy tissues. Thus, c(AmpRGD)-sunitinib conjugates such as compound 3 could serve as intriguing multiple-target agents to selectively reach melanoma cells and interfere with the progression of the disease.
•c(AmpRGD)-sunitinib conjugates were developed in view to reduce drug resistance and off-organ toxicity in cancer.•c(AmpRGD)-sunitinib compound 3 selectively enters melanoma cells by recognition of αVβ3 integrin receptors.•c(AmpRGD)-sunitinib compound 3 reduces xenografted melanoma growth and preferentially accumulates in the tumor tissue.•The use of RGD-targeted conjugates represents an appealing approach toward enhanced drug efficacy at a lowered drug dosage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Antimicrobial resistance (AMR) is an increasing threat to human health and an important issue also in the natural environment. For this study, an ecopathological approach was applied to the ...monitoring of the antimicrobial resistance in the province of Parma, Northern Italy. Fourteen monitoring sites and seventy-four faecal samples from four species of wild micromammals (Apodemus sylvaticus, Microtus savii, Mus domesticus and Suncus etruscus) were collected. Samples were subjected to bacteriological examination and antimicrobial susceptibility testing. Antibiotics belonging to 13 different antibiotic classes were tested. Collected data showed a prevalence of multi-drug resistant (MDR) strains of 55.13% and significant differences in the prevalence of MDR strains among the different micromammal species, while sex, age and anthropization level did not significantly affected MDR strains prevalence. Moreover, a high prevalence of bacterial strains resistant to colistin (95%), gentamicin (87%) and amikacin (83%) was observed. To our knowledge, this is the first report on antibiotic resistance in wild micromammals in the province of Parma.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The high glycolytic activity of multiple myeloma (MM) cells is the rationale for use of Positron Emission Tomography (PET) with
18
F-fluorodeoxyglucose (
18
FFDG) to detect both bone marrow (BM) and ...extramedullary disease. However, new tracers are actively searched because
18
FFDG-PET has some limitations and there is a portion of MM patients who are negative. Glutamine (Gln) addiction has been recently described as a typical metabolic feature of MM cells. Yet, the possible exploitation of Gln as a PET tracer in MM has never been assessed so far and is investigated in this study in preclinical models. Firstly, we have synthesized enantiopure (2
S
,4
R
)-4-fluoroglutamine (4-FGln) and validated it as a Gln transport analogue in human MM cell lines, comparing its uptake with that of
3
H-labelled Gln. We then radiosynthesized
18
F4-FGln, tested its uptake in two different
in vivo
murine MM models, and checked the effect of Bortezomib, a proteasome inhibitor currently used in the treatment of MM. Both
18
F4-FGln and
18
FFDG clearly identified the spleen as site of MM cell colonization in C57BL/6 mice, challenged with syngeneic Vk12598 cells and assessed by PET. NOD.SCID mice, subcutaneously injected with human MM JJN3 cells, showed high values of both
18
F4-FGln and
18
FFDG uptake. Bortezomib significantly reduced the uptake of both radiopharmaceuticals in comparison with vehicle at post treatment PET. However, a reduction of glutaminolytic, but not of glycolytic, tumor volume was evident in mice showing the highest response to Bortezomib. Our data indicate that
18
F(2
S
,4
R
)-4-FGln is a new PET tracer in preclinical MM models, yielding a rationale to design studies in MM patients.
SARS-CoV-2 infection in the pediatric age group has a milder course than in adults, but in some cases even children may present with severe forms or develop long-term consequences. The aim of this ...study was to analyze the clinical features, long-term effects, lifestyle changes and psychological effects of SARS-CoV-2 infection in a pediatric sample of the Italian population.
We conducted a telephone survey among 3075 children infected with SARS-CoV-2 in the Latina Local Health Authority. Outcomes included: clinical features of infection, long-term symptoms, lifestyle changes and emotional symptoms during the illness. The information obtained was automatically linked to a spreadsheet and analyzed.
One thousand four hundred thirteen children agreed to participate in the study; the mean age was 112.8 ± 21.9 months. Children were infected mainly inside familial clusters (59.6%; n = 842); 99% (n = 1399) of children were asymptomatic or exhibited mild symptoms. 20% (n = 259) of children experienced long-term symptoms; risk factors were: older age, higher body mass index and longer duration of infection. Throughout the period of infection, children spent most of the time on devices like tv-video, social media and mobile phone for non-educational activities. 58.8% (n = 620) of parents expressed a negative opinion about distance learning. Finally, we observed that 49,6% (n = 532) of children experienced psychological symptoms during quarantine period.
Despite a lower susceptibility to COVID-19 in children, it is important to keep the focus high in children, both because of the possible long symptoms after infection and the impact on a children's mental and physical health due to pandemic. We believe that the return to school or other extracurricular activities are important to correct some of the risk factors for the long COVID syndrome, as obesity, and to limit the cultural damage generated by distance learning and psychological effects related to restrictive measures.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In patients with COVID-19 pneumonia and mild hypoxaemia, the clinical benefit of high-flow nasal oxygen (HFNO) remains unclear. We aimed to examine whether HFNO compared with conventional oxygen ...therapy (COT) could prevent escalation of respiratory support in this patient population.
In this multicentre, randomised, parallel-group, open-label trial, patients with COVID-19 pneumonia and peripheral oxygen saturation (SpO
) ≤92% who required oxygen therapy were randomised to HFNO or COT. The primary outcome was the rate of escalation of respiratory support (ie, continuous positive airway pressure, non-invasive ventilation or invasive mechanical ventilation) within 28 days. Among secondary outcomes, clinical recovery was defined as the improvement in oxygenation (SpO
≥96% with fractional inspired oxygen (FiO
) ≤30% or partial pressure of arterial carbon dioxide/FiO
ratio >300 mm Hg).
Among 364 randomised patients, 55 (30.3%) of 181 patients assigned to HFNO and 70 (38.6%) of 181 patients assigned to COT underwent escalation of respiratory support, with no significant difference between groups (absolute risk difference -8.2% (95% CI -18% to +1.4%); RR 0.79 (95% CI 0.59 to 1.05); p=0.09). There was no significant difference in clinical recovery (69.1% vs 60.8%; absolute risk difference 8.2% (95% CI -1.5% to +18.0%), RR 1.14 (95% CI 0.98 to 1.32)), intensive care unit admission (7.7% vs 11.0%, absolute risk difference -3.3% (95% CI -9.3% to +2.6%)), and in hospital length of stay (11 (IQR 8-17) vs 11 (IQR 7-20) days, absolute risk difference -1.0% (95% CI -3.1% to +1.1%)).
Among patients with COVID-19 pneumonia and mild hypoxaemia, the use of HFNO did not significantly reduce the likelihood of escalation of respiratory support.
NCT04655638.
Similar to resting mature B cells, where the B-cell antigen receptor (BCR) controls cellular survival, surface BCR expression is conserved in most mature B-cell lymphomas. The identification of ...activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signalling is required for tumour cell survival. Consequently, the BCR signalling machinery has become an established target in the therapy of B-cell malignancies. Here we study the effects of BCR ablation on MYC-driven mouse B-cell lymphomas and compare them with observations in human Burkitt lymphoma. Whereas BCR ablation does not, per se, significantly affect lymphoma growth, BCR-negative (BCR
) tumour cells rapidly disappear in the presence of their BCR-expressing (BCR
) counterparts in vitro and in vivo. This requires neither cellular contact nor factors released by BCR
tumour cells. Instead, BCR loss induces the rewiring of central carbon metabolism, increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuates glycogen synthase kinase 3 beta (GSK3β) activity to support MYC-controlled gene expression. BCR
tumour cells exhibit increased GSK3β activity and are rescued from their competitive growth disadvantage by GSK3β inhibition. BCR
lymphoma variants that restore competitive fitness normalize GSK3β activity after constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate immunoglobulin-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR
tumour cells.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
We report here the preparation, physico-chemical characterization, and biological evaluation of a new liposome formulation as a tool for tumor angiogenesis inhibition. Liposomes are loaded with ...sunitinib, a tyrosine kinase inhibitor, and decorated with cyclo-aminoprolineRGD units (cAmpRGD), efficient and selective ligands for integrin αVβ3. The RGD units play multiple roles since they target the nanovehicles at the integrin αVβ3-overexpressing cells (e.g. activated endothelial cells), favor their active cell internalization, providing drug accumulation in the cytoplasm, and likely take part in the angiogenesis inhibition by interfering in the αVβ3-VEGFR2 cross-talk. Both in vitro and in vivo studies show a better efficacy of this integrated antiangiogenic tool with respect to the free sunitinib and untargeted sunitinib-loaded liposomes. This system could allow a lower administration of the drug and, by increasing the vector specificity, reduce side-effects in a prolonged antiangiogenic therapy.
Liposomes decorated with AmpRGD, an αVβ3 integrin-targeted ligand, and loaded with sunitinib, a known tyrosine-kinase inhibitor, were developed. This nanosized system was tested as an integrated antiangiogenic tool, and compared to free sunitinib and sunitinib-loaded untargeted liposomes, showing a potentiated activity both in vitro and in vivo. Display omitted
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a solid-like to a liquid-like state, ...which occurs in various tissues. Whether this tissue-level mechanical transition impacts phenotypes during carcinoma progression remains unclear. Here we report that the large fluctuations in cell density that accompany unjamming result in repeated mechanical deformations of cells and nuclei. This triggers a cellular mechano-protective mechanism involving an increase in nuclear size and rigidity, heterochromatin redistribution and remodelling of the perinuclear actin architecture into actin rings. The chronic strains and stresses associated with unjamming together with the reduction of Lamin B1 levels eventually result in DNA damage and nuclear envelope ruptures, with the release of cytosolic DNA that activates a cGAS-STING (cyclic GMP-AMP synthase-signalling adaptor stimulator of interferon genes)-dependent cytosolic DNA response gene program. This mechanically driven transcriptional rewiring ultimately alters the cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemoresistance in invasive breast carcinoma.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
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-4-Fluoroglutam...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/2234-943X/small "[18F](2S,4R)-4-Fluoroglutamine as a New Positron Emission Tomography Tracer in Myeloma")
