Fetal membranes (FM) derived mesenchymal stromal/stem cells (MSCs) are higher in number, expansion and differentiation abilities compared with those obtained from adult tissues, including bone ...marrow. Upon systemic administration, ex vivo expanded FM-MSCs preferentially home to damaged tissues promoting regenerative processes through their unique biological properties. These characteristics together with their immune-privileged nature and immune suppressive activity, a low infection rate and young age of placenta compared to other sources of SCs make FM-MSCs an attractive target for cell-based therapy and a valuable tool in regenerative medicine, currently being evaluated in clinical trials. In the present study we investigated the permissivity of FM-MSCs to all members of the human Herpesviridae family, an issue which is relevant to their purification, propagation, conservation and therapeutic use, as well as to their potential role in the vertical transmission of viral agents to the fetus and to their potential viral vector-mediated genetic modification. We present here evidence that FM-MSCs are fully permissive to infection with Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), Varicella zoster virus (VZV), and Human Cytomegalovirus (HCMV), but not with Epstein-Barr virus (EBV), Human Herpesvirus-6, 7 and 8 (HHV-6, 7, 8) although these viruses are capable of entering FM-MSCs and transient, limited viral gene expression occurs. Our findings therefore strongly suggest that FM-MSCs should be screened for the presence of herpesviruses before xenotransplantation. In addition, they suggest that herpesviruses may be indicated as viral vectors for gene expression in MSCs both in gene therapy applications and in the selective induction of differentiation.
To identify factors associated with cutaneous rash, we performed a retrospective multicentre analysis of HIV outpatients starting a highly active antiretroviral therapy regimen containing nevirapine. ...A total of 62 cutaneous adverse events were observed in 429 patients. Rash hazard was increased in women, by the prophylactic use of glucocorticoids or antihistaminics, and was reduced by escalating the initial dose of nevirapine. Women receiving glucocorticoids had a 3 month cumulative probability of rash of 0.41.
New substituted 1-aryl-5-(1
H-pyrrol-1-yl)-1
H-pyrazole-3-carboxamides were synthesized by replacing the 2,4-dichlorobenzyl and cyclohexyl moieties at the 3-carboxamide nitrogen of the previously ...reported CB
1 receptor antagonists/inverse agonists
4 and
5. Several ligands showed potent affinity for the hCB
1 receptor, with
K
i concentrations comparable to the reference compounds
1,
4 and
5, and exhibited CB
1 selectivity comparable to
1 and
2. Docking experiments and molecular dynamics (MD) simulations explained the potent hCB
1 binding affinity of compounds
31 and
37. According to our previous studies,
31 and
37 formed a H-bond with K3.28(192), which accounted for the high affinity for the receptor inactive state and the inverse agonist activity. The finding of inhibition of food intake following their acute administration to rats, supported the concept that the CB
1 selective compounds
4 and
52 act as antagonists/inverse agonists.
A series of
N-alkyl 1-aryl-5-(1
H-pyrrol-1-yl)-1
H-pyrazole-3-carboxamides were synthesized as new ligands of the human recombinant receptor hCB
1.
n-Alkyl carboxamides brought out different SARs ...from the branched subgroup. Unsubstituted pyrrole derivatives bearing a
tert-alkyl chain at the 3-carboxamide nitrogen showed greater hCB
1 receptor affinity than the corresponding unbranched compounds. In particular, the
tert-butyl group as a chain terminal moiety strongly improved hCB
1 receptor affinity (compound
24:
K
i = 45.6 nM;
29:
K
i = 37.5 nM). Acute administration of either compound
12 or
29 resulted in a specific, dose-dependent reduction in food intake in rats. Such results provide an useful basis for the design of new CB
1 ligands.
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Introduction Members of the human intestinal microbiota are key players in maintaining human health. Alterations in the composition of gut microbial community (dysbiosis) have been linked with ...important human diseases. Understanding the underlying processes that control community structure, including the bacterial interactions within the microbiota itself, is essential. Bdellovibrio bacteriovorus is a gram-negative bacterium that preys other gram-negative species for survival, acting as a population-balancer. It was found in terrestrial/aquatic ecosystems, and in animal intestines, postulating its presence also in the human gut. Methods The present study was aimed to evaluate, by end-point PCR and qPCR, the presence of B. bacteriovorus in intestinal and faecal biopsy specimens from 92 paediatric healthy subjects and patients, suffering from Inflammatory Bowel Diseases (IBD), Celiac disease and Cystic fibrosis (CF). Results i) B. bacteriovorus was present and abundant only in healthy individuals, while it was heavily reduced in patients, as in the case of IBD and Celiac, while in CF patients and relative controls we observed comparable results; ii) B. bacteriovorus seemed to be mucosa-associated, because all IBD and Celiac biopsies (and related controls) were treated with mucus-removing agents, leaving only the mucosa-attached microflora; iii) B. bacteriovorus abundance was district-dependent, with a major preponderance in duodenum, and gradually decreasing up to rectum; iv) B. bacteriovorus levels significantly dropped in disease status, in duodenum and ileum. Conclusions Results obtained in this study could represent the first step for new therapeutic strategies aimed to restore a balance in the intestinal ecosystem, utilizing Bdellovibrio as a probiotic.
Introduction. Previous uncontrolled studies have highlighted the activity of rituximab in patients with idiopathic thrombocytopenic purpura (ITP) relapsed or refractory to standard treatments. To ...better address this effect, a prospective randomized (1:1), multicenter, phase III study comparing treatment with dexamethasone alone (arm A) vs dexamethasone plus rituximab (arm B) was conducted from July 2005 through June 2007 for adult patients with previously untreated ITP and a platelet (PLT) count ≤20 × 109/L.
Material and methods. Patients randomized to arm A received a single course of oral dexamethasone 40 mg on days +1, +2, +3, +4, while patients randomized to arm B received dexamethasone (as in arm A) in association with rituximab 375 mg/m2 iv on days +7, +14, +21, +28. Patients in arm A who failed to achieve a sustained response and had a platelet count ≤20 × 109/L (from day +30 up to the end of 6 months) could receive salvage treatment with the experimental arm (dexamethasone plus rituximab). The primary objective of the study was to compare the sustained response (SR), i.e. PLT count 50 × 109/L at month + 6 of treatment. Secondary objectives were: evaluation of the safety, the initial response (PLT count 50 × 109/L) by day 30 after the initiation of treatment, the activity of salvage therapy with dexamethasone plus rituximab in patients non responding to dexamethasone monotherapy, the definition of clinical and laboratory factors predictive of response and to explore the pharmacokinetics parameters of rituximab and their potential relation with response. Results were analyzed by an intention to treat (ITT) and by a per-protocol (PP) analysis.
Results. One-hundred-one patients (52 for arm A and 49 for arm B) and 64 patients (38 for arm A and 26 for arm B) represented the ITT and PP population, respectively. Demographic baseline data were in accordance to what expected for a population of ITP patients. No significant differences among the two groups of randomization were present. There was a female prevalence and the mean age was 47 and 49 years in arm A and B, respectively. Table 1 summarizes the ITT and PP efficacy results considering 3 different levels of response (i.e. PLT count 50 × 109/L, 100 × 109/L and 150 × 109/L). A significant advantage for arm B patients was documented.
Table 1Initial responseInitial responseSustained responseSustained responseAnalysisIntention-to TreatPer-ProtocolIntention-to TreatPer-ProtocolTreatmentArm AArm BP valueArm AArm BP valueArm AArm BP valueArm AArm BP valueValuable patients4425321352493826PLT3 50×109/L27%68%.00131%69%.00936%63%.00439%85%<.001PLT3 100×109/L23%48%.01528%46%.12233%53%.01937%77%<.001PLT3 150×109/L18%36%.17822%38%.12725%43%.02929%65%.002
Twenty-seven patients initially allocated to arm A and who failed to achieve initial response or SR received salvage treatment with the dexamethasone plus rituximab. In this group, ITT and PP SR rate were 56% and 59%, respectively. No clinical or laboratory factors predictive of SR were identified. In arm B patients the serum concentrations of rituximab levels did not correlate with the rate of response. Twelve SR patients of arm A, 27 of arm B and 19 of salvage therapy group were systematically followed up beyond month 6 for a median period of observation of 18 months (range 10–34 months). The rate of SR loss (platelets < 50 × 109/L) in these three groups was 25 % (3/12), 11% (3/27) and 10.5% (2/19). The safety profile was good with no substantial difference between the two arms of randomization. No patient died during the study period.
Conclusion. The results of this study indicate that the association of dexamethasone plus rituximab improves patients outcome without worsening of the safety profile. This effect is characterized by prolongation of SR and reduction in relapse rate. The long period of relapse free survival registered in some patients suggests a possible curative effect. This treatment can be offered as an option before splenectomy, particularly in those patients where the surgical option is not well accepted or have higher risk of complications.
Several observations support the hypothesis that pathogenetic mechanisms of β amyloid formation in Alzheimer's disease may involve alterations in amyloid precursor protein (APP) gene expression. In ...this regard, molecular dissection of the APP gene transcriptional regulation is of primary importance. We report evidence that members of the family of transcription factors NFκB/Rel can specifically recognize two identical sequences located in the 5′-regulatory region of APP. These sequences, which we refer to as APPκB sites, interact preferentially with p50-containing members of the family. In particular, p50 homodimers and p50/p65 and p50/c-Rel heterodimers act as transcriptional activators at the APPκB site. Finally, the nuclear complex specifically binding to the APPκB sites proves to be an integral part of neurons and lymphocytes.
Introduction & HypothesisDiabetes is one of the major risk factor for cardiovascular diseases. Prolonged exposure to uncontrolled hyperglycaemia in the heart induces dramatic metabolic changes that ...alter tissue homeostasis providing basis for the so called “metabolic memory”. Although epigenetic mechanisms have been described contributing to this process, the molecular events that establish metabolic memory remain elusive. Recent reports revealed that stable oxidation derivatives of methylated cytosines (5mC) such as 5-hydroxymethyl (5hmC) and 5-formyl (5fC) cytosines may accumulate in the heart upon age but none of these changes has been associated yet to metabolic memory or diabetes. Prior work described that human cardiac stromal cells isolated from diabetic donors (D-CSMCs) displayed stable epigenetic alterations including enrichment of 5mC. We queried here about the existence of an epi-metabolic control circuit capable of regulating DNA demethylation enzymatic machinery and the onset of metabolic memory diabetic tissues and cells.Methods & ResultsAn integrated genomic, transcriptomic and metabolomic approach revealed that 5mC, 5hmC and 5fC accumulated in genomic and mitochondrial DNA from hearts of diabetic mice and in D-CMSCs. Specifically, RNA-seq indicated repression of genes associated to proliferation, transcription, DNA repair and metabolism while metabolomics provided evidence of a reduction in alpha-ketoglutaric acid (αKG) synthesis. Notably, αKG deficiency compromised ten eleven translocation (TET) and thymine DNA glycosylase (TDG) complex formation and function. Providing an exogenous source of αKG to cells, in fact, reactivated TET and TDG and reduced the genomic content of modified cytosines. To select more specific modulators a drug screening was performed to select small molecule regulators of αKG synthesis and DNA demethylation. The newly identified compound, AA6, increased the intracellular content of αKG and activated TET and TDG resulting in genomic demethylation and functional rescue of type 2 diabetic mice and human cells.ConclusionsThe epi-metabolic modulation of DNA demethylation promises novel future therapeutic strategies aimed at prevention/treatment of diabetic cardiac complications.
Eminente francesista, Liana Nissim ha dedicato la sua intensa attività di ricerca al XIX secolo, in particolare a Gustave Flaubert e Stéphane Mallarmé. I suoi studi si sono concentrati anche sulle ...letterature francofone dell’Africa Nera e del Québec, che ha contribuito a introdurre in Italia e a diffondere su scala internazionale. Questo trittico di volumi «La grâce de montrer son âme dans le vêtement». Scrivere di tessuti, abiti e accessori illustra e approfondisce in molteplici direzioni una tematica a lei cara e ampiamente presente nei suoi lavori. Tramite la ricchezza delle metodologie e delle prospettive critiche, la comunità scientifica che ha condiviso con lei la passione per la ricerca e la dedizione alla vita universitaria vuole renderle un omaggio riconoscente.
Vascular endothelial growth factor (VEGF) is known to play a key role in tumour angiogenesis. Our preliminary published data suggest that plasma-activated platelets rich (P-APR) rather than other ...plasma compartments (i.e. plasma, plasma-platelets poor) or serum is the more suitable blood fraction for measuring VEGF in a miscellaneous series of gastrointestinal cancer patients. The aim of this confirmatory study was to assess VEGF in P-APR blood compartments of 30 healthy control subjects (HCS) and a homogeneous series of 62 colorectal cancer patients (CRCP), prospectively collected, to evaluate its possible clinical-biological significance. Samples of plasma (P) in both sodium citrate (SC) and sodium citrate-theophylline-adenosine-dipyridamole (CTAD) were collected from venous blood. After the centrifugation and separation methods VEGF levels were detected by ELISA in P-APR. The best differentiation between HCS and CRCP in VEGF level was seen for P-APRCTAD (median value: 255 pg/ml versus 142 pg/ml; p=0.000 by Mann-Whitney U test). No significant correlation among the P-APR VEGF concentrations and the main clinical pathological features was found. We suggest that P-APRCTAD fraction, obtained according to well standardised conditions, could represent the suitable blood compartment for the assessment of VEGF as marker of malignant intestinal transformation.
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