126 research outputs found
CD56-OVEREXPRESSING MYELOMA CELLS ARE MORE VULNERABLE TO NAD+ EXHAUSTING STRATEGIES DUE TO DEPENDENCY ON CD38 ENZYMATIC ACTIVITY
No full textCD56, also known as NCAM1 (Neural Cell Adhesion Molecule 1), is a member of the immunoglobulin superfamily and is deregulated in many tumors including Multiple Myeloma (MM) where it is expressed on the surface of malignant plasma cells in almost 70% of patients. This glycoprotein, as previously reported, seems to have several functions, including role in adhesion, tumor growth and response to therapy. However, studies are required to fully elucidate its biological role in MM.
In this study, we analyzed CD56 surface levels on malignant plasma cells collected from our cohort of MM patients at Saint Martin Policlinic Hospital, Genoa, Italy. We confirmed that low CD56 expression correlates with extramedullary disease (EMD), while high CD56 levels are associated with a better prognosis. Additionally, we observed a positive correlation between CD56 and CD38, another therapeutic target in MM, in both patients and MM cell lines.
Given the clinical significance of this correlation, we investigated the sensitivity of different cell lines and MM patients’ cells with high CD56 expression to the anti-CD38 monoclonal antibodies (moAbs). An increased sensitivity to these therapies was observed in this subgroup.
Since CD38 acts as an ecto-enzyme that depletes NAD+, we observed higher CD38 enzymatic activity and lower intracellular NAD+ levels in CD56 overexpressing MM cells. This led us to speculate a potential role for CD56 in the NAD+ biosynthesis pathway. Indeed, we observed that CD56 overespressing cells are more sensitive to NAD+ lowering agents, such as NAMPT inhibitors.
In conclusion, this study highlights the importance of immunophenotypic analysis of bone marrow plasma cells to guide personalized treatment strategies for MM patients. These findings suggest that therapies incorporating anti-CD38 antibodies and/or NAMPT inhibitors may be particularly effective for MM patients with high CD56 expression on bone marrow plasma cells (BMPCs)
Who Cares For The Carers? The Impacts Of Immigrant Elderly Care Workers On The Female Labour Supply
No full textWe analyse how the availability of immigrant workers in the elderly care sector affects the labour force participation of Italian females aged between 45 and 65. We estimate a selection bias correction model and exploit an IV strategy based on the role of migration networks in determining the geographical distribution of immigrants over time. Our main findings show that the local availability of foreign–born caregivers has a positive impact on the number of hours worked by Italian women, especially those with high–educational levels and living in the Northern regions. The effect on participation rates are instead positive and significant only for low–educated women and for women living in Central Italy
The impact of Covid-19 lockdown on the gender gap in the Italian labour market
No full textWe study the gendered impact of the nationwide lockdown (March–May 2020) due to the Covid-19 pandemic on the Italian labour market. Based on Labour Force Survey data on the first three quarters of 2020, we define a Triple Difference-in-Differences (DDD) strategy by exploiting the exact timing of the lockdown implementation. After controlling for several individual and job-related characteristics, we found that in non essential sectors (treated group) the lockdown enlarged pre-existent gender inequalities in the extensive margin of employment: the probability of job loss got 0.7 p.p. higher among female workers compared to their male counterparts, and this difference was mainly detected during the reopening period rather than in the strict lockdown phase. The probability to benefit from the wage guarantee fund (CIG), a subsidy traditionally granted by the government for partial or full–time hours reduction, was also higher for female compared to male treated workers (3.6 p.p.), both during the lockdown and in the reopening phase. This marks a great change with respect to the past, as the application of short-term work compensation schemes was traditionally restricted to male-dominated sectors of employment. On the other hand, no significant gender differences emerged among the treated group either in the intensive margin (working hours) or in terms of remote working, at least in the medium-term
Chemosensorial G-proteins-Coupled Receptors: A Perspective from Computational Methods
No full textG-protein coupled receptors (GPCRs) constitute the targets of about 40 % of all the pharmaceutical drugs in the market and, among other functions, a large portion of the family detects odorants and a variety of tastant molecules. Computational techniques are instrumental to understand structure, dynamics and function of the cascades triggered by these receptors. As an example, here we report our own computational work aimed to dissect GPCR molecular mechanisms for chemical senses. The implications of our work for systems biology and for pharmacology are discussed
Profiling online recreational/prescription drugs' customers and overview of drug vending virtual marketplaces
No full textObjectivesInternet and social networking sites play a significant role in the marketing and distribution of recreational/prescription drugs without restrictions. We aimed here at reviewing data relating to the profile of the online drug customer and at describing drug vending websites.MethodsThe PubMed, Google Scholar, and Scopus databases were searched here in order to elicit data on the socio-demographic characteristics of the recreational marketplaces/online pharmacies' customers and the determinants relating to online drug purchasing activities.ResultsTypical online recreational drugs' customers seem to be Caucasian, men, in their 20s, highly educated, and using the web to impact as minimally as possible on their existing work/professional status. Conversely, people without any health insurance seemed to look at the web as a source of more affordable prescription medicines. Drug vending websites are typically presented here with a no prescription required approach, together with aggressive marketing strategies.ConclusionsThe online availability of recreational/prescriptions drugs remains a public health concern. A more precise understanding of online vending sites' customers may well facilitate the drafting and implementation of proper prevention campaigns aimed at counteracting the increasing levels of online drug acquisition and hence intake activities. Copyright (c) 2015 John Wiley & Sons, Ltd
Structural predictions of neurobiologically relevant G-protein coupled receptors and intrinsically disordered proteins
No full textG protein coupled receptors (GPCRs) and intrinsic disordered proteins (IDPs) are key players for neuronal function and dysfunction. Unfortunately, their structural characterization is lacking in most cases. From one hand, no experimental structure has been determined for the two largest GPCRs subfamilies, both key proteins in neuronal pathways. These are the odorant (450 members out of 900 human GPCRs) and the bitter taste receptors (25 members) subfamilies. On the other hand, also IDPs structural characterization is highly non-trivial. They exist as dynamic, highly flexible structural ensembles that undergo conformational conversions on a wide range of timescales, spanning from picoseconds to milliseconds. Computational methods may be of great help to characterize these neuronal proteins. Here we review recent progress from our lab and other groups to develop and apply in silico methods for structural predictions of these highly relevant, fascinating and challenging systems
Transfer and recovery of DNA and metal particles: A proof-of-concept application of a parallel strategy by DNA and environmental scanning electron microscopy analysis
No full textAccording to the principle of Locard "Every contact leaves a trace", when touching a surface, a bi-directional transfer of self and non-self-DNA residing on the hands and touched objects can occur. Metals are commonly encountered in forensic evidence and, during hand contact with these surfaces, a transfer of metal particles could occur together with the transfer of human DNA. This study proposes a proof-concept approach for the original detection of metal particles and touch DNA to track the activity performed by a donor and particularly to assess the metallic substrate touched before the contact with a subsequent surface. To this scope, a scenario of contact events was simulated by three volunteers, who participated in fingerprint deposition firstly on copper and then on plastic and glass surfaces. Twenty-four stubs were collected on the hands of volunteers and the secondary surfaces and then analyzed by environmental scanning electron microscopy (ESEM). DNA was quantified only from copper and plastic surfaces. Ten additional volunteers followed the same protocol of deposition on copper and then on plastic surfaces to evaluate DNA transfer only. On 20 touch DNA samples, the copper surface yielded significantly lower DNA amounts, ranging from 0.001 to 0.129 ng/μl, compared to the secondary touched plastic surface, ranging from 0.007 to 0.362 ng/μl. ESEM-EDS analysis showed that copper particles could be abundantly detected on the hands of the volunteers after contact with the copper surface. Particles containing silicates with copper were shown on plastic, while they were only found in 1/3 of samples on glass. Our proof-of-concept study has shown that ESEM-EDS analysis has the potential to detect copper particles transferred to the hands of volunteers during contact with a copper metallic surface and deposited on secondarily touched items. The results suggest that this original ESEM-DNA parallel approach could potentially allow the tracking of DNA transfer and metal particles at a crime scene, although this represents only a first step and further research on a wider casuistry could help to address the interpretation of results given activity level propositions
Role of Extracellular Loops and Membrane Lipids for Ligand Recognition in the Neuronal Adenosine Receptor Type 2A: An Enhanced Sampling Simulation Study
No full textHuman G-protein coupled receptors (GPCRs) are important targets for pharmaceutical intervention against neurological diseases. Here, we use molecular simulation to investigate the key step in ligand recognition governed by the extracellular domains in the neuronal adenosine receptor type 2A (hA2AR), a target for neuroprotective compounds. The ligand is the high-affinity antagonist (4-(2-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)ethyl)phenol), embedded in a neuronal membrane mimic environment. Free energy calculations, based on well-tempered metadynamics, reproduce the experimentally measured binding affinity. The results are consistent with the available mutagenesis studies. The calculations identify a vestibular binding site, where lipids molecules can actively participate to stabilize ligand binding. Bioinformatic analyses suggest that such vestibular binding site and, in particular, the second extracellular loop, might drive the ligand toward the orthosteric binding pocket, possibly by allosteric modulation. Taken together, these findings point to a fundamental role of the interaction between extracellular loops and membrane lipids for ligands’ molecular recognition and ligand design in hA2AR
- …
