Adenovirus as a new agent for multiple myeloma therapies: Opportunities and restrictions

Multiple myeloma is a malignancy of B-cells that is characterized by the clonal expansion and accumulation of malignant plasma cells in the bone marrow. This disease remains incurable, and a median survival of 3-5 years has been reported with the use of current treatments. Viral-based therapies offer promising alternatives or possible integration with current therapeutic regimens. Among several gene therapy vectors and oncolytic agents, adenovirus has emerged as a promising agent, and it is already being used for the treatment of solid tumors in humans. The main concern with the clinical use of this vector has been its high immunogenicity; adenovirus is often able to induce a strong immune response in the host. Furthermore, new limitations in the efficacy of this therapy, intrinsic to the nature of tumor cells, have been recently observed. For example, our group showed a strong antiviral phenotype in vitro and in vivo in a subset of tumors, shedding new insights that may explain the partial failure of clinical trials based on this promising new therapy. In this review, we describe novel therapeutic approaches that implement viral-based treatments in hematological malignancies and address the novelty as well as the possible limitations of these new therapies, especially in the context of the use of adenoviral vectors for treating multiple myeloma

Anti-viral state segregates two molecular phenotypes of pancreatic adenocarcinoma: potential relevance for adenoviral gene therapy

<p>Abstract</p> <p>Background</p> <p>Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer mortality for which novel gene therapy approaches relying on tumor-tropic adenoviruses are being tested.</p> <p>Methods</p> <p>We obtained the global transcriptional profiling of primary PDAC using RNA from eight xenografted primary PDAC, three primary PDAC bulk tissues, three chronic pancreatitis and three normal pancreatic tissues. The Affymetrix GeneChip HG-U133A was used. The results of the expression profiles were validated applying immunohistochemical and western blot analysis on a set of 34 primary PDAC and 10 established PDAC cell lines. Permissivity to viral vectors used for gene therapy, Adenovirus 5 and Adeno-Associated Viruses 5 and 6, was assessed on PDAC cell lines.</p> <p>Results</p> <p>The analysis of the expression profiles allowed the identification of two clearly distinguishable phenotypes according to the expression of interferon-stimulated genes. The two phenotypes could be readily recognized by immunohistochemical detection of the Myxovirus-resistance A protein, whose expression reflects the activation of interferon dependent pathways. The two molecular phenotypes discovered in primary carcinomas were also observed among established pancreatic adenocarcinoma cell lines, suggesting that these phenotypes are an intrinsic characteristic of cancer cells independent of their interaction with the host's microenvironment. The two pancreatic cancer phenotypes are characterized by different permissivity to viral vectors used for gene therapy, as cell lines expressing interferon stimulated genes resisted to Adenovirus 5 mediated lysis in vitro. Similar results were observed when cells were transduced with Adeno-Associated Viruses 5 and 6.</p> <p>Conclusion</p> <p>Our study identified two molecular phenotypes of pancreatic cancer, characterized by a differential expression of interferon-stimulated genes and easily recognized by the expression of the Myxovirus-resistance A protein. We suggest that the detection of these two phenotypes might help the selection of patients enrolled in virally-mediated gene therapy trials.</p

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Genome-wide association study identifies eight loci associated with blood pressure

Christopher Newton-Cheh and colleagues report a genome-wide association study for blood pressure traits as part of the Global BPgen consortium. They report eight loci with replicated association to systolic and/or diastolic blood pressure, with each also showing association to hypertension

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value &lt; 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p &lt; 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

Pancreatic cancer immunotherapy: search for new tumor antigens

L\u2019adenocarcinoma pancreatico rappresenta uno dei tumori pi\uf9 letali a causa della mancanza di trattamenti efficaci. Negli ultimi 15 anni \ue8 stato dedicato molto lavoro allo sviluppo di terapie alternative e adiuvanti per il cancro, tra le quali, l\u2019immunoterapia sembra una delle pi\uf9 promettenti. L\u2019identificazione di antigeni tumore associati \ue8 uno dei passi fondamentali, in quanto permetter\ue0 il loro uso come target dell\u2019immunoterapia ed inoltre favorir\ue0 il monitoraggio quantitativo della risposta immune specifica in pazienti con tumore prima e durante protocolli di immunoterapia. Il nuovo antigene \u201ccancer testis\u201d BORIS (Brother Of the Regulator of Imprinted Sites) \ue8 stato recentemente indicato come un target promettente per immunoterapia in quanto \ue8 over espresso a livello di messaggero in molti tumori di differente istotipo, incluso l\u2019adenocarcinoma pancreatico. Linfociti T citotossici (CTL) generati contro BORIS proteggono da un challenge di tumore in un modello murino di cancro al seno e sembrano essere altamente specifici. Nella prima parte di questo studio, abbiamo caratterizzato l\u2019espressione di BORIS in un pannello di tessuti normali e tumorali e di linee cellulari tumorali per valutare il suo possibile utilizzo come target per l\u2019immunoterapia pancreatica. Abbiamo trovato che l\u2019espressione di BORIS non \ue8 stabile, ma che dipende dal microambiente. Inoltre, abbiamo trovato che BORIS \ue8 espresso in quasi tutti i tessuti normali analizzati. Presi insieme questi risultati scoraggiano l\u2019uso di BORIS come target di un\u2019 immunoterapia attiva. Analisi di microarray di pancreas normale, confrontati con campioni di adenocarcinoma, hanno rivelato che Survivin, Mesothelin e CEACAM5 (gi\ue0 conosciuti in quanto riescono a produrre una risposta immunitaria) sono candidati pi\uf9 promettenti come target per immunoterapia, grazie alla loro ristretta espressione nel tumore. Nella seconda parte dello studio, abbiamo analizzato l\u2019entit\ue0 dell\u2019immunosoppressione, analizzando cellule T regolatorie (Treg) da sangue periferico di pazienti con adenocarcinoma duttale pancreatico con differenti stadi della malattia. Abbiamo trovato un aumento di Treg in pazienti localmente avanzati in confronto ai donator sani, mentre abbiamo notato una diminuzione nelle percentuali di Treg circolanti in pazienti metastatici. Poich\ue9 l\u2019esito dell\u2019immunoterapia \ue8 strettamente correlato alla funzionalit\ue0 del sistema immunitario del paziente, una valutazione del loro stato di immunosoppressione dovrebbe rappresentare un importante criterio di arruolamento in futuri protocolli immunoterapeutici.Pancreatic adenocarcinoma represents one of most lethal cancer due to the lack of effective treatments. In the last 15 years a lot of efforts have been dedicated to develop alternative and adjuvant therapies for cancer and, among others, immunotherapy appears one of the most promising. Identification of tumor associated antigens is one of the key steps because it will allow their use as targets for immunotherapy and also enable quantitative monitoring of immune responses to tumor cells in cancer patients and during immunotherapeutic protocols. The newly described \u201ccancer testis\u201d antigen BORIS (Brother Of the Regulator of Imprinted Sites) has been recently suggested as a promising target for immunotherapy since it is over expressed at the messenger level in several tumors of different histological origin, including pancreatic adenocarcinoma. Cytotoxic T Lymphocytes (CTL) generated against BORIS protect from tumor challenge in a mouse breast cancer model and seem to be highly specific. In the first part of this study, we characterized the BORIS expression in a panel of normal and cancer tissues and cancer cell lines in order to assess its possible utilization as tumor antigen target for pancreatic cancer immunotherapy. We found that BORIS expression is not stable in the cancer cells, but depends on the microenvironment. Furthermore, we found BORIS expressed in almost all normal tissues analysed. These results taken together discourage the use of BORIS as target of an active immunotherapy. Microarray analysis of normal pancreatic tissues, compared to adenocarcinoma samples, revealed that Survivin, Mesothelin and CEACAM5 (already known to be able to elicit an immune response) are more promising candidates as target of immunotherapy because of their restricted expression in tumor. In the second part of the study, we analysed the extent of immunosuppression by analysing regulatory T cells (Tregs) from peripheral blood of pancreatic ductal adenocarcinoma patients at different stages of disease. We found an increase of Tregs in locally advanced patients as compared to healthy donors, while we noticed a decrease in the percentages of circulating regulatory T cells in metastatic patients. Since immunotherapy outcome is strictly related to the patient\u2019s immune system functionality, an evaluation of their immunosuppression status should represent an important criterion for the enrolment in future immunotherapeutic protocols

A review of pectin-based material for applications in water treatment

This article belongs to the Section Green Materials.Climate change and water are inseparably connected. Extreme weather events cause water to become more scarce, polluted, and erratic than ever. Therefore, we urgently need to develop solutions to reduce water contamination. This review intends to demonstrate that pectin-based materials are an excellent route to detect and mitigate pollutants from water, with several benefits. Pectin is a biodegradable polymer, extractable from vegetables, and contains several hydroxyl and carboxyl groups that can easily interact with the contaminant ions. In addition, pectin-based materials can be prepared in different forms (films, hydrogels, or beads) and cross-linked with several agents to change their molecular structure. Consequently, the pectin-based adsorbents can be tuned to remove diverse pollutants. Here, we will summarize the existing water remediation technologies highlighting adsorption as the ideal method. Then, the focus will be on the chemical structure of pectin and, from a historical perspective, on its structure after applying different cross-linking methods. Finally, we will review the application of pectin as an adsorbent of water pollutants considering the pectin of low degree methoxylation.The present work was supported by CSIC (I-COOP2020 COOPB20502), the Ministerio de Ciencia, Innovación y Universidades code PID2019-104650 GB-C21 (MCIN/ AEI /10.13039/501100011033), IT1566-22 (Basque Government), UBA (UBACYT 2018-2020 N°20020170100381BA), ANPCyT (PICT 2017-2362), MINCyT (“Programa Ciencia y Tecnología Contra el Hambre” IF-2021-4378615-APN-SSCI#MCT).Peer reviewe

Bayesan approach for nonresponse

Studies on business have many sources of different origins, nature and contents but most of the information available have lake of infos: "elderly" (old data), "myopic" (deals only with the enterprise structure e.g. ASIA the ISTAT annual statistical enterprise archive). That is why sector surveys become an essential source of information to study a specific economic activity area. Several methodological problems arise in this research field also due to the complexity of the issues raised (and therefore of the questionnaire). In this domain the main problem is the nonresponse where it is possible to define two principle type of missing data: cases whose coverage information is guaranteed by other sources of information (e.g. company size) and on the contrary cases without (e.g. there is information on new skills but not on stocks - Excelsior by Chamber Union and Ministry of Labour). By these assumptions derives that missing data is the main issue that researchers have to face to, in such kinds of studies (cf. Little (1986), Rubin (1976), Rubin (1996), Rubin and Schenker (1986), Sisto (2006), Schafer and Graham (2002)). In literature many procedures have been presented to solve the missing data problem. Proposals by classic staticians can be catalogued in two main categories bookstrap and EM algorithms. Bayesian approaches are instead focused on the ways to obtain the posterior distribution used to estimate the missing data. In this paper we apply classic and Bayesian procedures in a study on Italian Information Technology sector. The study considers many information about the Italian IT firms such as the structure, areas of activity and technological skills; the costumers; the IT market (prospects/perception); the association/institutional participation and so on. The full list of Italian IT enterprises (and their attributes) was supplied by the Milan Chambers of Commerce. Starting from the population of interest and considered the specific source used, incomplete auxiliary variables were discarded, so the stratification in the sample design has been made by various types of companies in business and by region (Nuts2). It was carried out simulations related to the nonresponse based on the different approaches considered. The benchmark was used to measures the effectiveness and efficiency, and also the applicability and simplicity of the methods