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Background: Tregs trafficking is controlled by CXCR4. In Renal Cell Carcinoma (RCC), the effect of the new CXCR4 antagonist, R54, was explored in peripheral blood (PB)-Tregs isolated from primary RCC patients. Methods: PB-Tregs were isolated from 77 RCC patients and 38 healthy donors (HDs). CFSE-T effector-Tregs suppression assay, IL-35, IFN-γ, IL-10, TGF-β1 secretion, and Nrp-1+Tregs frequency were evaluated. Tregs were characterised for CTLA-4, PD-1, CD40L, PTEN, CD25, TGF-β1, FOXP3, DNMT1 transcriptional profile. PTEN-pAKT signalling was evaluated in the presence of R54 and/or triciribine (TCB), an AKT inhibitor. Methylation of TSDR (Treg-Specific-Demethylated-Region) was conducted. Results: R54 impaired PB-RCC-Tregs function, reduced Nrp-1+Tregs frequency, the release of IL-35, IL-10, and TGF-β1, while increased IFN-γ Teff-secretion. The CXCR4 ligand, CXCL12, recruited CD25+PTEN+Tregs in RCC while R54 significantly reduced it. IL-2/PMA activates Tregs reducing pAKT+Tregs while R54 increases it. The AKT inhibitor, TCB, prevented the increase in pAKT+Tregs R54-mediated. Moreover, R54 significantly reduced FOXP3-TSDR demethylation with DNMT1 and FOXP3 downregulation. Conclusion: R54 impairs Tregs function in primary RCC patients targeting PTEN/PI3K/AKT pathway, reducing TSDR demethylation and FOXP3 and DNMT1 expression. Thus, CXCR4 targeting is a strategy to inhibit Tregs activity in the RCC tumour microenvironment. [ABSTRACT FROM AUTHOR]

Background and purpose: While HCC is an inflammation-associated cancer, CRLM develops on permissive healthy liver microenvironment. To evaluate the immune aspects of these two different environments, peripheral blood-(PB), peritumoral-(PT) and tumoral tissues-(TT) from HCC and CRLM patients were evaluated. Methods: 40 HCC and 34 CRLM were enrolled and freshly TT, PT and PB were collected at the surgery. PB-, PT- and TT-derived CD4+CD25+ Tregs, M/PMN-MDSC and PB-derived CD4+CD25− T-effector cells (Teffs) were isolated and characterized. Tregs' function was also evaluated in the presence of the CXCR4 inhibitor, peptide-R29, AMD3100 or anti-PD1. RNA was extracted from PB/PT/TT tissues and tested for FOXP3, CXCL12, CXCR4, CCL5, IL-15, CXCL5, Arg-1, N-cad, Vim, CXCL8, TGFβ and VEGF-A expression. Results: In HCC/CRLM-PB, higher number of functional Tregs, CD4+CD25hiFOXP3+ was detected, although PB-HCC Tregs exert a more suppressive function as compared to CRLM Tregs. In HCC/CRLM-TT, Tregs were highly represented with activated/ENTPD-1+Tregs prevalent in HCC. As compared to CRLM, HCC overexpressed CXCR4 and N-cadherin/vimentin in a contest rich in arginase and CCL5. Monocytic MDSCs were highly represented in HCC/CRLM, while high polymorphonuclear MDSCs were detected only in HCC. Interestingly, the function of CXCR4-PB-Tregs was impaired in HCC/CRLM by the CXCR4 inhibitor R29. Conclusion: In HCC and CRLM, peripheral blood, peritumoral and tumoral tissues Tregs are highly represented and functional. Nevertheless, HCC displays a more immunosuppressive TME due to Tregs, MDSCs, intrinsic tumor features (CXCR4, CCL5, arginase) and the contest in which it develops. As CXCR4 is overexpressed in HCC/CRLM tumor/TME cells, CXCR4 inhibitors may be considered for double hit therapy in liver cancer patients. [ABSTRACT FROM AUTHOR]

Background: Dysbiotic biliary bacterial profile is reported in cancer patients and is associated with survival and comorbidities, raising the question of its effect on the influence of anticancer drugs and, recently, the suggestion of perichemotherapy antibiotics in pancreatic cancer patients colonized by the Escherichia coli and Klebsiella pneumoniae. Objective: In this study, we investigated the microbial communities that colonize tumours and which bacteria could aid in diagnosing pancreatic and biliary cancer and managing bile-colonized patients. Methods: A retrospective study on positive bile cultures of 145 Italian patients who underwent cholangiopancreatography with PC and EPC cancer hospitalized from January 2006 to December 2020 in a QA-certified academic surgical unit were investigated for aerobic/facultative-anaerobic bacteria and fungal organisms. Results: We found that among Gram-negative bacteria, Escherichia coli and Pseudomonas spp were the most frequent in the EPC group, while Escherichia coli, Klebsiella spp, and Pseudomonas spp were the most frequent in the PC group. Enterococcus spp was the most frequent Gram-positive bacteria in both groups. Comparing the EPC and PC, we found a significant presence of patients with greater age in the PC compared to the EPC group. Regarding Candida spp, we found no significant but greater rate in the PC group compared to the EPC group (11.7% vs 1.96%). We found that Alcaligenes faecalis was the most frequent bacteria in EPC than the PC group, among Gram-negative bacterial species. Conclusions: Age differences in gut microbiota composition may affect biliary habitats in our cancer population, especially in patients with pancreatic cancer. Alcaligenes faecalis isolated in the culture of bile samples could represent potential microbial markers for a restricted follow-up to early diagnosis of extra-pancreatic cancer. Finally, the prevalence of Candida spp in pancreatic cancer seems to trigger new aspects about debate about the role of fungal microbiota into their relationship with pancreatic cancer. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder characterized by chronic abdominal pain and altered bowel habits. It can be subclassified in different subtypes according to the main clinical manifestation: constipation, diarrhea, mixed, and unclassified. Over the past decade, the role of gut microbiota in IBS has garnered significant attention in the scientific community. Emerging research spotlights the intricate involvement of microbiota dysbiosis in IBS pathogenesis. Studies have demonstrated reduced microbial diversity and stability and specific microbial alterations for each disease subgroup. Microbiota-targeted treatments, such as antibiotics, probiotics, prebiotics, synbiotics, fecal microbiota transplantation, and even diet, offer exciting prospects for managing IBS. However, definitive conclusions are hindered by the heterogeneity of these studies. Further research should focus on elucidating the mechanisms, developing microbiome-based diagnostics, and enabling personalized therapies tailored to an individual's microbiome profile. This review takes a deep dive into the microscopic world inhabiting our guts, and its implications for IBS. Our aim is to elucidate the complex interplay between gut microbiota and each IBS subtype, exploring novel microbiota-targeted treatments and providing a comprehensive overview of the current state of knowledge. [ABSTRACT FROM AUTHOR]

Over the last years, the use of technology has become a crucial part of a visitor's experience in a cultural context. This proved to be even more important in the last months when the Covid-19 pandemic crisis spurred museums and other cultural institutions to use digital tools to deliver their services online. In this changing scenario, digital technologies appear as powerful tools also for corporate museums, held and run by private companies as precious vehicles to share organizational past, values and identity with different stakeholders. The present study is aimed at identifying the website elements that affect users' intentions in the unexplored context of corporate museums. To this aim, an innovative multimethod approach was used. Drawing on sample data from 736 users of four different Italian corporate museums' websites and combining Fuzzy-set. Qualitative Comparative Analysis (fsQCA) and Partial Least Squares Structural Equation Modelling (PLS-SEM), the current investigation shows that the intention to visit a corporate museum depends on elements that are related to both the digital environment and the social context. [ABSTRACT FROM AUTHOR]

Synthetic nucleic acid interactors represent an exciting research field due to their biotechnological and potential therapeutic applications. The translation of these molecules into drugs is a long and difficult process that justifies the continuous research of new chemotypes endowed with favorable binding, pharmacokinetic and pharmacodynamic properties. In this scenario, we describe the synthesis of two sets of homo-thymine nucleopeptides, in which nucleobases are inserted in a peptide structure, to investigate the role of the underivatized amino acid residue and the distance of the nucleobase from the peptide backbone on the nucleic acid recognition process. It is worth noting that the CD spectroscopy investigation showed that two of the reported nucleopeptides, consisting of alternation of thymine functionalized L-Orn and L-Dab and L-Arg as underivatized amino acids, were able to efficiently bind DNA and RNA targets and cross both cell and nuclear membranes. [ABSTRACT FROM AUTHOR]

Background: We previously reported rare regressive genetic trajectories of KRAS pathogenic mutations as a specific hallmark of the genuine oligometastatic status in colorectal cancer (CRC). Methods: Survival and prognostic impact of disease extent in 140 metastatic CRC patients were evaluated through the Kaplan-Meyer curves and the Log-Rank test. KRAS mutations were assessed through the Illumina NovaSeq 6000 platform and TruSight™ Oncology 500 kit. HLA typing was carried out by PCR with sequence-specific oligonucleotides. Lymphocyte densities in tumors were expressed as cells per square millimeter. NKs isolated and CD8+ from NK-depleted PBMCs were characterized through flow cytometry. CD107a externalization was evaluated as NKs/CD8 cytotoxicity toward human colon cancer cells HT29, SW620, HCT116, and LS174T carrying different KRAS mutations. Results: The oligometastatic status was a strong and independent variable for survival (HR: 0.08 vs. polymetastatic disease; 95% CI: 0.02-0.26; p < 0.001). Eighteen oligometastatic patients were selected. Twelve were alive at the last follow-up, and 9 were characterized. Genetic regression of KRAS was observed in 3 patients: patient (PAT)2, PAT5, and PAT8. PAT2 and PAT5 presented the highest levels of GrzB+ lymphocytes in the tumor cores of the metastases (120 ± 11.2 and 132 ± 12.2 cells/mm2, respectively). Six out of 9 patients (67%), including PAT2 and PAT5, expressed HLA-C7. Twopatients (PAT2 and PAT5) presented high CD3+/CD8+-dependent cytotoxicity against HLA-C7+ SW620 cells (p.G12V-mutated cells), which was consistent with their observed mutational regression (p.G12V/p.G13D in primary?p.G13D in metastatic tumor). Conclusions: We provide evidence that CD3+/CD8+ lymphocytes from oligometastatic CRC patients display differential cytotoxicity against human colon cancer cells carrying KRAS mutations. This could provide an interesting basis for monitoring oligometastatic disease and developing future adoptive immunotherapies. [ABSTRACT FROM AUTHOR]

Purpose: The main aim of the study is to empirically investigate the relationship between strategic orientation and a dual conceptualization of performance (i.e. non-economic performance and economic performance) in the research context of corporate museums, which are owned and run by private companies. Furthermore, the study aims to explore the nature of the relationship between the dual performance, shedding light on the relevance of non-economic results for this peculiar category of museums. Design/methodology/approach: The study is based on survey data from 105 Italian corporate museums, which represent almost the entire population in the country (91%). A structural model was estimated using SmartPLS software in order to examine the direct and indirect effects of strategic orientation on corporate museums' non-economic and economic performance. Findings: The findings show that only if corporate museums are able to achieve non-economic performance, creating value for the owning company and the local community, they can also have good results in economic terms. Thus, the non-economic performance acts as a mediator into the relationship between strategic orientation and economic performance. Originality/value: The current work is a pioneer study for the empirical investigation of performance within corporate museums. The empirical model of the study, based on a dual conceptualization of performance and a mediation analysis, is completely innovative in this research context. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite rapid progress in the research on epithelial ovarian cancer (EOC), it is usually diagnosed during the advanced stage with only 30% of patients surviving longer than 5 years. This is the first study in which the whole CXCR4-CXCL12-CXCR7 axis was systematically evaluated in tumor and stromal cells, through rigorous statistical methods in a prospective clinical trial. CXCL12 expression in cancer cells is associated with worse progression-free survival in stage III EOC patients, and deserves further attention as a potential prognostic and therapeutic target. This study investigated the prognostic role of the CXCR4-CXCL12-CXCR7 axis in advanced epithelial ovarian cancer (EOC) patients receiving first-line treatment within the MITO16A/MaNGO-OV2 phase-IV trial. CXCR4-CXCL12-CXCR7 expression was evaluated in the epithelial and stromal component of 308 EOC IHC-stained tumor samples. The statistical analysis focused on biomarkers' expression, their association with other variables and prognostic value. Zero-inflated tests, shrinkage, bootstrap procedures, and multivariable models were applied. The majority of EOC (75.0%) expressed CXCR4 and CXCR7, 56.5% expressed the entire CXCR4-CXCL12-CXCR7 axis, while only 4.6% were negative for CXCL12 and its cognate receptors, in regard to the epithelial component. Stromal CXCL12 and CXCR7, expressed in 11.2% and 65.5%, respectively, were associated with the FIGO stage. High CXCL12 in epithelial cancer cells was associated with shorter progression-free and overall survival. However, after adjusting for overfitting due to best cut-off multiplicity testing, the significance was lost. This is a wide-ranging, prospective study in which CXCR4-CXCL12-CXCR7 were systematically evaluated in epithelial and stromal components, in selected stage III-IV EOC. Although CXCL12 was not prognostic, epithelial expression identified high-risk FIGO stage III patients for PFS. These data suggest that it might be worth studying the CXCL12 axis as a therapeutic target to improve treatment efficacy in EOC patients. [ABSTRACT FROM AUTHOR]

Rationale: About 50% of hospitalized coronavirus disease 2019 (COVID-19) patients with diabetes mellitus (DM) developed myocardial damage. The mechanisms of direct SARS-CoV-2 cardiomyocyte infection include viral invasion via ACE2-Spike glycoprotein-binding. In DM patients, the impact of glycation of ACE2 on cardiomyocyte invasion by SARS-CoV-2 can be of high importance. Objective: To evaluate the presence of SARS-CoV-2 in cardiomyocytes from heart autopsy of DM cases compared to Non-DM; to investigate the role of DM in SARS-COV-2 entry in cardiomyocytes. Methods and results: We evaluated consecutive autopsy cases, deceased for COVID-19, from Italy between Apr 30, 2020 and Jan 18, 2021. We evaluated SARS-CoV-2 in cardiomyocytes, expression of ACE2 (total and glycosylated form), and transmembrane protease serine protease-2 (TMPRSS2) protein. In order to study the role of diabetes on cardiomyocyte alterations, independently of COVID-19, we investigated ACE2, glycosylated ACE2, and TMPRSS2 proteins in cardiomyocytes from DM and Non-DM explanted-hearts. Finally, to investigate the effects of DM on ACE2 protein modification, an in vitro glycation study of recombinant human ACE2 (hACE2) was performed to evaluate the effects on binding to SARS-CoV-2 Spike protein. The authors included cardiac tissue from 97 autopsies. DM was diagnosed in 37 patients (38%). Fourth-seven out of 97 autopsies (48%) had SARS-CoV-2 RNA in cardiomyocytes. Thirty out of 37 DM autopsy cases (81%) and 17 out of 60 Non-DM autopsy cases (28%) had SARS-CoV-2 RNA in cardiomyocytes. Total ACE2, glycosylated ACE2, and TMPRSS2 protein expressions were higher in cardiomyocytes from autopsied and explanted hearts of DM than Non-DM. In vitro exposure of monomeric hACE2 to 120 mM glucose for 12 days led to non-enzymatic glycation of four lysine residues in the neck domain affecting the protein oligomerization. Conclusions: The upregulation of ACE2 expression (total and glycosylated forms) in DM cardiomyocytes, along with non-enzymatic glycation, could increase the susceptibility to COVID-19 infection in DM patients by favouring the cellular entry of SARS-CoV2. [ABSTRACT FROM AUTHOR]

Copyright of Il Capitale Culturale: Studies on the Value of Cultural Heritage is the property of Il Capitale Culturale Studies on the Value of Cultural Heritage and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Il Capitale Culturale: Studies on the Value of Cultural Heritage is the property of Il Capitale Culturale Studies on the Value of Cultural Heritage and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

1 Nonpolypoid lesion on the resection scar following endoscopic submucosal dissection (ESD) of a mixed-type laterally spreading tumor of the rectum, marked for ESD using an external additional working channel. Improved endoscopic resection of large flat lesions and early cancers using an external additional working channel (AWC): a case series. [Extracted from the article]

In this study a novel auditory version of the Single Category Implicit Association Test (SC-IAT-A) was developed to investigate (a) the valence of adults’ associations to infant cries and laughs, (b) moderation of implicit associations by gender and empathy, and (c) the robustness of implicit associations controlling for auditory sensitivity. Eighty adults (50% females) were administered two SC-IAT-As, the Empathy Quotient, and the Weinstein Noise Sensitivity Scale. Adults showed positive implicit associations to infant laugh and negative ones to infant cry; only the implicit associations with the infant laugh were negatively related to empathy scores, and no gender differences were observed. Finally, implicit associations to infant cry were affected by noise sensitivity. The SC-IAT-A is useful to evaluate the valence of implicit reactions to infant auditory cues and could provide fresh insights into understanding processes that regulate the quality of adult–infant relationships. [ABSTRACT FROM PUBLISHER]

asda Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This case illustrates the use of elastic bands in a traction system during ERCP to expose an intradiverticular papillary orifice and allow bile duct cannulation. This technique allowed the duodenal fold around the diverticulum to be stretched, exposing the intradiverticular papilla outside the diverticulum. [Extracted from the article]

Somatostatin analogues and mTOR inhibitors have been used as medical therapy in lung carcinoids with variable results. No data are available on dopamine agonists as treatment for lung carcinoids. The main aim of the current study was to evaluate the effect of the combined treatment of somatostatin analogue octreotide and the dopamine agonist cabergoline with mTOR inhibitors in an in vitro model of typical lung carcinoids: the NCI-H727 cell line. In NCI-H727 cell line, reverse transcriptase-quantitative polymerase chain reaction and immunofluorescence were assessed to characterize the expression of the somatostatin receptor 2 and 5, dopamine receptor 2 and mTOR pathway components. Fifteen typical lung carcinoids tissue samples have been used for somatostatin receptor 2, dopamine receptor 2, and the main mTOR pathway component p70S6K expression and localization by immunohistochemistry. Cell viability, fluorescence-activated cell sorting analysis and western blot have been assessed to test the pharmacological effects of octreotide, cabergoline and mTOR inhibitors, and to evaluate the activation of specific cell signaling pathways in NCI-H727 cell line. NCI-H727 cell line expressed somatostatin receptor 2, somatostatin receptor 5 and dopamine receptor 2 and all mTOR pathway components at messenger and protein levels. Somatostatin receptor 2, dopamine receptor 2, and p70S6K (non phosphorylated and phosphorylated) proteins were expressed in most typical lung carcinoids tissue samples. Octreotide and cabergoline did not reduce cell viability as single agents but, when combined with mTOR inhibitors, they potentiate mTOR inhibitors effect after long-term exposure, reducing Akt and ERK phosphorylation, mTOR escape mechanisms, and increasing the expression DNA-damage-inducible transcript 4, an mTOR suppressor. In conclusion, the single use of octreotide and cabergoline is not sufficient to block cell viability but the combined approach of these agents with mTOR inhibitors might reduce the mTOR inhibitors-induced escape mechanisms and/or activate the endogenous mTOR suppressor, potentiating the effect of the mTOR inhibitors in an in vitro model of typical lung carcinoids. [ABSTRACT FROM AUTHOR]

Background: The tumor immunosuppressive microenvironment represents a major obstacle to an effective tumor-specific cellular immune response.Methods: In the present study, the counterbalance effect of a novel metronomic chemotherapy protocol on such an immunosuppressive microenvironment was evaluated in a mouse model upon sub-cutaneous ectopic implantation of B16 melanoma cells. The chemotherapy consisted of a novel multi-drug cocktail including taxanes and alkylating agents, administered in a daily metronomic fashion. The newly designed strategy was shown to be safe, well tolerated and significantly efficacious.Results: Treated animals showed a remarkable delay in tumor growth and prolonged survival as compared to control group. Such an effect was directly correlated with CD4(+) T cell reduction and CD8(+) T cell increase. Furthermore, a significant reduction in the percentage of both CD25(+)FoxP3(+) and CD25(+)CD127(low) regulatory T cell population was found both in the spleens and in the tumor lesions. Finally, the metronomic chemotherapy induced an intrinsic CD8(+) T cell response specific to B16 naturally expressed Trp2 TAA.Conclusion: The novel multi-drug daily metronomic chemotherapy evaluated in the present study was very effective in counterbalancing the immunosuppressive tumor microenvironment. Consequently, the intrinsic anti-tumor T cell immunity could exert its function, targeting specific TAA and significantly containing tumor growth. Overall, the results show that this represents a promising adjuvant approach to significantly enhance efficacy of intrinsic or vaccine-elicited tumor-specific cellular immunity. [ABSTRACT FROM AUTHOR]

Copyright of Il Capitale Culturale: Studies on the Value of Cultural Heritage is the property of Il Capitale Culturale Studies on the Value of Cultural Heritage and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Even if the domain of business longevity has been enriched by the multidisciplinary nature of approaches used to investigate the phenomenon, the lack of a unifying perspective has impeded systematic research and caused definitional ambiguity. The main aim of this special issue is to extend existing knowledge on business longevity by integrating theoretical and empirical studies that adopt different approaches and perspectives. This is essential in order to identify the key factors of long-term success and the effects of longevity on firm performance. The multifaceted nature of business longevity research is mirrored in the five articles included in this special issue, that offer different and interesting perspectives for the investigation of the domain. [ABSTRACT FROM AUTHOR]

The study analyzes the relationship between tourism satisfaction, cognitive and affective country image, destination image, and post-visit intentions. The proposed research model is tested with a survey on a sample of 542 international tourists intercepted in two Italian airports at the end of their journey. Results suggest that general country and destination images are able to mediate the effect of tourism satisfaction on post-visit behavioral intentions. Moreover, empirical findings show that a high-quality tourism experience is able to not only affect intention to return and willingness to recommend the country as a tourism destination but also induce more positive intentions toward the products made in the sojourn country. On the basis of results, the study concludes with discussion of managerial and research implications. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and represents the third and the fifth leading cause of cancer-related death worldwide in men and women, respectively. Hepatitis B virus (HBV) and hepatitis C virus (HCV) chronic infections account for pathogenesis of more than 80 % of primary HCC. HCC prognosis greatly varies according to stage at beginning of treatment, but the overall 5-year survival rate is approximately 5-6 %. Given the limited number of effective therapeutic strategies available, immunotherapies and therapeutic cancer vaccines may help in improving the clinical outcome for HCC patients. However, the few clinical trials conducted to date have shown contrasting results, indicating the need for improvements. In the present study, a novel combinatorial strategy, based on metronomic chemotherapy plus vaccine, is evaluated in a mouse model. The chemotherapy is a multi-drug cocktail including taxanes and alkylating agents, which is administered in a metronomic-like fashion. The vaccine is a multi-peptide cocktail including HCV as well as universal tumor antigen TERT epitopes. The combinatorial strategy designed and evaluated in the present study induces an enhanced specific T cell response, when compared to vaccine alone, which correlates to a reduced Treg frequency. Such results are highly promising and may pave way to relevant improvements in immunotherapeutic strategies for HCC and beyond. [ABSTRACT FROM AUTHOR]

Copyright of Il Capitale Culturale: Studies on the Value of Cultural Heritage is the property of Il Capitale Culturale Studies on the Value of Cultural Heritage and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In humans, two main metabolic enzymes synthesize hydrogen sulfide (H2S): cystathionine γ lyase ( CSE) and cystathionine β synthase ( CBS). A third enzyme, 3-mercaptopyruvate sulfurtransferase (3- MST), synthesizes H2S in the presence of the substrate 3-mercaptopyruvate (3- MP). The immunohistochemistry analysis performed on human melanoma samples demonstrated that CSE expression was highest in primary tumors, decreased in the metastatic lesions and was almost silent in non-lymph node metastases. The primary role played by CSE was confirmed by the finding that the overexpression of CSE induced spontaneous apoptosis of human melanoma cells. The same effect was achieved using different H2S donors, the most active of which was diallyl trisulfide ( DATS). The main pro-apoptotic mechanisms involved were suppression of nuclear factor- κB activity and inhibition of AKT and extracellular signal-regulated kinase pathways. A proof of concept was obtained in vivo using a murine melanoma model. In fact, either l-cysteine, the CSE substrate, or DATS inhibited tumor growth in mice. In conclusion, we have determined that the l-cysteine/ CSE/H2S pathway is involved in melanoma progression. [ABSTRACT FROM AUTHOR]

Despite the optimization of the local treatment of advanced rectal cancer (LARC), combination of preoperative chemoradiotherapy (CRT) and surgery, approximately one third of patients will develop distant metastases. Since the chemokine receptor CXCR4 has been implicated in metastasis development and prognosis in colorectal cancer, the role of the entire axis CXCR4-CXCL12-CXCR7 was evaluated to identify high relapse risk rectal cancer patients. Tumor specimens of 68 LARC patients undergoing surgery after neoadjuvant-CRT were evaluated for CXCR4, CXCR7, and CXCL12 expression through immunohistochemistry. Multivariable prognostic model was developed using classical prognostic factors along with chemokine receptor expression profiles. High CXCR4 correlated with a shorter relapse-free survival (RFS) ( p = 0.0006) and cancer specific survival (CSS) ( p = 0.0004). Concomitant high CXCR4-negative/low CXCR7 or high CXCR4-negative/low CXCL12 significantly impaired RFS ( p = 0.0003 and p = 0.0043) and CSS ( p = 0.0485 and p = 0.0026). High CXCR4/N+ identified the worst prognostic category for RFS ( p < 0.0001) and CSS ( p = 0.0003). The optimal multivariable predictive model for RFS was a five-variable model consisting of gender, pT stage, N status, CXCR4, and CXCR7 (AUC = 0.92, 95% CI = 0.77-0.98). The model is informative and supportive for adjuvant treatment and identifies CXCR4 as a new therapeutic target in rectal cancer.© 2013 UICC [ABSTRACT FROM AUTHOR]

The CXCR4/CXCL12 axis plays a role in cancer metastases, stem cell mobilization and chemosensitization. Proof of concept for efficient CXCR4 inhibition has been demonstrated in stem cell mobilization prior to autologous transplantation in hematological malignancies. Nevertheless CXCR4 inhibitors suitable for prolonged use as required for anticancer therapy are not available. To develop new CXCR4 antagonists a rational, ligand-based approach was taken, distinct from the more commonly used development strategy. A three amino acid motif (Ar-Ar-X) in CXCL12, also found in the reverse orientation (X-Ar-Ar) in the vMIP-II inhibitory chemokine formed the core of nineteen cyclic peptides evaluated for inhibition of CXCR4-dependent migration, binding, P-ERK1/2-induction and calcium efflux. Peptides R, S and I were chosen for evaluation in in vivo models of lung metastases (B16-CXCR4 and KTM2 murine osteosarcoma cells) and growth of a renal cells xenograft. Peptides R, S, and T significantly reduced the association of the 12G5-CXCR4 antibody to the receptor and inhibited CXCL12-induced calcium efflux. The four peptides efficiently inhibited CXCL12-dependent migration at concentrations as low as 10 nM and delayed CXCL12-mediated wound healing in PES43 human melanoma cells. Intraperitoneal treatment with peptides R, I or S drastically reduced the number of B16-CXCR4-derived lung metastases in C57/BL mice. KTM2 osteosarcoma lung metastases were also reduced in Balb/C mice following CXCR4 inhibition. All three peptides significantly inhibited subcutaneous growth of SN12C-EGFP renal cancer cells. A novel class of CXCR4 inhibitory peptides was discovered. Three peptides, R, I and S inhibited lung metastases and primary tumor growth and will be evaluated as anticancer agents. [ABSTRACT FROM AUTHOR]

Objective To identify a phenotype that could be informative and prognostic in patients with renal cell carcinoma ( RCC) peripheral blood was evaluated for TH1, TH2, regulatory T cells ( Tregs), natural killer ( NK) and NKT cells and for cytokines/chemokines., Patients and Methods Peripheral blood from 77 patients with RCC and 40 healthy controls was evaluated by flow cytometry using monoclonal antibodies against CD4, CD25, Fox P3, CD45RA, CD45RO, CD152, CD184, CD279, CD3, CD16, CD56, CD161, CD158a, CD4, CD26, CD30, CD183 and CD184., A concomitant evaluation of 38 molecules was conducted in patients' serum using a multiplex biometric ELISA-based immunoassay., Results The number of NK cells CD3−/ CD16+, CD3−/ CD16+/ CD161+ ( NK) and CD3−/ CD16+/ CD161+/ CD158a+ ( NK- Kir 2+) was greater in the patients with RCC ( P < 0.05); and the number of Treg cells CD4+/ CD25high+/ FOXP3+ and the subset CD4+/ CD25high+/ FOXP3+/ CD45RA+ (naïve) and CD45R0+(memory) cells, were greater in the patients with RCC ( P < 0.001)., An increase in the following was observed in the serum of patients with RCC compared with healthy controls: interleukin ( IL)-4, IL-6, IL-8, IL-10, G- CSF, CXCL10, CXCL11, hepatocyte growth factor ( HGF) and vascular endothelial growth factor ( VEGF). According to Ingenuity Pathway Analysis ( IPA), CXCL10, IL-6, IL-8, epidermal growth factor ( EGF), HGF and VEGF were associated with a network that controls cellular movement, tissue development and cellular growth., Kaplan-Meier analysis for disease-free survival showed that high numbers of CD4+/ CD25high+/ FOXP3+/ CD45RA+ (Treg naïve) and low numbers of CD3−/ CD16+/ CD161+/ CD158a+ ( NK- Kir+) cells predict short disease-free survival in patients with RCC., Conclusion Concomitant evaluation of Treg ( CD4+/ CD25high+/ FOXP3+ and CD4+/ CD25high+/ FOXP3+/ CD45RA+) and of six soluble factors ( IL-6, IL-8 , VEGF, CXCL10, CXCL11, EGF, HGF) might be a surrogate marker of host immunity in patients with RCC. [ABSTRACT FROM AUTHOR]

Background: Blood culturing remains the mainstream tool to inform an appropriate treatment in hospital-acquired bloodstream infections and to diagnose any bacteremia. Methods: A retrospective investigation on the prevalence of Gram-negative bacteria (GNB) and their resistance in hospitalized patients by age, sex, and units from blood cultures (BCs) was conducted from January 2018 to April 2020 at Sant'Elia hospital, Caltanissetta, southern Italy. We divided the patient age range into four equal intervals. Results: Multivariate demographic and microbiological variables did not show an association between bacteria distributions and gender and age. The distribution by units showed a higher prevalence of Klebsiella pneumoniae and Acinetobacter baumannii in the intensive care unit (ICU) and Escherichia coli in the non-intensive care units (non-ICUs). The analysis of antibiotic resistance showed that E. coli was susceptible to a large class of antibiotics such as carbapenem and trimethoprim-sulfamethoxazole. K. pneumoniae showed a significant susceptibility to colistin, tigecycline, and trimethoprim-sulfamethoxazole. From the survival analysis, patients with E. coli had a higher survival rate. Conclusions: The authors stress the importance of the implementation of large community-level programs to prevent E. coli bacteremia. K. pneumoniae and E. coli susceptibility patterns to antibiotics, including in the prescription patterns of general practitioners, suggest that the local surveillance and implementation of educational programs remain essential measures to slow down the spread of resistance and, consequently, increase the antibiotic lifespan. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) has been identified as one of the major risk factors for type II mixed cryoglobulinemia (MC), during the clinical evolution of chronic hepatitis, which may lead to development of B cell non-Hodgkin's lymphoma (NHL). We have previously shown that the candidate idiotype vaccine, based on the IGKV3-20 light chain protein, is able to induce activation and maturation of circulating antigen presenting cells (APCs) in both HCV-positive and HCV-negative healthy control subjects, with production of Th2-type cytokines. Here, the effect of the recombinant IGKV3-20 protein on human peripheral blood mononuclear cells (PBMCs) from HCV-positive subjects, with known blood levels of cryoglobulins, is shown via gene expression profiling analysis combined to multiparameter flow cytometry and multiplex analyses of cytokines. [ABSTRACT FROM AUTHOR]

Negative attributional style has been associated with depressive symptoms in children. Yet, it is unclear whether these cognitive biases reflect inherited characteristics of the broader depressive phenotype or are a product of children's environments. While existing data in adolescents show that negative attributions reflect a genetic predisposition, elevating depressive responses to stress, other data suggest that negative attributions in children are more likely to reflect early environmental experiences on symptoms. Here, we assess the degree to which negative attributional style and depressive symptoms arise from common genetic, shared and non-shared environmental influences in childhood. Monozygotic and dizygotic twins reported on attributional style and depressive symptoms at age 8 ( n = 300 pairs) and at age 10 ( n = 250 pairs). Two multivariate models with varying assumptions on the nature of the relationship between negative attributions and depressive symptoms within and across time were fit to the data. The Common Pathway model provided better fit than the Cholesky decomposition. A common, latent factor influenced both attributional style and depressive symptoms at both time-points in children. The only significant influences on this factor were shared and non-shared aspects of the environment. Placing the present findings with those of adolescents suggests possible developmental differences in the relationship between attributional style and depressive symptoms. [ABSTRACT FROM AUTHOR]

The purpose of this work was to evaluate the effect of flame-generated nucleation mode particles with an organic carbon structure on growth and apoptosis in immortalized human keratinocytes. In this study, cells were stimulated with nanoparticles collected from flames that produce only nucleation mode particles operating with a fuel:air mixture typical of low-emission combustion systems. Cytotoxicity as a function of particle concentration was monitored by fluorescence-activated cell sorting (FACS) analysis, and apoptosis was observed by FACS using DNA fragmentation and hypodiploidism and confirmed by annexin assay. A dose-dependent reduction in cell viability by apoptosis in incubation periods of 48 and 72 hours was observed with a statistically significant increase in apoptosis over controls for a dose larger than 7 μg/mL (1.4 μg/cm2). The results presented here may be relevant for understanding the association between exposure to traffic-generated particulate pollution and enhanced skin aging reported in epidemiology studies. [ABSTRACT FROM AUTHOR]

Background: Anti-EGFR monoclonal antibodies have shown efficacy in the treatment of metastatic colorectal cancer (mCRC). One of the mechanism is the antibody-dependent cell-mediated cytotoxicity (ADCC) in which Fc region of the antibody binds to the Fc gamma receptors (FcγR) expressed by immune cells. The present study investigated the association between single nucleotide polymorphisms of FcγRIIa and FcγRIIIa and clinical outcome in mCRC treated with anti-EGFR antibodies. Methods: Seventy-four consecutive patients with mCRC were analyzed. The genotypes for FcγRIIa-131 histidine (H)/arginine (R), FcγRIIIa-158 valine (V)/phenylanaline (F) polymorphisms were evaluated by directly sequencing. Multiplex allele-specific polymerase chain reaction was performed for FcγRIIIa-158 valine (V)/phenylanaline (F). Correlations between FcγR polymorphisms, baseline patient and tumor features were studied by contingency tables and the chi-square test. The Kaplan-Meier product limit method was applied to the progression-free survival (PFS) curves. Univariate analysis was performed with the log-rank test. Cox proportional-hazards regression was used to analyze the effect of multiple risk factors on PFS. Results: FcγRIIIa polymorphisms were significantly associated with response to anti-EGFR-based therapy in 49 patients with kras wt tumors (p=0.035). There was not association with response for FcγRIIa polymorphisms. Furthermore, obtained results suggested that prognosis is particularly unfavorable for patients carrying the FcγRIIIa-158F/F genotype (median PFS V/V, V/F, F/F: 18.2 vs 17.3 vs 9.4 months). No prognostic ability was identified for FcγRIIa polymorphisms. Conclusions: In mCRC patients the presence of FcγRIIIa-F can predict resistance to anti-EGFR therapy and unfavorable prognosis. [ABSTRACT FROM AUTHOR]

Treatment of breast cancer cells with a combination of the EGFR-tyrosine kinase inhibitor (EGFR-TKI) gefitinib and the anti-ErbB-2 monoclonal antibody trastuzumab results in a synergistic antitumor effect. In this study, we addressed the mechanisms involved in this phenomenon. The activation of signaling pathways and the expression of cell cycle regulatory proteins were studied in SK-Br-3 and BT-474 breast cancer cells, following treatment with EGFR and/or ErbB-2 inhibitors. Treatment with the gefitinib/trastuzumab combination produced, as compared with a single agent, a more prolonged blockade of AKT and MAPK activation, a more pronounced accumulation of cells in the G0/G1 phase of the cell cycle, a more significant increase in the levels of p27kip1 and of hypophosphorylated pRb2, and a decrease in the levels of Cyclin D1 and survivin. Similar findings were observed with the EGFR/ErbB-2 inhibitor lapatinib. Gefitinib, trastuzumab, and their combination increased the stability of p27kip1, with the combination showing the highest effects. Blockade of both receptors with gefitinib/trastuzumab or lapatinib induced a significant increase in the levels of p27kip1 mRNA and in the nuclear levels of the p27kip1 transcription factor FKHRL-1. Inhibition of PI3K signaling also produced a significant raise in p27kip1 mRNA. Finally, down-modulation of FKHRL-1 with siRNAs prevented the lapatinib-induced increase of p27kip1 mRNA. The synergism deriving from EGFR and ErbB-2 blockade is mediated by several different alterations in the activation of signaling proteins and in the expression of cell cycle regulatory proteins, including transcriptional and posttranscriptional regulation of p27kip1 expression. [ABSTRACT FROM AUTHOR]

Background: Despite theoretical and empirical support for an association between maternal control and child anxiety, few studies have examined the origins of this association. Furthermore, none use observer-ratings of maternal control within a genetically informative design. This study addressed three questions: 1) do children who experience maternal control report higher anxiety levels than those who do not?; 2) to what extent do genetic and environmental factors influence maternal control and child anxiety?; 3) to what extent do genetic and environmental factors influence the associations between child anxiety and maternal control? Method: Five hundred and thirty 8-year-old children (from 265 twin pairs) and their mothers were observed participating in an ‘etch-a-sketch’ task from which maternal control was rated. Children rated their anxiety using the Screen for Child Anxiety Related Emotional Disorders. Results: Children who experienced maternal behaviour rated as ‘extreme control’ reported higher anxiety levels than those who did not. Maternal control was highly heritable (A = .63), high self-rated anxiety less so (h2g = .36). The overlap between high child anxiety and maternal control was primarily due to shared genetic factors. Conclusions: These results suggest that maternal control is likely to have been elicited by children with high levels of anxiety. [ABSTRACT FROM AUTHOR]

The chemokine receptor CXCR4 was described as an independent predictor of poor prognosis in primary human melanoma. To investigate on a possible role of CXCR4 expression on peripheral blood lymphocytes (PBL) subsets, 195 patients with melanoma were evaluated for correlations between PBL subsets CXCR4 expressing and clinicopathological and prognostic features. One hundred ninety-five patients with stages I–III melanoma were enrolled in this study. Lymphocytes subsets were assayed by the direct fluorescence method for whole blood and staining with fluorochrome-conjugated monoclonal antibodies. Correlations between PBL subsets, baseline patient, and tumor features were studied by contingency tables and the χ2 test. The Kaplan–Meier product limit method was applied to plot disease-free- and overall-survival curves. Univariate analysis was performed with the log-rank test. Cox proportional-hazards regression was used to analyze the effect of multiple risk factors on disease-free survival (DFS). Melanoma patients characterized by CD4+CD45RA+CXCR4+ higher than 25% of PBL showed a longer DFS. Conversely, CD4+CD45RA+CXCR4+ <25% increased the risk of relapse. The 5-year DFS rate was 76% for patients with CD4+CD45RA+CXCR4+ lymphocytes <25% of PBL, and 94% for patients with CD4+CD45RA+CXCR4+ >25% ( p = 0.030 at log-rank test). Univariate and multivariate analysis for DFS confirmed the prognostic value of the CD4+CD45RA+CXCR4+ lymphocytes. Although further studies are needed to better define the involved subpopulation, the detection of cellular subset CD4+CD45RA+CXCR4+ is an easy and feasible evaluation of melanoma patients in concomitance with the established melanoma prognostic markers. [ABSTRACT FROM AUTHOR]

Background: High-dose interferon-alpha 2b (IFN-α 2b) is the only approved systemic therapy in the United States for the adjuvant treatment of melanoma. The study objective was to explore the immunomodulatory mechanism of action for IFN-α 2b by measuring serum regulatory T cell (Treg), serum transforming growth factor-β (TGF-β), interleukin (IL)-10, and autoantibody levels in patients with melanoma treated with the induction phase of the high-dose IFN-α 2b regimen. Methods: Patients with melanoma received IFN-α 2b administered intravenously (20 MU/m² each day from day 1 to day 5 for 4 consecutive weeks). Serum Treg levels were measured as whole lymphocytes in CD4+ cells using flow cytometry while TGF-β, IL-10, and autoantibody levels were measured using enzyme-linked immunosorbent assays. Results: Twenty-two patients with melanoma received IFN-α 2b treatment and were evaluated for Treg levels. Before treatment, Treg levels were significantly higher in patients with melanoma when compared with data from 20 healthy subjects (P = 0.001; Mann-Whitney test). Although a trend for reduction of Treg levels following IFN-α 2b treatment was observed (average decrease 0.29% per week), statistical significance was not achieved. Subgroup analyses indicated higher baseline Treg levels for stage III versus IV disease (P = 0.082), early recurrence versus no recurrence (P = 0.017), deceased versus surviving patients (P = 0.021), and preoperative neoadjuvant versus postoperative adjuvant treatment groups (not significant). No significant effects were observed on the levels of TGF-β, IL-10, and autoantibodies in patients with melanoma treated with IFN-α 2b. Conclusions: Patients with melanoma in this study showed increased basal levels of Treg that may be relevant to their disease and its progression. Treg levels shifted in patients with melanoma treated with IFN-α 2b, although no firm conclusions regarding the role of Tregs as a marker of treatment response or outcome can be made at present. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) is one of the major risk factors for chronic hepatitis, which may progress to cirrhosis and hepatocellular carcinoma, as well as for type II mixed cryoglobulinemia (MC), which may further evolve into an overt B-cell non-Hodgkin's lymphoma (NHL). It has been previously shown that B-cell receptor (BCR) repertoire, expressed by clonal B-cells involved in type II MC as well as in HCV-associated NHL, is constrained to a limited number of variable heavy (VH)- and light (VL)- chain genes. Among these, the VK3-20 light chain idiotype has been selected as a possible target for passive as well as active immunization strategy. In the present study, we describe the results of a multiparametric analysis of the innate and early adaptive immune response after ex vivo stimulation of human immune cells with the VK3-20 protein. This objective has been pursued by implementing high-throughput technologies such as multiparameter flow cytometry and multiplex analysis of cytokines and chemokines. [ABSTRACT FROM AUTHOR]

Purpose - The purpose of this paper is to provide some insights for the evaluation of town centre management (TCM) effectiveness, by proposing the importance-performance analysis (IPA) as a valuable tool to ensure a multi-perspective evaluation. The need for more empirical methods of measuring town centre effectiveness is related to the risk of commonly used evaluation methodologies reflecting only the success criteria of dominant stakeholders. Design/methodology/approach - By reviewing the service management literature, a definition of the "town centre product" is proposed, and how WA can be used to analyse the city users' quality perceptions is emphasized. The theoretical framework is enriched by an empirical case study: the city centre of Benevento. Findings - The results provide a clear guidance for the implementation of a TCM scheme in the historical centre of Benevento, by identifying the main area of intervention. Research limitations/implications - The paper addresses a gap in the academic literature by using the IPA as an alternative evaluating paradigm of TCM and providing a definition of the town centre servicescape. Further research could investigate the impact of the selected environmental variables on the city users' internal responses (e.g. satisfaction) and behaviours (e.g. desire to shop), beside on their quality perceptions. Practical implications - The paper proposes a handy tool both for the exante and the expost evaluation, As well, it could be used as a benchmarking tool. Originality/value - The paper has significant implications both for practitioners and for academics. It provides an original framework for further research and factual implementation. [ABSTRACT FROM AUTHOR]

Simple Summary: The management of advanced colorectal cancer (CRC) has been greatly improved with integrated strategies including stereotactic radiation therapy (SRT). It is a safe and effective option, particularly in oligo-metastatic (om) CRC patients. Interestingly, it has been demonstrated that SRT can induce regression of tumors in non-irradiated regions ("abscopal effect") through stimulation of anti-tumor immune effects ("radiation-induced immunity"). We have recently shown that lung-limited omCRC is characterized by regression of tumor clones bearing specific key driver gene mutations. The aim of the PRELUDE-1 study is to assess the genetic and immunologic evolutions on tumor cancer/host cells induced by SRT in lung-limited omCRC through liquid biopsies and Next Generation Sequencing of tumor exome, HLA repertoire assessment, peripheral immune cells, and cytokine dynamics characterizations. An important secondary objective is the first prospective evaluation of the abscopal effect. The PRELUDE-1 results will help to identify subsets of patients more prone to show the abscopal effect. The PRELUDE-1 trial was registered into the clinicaltrials.gov registry on 22 April 2021, with identifier NCT04854213. Background: in recent years, the management of advanced colorectal cancer (CRC) has been greatly improved with integrated strategies including stereotactic radiation therapy (SRT). The administration of SRT has been demonstrated, particularly in oligo-metastatic (om) CRC, to be a safe and effective option. Interestingly, it has been demonstrated that SRT can induce regression of tumors in non-irradiated regions ("abscopal effect") through stimulation of anti-tumor immune effects ("radiation-induced immunity"). We have recently shown that lung-limited omCRC is characterized by regression of tumor clones bearing specific key driver gene mutations. Aims: to assess the genetic evolution on tumor cancer cells induced by SRT in lung-limited omCRC. Secondary objectives included descriptions of the abscopal effect, responses' duration, toxicity, and progression-free survival. A translational research will be performed to evaluate tumor genetic evolution (through liquid biopsies and Next Generation Sequencing), HLA class I repertoire, peripheral immune cells, and cytokine dynamics. Methods: PRELUDE-1 is a prospective translational study. SRT will be administered only to the largest nodule (with a maximum diameter ≤ 25 mm) in omCRC with two or three radiologically evident lesions. The sample size is based on the innovative hypothesis that radiation-induced immunity could induce regression of tumor clones bearing KRAS oncogene mutations. According to the binomial test, considering the frequency of KRAS mutations and assuming a probability of mutant KRAS→wild type KRAS of p0 = 0.0077, with α = 0.05 and 1-β = 0.60, the final sample size is 25 patients. [ABSTRACT FROM AUTHOR]

Purpose – The purpose of this paper is to provide insights into the identification of stakeholders involved in town centre management (TCM) projects and the main areas of intervention according to their interests and needs. Design/methodology/approach – The proposed framework is tested in the town of Benevento, Italy. On the basis of stakeholder theory, key stakeholders were interviewed according to the different kinds of linkages they had with the TCM organisation. Findings – Results from the paper support a stakeholder-based approach to the development of TCM projects. In addition, a set of categories is proposed to define and evaluate the overall town centre offer. Practical implications – The proposed framework can be used by cities or towns for the evaluation of the role of different public and private stakeholders in TCM projects, and for the assessment of their "stake" in the town centre. Originality/value – Despite the need to promote a partnership approach between the public and private sectors having been recognised as a vital ingredient for the implementation of TCM, literature is still lacking which provides clear guidance for stakeholder analysis. This is one of the first papers to propose a theoretical framework addressing this issue. [ABSTRACT FROM AUTHOR]