Migration Stimulating Factor: New Marker for Tumour Progression?

The aims of my work were: a) to generate reagents (recombinant protein and antibodies) useful to identify MSF as a possible marker for TAMs in human tumours; b) to characterise the biological properties of MSF. MSF is a soluble oncofoetal isoform of human fibronectin 1, identical to the N-terminus portion of fibronectin and characterized by the presence of a unique 10 amino acids long sequence in the C-terminus end. MSF is expressed by epithelial and stromal cells during foetal development and in cancer patients, but not by adult normal cells. Our group found a selective expression of MSF by M2-polarized human macrophages and M2-like tumor-associated macrophages (TAMs). TAMs are major inflammatory cells infiltrating tumors, they support tumour growth and are associated to poor prognosis. These findings suggest that MSF could be a potential marker for tumor progression associated to M2-like polarization of TAM and a promising target for anti-cancer therapy. Human MSF has been expressed in CHO cells and purified by affinity chromatography. Recombinant MSF has a motogenic effect on cancer cell lines, human monocytes and murine peritoneal macrophages. Different levels of MSF expression were observed in human cancer cell lines and correlate with its motogenic effect. In vivo experiments showed that tumors derived from MSF-expressing cells had an higher growth rate compared to tumors derived from control cells. We also developed a monoclonal antibody (MoAb_E10) recognizing human MSF. A initial characterization on human tumour tissues (lung, breast, colon) showed MSF expression in tumor cells as well as stromal cells. In particular MSF expression is associated to M2-like TAM. Given that TAMs are promising target for anticancer therapy, the possibility to identify M2 polarized cells would be of considerable interest and further studies will be necessary to define the importance of MSF in the context of human tumours

miRNAs as Influencers of Cell-Cell Communication in Tumor Microenvironment

microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level, inducing the degradation of the target mRNA or translational repression. MiRNAs are involved in the control of a multiplicity of biological processes, and their absence or altered expression has been associated with a variety of human diseases, including cancer. Recently, extracellular miRNAs (ECmiRNAs) have been described as mediators of intercellular communication in multiple contexts, including tumor microenvironment. Cancer cells cooperate with stromal cells and elements of the extracellular matrix (ECM) to establish a comfortable niche to grow, to evade the immune system, and to expand. Within the tumor microenvironment, cells release ECmiRNAs and other factors in order to influence and hijack the physiological processes of surrounding cells, fostering tumor progression. Here, we discuss the role of miRNAs in the pathogenesis of multicomplex diseases, such as Alzheimer's disease, obesity, and cancer, focusing on the contribution of both intracellular miRNAs, and of released ECmiRNAs in the establishment and development of cancer niche. We also review growing evidence suggesting the use of miRNAs as novel targets or potential tools for therapeutic applications

Serum amyloid P component is an essential element of resistance against Aspergillus fumigatus

© The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Serum amyloid P component (SAP, also known as Pentraxin 2; APCS gene) is a component of the humoral arm of innate immunity involved in resistance to bacterial infection and regulation of tissue remodeling. Here we investigate the role of SAP in antifungal resistance. Apcs-/- mice show enhanced susceptibility to A. fumigatus infection. Murine and human SAP bound conidia, activate the complement cascade and enhance phagocytosis by neutrophils. Apcs-/- mice are defective in vivo in terms of recruitment of neutrophils and phagocytosis in the lungs. Opsonic activity of SAP is dependent on the classical pathway of complement activation. In immunosuppressed mice, SAP administration protects hosts against A. fumigatus infection and death. In the context of a study of hematopoietic stem-cell transplantation, genetic variation in the human APCS gene is associated with susceptibility to invasive pulmonary aspergillosis. Thus, SAP is a fluid phase pattern recognition molecule essential for resistance against A. fumigatus.The contribution of the European Commission (ERC project PHII-669415; FP7 project 281608 TIMER; ESA/ITN, H2020-MSCA-ITN-2015-676129), Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) (project FIRB RBAP11H2R9), Associazione Italiana Ricerca sul Cancro (AIRC IG-19014 and IG-21714, AIRC 5 × 1000 −9962 and −21147), the Italian Ministry of Health, the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023), the Fundação para a Ciência e Tecnologia (FCT) (UIDB/50026/2020, UIDP/50026/2020, PTDC/SAU-SER/29635/2017, PTDC/MED-GEN/28778/2017, CEECIND/04058/2018 and CEECIND/03628/2017), the European Union’s Horizon 2020 research and innovation program under grant agreement no. 847507 and the “la Caixa” Foundation (ID 100010434) and FCT under the agreement LCF/PR/HR17/52190003 is gratefully acknowledged.info:eu-repo/semantics/publishedVersio

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Two neuroendocrine G protein-coupled receptor molecules, somatostatin and melatonin: Physiology of signal transduction and therapeutic perspectives

Recent studies have shown that G protein-coupled receptors (GPCRs), the largest signal-conveying receptor family, are targets for mutations occurring frequently in different cancer types. GPCR alterations associated with cancer development represent significant challenges for the discovery and the advancement of targeted therapeutics. Among the different molecules that can activate GPCRs, we focused on two molecules that exert their biological actions regulating many typical features of tumorigenesis such as cellular proliferation, survival, and invasion: somatostatin and melatonin. The modulation of signaling pathways, that involves these two molecules, opens an interesting scenario for cancer therapy, with the opportunity to act at different molecular levels. Therefore, the aim of this review is the analysis of the biological activity and the therapeutic potential of somatostatin and melatonin, displaying a high affinity for GPCRs, that interfere with cancer development and maintenance

SARS-CoV-2 nucleocapsid-protein and ultrastructural modifications in small bowel of a four week negative COVID-19 patient

Dear Editor, HumanCoVs (HCoVs) account for up to 30% of infections of the upper respiratory tract and 8.1% of enteritis.1,2 However, related to the wide distribution of ACE2 in human tissues, several reports already hypothesized that SARS-CoV-2 may directly infect multiple organs, including liver, stomach, ileum and colon.3 Our patient, a man in his fifties with no prior medical history, had a positive to nop-swab for SARS-CoV-2 RNA four days after the start of symptoms. He was treated at home with hydroxychloroquine and azithromycin for seven days. The patient recovered and had a repeated two nop-swab, both with negative results. After two weeks he was admitted to the Emergency Department complaining of stomach pain followed by a syncopal episode and intestinal bleeding. Asymptomatic bilateral interstitial pneumonia was documented by CT scan. A colonscopy detected an ileocecal valve proximal ulceration (supplementary Fig 1), without active bleeding. The patient underwent emergency surgery due to an hypotensive episode associated with haematic stools. Terminal ileum and cecum were resected as well as Meckel diverticulum. At the histological examination, terminal ileum wall showed chronic inflammatory infiltrates with prevalence of lymphocytes, focal ulceration of both mucosa (Fig. 1d) and submucosa (Fig. 1e). Abnormally enlarged and tortuous thick-walled veins were seen in the submucosa. IHC analysis with anti-SARS-CoV-2 nucleocapsid-protein revealed the presence of viral protein expression in epithelial cell of ulcerated intestinal mucosa (cytoplasmic staining) and in a minority of lymphocytes (Fig. 1d); no staining in the submucosa (Fig. 1e). We also analyzed the expression of a non-classical MHC-I molecule, Human Leukocyte Antigen-G (HLA-G), that blocks endothelial cell proliferation and vessel formation.4 We observed HLA-G in epithelial cells of the intestinal mucosa and in some lymphocytes (Fig. 1d), in correspondence of SARS-CoV-2 positive sites. In the submucosa, HLA-G expression was detectable only in few lymphocytes (Fig. 1e). Transmission Electron Microscopy (TEM) analysis revealed a significantly different morphological microvilli profile,the intestinal tract of a normal ileum from a subject pre-COVID-19 appearance, showed well organized and aligned microvilli, with a regular distribution protruding from the apical cell membrane (acm) and an homogeneous glycocalyx (gc) (Fig. 1f and g). The tissue, examined in the area without focal ulceration showed a morphology similar to the control (Fig. 1h and i). Regarding the ulceration area, microvilli appeared shorter than those in the not ulcerated area, partially depeneed beyond the acm, and gc appeared disorganized and almost absent showing a relevant cytopatic effect (Fig. 1j and k)

Tumoral and immune heterogeneity in an anti-PD-1 responsive glioblastoma: a case study

Clinical benefit of immune checkpoint blockade in glioblastoma (GBM) is rare, and we hypothesize that tumor clonal evolution and the immune microenvironment are key determinants of response. Here, we present a detailed molecular characterization of the intratumoral and immune heterogeneity in an IDH wild-type, MGMT-negative GBM patient who plausibly benefited from anti-PD-1 therapy with an unusually long 25-mo overall survival time. We leveraged multiplex immunohistochemistry, RNA-seq, and whole-exome data from the primary tumor and three resected regions of recurrent disease to survey regional tumor-immune interactions, genomic instability, mutation burden, and expression profiles. We found significant regional heterogeneity in the neoantigenic and immune landscape, with a differential T-cell signature among recurrent sectors, a uniform loss of focal amplifications in EGFR, and a novel subclonal EGFR mutation. Comparisons with recently reported correlates of checkpoint blockade in GBM and with TCGA-GBM revealed appreciable intratumoral heterogeneity that may have contributed to a differential PD-1 blockade response

Erythrocyte Plasma Membrane Lipid Composition Mirrors That of Neurons and Glial Cells in Murine Experimental In Vitro and In Vivo Inflammation

Lipid membrane turnover and myelin repair play a central role in diseases and lesions of the central nervous system (CNS). The aim of the present study was to analyze lipid composition changes due to inflammatory conditions. We measured the fatty acid (FA) composition in erythrocytes (RBCs) and spinal cord tissue (gas chromatography) derived from mice affected by experimental allergic encephalomyelitis (EAE) in acute and remission phases; cholesterol membrane content (Filipin) and GM1 membrane assembly (CT-B) in EAE mouse RBCs, and in cultured neurons, oligodendroglial cells and macrophages exposed to inflammatory challenges. During the EAE acute phase, the RBC membrane showed a reduction in polyunsaturated FAs (PUFAs) and an increase in saturated FAs (SFAs) and the omega-6/omega-3 ratios, followed by a restoration to control levels in the remission phase in parallel with an increase in monounsaturated fatty acid residues. A decrease in PUFAs was also shown in the spinal cord. CT-B staining decreased and Filipin staining increased in RBCs during acute EAE, as well as in cultured macrophages, neurons and oligodendrocyte precursor cells exposed to inflammatory challenges. This regulation in lipid content suggests an increased cell membrane rigidity during the inflammatory phase of EAE and supports the investigation of peripheral cell membrane lipids as possible biomarkers for CNS lipid membrane concentration and assembly

Oceanographic and anthropogenic variables driving marine litter distribution in Mediterranean protected areas: Extensive field data supported by forecasting modelling

Marine litter concentration in the Mediterranean Sea is strongly influenced both by anthropogenic pressures and hydrodynamic factors that locally characterise the basin. Within the Plastic Busters MPAs (Marine Protected Areas) Interreg Mediterranean Project, a comprehensive assessment of floating macro- and microlitter in the Pelagos Sanctuary and the Tuscan Archipelago National Park was performed. An innovative multilevel experimental design has been planned ad-hoc according to a litter provisional distribution model, harmonising and implementing the current sampling methodologies. The simultaneous presence of floating macro- and microlitter items and the potential influences of environmental and anthropogenic factors affecting litter distribution have been evaluated to identify hotspot accumulation areas representing a major hazard for marine species. A total of 273 monitoring transects of floating macrolitter and 141 manta trawl samples were collected in the study areas to evaluate the abundance and composition of marine litter. High mean concentrations of floating macrolitter (399 items/km2) and microplastics (259,490 items/km2) have been found in the facing waters of the Gulf of La Spezia and Tuscan Archipelago National Park as well in the Genova canyon and Janua seamount area. Accordingly, strong litter inputs were identified to originate from the mainland and accumulate in coastal waters within 10–15 nautical miles. Harbours and riverine outfalls contribute significantly to plastic pollution representing the main sources of contamination as well as areas with warmer waters and weak oceanographic features that could facilitate its accumulation. The results achieved may indicate a potentially threatening trend of litter accumulation that may pose a serious risk to the Pelagos Sanctuary biodiversity and provide further indications for dealing with plastic pollution in protected areas, facilitating future management recommendations and mitigation actions in these fragile marines and coastal environments

Relevance of VEGF and CD147 in different SARS-CoV-2 positive digestive tracts characterized by thrombotic damage

Several evidence suggests that, in addition to the respiratory tract, also the gastrointestinal tract is a main site of severe acute respiratory syndrome CoronaVirus 2 (SARS-CoV-2) infection, as an example of a multi-organ vascular damage, likely associated with poor prognosis. To assess mechanisms SARS-CoV-2 responsible of tissue infection and vascular injury, correlating with thrombotic damage, specimens of the digestive tract positive for SARS-CoV-2 nucleocapsid protein were analyzed deriving from three patients, negative to naso-oro-pharyngeal swab for SARS-CoV-2. These COVID-19-negative patients came to clinical observation due to urgent abdominal surgery that removed different sections of the digestive tract after thrombotic events. Immunohistochemical for the expression of SARS-CoV-2 combined with a panel of SARS-CoV-2 related proteins angiotensin-converting enzyme 2 receptor, cluster of differentiation 147 (CD147), human leukocyte antigen-G (HLA-G), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 was performed. Tissue samples were also evaluated by electron microscopy for ultrastructural virus localization and cell characterization. The damage of the tissue was assessed by ultrastructural analysis. It has been observed that CD147 expression levels correlate with SARS-CoV-2 infection extent, vascular damage and an increased expression of VEGF and thrombosis. The confirmation of CD147 co-localization with SARS-CoV-2 Spike protein binding on gastrointestinal tissues and the reduction of the infection level in intestinal epithelial cells after CD147 neutralization, suggest CD147 as a possible key factor for viral susceptibility of gastrointestinal tissue. The presence of SARS-CoV-2 infection of gastrointestinal tissue might be consequently implicated in abdominal thrombosis, where VEGF might mediate the vascular damage