Microbiota and angiogenesis in the intestinal vasculature.

The gut microbiota is responsible for several metabolic functions, producing various metabolites with numerous roles for the host. The gut microbiota plays a key role in constructing the microvascular network in the intestinal villus, depending on the Paneth cells, strategically positioned to coordinate the development of both the microbiota and the microvasculature. The gut microbiota secretes several molecules and chemokines involved in the induction of the secretion of pro-angiogenic factors.

The role of endothelial junctions in the regulation of the extravasation of tumor cells. A historical reappraisal.

Endothelial cells lining the vessel wall are connected by adherent, tight and gap junctions. Adherent junctions are common to all endothelial cells, whereas tight and gap junctions graduate within different vascular segments. Endothelial cell-cell junctions sustain vascular homeostasis and to control the transendothelial migration of inflammatory cells. Tumor cells need to weaken endothelial cell-cell junctions to penetrate the endothelial barrier and transendothelial migration and metastasis of tumor cells are tightly controlled by endothelial cell-cell junctions.

Mast cell density in Merkel cell carcinoma and its correlation with prognostic features and MCPyV status: a pilot study.

Merkel cell carcinoma (MCC) is a rare, highly aggressive, primitive neuroendocrine carcinoma of the skin, the origin of which is not yet fully understood. Numerous independent prognostic factors have been investigated in an attempt to understand which are the most important parameters to indicate in the histological diagnostic report of MCC. Of these, mast cells have only been studied in one paper before this one. We present a retrospective descriptive study of 13 cases of MCC, received at the Department of Pathology over a 20-year period (2003-2023 inclusive) on which we performed a study using whole-slide (WSI) morphometric analysis scanning platform Aperio Scanscope CS for the detection and spatial distribution of mast cells, using monoclonal anti-tryptase antibody and anti-CD34 monoclonal antibody to study the density of microvessels. In addition, we analyzed MCPyV status with the antibody for MCPyV large T-antigen (Clone CM2B4). We found statistically significant correlation between mast cell density and local recurrence/distant metastasis/death-of-disease (p = 0.008). To our knowledge, we firstly reported that MCPyV ( -) MCC shows higher mast cells density compared to MCPyV ( +) MCC, the latter well known to be less aggressive. Besides, the median vascular density did not show no significant correlation with recurrence/metastasis/death-of-disease, (p = 0.18). Despite the small sample size, this paper prompts future studies investigating the role of mast cell density in MCC.

Combining RNAscope, Immunohistochemistry (IHC) and Digital Image Analysis to Assess Podoplanin (PDPN) Protein and PDPN_mRNA Expression on Formalin-Fixed Paraffin-Embedded Normal Human Placenta Tissues.

The expression and function of podoplanin (PDPN) in the normal human placenta has been debated in placental evaluation. This study emphasizes the importance of a multimodal approach of PDPN expression in normal human placentas. A complete examination is performed using immunohistochemistry, RNAscope and automated Digital Image examination (DIA) interpretation. QuPath DIA-based analysis automatically generated the stromal and histological scores of PDPN expression for immunohistochemistry and RNAscope stains. The umbilical cord's isolated fibroblasts and luminal structures expressed PDPN protein and PDPN_mRNA. RNAscope detected PDPN_mRNA upregulation in syncytial placental knots trophoblastic cells, but immunohistochemistry did not certify this at the protein level. The study found a significant correlation between the IHC and RNAscope H-Score (p = 0.033) and Allred Score (p = 0.05). A successful multimodal strategy for PDPN assessment in human placentas confirmed PDPN expression heterogeneity in the full-term human normal placenta and umbilical cord at the protein and mRNA level. In placental syncytial knots trophoblastic cells, PDPN showed mRNA overexpression, suggesting a potential role in placenta maturation.

[The stem cell and its context. Between the will to power and the will to relationship.] / La cellula staminale e il suo contesto. Tra volontà di potenza e volontà di relazione.

Stem cell biology today represents the cornerstone of studies on cell therapies and regenerative medicine and is about to become the basis of clinical practice. It is not easy to predict the times and ways of science; however, the results achieved on multiple fronts demonstrate that this is a very promising area of research, as it could open important new horizons in the fight against human diseases.

Angiogenesis Still Plays a Crucial Role in Human Melanoma Progression.

Angiogenesis plays a pivotal role in tumor progression, particularly in melanoma, the deadliest form of skin cancer. This review synthesizes current knowledge on the intricate interplay between angiogenesis and tumor microenvironment (TME) in melanoma progression. Pro-angiogenic factors, including VEGF, PlGF, FGF-2, IL-8, Ang, TGF-ß, PDGF, integrins, MMPs, and PAF, modulate angiogenesis and contribute to melanoma metastasis. Additionally, cells within the TME, such as cancer-associated fibroblasts, mast cells, and melanoma-associated macrophages, influence tumor angiogenesis and progression. Anti-angiogenic therapies, while showing promise, face challenges such as drug resistance and tumor-induced activation of alternative angiogenic pathways. Rational combinations of anti-angiogenic agents and immunotherapies are being explored to overcome resistance. Biomarker identification for treatment response remains crucial for personalized therapies. This review highlights the complexity of angiogenesis in melanoma and underscores the need for innovative therapeutic approaches tailored to the dynamic TME.

Mast cells in human choroid and their role in age-related macular degeneration (AMD).

The role of mast cells in physiologic and pathological processes extends far beyond the allergy processes: they are involved in wound healing, chronic inflammation, and tumor growth. This short article emphasizes the role played by mast cells in age-related macular degeneration (AMD). Mast cells can induce angiogenesis and are present around Bruch's membrane during the early and late stages of choroidal neovascularization in AMD. Proteolytic enzymes released by mast cells lead to thinning of the choroid in AMD as well as degradation of vascular basement membranes and Bruch's membrane, which in turn could result in retinal pigment epithelial death and choriocapillaris degeneration in geographical atrophy and exudative AMD.

Mast cells in meningiomas.

Meningioma represents the most frequent tumor of the central nervous system (CNS). Correlations between the presence of mast cells (MCs) and grade or other histological features of meningioma are still debated. Our study aimed to better understand the relationship between mast cells and meningiomas and to compare our results based on specific histological subtypes and novel 2021 CNS WHO grading system. We observed some differences as regards the number of MCs and meningioma grade. In low-grade (grade 1) meningiomas, MCs were observed in 7/22 cases, while they were consistently present in all eight high-grade cases (grade 2 and grade  3). Among the grade 1 meningiomas, we observed two "low-positive", two "intermediate-positive", and three "high-positive" cases. Among the group of high-grade meningiomas, the six cases grade 2 were considered as "low-positive", while the two grade 3 cases showed a higher number of MCs and were included in the "intermediate-positive" group. Even though with no statistical significance, due to the low number of cases, our results seem to confirm a sort of relationship between meningioma grading and the number of MCs, as demonstrated by the higher percentage of high-grade meningiomas showing MCs infiltrates, compared to low-grade meningiomas.

Lysosomal diacylglycerol pyrophosphate phosphatase is not essential in Trypanosoma brucei.

Mg2+-independent phosphatidic acid phosphatase (PAP2), diacylglycerol pyrophosphate phosphatase 1 (Dpp1) is a membrane-associated enzyme in Saccharomyces cerevisiae. The enzyme is responsible for inducing the breakdown of ß-phosphate from diacylglycerol pyrophosphate (DGPP) into phosphatidate (PA) and then removes the phosphate from PA to give diacylglycerol (DAG). In this study through RNAi suppression, we have demonstrated that Trypanosoma brucei diacylglycerol pyrophosphate phosphatase 1 (TbDpp1) procyclic form production is not required for parasite survival in culture. The steady-state levels of triacylglycerol (TAG), the number of lipid droplets, and the PA content are all maintained constant through the inducible down-regulation of TbDpp1. Furthermore, the localization of C-terminally tagged variants of TbDpp1 in the lysosome was demonstrated by immunofluorescence microscopy.

Aqueous humor as eye lymph: A crossroad between venous and lymphatic system.

Aqueous humor (AQH) is a transparent fluid with characteristics similar to those of the interstitial fluid, which fills the eyeball posterior and anterior chambers and circulates in them from the sites of production to those of drainage. The AQH volume and pressure homeostasis is essential for the trophism of the ocular avascular tissues and their normal structure and function. Different AQH outflow pathways exist, including a main pathway, quite well defined anatomically and referred to as the conventional pathway, and some accessory pathways, more recently described and still not fully morphofunctionally understood, generically referred to as unconventional pathways. The conventional pathway is based on the existence of a series of conduits starting with the trabecular meshwork and Schlemm's Canal and continuing with a system of intrascleral and episcleral venules, which are tributaries to veins of the anterior segment of the eyeball. The unconventional pathways are mainly represented by the uveoscleral pathway, in which AQH flows through clefts, interstitial conduits located in the ciliary body and sclera, and then merges into the aforementioned intrascleral and episcleral venules. A further unconventional pathway, the lymphatic pathway, has been supported by the demonstration of lymphatic microvessels in the limbal sclera and, possibly, in the uvea (ciliary body, choroid) as well as by the ocular glymphatic channels, present in the neural retina and optic nerve. It follows that AQH may be drained from the eyeball through blood vessels (TM-SC pathway, US pathway) or lymphatic vessels (lymphatic pathway), and the different pathways may integrate or compensate for each other, optimizing the AQH drainage. The present review aims to define the state-of-the-art concerning the structural organization and the functional anatomy of all the AQH outflow pathways. Particular attention is paid to examining the regulatory mechanisms active in each of them. The new data on the anatomy and physiology of AQH outflow pathways is the key to understanding the pathophysiology of AQH outflow disorders and could open the way for novel approaches to their treatment.

Aberrant tumor vasculature. Facts and pitfalls.

Endothelial cells form a single cell layer lining the inner walls of blood vessels and play critical roles in organ homeostasis and disease progression. Specifically, tumor endothelial cells are heterogenous, and highly permeable, because of specific interactions with the tumor tissue environment and through soluble factors and cell-cell interactions. This review article aims to analyze different aspects of endothelial cell heterogeneity in tumor vasculature, with particular emphasis on vascular normalization, vascular permeability, metabolism, endothelial-to-mesenchymal transition, resistance to therapy, and the interplay between endothelial cells and the immune system.

Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review. Comment.

In this letter to the Editor, the author reports his comment on the review article entitled "Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review", published in this Journal.

New insights into the role of mast cells as a therapeutic target in cancer through the blockade of immune checkpoint inhibitors.

Mast cells release different anti-and pro-inflammatory agents changing their role from protective to pro-inflammatory cells involved in the progression of different pathological conditions, including autoimmune diseases and tumors. Different mediators released by mast cells are involved in their biological activities which may be anti-tumorigenic and/or pro-tumorigenic. For these reasons, tumor mast cells have been considered a novel therapeutic target to prevent tumor progression and metastatic process. Many different agents have been suggested and used in the past pre-clinical and clinical settings. Among the novel immunotherapeutic approaches to cancer treatment, different immune checkpoint inhibitors targeting PD-1/PDL-1 have been used in the treatment of many human tumors improving overall survival. In this context, inhibition of mast cell activity may be considered a novel strategy to improve the efficacy of anti-PD-1/PDL-1 therapy. The blockade of the PD-1/PD-L1 interaction may be suggested as a useful and novel therapeutic approach in the treatment of tumors in which mast cells are involved.

Quantitative research assessment: using metrics against gamed metrics-comment.

In this letter to the Editor, the author reports his comment on the review article entitled. "Quantitative research assessment: using metrics against gamed metrics" published in this Journal.

Macrophages and angiogenesis in human lymphomas.

A link exists between chronic inflammation and cancer and immune cells, angiogenesis, and tumor progression. In hematologic malignancies, tumor-associated macrophages (TAMs) are a significant part of the tumor microenvironment. Macrophages are classified into M1/classically activated and M2/alternatively activated. In tumors, TAMs are mainly constituted by M2 subtype, which promotes angiogenesis, lymphangiogenesis, repair, and remodeling, suppressing adaptive immunity, increasing tumor cell proliferation, drug resistance, histological malignancy, and poor clinical prognosis. The aim of our review article is to define the role of TAMs and their relationship with the angiogenesis in patients with lymphoma reporting both an analysis of main published data and those emerging from our studies. Finally, we have discussed the anti-angiogenic approach in the treatment of lymphomas.

Tertiary lymphoid structures, a historical reappraisal.

Tertiary lymphoid structures (TLSs) are accumulations of lymphoid cells within non-lymphoid organs that share the cellular compartments, spatial organization, vasculature, chemokines, and function with secondary lymphoid organs, especially lymph nodes. TLSs are organized into a separate T cell and B cell compartments which contain germinal centers with follicular dendritic cells. In most cases, TLSs contain Peripheral Node addressin (PNAD) expressing high endothelial venules (HEVs). TLSs have been described in various mouse models of inflammation and are associated with a wide range of autoimmune diseases. Other than these, TLSs have been described in chronic allograft rejection and cancer.

Vascular co-option in resistance to anti-angiogenic therapy.

Three different mechanisms of neovascularization have been described in tumor growth, including sprouting angiogenesis, intussusceptive microvascular growth and glomeruloid vascular proliferation. Tumors can also grow by means of alternative mechanisms including vascular co-option, vasculogenic mimicry, angiotropism, and recruitment of endothelial precursor cells. Vascular co-option occurs in tumors independently of sprouting angiogenesis and the non-angiogenic cancer cells are described as exploiting pre-existing vessels. Vascular co-option is more frequently observed in tumors of densely vascularized organs, including the brain, lung and liver, and vascular co-option represents one of the main mechanisms involved in metastasis, as occurs in liver and lung, and resistance to anti-angiogenic therapy. The aim of this review article is to analyze the role of vascular co-option as mechanism through which tumors develop resistance to anti-angiogenic conventional therapeutic approaches and how blocking co-option can suppress tumor growth.

PTX3 shapes profibrotic immune cells and epithelial/fibroblast repair and regeneration in a murine model of pulmonary fibrosis.

The long pentraxin 3 (PTX3) is protective in different pathologies but was not analyzed in-depth in Idiopathic Pulmonary Fibrosis (IPF). Here, we have explored the influence of PTX3 in the bleomycin (BLM)-induced murine model of IPF by looking at immune cells (macrophages, mast cells, T cells) and stemness/regenerative markers of lung epithelium (SOX2) and fibro-blasts/myofibroblasts (CD44) at different time points that retrace the progression of the disease from onset at day 14, to full-blown disease at day 21, to incomplete regression at day 28. We took advantage of transgenic PTX3 overexpressing mice (Tie2-PTX3) and Ptx3 null ones (PTX3-KO) in which pulmonary fibrosis was induced. Our data have shown that PTX3 overexpression in Tie2-PTX3 compared to WT or PTX3-KO: reduced CD68+ and CD163+ macrophages and the Tryptase+ mast cells during the whole experimental time; on the contrary, CD4+ T cells are consistently present on day 14 and dramatically decreased on day 21; CD8+ T cells do not show significant differences on day 14, but are significantly reduced on day 21; SOX2 is reduced on days 14 and 21; CD44 is reduced on day 21. Therefore, PTX3 could act on the proimmune and fibrogenic microenvironment to prevent fibrosis in BLM-treated mice.