A novel aminopeptidase N/CD13 inhibitor selectively targets an endothelial form of CD13 after coupling to proteins.

Aminopeptidase N/CD13, a membrane-bound enzyme upregulated in tumor vasculature and involved in angiogenesis, can be used as a receptor for the targeted delivery of drugs to tumors through ligand-directed targeting approaches. We describe a novel peptide ligand (VGCARRYCS, called "G4") that recognizes CD13 with high affinity and selectivity. Enzymological and computational studies showed that G4 is a competitive inhibitor that binds to the catalytic pocket of CD13 through its N-terminal region.

Selective Trimmed Average: A Resilient Federated Learning Algorithm With Deterministic Guarantees on the Optimality Approximation.

The federated learning (FL) paradigm aims to distribute the computational burden of the training process among several computation units, usually called agents or workers, while preserving private local training datasets. This is generally achieved by resorting to a server-worker architecture where agents iteratively update local models and communicate local parameters to a server that aggregates and returns them to the agents. However, the presence of adversarial agents, which may intentionally exchange malicious parameters or may have corrupted local datasets, can jeopardize the FL process.

A simple and robust nanosystem for photoacoustic imaging of bladder cancer based on α5β1-targeted gold nanorods.

Background: Early detection and removal of bladder cancer in patients is crucial to prevent tumor recurrence and progression. Because current imaging techniques may fail to detect small lesions of in situ carcinomas, patients with bladder cancer often relapse after initial diagnosis, thereby requiring frequent follow-up and treatments.

Results: In an attempt to obtain a sensitive and high-resolution imaging modality for bladder cancer, we have developed a photoacoustic imaging approach based on the use of PEGylated gold nanorods (GNRs) as a contrast agent, functionalized with the peptide cyclic [CphgisoDGRG] (Iso4), a selective ligand of α5β1 integrin expressed by bladder cancer cells.

A stapled chromogranin A-derived peptide homes in on tumors that express αvβ6 or αvβ8 integrins.

: The αvβ6- and αvβ8-integrins, two cell-adhesion receptors upregulated in many tumors and involved in the activation of the latency associated peptide (LAP)/TGFβ complex, represent potential targets for tumor imaging and therapy. We investigated the tumor-homing properties of a chromogranin A-derived peptide containing an RGDL motif followed by a chemically stapled alpha-helix (called "), which selectively recognizes the LAP/TGFβ complex-binding site of αvβ6 and αvβ8. Peptide was labeled with IRDye 800CW (a near-infrared fluorescent dye) or with F-NOTA (a label for positron emission tomography (PET)); the integrin-binding properties of free peptide and conjugates were then investigated using purified αvβ6/αvβ8 integrins and various αvβ6/αvβ8 single - or double-positive cancer cells; tumor-homing, biodistribution and imaging properties of the conjugates were investigated in subcutaneous and orthotopic αvβ6-positive carcinomas of the pancreas, and in mice bearing subcutaneous αvβ8-positive prostate tumors.

The clinical utility of a comprehensive psychosomatic assessment in the program for colorectal cancer prevention: a cross-sectional study.

Few studies have investigated psychosocial characteristics and lifestyle behaviors of participants at programs for secondary prevention of colorectal cancer (CRC). This study aimed, through a comprehensive psychosomatic assessment based on clinimetric principles, to evaluate psychosocial characteristics and lifestyle behaviors in participants at CRC secondary prevention program, and to investigate the associations between these variables and endoscopic outcomes. In this cross-sectional study, the first 150 consecutive asymptomatic participants at the CRC prevention program who resulted positive to fecal occult blood test (FOBT) and were thus referred to colonoscopy, underwent a psychosomatic assessment including psychiatric diagnoses (DSM-5), psychosomatic syndromes (DCPR-R), psychological distress, psychological well-being and lifestyle behaviors.

Nanogold Functionalized With Lipoamide-DGR: A Simple, Robust and Versatile Nanosystem for αvβ3-Integrin Targeting.

Gold nanoparticles functionalized with DGR, a tripeptide motif that recognizes αvβ3 integrin overexpressed in tumor vessels, have been used as nano-vectors for the delivery of cytokines to tumors. Functionalization of nanogold with this peptide has been achieved by coating nanoparticles with a peptide-albumin conjugate consisting of heterogeneous molecules with a variable number of linkers and peptides. To reduce nanodrug heterogeneity we have designed, produced and preclinically evaluated a homogeneous and well-defined reagent for nanogold functionalization, consisting of a head-to-tail cyclized CGDGRG peptide () coupled its thiol group to maleimide-PEG-lipoamide (LPA).

Enhancement of doxorubicin anti-cancer activity by vascular targeting using IsoDGR/cytokine-coated nanogold.

Background: Gold nanospheres tagged with peptides containing isoDGR (isoAsp-Gly-Arg), an αvβ3 integrin binding motif, represent efficient carriers for delivering pro-inflammatory cytokines to the tumor vasculature. We prepared bi- or trifunctional nanoparticles bearing tumor necrosis factor-α (TNF) and/or interleukin-12 (IL12) plus a peptide containing isoDGR, and we tested their anti-cancer effects, alone or in combination with doxorubicin, in tumor-bearing mice.

Results: In vitro biochemical studies showed that both nanodrugs were monodispersed and functional in terms of binding to TNF and IL12 receptors and to αvβ3.

Circulating Chromogranin A Is Cleaved Into Vasoregulatory Fragments in Patients With Pancreatic Ductal Adenocarcinoma.

Chromogranin A (CgA), a secretory protein released in the blood by the neuroendocrine system, consists of a mixture of full-length molecules and fragments endowed of vasoregulatory activity. The extent and the role of CgA fragmentation were investigated in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC, n=172). Multivariate analysis showed that full-length CgA was associated with better progression free and overall survival, whereas CgA C-terminal fragmentation was associated with worse prognosis.

NGR-TNF Engineering with an N-Terminal Serine Reduces Degradation and Post-Translational Modifications and Improves Its Tumor-Targeting Activity.

The therapeutic index of cytokines in cancer therapy can be increased by targeting strategies based on protein engineering with peptides containing the CNGRC (NGR) motif, a ligand that recognizes CD13-positive tumor vessels. We show here that the targeting domain of recombinant CNGRC-cytokine fusion proteins, such as NGR-TNF (a CNGRC-tumor necrosis factor-α (TNF) conjugate used in clinical studies) and NGR-EMAP-II, undergoes various post-translational modification and degradation reactions that lead to the formation of markedly heterogeneous products. These modifications include N-terminal cysteine acetylation or the formation of various asparagine degradation products, the latter owing to intramolecular interactions of the cysteine α-amino group with asparagine and/or its succinimide derivative.

Boosting Interleukin-12 Antitumor Activity and Synergism with Immunotherapy by Targeted Delivery with isoDGR-Tagged Nanogold.

The clinical use of interleukin-12 (IL12), a cytokine endowed with potent immunotherapeutic anticancer activity, is limited by systemic toxicity. The hypothesis is addressed that gold nanoparticles tagged with a tumor-homing peptide containing isoDGR, an αvβ3-integrin binding motif, can be exploited for delivering IL12 to tumors and improving its therapeutic index. To this aim, gold nanospheres are functionalized with the head-to-tail cyclized-peptide CGisoDGRG (Iso1) and murine IL12.

Physiological levels of chromogranin A prevent doxorubicin-induced cardiotoxicity without impairing its anticancer activity.

The clinical use of doxorubicin (Doxo), a widely used anticancer chemotherapeutic drug, is limited by dose-dependent cardiotoxicity. We have investigated whether chromogranin A (CgA), a cardioregulatory protein released in the blood by the neuroendocrine system and by the heart itself, may contribute to regulation of the cardiotoxic and antitumor activities of Doxo. The effects of a physiologic dose of full-length recombinant CgA on Doxo-induced cardiotoxicity and antitumor activity were investigated in rats using and models and in murine models of melanoma, fibrosarcoma, lymphoma, and lung cancer, respectively.

Spatiotemporal Regulation of Tumor Angiogenesis by Circulating Chromogranin A Cleavage and Neuropilin-1 Engagement.

The unbalanced production of pro- and antiangiogenic factors in tumors can lead to aberrant vasculature morphology, angiogenesis, and disease progression. In this study, we report that disease progression in various murine models of solid tumors is associated with increased cleavage of full-length chromogranin A (CgA), a circulating vasoregulatory neurosecretory protein. Cleavage of CgA led to the exposure of the highly conserved PGPQLR site, which corresponds to residues 368-373 of human CgA, a fragment that has proangiogenic activity.

Platelet microparticles sustain autophagy-associated activation of neutrophils in systemic sclerosis.

Endothelial cell damage and platelet activation contribute to sustained vasculopathy, which is a key clinical characteristic of systemic sclerosis (SSc), also known as scleroderma. Microparticles released from activated platelets in the blood of SSc patients (SSc-microparticles) are abundant and express the damage-associated molecular pattern (DAMP) HMGB1. SSc-microparticles interacted with neutrophils in vitro and in immunocompromised mice and promoted neutrophil autophagy, which was characterized by mobilization of their granule content, enhanced proteolytic activity, prolonged survival, and generation of neutrophil extracellular traps (NETs).

Glycine -methylation in NGR-Tagged Nanocarriers Prevents Isoaspartate formation and Integrin Binding without Impairing CD13 Recognition and Tumor Homing.

NGR (asparagine-glycine-arginine) is a tumor vasculature-homing peptide motif widely used for the functionalization of drugs, nanomaterials and imaging compounds for cancer treatment and diagnosis. Unfortunately, this motif has a strong propensity to undergo rapid deamidation. This reaction, which converts NGR into DGR, is associated with receptor switching from CD13 to integrins, with potentially important manufacturing, pharmacological and toxicological implications.

Regulation of tumor growth by circulating full-length chromogranin A.

Chromogranin A (CgA), a neuroendocrine secretory protein, and its fragments are present in variable amounts in the blood of normal subjects and cancer patients. We investigated whether circulating CgA has a regulatory function in tumor biology and progression. Systemic administration of full-length CgA, but not of fragments lacking the C-terminal region, could reduce tumor growth in murine models of fibrosarcoma, mammary adenocarcinoma, Lewis lung carcinoma, and primary and metastatic melanoma, with U-shaped dose-response curves.

NGR-tagged nano-gold: A new CD13-selective carrier for cytokine delivery to tumors.

Colloidal gold (Au), a well-tolerated nanomaterial, is currently exploited for several applications in nanomedicine. We show that gold nanoparticles tagged with a novel tumor-homing peptide containing Asn-Gly-Arg (NGR), a ligand of CD13 expressed by the tumor neovasculature, can be exploited as carriers for cytokine delivery to tumors. Biochemical and functional studies showed that the NGR molecular scaffold/linker used for gold functionalization is critical for CD13 recognition.

Inhibition of chronic lymphocytic leukemia progression by full-length chromogranin A and its N-terminal fragment in mouse models.

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of leukemic B cells in peripheral blood, bone marrow (BM) and lymphoid tissues, and by their recirculation between these compartments. We observed that circulating chromogranin A (CgA) and its N-terminal fragment (called vasostatin-1, CgA1-76), two neuroendocrine secretory polypeptides that enhance the endothelial barrier function, are present in variable amounts in the blood of CLL patients. Studies in animal models showed that daily administration of full-length human CgA1-439 (0.

Chromogranin A Is Preferentially Cleaved into Proangiogenic Peptides in the Bone Marrow of Multiple Myeloma Patients.

Angiogenesis has been postulated to be critical for the pathogenesis of multiple myeloma, a neoplastic disease characterized by abnormal proliferation of malignant plasma cells in the bone marrow (BM). Cleavage of the N- and C-terminal regions of circulating chromogranin A (CgA, CHGA), classically an antiangiogenic protein, can activate latent antiangiogenic and proangiogenic sites, respectively. In this study, we investigated the distribution of CgA-derived polypeptides in multiple myeloma patients and the subsequent implications for disease progression.

Rigidity-Preserving Team Partitions in Multiagent Networks.

Motivated by the strong influence network rigidity has on collaborative systems, in this paper, we consider the problem of partitioning a multiagent network into two sub-teams, a bipartition, such that the resulting sub-teams are topologically rigid. In this direction, we determine the existence conditions for rigidity-preserving bipartitions, and provide an iterative algorithm that identifies such partitions in polynomial time. In particular, the relationship between rigid graph partitions and the previously identified Z-link edge structure is given, yielding a feasible direction for graph search.

A new chromogranin A-dependent angiogenic switch activated by thrombin.

Angiogenesis, the formation of blood vessels from pre-existing vasculature, is regulated by a complex interplay of anti and proangiogenic factors. We found that physiologic levels of circulating chromogranin A (CgA), a protein secreted by the neuroendocrine system, can inhibit angiogenesis in various in vitro and in vivo experimental models. Structure-activity studies showed that a functional anti-angiogenic site is located in the C-terminal region, whereas a latent anti-angiogenic site, activated by cleavage of Q76-K77 bond, is present in the N-terminal domain.

IsoDGR-tagged albumin: a new αvβ3 selective carrier for nanodrug delivery to tumors.

A new cyclic peptide containing the isoDGR motif that, after coupling to albumin, selectively binds αvβ3, an integrin overexpressed in the tumor vasculature. IsoDGR-tagged albumin binds tumor vessels and can be exploited as a carrier for the preparation of tumor vasculature-selective nanomedicines, such as gold nanoparticles (Au) carrying tumor necrosis factor α (TNF), a potent vascular damaging agent.

Chromogranin A binds to αvβ6-integrin and promotes wound healing in mice.

Chromogranin A (CgA), a secretory protein expressed by many neuroendocrine cells, neurons, cardiomyocytes, and keratinocytes, is the precursor of various peptides that regulate the carbohydrate/lipid metabolism and the cardiovascular system. We have found that CgA, locally administered to injured mice, can accelerate keratinocyte proliferation and wound healing. This biological activity was abolished by the Asp(45)Glu mutation.

The N-terminal fragment of chromogranin A, vasostatin-1 protects mice from acute or chronic colitis upon oral administration.

Background: Vasostatin-1 (VS-1), the N-terminal fragment of chromogranin A (CgA), decreases the permeability of endothelial cells in vitro and in vivo.

Aims: Here, we investigated whether a similar effect could be observed also on intestinal epithelial cells (IECs) in vitro and whether VS-1 could have favorable effects on animal models of acute or chronic colitis, which are characterized by increased permeability of the intestinal epithelium.

Methods: In vitro, VS-1 was tested on IEC monolayers showing increased permeability, on mechanically injured IEC monolayers, and on the production of the chemokine IL-8/KC by lipopolysaccharide (LPS)-stimulated IECs.

A networked transferable belief model approach for distributed data aggregation.

This paper focuses on the extension of the transferable belief model (TBM) to a multiagent-distributed context where no central aggregation unit is available and the information can be exchanged only locally among agents. In this framework, agents are assumed to be independent reliable sources which collect data and collaborate to reach a common knowledge about an event of interest. Two different scenarios are considered: In the first one, agents are supposed to provide observations which do not change over time (static scenario), while in the second one agents are assumed to dynamically gather data over time (dynamic scenario).

Chromogranin A restricts drug penetration and limits the ability of NGR-TNF to enhance chemotherapeutic efficacy.

NGR-TNF is a derivative of TNF-α that targets tumor blood vessels and enhances penetration of chemotherapeutic drugs. Because of this property, NGR-TNF is being tested in combination with chemotherapy in various phase II and III clinical trials. Here we report that chromogranin A (CgA), a protein present in variable amounts in the blood of normal subjects and cancer patients, inhibits the synergism of NGR-TNF with doxorubicin and melphalan in mouse models of lymphoma and melanoma.