Tryptophan Metabolism as Source of New Prognostic Biomarkers for FAP Patients

Familial adenomatous polyposis (FAP), a common inherited form of colorectal cancer (CRC), causes the development of hundreds to thousands of colonic adenomas in the colorectum beginning in early adolescence. In absence of a prophylactic surgery, FAP patients almost inevitably develop CRC by the age of 40 to 50. The lack of valuable prognostic biomarkers for FAP patients makes it difficult to predict when the progression from adenoma to malignant carcinoma occurs. Decreased tryptophan (TRP) plasma levels and increased indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan hydroxylase 1 (TPH1) enzymatic activities have been associated to tumour progression in CRC. In the present study, we aimed at investigating whether an altered TRP metabolism might also exist in FAP patients. Our results highlighted that plasma levels of TRP and its main catabolites are comparable between FAP patients and healthy subject. On the contrary, FAP patients presented significantly higher TRP levels with respect to high-grade adenoma (ADE) subjects and CRC patients. Obtained data lead us to evaluate IDO1 and TPH1 enzymes activity in the study groups. For both enzymes, it was possible to discriminate correctly between FAP subject and ADE/CRC patients with high sensitivities and specificities. By receiver operating characteristic (ROC) curve analysis, the cut-off values of IDO1 and TPH1 enzymatic activities associated to the presence of an active malignant transformation have been calculated as >38 and >5.5, respectively. When these cut-off values are employed, the area under the curve (AUC) is > 0.8 for both, indicating that TRP metabolism in patients with FAP may be used to monitor and predict the tumorigenic evolution

The Role of Early Revascularization and Biomarkers in the Management of Diabetic Foot Ulcers: A Single Center Experience

Diabetic neuropathy and Peripheral Arterial Disease (PAD) are the main etiological factors in foot ulceration. Herein, we report our experience of diabetic foot ulceration (DFU) management, with an analysis of the relationship between the rate of lower extremity amputation, in persons with infected DFU, after revascularization procedures performed to prevent major amputation. This study highlights the role of different biomarkers, showing their usefulness and potentiality in diabetic foot ulcer management, especially for the early diagnosis and therapy effectiveness monitoring. A retrospective analysis, from September 2016 to January 2021, of diabetic patients presenting diabetic foot with DFU, was performed. All patients were treated with at least one vascular procedure (endovascular, open, hybrid procedures) targeting PAD lesions. Outcomes measured were perioperative mortality and morbidity. Freedom from occlusion, primary and secondary patency, and amputation rate were registered. A total of 267 patients, with a mean age of 72.5 years, were included in the study. The major amputation rate was 6.2%, minor amputation rate was 17%. In our experience, extreme revascularization to obtain direct flow reduced the rate of amputations, with an increase in ulcer healing

Loss of Primary Cilia Potentiates BRAF/MAPK Pathway Activation in Rhabdoid Colorectal Carcinoma: A Series of 21 Cases Showing Ciliary Rootlet CoiledCoil (CROCC) Alterations

A rhabdoid colorectal tumor (RCT) is a rare cancer with aggressive clinical behavior. Recently, it has been recognized as a distinct disease entity, characterized by genetic alterations in the SMARCB1 and Ciliary Rootlet Coiled-Coil (CROCC). We here investigate the genetic and immunophenotypic profiling of 21 RCTs using immunohistochemistry and next-generation sequencing. Mismatch repair-deficient phenotypes were identified in 60% of RCTs. Similarly, a large proportion of cancers exhibited the combined marker phenotype (CK7-/CK20-/CDX2-) not common to classical adenocarcinoma variants. More than 70% of cases displayed aberrant activation of the mitogen-activated protein kinase (MAPK) pathway with mutations prevalently in BRAF V600E. SMARCB1/INI1 expression was normal in a large majority of lesions. In contrast, ciliogenic markers including CROCC and γ-tubulin were globally altered in tumors. Notably, CROCC and γ-tubulin were observed to colocalize in large cilia found on cancer tissues but not in normal controls. Taken together, our findings indicate that primary ciliogenesis and MAPK pathway activation contribute to the aggressiveness of RCTs and, therefore, may constitute a novel therapeutic target

Il Nibbio reale Milvus milvus svernante in Italia, sintesi di cinque anni di monitoraggio

Beginning in December 2011, CISO has promoted a monitoring project for Red kite\u2019s wintering population in Italy. This paper shows the results of the first five survey seasons, ie from December 2011 to January 2016. The censuses, always done at sunset, covered the eleven Central-Southern regions for which winter roosts were already known. The number of actual kites censuses each winter varied between about 1500 and over 1700 individuals, with strong oscillations for single roosts. The population is mainly concentrated in Basilicata with more than 64% of the entire winter population. Interesting data were also been found in Lazio, Abruzzo and Molise, which altogether host about 25% of the national population. Encouraging data come from Tuscany where, following a reintroduction project, a wintering roost of about 80 units was found. Bad results are from censuses conducted in Campania, Calabria, Sicily and Sardinia, where the population seems to be greatly reduced

Il Nibbio reale Milvus milvus svernante in Italia, sintesi di cinque anni di monitoraggio

Beginning in December 2011, CISO has promoted a monitoring project for Red kite\u2019s wintering population in Italy. This paper shows the results of the first five survey seasons, ie from December 2011 to January 2016. The censuses, always done at sunset, covered the eleven Central-Southern regions for which winter roosts were already known. The number of actual kites censuses each winter varied between about 1500 and over 1700 individuals, with strong oscillations for single roosts. The population is mainly concentrated in Basilicata with more than 64% of the entire winter population. Interesting data were also been found in Lazio, Abruzzo and Molise, which altogether host about 25% of the national population. Encouraging data come from Tuscany where, following a reintroduction project, a wintering roost of about 80 units was found. Bad results are from censuses conducted in Campania, Calabria, Sicily and Sardinia, where the population seems to be greatly reduced

NEMO: A Project for a km3^3 Underwater Detector for Astrophysical Neutrinos in the Mediterranean Sea

The status of the project is described: the activity on long term characterization of water optical and oceanographic parameters at the Capo Passero site candidate for the Mediterranean km$^3$ neutrino telescope; the feasibility study; the physics performances and underwater technology for the km$^3$; the activity on NEMO Phase 1, a technological demonstrator that has been deployed at 2000 m depth 25 km offshore Catania; the realization of an underwater infrastructure at 3500 m depth at the candidate site (NEMO Phase 2).Comment: Proceeding of ISCRA 2006, Erice 20-27 June 200

Measurement of the atmospheric muon flux with the NEMO Phase-1 detector

The NEMO Collaboration installed and operated an underwater detector including prototypes of the critical elements of a possible underwater km3 neutrino telescope: a four-floor tower (called Mini-Tower) and a Junction Box. The detector was developed to test some of the main systems of the km3 detector, including the data transmission, the power distribution, the timing calibration and the acoustic positioning systems as well as to verify the capabilities of a single tridimensional detection structure to reconstruct muon tracks. We present results of the analysis of the data collected with the NEMO Mini-Tower. The position of photomultiplier tubes (PMTs) is determined through the acoustic position system. Signals detected with PMTs are used to reconstruct the tracks of atmospheric muons. The angular distribution of atmospheric muons was measured and results compared with Monte Carlo simulations.Comment: Astrop. Phys., accepte

A JWST inventory of protoplanetary disk ices: The edge-on protoplanetary disk HH 48 NE, seen with the Ice Age ERS program

Ices are the main carriers of volatiles in protoplanetary disks and are crucial to our understanding of the chemistry that ultimately sets the organic composition of planets. The ERS program Ice Age on the JWST follows the ice evolution through all stages of star and planet formation. JWST/NIRSpec observations of the edge-on Class II protoplanetary disk HH~48~NE reveal spatially resolved absorption features of the major ice components H$_2$O, CO$_2$, CO, and multiple weaker signatures from less abundant ices NH$_3$, OCN$^-$, and OCS. Isotopologue $^{13}$CO$_2$ ice has been detected for the first time in a protoplanetary disk. Since multiple complex light paths contribute to the observed flux, the ice absorption features are filled in by ice-free scattered light. The $^{12}$CO$_2$/$^{13}$CO$_2$ ratio of 14 implies that the $^{12}$CO$_2$ feature is saturated, without the flux approaching 0, indicative of a very high CO$_2$ column density on the line of sight, and a corresponding abundance with respect to hydrogen that is higher than ISM values by a factor of at least a few. Observations of rare isotopologues are crucial, as we show that the $^{13}$CO$_2$ observation allows us to determine the column density of CO$_2$ to be at an order of magnitude higher than the lower limit directly inferred from the observed optical depth. Radial variations in ice abundance, e.g., snowlines, are significantly modified since all observed photons have passed through the full radial extent of the disk. CO ice is observed at perplexing heights in the disk, extending to the top of the CO-emitting gas layer. We argue that the most likely interpretation is that we observe some CO ice at high temperatures, trapped in less volatile ices like H$_2$O and CO$_2$. Future radiative transfer models will be required to constrain the implications on our current understanding of disk physics and chemistry.Comment: 16 pages, 8 figures, accepted for publication in A&

Status and perspectives of the 4 pi charged particles multidetector CHIMERA

The construction of the multidetector CHIMERA designed to detect and identify charged particles and fragments emitted in heavy ion reactions at intermediate energy is in progress and is coming to an end. The construction of this multidetector is presented in this paper as well as the status of the project

A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation

Background: In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer. Methods: We derived a combined prognostic model using retrospective clinical–pathological data on stromal tumour-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients who participated in the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed, node-positive, HER2-positive breast cancer or, if node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and randomly assigned them to adjuvant anthracycline plus taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter) for 18 doses or weekly (4 mg/kg loading dose in the first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. Median follow-up was 91·4 months (IQR 75·1–105·6). The primary objective of our study was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival (the time between randomisation and distant recurrence or death before recurrence), an exploratory endpoint in Short-HER. Patient samples in the training dataset were split into a training set (n=290) and a testing set (n=145), balancing for event and treatment group. The training set was further stratified into 100 iterations of Monte-Carlo cross validation (MCCV). Cox proportional hazard models were fit to MCCV training samples using Elastic-Net. A maximum of 92 features were assessed. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data. Findings: From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0·0001). HER2DX median score for quartiles 1–2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, and high-risk populations were 98·1% (95% CI 96·3–99·9), 88·9% (83·2–95·0), and 73·9% (66·0–82·7), respectively (low-risk vs high-risk hazard ratio [HR] 0·04, 95% CI 0·0–0·1, p<0·0001). In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2·77, 95% CI 1·4–5·6, p=0·0040) and as group categories (low-risk vs high-risk HR 0·27, 0·1–0·7, p=0·005). 5-year disease-free survival in the HER2DX low-risk group was 93·5% (89·0–98·3%) and in the high-risk group was 81·1% (71·5–92·1). Interpretation: The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting. Funding: Instituto Salud Carlos III, Save the Mama, Pas a Pas, Fundación Científica, Asociación Española Contra el Cáncer, Fundación SEOM, National Institutes of Health, Agenzia Italiana del Farmaco, International Agency for Research on Cancer, and the Veneto Institute of Oncology, and Italian Association for Cancer Research