Report: Fundamental Physics at Frascati

This report summarizes the scientific discussion of the workshop "Fisica Fondamentale a Frascati" that was held on January the 13th, 2021. The aim of the meeting was to brainstorm on the opportunities to continue to carry out at the LNF experimental activities that could contribute to the scientific exploration of fundamental open questions in particle physics. This initiative has been triggered by the awareness that while the ongoing DA NE scientific program is coming to an end, the EuPRAXIA project, identified as the major future activity of the LNF, has a time horizon of several years before entering the operation phase. Therefore, we asked ourselves to which fields in fundamental physics the LNF can give a sound contribution within the medium-term by exploiting the existing infrastructures or, in case some breakthrough for some specific research is foreseeable, by implementing minor upgrades. The topics that have been identified are: (i) the quest for dark matter candidates in terms of feebly interacting light particles; (ii) probing the axion solution to the strong CP puzzle by searching for dark matter axions with superconducting cavities and with large volume haloscopes; (iii) the study of the low energy QCD problems related to the role of strangeness in nuclear matter. Theoreticians and experimentalists convened to scrutinize the different aspects of these scientific issues. The format chosen for the workshop foresaw a theory talk introducing each subject, followed by experimental contributions describing in detail how the scientific goal can be best addressed. This document resumes the various contributions in a condensed form, and is intended to provide a guideline for who will be asked to evaluate this program. Additional material can be found at the webpage of the meeting (https://agenda.infn.it/event/25299/)

Influence of aging on peripheral nervous system: a morphological and morphometric study

It is well known that aging influences several functional and structural features of peripheral nerves (Verdù et al., 2000; Ceballos et al., 1999; Jeronimo et al., 2008). However, the role of these changes in the damage/repair mechanisms occurring in acquired peripheral neuropathies is still unclear. To this aim, a multimodal, long-term assessment in a mice model would represent an optimal tool to perform experimental neuropathy studies designed to evaluate the role of aging in relationship with a given nerve injury. In this study we used 40 females one-month-old C57B1/6 mice and we followed-up them for fifteen months. Digital and caudal nerve conduction velocity (NCV) studies were performed monthly to evaluate changes in electrophysiological features; moreover, four animals were sacrificed every two months in order to collect caudal nerve, sciatic nerve, dorsal root ganglia (DRG) and skin for morphological and morphometric analysis. The neurophysiological assessments showed a remarkable increase of caudal NCV until the age of 9 months and then it remained unchanged until the end of the observation period; in the same period, digital NCV increase was also present although less marked. At the pathological level, both caudal and sciatic nerves showed a decrease in fibres density related with age, whereas axon and fibres diameters tended to increase. These preliminary data can be considered a first step aiming at creating a background for future studies on the relationship between aging and peripheral nervous system induced damage

Morphofunctional characterization of peripheral nerve damage and recovery in sphyngomielinase deficient mice

Mutation of the acid sphingomyelinase (ASM) gene and its reduced enzymatic activity is the main cause of the Type A Niemann-Pick disease. Recent advances demonstrated that ASM is necessary and sufficient to control the formation and release of microvesiscles containing the proinflammatory cytokine interleukin-1β (IL-1β) by glial cells [1]. Since IL-1β modulates the events caused by nerve damage and repair and seems to act as a neuro-modulator between activated glia and neurons [2], the control of its production and secretion might represent a new strategy in nerve regeneration and in the control of neuropathic pain. In this study we used a well-characterized ASM knockout mouse (ASMKO, [3]) to evaluate, through a multimodal approach, the onset and the course of the morphological and functional nerve damage and of neuropathic pain after sciatic nerve crush. Adult (1 and 5 month-old) male ASMKO and age-matched wild-type (WT) mice underwent sciatic nerve crush lesion. Nerve conduction velocity (NCV), walking track analysis followed by ultra-structural and morphometric analysis of sciatic nerves were performed to evaluate the features of nerve damage. Thermal (Plantar test) and mechanical sensitivity (Dynamic Plantar Aesthesiometer apparatus) were used to measure the severity of neuropathic pain. Moreover, the rotarod test completed the analysis as an indicator of motor impairment. One or two months after the nerve crush motor functional recovery was similar in WT and KO mice and the NCV measures performed in the sciatic nerve demonstrated a moderate and progressive improvement of nerve function. The results of the morphological examination confirmed the expected course of nerve recovery, but also demonstrated defective nerve regeneration, particularly evident in older, but already present in younger ASMKO mice. Behavioral tests suggested that the mutated phenotype in ASMKO might have an effect on the onset and development of mechanical and thermal hyperalgesia after nerve crush in both 1 - month and 5 - months - old groups. In conclusion, these data suggest a possible role for ASM-related microvesicles in nerve regeneration and suggest that targeting the IL-1β production and release may represent a new therapeutic strategy for the treatment of nerve damage and neuropathic pain

Nationwide multidisciplinary consensus on the clinical management of Merkel cell carcinoma: a Delphi panel

Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous neuroendocrine carcinoma. The MCC incidence rate has rapidly grown over the last years, with Italy showing the highest increase among European countries. This malignancy has been the focus of active scientific research over the last years, focusing mainly on pathogenesis, new therapeutic trials and diagnosis. A national expert board developed 28 consensus statements that delineated the evolution of disease management and highlighted the paradigm shift towards the use of immunological strategies, which were then presented to a national MCC specialists panel for review. Sixty-five panelists answered both rounds of the questionnaire. The statements were divided into five areas: a high level of agreement was reached in the area of guidelines and multidisciplinary management, even if in real life the multidisciplinary team was not always represented by all the specialists. In the diagnostic pathway area, imaging played a crucial role in diagnosis and initial staging, planning for surgery or radiation therapy, assessment of treatment response and surveillance of recurrence and metastases. Concerning diagnosis, the usefulness of Merkel cell polyomavirus is recognized, but the agreement and consensus regarding the need for cytokeratin evaluation appears greater. Regarding the areas of clinical management and follow-up, patients with MCC require customized treatment. There was a wide dispersion of results and the suggestion to increase awareness about the adjuvant radiation therapy. The panelists unanimously agreed that the information concerning avelumab provided by the JAVELIN Merkel 200 study is adequate and reliable and that the expanded access program data could have concrete clinical implications. An immunocompromised patient with advanced MCC can be treated with immunotherapy after multidisciplinary risk/benefit assessment, as evidenced by real-world analysis and highlighted in the guidelines. A very high consensus regarding the addition of radiotherapy to treat the ongoing focal progression of immunotherapy was observed. This paper emphasizes the importance of collaboration and communication among the interprofessional team members and encourages managing patients with MCC within dedicated multidisciplinary teams. New insights in the treatment of this challenging cancer needs the contribution of many and different experts

TRAIL reduces impaired glucose tolerance and NAFLD in the high-fat diet-fed mouse

Recent studies suggest that a circulating protein called TRAIL (TNF-related apoptosis inducing ligand) may have an important role in the treatment of type 2 diabetes. It has been shown that TRAIL deficiency worsens diabetes and that TRAIL delivery, when it is given before disease onset, slows down its development. The present study aimed at evaluating whether TRAIL had the potential not only to prevent, but also to treat type 2 diabetes. Thirty male C57BL/6J mice were randomized to a standard or a high-fat diet (HFD). After 4 weeks of HFD, mice were further randomized to receive either placebo or TRAIL, which was delivered weekly for 8 weeks. Body weight, food intake, fasting glucose, and insulin were measured at baseline and every 4 weeks. Tolerance tests were performed before drug randomization and at the end of the study. Tissues were collected for further analyses. Parallel in vitro studies were conducted on HepG2 cells and mouse primary hepatocytes. TRAIL significantly reduced body weight, adipocyte hypertrophy, free fatty acid levels, and inflammation. Moreover, it significantly improved impaired glucose tolerance, and ameliorated non-alcoholic fatty liver disease (NAFLD). TRAIL treatment reduced liver fat content by 47% in vivo as well as by 45% in HepG2 cells and by 39% in primary hepatocytes. This was associated with a significant increase in liver peroxisome proliferator-activated receptor (PPAR) \u3b3 (PPAR\u3b3) co-activator-1 \u3b1 (PGC-1\u3b1) expression both in vivo and in vitro, pointing to a direct protective effect of TRAIL on the liver. The present study confirms the ability of TRAIL to significantly attenuate diet-induced metabolic abnormalities, and it shows for the first time that TRAIL is effective also when administered after disease onset. In addition, our data shed light on TRAIL therapeutic potential not only against impaired glucose tolerance, but also against NAFLD

The Multidisciplinary Management of Cutaneous Squamous Cell Carcinoma: A Comprehensive Review and Clinical Recommendations by a Panel of Experts

Simple Summary Cutaneous squamous cell carcinoma is one of the most common forms of cancer. Although most cases are cured with surgical excision, a few tumors are associated with a high risk of local or distant relapse; therefore, it is relevant to identify high-risk lesions among all other low-risk CSCCs for the proper diagnostic and therapeutic management. Chemotherapy achieves mostly short-lived responses that do not lead to a curative effect and are associated with severe toxicities. Recently, PD-1 inhibitor cemiplimab was approved by the regulatory authorities for the treatment of advanced cutaneous squamous cell carcinoma; subsequently, the anti-PD-1 agent pembrolizumab received the approval by the FDA only in the same setting. Here, we provide a literature review and clinical recommendations by a panel of experts regarding the diagnosis, treatment, and follow-up of cutaneous squamous cell carcinoma. Cutaneous squamous cell carcinomas (CSCC) account for about 20% of all keratinocyte carcinomas, which are the most common form of cancer. Heterogeneity of treatments and low mortality are a challenge in obtaining accurate incidence data and consistent registration in cancer registries. Indeed, CSCC mostly presents as an indolent, low-risk lesion, with five-year cure rates greater than 90% after surgical excision, and only few tumors are associated with a high-risk of local or distant relapse; therefore, it is particularly relevant to identify high-risk lesions among all other low-risk CSCCs for the proper diagnostic and therapeutic management. Chemotherapy achieves mostly short-lived responses that do not lead to a curative effect and are associated with severe toxicities. Due to an etiopathogenesis largely relying on chronic UV radiation exposure, CSCC is among the tumors with the highest rate of somatic mutations, which are associated with increased response rates to immunotherapy. Thanks to such strong pre-clinical rationale, clinical trials led to the approval of anti-PD-1 cemiplimab by the FDA (Food and Drug Administration) and EMA (European Medicines Agency), and anti-PD-1 pembrolizumab by the FDA only. Here, we provide a literature review and clinical recommendations by a panel of experts regarding the diagnosis, treatment, and follow-up of CSCC

Combined Large Cell Neuroendocrine Carcinomas of the Lung: Integrative Molecular Analysis Identifies Subtypes with Potential Therapeutic Implications

Combined large cell neuroendocrine carcinoma (CoLCNEC) is given by the association of LCNEC with adeno or squamous or any non-neuroendocrine carcinoma. Molecular bases of CoLCNEC pathogenesis are scant and no standardized therapies are defined

The future search for low-frequency axions and new physics with the FLASH resonant cavity experiment at Frascati National Laboratories

We present a proposal for a new experiment, the FINUDA magnet for Light Axion SearcH (FLASH), a large resonant-cavity haloscope in a high static magnetic field which is planned to probe new physics in the form of dark matter (DM) axions, scalar fields, chameleons, hidden photons, as well as high frequency gravitational waves (GWs). Concerning the QCD axion, FLASH will search for these particles as the DM in the mass range (0.49-1.49) ueV, thus filling the mass gap between the ranges covered by other planned searches. A dedicated Microstrip SQUID operating at ultra-cryogenic temperatures will amplify the signal. The frequency range accessible overlaps with the Very High Frequency (VHF) range of the radio wave spectrum and allows for a search in GWs in the frequency range (100-300) MHz. The experiment will make use of the cryogenic plant and magnet of the FINUDA experiment at INFN Frascati National Laboratories near Rome (Italy); the operations needed to restore the functionalities of the apparatus are currently underway. We present the setup of the experiment and the sensitivity forecasts for the detection of axions, scalar fields, chameleons, hidden photons, and GWs

Invasive meningococcal disease in three siblings with hereditary deficiency of the 8th component of complement: Evidence for the importance of an early diagnosis

Deficiency of the eighth component of complement (C8) is a very rare primary immunodeficiency, associated with invasive, recurrent infections mainly caused by Neisseria species. We report functional and immunochemical C8 deficiency diagnosed in three Albanian siblings who presented with severe meningococcal infections at the age of 15 years, 4 years and 17 months, respectively. The youngest suffered serious complications (necrosis of fingers and toes requiring amputation). METHODS: Functional activity of the classical, alternative and mannose-binding lectin complement pathways was measured in serum from the 3 siblings and their parents (37-year-old woman and 42-year-old man). Forty healthy subjects (20 males and 20 females aged 4-38 years) served as normal controls. Serum complement factors were measured by haemolytic assays and immunoblotting. Sequence DNA analysis of the C8B gene was performed. RESULTS: Analyses of the three complement pathways revealed no haemolytic activity and also absence of C8beta in serum samples from all three siblings. The genetic analysis showed that the three siblings were homozygous for the p.Arg428* mutation in the C8B gene on chromosome 1p32 (MIM 120960). The parents were heterozygous for the mutation and presented normal complement activities. A 2-year follow-up revealed no further infective episodes in the siblings after antibiotic prophylaxis and meningococcal vaccination. CONCLUSIONS: Complement deficiencies are rare and their occurrence is often underestimated. In presence of invasive meningococcal infection, we highlight the importance of complement screening in patients and their relatives in order to discover any genetic defects which would render necessary prophylaxis to prevent recurrent infections and severe complications