A Stage-Based Approach to Therapy in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder that features progressive, disabling motor symptoms, such as bradykinesia, rigidity, and resting tremor. Nevertheless, some non-motor symptoms, including depression, REM sleep behavior disorder, and olfactive impairment, are even earlier features of PD. At later stages, apathy, impulse control disorder, neuropsychiatric disturbances, and cognitive impairment can present, and they often become a heavy burden for both patients and caregivers. Indeed, PD increasingly compromises activities of daily life, even though a high variability in clinical presentation can be observed among people affected. Nowadays, symptomatic drugs and non-pharmaceutical treatments represent the best therapeutic options to improve quality of life in PD patients. The aim of the present review is to provide a practical, stage-based guide to pharmacological management of both motor and non-motor symptoms of PD. Furthermore, warning about drug side effects, contraindications, as well as dosage and methods of administration, are highlighted here, to help the physician in yielding the best therapeutic strategies for each symptom and condition in patients with PD

Killer Ig-Like Receptors (KIRs): Their Role in NK Cell Modulation and Developments Leading to Their Clinical Exploitation

Natural killer (NK) cells contribute to the first line of defense against viruses and to the control of tumor growth and metastasis spread. The discovery of HLA class I specific inhibitory receptors, primarily of killer Ig-like receptors (KIRs), and of activating receptors has been fundamental to unravel NK cell function and the molecular mechanisms of tumor cell killing. Stemmed from the seminal discoveries in early '90s, in which Alessandro Moretta was the major actor, an extraordinary amount of research on KIR specificity, genetics, polymorphism, and repertoire has followed. These basic notions on NK cells and their receptors have been successfully translated to clinical applications, primarily to the haploidentical hematopoietic stem cell transplantation to cure otherwise fatal leukemia in patients with no HLA compatible donors. The finding that NK cells may express the PD-1 inhibitory checkpoint, particularly in cancer patients, may allow understanding how anti-PD-1 therapy could function also in case of HLA class Ineg tumors, usually susceptible to NK-mediated killing. This, together with the synergy of therapeutic anti-checkpoint monoclonal antibodies, including those directed against NKG2A or KIRs, emerging in recent or ongoing studies, opened new solid perspectives in cancer therapy

Impacts of air pollution on human and ecosystem health, and implications for the National Emission Ceilings Directive. Insights from Italy

Across the 28 EU member states there were nearly half a million premature deaths in 2015 as a result of exposure to PM2.5, O3 and NO2. To set the target for air quality levels and avoid negative impacts for human and ecosystems health, the National Emission Ceilings Directive (NECD, 2016/2284/EU) sets objectives for emission reduction for SO2, NOx, NMVOCs, NH3 and PM2.5 for each Member State as percentages of reduction to be reached in 2020 and 2030 compared to the emission levels into 2005. One of the innovations of NECD is Article 9, that mentions the issue of “monitoring air pollution impacts” on ecosystems. We provide a clear picture of what is available in term of monitoring network for air pollution impacts on Italian ecosystems, summarizing what has been done to control air pollution and its effects on different ecosystems in Italy. We provide an overview of the impacts of air pollution on health of the Italian population and evaluate opportunities and implementation of Article 9 in the Italian context, as a case study beneficial for all Member States. The results showed that SO42− deposition strongly decreased in all monitoring sites in Italy over the period 1999–2017, while NO3− and NH4+ decreased more slightly. As a consequence, most of the acid-sensitive sites which underwent acidification in the 1980s partially recovered. The O3 concentration at forest sites showed a decreasing trend. Consequently, AOT40 (the metric identified to protect vegetation from ozone pollution) showed a decrease, even if values were still above the limit for forest protection (5000 ppb h−1), while PODy (flux-based metric under discussion as new European legislative standard for forest protection) showed an increase. National scale studies pointed out that PM10 and NO2 induced about 58,000 premature deaths (year 2005), due to cardiovascular and respiratory diseases. The network identified for Italy contains a good number of monitoring sites (6 for terrestrial ecosystem monitoring, 4 for water bodies monitoring and 11 for ozone impact monitoring) distributed over the territory and will produce a high number of monitored parameters for the implementation of the NECD

A Role for Nuclear Phospholipase Cβ1 in Cell Cycle Control

Phosphoinositide signaling resides in the nucleus, and among the enzymes of the cycle, phospholipase C (PLC) appears as the key element both in Saccharomyces cerevisiae and in mammalian cells. The yeast PLC pathway produces multiple inositol polyphosphates that modulate distinct nuclear processes. The mammalian PLCbeta(1), which localizes in the nucleus, is activated in insulin-like growth factor 1-mediated mitogenesis and undergoes down-regulation during murine erythroleukemia differentiation. PLCbeta(1) exists as two polypeptides of 150 and 140 kDa generated from a single gene by alternative RNA splicing, both of them containing in the COOH-terminal tail a cluster of lysine residues responsible for nuclear localization. These clues prompted us to try to establish the critical nuclear target(s) of PLCbeta(1) subtypes in the control of cell cycle progression. The results reveal that the two subtypes of PLCbeta(1) that localize in the nucleus induce cell cycle progression in Friend erythroleukemia cells. In fact when they are overexpressed in the nucleus, cyclin D3, along with its kinase (cdk4) but not cyclin E is overexpressed even though cells are serum-starved. As a consequence of this enforced expression, retinoblastoma protein is phosphorylated and E2F-1 transcription factor is activated as well. On the whole the results reveal a direct effect of nuclear PLCbeta(1) signaling in G(1) progression by means of a specific target, i.e. cyclin D3/cdk4

Serum amino acid profiles in normal subjects and in patients with or at risk of Alzheimer dementia

Background/Aims: Abnormalities in the plasma amino acid profile have been reported in Alzheimer disease (AD), but no data exist for the prodromal phase characterized by subjective memory complaint (SMC). It was our aim to understand if serum amino acid levels change along the continuum from normal to AD, and to identify possible diagnostic biomarkers. Methods: Serum levels of 15 amino acids and 2 organic acids were determined in 4 groups of participants – 29 with probable AD, 18 with mild cognitive impairment (MCI), 24 with SMC, and 46 cognitively healthy subjects (HS) – by electrospray tandem mass spectrometry. Results: Glutamate, aspartate, and phenylalanine progressively decreased, while citrulline, argi­ninosuccinate, and homocitrulline progressively increased, from HS over SMC and MCI to AD. The panel including these 6 amino acids and 4 ratios (glutamate/citrulline, citrulline/phenylalanine, leucine plus isoleucine/phenylalanine, and arginine/phenylalanine) discriminated AD from HS with about 96% accuracy. Other panels including 20 biomarkers discriminated SMC or MCI from AD or HS with an accuracy ranging from 88 to 75%. Conclusion: Amino acids contribute to a characteristic metabotype during the progression of AD along the continuum from health to frank dementia, and their monitoring in elderly individuals might help to detect at-risk subjects

An Historical Overview: The Discovery of How NK Cells Can Kill Enemies, Recruit Defense Troops, and More

Natural killer (NK) cells were originally defined as effector lymphocytes of innate immunity characterized by the unique ability of killing tumor and virally infected cells without any prior priming and expansion of specific clones. The \u201cmissing-self\u201d theory, proposed by Klas Karre, the seminal discovery of the first prototypic HLA class I-specific inhibitory receptors, and, later, of the Natural Cytotoxicity Receptors (NCRs) by Alessandro Moretta, provided the bases to understand the puzzling behavior of NK cells. Actually, those discoveries proved crucial also for many of the achievements that, along the years, have contributed to the modern view of these cells. Indeed, NK cells, besides killing susceptible targets, are now known to functionally interact with different immune cells, sense pathogens using TLR, adapt their responses to the local environment, and, even, mount a sort of immunological memory. In this review, we will specifically focus on the main activating NK receptors and on their crucial role in the ever-increasing number of functions assigned to NK cells and other innate lymphoid cells (ILCs)

Retrospective Study of Regorafenib Versus TAS-102 Efficacy and Safety in Chemorefractory Metastatic Colorectal Cancer (mCRC) Patients: A Multi-institution Real Life Clinical Data

INTRODUCTION: There have been significant developments in colorectal cancer (CRC) research over the last few years, with the introduction of new agents that have been prolonged median overall survival of metastatic colorectal cancer (mCRC). These therapies have improved patient outcomes; however, despite significant progress in strategies for cancer treatment, their use is limited by development of resistant mechanism. Almost 30% of patients with refractory mCRC will remain good candidates for further treatment. Regorafenib and TAS-102 are novel antitumor agents for patients with refractory mCRC. However, it is unclear which patients may derive a survival benefit from these drugs in real-life clinical practice.; METHODS: We performed a retrospective analysis evaluating safety and efficacy of TAS-102 and regorafenib in a cohort of refractory mCRC patients, in 3 different centers between January 1 2018 and May 31 2020, with the aim of assessing the optimal sequence treatment for these 2 drugs.; RESULTS: One hundred and forty mCRC patients were included in the analysis. Of these patients, 64 received regorafenib and 76 received TAS-102 as first treatment. After progression, in the regorafenib 24 (37%) patients switched to secondary treatment with TAS-102, instead, in the TAS-102 group, among 76 patients, 29 (45%) patients switched to secondary treatment with regorafenib. Disease control was achieved in 8 (12.5%) of 64 patients in the regorafenib group and 17 (22.4%) of 76 patients in the TAS-102 group. In terms of efficacy, the PFS and OS were similar in both treatment groups for primary and secondary treatments. AEs reported in this analysis were mostly consistent with the known safety profiles of regorafenib and TAS-102 in previous clinical trials.; CONCLUSION: The present study is the first one to compare the activity of the two agents in a large cohort of chemo-refractory mCRC patients providing more details about the best sequence, to be incorporated in clinical practice. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved