Pt(IV)Ac-POA: new platinum compound Induced caspase independent apoptosis In B50 neuroblastoma stem cells

Neuroblastoma is a tumour that affects adults and children, characterized by a stem cells component. To date, cisplatin is the main antitumor agent used in the clinical treatment of this tumour; however, it induces side effects such as neurotoxicity in healthy cells and induces chemo resistance to therapy in cancer cells. New platinum-based compounds, platinum (II) have recently been synthesized, and due to their chemical characteristics, they are able to identify new cellular targets. These complexes act as prodrugs and performing their cytotoxic effect as platinum (II) after a reduction reaction within the hypoxic tumour cells. Among these prodrugs, Pt(IV)Ac-POA appears to be very promising, thanks to the presence of ligand (2 propinyl)octanoic acid (POA), which acts as an inhibitor of histone deacetylase (HDACi) and leads to the increase of histone acetylation, decreasing the interactions between histone and DNA, so as to produce chemo-sensitization to DNA-damaging agents. The greater cytotoxic effect of Pt(IV)Ac-POA on tumour cells, would therefore be mainly due to the mechanism of inhibition of histone deacetylase, which would increase the accessibility of DNA to platination mechanisms that induce cell death. In this study the results show that Pt(IV)Ac-POA, used at a concentration ten times lower than cisplatin, can induce apoptosis in B50 cells in culture both through the intrinsic pathway and through the independent caspase pathway. The data, obtained by immunohistochemical techniques in fluorescence microscopy, show that treatment with Pt(IV)Ac-POA has a greater proapoptotic effect on stem cells compared to the cisplatin standard treatment

向精神薬服用患者の突然死症例におけるカリウムイオンチャネルに関する分子生物学的解析：QT延長症候群関連遺伝子の多型が危険因子となり得るか？

Psychotropic drugs can pose the risk of acquired long QT syndrome (LQTS). Unexpected autopsy-negative sudden death in patients taking psychotropic drugs may be associated with prolonged QT intervals and life-threatening arrhythmias. We analyzed genes that encode for cardiac ion channels and potentially associated with LQTS, examining specifically the potassium channel genes KCNQ1 and KCNH2 in 10 cases of sudden death involving patients administered psychotropic medication in which autopsy findings identified no clear cause of death. We amplified and sequenced all exons of KCNQ1 and KCNH2, identifying G643S, missense polymorphism in KCNQ1, in 6 of the 10 cases. A study analysis indicated that only 11% of 381 healthy Japanese individuals carry this polymorphism. Reports of previous functional analyses indicate that the G643S polymorphism in the KCNQ1 potassium channel protein causes mild IKs channel dysfunction. Our present study suggests that administering psychotropic drug therapy to individuals carrying the G643S polymorphism may heighten the risk of prolonged QT intervals and life-threatening arrhythmias. Thus, screening for the G643S polymorphism before prescribing psychotropic drugs may help reduce the risk of unexpected sudden death2013博士（歯学）松本歯科大

A high-performance 8 nV/root Hz 8-channel wearable and wireless system for real-time monitoring of bioelectrical signals

Background: It is widely accepted by the scientific community that bioelectrical signals, which can be used for the identification of neurophysiological biomarkers indicative of a diseased or pathological state, could direct patient treatment towards more effective therapeutic strategies. However, the design and realisation of an instrument that can precisely record weak bioelectrical signals in the presence of strong interference stemming from a noisy clinical environment is one of the most difficult challenges associated with the strategy of monitoring bioelectrical signals for diagnostic purposes. Moreover, since patients often have to cope with the problem of limited mobility being connected to bulky and mains-powered instruments, there is a growing demand for small-sized, high-performance and ambulatory biopotential acquisition systems in the Intensive Care Unit (ICU) and in High-dependency wards. Finally, to the best of our knowledge, there are no commercial, small, battery-powered, wearable and wireless recording-only instruments that claim the capability of recording electrocorticographic (ECoG) signals. Methods: To address this problem, we designed and developed a low-noise (8 nV/√Hz), eight-channel, battery-powered, wearable and wireless instrument (55 × 80 mm2). The performance of the realised instrument was assessed by conducting both ex vivo and in vivo experiments. Results: To provide ex vivo proof-of-function, a wide variety of high-quality bioelectrical signal recordings are reported, including electroencephalographic (EEG), electromyographic (EMG), electrocardiographic (ECG), acceleration signals, and muscle fasciculations. Low-noise in vivo recordings of weak local field potentials (LFPs), which were wirelessly acquired in real time using segmented deep brain stimulation (DBS) electrodes implanted in the thalamus of a non-human primate, are also presented. Conclusions: The combination of desirable features and capabilities of this instrument, namely its small size (~one business card), its enhanced recording capabilities, its increased processing capabilities, its manufacturability (since it was designed using discrete off-the-shelf components), the wide bandwidth it offers (0.5 – 500 Hz) and the plurality of bioelectrical signals it can precisely record, render it a versatile and reliable tool to be utilized in a wide range of applications and environments

Pt(Iv)Ac-POA: New Platinum Compound Induced Caspase Independent Apoptosis In B50 Neuroblastoma Stem Cells

Neuroblastoma is a tumour that affects adults and children, characterized by a stem cells component. To date, cisplatin is the main antitumor agent used in the clinical treatment of this tumour; however, it induces side effects such as neurotoxicity in healthy cells and induces chemo resistance to therapy in cancer cells. New platinum-based compounds, platinum (II) have recently been synthesized, and due to their chemical characteristics, they are able to identify new cellular targets. These complexes act as prodrugs and performing their cytotoxic effect as platinum (II) after a reduction reaction within the hypoxic tumour cells. Among these prodrugs, Pt(IV)Ac-POA appears to be very promising, thanks to the presence of ligand (2 propinyl)octanoic acid (POA), which acts as an inhibitor of histone deacetylase (HDACi) and leads to the increase of histone acetylation, decreasing the interactions between histone and DNA, so as to produce chemo-sensitization to DNA-damaging agents. The greater cytotoxic effect of Pt(IV)Ac-POA on tumour cells, would therefore be mainly due to the mechanism of inhibition of histone deacetylase, which would increase the accessibility of DNA to platination mechanisms that induce cell death. In this study the results show that Pt(IV)Ac-POA, used at a concentration ten times lower than cisplatin, can induce apoptosis in B50 cells in culture both through the intrinsic pathway and through the independent caspase pathway. The data, obtained by immunohistochemical techniques in fluorescence microscopy, show that treatment with Pt(IV)Ac-POA has a greater proapoptotic effect on stem cells compared to the cisplatin standard treatment

Hericium erinaceus in Neurodegenerative Diseases: From Bench to Bedside and Beyond, How Far from the Shoreline?

A growing number of studies is focusing on the pharmacology and feasibility of bioactive compounds as a novel valuable approach to target a variety of human diseases related to neurological degeneration. Among the group of the so-called medicinal mushrooms (MMs), Hericium erinaceus has become one of the most promising candidates. In fact, some of the bioactive compounds extracted from H. erinaceus have been shown to recover, or at least ameliorate, a wide range of pathological brain conditions such as Alzheimer’s disease, depression, Parkinson’s disease, and spinal cord injury. In a large body of in vitro and in vivo preclinical studies on the central nervous system (CNS), the effects of erinacines have been correlated with a significant increase in the production of neurotrophic factors. Despite the promising outcome of preclinical investigations, only a limited number of clinical trials have been carried out so far in different neurological conditions. In this survey, we summarized the current state of knowledge on H. erinaceus dietary supplementation and its therapeutic potential in clinical settings. The bulk collected evidence underlies the urgent need to carry out further/wider clinical trials to prove the safety and efficacy of H. erinaceus supplementation, offering significant neuroprotective applications in brain pathologies

New platinum-based prodrug Pt(IV)Ac-POA: antitumour effects in Rat C6 Glioblastoma cells

Gliomas are the most frequent primary tumours of the nervous system, characterised by high degree of malignancy, widespread invasion and high-rate proliferation. Cisplatin and analogue are currently employed in clinical trials as active chemotherapeutic agents for the systemic treatment of this type of malignancy. Despite therapy benefits, clinical use of these agents is hampered by severe side effects including neurotoxicity. Therefore, the aim of the present study was to analyse the effect of a new compound of platinum(IV) conjugate, named Pt(IV)Ac-POA, which can generate a synergistic antineoplastic action when released along with cisplatin, after a specific reduction reaction within tumour cells. To assess the effects of the novel compound on rat C6 glioma cells, cell cycle and cell death activation analyses were carried out using flow cytometry. Morphological changes and activation of different cell death pathways were evaluated by both transmission electron microscopy and immunofluorescence microscopy. Protein expression was investigated by western blotting analysis. The novel compound Pt(IV)Ac-POA, bearing as axial ligand (2-propynyl)octanoic acid (POA), which is a histone deacetylase inhibitor (HDACi), acts as a prodrug in tumour cells, inducing cell death through different pathways at a concentration lower than those tested for other platinum analogues. The current results showed that Pt(IV)Ac-POA could represent a promising improvement of Pt-based chemotherapy against gliomas, either inducing a chemosensitisation and reducing chemoresistance

A step towards non-invasive characterization of the human frontal eye fields of individual subjects

Background: Identifying eye movement related areas in the frontal lobe has a long history, with microstimulation in monkeys producing the most clear-cut results. For humans, however, there is still no consensus about the location and the extent of the frontal eye field (FEF). There is also no simple non-invasive method for unambiguously defining the FEF in individual subjects, a prerequisite for clinical applications. Here we explore the use of magnetoencephalography (MEG) for the non-invasive identification and characterization of FEF activity in an individual subject.Methods: We mapped human brain activity before, during and after saccades by applying tomographic analysis to MEG data. Statistical parametric maps and circular statistics produced plausible FEF loci, but no unambiguous definition for individual subjects. Here we first computed the spectral decomposition and correlation with electrooculogram (EOG) of the tomographic brain activations. For each of these two measures statistical comparisons were made between different saccades.Results: In this paper, we first review the frontal cortex activations identified in earlier animal and human studies and place the putative human FEFs in a well-defined anatomical framework. This framework is then used as reference for describing the results of new Fourier analysis of the tomographic solutions comparing active saccade tasks and their controls. The most consistent change in the dorsal frontal cortex was at the putative left FEF, for both saccades to the left and right. The asymmetric result is consistent with the 1-way callosal traffic theory. We also showed that the new correlation analysis had its most consistent change in the contralateral putative FEF. This result was obtained for EOG latencies before saccade onset with delays of a few hundreds of milliseconds (FEF activity leading the EOG) and only for visual cues signaling the execution of a saccade in a previously defined saccade direction.Conclusions: The FEF definition derived from microstimulation describes only one of the areas in the dorsal lateral frontal lobe that act together to plan, prepare and execute a saccade. The definition and characterization of these areas in an individual subject can be obtained from non-invasive MEG measurements.<br/

Incidence and Long-term Functional Outcome of Neurologic Disorders in Hospitalized Patients With COVID-19 Infected With Pre-Omicron Variants

Background and ObjectivesA variety of neurologic disorders have been reported as presentations or complications of coronavirus disease 2019 (COVID-19) infection. The objective of this study was to determine their incidence dynamics and long-term functional outcome.MethodsThe Neuro-COVID Italy study was a multicenter, observational, cohort study with ambispective recruitment and prospective follow-up. Consecutive hospitalized patients presenting new neurologic disorders associated with COVID-19 infection (neuro-COVID), independently from respiratory severity, were systematically screened and actively recruited by neurology specialists in 38 centers in Italy and the Republic of San Marino. The primary outcomes were incidence of neuro-COVID cases during the first 70 weeks of the pandemic (March 2020-June 2021) and long-term functional outcome at 6 months, categorized as full recovery, mild symptoms, disabling symptoms, or death.ResultsAmong 52,759 hospitalized patients with COVID-19, 1,865 patients presenting 2,881 new neurologic disorders associated with COVID-19 infection (neuro-COVID) were recruited. The incidence of neuro-COVID cases significantly declined over time, comparing the first 3 pandemic waves (8.4%, 95% CI 7.9-8.9; 5.0%, 95% CI 4.7-5.3; 3.3%, 95% CI 3.0-3.6, respectively; p = 0.027). The most frequent neurologic disorders were acute encephalopathy (25.2%), hyposmia-hypogeusia (20.2%), acute ischemic stroke (18.4%), and cognitive impairment (13.7%). The onset of neurologic disorders was more common in the prodromic phase (44.3%) or during the acute respiratory illness (40.9%), except for cognitive impairment whose onset prevailed during recovery (48.4%). A good functional outcome was achieved by most patients with neuro-COVID (64.6%) during follow-up (median 6.7 months), and the proportion of good outcome increased throughout the study period (r = 0.29, 95% CI 0.05-0.50; p = 0.019). Mild residual symptoms were frequently reported (28.1%) while disabling symptoms were common only in stroke survivors (47.6%).DiscussionIncidence of COVID-associated neurologic disorders decreased during the prevaccination phase of the pandemic. Long-term functional outcome was favorable in most neuro-COVID disorders, although mild symptoms commonly lasted more than 6 months after infection