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Abstract Tumor necrosis factor (TNF) is a pleiotropic cytokine regulating many physiological and pathological immune-mediated processes. Specifically, it has been recognized as an essential pro-inflammatory cytokine implicated in multiple sclerosis (MS) pathogenesis and progression. MS is a chronic immune-mediated disease of the central nervous system, characterized by multifocal acute and chronic inflammatory demyelination in white and grey matter, along with neuroaxonal loss. A recent concept in the field of MS research is disability resulting from Progression Independent of Relapse Activity (PIRA). PIRA recognizes that disability accumulation since the early phase of the disease can occur independently of relapse activity overcoming the traditional dualistic view of MS as either a relapsing-inflammatory or a progressive-neurodegenerative disease. Several studies have demonstrated an upregulation in TNF expression in both acute and chronic active MS brain lesions. Additionally, elevated TNF levels have been observed in the serum and cerebrospinal fluid of MS patients. TNF appears to play a significant role in maintaining chronic intrathecal inflammation, promoting axonal damage neurodegeneration, and consequently contributing to disease progression and disability accumulation. In summary, this review highlights the current understanding of TNF and its receptors in MS progression, specifically focusing on the relatively unexplored PIRA condition. Further research in this area holds promise for potential therapeutic interventions targeting TNF to mitigate disability in MS patients.

Objetivos: O objetivo deste trabalho é descrever o perfil epidemiológico dos pacientes diagnosticados com Doença de Hodgkin (DH), no estado do Rio de Janeiro nos últimos 10 anos. Dados de base populacional são relevantes para entendimento do perfil epidemiológico dessas doenças, para elaboração de intervenções de saúde direcionadas. Material e métodos: Estudo ecológico, realizado em maio de 2024, utilizando dados públicos referentes aos diagnósticos de DH no estado do Rio de Janeiro, por local de residência, entre os anos de 2014 a 2023. Os dados públicos foram obtidos do Painel de Oncologia Brasil do Sistema Único de Saúde (SUS), e as variáveis selecionadas foram: sexo, faixa etária, ano do diagnóstico, residência no estado do Rio de Janeiro, e casos. Não foi necessária a submissão ao Comite de Ética e Pesquisa pois são dados de acesso público. O programa Microsoft Excel foi utilizado para tabulação dos dados e cálculos realizados. Resultados: : Ao todo foram 1367 casos diagnosticados de DH no estado do Rio de Janeiro entre os anos de 2014 a 2023. De 2014 a 2023, foram registrados, respectivamente: 112 (8,2%), 124 (9,1%), 138 (10,1%), 160 (11,7%), 140 (10,2%), 145 (10,6%), 137 (10,0%), 159 (11,6%), 129 (9,4%), 123 (9,0%), casos no estado do Rio de Janeiro, sendo 2017 e 2021 os anos com maior número de casos registrados. Quanto ao sexo, 721 (52,7%) dos casos foram no sexo masculino, e 646 (47,3%) no sexo feminino. Quanto a faixa etária, a com maior número de casos foi a de 0 a 19 anos, e a com menor número foi a de 80 anos ou mais. A faixa etária com mais casos no sexo masculino foi a de 0 a 19 anos (18,2%), e no sexo feminino foi entre 25 a 29 anos (16,9%). Discussão: A DH é um tipo de linfoma maligno que se origina nas células do sistema linfático, caracterizada pela presença de células anormais chamadas células de Reed-Sternberg, e representa aproximadamente 0,5% de todos os casos de câncer. Segundo a literatura, sua incidência é ligeiramente maior em homens do que em mulheres, corroborando com os resultados encontrados neste trabalho. Quanto à faixa etária, a literatura descreve dois picos de incidência: o primeiro na adolescência e no início da idade adulta (entre 15 e 35 anos), e o segundo em pessoas com mais de 55 anos. Os dados deste estudo corroboram com o descrito, com 51,2% dos diagnósticos em pessoas entre 15 e 35 anos, com queda no número de casos com o avançar da faixa etária, com um novo aumento entre 50 a 54 anos, e nova queda até 80 anos ou mais. Cabe ressaltar que o Painel de Oncologia Brasil do SUS não dispõe nos registros dados referentes ao tipo de DH, estadiamento, e às comorbidades e outros dados referentes aos pacientes. Conclusão: Observou-se que a maioria dos casos diagnosticados de DH foram no sexo masculino, e na faixa etária de 15 a 35 anos, com um novo aumento entre 50 a 54 anos. Os dados encontrados corroboram com a literatura, e reforçam a necessidade de estratégias de saúde pública direcionadas para perfil epidemiológico mais acometido pela DH no estado do Rio de Janeiro. Trabalhos com outros desenhos de estudo são necessários para uma avaliação mais detalhada acerca do perfil epidemiológico da DH, levando em conta o tipo de DH, visto que cada tipo possui características distintas.

Objetivos: Descrever o perfil epidemiológico dos pacientes diagnosticados com síndromes mielodisplásicas (SMD) na região Sudeste do Brasil nos últimos 10 anos. Material e métodos: Estudo ecológico realizado em maio de 2024 utilizando dados públicos referentes aos diagnósticos de SMD na região Sudeste do Brasil, por local de residência, entre os anos de 2014 a 2023. Os dados públicos foram obtidos do Painel de Oncologia Brasil e as variáveis selecionadas foram: sexo, faixa etária, ano do diagnóstico, e residência na região Sudeste. Não foi necessária a submissão ao Comite de Ética e Pesquisa pois são dados de acesso público, relevantes para entendimento do perfil epidemiológico de doenças e elaboração de intervenções de saúde direcionadas. O programa Microsoft Excel foi utilizado para tabulação dos dados e cálculos realizados. Resultados: Foram diagnosticados 4.095 casos de SMD entre 2014 e 2023 na região Sudeste do Brasil, com aumento importante no número de casos diagnosticados a partir de 2019 em relação aos anos anteriores. De 2014 a 2023 foram registrados, respectivamente: 237 (5,8%), 208 (5,1%), 226 (5,5%), 242 (5,9%), 354 (8,6%), 612 (14,9%), 496 (12,1%), 491 (12,0%), 574 (14,0%), 655 (16,0%) casos na região Sudeste, sendo 2023 os ano com maior número. Quanto ao sexo, 48,9% dos casos foram no sexo masculino e 51,1% no feminino. A faixa etária com mais casos em ambos os sexos foi a de 80 anos ou mais (15,6%). Discussão: As SMD são um grupo heterogêneo de neoplasias hematológicas caracterizadas por uma displasia das células hematopoiéticas na medula óssea, levando a uma produção inadequada e disfuncional das células sanguíneas. Segundo a literatura, as SMD são ligeiramente mais comuns em homens do que em mulheres, diferentemente dos resultados encontrados neste estudo, no qual o predomínio entre os sexos variou ao longo dos anos, porém, no total dos anos estudados, a maioria dos casos foi no sexo feminino. Também é descrito que a taxa de incidência tende a aumentar com a idade, sendo significativamente mais alta em populações acima de 60 anos, corroborando os dados encontrados neste trabalho, no qual as faixas etárias com maior número de casos foi de 80 anos ou mais, seguida de 70 a 74 anos. Cabe ressaltar que o Painel de Oncologia Brasil não dispõe nos registros dados referentes à classificação das SMD e às comorbidades e outros dados referentes aos pacientes. Conclusão: Observou-se um aumento importante nos diagnósticos de SMD no Brasil nos últimos anos, principalmente a partir de 2019. Uma hipótese para esse aumento é a melhora das técnicas diagnósticas nesta área, sendo possível diagnosticar casos que anteriormente ficavam sem diagnóstico claro, associada ao aumento da expectativa de vida da população – já que é uma doença que acomete indivíduos mais velhos. Em relação ao sexo, a maioria dos casos foram no sexo feminino, diferente do descrito pela literatura. Já quanto à faixa etária, foi predominante em pacientes com 80 anos ou mais, o que corrobora com os dados da literatura. Esses dados reforçam a necessidade de estratégias de saúde pública direcionadas para perfil epidemiológico mais acometido pelas SMD no Brasil. Trabalhos com outros desenhos de estudo são necessários para uma avaliação mais detalhada acerca do perfil epidemiológico das SMD levando em conta sua classificação, visto que cada tipo possui características distintas.

Climate change, driven by elevated atmospheric CO2 levels, is recognized as a persistent and significant issue of the 21st century. Consequently, the creation of effective and suitable methods to decrease atmospheric CO2 emissions is urgently and critically needed. Various techniques, including membrane separation, chemical absorption, and adsorption, are currently employed to capture CO2. In particular, processes based on physisorption are noted for their energy efficiency and cost-effectiveness, making the choice of an effective adsorbent essential. Metal-organic frameworks (MOFs), which are porous structures formed from metal ions and organic linkers, have emerged as promising and adaptable solutions for advanced CO2 capture initiatives. These materials hold potential for application across a broad spectrum of domains, including gas adsorption and separation, catalysis, electron luminescence, magnetism, as well as in drug delivery and the health sciences. So far, MOFs have mainly been developed as promising materials for CO2 adsorption due to their large capacity for adsorption of gases and easy tailor ability of their structures, and metal sites. In this study, the fabrication of specific devise for controlling environmental remediation of CO2 through CCS techniques has been described also highlighting their potential utility for CO2 adsorption purposes. First of all, the synthesis of HKUST-1, a solid belonging to the class of copper-based MOF has been described and in particular ([Cu3(btc)2(H2O)3]-H2O), directly deposited on ceramic foam. A characterisation of the samples obtained under different synthetic conditions through X ray analysis, thermogravimetric analysis, porosimetry and electron scanning microscopy (SEM) has been shown. Ultimately, the degree of MOF coating on the supports was assessed, and their ability to adsorb CO2 was examined through experimental trials that tested the capture process under precise temperature and pressure conditions using a 10 mol% mixture of air and CO2. A fixed bed system, structured with coated foams, exhibited a CO2 capture capability of 0.40 mmol/gMOF, minimal pressure drops, and low temperatures for reactivation, all critical requirements for industrial applications.

Abstract Background Spinal Muscular Atrophy (SMA) is an autosomal-recessive neuromuscular disease affecting children. It is caused by the mutation or deletion of the survival motor neuron 1 (SMN1) gene resulting in lower motor neuron (MN) degeneration followed by motor impairment, progressive skeletal muscle paralysis and respiratory failure. In addition to the already existing therapies, a possible combinatorial strategy could be represented by the use of adipose-derived mesenchymal stem cells (ASCs) that can be obtained easily and in large amounts from adipose tissue. Their efficacy seems to be correlated to their paracrine activity and the production of soluble factors released through extracellular vesicles (EVs). EVs are important mediators of intercellular communication with a diameter between 30 and 100 nm. Their use in other neurodegenerative disorders showed a neuroprotective effect thanks to the release of their content, especially proteins, miRNAs and mRNAs. Methods In this study, we evaluated the effect of EVs isolated from ASCs (ASC-EVs) in the SMNΔ7 mice, a severe SMA model. With this purpose, we performed two administrations of ASC-EVs (0.5 µg) in SMA pups via intracerebroventricular injections at post-natal day 3 (P3) and P6. We then assessed the treatment efficacy by behavioural test from P2 to P10 and histological analyses at P10. Results The results showed positive effects of ASC-EVs on the disease progression, with improved motor performance and a significant delay in spinal MN degeneration of treated animals. ASC-EVs could also reduce the apoptotic activation (cleaved Caspase-3) and modulate the neuroinflammation with an observed decreased glial activation in lumbar spinal cord, while at peripheral level ASC-EVs could only partially limit the muscular atrophy and fiber denervation. Conclusions Our results could encourage the use of ASC-EVs as a therapeutic combinatorial treatment for SMA, bypassing the controversial use of stem cells.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving motor neuron (MN) loss in the motor cortex, brainstem and spinal cord leading to progressive paralysis and death. Due to the pathogenetic complexity, there are no effective therapies available. In this context the use of mesenchymal stem cells and their vesicular counterpart is an emerging therapeutic strategy to counteract neurodegeneration. The extracellular vesicles derived from adipose stem cells (ASC-EVs) recapitulate and ameliorate the neuroprotective effect of stem cells and, thanks to their small dimensions, makes their use suitable to develop novel therapeutic approaches for neurodegenerative diseases as ALS. Here we investigate a therapeutic regimen of ASC-EVs injection in SOD1(G93A) mice, the most widely used murine model of ALS. Repeated intranasal administrations of high doses of ASC-EVs were able to ameliorate motor performance of injected SOD1(G93A) mice at the early stage of the disease and produce a significant improvement at the end-stage in the lumbar MNs rescue. Moreover, ASC-EVs preserve the structure of neuromuscular junction without counteracting the muscle atrophy. The results indicate that the intranasal ASC-EVs administration acts in central nervous system sites rather than at peripheral level in SOD1(G93A) mice. These considerations allow us to identify future applications of ASC-EVs that involve different targets simultaneously to maximize the clinical and neuropathological outcomes in ALS in vivo models.

Activated cell-mediated immunity, as defined by four markers, has been studied in HIV-infected patients, and compared with the clinical stages of HIV infection. All the values obtained with such markers (interferon-y expressed on lymphocytes, soluble CD8, soluble IL-2 receptor, and serum neopterin) were observed to increase with the progressive stages of HIV infection, with the highest figures occurring in stage IV-C patients. Since the replication of HIV depend strictly on the stimulation of infected cells, T-cell activation in vitro might contribute to a further spread of HIV-1 in infected subjects. Thus permanent or multiple stimulation of the cellular immune system could be an important cofactor in the progression of this syndrome.

ObjectiveThe objective of this multicenter, observational, retrospective analysis was to evaluate the safety and efficacy of sacituzumab govitecan in metastatic triple-negative breast cancer (mTNBC) patients managed according to common clinical practice in Italy.MethodsData were retrieved by 7 sites. Triple-negative BC was defined by the lack of expression of estrogen receptor (ER

BackgroundCladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed.AimTo estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine.MethodsForty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The ‘no evidence of disease activity’ (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs.ResultsThree patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91).ConclusionsCSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug’s effect on chronic macrophage and microglia activation deserves further evaluation.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons (MNs) in the brain and spinal cord, leading to progressive paralysis and death. Increasing evidence indicates that neuroinflammation plays an important role in ALS’s pathogenesis and disease progression. Neuroinflammatory responses, primarily driven by activated microglia and astrocytes, and followed by infiltrating peripheral immune cells, contribute to exacerbate/accelerate MN death. In particular, the role of the microglia in ALS remains unclear, partly due to the lack of experimental models that can fully recapitulate the complexity of ALS’s pathology. In this study, we developed and characterized a microglial cell line, SIM-A9-expressing human mutant protein Cu+/Zn+ superoxide dismutase_1 (SIM-A9hSOD1(G93A)), as a suitable model in vitro mimicking the microglia activity in ALS. The expression of hSOD1(G93A) in SIM-A9 cells induced a change in their metabolic activity, causing polarization into a pro-inflammatory phenotype and enhancing reactive oxygen species production, which is known to activate cell death processes and apoptosis. Afterward, we used our microglial model as an experimental set-up to investigate the therapeutic action of extracellular vesicles isolated from adipose mesenchymal stem cells (ASC-EVs). ASC-EVs represent a promising therapeutic treatment for ALS due to their neuroprotective and immunomodulatory properties. Here, we demonstrated that treatment with ASC-EVs is able to modulate activated ALS microglia, reducing their metabolic activity and polarizing their phenotype toward an anti-inflammatory one through a mechanism of reduction of reactive oxygen species.

Background. As artificial intelligence is expanding its applications in medicine, metabolic imaging is gaining the ability to retrieve data otherwise missed by even an experienced naked eye. Also, new radiopharmaceuticals and peptides aim to increase the specificity of positron emission tomography (PET) scans. Herein, a preliminary experience is reported regarding searching for a texture signature in routinely performed [F18]Fluciclovine imaging in prostate cancer. Materials and methods. Twenty-nine patients who underwent a PET/computed tomography (CT) scan with [18F]Fluciclovine because of biochemical prostate cancer relapse were retrospectively enrolled. First- and second-order radiomic features were manually extracted in lesions visually considered pathologic from the Local Image Features Extraction (LIFEx) platform. Statistical analysis was performed on a database of 29 lesions, one1 per patient. The dataset was split to have 20 lesions for the model training set and 9 lesions for the validation set. The Wilcoxon–Mann–Whitney test was used on the training set to select the most significant features (p-value < 0.05) predicting the dichotomous outcome in a univariate analysis. Results. The best model for predicting the outcome was found to be a multiple logistic linear regression model with two features as variables: an intensity histogram type and a gray-level size zone-based type. Conclusions. Texture analysis of [F18]Fluciclovine PET scans helps in defining prostate cancer relapse in a daily clinical setting.

In this paper, I explore the properties and the uses of the past participles in the Arbëresh variety of S. Nicola dell’Alto, an Albanian dialect still spoken in Southern Italy, which has been in contact with Italo-Romance varieties for more than five centuries. The data are discussed in comparison to standard Albanian and the contact language, Italian. In Albanian grammar, there is only one type of participle: the past participle. It has both verbal and adjectival properties. As a verbal form, the participle is used in compound and in periphrastic tenses, in combination with both the auxiliaries KAM ‘have’ and JAM ‘be’. It can also be used in combination with other particles to create non-finite verbal forms such as gerund or infinitive or to build up temporal expressions. Finally, it can also be used after some modal impersonal verbs. Verbal participles never show agreement. Albanian participles can also be adjectival. All the adjectives derived by a participial verb take a linking article and always agree with the noun they modify in gender, number, Case and definiteness. The formal distinction of the verbal participles from adjectival participles seems to correlate with the aspectual properties of the construction: a verbal participle appears in eventive structures, whereas an adjectival participle occurs in stative structures. But, as we shall see, this is not always the case. Arbëresh participles have maintained the same morphological and syntactical properties of Albanian. They can be used both in stative and in eventive contexts, but in Arbëresh eventive passives, which are built up as in Italian rather than as in Albanian, the adjectival participles are always inflected. Agreement is obligatory in all the contexts where it is in Italian. This is a clear contact-induced change. The data presented in this paper show that Arbëresh, on the one hand, preserves features of Albanian grammar, whereas, on the other hand, it has undergone changes under the influence of the surrounding Italo-Romance varieties.

Superior mesenteric artery (SMA) and superior mesenteric vein (SMV) thrombotic occlusion is a rare but potentially fatal condition. Though isolated mesenteric arterial occlusion associated with COVID-19 has been reported in literature, combined superior mesenteric arterial and venous thrombosis is very rare. We report the case of an 88-years-old woman with a combined superior mesenteric arterial and venous thrombotic occlusion with a previous COVID-19 pneumonia of about 15 days before, diagnosed at computed tomography angiography (CTA) scan. CTA had an important key-role for the diagnosis and evaluation of the severity of the mesenteric venous and arterious thrombosis.

Acute Aortic Dissection (AAD) is one of the most common lifethreatening diseases that affects the aortic vessel. An its immediate and accurate diagnosis is crucial to initiate the appropriate treatment.The Covid-19 Coronavirus infectious pandemic started since December 2019 and was declared a pandemic by the World Health Organization in March 2020. It caused mainly bilateral interstitial pneumonia, up to causing a severe respiratory failure for the patients, and other complications.Now, we describe the case of a young man that was admitted to our hospital and was found positive for the Coronavirus disease 2019 (Covid-19). While we were performing Computed Tomography (CT) scan of the chest, we had suspected the concomitant presence of an aortic dissection, which was then immediately confirmed by Computed Tomography Angiography (CTA) study, that we had performed to complete the baseline CT scan.

Aurothiomalate (AuTM) is an FDA‐approved antiarthritic gold drug with unique anticancer properties. To enhance its anticancer activity, we prepared a bioconjugate with human apoferritin (HuHf) by attaching some AuTM moieties to surface protein residues. The reaction of apoferritin with excess AuTM yielded a single adduct, that was characterized by ESI MS and ICP‐OES analysis, using three mutant ferritins and trypsinization experiments. The adduct contains ~3 gold atoms per ferritin subunit, arranged in a small cluster bound to Cys90 and Cys102. MD simulations provided a plausible structural model for the cluster. The adduct was evaluated for its pharmacological properties and was found to be significantly more cytotoxic than free AuTM against A2780 cancer cells mainly due to higher gold uptake. NMR‐metabolomics showed that AuTM bound to HuHf and free AuTM induced qualitatively similar changes in treated cancer cells, indicating that the effects on cell metabolism are approximately the same, in agreement with independent biochemical experiments. In conclusion, we have demonstrated here that a molecularly precise bioconjugate formed between AuTM and HuHf exhibits anticancer properties far superior to the free drug, while retaining its key mechanistic features. Evidence is provided that human ferritin can serve as an excellent carrier for this metallodrug. [ABSTRACT FROM AUTHOR]

Abstract Parkinson’s disease (PD) is the neurological disorder showing the greatest rise in prevalence from 1990 to 2016. Despite clinical definition criteria and a tremendous effort to develop objective biomarkers, precise diagnosis of PD is still unavailable at early stage. In recent years, an increasing number of studies have used omic methods to unveil the molecular basis of PD, providing a detailed characterization of potentially pathological alterations in various biological specimens. Metabolomics could provide useful insights to deepen our knowledge of PD aetiopathogenesis, to identify signatures that distinguish groups of patients and uncover responsive biomarkers of PD that may be significant in early detection and in tracking the disease progression and drug treatment efficacy. The present work is the first large metabolomic study based on nuclear magnetic resonance (NMR) with an independent validation cohort aiming at the serum characterization of de novo drug-naive PD patients. Here, NMR is applied to sera from large training and independent validation cohorts of German subjects. Multivariate and univariate approaches are used to infer metabolic differences that characterize the metabolite and the lipoprotein profiles of newly diagnosed de novo drug-naive PD patients also in relation to the biological sex of the subjects in the study, evidencing a more pronounced fingerprint of the pathology in male patients. The presence of a validation cohort allowed us to confirm altered levels of acetone and cholesterol in male PD patients. By comparing the metabolites and lipoproteins levels among de novo drug-naive PD patients, age- and sex-matched healthy controls, and a group of advanced PD patients, we detected several descriptors of stronger oxidative stress.