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BACKGROUND: Organoids are approved by the US FDA as an alternative to animal experiments to guide drug development and for sensitivity screening. Stable organoids models of gastric cancer are desirable for personalized medicine and drug screening. METHODS: Tumor tissues from a primary cancer of the stomach and metastatic cancer of the lymph node were collected for 3D culture. By long-term culture for over 50 generations in vitro, we obtained stably growing organoid lines. We analyzed short tandem repeats (STRs) and karyotypes of cancer cells, and tumorigenesis of the organoids in nude mice, as well as multi-omics profiles of the organoids. A CCK8 method was used to determine the drugs sensitivity to fluorouracil (5-Fu), platinum and paclitaxel. RESULTS: Paired organoid lines from primary cancer (SPDO1P) and metastatic lymph node (SPDO1LM) were established with unique STRs and karyotypes. The organoid lines resulted in tumorigenesis in vivo and had clear genetic profiles. Compared to SPDO1P from primary cancer, upregulated genes of SPDO1LM from the metastatic lymph node were enriched in pathways of epithelial-mesenchymal transition and angiogenesis with stronger abilities of cell migration, invasion, and pro-angiogenesis. Based on drug sensitivity analysis, the SOX regimen (5-Fu plus oxaliplatin) was used for chemotherapy with an optimal clinical outcome. CONCLUSIONS: The organoid lines recapitulate the drug sensitivity of the parental tissues. The paired organoid lines present a step-change toward living biobanks for further translational usage.
Assuntos
Metástase Linfática , Camundongos Nus , Organoides , Medicina de Precisão , Neoplasias Gástricas , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamento farmacológico , Organoides/efeitos dos fármacos , Organoides/patologia , Humanos , Animais , Metástase Linfática/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linhagem Celular Tumoral , Carcinogênese/patologia , Carcinogênese/genética , Carcinogênese/efeitos dos fármacos , Camundongos , Repetições de Microssatélites/genéticaRESUMO
For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling and antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there has been limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal senescence, brain volume loss, the attenuation of gamma oscillations in electroencephalograms, and the oxidation of lipids in the plasma and mitochondrial membranes. We surmise that the aberrant activation of the aryl hydrocarbon receptor by toxins derived from gut microbes or the environment drives premature cellular and neuronal senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including the impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: (1) to summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders, and (2) to discuss novel strategies for improving long-term outcomes in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor antagonists.
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Antipsicóticos , Esquizofrenia , Humanos , Antipsicóticos/uso terapêutico , Antipsicóticos/farmacologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Senescência Celular/efeitos dos fármacosRESUMO
Long COVID, also called post-acute sequelae of SARS-CoV-2, is characterized by a multitude of lingering symptoms, including impaired cognition, that can last for many months. This symptom, often called "brain fog", affects the life quality of numerous individuals, increasing medical complications as well as healthcare expenditures. The etiopathogenesis of SARS-CoV-2-induced cognitive deficit is unclear, but the most likely cause is chronic inflammation maintained by a viral remnant thriving in select body reservoirs. These viral sanctuaries are likely comprised of fused, senescent cells, including microglia and astrocytes, that the pathogen can convert into neurotoxic phenotypes. Moreover, as the enteric nervous system contains neurons and glia, the virus likely lingers in the gastrointestinal tract as well, accounting for the intestinal symptoms of long COVID. Fusogens are proteins that can overcome the repulsive forces between cell membranes, allowing the virus to coalesce with host cells and enter the cytoplasm. In the intracellular compartment, the pathogen hijacks the actin cytoskeleton, fusing host cells with each other and engendering pathological syncytia. Cell-cell fusion enables the virus to infect the healthy neighboring cells. We surmise that syncytia formation drives cognitive impairment by facilitating the "seeding" of hyperphosphorylated Tau, documented in COVID-19. In our previous work, we hypothesized that the SARS-CoV-2 virus induces premature endothelial senescence, increasing the permeability of the intestinal and blood-brain barrier. This enables the migration of gastrointestinal tract microbes and/or their components into the host circulation, eventually reaching the brain where they may induce cognitive dysfunction. For example, translocated lipopolysaccharides or microbial DNA can induce Tau hyperphosphorylation, likely accounting for memory problems. In this perspective article, we examine the pathogenetic mechanisms and potential biomarkers of long COVID, including microbial cell-free DNA, interleukin 22, and phosphorylated Tau, as well as the beneficial effect of transcutaneous vagal nerve stimulation.
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COVID-19 , Tauopatias , Humanos , Síndrome de COVID-19 Pós-Aguda , SARS-CoV-2 , EncéfaloRESUMO
Forensic institutions throughout the world house patients with severe psychiatric illness and history of criminal violations. Improved medical care, hygiene, psychiatric treatment, and nutrition led to an unmatched longevity in this population, which previously lived, on average, 15 to 20 years shorter than the public at large. On the other hand, longevity has contributed to increased prevalence of age-related diseases, including neurodegenerative disorders, which complicate clinical management, increasing healthcare expenditures. Forensic institutions, originally intended for the treatment of younger individuals, are ill-equipped for the growing number of older offenders. Moreover, as antipsychotic drugs became available in 1950s and 1960s, we are observing the first generation of forensic detainees who have aged on dopamine-blocking agents. Although the consequences of long-term treatment with these agents are unclear, schizophrenia-associated gray matter loss may contribute to the development of early dementia. Taken together, increased lifespan and the subsequent cognitive deficit observed in long-term forensic institutions raise questions and dilemmas unencountered by the previous generations of clinicians. These include: does the presence of neurocognitive dysfunction justify antipsychotic dose reduction or discontinuation despite a lifelong history of schizophrenia and violent behavior? Should neurolipidomic interventions become the standard of care in elderly individuals with lifelong schizophrenia and dementia? Can patients with schizophrenia and dementia meet the Dusky standard to stand trial? Should neurocognitive disorders in the elderly with lifelong schizophrenia be treated differently than age-related neurodegeneration? In this article, we hypothesize that gray matter loss is the core symptom of schizophrenia which leads to dementia. We hypothesize further that strategies to delay or stop gray matter depletion would not only improve the schizophrenia sustained recovery, but also avert the development of major neurocognitive disorders in people living with schizophrenia. Based on this hypothesis, we suggest utilization of both receptor-dependent and independent therapeutics for chronic psychosis.
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Antipsicóticos , Transtornos Cognitivos , Demência , Transtornos Psicóticos , Esquizofrenia , Idoso , Humanos , Esquizofrenia/complicações , Esquizofrenia/epidemiologia , Esquizofrenia/induzido quimicamente , Transtornos Psicóticos/tratamento farmacológico , Demência/complicações , Demência/epidemiologia , Transtornos Cognitivos/tratamento farmacológico , Antipsicóticos/uso terapêutico , ComorbidadeRESUMO
In sub-Saharan Africa (SSA), urgent action is needed to curb a growing crisis in cancer incidence and mortality. Without rapid interventions, data estimates show a major increase in cancer mortality from 520 348 in 2020 to about 1 million deaths per year by 2030. Here, we detail the state of cancer in SSA, recommend key actions on the basis of analysis, and highlight case studies and successful models that can be emulated, adapted, or improved across the region to reduce the growing cancer crises. Recommended actions begin with the need to develop or update national cancer control plans in each country. Plans must include childhood cancer plans, managing comorbidities such as HIV and malnutrition, a reliable and predictable supply of medication, and the provision of psychosocial, supportive, and palliative care. Plans should also engage traditional, complementary, and alternative medical practices employed by more than 80% of SSA populations and pathways to reduce missed diagnoses and late referrals. More substantial investment is needed in developing cancer registries and cancer diagnostics for core cancer tests. We show that investments in, and increased adoption of, some approaches used during the COVID-19 pandemic, such as hypofractionated radiotherapy and telehealth, can substantially increase access to cancer care in Africa, accelerate cancer prevention and control efforts, increase survival, and save billions of US dollars over the next decade. The involvement of African First Ladies in cancer prevention efforts represents one practical approach that should be amplified across SSA. Moreover, investments in workforce training are crucial to prevent millions of avoidable deaths by 2030. We present a framework that can be used to strategically plan cancer research enhancement in SSA, with investments in research that can produce a return on investment and help drive policy and effective collaborations. Expansion of universal health coverage to incorporate cancer into essential benefits packages is also vital. Implementation of the recommended actions in this Commission will be crucial for reducing the growing cancer crises in SSA and achieving political commitments to the UN Sustainable Development Goals to reduce premature mortality from non-communicable diseases by a third by 2030.
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COVID-19 , Neoplasias , Doenças não Transmissíveis , África Subsaariana/epidemiologia , COVID-19/epidemiologia , COVID-19/prevenção & controle , Criança , Atenção à Saúde , Humanos , Neoplasias/epidemiologia , Neoplasias/terapia , PandemiasRESUMO
Clinical microbiology is experiencing revolutionary advances in the deployment of molecular, genome sequencing-based, and mass spectrometry-driven detection, identification, and characterization assays. Laboratory automation and the linkage of information systems for big(ger) data management, including artificial intelligence (AI) approaches, also are being introduced. The initial optimism associated with these developments has now entered a more reality-driven phase of reflection on the significant challenges, complexities, and health care benefits posed by these innovations. With this in mind, the ongoing process of clinical laboratory consolidation, covering large geographical regions, represents an opportunity for the efficient and cost-effective introduction of new laboratory technologies and improvements in translational research and development. This will further define and generate the mandatory infrastructure used in validation and implementation of newer high-throughput diagnostic approaches. Effective, structured access to large numbers of well-documented biobanked biological materials from networked laboratories will release countless opportunities for clinical and scientific infectious disease research and will generate positive health care impacts. We describe why consolidation of clinical microbiology laboratories will generate quality benefits for many, if not most, aspects of the services separate institutions already provided individually. We also define the important role of innovative and large-scale diagnostic platforms. Such platforms lend themselves particularly well to computational (AI)-driven genomics and bioinformatics applications. These and other diagnostic innovations will allow for better infectious disease detection, surveillance, and prevention with novel translational research and optimized (diagnostic) product and service development opportunities as key results.
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Serviços de Laboratório Clínico/organização & administração , Técnicas de Laboratório Clínico/métodos , Doenças Transmissíveis/diagnóstico , Animais , Inteligência Artificial , Automação , HumanosRESUMO
Gaps in the translation of research findings to clinical management have been recognized for decades. They exist for the diagnosis as well as the management of cancer. The international standards for cancer diagnosis are contained within the World Health Organization (WHO) Classification of Tumours, published by the International Agency for Research on Cancer (IARC) and known worldwide as the WHO Blue Books. In addition to their relevance to individual patients, these volumes provide a valuable contribution to cancer research and surveillance, fulfilling an important role in scientific evidence synthesis and international standard setting. However, the multidimensional nature of cancer classification, the way in which the WHO Classification of Tumours is constructed, and the scientific information overload in the field pose important challenges for the translation of research findings to tumour classification and hence cancer diagnosis. To help address these challenges, we have established the International Collaboration for Cancer Classification and Research (IC3 R) to provide a forum for the coordination of efforts in evidence generation, standard setting and best practice recommendations in the field of tumour classification. The first IC3 R meeting, held in Lyon, France, in February 2019, gathered representatives of major institutions involved in tumour classification and related fields to identify and discuss translational challenges in data comparability, standard setting, quality management, evidence evaluation and copyright, as well as to develop a collaborative plan for addressing these challenges.
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Detecção Precoce de Câncer/normas , Neoplasias/classificação , Neoplasias/diagnóstico , Medicina Baseada em Evidências , França , Humanos , Cooperação Internacional , Guias de Prática Clínica como Assunto , Organização Mundial da SaúdeRESUMO
BACKGROUND: To date, the clinical characteristics of coronavirus disease 19 (COVID-19)-infected urologic cancer patients are unknown. METHODS: We have analyzed all patients with prostate cancer undergoing hormonal or chemotherapy treatment and receiving telephone and in person pre-triage between March 1 and 27, 2020, at the Tortora Hospital, Pagani, Italy. RESULTS: Among 72 patients, 48 and 24 were hormone-sensitive (HS) and castration-resistant prostate cancer (CRPC), respectively; 0 HS and 2 (8.3%) CRPC (p < 0.05) were positive for COVID-19. Both patients were receiving LHRH agonist therapy, and 1 patient was receiving enzalutamide. Urgent intensive care unit admission was required due to clinical worsening. Blood tests showed severe lymphopenia, anemia, and an increase in platelets. Retroviral therapy, antibiotics, heparin, and chloroquine were prescribed at the beginning. One patient also received tocilizumab as a salvage treatment. After 3 weeks of hospitalization, the patients were discharged from the hospital. Both patients suffered from an aggressive COVID-19 course due to concomitant comorbidities. CONCLUSIONS: Investigating whether hormonal therapy, especially in advanced disease, acts as a protective factor or a risk factor during COVID-19 could be useful.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Heparina/uso terapêutico , Pneumonia Viral/complicações , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , COVID-19 , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Progressão da Doença , Quimioterapia Combinada , Hospitalização , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Prognóstico , Neoplasias de Próstata Resistentes à Castração/secundário , Neoplasias de Próstata Resistentes à Castração/virologia , Fatores de Risco , SARS-CoV-2RESUMO
Traditional epidemiological investigation of nosocomial transmission of influenza involves the identification of patients who have the same influenza virus type and who have overlapped in time and place. This method may misidentify transmission where it has not occurred or miss transmission when it has. We used influenza virus whole-genome sequencing (WGS) to investigate an outbreak of influenza A virus infection in a hematology/oncology ward and identified 2 separate introductions, one of which resulted in 5 additional infections and 79 bed-days lost. Results from WGS are becoming rapidly available and may supplement traditional infection control procedures in the investigation and management of nosocomial outbreaks.
Assuntos
Infecção Hospitalar/virologia , Vírus da Influenza A/genética , Influenza Humana/virologia , Infecção Hospitalar/epidemiologia , Surtos de Doenças , Humanos , Controle de Infecções/métodos , Influenza Humana/epidemiologia , Epidemiologia Molecular/métodos , Sequenciamento Completo do Genoma/métodosRESUMO
Background: Norovirus places a substantial burden on healthcare systems, arising from infected patients, disease outbreaks, beds kept unoccupied for infection control, and staff absences due to infection. In settings with high rates of bed occupancy, opportunity costs arise from patients who cannot be admitted due to beds being unavailable. With several treatments and vaccines against norovirus in development, quantifying the expected economic burden is timely. Methods: The number of inpatients with norovirus-associated gastroenteritis in England was modeled using infectious and noninfectious gastrointestinal Hospital Episode Statistics codes and laboratory reports of gastrointestinal pathogens collected at Public Health England. The excess length of stay from norovirus was estimated with a multistate model and local outbreak data. Unoccupied bed-days and staff absences were estimated from national outbreak surveillance. The burden was valued conventionally using accounting expenditures and wages, which we contrasted to the opportunity costs from forgone patients using a novel methodology. Results: Between July 2013 and June 2016, 17.7% (95% confidence interval [CI], 15.6%â21.6%) of primary and 23.8% (95% CI, 20.6%â29.9%) of secondary gastrointestinal diagnoses were norovirus attributable. Annually, the estimated median 290000 (interquartile range, 282000â297000) occupied and unoccupied bed-days used for norovirus displaced 57800 patients. Conventional costs for the National Health Service reached £107.6 million; the economic burden approximated to £297.7 million and a loss of 6300 quality-adjusted life-years annually. Conclusions: In England, norovirus is now the second-largest contributor of the gastrointestinal hospital burden. With the projected impact being greater than previously estimated, improved capture of relevant opportunity costs seems imperative for diseases such as norovirus.
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Infecções por Caliciviridae/economia , Surtos de Doenças/economia , Gastroenterite/economia , Hospitalização/economia , Controle de Infecções/economia , Absenteísmo , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções por Caliciviridae/epidemiologia , Efeitos Psicossociais da Doença , Infecção Hospitalar/economia , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/virologia , Surtos de Doenças/prevenção & controle , Inglaterra/epidemiologia , Feminino , Gastroenterite/epidemiologia , Gastroenterite/virologia , Humanos , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Norovirus/isolamento & purificaçãoRESUMO
We report the molecular investigations of a large influenza A(H3N2) outbreak, in a season characterised by sharp increase in influenza admissions since December 2016. Analysis of haemagglutinin (HA) sequences demonstrated co-circulation of multiple clades (3C.3a, 3C.2a and 3C.2a1). Most variants fell into a novel subclade (proposed as 3C.2a2); they possessed four unique amino acid substitutions in the HA protein and loss of a potential glycosylation site. These changes potentially modify the H3N2 strain antigenicity.
Assuntos
Doenças Transmissíveis Emergentes/genética , Epidemias , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Hemaglutininas/genética , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Criança , Pré-Escolar , Doenças Transmissíveis Emergentes/epidemiologia , Feminino , Deriva Genética , Variação Genética , Glicosilação , Humanos , Lactente , Recém-Nascido , Vírus da Influenza A Subtipo H3N2/classificação , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Influenza Humana/diagnóstico , Influenza Humana/virologia , Londres/epidemiologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Filogenia , RNA Viral/genética , RNA Viral/isolamento & purificação , Análise de Sequência de DNA , Adulto JovemRESUMO
Background: Indonesia has rapidly embraced digital health, particularly during the COVID-19 pandemic, with over 15 million daily health application users. To advance its digital health vision, the government is prioritizing the development of health data and application systems into an integrated health care technology ecosystem. This initiative involves all levels of health care, from primary to tertiary, across all provinces. In particular, it aims to enhance primary health care services (as the main interface with the general population) and contribute to Indonesia's digital health transformation. Objective: This study assesses the information and communication technology (ICT) maturity in Indonesian health care services to advance digital health initiatives. ICT maturity assessment tools, specifically designed for middle-income countries, were used to evaluate digital health capabilities in 9 provinces across 5 Indonesian islands. Methods: A cross-sectional survey was conducted from February to March 2022, in 9 provinces across Indonesia, representing the country's diverse conditions on its major islands. Respondents included staff from public health centers (Puskesmas), primary care clinics (Klinik Pratama), and district health offices (Dinas Kesehatan Kabupaten/Kota). The survey used adapted ICT maturity assessment questionnaires, covering human resources, software and system, hardware, and infrastructure. It was administered electronically and involved 121 public health centers, 49 primary care clinics, and 67 IT staff from district health offices. Focus group discussions were held to delve deeper into the assessment results and gain more descriptive insights. Results: In this study, 237 participants represented 3 distinct categories: 121 public health centers, 67 district health offices, and 49 primary clinics. These instances were selected from a sample of 9 of the 34 provinces in Indonesia. Collected data from interviews and focus group discussions were transformed into scores on a scale of 1 to 5, with 1 indicating low ICT readiness and 5 indicating high ICT readiness. On average, the breakdown of ICT maturity scores was as follows: 2.71 for human resources' capability in ICT use and system management, 2.83 for software and information systems, 2.59 for hardware, and 2.84 for infrastructure, resulting in an overall average score of 2.74. According to the ICT maturity level pyramid, the ICT maturity of health care providers in Indonesia fell between the basic and good levels. The need to pursue best practices also emerged strongly. Further analysis of the ICT maturity scores, when examined by province, revealed regional variations. Conclusions: The maturity of ICT use is influenced by several critical components. Enhancing human resources, ensuring infrastructure, the availability of supportive hardware, and optimizing information systems are imperative to attain ICT maturity in health care services. In the context of ICT maturity assessment, significant score variations were observed across health care levels in the 9 provinces, underscoring the diversity in ICT readiness and the need for regionally customized follow-up actions.
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Bacterial antimicrobial resistance (AMR) poses a significant global public health challenge. The escalation of AMR is primarily attributed to the horizontal gene transfer (HGT) of antibiotic resistance genes (ARGs), often facilitated by plasmids. This underscores the critical need for a comprehensive understanding of the resistance mechanisms and transmission dynamics of these plasmids. In this study, we utilized in vitro drug sensitivity testing, conjugation transfer assays, and whole-genome sequencing to investigate the resistance mechanism of an extensively drug-resistant (XDR) Pseudomonas aeruginosa clinical isolate, MAS152. We specifically focused on analyzing the drug-resistant plasmid pMAS152 it harbors and its potential for widespread dissemination. Bioinformatics analysis revealed that MAS152 carries a distinct IncpP-2A plasmid, pMAS152, characterized by a 44.8 kb multidrug resistance (MDR) region. This region houses a 16S rRNA methyltransferase (16S-RMTase) gene, rmtB, conferring high-level resistance to aminoglycoside antibiotics. Notably, this region also contains an extended-spectrum ß-Lactamase (ESBL) gene, blaPER-1, and an efflux pump operon, tmexCD-oprJ, which mediate resistance to ß-Lactams and quinolone antibiotics, respectively. Such a combination of ARGs, unprecedented in reported plasmids, could significantly undermine the effectiveness of first-line antibiotics in treating P. aeruginosa infections. Investigation into the genetic environment of the MDR region suggests that Tn2 and IS91 elements may be instrumental in the horizontal transfer of rmtB. Additionally, a complex Class I integron with an ISCR1 structure, along with TnAs1, seems to facilitate the horizontal transfer of blaPER-1. The conjugation transfer assay, coupled with the annotation of conjugation-related genes and phylogenetic analysis, indicates that the plasmid pMAS152 functions as a conjugative plasmid, with other genus Pseudomonas species as potential hosts. Our findings provide vital insights into the resistance mechanisms and transmission potential of the XDR P. aeruginosa isolate MAS152, underlining the urgent need for novel strategies to combat the spread of AMR. This study highlights the complex interplay of genetic elements contributing to antibiotic resistance and underscores the importance of continuous surveillance of emerging ARGs in clinical isolates.
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Diffuse-type gastric cancer (DGC) is a subtype of gastric cancer with aggressiveness and poor prognosis. It is of great significance to find sensitive drugs for DGC. In the current study, a total of 20 patient-derived organoids (PDOs) were analyzed for screening the therapeutic efficacy of small molecule kinases inhibitors on gastric cancers, especially the therapeutic difference between intestinal-type gastric cancer (IGCs) and DGCs. The IGCs are sensitive to multiple kinases inhibitors, while DGCs are resistant to most of these kinases inhibitors. It was found that DGCs showed drug-induced senescent phenotype after treatment by aurora kinases inhibitors (AURKi) Barasertib-HQPA and Danusertib. The cell diameter of cancer cells are increased with stronger staining of senescence-associated ß-galactosidase (SA-ß-GAL), and characteristic appearance of multinucleated giant cells. The senescent cancer cells secrete large amounts of chemokine MCP-1/CCL2, which recruit and induce macrophage to M2-type polarization in PDOs of DGC (DPDOs)-macrophage co-culture system. The up-regulation of local MCP-1/CCL2 can interact with MCP-1/CCL2 receptor (CCR2) expressed on macrophages and suppress their innate immunity to cancer cells. Overall, the special response of DGC to AURKi suggests that clinicians should select a sequential therapy with senescent cell clearance after AURKi treatment for DGC.
Assuntos
Senescência Celular , Imunidade Inata , Macrófagos , Organoides , Inibidores de Proteínas Quinases , Neoplasias Gástricas , Humanos , Organoides/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Senescência Celular/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Aurora Quinases/antagonistas & inibidores , Aurora Quinases/metabolismo , Técnicas de Cocultura , Animais , Quimiocina CCL2/metabolismoRESUMO
Virus infection of Aspergillus foetidus was first described in the 1970s, and the purified virus, named Aspergillus foetidus virus (AfV), contains at least two types of icosahedral particles, called AfV-fast (-F) and AfV-slow (-S) virions, based on their relative electrophoretic mobilities. AfV-S consists of a mixture of two viruses, the larger of which, called AfV-S1, is a dsRNA-containing member of the genus Victorivirus in the family Totiviridae, and its complete nucleotide sequence is described here.
Assuntos
Aspergillus/virologia , Totivirus/genética , Totivirus/isolamento & purificação , Sequência de Bases , Genoma Viral , Dados de Sequência Molecular , Filogenia , RNA Viral/genética , Totivirus/classificação , Proteínas Virais/genéticaRESUMO
Aspergillus foetidus virus (AfV) contains at least two icosahedral particle types named AfV-fast (-F) and AfV-slow (-S), based on relative electrophoretic mobility. AfV-F is a quadripartite double-stranded RNA (dsRNA) virus, and AfV-S contains AfV-S1, which is a member of the genus Victorivirus in the family Totiviridae, and AfV-S2, which may be a satellite RNA or satellite virus and is described here. Analysis of the complete AfV-S2 nucleotide sequence reveals it to be significantly similar to an unclassified RNA from the fungus Rosellinia necatrix and distantly related to the RNA-dependent RNA polymerases of several single-stranded RNA genomes.
Assuntos
Aspergillus/virologia , Vírus de RNA/genética , RNA de Cadeia Dupla/genética , RNA Satélite/genética , RNA Viral/genética , Análise de Sequência de DNA , Aspergillus/genética , Análise por Conglomerados , Dados de Sequência Molecular , Filogenia , Vírus de RNA/isolamento & purificação , RNA de Cadeia Dupla/isolamento & purificação , RNA Satélite/isolamento & purificação , Homologia de Sequência do Ácido NucleicoRESUMO
Virus infection of Aspergillus foetidus was documented over 40 years ago and was one of the first mycovirus infections described in a filamentous fungus. The virus, named Aspergillus foetidus virus (AfV), contains at least two types of icosahedral particles, called AfV-fast (-F) and AfV-slow (-S) virions, based on their relative electrophoretic mobilities. Here, we report the complete nucleotide sequence of the AfV-F genome isolated from virions purified from the prototype isolate of the fungus. The AfV-F double-stranded (ds) RNA genome is tetra-segmented, and the plus strands of each of the four segments, but not the minus strands, are polyadenylated. The organisation and sequences of the four AfV-F dsRNAs are similar to those described for Alternaria alternata virus 1, which we propose is a member of an emerging mycovirus genus ("Alternavirus") and family ("Alternaviridae"), which also includes AfV-F.
Assuntos
Aspergillus/virologia , Totivirus/genética , Totivirus/isolamento & purificação , Sequência de Bases , Genoma Viral , Dados de Sequência Molecular , Fases de Leitura Aberta , Filogenia , RNA Viral/genética , Totivirus/classificação , Proteínas Virais/genéticaRESUMO
The research area of adolescent health corresponds to the summary of a wide range of scientific interests and investigations, focusing on the first years of life of an individual [...].
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Saúde do Adolescente , Promoção da Saúde , Adolescente , HumanosRESUMO
Emil Kraepelin believed that dementia praecox, the disorder we now call schizophrenia, was caused by the brain being poisoned with toxins generated in other parts of the body, especially the mouth, intestine or genitals. In this regard, Kraepelin hinted at the microbiome and conceptualized microbial molecules as drivers of severe psychiatric illness. However, it was not until the coronavirus disease (COVID-19) pandemic that Kraepelin's paradigm gained traction, particularly because this virus was associated with both gut barrier disruption and new-onset psychosis.Likewise, despite numerous studies linking severe psychiatric illness to genomic damage and dysfunctional DNA repair, this pathogenetic mechanism was underappreciated before the COVID-19 pandemic. The use of the psychotomimetic anesthetic, ketamine, for treatment-resistant depression has reawakened the interest in endogenous serotonergic hallucinogens, especially tryptamine and N,N-dimethyltryptamine (DMT), which are beneficial for depression but associated with psychosis.In this editorial, we take a closer look at the role of the microbiome in psychopathology, attempting to answer 2 questions:1. Why may psychosis-predisposing serotonergic hallucinogens alleviate depression?2. Are microbiota-derived psychedelics part of an inbuilt antidepressant system similar to endogenous opioids?
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COVID-19 , Alucinógenos , Ketamina , Humanos , Pandemias , N,N-DimetiltriptaminaRESUMO
The vulnerability of healthcare and laboratory to potential infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has thus far been analyzed through the lens of the acute phase of the pandemic, including remote-based work, as well as emergency settings that are different from routine healthcare operations. However, as lockdowns ease and activities return to an identifiable pre-pandemic routine, the safety considerations also require to shift accordingly. As laboratory workers are likely to continue being exposed to unidentified SARS-CoV-2 positive samples through routine blood collection and processing operations, coronavirus disease 2019 (COVID-19) might have to be re-considered as an occupational disease within this context. Additionally, as per many such occupational diseases, a surveillance system is implemented for the medium- and long-term. This manuscript presents the views on the possible surveillance scenarios for laboratory staff, viewed from an immunological and biosafety perspective.