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1.
EMBO J ; 40(5): e104267, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33491217

RESUMO

Impairments in social relationships and awareness are features observed in autism spectrum disorders (ASDs). However, the underlying mechanisms remain poorly understood. Shank2 is a high-confidence ASD candidate gene and localizes primarily to postsynaptic densities (PSDs) of excitatory synapses in the central nervous system (CNS). We show here that loss of Shank2 in mice leads to a lack of social attachment and bonding behavior towards pubs independent of hormonal, cognitive, or sensitive deficits. Shank2-/- mice display functional changes in nuclei of the social attachment circuit that were most prominent in the medial preoptic area (MPOA) of the hypothalamus. Selective enhancement of MPOA activity by DREADD technology re-established social bonding behavior in Shank2-/- mice, providing evidence that the identified circuit might be crucial for explaining how social deficits in ASD can arise.


Assuntos
Transtorno Autístico/tratamento farmacológico , Modelos Animais de Doenças , Relações Interpessoais , Comportamento Materno/efeitos dos fármacos , Proteínas do Tecido Nervoso/fisiologia , Piperazinas/farmacologia , Área Pré-Óptica/efeitos dos fármacos , Animais , Transtorno Autístico/etiologia , Transtorno Autístico/metabolismo , Transtorno Autístico/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Área Pré-Óptica/metabolismo , Área Pré-Óptica/patologia , Sinapses
2.
J Minim Access Surg ; 20(2): 175-179, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37148104

RESUMO

INTRODUCTION: Colovesical fistula (CVF) is a condition with various aetiologies and presentations. Surgical treatment is necessary in most cases. Due to its complexity, open approach is preferred. However, laparoscopic approach is reported in the management of CVF due to diverticular disease. The aim of this study was to analyse the management and outcome of patients with CVF of different aetiologies treated with laparoscopic approach. PATIENTS AND METHODS: This was a retrospective study. We retrospectively reviewed all patients undergoing elective laparoscopic management of CVF from March 2015 to December 2019. STATISTICAL ANALYSIS USED: None. RESULTS: Nine patients underwent laparoscopic management of CVF. There were no intraoperative complications or conversions to open surgery. A sigmoidectomy was performed in eight cases. In one patient, a fistulectomy with sigmoid and bladder defect closure was performed. In two cases of locally advanced colorectal cancer with bladder invasion, a multi-stage procedure with temporary colostomy was chosen. In three cases, with no intraoperative leakage, we did not perform bladder suture. Four Clavien I-II complications were recorded. Two fragile patients died in the post-operative period. No patients required re-operation. At a median follow-up of 21 months (interquartile range: 6-47), none of the patients had recurrence of fistula. CONCLUSIONS: CVF can be managed with laparoscopic approach by skilled laparoscopic surgeons in different clinical scenarios. Bladder suture is not necessary if leakage is absent. Informed counselling to the patient must be guaranteed concerning the risk of major complications and mortality in case of CVF due to malignant disease.

3.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675087

RESUMO

PAX6 haploinsufficiency causes aniridia, a congenital eye disorder that involves the iris, and foveal hypoplasia. Comprehensive screening of the PAX6 locus, including the non-coding regions, by next-generation sequencing revealed four deep-intronic variants with potential effects on pre-RNA splicing. Nevertheless, without a functional analysis, their pathogenicity could not be established. We aimed to decipher their impact on the canonical PAX6 splicing using in vitro minigene splicing assays and nanopore-based long-read sequencing. Two multi-exonic PAX6 constructs were generated, and minigene assays were carried out. An aberrant splicing pattern was observed for two variants in intron 6, c.357+136G>A and c.357+334G>A. In both cases, several exonization events, such as pseudoexon inclusions and partial intronic retention, were observed due to the creation or activation of new/cryptic non-canonical splicing sites, including a shared intronic donor site. In contrast, two variants identified in intron 11, c.1032+170A>T and c.1033-275A>C, seemed not to affect splicing processes. We confirmed the high complexity of alternative splicing of PAX6 exon 6, which also involves unreported cryptic intronic sites. Our study highlights the importance of integrating functional studies into diagnostic algorithms to decipher the potential implication of non-coding variants, usually classified as variants of unknown significance, thus allowing variant reclassification to achieve a conclusive genetic diagnosis.


Assuntos
Aniridia , Splicing de RNA , Humanos , Processamento Alternativo/genética , Aniridia/genética , Íntrons/genética , Mutação , Fator de Transcrição PAX6/genética , Fator de Transcrição PAX6/metabolismo , Sítios de Splice de RNA , Splicing de RNA/genética
4.
Mol Psychiatry ; 26(8): 3778-3794, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-32051550

RESUMO

Older patients with severe physical trauma are at high risk of developing neuropsychiatric syndromes with global impairment of cognition, attention, and consciousness. We employed a thoracic trauma (TxT) mouse model and thoroughly analyzed age-dependent spatial and temporal posttraumatic alterations in the central nervous system. Up to 5 days after trauma, we observed a transient 50% decrease in the number of excitatory synapses specifically in hippocampal pyramidal neurons accompanied by alterations in attention and motor activity and disruption of contextual memory consolidation. In parallel, hippocampal corticotropin-releasing hormone (CRH) expression was highly upregulated, and brain-derived neurotrophic factor (BDNF) levels were significantly reduced. In vitro experiments revealed that CRH application induced neuronal autophagy with rapid lysosomal degradation of BDNF via the NF-κB pathway. The subsequent synaptic loss was rescued by BDNF as well as by specific NF-κB and CRH receptor 1 (CRHR1) antagonists. In vivo, the chronic application of a CRHR1 antagonist after TxT resulted in reversal of the observed histological, molecular, and behavioral alterations. The data suggest that neuropsychiatric syndromes (i.e., delirium) after peripheral trauma might be at least in part due to the activation of the hippocampal CRH/NF-κB/BDNF pathway, which results in a dramatic loss of synaptic contacts. The successful rescue by stress hormone receptor antagonists should encourage clinical trials focusing on trauma-induced delirium and/or other posttraumatic syndromes.


Assuntos
Delírio , Neurônios , Animais , Hormônio Liberador da Corticotropina , Humanos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Camundongos , Receptores de Hormônio Liberador da Corticotropina , Síndrome
5.
Microb Ecol ; 83(1): 83-99, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33864491

RESUMO

In this work, we studied the microbial community and the physicochemical conditions prevailing in an exploratory oil well, abandoned a century ago, located in the Cahuita National Park (Costa Rica). According to our analysis, Cahuita well is characterized by a continuous efflux of methane and the presence of a mixture of hydrocarbons including phenanthrene/anthracene, fluoranthene, pyrene, dibenzothiophene, tricyclic terpanes, pyrene, sesquiterpenes, sterane, and n-alkanes. Based on the analysis of 16S rRNA gene amplicons, we detected a significant abundance of methylotrophic bacteria such as Methylobacillus (6.3-26.0% of total reads) and Methylococcus (4.1-30.6%) and the presence of common genera associated with hydrocarbon degradation, such as Comamonas (0.8-4.6%), Hydrogenophaga (1.5-3.3%) Rhodobacter (1.0-4.9%), and Flavobacterium (1.1-6.5%). The importance of C1 metabolism in this niche was confirmed by amplifying the methane monooxygenase (MMO)-encoding gene (pmo) from environmental DNA and the isolation of two strains closely related to Methylorubrum rhodesianum and Paracoccus communis with the ability to growth using methanol and formate as sole carbon source respectively. In addition, we were able to isolated 20 bacterial strains from the genera Pseudomonas, Acinetobacter, and Microbacterium which showed the capability to grow using the hydrocarbons detected in the oil well as sole carbon source. This work describes the physicochemical properties and microbiota of an environment exposed to hydrocarbons for 100 years, and it not only represents a contribution to the understanding of microbial communities in environments with permanently high concentrations of these compounds but also has biotechnological implications for bioremediation of petroleum-polluted sites.


Assuntos
Microbiota , Petróleo , Bactérias , Biodegradação Ambiental , Hidrocarbonetos/metabolismo , Campos de Petróleo e Gás , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/metabolismo
6.
Arch Virol ; 167(9): 1727-1738, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35579715

RESUMO

Guanarito virus (GTOV) is a member of the family Arenaviridae and has been designated a category A bioterrorism agent by the US Centers for Disease Control and Prevention. It is endemic to Venezuela's western region, and it is the etiological agent of "Venezuelan hemorrhagic fever" (VHF). Similar to other arenaviral hemorrhagic fevers, VHF is characterized by fever, mild hemorrhagic signs, nonspecific symptoms, thrombocytopenia, and leukopenia. Patients with severe disease usually develop signs of internal bleeding. Due to the absence of reference laboratories that can handle GTOV in endemic areas, diagnosis is primarily clinical and epidemiological. No antiviral therapies are available; thus, treatment includes only supportive analgesia and fluids. GTOV is transmitted by contact with the excreta of its rodent reservoir, Zygodontomys brevicauda. The main reasons for the emergence of the disease may be the increase in the human population, migration, and changes in land use patterns in rural areas. Social and environmental changes could make VHF an important cause of underdiagnosed acute febrile illnesses in regions near the endemic areas. Although there is evidence that GTOV circulates among rodents in different Venezuelan states, VHF cases have only been reported in the states of Portuguesa and Barinas. However, due to the increased frequency of invasions by humans into wildlife habitats, it is probable that VHF could become a public health problem in the nearby regions of Colombia and Brazil. The current Venezuelan political crisis is causing an increase in the migration of people and livestock, representing a risk for the redistribution and re-emergence of infectious diseases.


Assuntos
Infecções por Arenaviridae , Arenaviridae , Arenavirus do Novo Mundo , Febres Hemorrágicas Virais , Animais , Febres Hemorrágicas Virais/diagnóstico , Febres Hemorrágicas Virais/epidemiologia , Humanos , Roedores , Sigmodontinae
7.
Pain Med ; 23(7): 1239-1248, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34908146

RESUMO

BACKGROUND: Chronic pain is one of the most common reason adults seek medical care in the United States, with prevalence estimates ranging from 11% to 40%. Mindfulness meditation has been associated with significant improvements in pain, depression, physical and mental health, sleep, and overall quality of life. Group medical visits are increasingly common and are effective at treating myriad illnesses, including chronic pain. Integrative Medical Group Visits (IMGV) combine mindfulness techniques, evidence based integrative medicine, and medical group visits and can be used as adjuncts to medications, particularly in diverse underserved populations with limited access to non-pharmacological therapies. OBJECTIVE AND DESIGN: The objective of the present study was to use a blended analytical approach of machine learning and regression analyses to evaluate the potential relationship between depression and chronic pain in data from a randomized clinical trial of IMGV in diverse, income-disadvantaged patients suffering from chronic pain and depression. METHODS: The analytical approach used machine learning to assess the predictive relationship between depression and pain and identify and select key mediators, which were then assessed with regression analyses. It was hypothesized that depression would predict the pain outcomes of average pain, pain severity, and pain interference. RESULTS: Our analyses identified and characterized a predictive relationship between depression and chronic pain interference. This prediction was mediated by high perceived stress, low pain self-efficacy, and poor sleep quality, potential targets for attenuating the adverse effects of depression on functional outcomes. CONCLUSIONS: In the context of the associated clinical trial and similar interventions, these insights may inform future treatment optimization, targeting, and application efforts in racialized, income-disadvantaged populations, demographics often neglected in studies of chronic pain.


Assuntos
Dor Crônica , Atenção Plena , Adulto , Dor Crônica/complicações , Dor Crônica/epidemiologia , Dor Crônica/terapia , Depressão/epidemiologia , Depressão/psicologia , Depressão/terapia , Humanos , Atenção Plena/métodos , Qualidade de Vida , Populações Vulneráveis
8.
Am J Respir Crit Care Med ; 204(1): 34-43, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33823118

RESUMO

Rationale: The role of and needs for extracorporeal membrane oxygenation (ECMO) at a population level during the coronavirus disease (COVID-19) pandemic have not been completely established. Objectives: To identify the cumulative incidence of ECMO use in the first pandemic wave and to describe the Nationwide Chilean cohort of ECMO-supported patients with COVID-19. Methods: We conducted a population-based study from March 3 to August 31, 2020, using linked data from national agencies. The cumulative incidence of ECMO use and mortality risk of ECMO-supported patients were calculated and age standardized. In addition, a retrospective cohort analysis was performed. Outcomes were 90-day mortality after ECMO initiation, ECMO-associated complications, and hospital length of stay. Cox regression models were used to explore risk factors for mortality in a time-to-event analysis. Measurements and Main Results: Ninety-four patients with COVID-19 were supported with ECMO (0.42 per population of 100,000, 14.89 per 100,000 positive cases, and 1.2% of intubated patients with COVID-19); 85 were included in the cohort analysis, and the median age was 48 (interquartile range [IQR], 41-55) years, 83.5% were men, and 42.4% had obesity. The median number of pre-ECMO intubation days was 4 (IQR, 2-7), the median PaO2/FiO2 ratio was 86.8 (IQR, 64-99) mm Hg, 91.8% of patients were prone positioned, and 14 patients had refractory respiratory acidosis. Main complications were infections (70.6%), bleeding (38.8%), and thromboembolism (22.4%); 52 patients were discharged home, and 33 died. The hospital length of stay was a median of 50 (IQR, 24-69) days. Lower respiratory system compliance and higher driving pressure before ECMO initiation were associated with increased mortality. A duration of pre-ECMO intubation ≥10 days was not associated with mortality. Conclusions: Documenting nationwide ECMO needs may help in planning ECMO provision for future COVID-19 pandemic waves. The 90-day mortality of the Chilean cohort of ECMO-supported patients with COVID-19 (38.8%) is comparable to that of previous reports.


Assuntos
COVID-19/terapia , Oxigenação por Membrana Extracorpórea/estatística & dados numéricos , Síndrome do Desconforto Respiratório/terapia , Adulto , Idoso , COVID-19/complicações , COVID-19/diagnóstico , COVID-19/epidemiologia , Chile/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Avaliação das Necessidades , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/epidemiologia , Síndrome do Desconforto Respiratório/virologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
9.
Health Commun ; 37(4): 438-449, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-33205663

RESUMO

Latino populations are disproportionately impacted by health disparities and face both connectivity and health literacy challenges. As evidenced by the current global pandemic, access to reliable online health-related information and the ability to apply that information is critical to achieving health equity. Through a qualitative study on how Latino families collaborate to access online health resources, this work frames health literacy as a family-level mechanism. Interviews with parent-child dyads combined with online search tasks reveal how families integrate their individual skillsets to obtain, process, and understand online information about illnesses, symptoms, and even medical diagnoses. As they engage in intergenerational online health information searching and brokering, families creatively navigate information and communication technologies (ICTs) to address a range of health needs. Bilingual children help immigrant parents obtain urgent and non-urgent health information needed to care for other family members. When children are tasked with addressing a health need critical to their parent's wellbeing, they collaborate with their parents to obtain, interpret, and apply online health information. Intergenerational online health information searching and brokering thus reveals family-level strengths that can be leveraged to promote both health and digital literacy among marginalized populations.


Assuntos
Emigrantes e Imigrantes , Letramento em Saúde , Família , Humanos , Pandemias , Pais
10.
Int J Mol Sci ; 23(11)2022 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-35682760

RESUMO

Autism spectrum disorders (ASDs) are characterized by repetitive behaviors and impairments of sociability and communication. About 1% of ASD cases are caused by mutations of SHANK3, a major scaffolding protein of the postsynaptic density. We studied the role of SHANK3 in plastic changes of excitatory synapses within the central nervous system by employing mild traumatic brain injury (mTBI) in WT and Shank3 knockout mice. In WT mice, mTBI triggered ipsi- and contralateral loss of hippocampal dendritic spines and excitatory synapses with a partial recovery over time. In contrast, no significant synaptic alterations were detected in Shank3∆11-/- mice, which showed fewer dendritic spines and excitatory synapses at baseline. In line, mTBI induced the upregulation of synaptic plasticity-related proteins Arc and p-cofilin only in WT mice. Interestingly, microglia proliferation was observed in WT mice after mTBI but not in Shank3∆11-/- mice. Finally, we detected TBI-induced increased fear memory at the behavioral level, whereas in Shank3∆11-/- animals, the already-enhanced fear memory levels increased only slightly after mTBI. Our data show the lack of structural synaptic plasticity in Shank3 knockout mice that might explain at least in part the rigidity of behaviors, problems in adjusting to new situations and cognitive deficits seen in ASDs.


Assuntos
Transtorno Autístico , Lesões Encefálicas Traumáticas , Animais , Transtorno Autístico/genética , Transtorno Autístico/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/genética , Sinapses/metabolismo
11.
Microbiology (Reading) ; 167(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33346729

RESUMO

Tellurium oxyanions are chemical species of great toxicity and their presence in the environment has increased because of mining industries and photovoltaic and electronic waste. Recovery strategies for this metalloid that are based on micro-organisms are of interest, but further studies of the transport systems and enzymes responsible for implementing tellurium transformations are required because many mechanisms remain unknown. Here, we investigated the involvement in tellurite uptake of the putative phosphate transporter PitB (PP1373) in soil bacterium Pseudomonas putida KT2440. For this purpose, through a method based on the CRISPR/Cas9 system, we generated a strain deficient in the pitB gene and characterized its phenotype on exposing it to varied concentrations of tellurite. Growth curves and transmission electronic microscopy experiments for the wild-type and ΔpitB strains showed that both were able to internalize tellurite into the cytoplasm and reduce the oxyanion to black nano-sized and rod-shaped tellurium particles, although the ΔpitB strain showed an increased resistance to the tellurite toxic effects. At a concentration of 100 µM tellurite, where the biomass formation of the wild-type strain decreased by half, we observed a greater ability of ΔpitB to reduce this oxyanion with respect to the wild-type strain (~38 vs ~16 %), which is related to the greater biomass production of ΔpitB and not to a greater consumption of tellurite per cell. The phenotype of the mutant was restored on over-expressing pitB in trans. In summary, our results indicate that PitB is one of several transporters responsible for tellurite uptake in P. putida KT2440.


Assuntos
Proteínas de Bactérias/metabolismo , Proteínas de Transporte de Fosfato/metabolismo , Pseudomonas putida/metabolismo , Telúrio/metabolismo , Proteínas de Bactérias/genética , Transporte Biológico , Biomassa , Biotransformação , Mutação , Nanoestruturas/química , Nanoestruturas/toxicidade , Proteínas de Transporte de Fosfato/genética , Pseudomonas putida/efeitos dos fármacos , Pseudomonas putida/crescimento & desenvolvimento , Telúrio/química , Telúrio/toxicidade
12.
Int J Mol Sci ; 22(22)2021 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-34830179

RESUMO

In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors. Pre-clinical experimental studies investigating the effects of various treatments (alone or combined) may discover how to overcome the immunotherapy-resistance in PC-patients. We performed a systematic literature review (PRISMA guidelines) to delineate the landscape of pre-clinical studies (including cell lines and mouse models) that tested treatments with effects on PD-L1 signaling in PC. NF-kB, MEK, JAK, or STAT inhibitors on human/mouse, primary/metastatic PC-cell lines variably down-modulated PD-L1-expression, reducing chemoresistance and tumor cell migration. If PC-cells were co-cultured with NK, CD8+ T-cells or CAR-T cells, the immune cell cytotoxicity increased when PD-L1 was downregulated (opposite effects for PD-L1 upregulation). In mouse models, radiotherapy, CDK4/6-inhibitors, and RB deletion induced PD-L1-upregulation, causing PC-immune-evasion. Epigenetic drugs may reduce PD-L1 expression. In some PC experimental models, blocking only the PD-1/PD-L1 pathway had limited efficacy in reducing the tumor growth. Anti-tumor effects could be increased by combining the PD-1/PD-L1 blockade with other approaches (inhibitors of tyrosine kinase, PI3K/mTOR or JAK/STAT3 pathways, p300/CBP; anti-RANKL and/or anti-CTLA-4 antibodies; cytokines; nitroxoline; DNA/cell vaccines; radiotherapy/Radium-223).


Assuntos
Antígeno B7-H1/imunologia , Modelos Animais de Doenças , Imunoterapia/métodos , Neoplasias da Próstata/terapia , Transdução de Sinais/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Masculino , Camundongos , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Transdução de Sinais/genética
13.
Int J Mol Sci ; 22(22)2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34830196

RESUMO

Epigenetic alterations (including DNA methylation or miRNAs) influence oncogene/oncosuppressor gene expression without changing the DNA sequence. Prostate cancer (PC) displays a complex genetic and epigenetic regulation of cell-growth pathways and tumor progression. We performed a systematic literature review (following PRISMA guidelines) focused on the epigenetic regulation of PD-L1 expression in PC. In PC cell lines, CpG island methylation of the CD274 promoter negatively regulated PD-L1 expression. Histone modifiers also influence the PD-L1 transcription rate: the deletion or silencing of the histone modifiers MLL3/MML1 can positively regulate PD-L1 expression. Epigenetic drugs (EDs) may be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion. EDs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) downregulated PD-L1, while EDs favoring a chromatin-active state (i.e., histone deacetylase inhibitors) increased PD-L1 expression. miRNAs can regulate PD-L1 at a post-transcriptional level. miR-195/miR-16 were negatively associated with PD-L1 expression and positively correlated to longer biochemical recurrence-free survival; they also enhanced the radiotherapy efficacy in PC cell lines. miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and inversely correlated to the methylation of PD-L1 promoter in a large series. miR-570, miR-34a and miR-513 may also be involved in epigenetic regulation.


Assuntos
Antígeno B7-H1/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Expressão Gênica , Neoplasias da Próstata/genética , Animais , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Ilhas de CpG/genética , Metilação de DNA/genética , Código das Histonas/genética , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , MicroRNAs/genética , Regiões Promotoras Genéticas/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia
14.
Int J Mol Sci ; 22(22)2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34830209

RESUMO

The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-ß, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients' serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Microambiente Tumoral/imunologia , Via de Sinalização Wnt/imunologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Linhagem Celular Tumoral , Citocinas/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias da Próstata/terapia , Linfócitos T Citotóxicos/imunologia , Evasão Tumoral , Microambiente Tumoral/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos
15.
Pathologica ; 113(2): 126-130, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34042094

RESUMO

The diagnosis of acute toxoplasmic lymphadenitis is traditionally based on the combination of lymph node excisional biopsy with specific tests. The classic triad (marked follicular hyperplasia, small irregular clusters of epithelioid histiocytes in germinal centers, and sinusoidal distension by monocytoid B lymphocytes) is considered diagnostic of the so-called Piringer-Kuchinka lymphadenitis. Toxoplasma gondii organisms have been exceptionally disclosed in such histopathological setting, establishing the diagnosis of toxoplasmic lymphadenitis. Two cases of Piringer-Kuchinka lymphadenitis with toxoplasma cyst demonstration are reported, along with a complete review of the literature.


Assuntos
Linfadenite , Toxoplasma , Toxoplasmose , Histiócitos , Humanos , Linfonodos , Linfadenite/diagnóstico , Toxoplasmose/diagnóstico
16.
BMC Gastroenterol ; 20(1): 336, 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33054767

RESUMO

BACKGROUND: Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract is a rare low-grade clonal lymphoid proliferation, included as a provisional entity in the current World Health Organization classification. The disease is generally localized to the gastrointestinal tract, mainly small bowel and colon. Involvement of other organs is infrequently reported. The majority of patients show a protracted clinical course with persistent disease. A prolonged survival, even without treatment, is common. CASE PRESENTATION: A 28-year-old woman had a 2-year history of dyspepsia and lactose intolerance. Autoimmune diseases and celiac disease were excluded. No gross lesions were identified by endoscopy. Multiple gastric biopsies showed a small-sized lymphoid infiltrate, expanding the lamina propria, with a non-destructive appearance. The lymphoid cells were positive for CD3, CD4, CD5, CD7 and negative for CD20, CD8, CD56, CD103, PD1, CD30, ALK1, CD10, BCL6, perforin, TIA-1, Granzyme B and Epstein-Barr virus-encoded RNA. KI-67 index was low (5%). Molecular analysis revealed a clonal T-cell receptor γ rearrangement. Bone marrow was microscopically free of disease, but molecular testing identified the same T-cell receptor γ rearrangement present in the gastric biopsies. After the diagnosis of indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, the patient received steroid therapy, only for 2 months. She is alive, with a stable disease restricted to the stomach, at 12 months from diagnosis. CONCLUSIONS: Indolent T-cell lymphoproliferative disorder is usually a disease of adulthood (median age: 51 yrs). The small bowel and colon are the sites most commonly involved. Our case occurred in a young woman and affected the stomach, sparing small intestine and colon. Clonality testing identified involvement of bone marrow, a site infrequently affected in this disease. Our aim is focusing on the main diagnostic issues. If appropriate immunostainings and molecular analysis are not performed, the subtle infiltrate may be easily overlooked. The risk of misdiagnosis as more aggressive lymphomas, causing patient overtreatment, needs also to be considered.


Assuntos
Infecções por Vírus Epstein-Barr , Transtornos Linfoproliferativos , Adulto , Feminino , Trato Gastrointestinal , Herpesvirus Humano 4 , Humanos , Transtornos Linfoproliferativos/diagnóstico , Pessoa de Meia-Idade , Estômago , Linfócitos T
17.
Rev Med Chil ; 148(12): 1725-1733, 2020 Dec.
Artigo em Espanhol | MEDLINE | ID: mdl-33844737

RESUMO

BACKGROUND: Since March, Chile experienced an exponential increase in SARS-CoV2 cases, which led to an almost full occupancy of the intensive care units (ICU). AIM: To characterize patients with SARS-CoV2 disease who required hospitalization in the ICU and invasive mechanical ventilation (IMV) in our hospital. MATERIAL AND METHODS: A prospective observational study was performed, which included the first 50 patients, aged 54 ± 13 years (58% men), with SARS-CoV2 disease, with ICU and IMV requirements between March 23 and June 2, 2020. Demographics, comorbidities, symptoms, laboratory and imaging, therapies performed and IMV characteristics were registered. The most relevant outcomes observed were lethality, number of days in the ICU and connection to an IMV. RESULTS: Ninety percent of patients were overweight or obese, 46% had hypertension and many had diabetes mellitus. They had elevated inflammatory parameters and typical patterns of COVID-19 in computed tomography. Most of the patients got protective lung ventilation with a high rate of use of neuromuscular blockade (NMB) and prone position. Antibiotics, hydroxychloroquine, and lopinavir/ritonavir were administered according to the protocol of the institution. Lethality was 16% (8 cases) at the end of this study. CONCLUSIONS: The information obtained in this study provides characteristics and early outcomes of hospitalized patients with confirmed COVID-19 and IMV, admitted to the ICU of our center.


Assuntos
COVID-19 , RNA Viral , Adulto , Idoso , Chile/epidemiologia , Feminino , Hospitalização , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Respiração Artificial , SARS-CoV-2
18.
Rev Med Chil ; 148(5): 674-683, 2020 May.
Artigo em Espanhol | MEDLINE | ID: mdl-33399761

RESUMO

Our country is suffering the effects of the ongoing pandemic of coronavirus disease (COVID-19). Because the vulnerability of healthcare systems, especially the intensive care areas they can rapidly be overloaded. That challenge the ICUs simultaneously on multiple fronts making urgent to increase the number of beds, without lowering the standards of care. The purpose of this article is to discuss some aspects of the national situation and to provide recommendations on the organizational management of intensive care units such as isolation protocols, surge in ICU bed capacity, ensure adequate supplies, protect and train healthcare workers maintaining quality clinical management.


Assuntos
COVID-19/epidemiologia , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/provisão & distribuição , Pandemias , Humanos , Capacidade de Resposta ante Emergências
19.
Haematologica ; 104(9): 1853-1865, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30573502

RESUMO

Embryonic megakaryopoiesis starts in the yolk sac on gestational day 7.5 as part of the primitive wave of hematopoiesis, and it continues in the fetal liver when this organ is colonized by hematopoietic progenitors between day 9.5 and 10.5, as the definitive hematopoiesis wave. We characterized the precise phenotype of embryo megakaryocytes in the liver at gestational day 11.5, identifying them as CD41++CD45-CD9++CD61+MPL+CD42c+ tetraploid cells that express megakaryocyte-specific transcripts and display differential traits when compared to those present in the yolk sac at the same age. In contrast to megakaryocytes from adult bone marrow, embryo megakaryocytes are CD45- until day 13.5 of gestation, as are both the megakaryocyte progenitors and megakaryocyte/erythroid-committed progenitors. At gestational day 11.5, liver and yolk sac also contain CD41+CD45+ and CD41+CD45- cells. These populations, and that of CD41++CD45-CD42c+ cells, isolated from liver, differentiate in culture into CD41++CD45-CD42c+ proplatelet-bearing megakaryocytes. Also present at this time are CD41-CD45++CD11b+ cells, which produce low numbers of CD41++CD45-CD42c+ megakaryocytes in vitro, as do fetal liver cells expressing the macrophage-specific Csf receptor-1 (Csf1r/CD115) from MaFIA transgenic mice, which give rise poorly to CD41++CD45-CD42c+ embryo megakaryocytes both in vivo and in vitro In contrast, around 30% of adult megakaryocytes (CD41++CD45++CD9++CD42c+) from C57BL/6 and MaFIA mice express CD115. We propose that differential pathways operating in the mouse embryo liver at gestational day 11.5 beget CD41++CD45-CD42c+ embryo megakaryocytes that can be produced from CD41+CD45- or from CD41+CD45+ cells, at difference from those from bone marrow.


Assuntos
Linhagem da Célula/genética , Embrião de Mamíferos/metabolismo , Antígenos Comuns de Leucócito/genética , Células Progenitoras de Megacariócitos/metabolismo , Megacariócitos/metabolismo , Animais , Antígenos CD/classificação , Antígenos CD/genética , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Diferenciação Celular , Embrião de Mamíferos/citologia , Citometria de Fluxo , Expressão Gênica , Hematopoese/genética , Imunofenotipagem/métodos , Antígenos Comuns de Leucócito/metabolismo , Fígado/citologia , Fígado/metabolismo , Células Progenitoras de Megacariócitos/classificação , Células Progenitoras de Megacariócitos/citologia , Megacariócitos/classificação , Megacariócitos/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Cultura Primária de Células , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Tetraploidia
20.
BMC Surg ; 19(1): 55, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138190

RESUMO

BACKGROUND: Duodenal stump fistula (DSF) remains one of the most serious complications following subtotal or total gastrectomy, as it endangers patient's life. DSF is related to high mortality (16-20%) and morbidity (75%) rates. DSF-related morbidity always leads to longer hospitalization times due to medical and surgical complications such as wound infections, intra-abdominal abscesses, intra-abdominal bleeding, acute pancreatitis, acute cholecystitis, severe malnutrition, fluids and electrolytes disorders, diffuse peritonitis, and pneumonia. Our systematic review aimed at improving our understanding of such surgical complication, focusing on nonsurgical and surgical DSF management in patients undergoing gastric resection for gastric cancer. METHODS: We performed a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines. PubMed/MEDLINE, EMBASE, Scopus, Cochrane Library and Web of Science databases were used to search all related literature. RESULTS: The 20 included articles covered an approximately 40 years-study period (1979-2017), with a total 294 patient population. DSF diagnosis occurred between the fifth and tenth postoperative day. Main DSF-related complications were sepsis, abdominal abscess, wound infection, pneumonia, and intra-abdominal bleeding. DSF treatment was divided into four categories: conservative (101 cases), endoscopic (4 cases), percutaneous (82 cases), and surgical (157 cases). Length of hospitalization was 21-39 days, ranging from 1 to 1035 days. Healing time was 19-63 days, ranging from 1 to 1035 days. DSF-related mortality rate recorded 18.7%. CONCLUSIONS: DSF is a rare but potentially lethal complication after gastrectomy for gastric cancer. Early DSF diagnosis is crucial in reducing DSF-related morbidity and mortality. Conservative and/or endoscopic/percutaneous treatments is/are the first choice. However, if the patient clinical condition worsens, surgery becomes mandatory and duodenostomy appears to be the most effective surgical procedure.


Assuntos
Gastrectomia/métodos , Fístula Intestinal/etiologia , Neoplasias Gástricas/cirurgia , Abscesso Abdominal/epidemiologia , Duodenopatias/etiologia , Humanos , Peritonite/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Cicatrização
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