RESUMO
Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103+ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61+ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.
Assuntos
Antígenos CD , Apirase , Cadeias alfa de Integrinas , Receptores de Antígenos de Linfócitos T , Transdução de Sinais , Animais , Humanos , Camundongos , Antígenos CD/metabolismo , Antígenos CD/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Cadeias alfa de Integrinas/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/imunologiaRESUMO
NP105-113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105-113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105-113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105-113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105-113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design.
Assuntos
Antígeno HLA-B7/imunologia , Epitopos Imunodominantes/imunologia , Proteínas do Nucleocapsídeo/imunologia , SARS-CoV-2/imunologia , Linfócitos T Citotóxicos/imunologia , Idoso , Sequência de Aminoácidos , Anticorpos Antivirais/imunologia , Afinidade de Anticorpos/imunologia , COVID-19/imunologia , COVID-19/patologia , Linhagem Celular Transformada , Feminino , Perfilação da Expressão Gênica , Humanos , Memória Imunológica/imunologia , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T/imunologia , Índice de Gravidade de Doença , Vaccinia virus/genética , Vaccinia virus/imunologia , Vaccinia virus/metabolismoRESUMO
MicroRNAs (miRNAs) regulate gene expression by base-pairing to target sequences in messenger RNAs (mRNAs) and recruiting factors that induce translational repression and mRNA decay. In animals, nucleotides 2-8 at the 5' end of the miRNA, called the seed region, are often necessary and sometimes sufficient for functional target interactions. MiRNAs that contain identical seed sequences are grouped into families where individual members have the potential to share targets and act redundantly. A rare exception seemed to be the miR-238/239ab family in Caenorhabditis elegans, as previous work indicated that loss of miR-238 reduced lifespan while deletion of the miR-239ab locus resulted in enhanced longevity and thermal stress resistance. Here, we re-examined these potentially opposing roles using new strains that individually disrupt each miRNA sister. We confirmed that loss of miR-238 is associated with a shortened lifespan but could detect no longevity or stress phenotypes in animals lacking miR-239a or miR-239b, individually or in combination. Additionally, dozens of genes were mis-regulated in miR-238 mutants but almost no gene expression changes were detected in either miR-239a or miR-239b mutants compared to wild type animals. We present evidence that the lack of redundancy between miR-238 and miR-239ab is independent of their sequence differences; miR-239a or miR-239b could substitute for the longevity role of miR-238 when expressed from the miR-238 locus. Altogether, these studies disqualify miR-239ab as negative regulators of aging and demonstrate that expression, not sequence, dictates the specific role of miR-238 in promoting longevity.
Assuntos
Proteínas de Caenorhabditis elegans , MicroRNAs , Animais , Humanos , Envelhecimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Longevidade , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genéticaRESUMO
The heat shock response (HSR) is a highly conserved cellular process that promotes survival during stress. A hallmark of the HSR is the rapid induction of heat shock proteins (HSPs), such as HSP-70, by transcriptional activation. Once the stress is alleviated, HSPs return to near basal levels through incompletely understood mechanisms. Here, we show that the microRNA pathway acts during heat shock recovery in Caenorhabditis elegans. Depletion of the miRNA Argonaute, Argonaute Like Gene 1 (ALG-1), after an episode of heat shock resulted in decreased survival and perdurance of high hsp-70 levels. We present evidence that regulation of hsp-70 is dependent on miR-85 and sequences in the hsp-70 3'UTR that contain target sites for this miRNA. Regulation of hsp-70 by the miRNA pathway was found to be particularly important during recovery from HS, as animals that lacked miR-85 or its target sites in the hsp-70 3'UTR overexpressed HSP-70 and exhibited reduced viability. In summary, our findings show that down-regulation of hsp-70 by miR-85 after HS promotes survival, highlighting a previously unappreciated role for the miRNA pathway during recovery from stress.
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Caenorhabditis elegans/genética , Resposta ao Choque Térmico/genética , MicroRNAs/genética , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico/genética , Resposta ao Choque Térmico/fisiologia , MicroRNAs/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Ativação TranscricionalRESUMO
To investigate the origins and stages of vertebrate adaptive radiation, we reconstructed the spatial and temporal histories of adaptive alleles underlying major phenotypic axes of diversification from the genomes of 202 Caribbean pupfishes. On a single Bahamian island, ancient standing variation from disjunct geographic sources was reassembled into new combinations under strong directional selection for adaptation to the novel trophic niches of scale-eating and molluscivory. We found evidence for two longstanding hypotheses of adaptive radiation: hybrid swarm origins and temporal stages of adaptation. Using a combination of population genomics, transcriptomics, and genome-wide association mapping, we demonstrate that this microendemic adaptive radiation of novel trophic specialists on San Salvador Island, Bahamas experienced twice as much adaptive introgression as generalist populations on neighboring islands and that adaptive divergence occurred in stages. First, standing regulatory variation in genes associated with feeding behavior (prlh, cfap20, and rmi1) were swept to fixation by selection, then standing regulatory variation in genes associated with craniofacial and muscular development (itga5, ext1, cyp26b1, and galr2) and finally the only de novo nonsynonymous substitution in an osteogenic transcription factor and oncogene (twist1) swept to fixation most recently. Our results demonstrate how ancient alleles maintained in distinct environmental refugia can be assembled into new adaptive combinations and provide a framework for reconstructing the spatiotemporal landscape of adaptation and speciation.
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Adaptação Fisiológica/genética , Especiação Genética , Peixes Listrados/genética , Filogenia , Análise Espaço-Temporal , Vertebrados/genética , Animais , Bahamas , Região do Caribe , Proteínas de Peixes/genética , Perfilação da Expressão Gênica/métodos , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Genótipo , Geografia , Peixes Listrados/anatomia & histologia , Peixes Listrados/classificação , Polimorfismo de Nucleotídeo Único , Vertebrados/anatomia & histologia , Vertebrados/classificaçãoRESUMO
The intercalated cell Cl-/HCO3- exchanger, pendrin, modulates ENaC subunit abundance and function. Whether ENaC modulates pendrin abundance and function is however unknown. Because αENaC mRNA has been detected in pendrin-positive intercalated cells, we hypothesized that ENaC, or more specifically the αENaC subunit, modulates intercalated cell function. The purpose of this study was therefore to determine if αENaC is expressed at the protein level in pendrin-positive intercalated cells and to determine if αENaC gene ablation or constitutively upregulating ENaC activity changes pendrin abundance, subcellular distribution, and/or function. We observed diffuse, cytoplasmic αENaC label in pendrin-positive intercalated cells from both mice and rats, with much lower label intensity in pendrin-negative, type A intercalated cells. However, while αENaC gene ablation within principal and intercalated cells of the CCD reduced Cl- absorption, it did not change pendrin abundance or subcellular distribution in aldosterone-treated mice. Further experiments used a mouse model of Liddle's syndrome to explore the effect of increasing ENaC channel activity on pendrin abundance and function. The Liddle's variant did not increase either total or apical plasma membrane pendrin abundance in aldosterone-treated or in NaCl-restricted mice. Similarly, while the Liddle's mutation increased total Cl- absorption in CCDs from aldosterone-treated mice, it did not significantly affect the change in Cl- absorption seen with pendrin gene ablation. We conclude that in rats and mice, αENaC localizes to pendrin-positive ICs where its physiological role remains to be determined. While pendrin modulates ENaC abundance, subcellular distribution, and function, ENaC does not have a similar effect on pendrin.
Assuntos
Aldosterona , Proteínas de Transporte de Ânions , Camundongos , Ratos , Animais , Proteínas de Transporte de Ânions/genética , Proteínas de Transporte de Ânions/metabolismo , Aldosterona/metabolismo , Canais Epiteliais de Sódio/genética , Canais Epiteliais de Sódio/metabolismo , Pressão Sanguínea/fisiologia , Transportadores de Sulfato/genéticaRESUMO
The urinary potassium (K+) excretion machinery is upregulated with increasing dietary K+, but the role of accompanying dietary anions remains inadequately characterized. Poorly absorbable anions, including [Formula: see text], are thought to increase K+ secretion through a transepithelial voltage effect. Here, we tested if they also influence the K+ secretion machinery. Wild-type mice, aldosterone synthase (AS) knockout (KO) mice, or pendrin KO mice were randomized to control, high-KCl, or high-KHCO3 diets. The K+ secretory capacity was assessed in balance experiments. Protein abundance, modification, and localization of K+-secretory transporters were evaluated by Western blot analysis and confocal microscopy. Feeding the high-KHCO3 diet increased urinary K+ excretion and the transtubular K+ gradient significantly more than the high-KCl diet, coincident with more pronounced upregulation of epithelial Na+ channels (ENaC) and renal outer medullary K+ (ROMK) channels and apical localization in the distal nephron. Experiments in AS KO mice revealed that the enhanced effects of [Formula: see text] were aldosterone independent. The high-KHCO3 diet also uniquely increased the large-conductance Ca2+-activated K+ (BK) channel ß4-subunit, stabilizing BKα on the apical membrane, the Cl-/[Formula: see text] exchanger, pendrin, and the apical KCl cotransporter (KCC3a), all of which are expressed specifically in pendrin-positive intercalated cells. Experiments in pendrin KO mice revealed that pendrin was required to increase K+ excretion with the high-KHCO3 diet. In summary, [Formula: see text] stimulates K+ excretion beyond a poorly absorbable anion effect, upregulating ENaC and ROMK in principal cells and BK, pendrin, and KCC3a in pendrin-positive intercalated cells. The adaptive mechanism prevents hyperkalemia and alkalosis with the consumption of alkaline ash-rich diets but may drive K+ wasting and hypokalemia in alkalosis.NEW & NOTEWORTHY Dietary anions profoundly impact K+ homeostasis. Here, we found that a K+-rich diet, containing [Formula: see text] as the counteranion, enhances the electrogenic K+ excretory machinery, epithelial Na+ channels, and renal outer medullary K+ channels, much more than a high-KCl diet. It also uniquely induces KCC3a and pendrin, in B-intercalated cells, providing an electroneutral KHCO3 secretion pathway. These findings reveal new K+ balance mechanisms that drive adaption to alkaline and K+-rich foods, which should guide new treatment strategies for K+ disorders.
Assuntos
Alcalose , Potássio , Animais , Camundongos , Proteínas de Transporte de Ânions/genética , Proteínas de Transporte de Ânions/metabolismo , Ânions/metabolismo , Dieta , Camundongos Knockout , Potássio/metabolismo , Potássio na Dieta/metabolismo , Sódio/metabolismo , Transportadores de Sulfato/genéticaRESUMO
BACKGROUND: The SAGES University Colorectal Masters Program is a structured educational curriculum that is designed to aid practicing surgeons develop and maintain knowledge and technical skills for laparoscopic colorectal surgery. The Colorectal Pathway is based on three anchoring procedures (laparoscopic right colectomy, laparoscopic left and sigmoid colectomy for uncomplicated and complex disease, and intracorporeal anastomosis for minimally invasive right colectomy) corresponding to three levels of performance (competency, proficiency and mastery). This manuscript presents focused summaries of the top 10 seminal articles selected for laparoscopic left and sigmoid colectomy for complex benign and malignant disease. METHODS: A systematic literature search of Web of Science for the most cited articles on the topic of laparoscopic complex left/sigmoid colectomy yielded 30 citations. These articles were reviewed and ranked by the SAGES Colorectal Task Force and invited subject experts according to their citation index. The top 10 ranked articles were then reviewed and summarized, with emphasis on relevance and impact in the field, study findings, strength and limitations and conclusions. RESULTS: The top 10 seminal articles selected for the laparoscopic left/sigmoid colectomy for complex disease anchoring procedure include advanced procedures such as minimally invasive splenic flexure mobilization techniques, laparoscopic surgery for complicated and/or diverticulitis, splenic flexure tumors, complete mesocolic excision, and other techniques (e.g., Deloyers or colonic transposition in cases with limited colonic reach after extended left-sided resection). CONCLUSIONS: The SAGES Colorectal Masters Program top 10 seminal articles selected for laparoscopic left and sigmoid colectomy for complex benign and malignant disease anchoring procedure are presented. These procedures were the most essential in the armamentarium of practicing surgeons that perform minimally invasive surgery for complex left and sigmoid colon pathology.
Assuntos
Neoplasias Colorretais , Laparoscopia , Neoplasias Esplênicas , Humanos , Colo Sigmoide/cirurgia , Laparoscopia/métodos , Anastomose Cirúrgica/métodos , Colectomia/métodos , Neoplasias Esplênicas/cirurgia , Neoplasias Colorretais/cirurgia , Resultado do TratamentoRESUMO
Pendrin is an intercalated cell Cl-/[Formula: see text] exchanger thought to participate in K+-sparing NaCl absorption. However, its role in K+ homeostasis has not been clearly defined. We hypothesized that pendrin-null mice will develop hypokalemia with dietary K+ restriction. We further hypothesized that pendrin knockout (KO) mice mitigate urinary K+ loss by downregulating the epithelial Na+ channel (ENaC). Thus, we examined the role of ENaC in Na+ and K+ balance in pendrin KO and wild-type mice following dietary K+ restriction. To do so, we examined the relationship between Na+ and K+ balance and ENaC subunit abundance in K+-restricted pendrin-null and wild-type mice that were NaCl restricted or replete. Following a NaCl-replete, K+-restricted diet, K+ balance and serum K+ were similar in both groups. However, following a Na+, K+, and Cl--deficient diet, pendrin KO mice developed hypokalemia from increased K+ excretion. The fall in serum K+ observed in K+-restricted pendrin KO mice was enhanced with ENaC stimulation but eliminated with ENaC inhibition. The fall in serum K+ observed in K+-restricted pendrin KO mice was enhanced with ENaC stimulation but eliminated with ENaC inhibition. However, reducing ENaC activity also reduced blood pressure and increased apparent intravascular volume contraction, since KO mice had lower serum Na+, higher blood urea nitrogen and hemoglobin, greater weight loss, greater metabolic alkalosis, and greater NaCl excretion. We conclude that dietary Na+ and K+ restriction induces hypokalemia in pendrin KO mice. Pendrin-null mice limit renal K+ loss by downregulating ENaC. However, this ENaC downregulation occurs at the expense of intravascular volume.NEW & NOTEWORTHY Pendrin is an apical Cl-/[Formula: see text] exchanger that provides renal K+-sparing NaCl absorption. The pendrin-null kidney has an inability to fully conserve K+ and limits renal K+ loss by downregulating the epithelial Na+ channel (ENaC). However, with Na+ restriction, the need to reduce ENaC for K+ balance conflicts with the need to stimulate ENaC for intravascular volume. Therefore, NaCl restriction stimulates ENaC less in pendrin-null mice than in wild-type mice, which mitigates their kaliuresis and hypokalemia but exacerbates volume contraction.
Assuntos
Hipopotassemia , Animais , Proteínas de Transporte de Ânions/metabolismo , Dieta , Canais Epiteliais de Sódio/metabolismo , Camundongos , Camundongos KnockoutRESUMO
This study explores the nature of precarity via the lens of the coronavirus disease (COVID-19) pandemic. Precarity refers to uncertainty, loss, disruption, and anxiety, which differentially impact people across contexts. We sought to (a) identify how people understand and resist precarity during the pandemic; (b) explore the potential of precarity to serve as an organizing concept for psychological praxis and research; and (c) explore ways in which psychology of working theory (PWT) may be enriched by an infusion of precarity into its theoretical tenets. Twenty-seven participants who experienced work-related disruptions completed an open-ended survey during the summer of 2020 about the multifaceted challenges they faced. We used conventional content analysis to analyze the responses and derived the following three themes: (a) disruptions at work elevate precarity; (b) relationships as a source of both stress and resilience/resistance; and (c) expanding critical consciousness and resistance. Using a critical qualitative research lens, we identified ways in which people were protected from, or vulnerable to, the threats to their security. We also explored the complex intersection of structural barriers and social identities in relation to precarity. We presented propositions to guide future scholarship on precarity and PWT. Implications for practice and advocacy conclude the article. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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COVID-19 , Pandemias , Ansiedade , Humanos , Pandemias/prevenção & controle , Pesquisa QualitativaRESUMO
Elevated temperatures activate a heat shock response (HSR) to protect cells from the pathological effects of protein mis-folding, cellular mis-organization, organelle dysfunction and altered membrane fluidity. This response includes activation of the conserved transcription factor heat shock factor 1 (HSF-1), which binds heat shock elements (HSEs) in the promoters of genes induced by heat shock (HS). The upregulation of protein-coding genes (PCGs), such as heat shock proteins and cytoskeletal regulators, is critical for cellular survival during elevated temperatures. While the transcriptional response of PCGs to HS has been comprehensively analyzed in a variety of organisms, the effect of this stress on the expression of non-coding RNAs (ncRNAs) has not been systematically examined. Here we show that in Caenorhabditis elegans HS induces up- and downregulation of specific ncRNAs from multiple classes, including miRNA, piRNA, lincRNA, pseudogene and repeat elements. Moreover, some ncRNA genes appear to be direct targets of the HSR, as they contain HSF-1 bound HSEs in their promoters and their expression is regulated by this factor during HS. These results demonstrate that multiple ncRNA genes respond to HS, some as direct HSF-1 targets, providing new candidates that may contribute to organismal survival during this stress.
Assuntos
Caenorhabditis elegans/genética , Fatores de Transcrição de Choque Térmico/genética , RNA não Traduzido/genética , Transcriptoma/genética , Animais , Proteínas de Caenorhabditis elegans/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica/genética , Fatores de Transcrição de Choque Térmico/química , Resposta ao Choque Térmico/genética , Regiões Promotoras Genéticas , Ativação Transcricional/genéticaRESUMO
INTRODUCTION: Gastrointestinal recovery describes the restoration of normal bowel function in patients with bowel disease. This may be prolonged in two common clinical settings: postoperative ileus and small bowel obstruction. Improving gastrointestinal recovery is a research priority but researchers are limited by variation in outcome reporting across clinical studies. This protocol describes the development of core outcome sets for gastrointestinal recovery in the contexts of postoperative ileus and small bowel obstruction. METHOD: An international Steering Group consisting of patient and clinician representatives has been established. As overlap between clinical contexts is anticipated, both outcome sets will be co-developed and may be combined to form a common output with disease-specific domains. The development process will comprise three phases, including definition of outcomes relevant to postoperative ileus and small bowel obstruction from systematic literature reviews and nominal-group stakeholder discussions; online-facilitated Delphi surveys via international networks; and a consensus meeting to ratify the final output. A nested study will explore if the development of overlapping outcome sets can be rationalized. DISSEMINATION AND IMPLEMENTATION: The final output will be registered with the Core Outcome Measures in Effectiveness Trials initiative. A multi-faceted, quality improvement campaign for the reporting of gastrointestinal recovery in clinical studies will be launched, targeting international professional and patient groups, charitable organizations and editorial committees. Success will be explored via an updated systematic review of outcomes 5 years after registration of the core outcome set.
Assuntos
Íleus , Obstrução Intestinal , Técnica Delphi , Humanos , Íleus/etiologia , Obstrução Intestinal/etiologia , Avaliação de Resultados em Cuidados de Saúde , Projetos de PesquisaRESUMO
AIM: Ileal pouch-anal anastomosis (IPAA) failure occurs in approximately 5%-10% of patients. We aimed to compare short-term (30-day) postoperative outcomes associated with pouch revision and pouch excision using a large international database. Our null hypothesis was that there is no statistically significant difference in overall postoperative complications between patients selected for pouch revision vs pouch excision. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program Participant User File from 2005 to 2016 we identified patients who underwent either IPAA revision via the combined abdominoperineal approach [Current Procedural Terminology (CPT) 46712] or IPAA excision (CPT 45136). Differences in baseline characteristics and short-term outcomes between groups were assessed with univariate and matched analyses. RESULTS: We identified 593 reoperative IPAA procedures: revision group 78 (13%) and excision group 515 (86%). The groups had similar age and body mass index (kg/m2 ), but the revision group had more women (65.4% vs 51.8%, P = 0.02) and fewer were on chronic steroids (3.9% vs 17.9%, P = 0.0008) relative to the excision group. Revision IPAA patients were more likely to have received a preoperative transfusion (5.1% vs 0.97%, P = 0.02). Revision and excision were associated with similar postoperative length of stay (9.3 vs 8.6 days, 0.44), mortality (nil vs 0.58%, respectively; P = 0.99) and short-term morbidity (34.6% vs 40.2%, respectively; P = 0.88) at 30 days. CONCLUSIONS: Pouch revision and excision have comparable short-term postoperative outcomes, but pouch excision appears to be more commonly utilized. Increased awareness of the indications for pouch revision or referral to specialized centres may improve pouch revision rates.
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Complicações Pós-Operatórias/cirurgia , Proctocolectomia Restauradora , Reoperação/estatística & dados numéricos , Estudos Transversais , Feminino , Mortalidade Hospitalar , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Melhoria de Qualidade , Estados UnidosRESUMO
AIM: The prognostic association between mesorectal grading and oncological outcome in patients undergoing resection for rectal adenocarcinoma is controversial. The aim of this retrospective chart review was to determine the individual impact of mesorectal grading on rectal cancer outcomes. METHOD: We compared oncological outcomes in patients with complete, near-complete and incomplete mesorectum who underwent rectal excision with curative intent from 2009 to 2014 for Stage cI-III rectal adenocarcinoma. We also assessed the independent association of mesorectal grading and oncological outcome using multivariate models including other relevant variables. RESULTS: Out of 505 patients (339 men, median age of 60 years), 347 (69%) underwent a restorative procedure. There were 452 (89.5%), 33 (6.5%) and 20 (4%) patients with a complete, near-complete and incomplete mesorectum, respectively. Local recurrence was seen in 2.4% (n = 12) patients after a mean follow-up of 3.1 ± 1.7 years. Unadjusted 3-year Kaplan-Meier analysis by mesorectal grade showed decreased rates of overall, disease-free and cancer-specific survival and increased rates of overall and distant recurrence with a near-complete mesorectum, while local recurrence was increased in cases of an incomplete mesorectum (all P < 0.05). On multivariate analyses, a near-complete mesorectum was independently associated with decreased cancer-specific survival (hazard ratio 0.26, 95% CI 0.1-0.7; P = 0.007). There were no associations between mesorectal grading and overall survival, disease-free survival, overall recurrence or distant recurrence (all P > 0.05). CONCLUSION: Mesorectal grading is independently associated with oncological outcome. It provides unique information for optimizing surgical quality in rectal cancer.
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Adenocarcinoma/mortalidade , Protectomia/mortalidade , Neoplasias Retais/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Mesocolo/cirurgia , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Herein we present a novel sensor for the detection of monosaccharides (e.g. glucose, fructose) in solution, using electrical impedance spectroscopy. The sensor is based on carbon interdigitated electrodes, printed on paper using screen printing. The surface of the electrodes was modified with a thin layer of hydrogel containing acrylamide copolymerised with 20 mol% 3-(Acrylamido)phenylboronic acid (PBA). It was observed that the hydrogel layers containing 20 mol% PBA swell considerably in the presence of glucose and fructose. This in turn changes the measured impedance across the electrodes, making it a suitable sensor for the quantitative detection of saccharides. We investigated the impedance and capacitance variations with different concentrations of glucose and fructose (0-5 mM) in aqueous phosphate buffer solutions. Variations in impedance were attributed to changes in the dielectric properties of the hydrogel under an applied electric field, due to swelling of the hydrogel layer induced by uptake and binding of sugar molecules to the boronate species within the gel. Impedance measurements at 1 kHz demonstrated that hydrogel swelling leads to an increased mobility of ions within the swollen hydrogel layer. The impedance decreased with increasing sugar concentration and the relative capacitance curves are markedly different for fructose and glucose, as the hydrogel exhibits greater swelling in the presence of fructose than glucose over the same concentration range. As the proposed sensor was shown to be suitable for the detection of glucose at concentration levels found in human sweat, future work will focus on the incorporation of these modified paper-based electrodes into wearable skin patches for non-invasive sugar monitoring in sweat.
Assuntos
Espectroscopia Dielétrica , Hidrogéis , Monossacarídeos/análise , Acrilamidas , Impedância Elétrica , Eletrodos , Frutose/análise , Glucose/análise , Humanos , Suor/químicaRESUMO
BACKGROUND: The creation of a diverting loop ileostomy is associated with the risk of readmission due to stoma-related complications. We hypothesized that the assessment of our institution-specific readmissions following ileostomy creation would help identifying at-risk groups which should be the focus of future preventative strategies. METHODS: Patients who underwent loop ileostomy formation from 2009 to 2013 were reviewed. We evaluated readmissions within 30 days after discharge following loop ileostomy construction. Possible associations between readmission and demographic, disease-related and treatment-related factors were assessed using univariate and multivariate analyses. RESULTS: Out of 1267 patients undergoing loop ileostomy construction, 163 patients (12.9%) were readmitted. The main causes of readmissions were organ/space infections (43, 3.4%), small bowel obstruction/ileus (42, 3.3%) and dehydration (38, 3%). Independent factors associated with overall readmission were cardiovascular (OR = 2.0) and renal comorbidity (OR = 2.9), preoperative chemo/radiotherapy (OR = 4.0), laparoscopic approach (OR = 1.7) and longer operative time (OR = 1.2). Cancer diagnosis was associated with reduced readmission rates (OR = 0.2). Independent factors associated with readmission due to dehydration were chemo/radiotherapy (OR = 4.7) and laparoscopic approach (OR = 2.6). CONCLUSIONS: Dehydration associated with diverting ileostomy creation was relevant as an individual cause of readmission, but its overall incidence was relatively rare. Dedicated strategies to prevent dehydration should be directed to patients who received chemoradiotherapy and/or laparoscopic surgery.
Assuntos
Doenças do Colo/cirurgia , Ileostomia/efeitos adversos , Readmissão do Paciente , Doenças Retais/cirurgia , Adulto , Idoso , Doenças Cardiovasculares/epidemiologia , Quimiorradioterapia Adjuvante , Doenças do Colo/epidemiologia , Comorbidade , Desidratação/etiologia , Feminino , Humanos , Ileostomia/métodos , Íleus/etiologia , Nefropatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Duração da Cirurgia , Complicações Pós-Operatórias/etiologia , Doenças Retais/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Infecção da Ferida Cirúrgica/etiologiaRESUMO
Excess calorie consumption, particularly of a diet high in fat, is a risk factor for both obesity and reproductive disorders. Animal model studies indicate that elevated dietary fat can influence some reproductive functions independent of obesity. In the current study we sought to determine whether a high-fat diet (HFD) impacts ovarian function, long-term fertility, and local and systemic markers of inflammation independent of obesity. Five-week-old mice were fed either low-fat diet (control group-LF-Ln) or HFD for 10 wk and were divided based on body weight into high-fat obese (HF-Ob: >25 g) and high-fat lean (HF-Ln: <22 g). Ovaries were collected to assess ovarian follicles and to determine the degree of local inflammation. Serum proinflammatory cytokines were also measured. A group of animals was followed for breeding trials for 5 mo while being exposed to LFD or HFD. We found that both 10-wk and 32-wk exposure to HFD resulted in depleted primordial follicles regardless of obesity phenotype. Macrophage counts revealed increased tissue inflammation in the ovary independent of obesity. In addition, serum proinflammatory cytokines were increased in HF-Ln and HF-Ob in comparison to LF-Ln mice. Moreover, HFD had a sustained effect on litter production rate and number of pups per litter regardless of obese phenotype. This study describes for the first time that exposure to HFD causes significant reduction in primordial follicles, compromised fertility, produced higher proinflammatory cytokine levels, and increased ovarian macrophage infiltration, independent of obesity. The negative effects of HFD on primordial follicles may be mediated by increased tissue inflammation.
Assuntos
Dieta Hiperlipídica , Infertilidade/etiologia , Obesidade/complicações , Doenças Ovarianas/etiologia , Ovário/efeitos dos fármacos , Ovário/fisiopatologia , Animais , Animais Recém-Nascidos , Gorduras na Dieta/farmacologia , Feminino , Tamanho da Ninhada de Vivíparos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos ObesosRESUMO
OBJECTIVE: This study assesses the impact of treadmill-based SET alone or in combination with resistance training on systemic inflammatory response, in patients with intermittent claudication (IC). METHODS: Thirty-five patients with IC were randomised to 12 weeks of treadmill-only SET (Group 1) or a combination of treadmill and lower-limb resistance SET (Group 2). A panel of pro- and anti-inflammatory markers were assessed before, during and after the SET. RESULTS: Over the duration of SET, homocysteine increased within Group 1 (12.0-15.5 µmol/L, p = 0.003) but not Group 2, (13.7-14.7 µmol/) while neutrophil elastase (NE) increased within Group 2 (174.5-238.2 ng/mL, p = 0.007) but not Group 1 (300.8-312.0 ng/mL). In both groups NE increased following acute exercise at the start of the SET. Differences in cytokine expression was evident between the two groups (in Group 1, pro-inflammatory cytokines interleukin-12 and interferon-gamma decreased following an acute bout of exercise at the end of SET, where as in Group 2 pro-inflammatory cytokines interleukin-6 and 8 were seen to increase after an acute bout of exercise at the end of SET). CONCLUSION: SET in patients with IC influences the complex immune-modulatory state of atherosclerosis through inflammatory pathways that induce both pro-inflammatory and immunosuppressive responses.
Assuntos
Citocinas/sangue , Terapia por Exercício/métodos , Mediadores da Inflamação/sangue , Inflamação/terapia , Claudicação Intermitente/terapia , Doença Arterial Periférica/terapia , Treinamento Resistido , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Terapia por Exercício/efeitos adversos , Feminino , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/fisiopatologia , Claudicação Intermitente/sangue , Claudicação Intermitente/diagnóstico , Claudicação Intermitente/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/fisiopatologia , Projetos Piloto , Austrália do Sul , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: Vascular surgical patients, including those with abdominal aortic aneurysm (AAA), are nutritionally vulnerable. The aim of this study was to compare resting energy expenditure (REE) of patients with AAA relative to age- and gender-matched controls and explore relationships between aneurysm size and muscle mass. METHODS: Twenty patients with AAA underwent assessment of REE using indirect calorimetry. Mid-arm circumference and triceps skinfold thickness were measured and corrected arm muscle area calculated. Twenty gender- and age-matched controls were assessed using the same procedures. RESULTS: Mean (SD) age of participants with AAA was 74.7 (7.7) years, size of AAA ranged from 45 to 70 mm. Median (IQR) REE was significantly higher than controls [5990 (5469, 7017) kJ/day versus 5086 (4536, 5886) kJ/day, p = .011; or 69 (64, 80) kJ/kg/day versus 66 (61, 69) kJ/kg/day, p = .046]. While weight-adjusted REE was independent of aneurysm size (r = .200; p = .397), as aneurysm size increased, weight-adjusted corrected arm muscle area decreased (r = -.576; p = .008). CONCLUSION: The raised REE and decline in muscle mass associated with larger AAA suggest that early detection and attention to nutritional requirements of patients with AAA may be warranted.
Assuntos
Aneurisma da Aorta Abdominal/complicações , Metabolismo Energético , Desnutrição/etiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/fisiopatologia , Calorimetria Indireta , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Desnutrição/metabolismo , Desnutrição/patologia , Desnutrição/fisiopatologia , Músculo Esquelético/fisiopatologia , Estado Nutricional , Tamanho do Órgão , Fatores de Risco , Dobras CutâneasRESUMO
Achieving a clear distal or circumferential resection margins with laparoscopic total mesorectal excision (TME) may be laborious, especially in obese males and when operating on advanced distal rectal tumors with a poor response to neoadjuvant treatment. Transanal (TaTME) is a new natural orifice translumenal endoscopic surgery modality in which the rectum is mobilized transanally using endoscopic techniques with or without laparoscopic assistance. We conducted a comprehensive systematic review of publications on this new technique in PubMed and Embase databases from January, 2008, to July, 2014. Experimental and clinical studies written in English were included. Experimental research with TaTME was done on pigs with and without survival models and on human cadavers. In these studies, laparoscopic or transgastric assistance was frequently used resulting in an easier upper rectal dissection and in a longer rectal specimen. To date, 150 patients in 16 clinical studies have undergone TaTME. In all but 15 cases, transabdominal assistance was used. A rigid transanal endoscopic operations/transanal endoscopic microsurgery (TEO/TEM) platform was used in 37 patients. Rectal adenocarcinoma was the indication in all except for nine cases of benign diseases. Operative times ranged from 90 to 460 min. TME quality was deemed intact, satisfactory, or complete. Involvement in circumferential resection margins was detected in 16 (11.8 %) patients. The mean lymph node harvest was equal or greater than 12 in all studies. Regarding morbidity, pneumoretroperitoneum, damage to the urethra, and air embolism were reported intraoperatively. Mean hospital stay varied from 4 to 14 days. Postoperative complications occurred in 34 (22.7 %) patients. TaTME with TEM is feasible in selected cases. Oncologic safety parameters seem to be adequate although the evidence relies on small retrospective series conducted by highly trained surgeons. Further studies are expected.