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1.
ACS Energy Lett ; 9(6): 2727-2735, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38903404

RESUMO

Materials-based H2 storage plays a critical role in facilitating H2 as a low-carbon energy carrier, but there remains limited guidance on the technical performance necessary for specific applications. Metal-organic framework (MOF) adsorbents have shown potential in power applications, but need to demonstrate economic promises against incumbent compressed H2 storage. Herein, we evaluate the potential impact of material properties, charge/discharge patterns, and propose targets for MOFs' deployment in long-duration energy storage applications including backup, load optimization, and hybrid power. We find that state-of-the-art MOF could outperform cryogenic storage and 350 bar compressed storage in applications requiring ≤8 cycles per year, but need ≥5 g/L increase in uptake to be cost-competitive for applications that require ≥30 cycles per year. Existing challenges include manufacturing at scale and quantifying the economic value of lower-pressure storage. Lastly, future research needs are identified including integrating thermodynamic effects and degradation mechanisms.

2.
Oxf J Leg Stud ; 44(2): 231-256, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38855117

RESUMO

Realist theories of legislative intent can be divided between aggregative theories (on which legislative intent is what some proportion of legislators intend) and common intent theories (on which legislative intent is a unanimous intent among legislators). In this article, we advance and defend an alternative realist conception of legislative intent: the rational unity account. On this account, the legislature is an agent with a distinctive 'rational point of view'-a concept we adopt from social ontology. The legislature's rational point of view is shaped by its procedures and structures, in ways not determined by either a common intention held by legislators or an aggregation of the intentions of legislators. We explain how our view improves on existing accounts. We then apply it to three cases to demonstrate its implications for legal interpretation. Importantly, on the proposed account, legislative intent can depart from what individual legislators think or know.

3.
J Vet Intern Med ; 38(3): 1725-1729, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38500407

RESUMO

Trypanosoma cruzi infection in dogs can cause heart failure and sudden death with few treatment options available. A litter of 4 dogs living in a T cruzi endemic area were randomized to prophylaxis and nonprophylaxis groups as part of a study evaluating a modified benznidazole dosing regimen administered twice weekly to prevent T cruzi infection during a vector transmission season. The 2 dogs that received prophylaxis remained healthy without T cruzi infection or cardiac disease for >2 years. One dog that did not receive prophylaxis died unexpectedly with acute T cruzi-induced pancarditis, and the second dog tested positive for T cruzi and developed complex arrhythmias with markedly increased cardiac troponin I and improved with a higher benznidazole treatment dose. Although the small sample size precludes definitive conclusions, we describe the potential clinical benefit of prophylactic and early treatment with modified benznidazole dosing regimens for dogs with T cruzi infection.


Assuntos
Doença de Chagas , Doenças do Cão , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Cães , Animais , Nitroimidazóis/uso terapêutico , Nitroimidazóis/administração & dosagem , Doenças do Cão/tratamento farmacológico , Doença de Chagas/veterinária , Doença de Chagas/tratamento farmacológico , Trypanosoma cruzi/efeitos dos fármacos , Tripanossomicidas/uso terapêutico , Tripanossomicidas/administração & dosagem , Feminino , Masculino
4.
Nature ; 626(8000): 859-863, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38326609

RESUMO

Bacteria in the gastrointestinal tract produce amino acid bile acid amidates that can affect host-mediated metabolic processes1-6; however, the bacterial gene(s) responsible for their production remain unknown. Herein, we report that bile salt hydrolase (BSH) possesses dual functions in bile acid metabolism. Specifically, we identified a previously unknown role for BSH as an amine N-acyltransferase that conjugates amines to bile acids, thus forming bacterial bile acid amidates (BBAAs). To characterize this amine N-acyltransferase BSH activity, we used pharmacological inhibition of BSH, heterologous expression of bsh and mutants in Escherichia coli and bsh knockout and complementation in Bacteroides fragilis to demonstrate that BSH generates BBAAs. We further show in a human infant cohort that BBAA production is positively correlated with the colonization of bsh-expressing bacteria. Lastly, we report that in cell culture models, BBAAs activate host ligand-activated transcription factors including the pregnane X receptor and the aryl hydrocarbon receptor. These findings enhance our understanding of how gut bacteria, through the promiscuous actions of BSH, have a significant role in regulating the bile acid metabolic network.


Assuntos
Aciltransferases , Amidoidrolases , Aminas , Ácidos e Sais Biliares , Biocatálise , Microbioma Gastrointestinal , Humanos , Aciltransferases/metabolismo , Amidoidrolases/metabolismo , Aminas/química , Aminas/metabolismo , Bacteroides fragilis/enzimologia , Bacteroides fragilis/genética , Bacteroides fragilis/metabolismo , Ácidos e Sais Biliares/química , Ácidos e Sais Biliares/metabolismo , Estudos de Coortes , Escherichia coli/enzimologia , Escherichia coli/genética , Escherichia coli/metabolismo , Microbioma Gastrointestinal/fisiologia , Ligantes , Receptor de Pregnano X/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Fatores de Transcrição/metabolismo , Lactente , Técnicas de Cultura de Células
5.
Nature ; 626(7998): 419-426, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38052229

RESUMO

Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis1,2, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn's disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4+ T cells3 and agonism of the pregnane X receptor4. Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover other molecules from human and animal ecosystems.


Assuntos
Amidas , Ácidos e Sais Biliares , Ésteres , Ácidos Graxos , Metabolômica , Animais , Humanos , Bifidobacterium/metabolismo , Ácidos e Sais Biliares/química , Ácidos e Sais Biliares/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Clostridium/metabolismo , Estudos de Coortes , Doença de Crohn/metabolismo , Enterococcus/metabolismo , Ésteres/química , Ésteres/metabolismo , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Metabolômica/métodos , Fenótipo , Receptor de Pregnano X/metabolismo , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Amidas/química , Amidas/metabolismo
6.
Clin Breast Cancer ; 23(6): 658-663, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37296062

RESUMO

BACKGROUND: Palbociclib is indicated for the treatment of hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC) in combination with an aromatase inhibitor or fulvestrant. Two retrospective studies found that concurrent proton pump inhibitor (PPI) use with palbociclib capsules significantly reduced progression free survival (PFS) versus patients without a PPI. Palbociclib tablets were released in 2020 without restriction on PPI use. No study to date has evaluated the combination of palbociclib tablets with concurrent PPI use. METHODS: Patients were retrospectively evaluated after they received palbociclib tablets for the treatment of HR+ HER2- MBC in the first line setting with or without a PPI. Patients were assigned to the no PPI use arm if they never used a PPI and the PPI use arm if they used a PPI for >50% of the duration of palbocicib therapy. The primary endpoint was PFS. The secondary endpoints included overall survival (OS) and adverse events. RESULTS: Eighty-two patients were identified; 50 in the no PPI use group and 32 in the PPI use group. The median PFS was 20.6 months (95% confidence interval [CI], 16.07 to not estimable) in the no PPI use arm versus 21.0 months (95% CI, 15.15 to not estimable) in the PPI use arm (P = 0.95). Median OS was not reached in either arm. Adverse effects did not differ between arms. CONCLUSION: Use of a concurrent PPI with palbociclib tablets does not significantly reduce PFS in patients treated for HR+ HER2- MBC.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Inibidores da Bomba de Prótons/uso terapêutico , Estudos Retrospectivos , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
7.
Nat Rev Microbiol ; 21(4): 236-247, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36253479

RESUMO

Despite decades of bile acid research, diverse biological roles for bile acids have been discovered recently due to developments in understanding the human microbiota. As additional bacterial enzymes are characterized, and the tools used for identifying new bile acids become increasingly more sensitive, the repertoire of bile acids metabolized and/or synthesized by bacteria continues to grow. Additionally, bile acids impact microbiome community structure and function. In this Review, we highlight how the bile acid pool is manipulated by the gut microbiota, how it is dependent on the metabolic capacity of the bacterial community and how external factors, such as antibiotics and diet, shape bile acid composition. It is increasingly important to understand how bile acid signalling networks are affected in distinct organs where the bile acid composition differs, and how these networks impact infectious, metabolic and neoplastic diseases. These advances have enabled the development of therapeutics that target imbalances in microbiota-associated bile acid profiles.


Assuntos
Microbioma Gastrointestinal , Microbiota , Humanos , Ácidos e Sais Biliares/metabolismo , Bactérias/metabolismo , Transdução de Sinais
8.
PLoS Negl Trop Dis ; 16(10): e0010688, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36315597

RESUMO

Trypanosoma cruzi naturally infects a wide variety of wild and domesticated mammals, in addition to humans. Depending on the infection dose and other factors, the acute infection can be life-threatening, and in all cases, the risk of chagasic heart disease is high in persistently infected hosts. Domestic, working, and semi-feral dogs in the Americas are at significant risk of T. cruzi infection and in certain settings in the southern United States, the risk of new infections can exceed 30% per year, even with the use of vector control protocols. In this study, we explored whether intermittent low-dose treatment with the trypanocidal compound benznidazole (BNZ) during the transmission season, could alter the number of new infections in dogs in an area of known, intense transmission pressure. Preliminary studies in mice suggested that twice-weekly administration of BNZ could prevent or truncate infections when parasites were delivered at the mid-point between BNZ doses. Pre-transmission season screening of 126 dogs identified 53 dogs (42.1%) as T. cruzi infection positive, based upon blood PCR and Luminex-based serology. Serial monitoring of the 67 uninfected dogs during the high transmission season (May to October) revealed 15 (22.4%) new infections, 6 in the untreated control group and 9 in the group receiving BNZ prophylaxis, indicating no impact of this prophylaxis regimen on the incidence of new infections. Although these studies suggest that rigorously timed and more potent dosing regimen may be needed to achieve an immediate benefit of prophylaxis, additional studies would be needed to determine if drug prophylaxis reduced disease severity despite this failure to prevent new infections.


Assuntos
Doença de Chagas , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Humanos , Cães , Animais , Camundongos , Tripanossomicidas/uso terapêutico , Doença de Chagas/tratamento farmacológico , Doença de Chagas/prevenção & controle , Doença de Chagas/veterinária , Nitroimidazóis/uso terapêutico , Mamíferos
9.
J Oncol Pharm Pract ; 28(8): 1885-1888, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36000299

RESUMO

Telehealth applications are demonstrated to be useful tools for patients with cancer to facilitate improvements in quality of care. The use of electronic patient-reported outcomes is one way to leverage telehealth to better understand outcomes important to patients. However, use of electronic patient-reported outcomes and direct involvement of pharmacists is not yet a standard practice across cancer centers. The use of pharmacist-led telehealth services offers a unique opportunity for pharmacists to provide cost-effective and convenient patient care interventions. This survey work describes the current practices of pharmacy utilization of electronic patient-reported outcomes in oncology populations at National Comprehensive Cancer Network member institutions. Of survey respondents, only 33% of the institutions reported current engagement with electronic patient-reported outcomes. These initiatives largely focused on symptom management. Limitations in staff, resources, and competing priorities limit many institutions from introducing or expanding upon direct pharmacist involvement in electronic patient-reported outcomes. Further work developing the involvement of pharmacists in electronic patient-reported outcomes will be an important way to leverage the growing landscape of telehealth within oncology and highlight the value of the pharmacist.


Assuntos
Assistência Farmacêutica , Farmácia , Humanos , Papel Profissional , Farmacêuticos , Medidas de Resultados Relatados pelo Paciente , Eletrônica
10.
Target Oncol ; 17(2): 167-175, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35325355

RESUMO

BACKGROUND: Neoadjuvant chemotherapy is the cornerstone treatment for locally advanced breast cancer. Balancing toxicity and efficacy are a common concern of patients treated with chemotherapy. OBJECTIVE: The objective of this study was to determine the impact of dose intensity on pathologic complete response (pCR) at the time of surgery in patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. PATIENTS AND METHODS: A retrospective, single-center review was conducted on patients with HER2+ breast cancer who received neoadjuvant docetaxel, carboplatin, trastuzumab and pertuzumab (TCHP) followed by definitive surgery. RESULTS: A total of 159 patients were included in the analysis; pCR was obtained in 66 patients (42%). There was no statistically significant difference between the mean dose intensity of each of the individual agents in TCHP and pCR rates. The mean overall dose intensity of docetaxel, carboplatin, trastuzumab and pertuzumab was 90.5%, 90.9%, 97.5%, and 93.9%, respectively. Although higher chemotherapy dose intensity (> 85%) was associated with higher pCR rates, no statistically significant difference was found compared with chemotherapy dose intensity < 85%. The TCHP regimen was difficult to tolerate; 104 patients (65%) required a dose reduction or dose delay during treatment due to toxicity. CONCLUSION: The TCHP regimen, which combines chemotherapy and HER2-directed therapy is effective at obtaining pCR in patients with locally advanced HER2+ breast cancer. These results suggest that the dose intensity of the individual agents did not have a significant impact on pCR rates. Given these findings, providers may be more comfortable allowing dose reductions for greater patient tolerability without sacrificing efficacy.


Assuntos
Neoplasias da Mama , Terapia Neoadjuvante , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Feminino , Humanos , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico
11.
Inorg Chem ; 61(3): 1228-1235, 2022 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-34982547

RESUMO

The syntheses and photophysical characterization of five new gold(I) complexes bearing diphenylamine-substituted fluorenyl moieties are reported; four are characterized by X-ray diffraction crystallography. Ancillary ligation on gold(I) is provided by organophosphine and N-heterocyclic carbene ligands. Two complexes, Au-DPA0 and Au-DPA1, are σ-aryls, two, Au-ADPA0 and Au-ADPA1, are σ-alkynyls, and one, Au-TDPA1, is a σ-triazolyl bound through carbon. All complexes show vibronically structured absorption and luminescence bands that are assignable to π-π* transitions localized on the diphenylamine-substituted fluorenyl π system. The excited-state dynamics of all five chromophores are governed by selection of the ancillary ligand and σ attachment of the diphenylamine-substituted fluorenyl moiety. All of these chromophores are dual luminescent in a toluene solution at 298 K. The luminescence from the aryl derivatives, Au-ADPA0 and Au-DPA1, appears green. The alkynyl derivative containing a phosphine ancillary ligand, Au-ADPA0, is a white-light emitter, while the alkynyl derivative containing an N-heterocyclic carbene ancillary ligand, Au-ADPA1, is a yellow-light emitter. The luminescence from the triazolyl-linked chromophore, Au-TDPA1, appears as yellow-green. Spin-restricted density functional theory calculations support the assignments of ligand-centric optical transitions but with contributions of ligand-to-metal charge transfer involving the vacant Au 6p orbital.

12.
Annu Rev Anal Chem (Palo Alto Calif) ; 14(1): 467-487, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34314226

RESUMO

High-resolution mass spectrometry (MS) has advanced the study of metabolism in living systems by allowing many metabolites to be measured in a single experiment. Although improvements in mass detector sensitivity have facilitated the detection of greater numbers of analytes, compound identification strategies, feature reduction software, and data sharing have not kept up with the influx of MS data. Here, we discuss the ongoing challenges with MS-based metabolomics, including de novo metabolite identification from mass spectra, differentiation of metabolites from environmental contamination, chromatographic separation of isomers, and incomplete MS databases. Because of their popularity and sensitive detection of small molecules, this review focuses on the challenges of liquid chromatography-mass spectrometry-based methods. We then highlight important instrumentational, experimental, and computational tools that have been created to address these challenges and how they have enabled the advancement of metabolomics research.


Assuntos
Metabolômica , Software , Cromatografia Líquida , Bases de Dados Factuais , Espectrometria de Massas
13.
Nature ; 595(7866): 272-277, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34163067

RESUMO

Diet is a major factor that shapes the gut microbiome1, but the consequences of diet-induced changes in the microbiome for host pathophysiology remain poorly understood. We conducted a randomized human intervention study using a very-low-calorie diet (NCT01105143). Although metabolic health was improved, severe calorie restriction led to a decrease in bacterial abundance and restructuring of the gut microbiome. Transplantation of post-diet microbiota to mice decreased their body weight and adiposity relative to mice that received pre-diet microbiota. Weight loss was associated with impaired nutrient absorption and enrichment in Clostridioides difficile, which was consistent with a decrease in bile acids and was sufficient to replicate metabolic phenotypes in mice in a toxin-dependent manner. These results emphasize the importance of diet-microbiome interactions in modulating host energy balance and the need to understand the role of diet in the interplay between pathogenic and beneficial symbionts.


Assuntos
Bactérias/isolamento & purificação , Bactérias/metabolismo , Restrição Calórica , Dieta Redutora , Microbioma Gastrointestinal/fisiologia , Adiposidade , Animais , Bactérias/crescimento & desenvolvimento , Bactérias/patogenicidade , Toxinas Bacterianas/metabolismo , Ácidos e Sais Biliares/metabolismo , Peso Corporal , Clostridioides difficile/crescimento & desenvolvimento , Clostridioides difficile/isolamento & purificação , Clostridioides difficile/metabolismo , Metabolismo Energético , Humanos , Absorção Intestinal , Masculino , Camundongos , Nutrientes/metabolismo , Simbiose , Redução de Peso
14.
BMC Med Genomics ; 14(1): 167, 2021 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-34174888

RESUMO

BACKGROUND: Data on the modalities of disclosing genomic secondary findings (SFs) remain scarce. We explore cancer patients' and the general public's perspectives about disclosing genomic SFs and the modalities of such disclosure. METHODS: Sixty-one cancer patients (n = 29) and members of the public (n = 32) participated in eight focus groups in Montreal and Quebec City, Canada. They were asked to provide their perspectives of five fictitious vignettes related to medically actionable and non-actionable SFs. Two researchers used a codification framework to conduct a thematic content analysis of the group discussion transcripts. RESULTS: Cancer patients and members of the public were open to receive genomic SFs, considering their potential clinical and personal utility. They believed that the right to know or not and share or not such findings should remain the patient's decision. They thought that the disclosure of SFs should be made mainly in person by the prescribing clinician. Maintaining confidentiality when so requested and preventing genetic discrimination were considered essential. CONCLUSION: Participants in this study welcomed the prospect of disclosing genomic SFs, as long as the right to choose to know or not to know is preserved. They called for the development of policies and practice guidelines that aim to protect genetic information confidentiality as well as the autonomy, physical and psychosocial wellbeing of patients and families.


Assuntos
Genômica
15.
Fluids Barriers CNS ; 18(1): 8, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33579319

RESUMO

BACKGROUND: Astronauts undergoing long-duration spaceflight are exposed to numerous health risks, including Spaceflight-Associated Neuro-Ocular Syndrome (SANS), a spectrum of ophthalmic changes that can result in permanent loss of visual acuity. The etiology of SANS is not well understood but is thought to involve changes in cerebrovascular flow dynamics in response to microgravity. There is a paucity of knowledge in this area; in particular, cerebrospinal fluid (CSF) flow dynamics have not been well characterized under microgravity conditions. Our study was designed to determine the effect of simulated microgravity (head-down tilt [HDT]) on cerebrovascular flow dynamics. We hypothesized that microgravity conditions simulated by acute HDT would result in increases in CSF pulsatile flow. METHODS: In a prospective cohort study, we measured flow in major cerebral arteries, veins, and CSF spaces in fifteen healthy volunteers using phase contrast magnetic resonance (PCMR) before and during 15° HDT. RESULTS: We found a decrease in all CSF flow variables [systolic peak flow (p = 0.009), and peak-to-peak pulse amplitude (p = 0.001)]. Cerebral arterial average flow (p = 0.04), systolic peak flow (p = 0.04), and peak-to-peak pulse amplitude (p = 0.02) all also significantly decreased. We additionally found a decrease in average cerebral arterial flow (p = 0.040). Finally, a significant increase in cerebral venous cross-sectional area under HDT (p = 0.005) was also observed. CONCLUSIONS: These results collectively demonstrate that acute application of -15° HDT caused a reduction in CSF flow variables (systolic peak flow and peak-to-peak pulse amplitude) which, when coupled with a decrease in average cerebral arterial flow, systolic peak flow, and peak-to-peak pulse amplitude, is consistent with a decrease in cardiac-related pulsatile CSF flow. These results suggest that decreases in cerebral arterial inflow were the principal drivers of decreases in CSF pulsatile flow.


Assuntos
Artérias Cerebrais/diagnóstico por imagem , Veias Cerebrais/diagnóstico por imagem , Líquido Cefalorraquidiano/diagnóstico por imagem , Líquido Cefalorraquidiano/fisiologia , Circulação Cerebrovascular/fisiologia , Decúbito Inclinado com Rebaixamento da Cabeça/fisiologia , Hidrodinâmica , Fluxo Pulsátil/fisiologia , Simulação de Ausência de Peso , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Estudos Prospectivos , Adulto Jovem
16.
Asia Pac J Clin Oncol ; 17(1): 84-93, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32978897

RESUMO

AIM: Colorectal cancer (CRC) is the third most common cancer in Australia, and survival after diagnosis of metastatic disease is improving. Our aim was to assess trends in epidemiology, treatment, molecular testing and survival in patients with metastatic CRC (mCRC). METHODS: Clinical data from February 2013 to December 2018 was recorded in a prospective, observational, multicenter cohort study conducted in Queensland, Australia, examining clinical and molecular biomarkers in cases of mCRC. RESULTS: A total of 159 patients who had metastasis diagnosed after February 2013 were included in survival analysis. Median age at diagnosis was 63.9 years, but 29% had early-onset disease (diagnosis aged <50 years). Median overall survival was 2.5 years (95% confidence interval [CI], 2.2-3.0) for the 159 patients included in survival analysis. Independent factors correlated with poor prognosis included right-sided primary tumor, neutrophil-lymphocyte ratio >5, increased alkaline phosphatase level (ALP) and an increasing number of sites of metastatic disease. In contrast, metastasectomy was associated with improved overall survival (adjusted HR = 0.29' 95% CI, 0.16-0.54), with similar survival between patients who had liver and non-liver metastasectomy sites. Half (10/20) of the BRAF mutant CRC were also microsatellite unstable. The proportion of detected mutations amongst tested samples increased over time for Kirsten Rat Sarcoma (KRAS; OR [per year] = 1.19; 95% CI, 1.01-1.39). Concurrently, the methods of molecular genetics testing employed in routine clinical practice changed towards the adoption of next-generation sequencing. CONCLUSIONS: Metastasectomy in mCRC may be beneficial regardless of the anatomical site of metastasis. The adoption of next-generation sequencing techniques for molecular genetics testing coincided with a slightly increased rate of detection of KRAS and BRAF mutations, potentially reflecting greater test sensitivity. Further translational research is required in mCRC to define novel targets for treatment.


Assuntos
Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Feminino , Humanos , Masculino , Metastasectomia , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Prognóstico , Estudos Prospectivos , Queensland/epidemiologia , Análise de Sobrevida
17.
J Food Prot ; 84(4): 611-627, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33232460

RESUMO

ABSTRACT: The Canadian Food Inspection Agency is developing an Establishment-based Risk Assessment (ERA) model for commercial and on-farm mills involved in the manufacture, storage, packaging, labeling, or distribution of livestock feed (ERA-Feed Mill model). This model will help inform the allocation of inspection resources on the basis of feed safety risk, including animal health and food safety risk. In a previous study, 34 risk factors, grouped into inherent, mitigation, and compliance clusters, along with assessment criteria were selected. The objective of this current study was to estimate the relative risk (RR) of the 203 assessment criteria on the basis of the impact on feed safety to design an ERA-Feed Mill model algorithm. Furthermore, the intent of this study was to assess the maximum increase or decrease of risk obtained when multiple criteria belonging to a same cluster were identified in a specific feed mill. To do so, a two-round face-to-face expert elicitation was conducted with 28 Canadian feed experts. Results showed no significant association between respondent profiles (years of experience and work sector) and estimated RR. Uniformity of answers between experts improved between rounds. Criteria having the highest increase in risk (median RR ≥ 4) included the presence of materials prohibited to be fed to ruminants in a facility that produces ruminant feed, the presence of multiple livestock species on-site, and historical noncompliances related to the inspection of the feed mill's process control and end-product control programs. Risk mitigation criteria having the highest impact on decreasing the risk were the implementation of feed safety certifications, the use of dedicated manufacturing lines (prohibited materials or medications), and having a hazard sampling plan in place for finished feed. The median RR assigned to each criterion and cluster will be used to build an algorithm of the Canadian Food Inspection Agency's ERA-Feed Mill model.


Assuntos
Inspeção de Alimentos , Inocuidade dos Alimentos , Ração Animal , Animais , Canadá , Medição de Risco , Fatores de Risco
18.
Food Chem Toxicol ; 147: 111854, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33197547

RESUMO

Of the five agriculturally important mycotoxins, AFB1, FB1, DON, ZEA and OTA, a well-characterized biomarker of exposure in blood is only available for aflatoxin. Working with a population of 139 women of childbearing age in Rwanda, we undertook a comprehensive assessment of their dietary mycotoxin exposure. Using high-resolution LC-MS/MS with stable isotope dilution analysis, the albumin-aflatoxin adduct was quantitated in plasma. Similarly, AFM1, AFB1, AFG1, FB1 and B2, OTA, zearalenone, α-zearalenol, deoxynivalenol, deoxynivalenol-15-glucuronide and deoxynivalenol-3-glucuronide were quantitated in urine. AFB1-Lys was detected in plasma from 81% of the women, indicative of exposures 1-2 orders of magnitude above current guidance. Zearalenone and/or α-zearalenol were detected in the urine of 61% of the women, the majority of whom had estimated exposures 2-5 times the PMTDI, with one third more than an order of magnitude above. Urinary deoxynivalenol or the two glucuronide conjugates were found in 77% of the participants. Of these, 60% were below the PMTDI, 28% were twice and 12% were >10x the PMTDI. Fumonisin B1 (30%) and ochratoxin A (71%) were also detected in urine. Exposures observed in these Rwandan women raise serious food safety concerns and highlight the need for authorities to help manage multiple mycotoxins in their diet.


Assuntos
Contaminação de Alimentos , Micotoxinas/toxicidade , Complicações na Gravidez/induzido quimicamente , Adulto , Biomarcadores/sangue , Feminino , Humanos , Micotoxinas/sangue , Micotoxinas/química , Gravidez , Complicações na Gravidez/prevenção & controle , Ruanda
19.
Acta Pharm Sin B ; 10(1): 19-32, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31998605

RESUMO

Microbes inhabiting the intestinal tract of humans represent a site for xenobiotic metabolism. The gut microbiome, the collection of microorganisms in the gastrointestinal tract, can alter the metabolic outcome of pharmaceuticals, environmental toxicants, and heavy metals, thereby changing their pharmacokinetics. Direct chemical modification of xenobiotics by the gut microbiome, either through the intestinal tract or re-entering the gut via enterohepatic circulation, can lead to increased metabolism or bioactivation, depending on the enzymatic activity within the microbial niche. Unique enzymes encoded within the microbiome include those that reverse the modifications imparted by host detoxification pathways. Additionally, the microbiome can limit xenobiotic absorption in the small intestine by increasing the expression of cell-cell adhesion proteins, supporting the protective mucosal layer, and/or directly sequestering chemicals. Lastly, host gene expression is regulated by the microbiome, including CYP450s, multi-drug resistance proteins, and the transcription factors that regulate them. While the microbiome affects the host and pharmacokinetics of the xenobiotic, xenobiotics can also influence the viability and metabolism of the microbiome. Our understanding of the complex interconnectedness between host, microbiome, and metabolism will advance with new modeling systems, technology development and refinement, and mechanistic studies focused on the contribution of human and microbial metabolism.

20.
Sante Publique ; Vol. 31(4): 485-495, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31959249

RESUMO

INTRODUCTION: ‘Dementia’ is usually presented as a syndrome characterized by the decline of one or more cognitive abilities such as memory loss. However, memory loss does not necessarily mean dementia. The most common type of dementia is Alzheimer’s disease. Its incidence increases with age. In medical anthropology, diseases represent socio-cultural constructs that are not recognized and interpreted in the same way by everyone. Moreover, the migratory context is a source of difficulties in the field of dementia. In this article, we discuss the links between old age, dementia and seeking help in this context. METHOD: This is an exploratory qualitative study. Ten semi-structured interviews were conducted with women and men born in Haiti who then immigrated to Quebec. These interviews allowed us to discuss seniors’ status issues, the meaning of memory loss and seeking help. RESULTS: Interview data reveal a plurality of representations about memory loss and Alzheimer’s disease. They highlight a diversity of beliefs, attitudes and values that reflect cultural and social changes within the same community. Taking into account the context makes it possible to consider the transformation or continuity of representations and behaviors vis-à-vis loss of memory. CONCLUSION: Dementia does not seem to be a phenomenon that is easily approached in the Haitian community in Quebec. Our study reveals a lack of information in this regard.


Assuntos
Envelhecimento , Conhecimentos, Atitudes e Prática em Saúde , Transtornos da Memória , Migrantes/psicologia , Envelhecimento/fisiologia , Envelhecimento/psicologia , Atitude , Feminino , Grupos Focais , Haiti/etnologia , Humanos , Entrevistas como Assunto , Masculino , Pesquisa Qualitativa , Quebeque
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