The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders ...such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.
Meaningful clinical decision support (CDS) recommendations are vital for implementation of pharmacogenomics (PGx) into routine clinical care. PGx CDS alerts include interruptive and noninterruptive ...alerts. The objective of this study was to evaluate provider ordering behavior after noninterruptive alerts are displayed. A retrospective manual chart review was conducted from the time of noninterruptive alert implementation to the time of data analysis to determine congruence with CDS recommendations. The congruence rate for noninterruptive alerts was 89.8% across all drug-gene interactions. The drug-gene interaction with the most alerts for analysis included metoclopramide (n = 138). The high rate of medication order congruence after noninterruptive alerts were deployed suggests this modality may be appropriate for PGx CDS as a method for best practice adherence.
Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) that shares many features with the human disease. This review will focus on the role of IL-17-secreting ...CD4 and γδ T cells in EAE and MS, the plasticity of Th17 cells in vivo and the application of these findings to the understating of the pathogenesis and the development of new treatments for MS. There is convincing evidence that IL-17-secreting CD4 T cells (Th17 cells) and IL-17-secreting γδ T cells play a critical pathogenic role in central nervous system (CNS) inflammation in EAE and MS. Indeed a significant number of the major discoveries on the pathogenic role of IL-17-secreting T cells in autoimmunity were made in the EAE model. These included the first demonstration that IL-23-activated IL-17-secreting T cells are the key T cells in driving autoimmune disease pathology. Although the early studies on IL-17 focused on Th17 cells, it was later demonstrated that γδ T cells were an important early source of IL-17 and IL-21 that helped amplify IL-17 production by Th17 cells in autoimmune diseases. Furthermore, it emerged that Th1 cells can also have encephalitogenic activity and that there was considerable plasticity in these T cell responses, with Th17 cells reverting to a Th1 phenotype in vivo. This questioned the pathogenic role of IL-17 and suggested that other cytokines, such as IFN-γ, GM-CSF and TNF, may be important. Nevertheless, biological drugs that target the IL-23-IL-17 pathway are highly effective in treating human psoriasis and are showing promise in the treatment of relapsing remitting MS and other T-cell mediated autoimmune diseases.
•Th17 cells and IL-17-secreting γδ T cells are pathogenic in EAE and MS.•IL-17-secreting γδ T cells kick start the inflammatory process in EAE.•Pathogenic Th17 cells can revert to Th1-type cells in vivo in EAE.•Drugs that target IL-23 and IL-17 pathways have potential for the treatment of MS.
Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by deposits of amyloid-β and neurofibrillary tangles. It has been suggested that inflammatory changes are ...associated with disease; however, it has not been established whether these are a consequence of ongoing neurodegeneration or whether inflammation itself contributes to disease pathogenesis. Recent studies suggest that exposure to infection can accelerate cognitive decline in AD patients, and pathogens have been detected in the AD brain. However, the influence of infection on neuroinflammation and pathology remains poorly understood. In this study, we examined the effect of a peripheral infection on AD pathology in APP/PS1 mice. We found that, 8 weeks after infection with the Gram negative respiratory pathogen Bordetella pertussis , there was significant infiltration of IFNγ- and IL-17–producing T cells and NKT cells in older APP/PS1 mice. This was accompanied by increased glial activation and amyloid-β deposition. The data suggest that infection is a critical factor in the progression of AD, emphasising the importance of early diagnosis and treatment of infections in elderly individuals.
Whole cell pertussis vaccines (Pw) induce Th1 responses and protect against Bordetella pertussis infection, whereas pertussis acellular vaccines (Pa) induce Ab and Th2-biased responses and also ...protect against severe disease. In this study, we show that Pw failed to generate protective immunity in TLR4-defective C3H/HeJ mice. In contrast, protection induced with Pa was compromised, but not completely abrogated, in C3H/HeJ mice. Immunization with Pw, but not Pa, induced a population of IL-17-producing T cells (Th-17), as well as Th1 cells. Ag-specific IL-17 and IFN-gamma production was significantly lower in Pw-immunized TLR4-defective mice. Furthermore, treatment with neutralizing anti-IL-17 Ab immediately before and after B. pertussis challenge significantly reduced the protective efficacy of Pw. Stimulation of dendritic cells (DC) with Pw promoted IL-23, IL-12, IL-1beta, and TNF-alpha production, which was impaired in DC from TLR4-defective mice. B. pertussis LPS, which is present in high concentrations in Pw, induced IL-23 production by DC, which enhanced IL-17 secretion by T cells, but the induction of Th-17 cells was also dependent on IL-1. In addition, we identified a new effector function for IL-17, activating macrophage killing of B. pertussis, and this bactericidal activity was less efficient in macrophages from TLR4-defective mice. These data provide the first definitive evidence of a role for TLRs in protective immunity induced by a human vaccine. Our findings also demonstrate that activation of innate immune cells through TLR4 helps to direct the induction of Th1 and Th-17 cells, which mediate protective cellular immunity to B. pertussis.
Highlights • A concurrent respiratory infection can ameliorate CNS disease in the EAE model. • Bacterial pathogens can exert bystander suppression on autoimmunity. • Bacterial-induced IL-10 can ...protect against CNS inflammation. • IL-10 suppresses licensing of autoaggressive T cells in the lungs.
Fluoropyrimidines (fluorouracil, capecitabine, and other analogs) are highly used anticancer drugs worldwide. However, patients with cancer treated with these drugs might experience severe, ...life-threatening toxicity because of germline genetic variation in the
gene. This is a genetic predisposition with an established mechanistic basis that links genetic variation in the
gene to an increase in systemic drug exposure, resulting in an increased risk of toxicity. Pharmacology guidelines provide recommendations on avoiding treatment with fluoropyrimidines or reducing their dose in patients carrying
genetic variants conferring an increased risk of toxicity. However, oncology societies in the United States do not recommend systematic testing. Instead, on April 30, 2020, the European Society for Medical Oncology issued a document recommending genetic testing. In this scenario of contradicting information, practicing oncologists struggle with reaching an informed decision on whether genetic testing should be applied before treatment. This is mostly due to uncertainty about the clinical relevance of genetic testing from the perspective of a practicing oncologist. To reach an informed decision, practicing oncologists need access to concise information on the genetic variants to be tested and a practitioner-friendly interpretation of the test results. We believe this information is currently lacking. To our knowledge, for the first time, we provide a single guide for health care professionals to make an evidence-based decision about
testing for patients with cancer. This article provides the essential knowledge base for oncologists to have an informed discussion with their patients about the genetic testing for
. This document assists practitioners in quickly evaluating whether, when, where, and how to order a
genetic test.
Anal Squamous Cell Carcinoma (ASCC) is a rare cancer that has a rapidly increasing incidence in areas with highly developed economies. ASCC is strongly associated with HIV and there appears to be ...increasing numbers of younger male persons living with HIV (PLWH) diagnosed with ASCC. This is a retrospective cohort study of HIV positive and HIV negative patients diagnosed with primary ASCC between January 2000 and January 2020 in a demographic group with high prevalence rates of HIV. One Hundred and seventy six patients were included, and clinical data was retrieved from multiple, prospective databases. A clinical subgroup was identified in this cohort of younger HIV positive males who were more likely to have had a prior diagnosis of Anal Intraepithelial Neoplasia (AIN). Gender and HIV status had no effect on staging or disease-free survival. PLWH were more likely to develop a recurrence (p < 0.000) but had a longer time to recurrence than HIV negative patients, however this was not statistically significant (46.1 months vs. 17.5 months; p = 0.077). Patients known to have a previous diagnosis of AIN were more likely to have earlier staging and local tumour excision. Five-year Disease-Free Survival was associated with tumour size and the absence of nodal or metastatic disease (p < 0.000).
To identify patient factors associated with a clinically significant improvement in semen parameters among infertile men treated with the aromatase inhibitor anastrozole.
Multi-institutional ...retrospective cohort study.
Two Tertiary Academic Medical Centers.
A total of 90 infertile men treated at 2 tertiary academic medical centers who met inclusion criteria and obtained pretreatment and posttreatment semen analyses.
Prescription of anastrozole (median 3 mg/wk).
Upgrade in the World Health Organization sperm concentration category (WHO-SCC). Univariate logistic regression, multivariable logistic regression, and partitioning analyses were performed to identify statistically significant patient factors capable of predicting treatment response.
With anastrozole treatment, 46% (n = 41/90) of men responded favorably with a WHO-SCC upgrade, and 12% (n = 11/90) experienced a downgrade. Responders exhibited lower pretreatment levels of luteinizing hormone (LH, 4.7 vs. 8.3 IU/L) and follicle-stimulating hormone (4.7 vs. 6.7 IU/mL), higher pretreatment levels of testosterone (T, 356 vs. 265 ng/dL), and similar baseline level of estradiol (E2, 73% vs. 70% with detectible level). Baseline semen parameters differed, with anastrozole responders demonstrating higher baseline semen concentration (3.6 vs. 0.3 M/mL) and higher total motile sperm counts (3.7 vs. 0.1 M). Anastrozole therapy converted 29% (n = 26/90) of the cohort to normozoospermia and enabled intrauterine insemination access in 31% (n = 20/64) of previously ineligible patients. Interestingly, neither body mass index nor the baseline E2 level or E2-T ratio was associated with WHO-SCC upgrade. Multivariable logistic regression revealed the T-LH ratio (odds ratio: 1.02, 95% confidence interval: 1.00–1.03) and baseline nonazoospermia (odds ratio: 9.4, 95% confidence interval: 1.1–78.9) to be statistically significant predictors of WHO-SCC upgrade (area under receiver operating characteristic curve: 0.77). The final user-friendly partitioning model consisting of the T-LH ratio ≥100 and baseline non-azoospermia was 98% sensitive and 33% specific for WHO-SCC upgrades (area under the curve: 0.77).
Anastrozole therapy decreases serum E2 levels, increases serum gonadotropins, and clinically improves semen parameters in half of men with idiopathic infertility. Nonazoospermic infertile men with T-LH ratios ≥100 are likely to benefit from anastrozole treatment irrespective of baseline E2 level or E2-T ratio. Men with azoospermia rarely respond to anastrozole and should be counseled on alternative treatments.
La testosterona y la hormona luteinizante predicen la mejoría en los parámetros seminales en hombres infértiles tratados con anastrazol
Identificar los factores de los pacientes asociados con una mejoría clínicamente significativa en los parámetros del semen entre hombres infértiles tratados con el inhibidor de la aromatasa anastrazol.
Estudio de cohorte retrospectivo multi institucional.
Dos centros médicos académicos terciarios.
Un total de 90 hombres infértiles tratados en 2 centros médicos académicos terciarios quienes cumplieron con los criterios de inclusión y obtuvieron análisis de semen previo y post tratamiento.
Prescripción de anastrazol (mediana 3 mg/semana).
Aumento en la categoría de concentración de semen de la Organización Mundial de la Salud (OMS-SCC). Se realizaron análisis de regresión logística univariada, regresión logística multivariable y partición para identificar factores estadísticamente significativos de los pacientes capaces de predecir la respuesta al tratamiento.
Con el tratamiento con anastrazol, el 46 % (n = 41/90) de los hombres respondieron favorablemente con un aumento en OMS-SCC y el 12 % (n = 11/90) experimentó una disminución. Los que respondieron exhibieron niveles previos al tratamiento más bajos de hormona luteinizante (LH, 4,7 versus 8,3 UI/L) y hormona folículo estimulante (4,7 versus 6,7 UI/mL), niveles más altos de testosterona previo al tratamiento (T, 356 versus 265 ng/dL) y nivel basal similar de estradiol (E2, 73% vs. 70% con nivel detectable). Los parámetros basales del semen difirieron, los que respondieron al anastrazol demostraron mayor concentración inicial de semen (3,6 frente a 0,3 M/ml) y mayores recuentos totales de espermatozoides móviles (3,7 frente a 0,1 M). La terapia con anastrazol convirtió el 29% (n = 26/90) de la cohorte a normozoospermia y permitió el acceso a la inseminación intrauterina en el 31% (n = 20/64) de pacientes previamente no elegibles. De manera interesante, ni el índice de masa corporal ni el nivel inicial de E2 o la tasa E2-T se asociaron con cambios en OMS-SCC. La regresión logística multivariable reveló que la relación T-LH (odds ratio: 1,02, intervalo de confianza del 95 %: 1,00–1,03) y la no azoospermia inicial (odds ratio: 9,4; intervalo de confianza del 95%: 1,1–78,9) son predictores estadísticamente significativos de la mejora del WHOSCC (área bajo la curva característica operativa del receptor: 0,77). El modelo de partición final fácil de usar que consta de la relación T-LH R100 y la no azoospermia inicial fueron 98 % sensibles y 33 % específicas para las mejoras de WHO-SCC (área bajo la curva:0,77).
La terapia con anastrazol disminuye los niveles séricos de E2, aumenta las gonadotropinas séricas y mejora clínicamente los parámetros seminales en la mitad de los hombres con infertilidad idiopática. Los hombres infértiles no azoospérmicos con ratios T-LH R100 probablemente se beneficien del tratamiento con anastrazol independientemente del nivel inicial de E2 o la relación E2-T. Los hombres con azoospermia rara vez responden al anastrazol y se les debe aconsejar tratamientos alternativos.
T cells are classically recognized as distinct subsets that express αβ or γδ TCRs. We identify a novel population of T cells that coexpress αβ and γδ TCRs in mice and humans. These hybrid αβ-γδ T ...cells arose in the murine fetal thymus by day 16 of ontogeny, underwent αβ TCR-mediated positive selection into CD4+ or CD8+ thymocytes, and constituted up to 10% of TCRδ+ cells in lymphoid organs. They expressed high levels of IL-1R1 and IL-23R and secreted IFN-γ, IL-17, and GM-CSF in response to canonically restricted peptide antigens or stimulation with IL-1β and IL-23. Hybrid αβ-γδ T cells were transcriptomically distinct from conventional γδ T cells and displayed a hyperinflammatory phenotype enriched for chemokine receptors and homing molecules that facilitate migration to sites of inflammation. These proinflammatory T cells promoted bacterial clearance after infection with Staphylococcus aureus and, by licensing encephalitogenic Th17 cells, played a key role in the development of autoimmune disease in the central nervous system.
PDF
