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Background: Recurrent urinary tract infection (rUTI) remains a major health burden for women. A randomized, double-blind, placebo-controlled trial (RCT; NCT02543827) reported that female patients with rUTI receiving a sublingual vaccine, MV140, had a reduction in rUTI and increase in UTI-free rate compared with placebo. Objective: To determine the impact of MV140 on the personal burden of disease in women with rUTI using secondary endpoint data from the pivotal RCT evaluating MV140. Design setting and participants: In the primary RCT, female patients with rUTI enrolled in Spain and UK (from October 2015 to April 2019) were randomized to placebo (6 mo) or MV140 (3 or 6 mo), and followed for 12 mo. Individuals analyzed in this secondary analysis included those in the placebo and 3-mo (recommended dose) groups. Intervention: A polybacterial sublingual vaccine, MV140 (four inactivated whole-cell bacteria-Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, and Enterococcus faecalis), or placebo. Outcome measurements and statistical analysis: Symptom severity scoring, antibiotic use, safety, and multiple aspects of quality of life (QoL; Short-Form Questionnaire [SF-36]) were assessed. Results and limitations: Compared with the placebo group (n = 76), the 3-mo vaccinated group (n = 74) experienced fewer overall UTI symptoms (mean symptom score 102.2 ± 222.9 vs 194.2 ± 178.8; p = 0.0002), fewer days on antibiotics (12.4 ± 17.7 vs 28.7 ± 25.2; p = 0.0001), and improved total, general, and physical SF-36 QoL improvement (differences in means for total SF-36 score 15.7; 95% confidence interval [CI] 8.80, 22.64; p < 0.0001), with only social function QoL showing no impact (4.07; 95% CI -4.93, 13.08; p = 0.3744). Conclusions: Three months of MV140 is associated with a reduction of the personal burden of UTI by reducing overall UTI symptoms and antibiotic use, improving QoL in women with rUTI. Patient summary: Three months of MV140 vaccine, which has previously been shown to reduce the risk of urinary tract infection safely, is associated with a reduction in the personal burden of disease.
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Background and study aims The aim of this study was to assess the effect of an educational video on the quality of bowel preparation of patients from a UK population attending for their first colonoscopy. Patients and methods A prospective, endoscopist-blinded trial with 1:1 allocation was performed. Patients referred for their first colonoscopy were recruited between February 2019 and December 2019. All participants were prescribed Moviprep and received the trial site's standard written bowel preparation instructions, with the intervention group also receiving a bespoke educational video. Adequacy of bowel preparation (defined as a Boston Bowel Preparation Scale of ≥2 in each segment of the bowel) and polyp detection rates (PDRs) were compared. Fisher's chi squared test was utilized with P <0.05 as the threshold for significance. Results A total of 509 participants completed the trial from six centers; 251 were randomized to the intervention group. The mean age was 57 years and 52.3% were female. The primary endpoint was met with an adequacy rate of 216 of 251 (86.1%) in the intervention group, compared with 205 of 259 (79.1%) in the control group ( P <0.05, odds ratio [OR] 1.626, 95% CI 1.017-2.614). The PDR was significantly higher in the intervention group (39% vs 30%, OR 1.51, 95% CI 1.04-2.19, P <0.05). Conclusions An educational video leads to improved bowel preparation for patients attending for their first colonoscopy, and is also associated with greater detection of polyps. Widespread adoption of an educational video incurs minimal investment, but would reduce the number of inadequate procedures, missed pathology, and the cost that both these incur.
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The cell cycle is governed by stringent epigenetic mechanisms that, in response to intrinsic and extrinsic regulatory cues, support fidelity of DNA replication and cell division. We will focus on (1) the complex and interdependent processes that are obligatory for control of proliferation and compromised in cancer, (2) epigenetic and topological domains that are associated with distinct phases of the cell cycle that may be altered in cancer initiation and progression, and (3) the requirement for mitotic bookmarking to maintain intranuclear localization of transcriptional regulatory machinery to reinforce cell identity throughout the cell cycle to prevent malignant transformation.
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Epigênese Genética , Neoplasias , Humanos , Ciclo Celular/genética , Divisão Celular , Neoplasias/genética , Neoplasias/patologia , Cromatina , Regulação da Expressão GênicaRESUMO
Epigenetic gene regulatory mechanisms play a central role in the biological control of cell and tissue structure, function, and phenotype. Identification of epigenetic dysregulation in cancer provides mechanistic into tumor initiation and progression and may prove valuable for a variety of clinical applications. We present an overview of epigenetically driven mechanisms that are obligatory for physiological regulation and parameters of epigenetic control that are modified in tumor cells. The interrelationship between nuclear structure and function is not mutually exclusive but synergistic. We explore concepts influencing the maintenance of chromatin structures, including phase separation, recognition signals, factors that mediate enhancer-promoter looping, and insulation and how these are altered during the cell cycle and in cancer. Understanding how these processes are altered in cancer provides a potential for advancing capabilities for the diagnosis and identification of novel therapeutic targets.
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Epigênese Genética , Neoplasias , Humanos , Fenótipo , Neoplasias/genética , Neoplasias/patologia , Regulação da Expressão Gênica , CromatinaRESUMO
BACKGROUND: In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort. METHODS: In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0-1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 108 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov, NCT02445248, and is ongoing. FINDINGS: Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8-43·8), the overall response rate was 53·0% (95% CI 43·5-62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3-4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported. INTERPRETATION: Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk-benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy). FUNDING: Novartis Pharmaceuticals.
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Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Linfócitos T/transplante , Austrália , Europa (Continente) , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/mortalidade , Japão , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , América do Norte , Intervalo Livre de Progressão , Recidiva , Linfócitos T/imunologia , Fatores de TempoRESUMO
Tisagenlecleucel is indicated for pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and adult patients with r/r diffuse large B-cell lymphoma (DLBCL). The tisagenlecleucel chimeric antigen receptor (CAR) contains a murine single-chain variable fragment domain; we examined the effects of humoral and cellular immune responses to tisagenlecleucel on clinical outcomes using 2 validated assays. Data were pooled from the ELIANA (registered at www.clinicaltrials.gov as #NCT02435849) and ENSIGN (#NCT02228096) trials in r/r B-ALL (N = 143) and the JULIET trial (#NCT02445248) in r/r DLBCL (N = 115). Humoral responses were determined by flow cytometric measurement of anti-murine CAR19 (mCAR19) antibodies in serum. Cellular responses were determined using T-cell production of interferon-γ in response to 2 different pools of mCAR19 peptides. Pretreatment anti-mCAR19 antibodies were detected in 81% of patients with r/r B-ALL and 94% of patients with r/r DLBCL. Posttreatment anti-mCAR19 antibodies were higher than patient-specific baseline in 42% of r/r B-ALL and 9% of r/r DLBCL patients. Pretreatment and posttreatment anti-mCAR19 antibodies did not affect tisagenlecleucel cellular kinetics, including maximum concentration and persistence (r2 < 0.05), clinical response (day-28 response, duration of response, and event-free survival), and safety. T-cell responses were consistent over time, with net responses <1% at baseline and posttreatment time points in a majority of patients and no effect on transgene expansion or persistence or outcomes. Presence of baseline and/or posttreatment anti-mCAR19 antibodies or T-cell responses did not alter the activity of tisagenlecleucel in patients with r/r B-ALL or r/r DLBCL.
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Linfoma Difuso de Grandes Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animais , Criança , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Intervalo Livre de Progressão , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
PURPOSE: Clinical trials have demonstrated efficacy of vedolizumab in ulcerative colitis (UC) and Crohn's disease (CD). Further real-world data is needed to inform clinical practice. The primary outcome was to assess corticosteroid-free and clinical remission after vedolizumab initiation. Secondary outcomes included effect on disease activity scores, biochemical markers, concomitant drug use, endoscopic remission, surgical intervention, hospital admissions and adverse events. MATERIALS AND METHODS: A multi-centre retrospective observational study was conducted with patients initiated on vedolizumab across seven UK hospitals 1/11/14-30/11/16. Clinical disease activity was assessed using the partial Mayo Scores (pMS) and Harvey Bradshaw Index (HBI). Clinical remission was defined as HBI ≤4 or pMS <2 with a combined stool frequency and rectal bleeding sub score of ≤1. Clinical response was defined as ≥2-point decrease from baseline in pMS and ≥3-point decrease from baseline in HBI. RESULTS: One hundred ninety-two patients were included in the final analysis. 45% of UC and 10% of CD patients were anti-TNF naive. Over the observation period corticosteroid-free remission rates for UC and CD were 46% and 45%, while clinical remission rates were 52% and 44%, respectively. Time to corticosteroid free remission for UC and CD was 17.6 [IQR: 8.7-29.6] and 14.1 [QR: 6.0-21.7] weeks, respectively. Time to clinical response for UC was 9.4 [IQR: 5.7-15.4] and CD was 9.5 [IQR: 6.1-18.2] weeks. There was a substantial decrease in the concomitant use of immunomodulators and a similar decrease in concomitant corticosteroid use over the study period. CONCLUSIONS: Results in this predominately anti-TNF experienced population mirror other published real-world data, demonstrating good clinical effectiveness and a comparable safety profile.
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Anticorpos Monoclonais Humanizados , Colite Ulcerativa , Doenças Inflamatórias Intestinais , Anticorpos Monoclonais Humanizados/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral , Reino UnidoRESUMO
The JULIET phase 2 trial evaluated a single infusion of tisagenlecleucel in adult patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The objective of the current analysis was to evaluate patient-reported health-related quality of life (HRQoL) with a median follow-up of 19.3 months among patients infused with a single dose of tisagenlecleucel. Patients enrolled were ≥18 years of age with r/r DLBCL after ≥2 lines of therapy and had either undergone a failed autologous stem cell transplant or were ineligible for the procedure. Two validated HRQoL instruments, Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and Short Form-36 (SF-36) Health Survey, were used to measure HRQoL at baseline and months 3, 6, 12, and 18. At data cutoff (21 May 2018), 115 patients had received tisagenlecleucel infusion. Among the 99 patients evaluated, overall response rate was 54%, and 40% of patients achieved complete response (CR). Initially, 108 patients completed the HRQoL assessments at baseline, including 57 patients who eventually achieved CR or partial response (PR). Further, 30 and 21 patients in clinical response who completed assessments at baseline also completed assessments at months 12 and 18, respectively. Patients who achieved CR or PR sustained HRQoL improvement in all FACT scores at all time points. SF-36 instruments showed improvement above the minimal clinically important differences on 5 of 8 subscales. Long-term follow-up in the phase 2 JULIET study demonstrated that patients with r/r DLBCL who respond to tisagenlecleucel therapy had sustained, clinically meaningful improvements in HRQoL. This trial was registered at www.clinicaltrials.gov as #NCT02445248.
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Linfoma Difuso de Grandes Células B , Qualidade de Vida , Adulto , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Receptores de Antígenos de Linfócitos TRESUMO
The anti-CD19 chimeric antigen receptor (CAR)-T cell therapy tisagenlecleucel was evaluated in the global, phase 2 JULIET study in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We correlated tisagenlecleucel cellular kinetics with clinical/product parameters in 111 patients treated in JULIET. Tisagenlecleucel persistence in responders and nonresponders, respectively, was demonstrated for 554 and 400 days maximum by flow cytometry and for 693 and 374 days maximum by quantitative polymerase chain reaction (qPCR). No relationships were identified between cellular kinetics (qPCR) and product characteristics, intrinsic/extrinsic factors, dose, or immunogenicity. Most patients with 3-month response had detectable transgene at time of response and continued persistence for ≥6 months. Expansion (maximal expansion of transgene/CAR-positive T-cell levels in vivo postinfusion [Cmax]) was potentially associated with response duration but this did not reach statistical significance (hazard ratio for a twofold increase in Cmax, 0.79; 95% confidence interval, 0.61-1.01). Tisagenlecleucel expansion was associated with cytokine-release syndrome (CRS) severity and tocilizumab use; no relationships were observed with neurologic events. Transgene levels were associated with B-cell levels. Dose was associated with CRS severity, but this was not statistically significant after adjusting for baseline tumor burden. In contrast to the results from B-cell precursor acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia, similar exposure was observed in DLBCL in this study regardless of response and expansion was lower in DLBCL than B-ALL, likely from differences in cancer location and/or T-cell intrinsic factors. Relationships between expansion and CRS severity, and lack of relationships between dose and exposure, were similar between DLBCL and B-ALL. Tisagenlecleucel cellular kinetics in adult relapsed/refractory DLBCL improve current understanding of in vivo expansion and its relationships with safety/efficacy endpoints. This trial was registered at www.clinicaltrials.gov as #NCT02445248.
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Linfoma Difuso de Grandes Células B , Receptores de Antígenos de Linfócitos T , Adulto , Antígenos CD19 , Humanos , Cinética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
Background and aims: The regular overnight migrating motor complex (MMC) ensures that the normal fasting small-bowel water content (SBWC) is minimised. We have applied our recently validated non-invasive magnetic resonance technique to assess SBWC in newly diagnosed coeliac disease (CD), scleroderma (SCD) and irritable bowel syndrome (IBS), conditions possibly associated with small intestinal bacterial overgrowth (SIBO). Methods: A total of 20 CD and 15 SCD patients with gastrointestinal symptoms were compared to 20 healthy volunteers (HV) and 26 IBS with diarrhoea (IBS-D) patients, as previously reported. All underwent a fasting magnetic resonance imaging (MRI) scan on a 1.5 T Philips Achieva MRI scanner to assess fasting SBWC and colonic volumes. Stool and symptom diaries were completed for one week. Results: Compared to HV, all patients had significantly increased stool frequency and Bristol stool form score. SBWC was significantly increased in CD (median 109 mL; interquartile range (IQR) 53-224 mL) compared to HV (median 53 mL; IQR 31-98 mL; p < 0.01) and IBS-D (median 42 mL; IQR 28-67 mL; p < 0.01). A variable increase in SBWC was also found in SCD (median 77 mL; IQR 39-158 mL), but this was not significant (p = 0.2). Colonic volumes were similar for all groups, being a median of 547 mL (IQR 442-786 mL) for CD, 511 mL (453-789 mL) for SCD, 612 mL (445-746 mL) for HV and 521 mL (428-757 mL) for IBS-D. When CD patients were subdivided according to the Marsh classification, the higher grades had larger colonic volumes. Conclusion: Fasting SBWC as assessed by MRI is significantly increased in newly diagnosed CD and SCD but decreased in IBS-D. Future studies should test whether increased resting fluid predisposes to SIBO.
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Doença Celíaca/diagnóstico , Doença Celíaca/metabolismo , Jejum/metabolismo , Conteúdo Gastrointestinal , Imageamento por Ressonância Magnética , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/metabolismo , Água/metabolismo , Adulto , Idoso , Biópsia , Doença Celíaca/psicologia , Feminino , Humanos , Síndrome do Intestino Irritável/diagnóstico , Síndrome do Intestino Irritável/metabolismo , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-IdadeRESUMO
Air and moisture stable homoleptic bis(diimidazolylidine)nickel(II) complexes, ([(diNHC)(2)Ni](2+)) 3a,b and their corresponding silver(I) 4a,b and palladium(II) 5a,b complexes were synthesized and characterized by NMR and single crystal X-ray analysis. The catalytic potential of complex 3a was assessed in Mizoroki-Heck and Suzuki-Miyaura coupling reactions. In the Suzuki-Miyaura coupling reaction, nickel precatalyst 3a was active for the coupling of aryl chlorides as well as aryl fluorides. The analogously synthesized Pd(II) complexes resulted in formation of (diNHC)PdCl(2) species which were not active for the coupling of aryl fluorides. For the Mizoroki-Heck reaction, it was found that aryl iodides could be activated in the absence of nickel or palladium precatalysts when using Na(2)CO(3) or NEt(3) as base while aryl iodides and aryl bromides could be activated in the Suzuki-Miyaura reaction sans precatalyst when K(3)PO(4) was used as base.
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BACKGROUND & AIMS: Patients with irritable bowel syndrome with diarrhea (IBS-D) have increased mucosal serotonin (5-hydroxytryptamine [5-HT]) availability, possibly because immune activation reduces activity of the 5-HT transporter (SERT). We investigated the relationship between mucosal and platelet SERT and immune activation of the duodenal mucosa in patients with IBS-D. METHODS: We quantified mucosal intraepithelial lymphocytes (IELs), mast cells, and enterochromaffin cells in blood samples, measured levels of SERT messenger RNA (mRNA) in mucosal samples, and assessed platelet uptake of 5-HT and platelet membrane binding of (3)H-paroxetine in samples from 29 healthy volunteers (HVs), 20 patients with IBS-D, and 20 untreated patients with celiac disease. RESULTS: Patients with IBS-D or celiac disease had increased numbers of IELs and mast cells compared with HVs (both P < .001). Levels of SERT mRNA were reduced in the mucosa of patients with IBS-D or celiac disease and were inversely correlated with numbers of IELs (r = -0.72, P < .0001). Uptake of 5-HT by platelets from patients with IBS-D or celiac disease was reduced (mean, 17.1 ± 3.5 and 28.3 ± 4.1 nmol·min(-1)·mg(-1), respectively) compared with HVs (50.8 ± 8.0 nmol·min(-1)·mg(-1), P < .01 and P = .05, respectively). Binding of paroxetine to membranes of platelets from patients with IBS-D (median [interquartile range], 226 [92-405] fmol/mg protein) was significantly greater than that from HVs (109 [69-175] fmol/mg protein) and correlated inversely with platelet uptake of 5-HT (r = -0.62, P = .03). Tryptase release from incubated biopsy samples was significantly increased in patients with IBS-D (2.2 [0.42-3.5] vs 0.50 [0.25-0.86] ng·mL(-1)·mg(-1) for HVs; P = .03). CONCLUSIONS: Platelet SERT is reduced in IBS-D and associated with reduced levels of SERT mRNA and duodenal immune activation.
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Plaquetas/metabolismo , Duodeno/imunologia , Imunidade Celular , Mucosa Intestinal/imunologia , Síndrome do Intestino Irritável/imunologia , Serotonina/metabolismo , Adulto , Transporte Biológico , Biópsia , Duodeno/metabolismo , Duodeno/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Síndrome do Intestino Irritável/metabolismo , Síndrome do Intestino Irritável/patologia , Masculino , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Antigen-based (as opposed to whole organism) vaccines are actively being pursued for numerous indications. Even though different formulations may produce similar levels of total antigen-specific antibody, the composition of the antibody response can be quite distinct resulting in different levels of therapeutic activity. METHODOLOGY/PRINCIPAL FINDINGS: Using plasmid-based immunization against the proto-oncogene HER-2 as a model, we have demonstrated that affinity-selected epitope mimetics (mimotopes) can provide a defined signature of a polyclonal antibody response. Further, using novel computer algorithms that we have developed, these mimotopes can be used to predict epitope targets. CONCLUSIONS/SIGNIFICANCE: By combining our novel strategy with existing methods of epitope prediction based on physical properties of an individual protein, we believe that this method offers a robust method for characterizing the breadth of epitope-specificity within a specific polyserum. This strategy is useful as a tool for monitoring immunity following vaccination and can also be used to define relevant epitopes for the creation of novel vaccines.
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Epitopos/química , Epitopos/imunologia , Soros Imunes/imunologia , Algoritmos , Animais , Proliferação de Células , Imunização , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Biblioteca de Peptídeos , Ratos , Receptor ErbB-2/metabolismoRESUMO
Rituximab is a chimeric monoclonal antibody that targets the human CD-20 antigen present on malignant and normal B lymphocytes. Recent clinical studies have shown a significant response rate when this drug is given to selected patients with thrombotic thrombocytopenic purpura (TTP). Given that the clinical manifestations of TTP may be the direct result of an auto-antibody against a regulatory Von Willebrand factor enzyme (ADAMTS13), it makes biological sense to consider a therapy that has the ability to diminish or eradicate antibody-producing B cells. Despite initial positive results, there is a need to identify which patients derive durable benefit from this agent. As in other conditions that utilize therapeutic immunosuppression, there is a risk that the addition of rituximab may also lead to serious opportunistic infections.
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Anticorpos Monoclonais/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Imunossupressores/uso terapêutico , Púrpura Trombocitopênica Trombótica/tratamento farmacológico , Proteínas ADAM/imunologia , Proteína ADAMTS13 , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Murinos , Autoanticorpos/sangue , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Canadá , Humanos , Imunossupressores/efeitos adversos , Seleção de Pacientes , Troca Plasmática , Púrpura Trombocitopênica Trombótica/sangue , Púrpura Trombocitopênica Trombótica/imunologia , Recidiva , Medição de Risco , Rituximab , Falha de Tratamento , Fator de von Willebrand/metabolismoRESUMO
In the title compound, (C(20)H(17)N(2))(2)[Pd(2)Cl(6)]·2C(6)H(6), the dichloride-bridged [Pd(2)Cl(6)](2-) anion lies across an inversion center with each Pd(II) ion in a slightly distorted square-planar environment. In the crystal structure, two cations and an anion are connected via N-Hâ¯Cl hydrogen bonds between the NH groups of the iminioisoindoline cations and terminal Cl atoms of a hexa-chloridodipalladate(II) anion. The Pd-Cl distance of the terminal chloride engaged in hydrogen bonding is slightly longer than the Pd-Cl distance of the adjacent terminal chloride which is not involved in hydrogen bonding.
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BACKGROUND AND AIMS: Serotonin (5-hydroxytryptamine [5-HT]) is a key modulator of gut function that in excess causes nausea, vomiting, and diarrhea. We recently showed that patients with post-infective irritable bowel syndrome have increased postprandial release of 5-HT associated with low-grade T-cell mediated inflammation. Celiac disease is another common disease in which a T-cell enteropathy is associated with increased mucosal 5-HT levels. Our aim was to determine how this inflammatory lesion influenced 5-HT bioavailability and how changes in 5-HT related to the symptoms of nausea, vomiting, and diarrhea seen in untreated celiac patients. METHODS: Fasting plasma and platelet 5-HT and postprandial plasma 5-HT levels were measured after a high-carbohydrate meal in celiac patients (n = 18) and healthy controls (n = 18) using high-pressure liquid chromatography. Dyspepsia was assessed during the postprandial period using a questionnaire. Finally, we compared the histology and mucosal 5-HT levels in duodenal biopsy specimens from celiac patients and controls. RESULTS: Celiac patients had increased 5-HT-containing enterochromaffin cell numbers and significantly higher peak plasma 5-HT levels (P = .0002), postprandial area under the curve (P = .0006), and platelet 5-HT stores (P = .031) than controls. Peak 5-HT levels correlated significantly with postprandial dyspepsia scores (P = .005). Celiac patients had higher duodenal 5-HT levels (P = .007) than controls. CONCLUSIONS: Celiac disease is associated with increased mucosal 5-HT content and enhanced 5-HT release from the upper small bowel, which correlates with postprandial dyspepsia. Serotonin excess may mediate dyspeptic symptoms in untreated celiac disease.
Assuntos
Doença Celíaca/metabolismo , Dispepsia/metabolismo , Período Pós-Prandial/fisiologia , Serotonina/metabolismo , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Doença Celíaca/complicações , Doença Celíaca/patologia , Duodeno/metabolismo , Duodeno/patologia , Dispepsia/etiologia , Dispepsia/patologia , Feminino , Humanos , Ácido Hidroxi-Indolacético/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
The reactions of three types of group 4 metal olefin polymerization catalysts, (C(5)R(5))(2)ZrX(2)/activator, (C(5)Me(5))TiX(3)/MAO (MAO = methylalumoxane), and (C(5)Me(4)SiMe(2)N(t)Bu)MX(2)/activator (M = Ti, Zr), with vinyl chloride (VC) and VC/propylene mixtures have been investigated. Two general pathways are observed: (i) radical polymerization of VC initiated by radicals derived from the catalyst and (ii) net 1,2 VC insertion into L(n)MR(+) species followed by beta-Cl elimination. rac-(EBI)ZrMe(mu-Me)B(C(6)F(5))(3) (EBI = 1,2-ethylenebis(indenyl)) reacts with 2 equiv of VC to yield oligopropylene, rac-(EBI)ZrCl(2), and B(C(6)F(5))(3). This reaction proceeds by net 1,2 VC insertion into rac-(EBI)ZrMe(+) followed by fast beta-Cl elimination to yield [rac-(EBI)ZrCl][MeB(C(6)F(5))(3)] and propylene. Methylation of rac-(EBI)ZrCl(+) by MeB(C(6)F(5))(3)(-) enables a second VC insertion/beta-Cl elimination to occur. The evolved propylene is oligomerized by rac-(EBI)ZrR(+) as it is formed. At high Al/Zr ratios, rac-(EBI)ZrMe(2)/MAO catalytically converts VC to oligopropylene by 1,2 VC insertion into rac-(EBI)ZrMe(+), beta-Cl elimination, and realkylation of rac-(EBI)ZrCl(+) by MAO; this process is stoichiometric in Al-Me groups. The evolved propylene is oligomerized by rac-(EBI)ZrR(+). Oligopropylene end group analysis shows that the predominant chain transfer mechanism is VC insertion/beta-Cl elimination/realkylation. In the presence of trace levels of O(2), rac-(EBI)ZrMe(2)/MAO polymerizes VC to poly(vinyl chloride) (PVC) by a radical mechanism initiated by radicals generated by autoxidation of Zr-R and/or Al-R species. CpTiX(3)/MAO (Cp = C(5)Me(5); X = OMe, Cl) initiates radical polymerization of VC in CH(2)Cl(2) solvent at low Al/Ti ratios under anaerobic conditions; in this case, the source of initiating radicals is unknown. Radical VC polymerization can be identified by the presence of terminal and internal allylic chloride units and other "radical defects" in the PVC which arise from the characteristic chemistry of PCH(2)CHCl(*) macroradicals. However, this test must be used with caution, since the defect units can be consumed by postpolymerization reactions with MAO. (C(5)Me(4)SiMe(2)N(t)Bu)MMe(2)/[Ph(3)C]][B(C(6)F(5))(4)] catalysts (M = Ti, Zr) react with VC by net 1,2 insertion/beta-Cl elimination, yielding [(C(5)Me(4)SiMe(2)N(t)Bu)MCl][B(C(6)F(5))(4)] species which can be trapped as (C(5)Me(4)SiMe(2)N(t)Bu)MCl(2) by addition of a chloride source. The reaction of rac-(EBI)ZrMe(2)/MAO or [(C(5)Me(4)SiMe(2)N(t)Bu)ZrMe][B(C(6)F(5))(4)] with propylene/VC mixtures yields polypropylene containing both allylic and vinylidene unsaturated chain ends rather than strictly vinylidene chain ends, as observed in propylene homopolymerization. These results show that the VC insertion of L(n)M(CH(2)CHMe)(n)R(+) species is also followed by beta-Cl elimination, which terminates chain growth and precludes propylene/VC copolymerization. Termination of chain growth by beta-Cl elimination is the most significant obstacle to metal-catalyzed insertion polymerization/copolymerization of VC.