Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 227
Filtrar
1.
Open Heart ; 8(2)2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34782369

RESUMO

OBJECTIVE: To determine the prevalence of cardiac abnormalities and their relationship to markers of myocardial injury and mortality in patients admitted to hospital with COVID-19. METHODS: A retrospective and prospective observational study of inpatients referred for transthoracic echocardiography for suspected cardiac pathology due to COVID-19 within a London NHS Trust. Echocardiograms were performed to assess left ventricular (LV), right ventricular (RV) and pulmonary variables along with collection of patient demographics, comorbid conditions, blood biomarkers and outcomes. RESULT: In the predominant non-white (72%) population, RV dysfunction was the primary cardiac abnormality noted in 50% of patients, with RV fractional area change <35% being the most common marker of this RV dysfunction. By comparison, LV systolic dysfunction occurred in 18% of patients. RV dysfunction was associated with LV systolic dysfunction and the presence of a D-shaped LV throughout the cardiac cycle (marker of significant pulmonary artery hypertension). LV systolic dysfunction (p=0.002, HR 3.82, 95% CI 1.624 to 8.982), pulmonary valve acceleration time (p=0.024, HR 0.98, 95% CI 0.964 to 0.997)-marker of increased pulmonary vascular resistance, age (p=0.047, HR 1.027, 95% CI 1.000 to 1.055) and an episode of tachycardia measured from admission to time of echo (p=0.004, HR 6.183, 95% CI 1.772 to 21.575) were independently associated with mortality. CONCLUSIONS: In this predominantly non-white population hospitalised with COVID-19, the most common cardiac pathology was RV dysfunction which is associated with both LV systolic dysfunction and elevated pulmonary artery pressure. The latter two, not RV dysfunction, were associated with mortality.


Assuntos
COVID-19/etnologia , Grupos Étnicos , Cardiopatias/etnologia , Ventrículos do Coração/diagnóstico por imagem , Vigilância da População , Comorbidade , Estudos Transversais , Ecocardiografia Doppler , Cardiopatias/diagnóstico , Hospitalização/tendências , Humanos , Pandemias , Prevalência , Quebeque/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida/tendências
2.
J Thorac Dis ; 13(9): 5477-5486, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34659814

RESUMO

Background: To improve nutritional status and dysphagia, esophageal cancer patients starting neoadjuvant therapy in advance of curative-intent surgery may receive a jejunostomy tube (J-tube) or esophageal stent, or they may be managed without a feeding modality. We examined percent total weight loss (%TWL), reinterventions, and progression to surgery in relation to these options. Methods: The retrospective cohort study included stage II-III esophageal cancer patients diagnosed during 2010-2017 who received J-tube, stent, or nutritional counseling only, without a procedure, when starting chemotherapy or combined modality chemoradiation. Data were obtained from the electronic medical record and chart review. We compared median %TWL between intervention groups and reinterventions using Chi-square and Kruskal-Wallis tests. Results: Among the 366 patients, median %TWL reached a nadir at 120 days, when it was 7% for patients with no procedure (N=307), 4% for J-tube (N=39), and 16% for stent (N=20) (P=0.01). Individual case analysis revealed 72-80% of the patients in the three groups started chemotherapy or chemoradiation as neoadjuvant curative-intent therapy (P difference =0.79). In J-tube patients, the reasons for intervention was anticipation of weight loss in 49% and mitigation of actual weight loss in 15%, whereas 95% of stent patients received the stent for dysphagia (P<0.001). A complication of the procedure was recorded in 85% of stent patients and 74% of J-tube patients (P<0.001). Among those who received no procedure initially, 25% received one later, compared with 15% of J-tube patients and 70% of stent patients who received a second procedure (P<0.001). Progression to surgery was observed in 65% of patients with no procedure, 51% of patients with J-tube, and 40% of stent patients, P=0.28). Conclusions: For stage II-III esophageal cancer patients starting chemotherapy, this study gives evidence that stents were associated with significant %TWL and risk of reintervention. Although J-tube patients returned to baseline weight sooner than those with no procedure, they experienced complications from their J-tubes. For esophageal cancer patients undergoing curative-intent treatment and with acceptable levels of weight loss, no procedure at all may be superior to placing a J-tube in terms of complications, weight loss, and progression to curative-intent surgery.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34702156

RESUMO

World Health Organization categorized breast cancer as one of the leading cancer types in females worldwide, and its treatment remains challenging. Accumulated evidence suggested the role of estrogen and its metabolites in pre- and post-menopausal women. Upregulation of estrogen-dependent aromatase is significantly involved in the pathogenesis of breast cancer. Several aromatase inhibitors, such as exemestane, formestane, and letrozole, are being used clinically, owing to their estrogen suppression role. Apart from these drugs, several other molecules, such as natural and synthetic flavonoids, have been reported widely for a similar biological activity. However, some reasonable modifications are required for these structures to achieve desired efficacy and to alleviate toxicity. Designing a novel aromatase inhibitor will be possible if we can establish a rational correlation between the chemistry and biological features of the existing molecules. The benzopyranone-ring system, present in the flavonoid molecules, has been reported as a pharmacophore due to its inhibitory activity on aromatase, which helps repress breast cancer progression. This essential feature has been utilized to modify several natural flavonoids into 5 and 7 hydroxy/methoxy flavone, 4-imidazolyl/triazolyl flavone, 5,4'- diamino flavone, 7,8- benzo-4-imidazolyl flavone, α-naphthoflavone, and 2-azole/thiazolyl isoflavone derivatives. These scaffolds have been considered in this review for meticulous study in aspects of the structure-activity relationship for aromatase inhibitory activity, and it would likely pave the way for designing a potential lead candidate in the future.

4.
Clin Sports Med ; 40(4): 625-639, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34509202

RESUMO

Injuries to the wrist and hands occur frequently in athletes from the high forces applied during sporting events. The examples presented illustrate the important role imaging has in the diagnosis of wrist and hand injuries. In addition, different imaging modalities are complementary and various examinations may be needed to help guide the management of wrist and hand traumatic pathology.


Assuntos
Traumatismos em Atletas , Traumatismos da Mão , Traumatismos do Punho , Atletas , Traumatismos em Atletas/diagnóstico por imagem , Diagnóstico por Imagem/métodos , Traumatismos da Mão/diagnóstico por imagem , Humanos , Punho/diagnóstico por imagem , Traumatismos do Punho/diagnóstico por imagem
5.
JCI Insight ; 6(18)2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34403370

RESUMO

Venous valve (VV) failure causes chronic venous insufficiency, but the molecular regulation of valve development is poorly understood. A primary lymphatic anomaly, caused by mutations in the receptor tyrosine kinase EPHB4, was recently described, with these patients also presenting with venous insufficiency. Whether the venous anomalies are the result of an effect on VVs is not known. VV formation requires complex "organization" of valve-forming endothelial cells, including their reorientation perpendicular to the direction of blood flow. Using quantitative ultrasound, we identified substantial VV aplasia and deep venous reflux in patients with mutations in EPHB4. We used a GFP reporter in mice to study expression of its ligand, ephrinB2, and analyzed developmental phenotypes after conditional deletion of floxed Ephb4 and Efnb2 alleles. EphB4 and ephrinB2 expression patterns were dynamically regulated around organizing valve-forming cells. Efnb2 deletion disrupted the normal endothelial expression patterns of the gap junction proteins connexin37 and connexin43 (both required for normal valve development) around reorientating valve-forming cells and produced deficient valve-forming cell elongation, reorientation, polarity, and proliferation. Ephb4 was also required for valve-forming cell organization and subsequent growth of the valve leaflets. These results uncover a potentially novel cause of primary human VV aplasia.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34455966

RESUMO

BACKGROUND: Many natural and synthetic flavonoids have been studied and documented by inhibiting aromatase enzymes for their anti-cancer activity against breast carcinoma. The aromatase enzyme is a possible target for the estrogen's positive breast cancer receptor. OBJECTIVE: Hence, a series of flavonoids have been synthesized and assessed for their in vitro cytotoxicity and aromatase inhibitory activity. METHODS: 39 flavonoids were synthesized and characterized by spectroscopic techniques, and their computational study was performed using the maestro version of the Schrodinger. In-silico ADME properties were checked by QikPro software. A total of 18 compounds were evaluated based on the docking score using cytotoxicity assay in human breast cancer cell line MCF-7. RESULTS: Of the 18 compounds tested, 07 compounds, namely 2b, 8b, 14b, 15b, 19b, 24b, and 30b flavonoids were found to be more active with their IC50 values of 20.73 µM, 1.636 µM, 16.08 µM, 22.02 µM, 15.75 µM, 0.345 µM and 16.08 µM, respectively, compared with the reference drug letrozole. The in-vitro aromatase inhibitory activity of six compounds 2b, 8b, 14b, 19b, 24b, and 30b was conducted using a fluorogenic assay kit. The values of IC50 for compounds 2b and 24b were found to be 0.31 µM and 0.36 µM, respectively. CONCLUSION: Therefore, it was concluded that compounds 2b and 24b had a potent inhibitory effect of aromatase compared with letrozole with an IC50 value of 0.86 µM. At the same time, the other compounds 8b, 14b, 30b, and 19b were considered to have similar aromatase inhibitory activity. Hence, their essential aromatase inhibitory activities make them good lead candidates for developing potent inhibitors of aromatase.

7.
Am J Hum Genet ; 108(9): 1765-1779, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34450030

RESUMO

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.


Assuntos
Colectomia/estatística & dados numéricos , Colite Ulcerativa/cirurgia , Doença de Crohn/cirurgia , Locos de Características Quantitativas , Transcriptoma , Bancos de Espécimes Biológicos , Estudos de Coortes , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/genética , Colo/metabolismo , Colo/patologia , Colo/cirurgia , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Doença de Crohn/genética , Conjuntos de Dados como Assunto , Progressão da Doença , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial , Prognóstico , Medição de Risco , Reino Unido
8.
Oral Maxillofac Surg Clin North Am ; 33(3): 359-372, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34210400

RESUMO

This article includes updates in the management of mandibular trauma and reconstruction as they relate to maxillomandibular fixation screws, custom hardware, virtual surgical planning, and protocols for use of computer-aided surgery and navigation when managing composite defects from gunshot injuries to the face.


Assuntos
Traumatismos Mandibulares , Reconstrução Mandibular , Cirurgia Assistida por Computador , Ferimentos por Arma de Fogo , Humanos , Mandíbula , Traumatismos Mandibulares/cirurgia , Ferimentos por Arma de Fogo/cirurgia
9.
Ann Surg ; 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34261883

RESUMO

OBJECTIVE: The aim of this study was to investigate whether our previously reported improvements in short-term cancer esophagectomy outcomes after large-scale regionalization in the U.S. translated to longer-term survival benefit. BACKGROUND: Regionalization is associated with better early postoperative outcomes following cancer esophagectomy; however, data regarding its effect on long-term survival is mixed. METHODS: We retrospectively reviewed 461 patients undergoing cancer esophagectomy before (2009-2013, N = 272) and after (2014-2016, N = 189) regionalization. Kaplan-Meier curves and χ2 tests were used to describe 1- and 3-year survival in each era. Hierarchical logistic regression models examined the adjusted effect of regionalization on mortality. RESULTS: Compared to pre-regionalization patients, post-regionalization patients had significantly higher 1-year survival (83.1% versus 73.9%, p = 0.02) but not 3-year survival (52.9% versus 58.2%, p = 0.26).Subgroup analysis by cancer stage revealed that 1-year survival benefit was only significant among mid-stage (IIB-IIIB) patients, whereas differences in 3-year survival only approached significance among early-stage (IA-IIA) patients.In multivariable analysis, only regionalization was a predictor of lower mortality at 1 year (OR 0.54, 95%CI:0.29,1.00), and only thoracic specialty at 3 years (OR 0.62, 95%CI:0.38,0.99). Older age, more advanced stage, and complications were associated with higher 1- and 3-year mortality. Comorbidity, minimally invasive approach, surgeon volume, facility volume, and neoadjuvant treatment were not significant in this model. CONCLUSIONS: Regionalization was associated with improved 1-year survival after cancer esophagectomy, independent of factors such as morbidity or volume in our adjusted models. This survival benefit did not persist at 3 years, likely due to the aggressive nature of the disease.

10.
Mini Rev Med Chem ; 2021 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-34254913

RESUMO

Cancer is a frightful disease that still poses a 'nightmare' worldwide, causing millions of casualties annually due to one of the human race's most significant healthcare challenges that requires a pragmatic treatment strategy. However, plants and plant-derived products revolutionize the field as they are quick, cleaner, eco-friendly, low-cost, effective, and less toxic than conventional treatment methods. Plants are repositories for new chemical entities and have a promising cancer research path, supplying 60% of the anticancer agents currently used. Alkaloids are important chemical compounds that serve as a rich reservoir for drug discovery and development. However, some alkaloids derived from natural herbs display anti-proliferation and antimetastatic activity on different forms of cancer, both in vitro and in vivo. Alkaloids have also been widely formulated as anticancer medications, such as camptothecin and vinblastine. Still, more research and clinical trials are required before final recommendations can be made on specific alkaloids. This review focuses on the naturally-derived bioactive alkaloids with prospective anticancer properties based on the information in the literature.

11.
Biomark Res ; 9(1): 42, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34090518

RESUMO

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a capricious cancer with poor survival rates, even for early-stage patients. There is a pressing need to develop more precise risk assessment methods to appropriately tailor clinical treatment. Genome-wide association studies have not produced a viable biomarker. However, these studies are limited by using heterogeneous cohorts, not focusing on methylation although OSCC is a heavily epigenetically-regulated cancer, and not combining molecular data with clinicopathologic data for risk prediction. In this study we focused on early-stage (I/II) OSCC and created a risk score called the REASON score, which combines clinicopathologic characteristics with a 12-gene methylation signature, to predict the risk of 5-year mortality. METHODS: We combined data from an internal cohort (n = 515) and The Cancer Genome Atlas (TCGA) cohort (n = 58). We collected clinicopathologic data from both cohorts to derive the non-molecular portion of the REASON score. We then analyzed the TCGA cohort DNA methylation data to derive the molecular portion of the risk score. RESULTS: 5-year disease specific survival was 63% for the internal cohort and 86% for the TCGA cohort. The clinicopathologic features with the highest predictive ability among the two the cohorts were age, race, sex, tobacco use, alcohol use, histologic grade, stage, perineural invasion (PNI), lymphovascular invasion (LVI), and margin status. This panel of 10 non-molecular features predicted 5-year mortality risk with a concordance (c)-index = 0.67. Our molecular panel consisted of a 12-gene methylation signature (i.e., HORMAD2, MYLK, GPR133, SOX8, TRPA1, ABCA2, HGFAC, MCPH1, WDR86, CACNA1H, RNF216, CCNJL), which had the most significant differential methylation between patients who survived vs. died by 5 years. All 12 genes have already been linked to survival in other cancers. Of the genes, only SOX8 was previously associated with OSCC; our study was the first to link the remaining 11 genes to OSCC survival. The combined molecular and non-molecular panel formed the REASON score, which predicted risk of death with a c-index = 0.915. CONCLUSIONS: The REASON score is a promising biomarker to predict risk of mortality in early-stage OSCC patients. Validation of the REASON score in a larger independent cohort is warranted.

12.
Eur Heart J Case Rep ; 5(3): ytaa575, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34104860

RESUMO

Background: Coronavirus disease 2019 (COVID-19) infection is associated with a coagulopathy with high incidence of venous thrombo-embolism. However, bleeding risk is also significant, causing difficulty in initiating and adjusting anticoagulation therapy in case of suspected thrombi. Cardiac masses can be challenging to be identified properly in the context of this disease. The use of bedside contrast echocardiography (CE) can be of a great value in this situation decreasing procedure-related risk and allowing proper diagnosis and management of a cardiac mass. Cases summary: We present two cases who were admitted with severe COVID-19 infection. Both cases had additional risk factors for hypercoagulability. Un-enhanced echocardiography was performed and revealed right ventricular (RV) dysfunction with a suspected RV mass. The use of bedside CE could confirm a RV thrombus in the first case and exclude it in the second case. Hence, anticoagulation therapy could be adjusted accordingly in both patients. Discussion: Coronavirus disease 2019 infection is associated with peripheral thrombo-embolism and cardiac thrombi. Given the critical condition of many patients affected by COVID-19, imaging for thrombo-embolic events is often restricted. With the use of bedside CE, cardiac masses may be correctly identified, aiding proper adjustment of anticoagulation therapy.

13.
J Thromb Haemost ; 19(10): 2583-2595, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34161660

RESUMO

BACKGROUND: Rivaroxaban, a direct oral factor Xa inhibitor, mediates anti-inflammatory and cardiovascular-protective effects besides its well-established anticoagulant properties; however, these remain poorly characterized. Extracellular vesicles (EVs) are important circulating messengers regulating a myriad of biological and pathological processes and may be highly relevant to the pathophysiology of atrial fibrillation as they reflect alterations in platelet and endothelial biology. However, the effects of rivaroxaban on circulating pro-inflammatory EVs remain unknown. OBJECTIVES: We hypothesized that rivaroxaban's anti-inflammatory properties are reflected upon differential molecular profiles of circulating EVs. METHODS: Differences in circulating EV profiles were assessed using a combination of single vesicle analysis by Nanoparticle Tracking Analysis and flow cytometry, and proteomics. RESULTS: We demonstrate, for the first time, that rivaroxaban-treated non-valvular atrial fibrillation (NVAF) patients (n=8) exhibit attenuated inflammation compared with matched warfarin controls (n=15). Circulating EV profiles were fundamentally altered. Moreover, quantitative proteomic analysis of enriched plasma EVs from six pooled biological donors per treatment group revealed a profound decrease in highly pro-inflammatory protein expression and complement factors, together with increased expression of negative regulators of inflammatory pathways. Crucially, a reduction in circulating levels of soluble P-selectin was observed in rivaroxaban-treated patients (compared with warfarin controls), which negatively correlated with the patient's time on treatment. CONCLUSION: Collectively, these data demonstrate that NVAF patients anticoagulated with rivaroxaban (compared with warfarin) exhibit both a reduced pro-inflammatory state and evidence of reduced endothelial activation. These findings are of translational relevance toward characterizing the anti-inflammatory and cardiovascular-protective mechanisms associated with rivaroxaban therapy.


Assuntos
Fibrilação Atrial , Vesículas Extracelulares , Acidente Vascular Cerebral , Anticoagulantes , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa , Humanos , Proteômica , Estudos Retrospectivos , Rivaroxabana , Varfarina
14.
Artigo em Inglês | MEDLINE | ID: mdl-33934900

RESUMO

OBJECTIVE: Existing evidence demonstrates some benefit of regionalization on early postoperative outcomes following lung cancer resection, but data regarding the persistence of this effect in long-term mortality are lacking. We investigated whether previously reported improvements in short-term outcomes translated to long-term survival benefit. METHODS: We retrospectively reviewed patients undergoing major pulmonary resection (lobectomy, bilobectomy, or pneumonectomy) for cancer within our integrated health care system before (2011-2013; n = 782) and after (2015-2017; n = 845) thoracic surgery regionalization. Overall survival was compared by Kaplan-Meier analysis, and 1- and 3-year mortality was compared by the by χ2 or Fisher exact test. Multivariable Cox regression models evaluated the effect of regionalization on mortality adjusted for relevant factors. RESULTS: Kaplan-Meier curves showed that overall survival was better among patients undergoing surgery postregionalization (log-rank test, P < .0001). Both 1- and 3-year mortality were decreased after regionalization: to 5.7% from 11.1% (P < .0001) for 1 year and to 17.0% from 25.5% (P = .0002) for 3 years. The multivariable adjusted Cox regression analysis revealed that only regionalization (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.42-0.76), age (HR, 1.03; 95% CI, 1.02-1.04), cancer stage (HR, 1.72, 1.83, and 2.56 for stages II, III, and IV, respectively), and Charlson comorbidity index (HR, 1.80 for 1-2; 2.05 for ≥3) were independent predictors of mortality. CONCLUSIONS: We found that overall mortality as well as 1- and 3-year mortality for lung cancer resection were lower after thoracic surgery regionalization. The association between regionalization and reduced mortality was significant even after adjusting for other related factors in a multivariable Cox analysis. Notably, surgeon volume, facility volume, surgeon specialty, neoadjuvant treatment, and video-assisted thoracoscopic surgery approach did not significantly affect mortality in the adjusted model.

15.
Mol Oncol ; 15(8): 2065-2083, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33931939

RESUMO

Resistance to adjuvant chemotherapy is a major clinical problem in the treatment of colorectal cancer (CRC). The aim of this study was to elucidate the role of an epithelial to mesenchymal transition (EMT)-inducing protein, ZEB2, in chemoresistance of CRC, and to uncover the underlying mechanism. We performed IHC for ZEB2 and association analyses with clinical outcomes on primary CRC and matched CRC liver metastases in compliance with observational biomarker study guidelines. ZEB2 expression in primary tumours was an independent prognostic marker of reduced overall survival and disease-free survival in patients who received adjuvant FOLFOX chemotherapy. ZEB2 expression was retained in 96% of liver metastases. The ZEB2-dependent EMT transcriptional programme activated nucleotide excision repair (NER) pathway largely via upregulation of the ERCC1 gene and other components in NER pathway, leading to enhanced viability of CRC cells upon oxaliplatin treatment. ERCC1-overexpressing CRC cells did not respond to oxaliplatin in vivo, as assessed using a murine orthotopic model in a randomised and blinded preclinical study. Our findings show that ZEB2 is a biomarker of tumour response to chemotherapy and risk of recurrence in CRC patients. We propose that the ZEB2-ERCC1 axis is a key determinant of chemoresistance in CRC.

16.
J Immunother Cancer ; 9(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33963014

RESUMO

BACKGROUND: Checkpoint inhibitors targeting programmed death receptor-1 (PD-1) have been tested in the neoadjuvant setting for the treatment of locoregionally advanced head and neck squamous cell carcinoma (HNSCC); however, response rates are modest. We hypothesized that adding stereotactic body radiation therapy (SBRT) to anti-PD-1 would be safe prior to definitive surgical resection and would enhance pathological response compared with historical cohorts of patients with locoregionally advanced HNSCC treated with checkpoint inhibitor alone. METHODS: The Neoadjuvant Immuno-Radiotherapy Trial was an investigator-initiated single institution phase Ib clinical trial that enrolled patients with previously untreated locally advanced HPV-positive and HPV-negative HNSCC between 2018 and 2019. Eligible patients were treated with neoadjuvant SBRT at a total dose of either 40 Gy in 5 fractions or 24 Gy in 3 fractions, delivered in a 1-week timespan, with or without nivolumab, prior to definitive surgical resection. Patients were then planned for treatment with adjuvant nivolumab for 3 months. The primary safety endpoint was unplanned delay in surgery considered to be at least possibly related to neoadjuvant treatment. The primary efficacy endpoints included pathological complete response (pCR), major pathological response (mPR), and the rate of clinical to pathological downstaging after neoadjuvant treatment. RESULTS: Twenty-one patients underwent neoadjuvant treatment, which was well tolerated and did not delay surgery, thus meeting the primary endpoint. Tissue responses were characterized by robust inflammatory infiltrates in the regression bed, plasma cells and cholesterol clefts. Among the entire study group, the mPR and pCR rate was 86% and 67%, respectively. Clinical to pathological downstaging occurred in 90% of the patients treated. CONCLUSION: These data demonstrate that radiation delivered only to the gross tumor volume combined with immunotherapy was safe, resulted in a high rate of mPR and should be further evaluated as a locally focused neoadjuvant therapy for patients with head and neck cancer. TRIAL REGISTRATION NUMBER: This study is registered with clinicaltrials.gov (NCT03247712) and is active, but closed to patient accrual.

17.
Clin Cardiol ; 44(6): 839-847, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33982795

RESUMO

BACKGROUND: After myocardial infarction, guidelines recommend higher-potency P2Y12 receptor inhibitors, namely ticagrelor and prasugrel, over clopidogrel. HYPOTHESIS: We aimed to determine the contemporary use of higher-potency antiplatelet therapy in Canadian patients with non-ST-elevation myocardial infarction (NSTEMI). METHODS: A total of 684 moderate-to-high risk NSTEMI patients were enrolled in the prospective Canadian ACS Reflective II registry at 12 Canadian hospitals and three clinics in five provinces between July 2016 and May 2018. Multivariable logistic regression modeling was performed to assess factors independently associated with higher-potency P2Y12 receptor inhibitor use at discharge. RESULTS: At hospital discharge, 78.3% of patients were treated with a P2Y12 receptor inhibitor. Among patients discharged on a P2Y12 receptor inhibitor, use of higher-potency P2Y12 receptor inhibitor was 61.4%. After adjustment, treatment in-hospital with PCI (OR 4.48, 95%CI 3.34-6.03, p < .0001) was most strongly associated with higher use of higher-potency P2Y12 receptor inhibitor, while oral anticoagulant use at discharge (OR 0.03, 95%CI 0.01-0.12, p < .0001), and atrial fibrillation (OR 0.40, 95%CI 0.17-0.98, p = .046) were most strongly associated with lower use of higher-potency P2Y12 receptor inhibitor. Use of higher-potency P2Y12 receptor inhibitor varied across provinces (range, 21.6%-78.9%). DISCUSSION: In contemporary Canadian practice, approximately 60% of moderate-to-high risk NSTEMI patients discharged on a P2Y12 receptor inhibitor are treated with a higher-potency P2Y12 receptor inhibitor. In addition to factors that increase risk of bleeding, interprovincial differences in practice patterns were associated with use of higher-potency P2Y12 receptor inhibitor at discharge. Opportunities remain for further optimization of evidence-based, guideline-recommended antiplatelet therapy use.


Assuntos
Infarto do Miocárdio , Infarto do Miocárdio sem Supradesnível do Segmento ST , Intervenção Coronária Percutânea , Canadá , Estudos Transversais , Humanos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio sem Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio sem Supradesnível do Segmento ST/tratamento farmacológico , Inibidores da Agregação Plaquetária/efeitos adversos , Cloridrato de Prasugrel , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Ticlopidina , Resultado do Tratamento
18.
Inflamm Bowel Dis ; 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33904583

RESUMO

BACKGROUND: Develop a clinical and biological predictive model for colectomy risk in children newly diagnosed with ulcerative colitis (UC). METHODS: This was a multicenter inception cohort study of children (ages 4-17 years) newly diagnosed with UC treated with standardized initial regimens of mesalamine or corticosteroids (CS) depending upon initial disease severity. Therapy escalation to immunomodulators or infliximab was based on predetermined criteria. Patients were phenotyped by clinical activity per the Pediatric Ulcerative Colitis Activity Index (PUCAI), disease extent, endoscopic/histologic severity, and laboratory markers. In addition, RNA sequencing defined pretreatment rectal gene expression and high density DNA genotyping by the Affymetrix UK Biobank Axiom Array. Coprimary outcomes were colectomy over 3 years and time to colectomy. Generalized linear models, Cox proportional hazards multivariate regression modeling, and Kaplan-Meier plots were used. RESULTS: Four hundred twenty-eight patients (mean age 13 years) started initial theapy with mesalamine (n = 136), oral CS (n = 144), or intravenous CS (n = 148). Twenty-five (6%) underwent colectomy at ≤1 year, 33 (9%) at ≤2 years, and 35 (13%) at ≤3 years. Further, 32/35 patients who had colectomy failed infliximab. An initial PUCAI ≥ 65 was highly associated with colectomy (P = 0.0001). A logistic regression model predicting colectomy using the PUCAI, hemoglobin, and erythrocyte sedimentation rate had a receiver operating characteristic area under the curve of 0.78 (95% confidence interval [0.73, 0.84]). Addition of a pretreatment rectal gene expression panel reflecting activation of the innate immune system and response to external stimuli and bacteria to the clinical model improved the receiver operating characteristic area under the curve to 0.87 (95% confidence interval [0.82, 0.91]). CONCLUSIONS: A small group of children newly diagnosed with severe UC still require colectomy despite current therapies. Our gene signature observations suggest additional targets for management of those patients not responding to current medical therapies.

19.
J Med Chem ; 64(9): 6329-6357, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33929852

RESUMO

Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV via binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound 25, which has potent activity against Gram-positive bacteria, a favorable in vitro safety profile, and excellent in vivo pharmacokinetic properties. Compound 25 was found to be efficacious against fluoroquinolone-sensitive Staphylococcus aureus infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from Klebsiella pneumoniae, compound 25, and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of 25 compared to fluoroquinolones.


Assuntos
Antibacterianos/farmacologia , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , Desenho de Fármacos , Fluoroquinolonas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Inibidores da Topoisomerase II/farmacologia , Animais , Antibacterianos/química , Farmacorresistência Bacteriana/efeitos dos fármacos , Camundongos , Inibidores da Topoisomerase II/química
20.
Glia ; 69(8): 1950-1965, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33811383

RESUMO

It is well recognized that astrocytes can produce factors known to affect the myelination process. One such factor, brain-derived neurotrophic factor (BDNF), can enhance the differentiation of oligodendrocyte lineage cells following a demyelinating lesion. Our previous work indicated that enhancing astrocyte-derived BDNF via injection of a general agonist of Group I/II metabotropic glutamate receptors (mGluRs) into the lesion increased myelin proteins in the cuprizone model of demyelination after 4 hr. To determine if this observation has potential therapeutic significance, we now use a more specific mGluR agonist, 2-chloro-5-hydroxyphenylglycine (CHPG), which binds to mGluR5, to examine effects on myelination through the clinically relevant approach of a peripheral injection. In initial studies, intraperitoneal injection of CHPG resulted in an increase in myelin proteins within the lesioned corpus callosum. These effects were blocked when either BDNF or the CHPG receptor, mGluR5, was deleted from glial fibrillary acidic protein (GFAP)+ astrocytes or when the BDNF receptor, tropomyosin receptor kinase B (TrkB), was deleted from proteolipid protein (PLP)+ oligodendrocytes. Moreover, injection of CHPG over 2 weeks not only elevated BDNF and myelin proteins, but also enhanced myelination and reversed behavioral deficits. Interestingly, effects on myelin and myelin proteins were not seen in the control animals, indicating that a lesion is critical in eliciting effects. Taken together, the data suggest that the mGluR agonist CHPG may be a potential therapeutic strategy for treating demyelinating diseases and that it works by enhancing the release of BDNF from astrocytes.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...