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BACKGROUND: Pulmonary vein stenosis (PVS) is a rare condition in which neointimal proliferation leads to venous and arterial hypertension. Little is known about PVS after heart transplant (HTx) in children. We sought to describe the characteristics and outcomes of children who develop PVS after HTx. METHODS: We performed a retrospective review of patients ≤18 years old who underwent HTx at two HTx centers between April 2012 and October 2023. Patients with PVS were identified via database queries. Cardiac diagnosis, PVS location and extent, and outcomes were recorded. RESULTS: Over 11.5 years, 422 patients underwent HTx across both centers. Nineteen patients with PVS (10 male) were identified, 15 with de novo PVS. Sixteen had underlying congenital heart disease (CHD), two with anomalous pulmonary venous return. PVS was diagnosed at a median of 2 months (range 2 weeks to 14 years) after HTx. At time of initial diagnosis, 13 patients had one-vessel PVS. At final follow-up, 7/19 (37%) had increases in the number of vessels involved. Six patients underwent surgery, and nine patients had stent or balloon angioplasty. Two patients were treated for pulmonary hypertension following PVS diagnosis. Three patients died from right heart failure secondary to PVS. CONCLUSIONS: This is the largest study to describe the characteristics of post-HTx PVS in children. PVS occurs in 4.5% of HTx, and underlying CHD is a strong risk factor. Multiple vessels can be involved and may require catheter-based or surgical intervention. Clinicians must be vigilant in monitoring the development of PVS in this population.
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Transplante de Coração , Complicações Pós-Operatórias , Estenose de Veia Pulmonar , Humanos , Estudos Retrospectivos , Masculino , Transplante de Coração/efeitos adversos , Feminino , Criança , Pré-Escolar , Estenose de Veia Pulmonar/etiologia , Lactente , Adolescente , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Recém-Nascido , Progressão da Doença , Cardiopatias Congênitas/cirurgia , Cardiopatias Congênitas/complicações , SeguimentosRESUMO
Redo ascending and aortic arch surgeries following previous cardiac or aortic surgery are associated with high risk of morbidity and mortality due to multiple factors included sternal re-entry injury, extensive aortic arch surgery, emergency aortic surgery, prolonged cardiopulmonary bypass duration, poor heart function, and patients with older age. Therefore, appropriate surgical strategies are important. We report a case of a 72-year-old gentleman with previous surgery of aortic root replacement who presented with acute Type A aortic dissecting aneurysm of ascending and aortic arch complicated with left hemothorax, which was successfully treated by emergency redo aortic surgery with frozen elephant trunk (FET) technique.
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Aneurisma da Aorta Torácica , Dissecção Aórtica , Implante de Prótese Vascular , Masculino , Humanos , Idoso , Aorta Torácica/cirurgia , Prótese Vascular , Aneurisma da Aorta Torácica/cirurgia , Implante de Prótese Vascular/métodos , Valva Aórtica/cirurgia , Dissecção Aórtica/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , StentsRESUMO
BACKGROUND AND AIMS: This study aimed to identify microbial drivers of inflammatory bowel disease [IBD], by investigating mucosal-associated bacteria and their detrimental products in IBD patients. METHODS: We directly cultured bacterial communities from mucosal biopsies from paediatric gastrointestinal patients and examined for pathogenicity-associated traits. Upon identifying Clostridium perfringens as toxigenic bacteria present in mucosal biopsies, we isolated strains and further characterized toxicity and prevalence. RESULTS: Mucosal biopsy microbial composition differed from corresponding stool samples. C. perfringens was present in eight of nine patients' mucosal biopsies, correlating with haemolytic activity, but was not present in all corresponding stool samples. Large IBD datasets showed higher C. perfringens prevalence in stool samples of IBD adults [18.7-27.1%] versus healthy controls [5.1%]. In vitro, C. perfringens supernatants were toxic to cell types beneath the intestinal epithelial barrier, including endothelial cells, neuroblasts, and neutrophils, while the impact on epithelial cells was less pronounced, suggesting C. perfringens may be particularly damaging when barrier integrity is compromised. Further characterization using purified toxins and genetic insertion mutants confirmed perfringolysin O [PFO] toxin was sufficient for toxicity. Toxin RNA signatures were found in the original patient biopsies by PCR, suggesting intestinal production. C. perfringens supernatants also induced activation of neuroblast and dorsal root ganglion neurons in vitro, suggesting C. perfringens in inflamed mucosal tissue may directly contribute to abdominal pain, a frequent IBD symptom. CONCLUSIONS: Gastrointestinal carriage of certain toxigenic C. perfringens may have an important pathogenic impact on IBD patients. These findings support routine monitoring of C. perfringens and PFO toxins and potential treatment in patients.
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Toxinas Bacterianas , Clostridium perfringens , Fezes , Doenças Inflamatórias Intestinais , Mucosa Intestinal , Humanos , Clostridium perfringens/isolamento & purificação , Clostridium perfringens/genética , Clostridium perfringens/patogenicidade , Criança , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Doenças Inflamatórias Intestinais/microbiologia , Toxinas Bacterianas/genética , Fezes/microbiologia , Feminino , Masculino , Adolescente , Biópsia , Infecções por Clostridium/microbiologia , Proteínas HemolisinasRESUMO
BACKGROUND: We assessed nofazinlimab, an anti-PD-1 antibody, in solid tumors and combined with regorafenib in metastatic colorectal cancer (mCRC). METHODS: This phase 1 study comprised nofazinlimab dose escalation (phase 1a) and expansion (phase 1b), and regorafenib dose escalation (80 or 120 mg QD, days 1-21 of 28-day cycles) combined with 300-mg nofazinlimab Q4W (part 2a) to determine safety, efficacy, and RP2D. RESULTS: In phase 1a (N = 21), no dose-limiting toxicity occurred from 1 to 10 mg/kg Q3W, with 200 mg Q3W determined as the monotherapy RP2D. In phase 1b (N = 87), 400-mg Q6W and 200-mg Q3W regimens were found comparable. In part 2a (N = 14), both regimens were deemed plausible RP2Ds. Fatigue was the most frequent treatment-emergent adverse event (AE) in this study. Any-grade and grade 3/4 nofazinlimab-related AEs were 71.4% and 14.3%, 56.3% and 5.7%, and 57.1% and 21.4% in phases 1a, 1b, and part 2a, respectively. ORRs were 14.3% and 25.3% in phases 1a and 1b, respectively. In part 2a, no patients had radiological responses. CONCLUSIONS: Nofazinlimab monotherapy was well tolerated and demonstrated preliminary anti-tumor activity in multiple tumor types. Regorafenib plus nofazinlimab had a manageable safety profile but was not associated with any response in mCRC. CLINICAL TRIAL REGISTR ATION: Clinicaltrials.gov (NCT03475251).
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Neoplasias do Colo , Neoplasias Retais , Humanos , Piridinas , Compostos de Fenilureia , Neoplasias do Colo/tratamento farmacológico , Neoplasias Retais/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Background: The Occlutech Atrial Flow Regulator (AFR) is a self-expandable double-disc nitinol device with a central fenestration. Its use has been approved in the adult population with heart failure and described for pulmonary hypertension (PH). Only case reports and small series have been published about its use in the paediatric population and for congenital heart disease (CHD). Objectives: The authors sought to investigate the feasibility, safety, and short-term follow-up of AFR implantation in patients with CHD or children with PH or cardiomyopathy. Methods: This is a multicenter retrospective study involving 10 centers worldwide. Patients of any age with CHD or patients aged < 18 years with PH or cardiomyopathy needing AFR implantation were included. Results: A total of 40 patients underwent AFR implantation. The median age of the population at the time of the procedure was 58.5 months (IQR: 31.5-142.5) and the median weight was 17â kg (IQR: 10-46). A total of 26 (65.0%) patients had CHD, nine (22.5%) children, a cardiomyopathy, and five (12.5%), a structurally normal heart. The implantation success rate was 100%. There were two early and one late device thrombosis. Two patients (5.0%) with dilated cardiomyopathy on extracorporeal membrane oxygenator (ECMO) died during the hospital stay. At a median follow-up of 330 days (IQR: 125-593), 37 (92.5%) patients were alive. At follow-up, 20 patients improved their New York Heart Association (NYHA) class, 12 patients did not change their NYHA class, and one patient with idiopathic PH worsened. Conclusions: AFR implantation in patients with CHD and children with severe PH or cardiomyopathy is promising and seems to have beneficial effects at short-term follow-up.
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Transcatheter electrosurgery is a wire-based technique used to traverse or cut tissue within blood-filled spaces using alternating current delivered by guidewires or catheters. The use of transcatheter electrosurgical techniques in the pediatric population has been limited. We are reporting the first case of retrograde pulmonary vein recanalization using transcatheter electrosurgery. (Level of Difficulty: Advanced.).
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[This corrects the article DOI: 10.1093/ehjcr/ytab003.].
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Pulmonary vein stenosis (PVS) is a difficult condition to treat due to recurrence and progression. In 2017, we developed a comprehensive PVS Program at our center to address the multidisciplinary needs of these patients. We discuss the components of our program and our approach to these patients, using a combination of primary (medical) therapy in addition to anatomic therapy to preserve vessel patency. A multidisciplinary approach to treating these challenging patients is critical.
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Background: The prevalence of culture negative infective endocarditis (IEC) is reported as 2-7% though this figure may be as high as 70% in developing countries.1 This higher rate will, at least in part, be due to reduced diagnostic facilities though some data suggests higher rates even when appropriate cultures were taken. The frequency is significantly elevated in patients who have already been exposed to antibiotics prior to blood cultures.1 , 2 A rare cause of culture negative IEC is the HACEK group of organisms that are normal habitants of the oropharyngeal flora and account for 1-3% of native valve endocarditis.3 Aggregatibacter aphrophilus (A. aphrophilus) is a member of the HACEK group of organisms. Case summary: A 32-year-old gentleman with a previous bioprosthetic aortic valve presented with a 1-week history of diarrhoea, vomiting, malaise, and weight loss. He was awaiting redo surgery for stenosis of the bioprosthesis, which had been inserted aged 17 for aortic stenosis secondary to a bicuspid valve. The initial blood tests revealed liver and renal impairment with anaemia. A transoesophageal echocardiogram demonstrated a complex cavitating aortic root abscess, complicated by perforation into the right ventricle. He underwent emergency redo surgery requiring debridement of the aortic abscess, insertion of a mechanical aortic prosthesis (St Jude Medical, USA), annular reconstruction and graft replacement of the ascending aorta. Despite antibiotic therapy, he remained septic with negative blood and tissue cultures. Bacterial 16S rRNA gene sequencing confirmed A. aphrophilus infection, for which intravenous ceftriaxone was initiated. This was subsequently changed to ciprofloxacin due to neutropenia. The patient self-discharged from the hospital during the third week of antibiotic therapy. One week later, he was re-admitted with fever, night sweats, and dyspnoea. Transthoracic echocardiogram revealed a large recurrent aortic abscess cavity around the aortic annulus fistulating into the right heart chambers; this was confirmed by a computed tomography scan. There was dehiscence of the patch repair. Emergency redo aortic root replacement (25 mm mechanical valve conduit, ATS Medical, USA) and annular reconstruction was performed with venoarterial extracorporeal membrane oxygenation (VA-ECMO) support. VA-ECMO was weaned after 3 days. The patient completed a full course of intravenous meropenem and ciprofloxacin and made a good recovery. Discussion: IEC with oropharyngeal HACEK organisms is rare and difficult to diagnose, due to negative blood culture results. The broad-range polymerase chain reaction and gene sequencing with comparison to the DNA database is useful in these circumstances. This case demonstrates the importance of the 16S rRNA gene sequencing for HACEK infection diagnosis and appropriate antibiotic treatment.
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PURPOSE: This phase I study was conducted to evaluate the safety and Maximum Tolerated Dose of PENAO (4-(N-(S-penicillaminylacetyl)amino)-phenylarsonous acid), a second-generation organic arsenical with anti-mitochondrial activity, when given as a continuous intravenous infusion (CIVI), in patients with advanced solid tumours. METHODS: Eligibility criteria for this trial included age ≥ 18 years, advanced solid tumour, ECOG Performance Status ≤ 1 and adequate organ function. PENAO was administered by CIVI, with dose levels initially increased by infusion duration in a 21-day cycle at a fixed daily dose and then increased daily dose. Standard dose-limiting toxicity (DLT) definitions were used in a "3 + 3" design. Patients had regular monitoring of toxicity and efficacy. Pharmacokinetic assays of serum and urine As were performed. RESULTS: Twenty-six patients were treated across 8 dose levels. The only dose-limiting toxicity (DLT) observed was fatigue, that occurred in one patient treated at the highest dose level of 9 mg/m2/day. No significant organ toxicity or objective responses were observed, although there were two patients with stable disease lasting up to 7 months. Pharmacokinetic analysis unexpectedly indicated a half-life of 9-19 days, invalidating the CIVI dosing resulting in discontinuation of the study before the RP2D was defined. CONCLUSIONS: PENAO was administered by CIVI at dose levels up to 9 mg/m2/day with only one DLT noted. Pharmacokinetic studies invalidated the rationale for continuous dosing and led to discontinuation of the trial without defining a RP2D. Future clinical development of PENAO will use intermittent dosing schedule, alone and in combination with rapamycin.
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Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We describe our experience with aortic root distortion in transcatheter pulmonary valve implantation (TPVI). Aortic root distortion (AD) can be observed with balloon angioplasty of the right ventricular outflow tract (RVOT), but its long-term significance is unknown. This has been a common finding in our institution, though not fully appreciated in our early experience. Retrospective review of procedural angiograms prior to TPVI and follow up imaging was performed. Between June 2012 and October 2017, 47 patients underwent catheterization to attempt TPVI. Five patients had coronary compression which precluded TPVI (one with significant AD as well). Four patients had significant AD and did not receive TPVI. Of the remaining 38 successful TPVI, 20 had adequate imaging to assess the aortic root. Four patients had severe AD, 7 had mild AD, and 9 with no AD. Severity of AI did not correlate with degree of AD. Median follow up after TPVI was 46 months (IQR 21-67). Of the 4 patients with severe AD who received TPVI, 1 has new mild AI with 78 months follow up. Of the 18 patients who received TPVI without adequate arch imaging, 2 patients have new mild AI with 86 and 75 months follow up. AD during RVOT angioplasty is a relatively common finding. In our early experience, some patients who were retrospectively identified to have severe AD received TPVI. These patients have done well, though further data is needed before considering severe AD a benign finding.
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Angioplastia Coronária com Balão/métodos , Aorta/cirurgia , Cardiopatias Congênitas/cirurgia , Implante de Prótese de Valva Cardíaca/métodos , Valva Pulmonar/cirurgia , Adolescente , Angiografia/métodos , Aorta/diagnóstico por imagem , Aorta/patologia , Cateterismo Cardíaco/métodos , Criança , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Função Ventricular Direita , Adulto JovemRESUMO
BACKGROUND: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. METHODS: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. CONCLUSIONS: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
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Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Piperazinas/administração & dosagem , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridinas/efeitos adversos , Piridinas/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinéticaRESUMO
In synthetic circuits, CRISPR-Cas systems have been used effectively for endpoint changes from an initial state to a final state, such as in logic gates. Here, we use deactivated Cas9 (dCas9) and deactivated Cas12a (dCas12a) to construct dynamic RNA ring oscillators that cycle continuously between states over time in bacterial cells. While our dCas9 circuits using 103-nt guide RNAs showed irregular fluctuations with a wide distribution of peak-to-peak period lengths averaging approximately nine generations, a dCas12a oscillator design with 40-nt CRISPR RNAs performed much better, having a strongly repressed off-state, distinct autocorrelation function peaks, and an average peak-to-peak period length of â¼7.5 generations. Along with free-running oscillator circuits, we measure repression response times in open-loop systems with inducible RNA steps to compare with oscillator period times. We track thousands of cells for 24+ h at the single-cell level using a microfluidic device. In creating a circuit with nearly translationally independent behavior, as the RNAs control each others' transcription, we present the possibility for a synthetic oscillator generalizable across many organisms and readily linkable for transcriptional control.
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Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas , Microfluídica/métodos , Periodicidade , RNA Guia de Cinetoplastídeos/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteína 9 Associada à CRISPR/genética , Proteínas Associadas a CRISPR/genética , Proteínas Associadas a CRISPR/metabolismo , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Escherichia coli , Microfluídica/instrumentação , RNA Guia de Cinetoplastídeos/genética , Análise de Célula Única/instrumentação , Análise de Célula Única/métodosRESUMO
Several Nocardia strains associated with nocardiosis, a potentially life-threatening disease, house a nonamodular assembly line polyketide synthase (PKS) that presumably synthesizes an unknown polyketide. Here, we report the discovery and structure elucidation of the NOCAP (nocardiosis-associated polyketide) aglycone by first fully reconstituting the NOCAP synthase in vitro from purified protein components followed by heterologous expression in E. coli and spectroscopic analysis of the purified products. The NOCAP aglycone has an unprecedented structure comprised of a substituted resorcylaldehyde headgroup linked to a 15-carbon tail that harbors two conjugated all-trans trienes separated by a stereogenic hydroxyl group. This report is the first example of reconstituting a trans-acyltransferase assembly line PKS in vitro and of using these approaches to "deorphanize" a complete assembly line PKS identified via genomic sequencing. With the NOCAP aglycone in hand, the stage is set for understanding how this PKS and associated tailoring enzymes confer an advantage to their native hosts during human Nocardia infections.
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Proteínas de Bactérias/metabolismo , Nocardiose/microbiologia , Nocardia/metabolismo , Policetídeo Sintases/metabolismo , Policetídeos/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Humanos , Família Multigênica , Nocardia/química , Nocardia/genética , Policetídeo Sintases/química , Policetídeo Sintases/genéticaRESUMO
KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity3-5. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRASG12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRASG12D tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.
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Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Imunoterapia , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Fosforilação/efeitos dos fármacos , Piperazinas/administração & dosagem , Piperazinas/química , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridinas/administração & dosagem , Piridinas/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
Diseases of the thoracic aorta are increasing in prevalence worldwide. Recent data indicated wide regional variation in the volume and complexity of aortic cases undertaken in United Kingdom cardiac centers, especially in case of acute type A aortic dissection (ATAAD) conditions. Patients treated in high-volume centers with a specific multidisciplinary aortic program had a significant reduction in ATAAD mortality when compared with low-volume centers. Following the initial phase of a national aortic center reorganization, the current study reflects the initial experience of a national collective of cardiothoracic surgeons with expertise in complex aortic surgery, using frozen elephant trunk as standard technique for the surgical treatment of patients affected by ATAAD. Between June 2013 and October 2017, 66 ATAAD patients (45% women) underwent hybrid aortic arch and frozen elephant trunk repair with the Thoraflex hybrid graft at 8 UK high-volume aortic centers. The in-hospital mortality accounted for 8 patients (12%). Postoperative temporary or permanent neurologic events and temporary renal replacement therapy occurred in 17% and 20% of patients, respectively. No spinal cord injury events were documented. Our data were similar to those reported in literature in the 2 largest experiences with the use of frozen elephant technique in ATAAD condition (in-hospital/30-day mortality: 11-12%). This initial experience demonstrated that frozen elephant technique can potentially be adopted as standard approach in life-threatening aortic diseases, with acceptable complication and mortality rates.
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Aneurisma da Aorta Torácica/cirurgia , Dissecção Aórtica/cirurgia , Implante de Prótese Vascular/instrumentação , Prótese Vascular , Procedimentos Endovasculares/instrumentação , Stents , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/mortalidade , Dissecção Aórtica/fisiopatologia , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/mortalidade , Aneurisma da Aorta Torácica/fisiopatologia , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/mortalidade , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/mortalidade , Desenho de Prótese , Fatores de Risco , Resultado do Tratamento , Reino UnidoRESUMO
Park et al. (2019) create a synthetic self-propagating adenine methylation system for epigenetic control in human cells. Targeting adenine allows their modular system to act orthogonally to most epigenetic processes, thereby opening the door for novel methods of controlling gene expression.
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Metilação de DNA , Epigênese Genética , Expressão Gênica , HumanosRESUMO
OBJECTIVE: Various options exist for right ventricular outflow tract (RVOT) reconstruction in congenital heart disease. The Freestyle porcine aortic root may be used but its longevity is not well defined. DESIGN: We performed a retrospective review of all non-Ross RVOT reconstructions using the Freestyle root in our institution. Survival and reintervention, either by surgery, transcatheter valve implantation, balloon valvuloplasty, or bare metal stent placement, were recorded. Factors associated with reintervention were assessed using Cox regression. RESULTS: Between January 2002 and December 2015, there were 182 patients identified. Sixteen patients were lost to follow-up and 3 patients died, unrelated to cardiac surgery. Of the remaining 163 patients, the median age was 12.2 years (interquartile range 6.4-16.4), median weight was 39.0 kg (interquartile range 19.9-59.3), and the median body surface area was 1.23 m2 (interquartile range 0.79-1.64). Ninety-three (57%) patients had tetralogy of Fallot. The median follow-up was 5.4 years (interquartile range 2.9-8 years). There were no operative or cardiac-related deaths. Thirty-eight patients (23%) required reintervention. The rate of freedom from reintervention was 93.2% (95% CI 86.7%-96.6%) at 5 years and 48.4% (95% CI 34.9%-60.6%) at 10 years. Age < 10 years, weight < 39 kg, and body surface area <1.2 m2 at the time of valve placement, as well as valve size ≤25 mm were significantly associated with need for earlier reintervention. CONCLUSIONS: The Freestyle root in the RVOT is associated with excellent survival and low midterm need for reintervention. Its longevity is comparable to published data on homografts and other bioprosthetic valves.
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Bioprótese , Implante de Prótese de Valva Cardíaca/métodos , Ventrículos do Coração/cirurgia , Valva Pulmonar/cirurgia , Obstrução do Fluxo Ventricular Externo/cirurgia , Adolescente , Animais , Cateterismo Cardíaco , Criança , Feminino , Seguimentos , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Xenoenxertos , Humanos , Masculino , Desenho de Prótese , Valva Pulmonar/diagnóstico por imagem , Estudos Retrospectivos , Suínos , Fatores de Tempo , Resultado do Tratamento , Obstrução do Fluxo Ventricular Externo/diagnóstico , Obstrução do Fluxo Ventricular Externo/fisiopatologiaRESUMO
After publication of this supplement [1, 2], it was brought to our attention that due to an error authors were missing in the following abstracts. This has now been included in this correction.
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Harnessing CRISPR-Cas9 technology provides an unprecedented ability to modify genomic loci via DNA double-strand break (DSB) induction and repair. We analyzed nonhomologous end-joining (NHEJ) repair induced by Cas9 in budding yeast and found that the orientation of binding of Cas9 and its guide RNA (gRNA) profoundly influences the pattern of insertion/deletions (indels) at the site of cleavage. A common indel created by Cas9 is a 1-bp (+1) insertion that appears to result from Cas9 creating a 1-nt 5' overhang that is filled in by a DNA polymerase and ligated. The origin of +1 insertions was investigated by using two gRNAs with PAM sequences located on opposite DNA strands but designed to cleave the same sequence. These templated +1 insertions are dependent on the X-family DNA polymerase, Pol4. Deleting Pol4 also eliminated +2 and +3 insertions, which are biased toward homonucleotide insertions. Using inverted PAM sequences, we also found significant differences in overall NHEJ efficiency and repair profiles, suggesting that the binding of the Cas9:gRNA complex influences subsequent NHEJ processing. As with events induced by the site-specific HO endonuclease, CRISPR-Cas9-mediated NHEJ repair depends on the Ku heterodimer and DNA ligase 4. Cas9 events are highly dependent on the Mre11-Rad50-Xrs2 complex, independent of Mre11's nuclease activity. Inspection of the outcomes of a large number of Cas9 cleavage events in mammalian cells reveals a similar templated origin of +1 insertions in human cells, but also a significant frequency of similarly templated +2 insertions.