To compare efficiency and safety of epithelium-off corneal cross-linking (CXL) and transepithelial cross-linking (TE-CXL) in pediatric patients with progressive keratoconus.
Uncorrected and corrected ...visual acuity, corneal topography and pachymetry (Pentacam; Oculus Pentacam), and in vivo confocal microscopy (HRT II, Rostock Cornea Module, Heidelberg Engineering, Heidelberg, Germany) were evaluated at baseline and at 3, 6, and 12 months.
In the epithelium-off CXL group (19 patients, 23 eyes; mean age, 14.75 ± 2.1 years), a significant improvement at month 12 was present for Kmax -1.11 diopters (D), P = 0.01, Kmin (-3.2 D, P = 0.001), mean K (-1.47 D, P = 0.01), surface asymmetry index (-0.64 D, P = 0.001), inferior-superior symmetry index (-0.54 D, P = 0.01), index of height asymmetry (-2.97, P = 0.03), and anterior elevation at the thinnest location (-2.82 D, P = 0.01) and at the apex (-2.27 D, P = 0.01). Postoperative corneal edema lasted 3 months in 16 eyes (69.5%) and more than 6 months in 2 eyes (8.7%). In the TE-CXL group (10 patients, 14 eyes; mean age, 15 ± 4.2 years), a significant improvement at month 12 was present for Kmax (-1.14 D, P = 0.02), Kmin (-2.04 D, P = 0.01), mean K (-1.63 D, P = 0.01), surface asymmetry index (-0.86 D, P = 0.001), inferior-superior symmetry index (-0.55 D, P = 0.001), index of height asymmetry (-2.95, P = 0.01), and anterior elevation at the thinnest location (-2.96 D, P = 0.01) and at the apex (-2.19 D, P = 0.01). No postoperative corneal edema after TE-CXL was observed. Changes at month 12 from baseline were not significantly different between the 2 groups (P > 0.05). TE-CXE was significantly less painful than epithelium-off CXL.
In pediatric patients with progressive keratoconus, TE-CXL was less painful, provided similar effectiveness and fewer complications than epithelium-off CXL at 12-month follow-up.
Pathological studies on Parkinson's disease (PD) patients suggest that PD pathology progresses from the enteric nervous system (ENS) and the olfactory bulb into the central nervous system. We have ...previously shown that environmental toxins acting locally on the ENS mimic this PD-like pathology progression pattern in mice. Here, we show for the first time that the resection of the autonomic nerves stops this progression. Moreover, our results show that an environmental toxin (i.e. rotenone) promotes the release of alpha-synuclein by enteric neurons and that released enteric alpha-synuclein is up-taken by presynaptic sympathetic neurites and retrogradely transported to the soma, where it accumulates. These results strongly suggest that pesticides can initiate the progression of PD pathology and that this progression is based on the transneuronal and retrograde axonal transport of alpha-synuclein. If confirmed in patients, this study would have crucial implications in the strategies used to prevent and treat PD.
To examine the prevalence and dynamics of circulating tumor DNA (ctDNA) and its association with metastatic recurrence in patients with high-risk early-stage hormone receptor-positive breast cancer ...(HR+ BC) more than 5 years from diagnosis.
We enrolled 103 patients with high-risk stage II-III HR+ BC diagnosed more than 5 years prior without clinical evidence of recurrence. We performed whole-exome sequencing (WES) on primary tumor tissue to identify somatic mutations tracked via a personalized, tumor-informed ctDNA test to detect minimal residual disease (MRD). We collected plasma at the time of consent and at routine visits every 6-12 months. Patients were followed for clinical recurrence.
In total, 85 of 103 patients had sufficient tumor tissue; of them, 83 of 85 (97.6%) patients had successful whole-exome sequencing. Personalized ctDNA assays were designed targeting a median of 36 variants to test 219 plasma samples. The median time from diagnosis to first sample was 8.4 years. The median follow-up was 10.4 years from diagnosis and 2.0 years from first sample. The median number of plasma samples per patient was two. Eight patients (10%) had positive MRD testing at any time point. Six patients (7.2%) developed distant metastatic recurrence, all of whom were MRD-positive before overt clinical recurrence, with median ctDNA lead time of 12.4 months. MRD was not identified in one patient (1.2%) with local recurrence. Two of eight MRD-positive patients had not had clinical recurrence at last follow-up.
In this prospective study, in patients with high-risk HR+ BC in the late adjuvant setting, ctDNA was identified a median of 1 year before all cases of distant metastasis. Future studies will determine if ctDNA-guided intervention in patients with HR+ BC can alter clinical outcomes.
The transcription factor FOXM1 binds to sequence-specific motifs on DNA (C/TAAACA) through its DNA-binding domain (DBD) and activates proliferation- and differentiation-associated genes. Aberrant ...overexpression of FOXM1 is a key feature in oncogenesis and progression of many human cancers. Here--from a high-throughput screen applied to a library of 54,211 small molecules--we identify novel small molecule inhibitors of FOXM1 that block DNA binding. One of the identified compounds, FDI-6 (NCGC00099374), is characterized in depth and is shown to bind directly to FOXM1 protein, to displace FOXM1 from genomic targets in MCF-7 breast cancer cells, and induce concomitant transcriptional downregulation. Global transcript profiling of MCF-7 cells by RNA-seq shows that FDI-6 specifically downregulates FOXM1-activated genes with FOXM1 occupancy confirmed by ChIP-PCR. This small molecule-mediated effect is selective for FOXM1-controlled genes with no effect on genes regulated by homologous forkhead family factors.
Human pancreatic ductal adenocarcinoma (PDAC) involves the dysregulation of multiple signaling pathways. A novel approach to the treatment of PDAC is described, involving the targeting of cancer ...genes in PDAC pathways having over-representation of G-quadruplexes, using the trisubstituted naphthalene diimide quadruplex-binding compound 2,7-bis(3-morpholinopropyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)benzolmn3,8phenanthroline-1,3,6,8(2H,7H)-tetraone (CM03). This compound has been designed by computer modeling, is a potent inhibitor of cell growth in PDAC cell lines, and has anticancer activity in PDAC models, with a superior profile compared to gemcitabine, a commonly used therapy. Whole-transcriptome RNA-seq methodology has been used to analyze the effects of this quadruplex-binding small molecule on global gene expression. This has revealed the down-regulation of a large number of genes, rich in putative quadruplex elements and involved in essential pathways of PDAC survival, metastasis, and drug resistance. The changes produced by CM03 represent a global response to the complexity of human PDAC and may be applicable to other currently hard-to-treat cancers.
Pharmacological modulators of host-microbial interactions can in principle be identified using high-content screens. However, a severe limitation of this approach is the lack of insights into the ...mode of action of compounds selected during the primary screen. To overcome this problem, we developed a combined experimental and computational approach. We designed a quantitative multiparametric image-based assay to measure intracellular mycobacteria in primary human macrophages, screened a chemical library containing FDA-approved drugs, and validated three compounds for intracellular killing of M. tuberculosis. By integrating the multiparametric profiles of the chemicals with those of siRNAs from a genome-wide survey on endocytosis, we predicted and experimentally verified that two compounds modulate autophagy, whereas the third accelerates endosomal progression. Our findings demonstrate the value of integrating small molecules and genetic screens for identifying cellular mechanisms modulated by chemicals. Furthermore, selective pharmacological modulation of host trafficking pathways can be applied to intracellular pathogens beyond mycobacteria.
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► A high-content chemical screen identifies modulators of intracellular mycobacteria ► Three compounds that kill bacteria by altering host processes were validated ► Multiparametric chemical and genetic data sets integrated to identify mode of action ► Modulation of autophagy and endosomal trafficking identified as mode of action
Complex pulmonary aspergilloma treated by cavernostomy Silva, Paula dos Santos Marsico Pereira da; Marsico, Giovanni Antonio; Araujo, Marcell Alex Ferraz ...
Revista do Colégio Brasileiro de Cirurgiões,
12/2014, Letnik:
41, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Objective: To evaluate the effectiveness of cavernostomy in patients with complex fungal balls.Methods: We analyzed the medical records of patients undergoing cavernostomy between January 2005 and ...May 2013, evaluating: age, gender, preoperative signs and symptoms, predisposing disease, preoperative tests, location of the aspergilloma, etiologic agent, cavernostomy indication, postoperative outcome.Results: Ten patients were male. The mean age was 42.9 years (34-56). The most frequent symptom was repeated pulmonary bleeding. Cavernostomy was proposed for patients at high risk for lung resection. It was performed in 17 patients and all of them had pulmonary tuberculosis sequelae, with cavitations. The indication in all cases was hemoptysis and elimination of phlegm. The cavernostomies were performed in a single surgical procedure. In all 17 patients the cavity was left open after the withdrawal of the mycetoma. In all patients hemoptysis ceased immediately. Operative mortality was 9.5% (1).Conclusion: cavernostomy is an effective treatment alternative in patients at high risk. It may be useful in some patients with complex aspergilloma, irrespective of lung function or bilateral disease. It is technically easy, has low-risk, saves parenchyma, and may be performed in a single operative time.
Objetivo: avaliar a efetividade da cavernostomia nos pacientes com bola fúngica complexa.Métodos: foram analisados os prontuários de pacientes submetidos à cavernostomia entre janeiro de 2005 e maio de 2013. Foram avaliados: idade, sexo, sinais e sintomas pré-operatórios, doença predisponente, exames pré-operatórios, localização do aspergiloma, agente etiológico, indicação da cavernostomia, evolução pós-operatória.Resultados: dez pacientes eram do sexo masculino. A média de idade foi 42,9 anos (34-56). O sintoma mais frequente foi o sangramento pulmonar repetido. A cavernostomia foi proposta para os pacientes com risco elevado para ressecção pulmonar, foi realizada em 17 pacientes e todos eles apresentavam sequelas de tuberculose pulmonar com lesões cavitárias. A indicação em todos os casos foi hemoptise e eliminação de catarro. As cavernostomias foram realizadas em tempo cirúrgico único. Nos 17 pacientes a caverna foi deixada aberta após a retirada do micetoma. Em todos os pacientes a hemoptise cessou imediatamente. A mortalidade operatória foi 1 (9.5%).Conclusão: a cavernostomia é uma alternativa de tratamento efetivo em pacientes com risco elevado. Pode ser útil em alguns pacientes com aspergiloma complexo, independentemente da função pulmonar ou doença bilateral. É tecnicamente fácil, de baixo risco, poupa parênquima, e realizada em tempo operatório único.
Symptomatic mucocele after esophageal exclusion Haddad, Rui; Teixeira Lima, Rodrigo; Henrique Boasquevisque, Carlos ...
Interactive cardiovascular and thoracic surgery,
08/2008, Letnik:
7, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Thoracic Surgery Division, Department of Surgery, Faculty of Medicine and Thoracic Diseases Institute, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
*Corresponding author. ...Rua Barão de Lucena 48, Sala 03 22260-020, Botafogo, Rio de Janeiro, RJ, Brazil. Tel./fax: +55-21-33221545. E-mail address : haddad{at}ufrj.br (R. Haddad).
Surgical exclusion of the thoracic esophagus can result in the accumulation of secretions and dilatation of the esophageal remnant, a clinical picture known as esophageal mucocele. Although it is usually asymptomatic, if it increases in size it can produce a variety of compressive symptoms such as coughing, chest pain and respiratory distress. We present two cases of symptomatic mucocele after esophageal exclusion treated successfully with surgical resection. We believe that surgical resection should be considered for symptomatic patients, and that esophageal bypass surgery should be used with caution and indicated mostly in patients with a limited life span or with contraindications for esophagectomy.
Key Words: Esophageal mucocele; Complication esophageal bypass; Mediastinum; Cyst
Cohort 1 of the phase 1B NABUCCO trial showed high pathological complete response (pCR) rates with preoperative ipilimumab plus nivolumab in stage III urothelial cancer (UC). In cohort 2, the aim was ...dose adjustment to optimize responses. Additionally, we report secondary endpoints, including efficacy and tolerability, in cohort 2 and the association of presurgical absence of circulating tumor DNA (ctDNA) in urine and plasma with clinical outcome in both cohorts. Thirty patients received two cycles of either ipilimumab 3 mg kg
plus nivolumab 1 mg kg
(cohort 2A) or ipilimumab 1 mg kg
plus nivolumab 3 mg kg
(cohort 2B), both followed by nivolumab 3 mg kg
. We observed a pCR in six (43%) patients in cohort 2A and a pCR in one (7%) patient in cohort 2B. Absence of urinary ctDNA correlated with pCR in the bladder (ypT0Nx) but not with progression-free survival (PFS). Absence of plasma ctDNA correlated with pCR (odds ratio: 45.0; 95% confidence interval (CI): 4.9-416.5) and PFS (hazard ratio: 10.4; 95% CI: 2.9-37.5). Our data suggest that high-dose ipilimumab plus nivolumab is required in stage III UC and that absence of ctDNA in plasma can predict PFS. ClinicalTrials.gov registration: NCT03387761 .
Most delivery systems for small interfering RNA therapeutics depend on endocytosis and release from endo-lysosomal compartments. One approach to improve delivery is to identify small molecules ...enhancing these steps. It is unclear to what extent such enhancers can be universally applied to different delivery systems and cell types. Here, we performed a compound library screen on two well-established siRNA delivery systems, lipid nanoparticles and cholesterol conjugated-siRNAs. We identified fifty-one enhancers improving gene silencing 2-5 fold. Strikingly, most enhancers displayed specificity for one delivery system only. By a combination of quantitative fluorescence and electron microscopy we found that the enhancers substantially differed in their mechanism of action, increasing either endocytic uptake or release of siRNAs from endosomes. Furthermore, they acted either on the delivery system itself or the cell, by modulating the endocytic system via distinct mechanisms. Interestingly, several compounds displayed activity on different cell types. As proof of principle, we showed that one compound enhanced siRNA delivery in primary endothelial cells in vitro and in the endocardium in the mouse heart. This study suggests that a pharmacological approach can improve the delivery of siRNAs in a system-specific fashion, by exploiting distinct mechanisms and acting upon multiple cell types.
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