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1.
Cell Commun Signal ; 22(1): 152, 2024 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-38414029

RESUMO

BACKGROUND: Germline mutations of E-cadherin contribute to hereditary diffuse gastric cancer (HDGC) and congenital malformations, such as oral facial clefts (OFC). However, the molecular mechanisms through which E-cadherin loss-of-function triggers distinct clinical outcomes remain unknown. We postulate that E-cadherin-mediated disorders result from abnormal interactions with the extracellular matrix and consequent aberrant intracellular signalling, affecting the coordination of cell migration. METHODS: Herein, we developed in vivo and in vitro models of E-cadherin mutants associated with either OFC or HDGC. Using a Drosophila approach, we addressed the impact of the different variants in cell morphology and migration ability. By combining gap closure migration assays and time-lapse microscopy, we further investigated the migration pattern of cells expressing OFC or HDGC variants. The adhesion profile of the variants was evaluated using high-throughput ECM arrays, whereas RNA sequencing technology was explored for identification of genes involved in aberrant cell motility. RESULTS: We have demonstrated that cells expressing OFC variants exhibit an excessive motility performance and irregular leading edges, which prevent the coordinated movement of the epithelial monolayer. Importantly, we found that OFC variants promote cell adhesion to a wider variety of extracellular matrices than HDGC variants, suggesting higher plasticity in response to different microenvironments. We unveiled a distinct transcriptomic profile in the OFC setting and pinpointed REG1A as a putative regulator of this outcome. Consistent with this, specific RNAi-mediated inhibition of REG1A shifted the migration pattern of OFC expressing cells, leading to slower wound closure with coordinated leading edges. CONCLUSIONS: We provide evidence that E-cadherin variants associated with OFC activate aberrant signalling pathways that support dynamic rearrangements of cells towards improved adaptability to the microenvironment. This proficiency results in abnormal tissue shaping and movement, possibly underlying the development of orofacial malformations.


Assuntos
Adenocarcinoma , Neoplasias Gástricas , Humanos , Caderinas/genética , Caderinas/metabolismo , Adesão Celular , Movimento Celular , Mutação em Linhagem Germinativa , Litostatina/genética , Neoplasias Gástricas/metabolismo , Microambiente Tumoral , Animais , Drosophila melanogaster
2.
Cancers (Basel) ; 15(17)2023 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-37686684

RESUMO

Cancer stem cells (CSCs) are relevant therapeutic targets for cancer treatment. Still, the molecular circuits behind CSC characteristics are not fully understood. The low number of CSCs can sometimes be an obstacle to carrying out assays that explore their properties. Thus, increasing CSC numbers via small molecule-mediated cellular reprogramming appears to be a valid alternative tool. Using the SORE6-GFP reporter system embedded in gastric non-CSCs (SORE6-), we performed a high-throughput image-based drug screen with 1200 small molecules to identify compounds capable of converting SORE6- to SORE6+ (CSCs). Here, we report that the antifungal agent ciclopirox olamine (CPX), a potential candidate for drug repurposing in cancer treatment, is able to reprogram gastric non-CSCs into cancer stem-like cells via activation of SOX2 expression and increased expression of C-MYC, HIF-1α, KLF4, and HMGA1. This reprogramming depends on the CPX concentration and treatment duration. CPX can also induce cellular senescence and the metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis. We also disclose that the mechanism underlying the cellular reprogramming is similar to that of cobalt chloride (CoCl2), a hypoxia-mimetic agent.

3.
Mol Biol Cell ; 34(5): ar47, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36989031

RESUMO

DNA damage response (DDR) during interphase involves active signaling and repair to ensure genomic stability. However, how mitotic cells respond to DNA damage remains poorly understood. Supported by correlative live-/fixed-cell microscopy, it was found that mitotic cells exposed to several cancer chemotherapy compounds acquire and signal DNA damage, regardless of how they interact with DNA. In-depth analysis upon DNA damage during mitosis revealed a spindle assembly checkpoint (SAC)-dependent, but ataxia telangiectasia mutated-independent, mitotic delay. This delay was due to the presence of misaligned chromosomes that ultimately satisfy the SAC and missegregate, leading to micronuclei formation. Mechanistically, it is shown that mitotic DNA damage causes missegregation of polar chromosomes due to the action of arm-ejection forces by chromokinesins. Importantly, with the exception of DNA damage induced by etoposide-a topoisomerase II inhibitor-this outcome was independent of a general effect on kinetochore microtubule stability. Colony formation assays in pan-cancer cell line models revealed that mitotic DNA damage causes distinct cytotoxic effects, depending on the nature and extent of the damage. Overall, these findings unveil and raise awareness that therapeutic DNA damage regimens may contribute to genomic instability through a surprising link with chromokinesin-mediated missegregation of polar chromosomes in cancer cells.


Assuntos
Neoplasias , Proteínas Nucleares , Proteínas Nucleares/metabolismo , Proteínas de Ligação a DNA/metabolismo , Dano ao DNA , Cromossomos/metabolismo , Neoplasias/genética
4.
Retina ; 43(4): 555-559, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36727800

RESUMO

PURPOSE: To investigate closure rates and functional outcomes of surgery for refractory and recurrent macular holes (MHs) in a real-world setting. METHODS: Retrospective review of secondary MH surgeries. RESULTS: A total of 72 eyes from 72 patients were included. Eyes had a mean of 1.51 surgeries before inclusion into this study with a mean MH size of 762 µ m and a mean baseline logarithm of the minimum angle of resolution best-corrected visual acuity of 1.11 (∼20/260 Snellen). Closure rates were 89.3% for tissue transplantation, 77.3% for internal limiting membrane (ILM) flaps, 92.9% for MH manipulation, and 12.5% for repeat ILM peeling ( P < 0.05). Best-corrected visual acuity changes in logarithm of the minimum angle of resolution from baseline to postoperative month six were +0.29 for ILM peeling alone (15 Early Treatment Diabetic Retinopathy Study letters worse), -0.39 for MH manipulation (20 Early Treatment Diabetic Retinopathy Study letters improved), -0.23 for tissue transplantation (13 Early Treatment Diabetic Retinopathy Study letters improved), and -0.2 for ILM flaps (10 Early Treatment Diabetic Retinopathy Study letters improved; P < 0.05). CONCLUSION: Secondary MH closure is possible using various surgical techniques with acceptable anatomical closure rates. Repeat ILM peeling is associated with the lowest closure rates and poorest functional results. To distinguish between techniques would require a large sample size of approximately 750 eyes.


Assuntos
Retinopatia Diabética , Perfurações Retinianas , Humanos , Vitrectomia/métodos , Retinopatia Diabética/complicações , Retina , Acuidade Visual , Estudos Retrospectivos , Resultado do Tratamento , Membrana Basal/cirurgia , Tomografia de Coerência Óptica
5.
Ophthalmol Retina ; 7(1): 59-66, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35850442

RESUMO

PURPOSE: To determine the long-term anatomic outcomes and surgical complications of pars plana vitrectomy (PPV) and 4-point Gore-Tex-sutured Akreos AO60 intraocular lens (IOL) scleral fixation. DESIGN: Retrospective, multicenter, multisurgeon case series. PARTICIPANTS: Ninety-seven patients in tertiary eye care centers. METHODS: The patients underwent PPV and intraocular fixation of the Akreos AO60 IOL using Gore-Tex CV-8 sutures between January 2015 and April 2020. The inclusion criteria were aphakia, no capsular support, and a minimal 1 year of follow-up. MAIN OUTCOME MEASURES: Uncorrected visual acuity (VA), complication rates or types, and refraction. RESULTS: Data from 101 eyes of the 97 patients were analyzed (mean follow-up duration, 33.4 months; range, 12-62 months). The mean ± standard deviation uncorrected logarithm of the minimum angle of resolution VA improved from 1.04 ± 0.73 (20/200 Snellen equivalent) before surgery to 0.66 ± 0.65 (20/80) at 6 months after surgery (P < 0.001). The most prevalent complications included hypotony (12.9%), ocular hypertension (12.9%), corneal edema (8.9%), cystoid macular edema (6.9%), and vitreous hemorrhage (5.9%). Refraction was measured between 3 and 6 months after surgery, and 61.8% of the patients had spherical equivalent of ± 2.0 diopters. Most complications occurred in the first postoperative month and resolved spontaneously or with medical treatment. CONCLUSIONS: The results demonstrated that this surgical technique is well tolerated by the eyes, with a low complication rate in the long term. The rates of IOL opacification were infrequent for up to 62 months of follow-up.


Assuntos
Implante de Lente Intraocular , Lentes Intraoculares , Humanos , Implante de Lente Intraocular/métodos , Vitrectomia/métodos , Estudos Retrospectivos , Politetrafluoretileno
6.
Cancers (Basel) ; 14(20)2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36291838

RESUMO

Colorectal cancer (CRC) has been addressed in the framework of molecular, cellular biology, and biochemical traits. A new approach to studying CRC is focused on the relationship between biochemical pathways and biophysical cues, which may contribute to disease understanding and therapy development. Herein, we investigated the mechanical properties of CRC cells, namely, HCT116, HCT15, and SW620, using static and dynamic methodologies by atomic force microscopy (AFM). The static method quantifies Young's modulus; the dynamic method allows the determination of elasticity, viscosity, and fluidity. AFM results were correlated with confocal laser scanning microscopy and cell migration assay data. The SW620 metastatic cells presented the highest Young's and storage moduli, with a defined cortical actin ring with distributed F-actin filaments, scarce vinculin expression, abundant total focal adhesions (FAK), and no filopodia formation, which could explain the lessened migratory behavior. In contrast, HCT15 cells presented lower Young's and storage moduli, high cortical tubulin, less cortical F-actin and less FAK, and more filopodia formation, probably explaining the higher migratory behavior. HCT116 cells presented Young's and storage moduli values in between the other cell lines, high cortical F-actin expression, intermediate levels of total FAK, and abundant filopodia formation, possibly explaining the highest migratory behavior.

7.
Ophthalmic Genet ; 43(4): 550-554, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35416119

RESUMO

PURPOSE: To report the first Brazilian patient with RPE65 deficiency-inherited retinal dystrophy (RPE65-IRD) treated with voretigene neparvovec-rzyl (VN). METHODS: An adult patient with Leber congenital amaurosis-2 with a homozygous mutation in the RPE65 gene (p.Phe83Leu) was treated bilaterally with VN. The clinical and surgical aspects are described. The baseline and 4-month postoperative ophthalmologic examinations included measurement of the best-corrected visual acuity (BCVA), full-field stimulus threshold (FST) test, Octopus 900 semiautomated kinetic visual fields (VFs), and microperimetry. RESULTS: No complications developed in this patient. The BCVA remained stable. The full-field stimulus threshold test (FST) and VFs showed clinically significant improvements bilaterally. The patient reported significant improvements in the ability to perform daily activities, mainly for those requiring the VFs and vision in a low-luminescence environment. CONCLUSIONS: The treatments were beneficial for this patient who was homozygous for RPE65 p.Phe83Leu. The first VN treatments in an adult Brazilian patient in clinical practice showed measurable improvements in visual outcomes that were meaningful for the patient's daily activities. TRANSLATIONAL RELEVANCE: This case reinforces the clinical trial results and proves that the procedure is feasible in countries such as Brazil.


Assuntos
Amaurose Congênita de Leber , Distrofias Retinianas , Adulto , Brasil , Terapia Genética/métodos , Humanos , Amaurose Congênita de Leber/genética , Amaurose Congênita de Leber/terapia , Mutação , Distrofias Retinianas/genética , Distrofias Retinianas/terapia , cis-trans-Isomerases/genética
9.
ACS Med Chem Lett ; 13(3): 443-448, 2022 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-35300075

RESUMO

Reversing protein aggregation within cells may be an important tool to fight protein-misfolding disorders such as Alzheimer's, Parkinson's, and cardiovascular diseases. Here we report the design and synthesis of a family of steroid-quinoline hybrid compounds based on the framework combination approach. This set of hybrid compounds effectively inhibited Aß1-42 self-aggregation in vitro by delaying the exponential growth phase and/or reducing the quantity of fibrils in the steady state. Their disaggregation efficacy was further demonstrated against preaggregated Aß1-42 peptides in cellular assays upon their endocytosis by neuroblastoma cells, as they reverted both the number and the average area of fibrils back to basal levels. The antiaggregation effect of these hybrids was further tested and demonstrated in a cellular model of general protein aggregation expressing a protein aggregation fluorescent sensor. Together, our results show that the new cholesterol-quinoline hybrids possess wide and marked disaggregation capacities and are therefore promising templates for the development of new drugs to deal with conformational disorders.

10.
Br J Ophthalmol ; 106(1): 32-36, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33093153

RESUMO

BACKGROUND/AIMS: We analysed the ability of B-scan ultrasound, ocular electrophysiology testing and videoendoscopic examination for predicting visual prognosis in Boston Type 1 keratoprosthesis (KPro-1) candidates. Indirect anatomical and electrophysiological findings and results from direct endoscopic evaluations were correlated with postoperative functional data. METHODS: In this prospective and interventional study, we included 13 individuals who had previously been indicated for Kpro-1 surgery. All subjects underwent preoperative screening, including ophthalmic evaluation, B-scan ultrasound, electrophysiological testing, and perioperative intraocular videoendoscopic evaluation (VE). B-scan ultrasound, electrophysiological testing, and VE evaluation results were categorised as favourable or unfavourable predictors of postoperative functional results according to predefined criteria. The predictability values of B-scan ultrasound, electrophysiological testing, and VE prognostication were calculated based on the visual acuity level achieved. RESULTS: All surgeries and perioperative VEs were uneventful. Preoperative best-corrected visual acuity (BCVA) ranged from light perception to counting fingers. The 1-year postoperative BCVA was better than 20/200 (satisfactory visual acuity result) in 10 eyes (76.9%) and 20/40 or better in 5 eyes (38.5%). B-scan ultrasound presented a positive predictive value (PPV) of 85.7% for satisfactory postoperative visual acuity, electroretinography showed a PPV of 66.7%, and visual evoked potential presented a PPV of 66.7%. The perioperative VE PPV of a negative finding for satisfactory visual acuity was 100%. CONCLUSIONS: Fundoscopic visualisation by intraocular VE is a minimally invasive procedure that can be used to predict functional outcomes in keratoprosthesis candidates. This technique demonstrated better prognostication in keratoprosthesis candidates than B-scan ultrasound and electrophysiological testing.


Assuntos
Órgãos Artificiais , Doenças da Córnea , Córnea/diagnóstico por imagem , Córnea/cirurgia , Doenças da Córnea/diagnóstico , Doenças da Córnea/cirurgia , Eletrofisiologia , Potenciais Evocados Visuais , Humanos , Complicações Pós-Operatórias/cirurgia , Estudos Prospectivos , Próteses e Implantes , Implantação de Prótese/métodos , Estudos Retrospectivos
11.
Gastric Cancer ; 25(1): 124-137, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34486077

RESUMO

BACKGROUND: Tumour progression relies on the ability of cancer cells to penetrate and invade neighbouring tissues. E-cadherin loss is associated with increased cell invasion in gastric carcinoma, and germline mutations of the E-cadherin gene are causative of hereditary diffuse gastric cancer. Although E-cadherin dysfunction impacts cell-cell adhesion, cell dissemination also requires an imbalance of adhesion to the extracellular matrix (ECM). METHODS: To identify ECM components and receptors relevant for adhesion of E-cadherin dysfunctional cells, we implemented a novel ECM microarray platform coupled with molecular interaction networks. The functional role of putative candidates was determined by combining micropattern traction microscopy, protein modulation and in vivo approaches, as well as transcriptomic data of 262 gastric carcinoma samples, retrieved from the cancer genome atlas (TCGA). RESULTS: Here, we show that E-cadherin mutations induce an abnormal interplay of cells with specific components of the ECM, which encompasses increased traction forces and Integrin ß1 activation. Integrin ß1 synergizes with E-cadherin dysfunction, promoting cell scattering and invasion. The significance of the E-cadherin-Integrin ß1 crosstalk was validated in Drosophila models and found to be consistent with evidence from human gastric carcinomas, where increased tumour grade and poor survival are associated with low E-cadherin and high Integrin ß1 levels. CONCLUSIONS: Integrin ß1 is a key mediator of invasion in carcinomas with E-cadherin impairment and should be regarded as a biomarker of poor prognosis in gastric cancer.


Assuntos
Integrina beta1 , Neoplasias Gástricas , Animais , Caderinas/genética , Caderinas/metabolismo , Adesão Celular/fisiologia , Drosophila melanogaster , Matriz Extracelular/metabolismo , Humanos , Integrina beta1/genética , Integrina beta1/metabolismo , Invasividade Neoplásica , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
12.
Int J Retina Vitreous ; 7(1): 38, 2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-33964971

RESUMO

BACKGROUND: The purpose of the current study is to report the anatomical and functional results of off-label human amniotic membrane graft as primary intervention to repair large to giant macular holes and in reoperations when wide internal limiting membrane peeling was unsuccessful. METHODS: Retrospective chart review was carried out in five different centers to identify all cases that had undergone off-label human amniotic membrane graft for the treatment of large or failed macular holes (MH). Data collected included age, gender, other concomitant diagnosis, symptoms duration, lens status, number of previous surgeries, macular hole measurements (minimum and base linear diameters), mean post-operative follow-up (months), and pre- and post-operative best corrected visual acuity (BCVA). Main outcome measures were anatomical MH closure rates and final BCVA (in logMAR). Nonparametric Wilcoxon rank-sum test was used because the data was not normally distributed, a P values < 0.05 were considered statistically significant. RESULTS: Nineteen eyes of 19 patients were identified and included in the study. Mean age was 66.21 ± 14.96 years and predominantly females (84%). All eyes had successfully closed MH with a single intervention with no recurrences during a mean of 9 ± 3.87 months follow-up. The median BCVA in logMAR preoperative was 1.30 ± 0.44 (0.80-2.0), approximately 20/400 on Snellen chart and the median BCVA in logMAR postoperative was 1.0 ± 0.72 (0.4-3.0) approximately 20/200 (p < 0.0001) with median of three lines of visual improvement. CONCLUSION: The use of human amniotic membrane graft seems to be a viable and effective alternative for the treatment of large and persistent macular holes. However, further larger prospective controlled studies are necessary to confirm our preliminary results of this new surgical technique.

13.
Int J Retina Vitreous ; 7(1): 27, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795031

RESUMO

BACKGROUND: To report a case of acute exudative polymorphous paraneoplastic vitelliform maculopathy in a patient with a history of choroidal melanoma, with metastases to the pancreas, liver, and central nervous system. CASE PRESENTATION: A 63-year-old patient, with a history of enucleation of the right eye due to choroidal melanoma, complained of progressive visual loss during a follow-up visit. Fundoscopic examination revealed multiple small areas of serous retinal detachment scattered throughout the posterior pole and ancillary tests confirmed the diagnosis of acute exudative polymorphous paraneoplastic vitelliform maculopathy (AEPPVM). Screening for systemic metastases showed pancreatic, hepatic, and central nervous system involvement. CONCLUSIONS: We describe a rare case of acute exudative polymorphous paraneoplastic vitelliform maculopathy, which should be considered in patients with or without a history of melanoma, who have vitelliform retinal detachments. Nevertheless, no previous reviews of literature have shown a correlation between AEPPVM and pancreatic metastasis.

14.
Retin Cases Brief Rep ; 15(2): 110-113, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29975259

RESUMO

PURPOSE: There are currently limited data addressing the surgical outcomes of pars plana vitrectomy (PPV) in toxoplasmosis-related macular hole (tMH). We aim to report and discuss safety and efficacy of PPV for tMH. METHODS: Surgical case series (n = 11), with minimum postoperative follow-up time of 6 months. Consecutive patients who underwent PPV for tMH from 2013 to 2016 were included. Indications for surgery were: visual acuity ≥ 0.6 logarithm of the minimum angle of resolution (Snellen 20/80 or less), no intraocular inflammation for more than 6 months, extrafoveal toxoplasmosis scar, elevated tMH borders on optical coherence tomography, and patient agreement with surgery. Surgery was performed-PPV with epiretinal (if present) and internal limiting membrane peeling. Safety and efficacy of PPV for tMH were addressed by evaluating: 1) surgery-related complications and 2) visual acuity improvement. RESULTS: A total of 11 patients (6 male), with a mean age of 33.2 ± 11.0 years were studied. Mean preoperative best-corrected visual acuity significantly improved from 1.10 ± 0.24 (Snellen 20/252) to 0.43 ± 0.18 logarithm of the minimum angle of resolution (Snellen 20/54) at last follow-up visit (P < 0.01). The rate of visual acuity improvement (i.e., a gain of at least three lines) and tMH closure was 100% for both. The only reported surgery-related complication was cataract in one case. CONCLUSION: Our results suggest that PPV is a safe and effective option in tMH cases. A controlled, longitudinal study would contribute to confirm these findings.


Assuntos
Perfurações Retinianas/cirurgia , Toxoplasmose Ocular/cirurgia , Vitrectomia , Adolescente , Adulto , Membrana Basal/cirurgia , Membrana Epirretiniana/cirurgia , Feminino , Humanos , Masculino , Perfurações Retinianas/parasitologia , Perfurações Retinianas/fisiopatologia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Toxoplasmose Ocular/parasitologia , Toxoplasmose Ocular/fisiopatologia , Acuidade Visual/fisiologia , Adulto Jovem
16.
Asia Pac J Ophthalmol (Phila) ; 10(1): 26-38, 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33252365

RESUMO

ABSTRACT: Chromovitrectomy, the intraocular application of dyes to assist visualization of preretinal tissues during vitreoretinal surgery, was introduced to avoid ocular complications related to internal limiting membrane peeling, inadequate removal of the vitreous, and incomplete removal of epiretinal membranes. Since 2000, chromovitrectomy has become a popular approach among vitreoretinal specialists. The first vital dye used in chromovitrectomy, indocyanine green, facilitated identification of the fine and transparent internal limiting membrane. Following indocyanine green, trypan blue was introduced to identify epiretinal membranes, and triamcinolone acetonide stained the vitreous well. Recently, additional natural dyes such as lutein and anthocyanin from the açaí fruit have been proposed for intraocular application during vitrectomy. The main goal of this review was to study the role of vital stains in chromovitrectomy and report the latest findings in the literature.


Assuntos
Corantes/administração & dosagem , Vitrectomia/métodos , Cirurgia Vitreorretiniana/métodos , Corpo Vítreo/cirurgia , Membrana Epirretiniana/metabolismo , Humanos , Verde de Indocianina/administração & dosagem , Procedimentos Cirúrgicos Oftalmológicos , Coloração e Rotulagem/métodos , Azul Tripano/administração & dosagem
17.
Acta Biomater ; 114: 206-220, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622054

RESUMO

Persistent Helicobacter pylori (H. pylori) infection is related to 90% of gastric cancers. With bacterial resistance rising and treatment inefficiency affecting 15% of the patients, alternative treatments urge. Chitosan microspheres (ChMics) have been proposed as an H. pylori-binding system. This work evaluates ChMics biocompatibility, mucopenetration and capacity to treat H. pylori infection in mice after oral administration. ChMics of different size (XL, ∼120 µm and XS, ∼40 µm) and degree of acetylation (6% and 16%) were developed and revealed to be able to adhere both human and mouse-adapted H. pylori strains without cytotoxicity towards human gastric cells. Ex vivo studies showed that smaller (XS) microspheres penetrate further within the gastric foveolae, suggesting their ability to reach deeply adherent bacteria. In vivo assays showed 88% reduction of infection when H. pylori-infected mice (C57BL/6) were treated with more mucoadhesive XL6 and XS6 ChMics. Overall, ChMics clearly demonstrate ability to reduce H. pylori gastric infection in mice, with chitosan degree of acetylation being a dominant factor over microspheres' size on H. pylori removal efficiency. These results evidence the strong potential of this strategy as an antibiotic-free approach to fight H. pylori infection, where microspheres are orally administered, bind H. pylori in the stomach, and remove them through the gastrointestinal tract. STATEMENT OF SIGNIFICANCE: Approximately 90% of gastric cancers are caused by the carcinogenic agent Helicobacter pylori, which infects >50% of the world population. Bacterial resistance, reduced antibiotic bioavailability, and the intricate distribution of bacteria in mucus and within gastric foveolae hamper the success of most strategies to fight H. pylori. We demonstrate that an antibiotic-free therapy based on bare chitosan microspheres that bind and remove H. pylori from stomach can achieve 88% reduction of infection from H. pylori-infected mice. Changing size and mucoadhesive properties, microspheres can reach different areas of gastric mucosa: smaller and less mucoadhesive can penetrate deeper into the foveolae. This promising, simple and inexpensive strategy paves the way for a faster bench-to-bedside transition, therefore holding great potential for clinical application.


Assuntos
Quitosana , Infecções por Helicobacter , Helicobacter pylori , Animais , Quitosana/farmacologia , Mucosa Gástrica , Infecções por Helicobacter/tratamento farmacológico , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Microesferas
18.
Cancers (Basel) ; 12(2)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093282

RESUMO

Gastric cancer remains a serious health burden with few therapeutic options. Therefore, the recognition of cancer stem cells (CSCs) as seeds of the tumorigenic process makes them a prime therapeutic target. Knowing that the transcription factors SOX2 and OCT4 promote stemness, our approach was to isolate stem-like cells in human gastric cancer cell lines using a traceable reporter system based on SOX2/OCT4 activity (SORE6-GFP). Cells transduced with the SORE6-GFP reporter system were sorted into SORE6+ and SORE6- cell populations, and their biological behavior characterized. SORE6+ cells were enriched for SOX2 and exhibited CSC features, including a greater ability to proliferate and form gastrospheres in non-adherent conditions, a larger in vivo tumor initiating capability, and increased resistance to 5-fluorouracil (5-FU) treatment. The overexpression and knockdown of SOX2 revealed a crucial role of SOX2 in cell proliferation and drug resistance. By combining the reporter system with a high-throughput screening of pharmacologically active small molecules we identified monensin, an ionophore antibiotic, displaying selective toxicity to SORE6+ cells. The ability of SORE6-GFP reporter system to recognize cancer stem-like cells facilitates our understanding of gastric CSC biology and serves as a platform for the identification of powerful therapeutics for targeting gastric CSCs.

19.
Retina ; 40(5): 825-832, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-30789460

RESUMO

PURPOSE: To establish the prevalence and risk factors for intravitreal dexamethasone implant migration into the anterior chamber in eyes with macular edema. METHODS: This was a multicenter, retrospective, observational chart review of data that included patients with macular edema who had been treated with at least one intravitreal dexamethasone injection. Patients with incomplete chart information during the follow-up period were excluded. RESULTS: The prevalence of implant migration in 468 patients, considering the number of injections, was 1.6%, with significant associations between implant migration and cataract surgery (P = 0.043) and intraocular lens status (P = 0.005) and a trend toward statistical significance (P = 0.057) with vitrectomy. A higher rate of implant migration into the anterior chamber was observed in vitrectomized eyes (4.8%) when compared with patients who did not undergo a vitrectomy (1.6%). The implants that migrated were removed with forceps with/without viscoelastic expression or with 20-gauge cannulas connected to the vitreous cutter machine. CONCLUSION: The risk of implant migration into the anterior chamber was 1.6%. Risk factors were a history of cataract surgery or vitrectomy and aphakia. When anterior migration occurs, rapid removal is advised, especially if corneal edema is present.


Assuntos
Câmara Anterior , Dexametasona/administração & dosagem , Implantes de Medicamento/efeitos adversos , Migração de Corpo Estranho/diagnóstico , Acuidade Visual , Idoso , Feminino , Migração de Corpo Estranho/epidemiologia , Glucocorticoides/administração & dosagem , Humanos , Incidência , Injeções Intravítreas , Edema Macular/diagnóstico , Edema Macular/tratamento farmacológico , Masculino , Estudos Retrospectivos , Estados Unidos/epidemiologia
20.
Retin Cases Brief Rep ; 14(4): 386-389, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-29470298

RESUMO

PURPOSE: To report a patient presenting a retinal pigment epithelial tear in which optical coherence tomography angiography enabled the visualization of subfoveal choroidal neovascularization (CNV) not evidenced by the fluorescein angiography. She was treated with 3 monthly intravitreous anti-VEGF injections and intraretinal fluid resolution occurred. METHODS: Observational case report. RESULTS: A 62-year-old Caucasian woman presented with decreased visual acuity in the right eye for 3 months. Fundus biomicroscopy revealed a yellowish macular lesion associated with intraretinal hemorrhage. Fluorescein angiography showed a large hyperfluorescent area consistent with window defect. Optical coherence tomography showed a retinal pigment epithelial tear with subretinal fluid. However, there was no clear evidence of CNV on fluorescein angiography or OCT. Optical coherence tomography angiography confirmed the presence of an active CNV by the visualization of the neovascular network in the region corresponding to the scrolled up retinal pigment epithelium. CONCLUSION: This case report demonstrates that optical coherence tomography angiography can be useful to confirm the presence of CNV in cases where fluorescein angiography and OCT cannot establish the diagnosis. The reported case suggests the applicability of optical coherence tomography angiography in patients in whom retinal pigment epithelial tear is detected and associated CNV is suspected.


Assuntos
Neovascularização de Coroide/etiologia , Perfurações Retinianas/etiologia , Epitélio Pigmentado da Retina/lesões , Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Neovascularização de Coroide/diagnóstico , Neovascularização de Coroide/tratamento farmacológico , Feminino , Angiofluoresceinografia , Humanos , Injeções Intravítreas , Pessoa de Meia-Idade , Perfurações Retinianas/diagnóstico , Perfurações Retinianas/tratamento farmacológico , Epitélio Pigmentado da Retina/diagnóstico por imagem , Epitélio Pigmentado da Retina/efeitos dos fármacos , Líquido Sub-Retiniano , Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual
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