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1.
Breast ; 49: 8-16, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31675684

RESUMO

PURPOSE: Metaplastic breast cancer (MBC) is a rare, aggressive variant of breast cancer that has been associated with poor clinical outcomes, as has triple-negative breast (TNBC) cancer. Limited studies compare the clinical characteristics and prognosis of MBC to TNBC. This study uses a large, contemporary US cancer database to compare clinical characteristics and survival outcomes for patients with MBC to those with TNBC. METHODS: The National Cancer Database was queried for women with cT1-4N1-3M0 MBC or TNBC diagnosed between 2004 and 2013 and treated with definitive surgery. Chi-squared analysis was performed to determine differences between the cohorts. Kaplan-Meier curves compared overall survival (OS), and Cox regression determined patient factors associated with OS. RESULTS: Altogether, 55,847 patients met the inclusion criteria; 50,705 (90.8%) had TNBC and 5,142 (9.2%) had MBC. Most patients had no comorbid conditions (82%), N0 disease (71%), poorly differentiated histology (77%), received chemotherapy (87%), and received radiation therapy (60%). Amongst all patients, patients with TNBC disease were observed to have greater OS than those with MBC (5-year OS 72.0% vs 55.8%, p < 0.001). The greater observed OS for patients with TNBC persisted when controlling for stage and when comparing propensity score matched cohorts. On Cox regression, lower age, T1 status, N0 status, chemotherapy, TNBC disease, and radiation therapy (RT) were associated with improved OS. CONCLUSIONS: MBC had an association with poorer OS compared to TNBC, while RT and chemotherapy receipt were associated with improved OS for patients regardless of stage. Further studies are needed to corroborate the conclusions herein.

2.
J Pediatr Surg ; 54(2): 223-228, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30527758

RESUMO

This is based on the 2018 Storz Urology Lecture at the BAPS Conference and is a personal review of three reconstructive paediatric urological conditions: hypospadias, congenital adrenal hyperplasia, and bladder exstrophy from the perspective of changing expectations and outcomes. LEVEL OF EVIDENCE: V (Expert Opinion).


Assuntos
Hiperplasia Suprarrenal Congênita/cirurgia , Extrofia Vesical/cirurgia , Hipospadia/cirurgia , Procedimentos Cirúrgicos Reconstrutivos , Procedimentos Cirúrgicos Urológicos , Criança , Feminino , Humanos , Masculino
3.
Anal Chem ; 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30444965

RESUMO

Preeclampsia (PE) is a hypertensive disorder of pregnancy and one of the leading contributors to both maternal and perinatal morbidity and mortality. Reliable diagnostic parameters unique to the disorder that accurately define and diagnose PE are currently unavailable. Recent studies have revealed that PE is accompanied by the accumulation of amyloidogenic deposits in the placenta and the presence of congophilic amyloid-like protein aggregates in the urine. Here, we evaluate the capability of an amyloid-targeting aryl cyano amide (ARCAM-1) fluorophore to identify PE patients from analysis of urine samples. Our results reveal that this probe can distinguish patients with PE from gestationally healthy patients and patients suffering from non-PE hypertension, highlighting the potential for amyloid-targeting fluorophores to help identify PE patients during pregnancy.

4.
FASEB J ; : fj201800736R, 2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30188753

RESUMO

The 5-hydroxymethylcytosine (5hmc) is a newly identified epigenetic modification thought to be regulated by the TET family of proteins. Little information is available about how ethanol consumption may modulate 5hmC formation and alcoholic liver disease (ALD) progression. A rat ALD model was used to study 5hmC in relationship to hepatocyte apoptosis. Human ALD liver samples were also used to validate these findings. It was found that chronic ethanol feeding significantly reduced 5hmC formation in a rat ALD model. There were no significant changes in TET2 and TET3 between the control- and ethanol-fed animals. In contrast, methylcytosine dioxygenase TET1 (TET1) expression was substantially reduced in the ethanol-fed rats and was accompanied by increased hepatocyte apoptosis. Similarly, knockdown of TET1 in human hepatocyte-like cells also significantly promoted apoptosis. Down-regulation of TET1 resulted in elevated expression of the DNA damage marker, suggesting a role for 5hmc in hepatocyte DNA damage as well. Mechanistic studies revealed that inhibition of TET1 promoted apoptotic gene expression. Similarly, targeting TET1 activity by removing cosubstrate promoted apoptosis and DNA damage. Furthermore, treatment with 5-azacitidine significantly mimics these effects, suggesting that chronic ethanol consumption promotes hepatocyte apoptosis and DNA damage by diminishing TET1-mediated 5hmC formation and DNA methylation. In summary, the current study provides a novel molecular insight that TET1-mediated 5hmC is involved in hepatocyte apoptosis in ALD progression.-Ji, C., Nagaoka, K., Zou, J., Casulli, S., Lu, S., Cao, K. Y., Zhang, H., Iwagami, Y., Carlson, R. I., Brooks, K., Lawrence, J., Mueller, W., Wands, J. R., Huang, C.-K. Chronic ethanol-mediated hepatocyte apoptosis links to decreased TET1 and 5-hydroxymethylcytosine formation.

5.
JAMA Dermatol ; 154(8): 912, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30090943
6.
Diagnostics (Basel) ; 8(3)2018 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-30060509

RESUMO

Prostate cancer is the third highest cause of male mortality in the developed world, with the burden of the disease increasing dramatically with demographic change. There are significant limitations to the current diagnostic regimens and no established effective screening modality. To this end, research has discovered hundreds of potential 'biomarkers' that may one day be of use in screening, diagnosis or prognostication. However, the barriers to bringing biomarkers to clinical evaluation and eventually into clinical usage have yet to be realised. This is an operational challenge that requires some new thinking and development of paradigms to increase the efficiency of the laboratory process and add 'value' to the clinician. Value comes in various forms, whether it be a process that is seamlessly integrated into the hospital laboratory environment or one that can provide additional 'information' for the clinical pathologist in terms of risk profiling. We describe, herein, an efficient and tissue-conserving pipeline that uses Tissue Microarrays in a semi-automated process that could, one day, be integrated into the hospital laboratory domain, using seven putative prostate cancer biomarkers for illustration.

7.
Chem Commun (Camb) ; 54(66): 9107-9118, 2018 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-29993065

RESUMO

Advances in diagnostic medicine have led to an increased awareness and heightened concern for the high prevalence of amyloid-associated neurodegenerative diseases, especially in the elderly. These diseases have characteristic late stage symptoms that often make it possible to distinguish one disorder from another, though methods to diagnose neurodegeneration pre-symptomatically remain a critical challenge. At the molecular level, misfolded protein aggregates known as amyloids are ubiquitously found in many neurodegenerative diseases, and have been suggested to appear before clinical symptoms manifest. Amyloids have, thus, become a valuable potential diagnostic target for chemists, and recent work by many groups have shown that they can be selectively targeted by small molecule fluorescent probes. Here, we summarize some of the exciting work currently under investigation in the area of fluorescence-based amyloid detection and highlight recent efforts to expand the utility of amyloid-targeting fluorophores as clinical tools for disease diagnostics.


Assuntos
Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Corantes Fluorescentes/metabolismo , Corantes Fluorescentes/farmacologia , Doença de Alzheimer/diagnóstico por imagem , Proteínas Amiloidogênicas/urina , Amiloidose/diagnóstico por imagem , Animais , Feminino , Fluorescência , Humanos , Microscopia de Força Atômica , Microscopia de Fluorescência , Ligação Proteica
8.
JAMA Dermatol ; 154(7): 788, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29998311
9.
JAMA Dermatol ; 154(7): 813, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29998312
10.
J Cell Mol Med ; 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29873178

RESUMO

MicroRNAs (miRs) have been recently shown to be heavily involved in the development of alcoholic liver disease (ALD) and suggested as a potential therapeutic target in ALD. The miR-34a was consistently reported to be significantly elevated in several ALD rodent models, but it remains unclear how miR-34a modulates the cellular behaviours of hepatocytes in ALD development and progression. This study aims to characterize alcohol-induced miR-34a impact on hepatocytes growth and apoptosis. The miRNA array was performed to assess changes in miRNA after chronic alcohol feeding. Liver and blood samples were used to examine ALD progression. The miR-34a was overexpressed in human hepatocytes to evaluate its impact on cell growth and apoptosis. Real-time quantitative PCR and Western blot were used to determine the growth and apoptosis molecular signalling pathways associated with miR-34a. Alcohol feeding significantly promoted fatty liver progression, serum ALT levels, apoptosis and miR-34a expression in rat liver. Overexpression of miR-34a in human hepatocytes suppressed cell growth signallings, including c-Met, cyclin D1 and cyclin-dependent kinase 6 (CDK6). The miR-34a might also inhibit the expression of sirtuin 1 (Sirt1) and its target, B-cell lymphoma 2. Interestingly, the expression of miR-34a reverses the suppressive effects of ethanol on cell growth. But, miR-34a promotes hepatocyte senescence and apoptosis. Although the miR-34a-mediated down-regulation of cell growth-associated genes may contribute to cell growth retardation, other miR-34a targets, such as Sirt1, may reverse this phenotype. Future studies will be needed to clarify the role of miR-34a in ALD progression.

11.
Sci Rep ; 8(1): 6950, 2018 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-29725045

RESUMO

The deposition of insoluble protein aggregates in the brain is a hallmark of many neurodegenerative diseases. While their exact role in neurodegeneration remains unclear, the presence of these amyloid deposits often precedes clinical symptoms. As a result, recent progress in imaging methods that utilize amyloid-specific small molecule probes have become a promising avenue for antemortem disease diagnosis. Here, we present a series of amino-aryl cyanoacrylate (AACA) fluorophores that show a turn-on fluorescence signal upon binding to amyloids in solution and in tissue. Using a theoretical model for environmental sensitivity of fluorescence together with ab initio computational modeling of the effects of polar environment on electron density distribution and conformational dynamics, we designed, synthesized, and evaluated a set of fluorophores that (1) bind to aggregated forms of Alzheimer's-related ß-amyloid peptides with low micromolar to high nanomolar affinities and (2) have the capability to fluorescently discriminate different amyloids based on differences in amino acid composition within the binding pocket through exploitation of their solvatochromic properties. These studies showcase the rational design of a family of amyloid-binding imaging agents that could be integrated with new optical approaches for the clinical diagnosis of amyloidoses, where accurate identification of the specific neurodegenerative disease could aid in the selection of a proper course for treatment.

12.
Cancer Lett ; 429: 1-10, 2018 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-29733964

RESUMO

Cholangiocarcinoma (CCA) is a highly lethal and aggressive disease. Recently, IDH1/2 mutations have been identified in approximately 20% of CCAs which suggests an involvement of 2-oxoglutarate (2-OG) -dependent dioxygenases in oncogenesis. We investigated if the 2-OG dependent dioxygenase, aspartate beta-hydroxylase (ASPH) was important in tumor development and growth. Immunoassays were used to clarify how ASPH modulates CCA progression by promoting phosphorylation of the retinoblastoma protein (RB1). A xenograft model was employed to determine the role of ASPH on CCA growth. Knockdown of ASPH expression inhibited CCA development and growth by reducing RB1 phosphorylation. Expression of ASPH promoted direct protein interaction between RB1, cyclin-dependent kinases, and cyclins. Treatment with 2-OG-dependent dioxygenase and ASPH inhibitors suppressed the interaction between RB1 and CDK4 as well as RB1 phosphorylation. Knockdown of ASPH expression inhibited CCA progression and RB1 phosphorylation in vivo and they were found to be highly expressed in human CCAs. Knockdown of ASPH expression altered CCA development by modulating RB1 phosphorylation, as one of the major factors regulating the growth of these tumors.

13.
JAMA Dermatol ; 154(5): 521, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29801070
14.
Prenat Diagn ; 38(7): 475-481, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29663461

RESUMO

The specialty of fetal surgery or fetal intervention is one of the most exciting emerging fields of modern medicine. It is made possible by decades of major developments in antenatal imaging, obstetric anaesthesia, fetal medicine, paediatric surgery, and of course by the bold and novel practitioners willing to take new steps to advance the field. Beginning in the 1970s, it has now reached a stage of maturity where there are several established in utero procedures and countless clinical trials and studies to develop more. But what is the legal situation that fetal surgeons find themselves in? What are the rights and legal protections for the fetus and the mother, both of which are arguably the patient? This article will address this question, discussing and summarising the current legal frameworks governing fetal surgery in the jurisdictions of the United Kingdom, European Court of Human Rights, and the United States of America as well as discuss what the future may hold and how researchers and physicians in the specialty can best navigate the legal environment.

15.
JAMA Dermatol ; 154(3): 375, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29541778
16.
JAMA Dermatol ; 154(3): 308, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29541780
17.
Nat Commun ; 9(1): 1112, 2018 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-29535310

RESUMO

Kevin J. Cao and Richard H. Kramer, who developed extended release with beta cyclodextrin, were inadvertently omitted from the author list and author contributions section of this Article. These errors have now been corrected in both the PDF and HTML versions of the Article.

18.
Nat Commun ; 8(1): 1862, 2017 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-29192252

RESUMO

Retinitis pigmentosa results in blindness due to degeneration of photoreceptors, but spares other retinal cells, leading to the hope that expression of light-activated signaling proteins in the surviving cells could restore vision. We used a retinal G protein-coupled receptor, mGluR2, which we chemically engineered to respond to light. In retinal ganglion cells (RGCs) of blind rd1 mice, photoswitch-charged mGluR2 ("SNAG-mGluR2") evoked robust OFF responses to light, but not in wild-type retinas, revealing selectivity for RGCs that have lost photoreceptor input. SNAG-mGluR2 enabled animals to discriminate parallel from perpendicular lines and parallel lines at varying spacing. Simultaneous viral delivery of the inhibitory SNAG-mGluR2 and excitatory light-activated ionotropic glutamate receptor LiGluR yielded a distribution of expression ratios, restoration of ON, OFF and ON-OFF light responses and improved visual acuity. Thus, SNAG-mGluR2 restores patterned vision and combinatorial light response diversity provides a new logic for enhanced-acuity retinal prosthetics.


Assuntos
Luz , Células Fotorreceptoras de Vertebrados/metabolismo , Engenharia de Proteínas , Receptores de Glutamato/metabolismo , Receptores de Glutamato Metabotrópico/genética , Retina/metabolismo , Células Ganglionares da Retina/metabolismo , Visão Ocular/fisiologia , Acuidade Visual , Animais , Modelos Animais de Doenças , Camundongos , Células Fotorreceptoras de Vertebrados/fisiologia , Receptores Ionotrópicos de Glutamato , Receptores de Glutamato Metabotrópico/química , Receptores de Glutamato Metabotrópico/metabolismo , Retina/fisiologia , Células Ganglionares da Retina/fisiologia , Retinite Pigmentosa
19.
Chemistry ; 23(28): 6757-6762, 2017 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-28370726

RESUMO

This paper presents a new hybrid lipid that fuses the ideas of molecular tethering of lipid tails used by archaea and the integration of cholesterol groups used by eukaryotes, thereby leveraging two strategies employed by nature to increase lipid packing in membranes. Liposomes comprised of pure hybrid lipids exhibited a 5-30-fold decrease in membrane leakage of small ions and molecules compared to liposomes that used only one strategy (lipid tethering or cholesterol incorporation) to increase membrane integrity. Molecular dynamics simulations reveal that tethering of lipid tails and integration of cholesterol both reduce the disorder in lipid tails and time-dependent variance in area per lipid within a membrane, leading to tighter lipid packing. These hybrid lipid membranes have exceptional stability in serum, yet can support functional ion channels, can serve as a substrate for phospholipase enzymes, and can be used for liposomal delivery of molecules into living cells.


Assuntos
Eucariotos/metabolismo , Lipídeos/química , Lipossomos/química , Soro/química , Archaea/metabolismo , Linhagem Celular , Colesterol/química , Eucariotos/química , Humanos , Íons/química , Lipídeos/síntese química , Lipossomos/metabolismo , Microscopia de Fluorescência , Simulação de Dinâmica Molecular
20.
Curr Cancer Drug Targets ; 16(7): 618-30, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26881932

RESUMO

Membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) is associated with cancer invasion and metastasis leading to poor patient prognosis. MT1-MMP mediates cancer cell invasion via degradation of basement membrane and extracellular matrix, and induction of cell migration. However, MT1-MMP expression in the cancer stroma can drive invasion of carcinoma cells in vivo, suggesting MT1-MMP may also promote cancer invasiveness via paracrinemediated mechanisms. A major step in cancer cell metastasis is thought to be an epithelial-mesenchymal transition (EMT), in which carcinoma cells evolve from a stationary epithelial phenotype to a more motile mesenchymal phenotype. We demonstrate here that EMT is triggered by MT1-MMP-mediated activation of TGF-. signaling, involving induction of CUTL1 and subsequently, of Wnt5a. Mesenchymal-like cancer cells expressing endogenous MT1-MMP reverted to an epithelial phenotype when MT1-MMP, SMAD4, CUTL1, or Wnt5a expression or TGF-. activity was inhibited. Wnt5a knockdown in MT1- MMP expressing LNCaP cells caused decreased cell migration and cell growth in soft agar. While MT1-MMP expression did not affect total TGF-. level, MT1-MMP catalytic activity increased the availability of active TGF-., enabling MT1-MMP-expressing cells to activate the EMT in nearby cells. MT1-MMP-expressing cells induced co-cultured non-MT1-MMP-expressing cells to undergo EMT by a TGF-.-dependent process. These results highlight a pathway by which tumor invasiveness may be expanded via MT1-MMP-mediated activation of TGF-. signaling, enabling autocrine and paracrine-mediated induction of EMT.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Metaloproteinase 14 da Matriz/metabolismo , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Proteínas de Homeodomínio/metabolismo , Humanos , Invasividade Neoplásica/patologia , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Proteína Wnt-5a/metabolismo
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