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1.
Front Physiol ; 13: 836789, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35350699

RESUMO

Membrane protein function is regulated by the lipid bilayer composition. In many cases the changes in function correlate with changes in the lipid intrinsic curvature (c 0), and c 0 is considered a determinant of protein function. Yet, water-soluble amphiphiles that cause either negative or positive changes in curvature have similar effects on membrane protein function, showing that changes in lipid bilayer properties other than c 0 are important-and may be dominant. To further investigate the mechanisms underlying the bilayer regulation of protein function, we examined how maneuvers that alter phospholipid head groups effective "size"-and thereby c 0-alter gramicidin (gA) channel function. Using dioleoylphospholipids and planar bilayers, we varied the head groups' physical volume and the electrostatic repulsion among head groups (and thus their effective size). When 1,2-dioleyol-sn-glycero-3-phosphocholine (DOPC), was replaced by 1,2-dioleyol-sn-glycero-3-phosphoethanolamine (DOPE) with a smaller head group (causing a more negative c 0), the channel lifetime (τ) is decreased. When the pH of the solution bathing a 1,2-dioleyol-sn-glycero-3-phosphoserine (DOPS) bilayer is decreased from 7 to 3 (causing decreased head group repulsion and a more negative c 0), τ is decreased. When some DOPS head groups are replaced by zwitterionic head groups, τ is similarly decreased. These effects do not depend on the sign of the change in surface charge. In DOPE:DOPC (3:1) bilayers, pH changes from 5→9 to 5→0 (both increasing head group electrostatic repulsion, thereby causing a less negative c 0) both increase τ. Nor do the effects depend on the use of planar, hydrocarbon-containing bilayers, as similar changes were observed in hydrocarbon-free lipid vesicles. Altering the interactions among phospholipid head groups may alter also other bilayer properties such as thickness or elastic moduli. Such changes could be excluded using capacitance measurements and single channel measurements on gA channels of different lengths. We conclude that changes gA channel function caused by changes in head group effective size can be predicted from the expected changes in c 0.

2.
Oncol Res Treat ; 40(9): 508-514, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28796995

RESUMO

AIM: The aim of this study was to clarify and examine the outcomes of prostate cancer patients classified as intermediate risk (IR) using the D'Amico risk classification system, specifically focusing on the influence of primary and secondary biopsy Gleason score (BGS). PATIENTS AND METHODS: An institutional review board-approved database of robotic-assisted radical prostatectomies performed after 2006 was stratified by standard D'Amico criteria. IR patients were then sub-stratified by BGS. Pathologic and intermediate-term biochemical disease-free survival (BDFS) outcomes were analyzed. RESULTS: Overall, 1,090 patients were classified as D'Amico low-risk, 896 as IR, and 240 as high-risk. Of the 896 IR patients, 63 had BGS 6, 630 were 3 + 4 = 7, and 203 4 + 3 = 7. Among IR patients, as the BGS increased, there was an increasing likelihood of extracapsular extension (21, 28, and 38%, respectively; p = 0.005), positive surgical margins (14, 26, 31%; p = 0.048), and worse 3-year BDFS (96, 94, 88%; p = 0.01). Multivariable logistic regression and Cox regression analyses confirmed differences among IR groups. CONCLUSION: D'Amico IR patients demonstrate significant heterogeneity in both pathologic outcomes and BDFS. IR patients with a BGS of 6 appear to have similar intermediate-term BDFS as low-risk patients. An increasing BGS from 3 + 3 to 3 + 4 to 4 + 3 results in a higher likelihood of locally-advanced disease and intermediate-term biochemical failure.


Assuntos
Laparoscopia/métodos , Gradação de Tumores , Prostatectomia/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Resultado do Tratamento , Adulto , Idoso , Biópsia , Intervalo Livre de Doença , Humanos , Masculino , Pessoa de Meia-Idade , Próstata/patologia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/mortalidade , Análise de Regressão , Medição de Risco
3.
Arab J Urol ; 14(4): 256-261, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27900214

RESUMO

OBJECTIVE: To investigate whether tumours at threshold values for detection on magnetic resonance imaging (MRI) represent clinically significant tumours or not, and therefore the utility of MRI in active surveillance (AS) protocols. PATIENTS AND METHODS: A retrospective analysis of a single institution database was performed after Institutional Review Board approval. Between 2010 and 2013, 1633 patients underwent robot-assisted laparoscopic prostatectomy (RALP) at a single institution by a single surgeon. Of these, 1361 had complete clinical data and were included in analysis. Multivariate logistic regression was used to assess histopathological grade compared to tumour size whilst controlling for biopsy Gleason score, prostate-specific antigen level, body mass index, race, and age. RESULTS: Of 120 tumours <5 mm in size, four were Gleason score 4 + 3. Of 276 tumours of 5-10 mm, 22 (8.1%) were Gleason score 4 + 3 and one (0.2%) was Gleason score 8. On multivariate regression analyses, tumours of <5 mm were much less likely to be high grade (Gleason score >3 + 4) at RALP compared to larger tumours (3.3% vs 25.1%, P < 0.001), or Gleason score ⩾8 (0.0% vs 7.6%, P < 0.001). Size was further shown to significantly correlate with grade on multivariate regression (P < 0.001). CONCLUSIONS: Prostate tumours below the detection threshold for MRI (5 mm) most probably represent clinically insignificant tumours, which alone would not necessitate leaving AS in favour of more aggressive therapy. These findings point to a possible role of MRI in modern AS protocols.

4.
Case Rep Urol ; 2014: 538382, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24653856

RESUMO

We conducted a retrospective chart review of robotic prostatectomies done by a single surgeon between 2003 and 2012. During that time period, we identified two patients within the year 2012, with ileal pouch-anal anastomosis (IPPA) who also underwent robotic prostatectomies. The demographics and postoperative characteristics of the two patients were assessed. In both patients, prostatectomy, bilateral nerve sparing, and pelvic lymphadenectomy were successfully performed and the integrity of ileal pouch was maintained. There was a mean surgical time of 144.5 minutes, and an average estimated blood loss was 125 mL. Both patients were discharged on the second day postoperatively. In both patients there was a Gleason upgrade to 3 + 4, with negative margins, and preservation of fecal and urinary continence by their six-month followup. Owing to surgical modifications, these two surgeries represent the first successful robotic prostatectomies in patients with a J-pouch.

5.
Urol Oncol ; 32(4): 419-25, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24411791

RESUMO

OBJECTIVES: Longitudinal studies report racial disparities in prostate cancer (PCa) including greater incidence, more aggressive tumor biology, and increased cancer-specific mortality in African American (AA) men. Regret concerning primary treatment selection is underevaluated in patients with PCa. We investigated the relationships between clinicopathologic variables across racial and socioeconomic lines following robotic-assisted laparoscopic prostatectomy. MATERIALS AND METHODS: We assessed treatment decisional regret using a validated questionnaire in a total of 484 white and 72 AA patients with PCa who were followed up for a median of 16.6 months post-robotic-assisted laparoscopic prostatectomy. Socioeconomic status (SES) information was aggregated from 2010 US census zip code data. Perioperative clinicopathologic characteristics and functional outcomes were compared between groups. Univariate and multivariate regression analyses were used to evaluate the influence of race, aggregate SES, and other clinical and demographic characteristics on decisional regret. RESULTS: The majority (87.7%) of the population was not regretful of their decision to undergo treatment. However, a greater proportion of AA vs. white patients were regretful (20.6% vs. 11.2%, respectively; P = 0.03). AA and white men were similar on all functional, clinical, and pathologic features with the exception of younger age among AA men (56 vs. 60 y, respectively; P<0.001). Although there were significant differences in SES by race (P<0.001), regret did not differ by SES (ß =-1.53; P = 0.15). Race, postoperative sexual dysfunction, pad usage, and length of hospital stay, however, were significantly associated with decisional regret. CONCLUSIONS: AA men were more regretful than white men, after adjusting for clinicopathologic characteristics and postoperative functional outcomes.


Assuntos
Negro ou Afro-Americano/psicologia , Tomada de Decisões , Emoções , Laparoscopia/psicologia , Prostatectomia/psicologia , Neoplasias da Próstata/psicologia , Robótica , Adulto , Idoso , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Próstata/cirurgia , Qualidade de Vida , Inquéritos e Questionários , População Branca/psicologia
6.
Urol Oncol ; 32(1): 40.e9-16, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23820091

RESUMO

OBJECTIVES: Metabolic syndrome (MetS), the constellation of obesity and related risk factors for cardiovascular disease, is an expanding epidemiologic concern in the United States and the developed world. However, the relationship between MetS and prostate cancer remains to be definitively assessed. We evaluated the association between obesity and MetS with prostate cancer pathology and surgical and functional outcomes. MATERIALS AND METHODS: A total of 2,639 patients underwent robotic-assisted laparoscopic prostatectomy (RALP) for localized prostate cancer between March 2003 and July 2012. Of them, 186 patients met the criteria for MetS as defined by the presence of obesity (body mass index [BMI] ≥ 30 kg/m(2)) in conjunction with 2 or more of the following: hypertension (HTN), dyslipidemia (D), and diabetes (DM). Additionally, reference cohorts of (1) 663 nonobese men without HTN, D, or DM; (2) 184 obese patients without HTN, D, or DM; and (3) 211 obese men with solitary risk factors were identified for comparison. Demographic, histopathologic, and perioperative clinical parameters were compared. RESULTS: In comparison with patients without MetS, patients with MetS had larger prostates (Odds Ratio (OR) = 1.609, 95% Confidence Interval (CI) = 1.04-2.49, P = 0.03), increased blood loss (OR = 1.592, 95% CI = 1.15-2.21, P = 0.01), and surgical complexity (OR = 4.940, 95% CI = 2.29-10.69, P<0.001). There was no statistical difference observed between these groups in regard to complication rates, pathologic grade, stage, and postoperative continence or erectile function. With the exception of larger prostates found among men with MetS, men with obesity alone and obesity with 1 additional risk factor appeared similar to those with MetS. CONCLUSIONS: Patients with MetS had similar perioperative, histopathologic, and functional outcomes compared with reference cohorts undergoing RALP. RALP is safe, feasible, and efficacious in men with MetS.


Assuntos
Laparoscopia/métodos , Síndrome Metabólica/complicações , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Adulto , Estudos de Coortes , Estudos de Viabilidade , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Tamanho do Órgão , Próstata/patologia , Próstata/cirurgia , Neoplasias da Próstata/complicações , Reprodutibilidade dos Testes , Fatores de Risco , Robótica , Resultado do Tratamento
7.
J R Soc Interface ; 7(44): 373-95, 2010 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-19940001

RESUMO

Membrane protein function is regulated by the host lipid bilayer composition. This regulation may depend on specific chemical interactions between proteins and individual molecules in the bilayer, as well as on non-specific interactions between proteins and the bilayer behaving as a physical entity with collective physical properties (e.g. thickness, intrinsic monolayer curvature or elastic moduli). Studies in physico-chemical model systems have demonstrated that changes in bilayer physical properties can regulate membrane protein function by altering the energetic cost of the bilayer deformation associated with a protein conformational change. This type of regulation is well characterized, and its mechanistic elucidation is an interdisciplinary field bordering on physics, chemistry and biology. Changes in lipid composition that alter bilayer physical properties (including cholesterol, polyunsaturated fatty acids, other lipid metabolites and amphiphiles) regulate a wide range of membrane proteins in a seemingly non-specific manner. The commonality of the changes in protein function suggests an underlying physical mechanism, and recent studies show that at least some of the changes are caused by altered bilayer physical properties. This advance is because of the introduction of new tools for studying lipid bilayer regulation of protein function. The present review provides an introduction to the regulation of membrane protein function by the bilayer physical properties. We further describe the use of gramicidin channels as molecular force probes for studying this mechanism, with a unique ability to discriminate between consequences of changes in monolayer curvature and bilayer elastic moduli.


Assuntos
Gramicidina/metabolismo , Bicamadas Lipídicas/química , Proteínas de Membrana Transportadoras/fisiologia , Interações Hidrofóbicas e Hidrofílicas , Cinética , Fluidez de Membrana , Proteínas de Membrana/química , Proteínas de Membrana/fisiologia , Proteínas de Membrana Transportadoras/química , Modelos Biológicos , Sondas Moleculares/química , Sondas Moleculares/metabolismo , Sondas Moleculares/fisiologia
8.
J Vis Exp ; (21)2008 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-19066527

RESUMO

Membrane protein function is regulated by the cell membrane lipid composition. This regulation is due to a combination of specific lipid-protein interactions and more general lipid bilayer-protein interactions. These interactions are particularly important in pharmacological research, as many current pharmaceuticals on the market can alter the lipid bilayer material properties, which can lead to altered membrane protein function. The formation of gramicidin channels are dependent on conformational changes in gramicidin subunits which are in turn dependent on the properties of the lipid. Hence the gramicidin channel current is a reporter of altered properties of the bilayer due to certain compounds.


Assuntos
Bicamadas Lipídicas/química , Técnicas de Patch-Clamp/métodos , Membrana Celular/química , Elasticidade , Eletrodos , Gramicidina/química , Canais Iônicos/química , Proteínas de Membrana/química
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