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1.
Ann Diagn Pathol ; 57: 151864, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34972038

RESUMO

As the assessment for radiologic-pathologic concordance, particularly for benign image-guided breast biopsies, is crucial in the management of patients with imaging abnormalities, many health institutions now conduct multidisciplinary conferences to assess the imaging and pathology findings in patients who had image-guided needle biopsy. We aimed to identify the radiologic-pathologic discordance rates and changes in patient outcomes resulting from the implementation of radiologic-pathologic correlation conferences in a community teaching hospital. Twenty-two (5.6%) out of 393 cases presented were deemed discordant given that the imaging characteristics of the lesions were far too suspicious radiologically to correlate with the benign pathology. Six cases were recommended for further imaging (four had stable lesion on follow- up, one was lost to follow-up and one case eventually had surgical excision which showed atypia); 14 cases for repeat core needle/excisional biopsy (seven had surgical excision with benign histology, five did not have surgery but showed stable lesion on imaging, two were lost to follow-up); one case for close imaging follow-up (lesion ultimately disappeared); the remaining case for second opinion (no follow-up data). The rad-path correlation conference led to a higher level of patient care with significant change in practice across our hospital network.


Assuntos
Neoplasias da Mama , Mama , Biópsia com Agulha de Grande Calibre , Mama/diagnóstico por imagem , Mama/patologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/cirurgia , Feminino , Hospitais Comunitários , Hospitais de Ensino , Humanos , Biópsia Guiada por Imagem/métodos , Estudos Retrospectivos
2.
Clin Invest Med ; 44(3): E55-63, 2021 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-34600460

RESUMO

Purpose: Obstructive sleep apnea (OSA) leads to endothelial dysfunction and platelet hyperactivity, which are linked to increased risk of cardiovascular disease and implicated in the development of aspirin resistance. We hypothesized that aspirin resistance is prevalent among OSA patients and aimed to explore effects of continuous positive airway pressure (CPAP) therapy on aspirin responsiveness. Methods: In Phase 1, prevalence of aspirin resistance was determined cross-sectionally in a group of OSA patients (n=59) on daily low-dose aspirin (81 mg) taken before entering the study, for primary or secondary prevention. In Phase 2, aspirin responsiveness before and after initiation of CPAP therapy was compared and stratified by endothelial function in a cohort of aspirin-naïve patients with newly diagnosed OSA (n=18). Results: In Phase 1, prevalence of aspirin resistance was 17%; most patients (56%) were on CPAP therapy. In Phase 2, initiation of CPAP therapy was associated with significant improvement in endothelial function (p=0.03). The mean pre-CPAP aspirin resistance units (ARU) was 569 (SD=75). In subjects with endothelial dysfunction (44%), the mean decrease after initiation of CPAP therapy was 43 ARU (SD=81, p=0.18). In contrast, subjects with normal endothelial function experienced the mean decrease of 8 ARU (SD=116, p=0.83). Conclusion: Aspirin resistance may be prevalent among OSA patients. After initiation of CPAP therapy, we observed a trend towards improvement in aspirin responsiveness among patients with endothelial dysfunction. The role of endothelial dysfunction and aspirin resistance should be explored in further studies that focus on the effect of CPAP on cardiovascular outcomes.


Assuntos
Apneia Obstrutiva do Sono , Aspirina , Humanos , Projetos Piloto , Apneia Obstrutiva do Sono/tratamento farmacológico
3.
Gynecol Oncol Rep ; 47: 101203, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37251783

RESUMO

Background: To evaluate whether incisional infiltration of liposomal bupivacaine would decrease opioid requirement and pain scores after midline vertical laparotomy for suspected or known gynecologic malignancy compared with transversus abdominis plane (TAP) block with liposomal bupivacaine. Methods: A prospective, single blind randomized controlled trial compared incisional infiltration of liposomal bupivacaine plus 0.5% bupivacaine versus TAP block with liposomal bupivacaine plus 0.5% bupivacaine. In the incisional infiltration group, patients received 266 mg free base liposomal bupivacaine with 150 mg bupivacaine hydrochloride. In the TAP block group, 266 mg free base bupivacaine with 150 mg bupivacaine hydrochloride was administered bilaterally. The primary outcome was total opioid use during the first 48-hour postoperative period. Secondary outcomes included pain scores at rest and with exertion at 2, 6, 12, 24 and 48 h after surgery. Results: Forty three patients were evaluated. After interim analysis, a three-fold higher sample size than originally calculated was required to detect a statistically significant difference. There was no clinical difference between the two arms in mean opioid requirement (morphine milligram equivalents) for the first 48 h after surgery (59.9 vs. 80.8, p = 0.13). There were no differences in pain scores at rest or with exertion between the two groups at pre-specified time intervals. Conclusion: In this pilot study, incisional infiltration of liposomal bupivacaine and TAP block with liposomal bupivacaine demonstrated clinically similar opioid requirement after gynecologic laparotomy for suspected or known gynecologic cancer. Given the underpowered study, these findings cannot support the superiority of either modality after open gynecologic surgery.

4.
J Pharmacol Exp Ther ; 340(1): 134-42, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22001257

RESUMO

In overdose acetaminophen (APAP) is hepatotoxic. Toxicity occurs by metabolism to N-acetyl-p-benzoquinone imine, which depletes GSH and covalently binds to proteins followed by protein nitration. Nitration can occur via the strong oxidant and nitrating agent peroxynitrite, formed from superoxide and nitric oxide (NO). In hepatocyte suspensions we reported that an inhibitor of neuronal nitric-oxide synthase (nNOS; NOS1), which has been reported to be in mitochondria, inhibited toxicity and protein nitration. We recently showed that manganese superoxide dismutase (MnSOD; SOD2) was nitrated and inactivated in APAP-treated mice. To understand the role of nNOS in APAP toxicity and MnSOD nitration, nNOS knockout (KO) and wild-type (WT) mice were administered APAP (300 mg/kg). In WT mice serum alanine aminotransferase (ALT) significantly increased at 6 and 8 h, and serum aspartate aminotransferase (AST) significantly increased at 4, 6 and 8 h; however, in KO mice neither ALT nor AST significantly increased until 8 h. There were no significant differences in hepatic GSH depletion, APAP protein binding, hydroxynonenal covalent binding, or histopathological assessment of toxicity. The activity of hepatic MnSOD was significantly lower at 1 to 2 h in WT mice and subsequently increased at 8 h. MnSOD activity was not altered at 0 to 6 h in KO mice but was significantly decreased at 8 h. There were significant increases in MnSOD nitration at 1 to 8 h in WT mice and 6 to 8 h in KO mice. Significantly more nitration occurred at 1 to 6 h in WT than in KO mice. MnSOD was the only observed nitrated protein after APAP treatment. These data indicate a role for nNOS with inactivation of MnSOD and ALT release during APAP toxicity.


Assuntos
Acetaminofen/toxicidade , Analgésicos não Narcóticos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Nitratos/metabolismo , Óxido Nítrico Sintase Tipo I/fisiologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Western Blotting , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cisteína/metabolismo , Citoplasma/enzimologia , Citoplasma/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Superóxido Dismutase/metabolismo
5.
J Pharmacol Exp Ther ; 337(1): 110-6, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21205919

RESUMO

In overdose the analgesic/antipyretic acetaminophen (APAP) is hepatotoxic. Toxicity is mediated by initial hepatic metabolism to N-acetyl-p-benzoquinone imine (NAPQI). After low doses NAPQI is efficiently detoxified by GSH. However, in overdose GSH is depleted, NAPQI covalently binds to proteins as APAP adducts, and oxygen/nitrogen stress occurs. Toxicity is believed to occur by mitochondrial dysfunction. Manganese superoxide dismutase (MnSOD) inactivation by protein nitration has been reported to occur during other oxidant stress-mediated diseases. MnSOD is a critical mitochondrial antioxidant enzyme that prevents peroxynitrite formation within the mitochondria. To examine the role of MnSOD in APAP toxicity, mice were treated with 300 mg/kg APAP. GSH was significantly reduced by 65% at 0.5 h and remained reduced from 1 to 4 h. Serum alanine aminotransferase did not significantly increase until 4 h and was 2290 IU/liter at 6 h. MnSOD activity was significantly reduced by 50% at 1 and 2 h. At 1 h, GSH was significantly depleted by 62 and 80% at nontoxic doses of 50 and 100 mg/kg, respectively. No further GSH depletion occurred with hepatotoxic doses of 200 and 300 mg/kg APAP. A dose response decrease in MnSOD activity was observed for APAP at 100, 200, and 300 mg/kg. Immunoprecipitation of MnSOD from livers of APAP-treated mice followed by Western blot analysis revealed nitrated MnSOD. APAP-MnSOD adducts were not detected. Treatment of recombinant MnSOD with NAPQI did not produce APAP protein adducts. The data indicate that MnSOD inactivation by nitration is an early event in APAP-induced hepatic toxicity.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/enzimologia , Superóxido Dismutase/antagonistas & inibidores , Superóxido Dismutase/metabolismo , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitratos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia
6.
Mol Cell Biochem ; 345(1-2): 61-8, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20725767

RESUMO

Accumulations of higher inositol polyphosphates, diphosphoinositol polyphosphates or pyrophosphates, have been implicated to mediate cellular apoptosis. Whether cellular levels of lower inositol phosphates (lower than inositol hexakisphosphates) change during apoptosis is not known, although these inositol phosphates are known to play crucial roles in a number of cellular signaling processes including calcium mobilization. Therefore, in this study, we have examined changes in cellular levels of inositol phosphates following metabolic labeling of these compounds by [(3)H]myo-inositol and induction of apoptosis. The levels of inositol mono- and bis-phosphates were increased, whereas the levels of inositol tris- and tetrakis-phosphates decreased significantly with an increasing rate of apoptosis induced by etoposide in a dose-dependent manner. NaF treatment, which increased the rate of apoptosis in a time- and dose-dependent manner, also increased the levels of inositol mono- and bis-phosphates and drastically reduced the levels of inositol tris- and tetrakis-phosphates. Prior treatment with antimycin A, a strategy used to reverse the NaF-induced accumulations of higher InsPs, partially reduced the effects of NaF on apoptosis as well as the levels of lower InsPs. Taken together, our results suggest that cellular levels of lower InsPs are altered during apoptosis.


Assuntos
Apoptose , Fosfatos de Inositol/análise , Polifosfatos/análise , Células 3T3 , Animais , Relação Dose-Resposta a Droga , Etoposídeo/farmacologia , Fosfatos de Inositol/metabolismo , Camundongos , Polifosfatos/metabolismo , Fluoreto de Sódio/farmacologia , Trítio/metabolismo
7.
Mol Cell Biochem ; 328(1-2): 155-65, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19322641

RESUMO

The role of inositol polyphosphates (InsPs) in the mediation of cellular apoptosis was investigated in mouse MC3T3 osteoblastic cell line. Extracellular administration of InsP(4), InsP(5), and InsP(6) increased apoptosis in a dose-dependent manner. InsP(6) was more potent than InsP(5) and InsP(4) in promoting apoptosis. Inositol hexasulfate (InsS(6)), a structural analog of InsP(6), was used to determine specificity of InsP(6)-induced apoptosis as measured by acridine orange/ethidium bromide, flow cytometry, and DNA degradation. In order to study the effects of endogenous InsPs on apoptosis, we used NaF and antimycin A as treatment agents to manipulate intracellular levels of InsPs. NaF is known to increase levels of higher InsPs by inhibiting InsPs phosphatases, a process that is reversed by antimycin A because InsPs kinases are inhibited as a result of depletion of cellular ATP pools. Apoptosis was induced in MC3T3 cells in a NaF dose- and time-dependent manner. Approximately 50% apoptosis was observed at 1 mM NaF in 8 h. Prior treatment with 10 microM antimycin A for 30 min significantly reduced the NaF-induced apoptosis as compared with its control. Additionally, we measured changes in AKT phosphorylation, cleavage of caspase-3 and caspase-9, and release of cytochrome C from mitochondria into cytosol. These changes coincided with total cellular InsPs under similar conditions. The data indicated that NaF-induced changes in apoptotic markers could be due to an increased endogenous InsPs that were partially reversed by antimycin A treatment.


Assuntos
Apoptose , Fosfatos de Inositol/fisiologia , Animais , Antimicina A/farmacologia , Caspases/metabolismo , Linhagem Celular , Citocromos c/metabolismo , Camundongos , Osteoblastos/citologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fluoreto de Sódio/farmacologia
9.
Cell Stress Chaperones ; 21(4): 593-608, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27038811

RESUMO

Inositol polyphosphates represent a group of differentially phosphorylated inositol metabolites, many of which are implicated to regulate diverse cellular processes such as calcium mobilization, vesicular trafficking, differentiation, apoptosis, etc. The metabolic network of these compounds is complex and tightly regulated by various kinases and phosphatases present predominantly in the cytosol. Multiple inositol polyphosphate phosphatase 1 (Minpp1) is the only known endoplasmic reticulum (ER) luminal enzyme that hydrolyzes various inositol polyphosphates in vitro as well as in vivo conditions. However, access of the Minpp1 to cytosolic substrates has not yet been demonstrated clearly and hence its physiological function. In this study, we examined a potential role for Minpp1 in ER stress-induced apoptosis. We generated a custom antibody and characterized its specificity to study the expression of Minpp1 protein in multiple mammalian cells under experimentally induced cellular stress conditions. Our results demonstrate a significant increase in the expression of Minpp1 in response to a variety of cellular stress conditions. The protein expression was corroborated with the expression of its mRNA and enzymatic activity. Further, in an attempt to link the role of Minpp1 to apoptotic stress, we studied the effect of Minpp1 expression on apoptosis following silencing of the Minpp1 gene by its specific siRNA. Our results suggest an attenuation of apoptotic parameters following knockdown of Minpp1. Thus, in addition to its known role in inositol polyphosphate metabolism, we have identified a novel role for Minpp1 as a stress-responsive protein. In summary, our results provide, for the first time, a probable link between ER stress-induced apoptosis and Minpp1 expression.


Assuntos
Apoptose/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Monoéster Fosfórico Hidrolases/metabolismo , Estresse Fisiológico/fisiologia , Células 3T3 , Animais , Anticorpos/imunologia , Apoptose/genética , Linhagem Celular Tumoral , Retículo Endoplasmático/metabolismo , Humanos , Camundongos , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/imunologia , Interferência de RNA , RNA Interferente Pequeno , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
10.
Nanomedicine (Lond) ; 4(8): 883-93, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19958225

RESUMO

AIM: In previous pharmacological applications, single-wall carbon nanotubes (CNTs) have primarily been explored as potential drug carriers and delivery vehicles. Here, we investigate and demonstrate for the first time, that CNTs can be considered as anti-tumor agents and, when in combination with conventional drugs, can significantly enhance their chemotherapeutic effects. METHOD & MATERIALS: HeLa and human Panc1 cancer cells were treated with CNTs (24 h, 10 and 20 microg/ml), etoposide (6 h, 75 x 10(-6) M) and their combination. The cell viability was controlled by flow cytometry, caspase-3 assay and trypan blue dye. RESULTS: A highly increased anti-tumor activity of the combination of etoposide and CNTs against cancer cells, compared with the administration of etoposide and CNTs alone, is reported. Data provided by viability assays suggest a strong interaction between CNTs and the cellular structures, thereby improving the effectiveness of conventional chemotherapeutic agents. CONCLUSION: We believe this finding could lead to the development of new cancer therapies by carefully selecting the cytostatic drugs and nanostructural materials that, in combination, may provide synergistic curative rates.


Assuntos
Antineoplásicos/uso terapêutico , Etoposídeo/uso terapêutico , Neoplasias/tratamento farmacológico , Linhagem Celular Tumoral , Sinergismo Farmacológico , Citometria de Fluxo , Células HeLa , Humanos , Microscopia Eletrônica de Transmissão , Nanotubos de Carbono/ultraestrutura
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