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1.
Proc Natl Acad Sci U S A ; 118(50)2021 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-34876527

RESUMEN

Pancreatic cancer is usually asymptomatic in the early stages; the 5-y survival rate is around 9%; and there is a lack of effective treatment. Here we show that SSEA-4 is more expressed in all pancreatic cancer cell lines examined but not detectable in normal pancreatic cells; and high expression of SSEA-4 or the key enzymes B3GALT5 + ST3GAL2 associated with SSEA-4 biosynthesis significantly lowers the overall survival rate. To evaluate potential new treatments for pancreatic cancer, homogeneous antibodies with a well-defined Fc glycan for optimal effector functions and CAR-T cells with scFv construct designed to target SSEA-4 were shown highly effective against pancreatic cancer in vitro and in vivo. This was further supported by the finding that a subpopulation of natural killer (NK) cells isolated by the homogeneous antibody exhibited enhancement in cancer-cell killing activity compared to the unseparated NK cells. These results indicate that targeting SSEA-4 by homologous antibodies or CAR-T strategies can effectively inhibit cancer growth, suggesting SSEA-4 as a potential immunotherapy target for treating pancreatic disease.


Asunto(s)
Anticuerpos/inmunología , Neoplasias Pancreáticas/tratamiento farmacológico , Antígenos Embrionarios Específico de Estadio/inmunología , Animales , Línea Celular Tumoral , Tratamiento Basado en Trasplante de Células y Tejidos , Regulación de la Expresión Génica , Humanos , Inmunoterapia , Inmunoterapia Adoptiva , Ratones , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Mol Ther ; 30(11): 3450-3461, 2022 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-35933584

RESUMEN

MicroRNA (miRNAs) are pleiotropic post-transcriptional modulators of gene expression. Their inherently pleiotropic nature makes miRNAs strong candidates for the development of cancer therapeutics, yet despite their potential, there remains a challenge to deliver nucleic acid-based therapies into cancer cells. We developed a novel approach to modify miRNAs by replacing the uracil bases with 5-fluorouracil (5-FU) in the guide strand of tumor suppressor miRNAs, thereby combining the therapeutic effect of 5-FU with tumor-suppressive effect of miRNAs to create a potent, multi-targeted therapeutic molecule without altering its native RNAi function. To demonstrate the general applicability of this approach to other tumor-suppressive miRNAs, we screened a panel of 12 novel miRNA mimetics in several cancer types, including leukemia, breast, gastric, lung, and pancreatic cancer. Our results show that 5-FU-modified miRNA mimetics have increased potency (low nanomolar range) in inhibiting cancer cell proliferation and that these mimetics can be delivered into cancer cells without delivery vehicle both in vitro and in vivo, thus representing significant advancements in the development of therapeutic miRNAs for cancer. This work demonstrates the potential of fluoropyrimidine modifications that can be broadly applicable and may serve as a platform technology for future miRNA and nucleic acid-based therapeutics.


Asunto(s)
MicroARNs , Neoplasias Pancreáticas , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Genes Supresores de Tumor , Fluorouracilo/farmacología , Neoplasias Pancreáticas/genética , Interferencia de ARN , Regulación Neoplásica de la Expresión Génica
3.
Hum Psychopharmacol ; 34(6): e2713, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31837050

RESUMEN

OBJECTIVES: The objectives of this study were primarily to assess the efficacy and safety of SM-1 in a circadian challenge model of transient insomnia and secondarily, to assess the contribution of diphenhydramine to the combination. METHODS: Randomized, double-blind, placebo-controlled three-way cross-over study with a 5-hr phase advance. Subjects were 39 healthy adults reporting a history of transient insomnia. All treatments (SM-1, SM-1 without diphenhydramine, or placebo) were administered to all subjects in a randomly assigned sequence, with at least 1 week between treatments. The primary endpoint was total sleep time (TST) determined by polysomnography. Secondary endpoints included wakefulness after sleep onset (WASO), latency to persistent sleep, number of awakenings (NAW), subjective TST (sTST) and sleep latency (sSL), TST, and NAW by quarters of the night and sleep quality. Safety endpoints included adverse events, Karolinska Sleepiness Scale digit symbol substitution test, and subject-reported alertness level. RESULTS: SM-1 provided an increase of 126.7 min in TST over placebo (p < .001). WASO, sTST, sleep quality, and sSL also showed significant improvement. Diphenhydramine demonstrated a significant (p = .014) contribution of 43.7 min to TST. SM-1 was well-tolerated with type and frequency of adverse events comparable with placebo, and no residual sleepiness upon awakening after 8 hr. CONCLUSIONS: SM-1 provided a robust and statistically significant increase in TST compared with placebo in a circadian model of transient insomnia, without evidence of next-day impairment. Diphenhydramine contributed to the effect.


Asunto(s)
Difenhidramina/uso terapéutico , Lorazepam/uso terapéutico , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Zolpidem/uso terapéutico , Adulto , Estudios Cruzados , Método Doble Ciego , Combinación de Medicamentos , Femenino , Humanos , Hipnóticos y Sedantes/uso terapéutico , Masculino , Persona de Mediana Edad , Polisomnografía , Resultado del Tratamiento
4.
Hum Psychopharmacol ; 34(6): e2716, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31794072

RESUMEN

OBJECTIVE: The primary objective was to characterize the pharmacokinetics and pharmacodynamics of SM-1 after administration of a single oral dose to healthy volunteers in a placebo-controlled double-blind trial of daytime sedation. Secondary objectives were to determine the onset, duration, and offset of the sedative effects using subjective and objective measures of sedation. Safety and tolerability of SM-1 were also investigated. METHODS: Males and females 18-45 years of age received SM-1, a combination drug product comprised of diphenhydramine, zolpidem (delayed release), and lorazepam (delayed release). The pharmacokinetic profile of each drug was determined from blood samples. Sedative effects were assessed by visual analog scale, digit symbol substitution test, memory test, and quantitative electroencephalography. RESULTS: Similar number and severity of adverse events were observed following administration of SM-1 and placebo. Onset of sedation, as determined by subjective, performance, and electroencephalography measures, occurred 0.5-1 hr postdose, lasting about 7-7.5 hr. Plasma concentration curves for the two delayed-release components were altered compared with published data for unmodified drugs. Exposure values obtained with the combination product were in good agreement with published values of the drugs given individually. CONCLUSIONS: SM-1 was well tolerated and has pharmacologic activity starting within an hour of ingestion, lasting approximately 7-8 hr. Sedative activity was seen with subjective, psychomotor, and electroencephalography assays.


Asunto(s)
Azepinas/farmacología , Azepinas/farmacocinética , Hidrazonas/farmacología , Hidrazonas/farmacocinética , Hipnóticos y Sedantes/farmacología , Hipnóticos y Sedantes/farmacocinética , Sueño/efectos de los fármacos , Zolpidem/farmacología , Zolpidem/farmacocinética , Adolescente , Adulto , Estudios Cruzados , Método Doble Ciego , Combinación de Medicamentos , Electroencefalografía , Femenino , Humanos , Hipnóticos y Sedantes/sangre , Masculino , Persona de Mediana Edad , Polisomnografía , Pruebas Psicológicas , Factores de Tiempo , Adulto Joven , Zolpidem/efectos adversos , Zolpidem/sangre
5.
Zhonghua Gan Zang Bing Za Zhi ; 21(5): 363-6, 2013 May.
Artículo en Zh | MEDLINE | ID: mdl-24025138

RESUMEN

OBJECTIVE: To observe the dynamic change in expression of protease-activated receptor 2 (PAR2) during onset and progression of liver fibrosis by using a rat model. METHODS: A cholestatic liver fibrosis model was established in Sprague-Dawley rats (aged 8-9 weeks, body weight 350 - 400 g) by bile duct ligation surgery. Rats receiving a sham operation and unoperated rats served as the negative and normal control groups, respectively. At baseline (pre-surgery) and post-surgery weeks 2, 4, 6, and 8, five rats from each group were sacrificed for whole liver resection. The protein and mRNA expressions of PAR2 and collagen I/III were detected by western blotting and RT-PCR, respectively. Between-group differences were assessed by analysis of variance testing. RESULTS: At post-surgery week 2, the liver fibrosis group showed higher expression of PAR2 mRNA and protein than either control group. The expression levels of PAR2 continued to rise over time in the liver fibrosis group (peaking at week 8), and were significantly higher than those detected in the control groups (weeks 4-6: P less than 0.05; week 8, P less than 0.05). A similar trend was observed for the expression of collagen I/III. CONCLUSION: Dynamic expression of PAR2 observed in a cholestatic liver fibrosis rat model may indicate a role for this factor in the formation of liver fibrosis.


Asunto(s)
Cirrosis Hepática Biliar/metabolismo , Hígado/metabolismo , Receptor PAR-2/metabolismo , Animales , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Modelos Animales de Enfermedad , Hígado/patología , Cirrosis Hepática Biliar/patología , Masculino , Ratas , Ratas Sprague-Dawley
6.
Sleep Biol Rhythms ; 20(1): 47-52, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38469063

RESUMEN

Thomas Dahl, PO Box 404, Guilford, CT 06437 USA. Email: tadahl@outlook.com. The objectives of the study were to demonstrate the efficacy and safety of SM-1 in a circadian challenge model of transient insomnia. Randomized, double-blind, placebo-controlled cross-over study utilizing a 5-h phase advance model of transient insomnia. Subjects were 85 healthy adults reporting a history of transient insomnia, with an average age of 38.9 years. Both SM-1 and placebo were administered to all subjects in a randomly assigned sequence, with at least 1 week between treatments. The primary endpoint was total sleep time determined by polysomnography. Secondary endpoints included wakefulness after sleep onset, latency to persistent sleep, number of awakenings, subjective total sleep time and subjective sleep onset latency, total sleep time by quarters of the night, subjective number of awakenings, and sleep quality. Safety endpoints included adverse events, Karolinska Sleepiness Scale, Digit Symbol Substitution Test, and predischarge evaluation (tandem gait and Romberg tests). SM-1 provided an increase of 94.4 min in total sleep time over placebo (p < 0.0001). Wakefulness after sleep onset, subjective total sleep time, subjective sleep onset latency, and total sleep time in the first quarter of the night also showed significant improvement. SM-1 was well-tolerated with both type and frequency of adverse events being comparable to placebo, and no residual sleepiness upon awakening (i.e., after 8 h). SM-1 provided a robust and statistically significant increase in total sleep time compared to placebo in a circadian model of transient insomnia, without evidence of next-day impairment.

7.
J Clin Invest ; 115(6): 1492-502, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15902309

RESUMEN

Overcoming resistance to chemotherapy and radiation therapy has been a difficult but important goal in the effort to cure cancer. We used gene-expression microarrays to identify differentially expressed genes involved in colorectal cancer resistance to chemotherapy and identified secreted protein, acidic and rich in cysteine (osteonectin) (SPARC) as a putative resistance-reversal gene by demonstrating low SPARC expression in refractory human MIP101 colon cancer cells. We were able to achieve restoration of their radiosensitivity and sensitivity to 5-fluorouracil and irinotecan by reexpression of SPARC in tumor xenografts. Moreover, treatment of mice with SPARC conferred increased sensitivity to chemotherapy and led to significant regression of xenografted tumors. The results show that modulation of SPARC expression affects colorectal cancer sensitivity to radiation and chemotherapy. SPARC-based gene or protein therapy may ameliorate the emergence of resistant clones and eradicate existing refractory clones and offers a novel approach to treating cancer.


Asunto(s)
Antineoplásicos/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias del Colon/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Experimentales/tratamiento farmacológico , Osteonectina/administración & dosificación , Animales , Camptotecina/administración & dosificación , Línea Celular Tumoral , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Fluorouracilo/administración & dosificación , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Irinotecán , Ratones , Ratones Desnudos , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Osteonectina/metabolismo , Trasplante Heterólogo
8.
Mol Biol Cell ; 13(3): 767-81, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11907260

RESUMEN

Here we demonstrate that multiple tetraspanin (transmembrane 4 superfamily) proteins are palmitoylated, in either the Golgi or a post-Golgi compartment. Using CD151 as a model tetraspanin, we identified and mutated intracellular N-terminal and C-terminal cysteine palmitoylation sites. Simultaneous mutations of C11, C15, C242, and C243 (each to serine) eliminated >90% of CD151 palmitoylation. Notably, palmitoylation had minimal influence on the density of tetraspanin protein complexes, did not promote tetraspanin localization into detergent-resistant microdomains, and was not required for CD151-alpha 3 beta 1 integrin association. However, the CD151 tetra mutant showed markedly diminished associations with other cell surface proteins, including other transmembrane 4 superfamily proteins (CD9, CD63). Thus, palmitoylation may be critical for assembly of the large network of cell surface tetraspanin-protein interactions, sometimes called the "tetraspanin web." Also, compared with wild-type CD151, the tetra mutant was much more diffusely distributed and showed markedly diminished stability during biosynthesis. Finally, expression of the tetra-CD151 mutant profoundly altered alpha 3 integrin-deficient kidney epithelial cells, such that they converted from a dispersed, elongated morphology to an epithelium-like cobblestone clustering. These results point to novel biochemical and biological functions for tetraspanin palmitoylation.


Asunto(s)
Antígenos CD/metabolismo , Tamaño de la Célula , Integrina alfa3beta1/metabolismo , Proteínas de la Membrana/metabolismo , Palmitatos/metabolismo , Secuencia de Aminoácidos , Antígenos CD/genética , Transporte Biológico/fisiología , Brefeldino A/farmacología , Línea Celular , Proteínas Fluorescentes Verdes , Humanos , Indicadores y Reactivos/metabolismo , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Inhibidores de la Síntesis de la Proteína/farmacología , Proteínas Recombinantes de Fusión/metabolismo , Alineación de Secuencia , Tetraspanina 24
9.
Atherosclerosis ; 188(2): 292-300, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16325820

RESUMEN

OBJECTIVE: Periostin is dramatically upregulated in rat carotid arteries after balloon injury. The objective of the present study was to understand mechanisms underlying periostin upregulation in balloon-injured rat carotid arteries and in cultured vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: Periostin protein was strongly expressed at 3 days (in the medial SMCs) and 7 days (in the neointima) after injury. It was also abundantly expressed in the neointima in the late phase (at 14 and 28 days) after injury. Periostin upregulation was mediated through PI-3-kinase-dependent signaling pathway. In vivo, wortmannin, a PI-3-kinase inhibitor, inhibited balloon injury-induced Akt phosphorylation and periostin mRNA expression. In vitro, periostin mRNA expression in cultured VSMCs was stimulated by growth factors (transforming growth factor-beta1 (TGF-beta1), fibroblast growth factors (FGFs), PDGF-BB, and angiotensin II). This stimulatory effect was inhibited by the PI-3-kinase inhibitor LY294002. Further, periostin protein was mostly located in the cytoplasma of VSMCs in culture and abundantly secreted into the culture medium (CM) after stimulation with FGF-2, which significantly promoted VSMC migration in vitro. Immunodepletion of periostin from the VSMC-CM or blockade of periostin function with an anti-periostin antibody significantly reduced VSMC migration. CONCLUSIONS: Upregulation of periostin expression in rat carotid arteries following balloon injury and in cultured VSMCs after stimulation by growth factors is mediated through PI-3-kinase-dependent signaling pathway. Periostin protein secreted by VSMCs plays a significant role in regulating VSMC migration in vitro.


Asunto(s)
Traumatismos de las Arterias Carótidas/metabolismo , Cateterismo/efectos adversos , Moléculas de Adhesión Celular/metabolismo , Regulación de la Expresión Génica/fisiología , Miocitos del Músculo Liso/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/fisiología , Androstadienos/farmacología , Animales , Northern Blotting , Western Blotting , Movimiento Celular/fisiología , Cartilla de ADN , Regulación de la Expresión Génica/efectos de los fármacos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intercelular/farmacología , Masculino , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Wortmanina
10.
Oncogene ; 21(9): 1346-58, 2002 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-11857078

RESUMEN

Our previous studies have characterized Dexamethasone (Dex)-induced apoptotic signaling pathways in multiple myeloma (MM) cells; however, related transcriptional events are not fully defined. In the present study, gene expression profiles of Dex-treated MM cells were determined using oligonucleotide arrays. Dex triggers early transient induction of many genes involved in cell defense/repair-machinery. This is followed by induction of genes known to mediate cell death and repression of growth/survival-related genes. The molecular and genetic alterations associated with Dex resistance in MM cells are also unknown. We compared the gene expression profiles of Dex-sensitive and Dex-resistant MM cells and identified a number of genes which may confer Dex-resistance. Finally, gene profiling of freshly isolated MM patient cells validates our in vitro MM cell line data, confirming an in vivo relevance of these studies. Collectively, these findings provide insights into the basic mechanisms of Dex activity against MM, as well as mechanisms of Dex-resistance in MM cells. These studies may therefore allow improved therapeutic uses of Dex, based upon targeting genes that regulate MM cell growth and survival.


Asunto(s)
Dexametasona/farmacología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Mieloma Múltiple/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Apoptosis/efectos de los fármacos , Apoptosis/genética , Western Blotting , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Cisteína Endopeptidasas/metabolismo , Reparación del ADN/efectos de los fármacos , Reparación del ADN/genética , Resistencia a Antineoplásicos/genética , Citometría de Flujo , Proteínas de Choque Térmico/genética , Humanos , Complejos Multienzimáticos/metabolismo , FN-kappa B/metabolismo , Complejo de la Endopetidasa Proteasomal , ARN Mensajero/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Interleucina-6/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Transducción de Señal , Células Tumorales Cultivadas , Ubiquitina/metabolismo , Regulación hacia Arriba/efectos de los fármacos
11.
Clin Cancer Res ; 10(9): 3020-8, 2004 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-15131038

RESUMEN

PURPOSE: The purpose of this study was to assess the feasibility of using rare event imaging system (REIS)-assisted analysis to detect occult tumor cells (OTCs) in peripheral blood (PB). The study also sought to determine whether REIS-assisted OTC detection presents a clinically viable alternative to manual microscopic detection to establish the true significance of OTC from solid epithelial tumors. EXPERIMENTAL DESIGN: We recently demonstrated proof of concept using a fluorescence-based automated microscope system, REIS, for OTC detection from the PB. For this study, the prototype of the system was adopted for high-throughput and high-content cellular analysis. RESULTS: The performance of the improved REIS was examined using normal blood (n = 10), normal blood added to cancer cells (n = 20), and blood samples obtained from cancer patients (n = 80). Data from the screening of 80 clinical slides from breast and lung cancer patients, by manual microscopy and by the REIS, revealed that as many as 14 of 35 positive slides (40%) were missed by manual screening but positively identified by REIS. In addition, REIS-assisted scanning reliably and reproducibly quantified the total number of cells analyzed in the assay and categorized positive cells based on their marker expression profile. CONCLUSIONS: REIS-assisted analysis provides excellent sensitivity and reproducibility for OTC detection. This approach may enable an improved method for screening of PB samples and for obtaining novel information about disease staging and about risk evaluation in cancer patients.


Asunto(s)
Neoplasias de la Mama/diagnóstico , Carcinoma de Células Pequeñas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Microscopía Fluorescente/métodos , Neoplasias de la Mama/sangre , Carcinoma de Células Pequeñas/sangre , Recuento de Células , Línea Celular Tumoral , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Inmunohistoquímica , Queratinas/análisis , Neoplasias Pulmonares/sangre , Células Neoplásicas Circulantes/química , Células Neoplásicas Circulantes/patología , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
12.
Exp Hematol ; 30(3): 212-20, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11882358

RESUMEN

OBJECTIVE: Since the central hallmarks of human multiple myeloma (MM) are abnormalities in immunoglobulin (Ig) gene rearrangement, IgH class switching, and DNA damage repair, and since Ku86 and Ku70 proteins are central to these processes, aberrant Ku function may play a role in MM pathogenesis. Our prior studies demonstrated a 69-kDa Ku86 variant in freshly isolated patient MM cells that confers sensitivity to DNA damage. We also showed that Ku86 on the cell surface of CD40-activated MM cells mediates homotypic tumor cell adhesion, as well as heterotypic adhesion to bone marrow stromal cells. We here define the mechanism and functional significance of CD40-induced Ku translocation from the cytoplasm to the cell membrane in MM cells vs normal B cells. MATERIALS AND METHODS: We examined Ku86 and Ku70 translocation following CD40 activation in human MM cells vs normal tonsillar B lymphocytes. We then identified the functional sequelae of membrane Ku86 and Ku70 expression on CD40-activated human MM cells. RESULTS: CD40 activation induces translocation of both Ku86 and Ku70 to the cell surface of MM cells, but not normal tonsillar B cells. Moreover, CD40 activation triggers Ku association with CD40 only in CD40-activated MM cells. Finally, CD40-activated MM cells adhere to fibronectin and are protected against apoptosis triggered by irradiation or doxorubicin; conversely, antibodies to Ku both inhibit tumor cell binding and restore sensitivity to these agents. CONCLUSION: These results demonstrate functional significance of Ku translocation to the cell membrane of CD40-activated human MM cells. Therefore, targeting Ku86 and Ku70, with blocking peptides for example, might serve as a novel treatment strategy in human MM.


Asunto(s)
Antígenos Nucleares , Membrana Celular/inmunología , ADN Helicasas , Proteínas de Unión al ADN/fisiología , Mieloma Múltiple/inmunología , Proteínas Nucleares/fisiología , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Linfocitos B/inmunología , Transporte Biológico , Antígenos CD40/inmunología , Adhesión Celular , Fraccionamiento Celular , Citoplasma/metabolismo , Doxorrubicina/farmacología , Fibronectinas/metabolismo , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Autoantígeno Ku , Mieloma Múltiple/ultraestructura , Tonsila Palatina/citología
13.
Anticancer Res ; 23(1A): 49-62, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12683352

RESUMEN

Lung cancer accounts for approximately 30% of all cancer mortalities in the United States. Small cell lung cancer (SCLC), which is an aggressive malignancy with frequent and early metastases, accounts for about 15% of all of the lung cancer cases with a dismal 5-year survival rate of < 5% with current standard therapies. Early detection of SCLC is challenging, in part due to the lack of adequate serum tumor markers. The goal of this review is to summarize the current knowledge of circulating tumor cells and serum biomarkers in small cell lung cancer. The role of circulating tumor cells in prognostication is controversial, but may be better defined with advancing technologies of detection of such cells with higher precision, and improved clinico-pathological correlations. The current knowledge on the known serum cytokines and tumor biomarkers of SCLC, such as CEA, chromogranin-A and neuron-specific enolase will be presented. Serum cytokines, such as vascular endothelial growth factor (VEGF), stem cell factor (SCF) and hepatocyte growth factor/scatter factor (HGF/SF) are also discussed. New findings in the search for novel diagnostic and therapeutic molecular markers using the emerging genomics and proteomics technologies are emphasized. It is our hope that validation of these new research platforms and technologies will result in improved early detection, prognostication and finally treatment of SCLC with potential novel molecularly-targeted therapeutics.


Asunto(s)
Biomarcadores de Tumor/sangre , Carcinoma de Células Pequeñas/sangre , Neoplasias Pulmonares/sangre , Células Neoplásicas Circulantes/patología , Carcinoma de Células Pequeñas/patología , Humanos , Neoplasias Pulmonares/patología
14.
Cell Biochem Biophys ; 70(3): 1829-32, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25085619

RESUMEN

The objective of this study was to analyze the clinical feature of hepatitis delta virus (HDV)-infected patients and to discuss the pathological mechanism of hepatitis D. A total of 507 patients with hepatitis due to the infection of HDV were included. The incidence rates of various hepatitis subtypes, the sequelae, the clinical manifestation, the hepatic function, and the hepatic virus makers for all the 507 patients were analyzed statistically. A cohort of 213 patients with hepatitis B, who were also HDV free, served as the control. HDV infection significantly contributed to the increased incidence rate and mortality of severe hepatitis (SH) and cirrhosis (P < 0.01). HDV was also associated with higher incidence rates of hemorrhage in the gastrointestinal tract, abdominal ascites and hepatic encephalopathy, repetitive augmentation of alanine transaminase, and its enhanced magnitude (P < 0.01 or 0.05). The major liver function changes in patients with SH or chronic serious hepatitis was significant compared to the control (P < 0.01). Within the HDV(+) category, HBeAg(-) expression was significantly higher in the HBV DNA(-) group than the HBV DNA(+) group (P < 0.01). The expression of HDAg(+) HBeAg(-) in acute hepatitis, SH, and cirrhosis was significantly higher than that of HDAg(+) HBeAg(+) (P < 0.01 or P < 0.05). The HDV infection was closely associated with the development and prognosis of chronic serious hepatitis, SH, and cirrhosis. HDV infection could inhibit the HBV DNA replication or the HBcAg expression. The direct cytotoxicity of HDV might be the leading pathological factor in AH. HDV might play a major role in the deterioration and chronicization of HDV-co-infected hepatitis B and was responsible for the increased mortality of HBV/HDV patients.


Asunto(s)
Hepatitis D/diagnóstico , Adulto , Alanina Transaminasa/sangre , Bilirrubina/sangre , Estudios de Cohortes , Femenino , Hemorragia Gastrointestinal/epidemiología , Hemorragia Gastrointestinal/etiología , Encefalopatía Hepática/epidemiología , Encefalopatía Hepática/etiología , Anticuerpos Antihepatitis/sangre , Hepatitis B/diagnóstico , Hepatitis B/virología , Anticuerpos contra la Hepatitis B/sangre , Antígenos e de la Hepatitis B/sangre , Hepatitis D/complicaciones , Hepatitis D/virología , Virus de la Hepatitis Delta/metabolismo , Antígenos de Hepatitis delta/sangre , Humanos , Incidencia , Cirrosis Hepática/epidemiología , Cirrosis Hepática/etiología , Masculino , Persona de Mediana Edad , Tiempo de Protrombina , Índice de Severidad de la Enfermedad
16.
Pigment Cell Melanoma Res ; 21(4): 451-6, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18710373

RESUMEN

Melanoma is a common malignancy which is poorly responsive to chemotherapy and radiation. One of the major reasons melanoma responds poorly to these modalities is constitutive expression of Akt, which protects against apoptosis. The antidepressant sertraline was found to be a potent cytotoxic agent against A375 human melanoma. To determine the mechanism by which sertraline kills melanoma cells, Western blot analysis of signaling molecules, including phosphorylated Akt, caspase 9 and phospho-p70 S6 kinase was performed. Finally, the effects of sertraline on A375 xenografts in mice were assessed. Sertaline potently inhibited the phosphorylation of Akt, and caused cell death through induction of endoplasmic reticulum in vitro. Sertraline monotherapy demonstrated activity against A375 xenografts in vivo. Akt is a major cause of resistance of melanoma to current therapy. Antidepressants are commonly used to prevent interferon-induced depression. Use of antidepressants that decrease Akt may improve the efficacy of interferon and other therapies against melanoma. Further studies are needed to elucidate whether sertraline acts as an Akt inhibitor in melanoma.


Asunto(s)
Antineoplásicos/farmacología , Melanoma/patología , Proteína Oncogénica v-akt/metabolismo , Sertralina/farmacología , Animales , Antidepresivos/farmacología , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Humanos , Masculino , Melanoma/genética , Ratones , Ratones Desnudos , Fosforilación/efectos de los fármacos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Carcinogenesis ; 26(5): 908-15, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15731169

RESUMEN

Several factors have been shown to promote the growth of colorectal cancers. Here, we provide evidence that periostin, a protein with structural and sequence homology with a TGF-beta-inducible gene, beta ig-h3, is upregulated in colorectal cancers and their liver metastasis, and it may play a role in promoting growth in these tumors. In vitro studies reveal that periostin promotes growth and cell proliferation in colorectal cancers and that this effect can be abrogated with antibodies to periostin. Furthermore, exposure of colorectal cancer cells to anti-periostin antibodies activates apoptosis and potentiates the effects of 5-fluorouracil chemotherapy. The results demonstrate the growth-promoting properties of periostin, and a possible role of targeting this protein as a therapeutic option in colorectal cancers.


Asunto(s)
Anticuerpos/inmunología , Moléculas de Adhesión Celular/metabolismo , Proliferación Celular , Neoplasias Colorrectales/metabolismo , Apoptosis/inmunología , Moléculas de Adhesión Celular/inmunología , Colon/metabolismo , Colon/patología , Colon/ultraestructura , Neoplasias Colorrectales/inmunología , Humanos , Intestino Delgado/metabolismo , Intestino Delgado/ultraestructura , Hígado/patología , Hígado/ultraestructura , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/secundario , Regulación hacia Arriba
18.
Am J Obstet Gynecol ; 186(1): 103-8, 2002 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-11810094

RESUMEN

OBJECTIVE: We recently developed a novel sandwich chemiluminescence assay to determine serum concentrations of periostin. Periostin has high amino acid homology with transforming growth factor-beta-induced protein beta igh3, a molecule induced by transforming growth factor-beta(1), which promotes the adhesion and spreading of fibroblasts. It is also homologous with the insect cell adhesion molecule fasciclin I. We determined serum periostin concentrations in women with preeclampsia and in normotensive pregnant women. STUDY DESIGN: The study groups included 30 women with preeclampsia and 30 normotensive pregnant women at Magee-Womens Hospital. Blood samples collected from these women were assayed for periostin by use of newly developed monoclonal and polyclonal antibodies. We studied periostin messenger ribonucleic acid (mRNA) expression in human tissues by using reverse transcriptase-polymerase chain reaction and in situ hybridization. RESULTS: Serum periostin concentrations were elevated in patients with preeclampsia (mean +/- SD, 311.8 +/- 56.3 ng/mL) compared with normotensive pregnant women (218.8 +/- 37.3 ng/mL). No correlation was found between serum concentrations of periostin and concentrations of TGF-beta(1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and interleukin-6. Reverse transcriptase-polymerase chain reaction analysis demonstrated human periostin expression in lung, kidney, and placenta but not in the heart, liver, brain, or skeletal muscle. For periostin complementary deoxyribonucleic acid cloned from placenta, there was a splicing deletion within the C-terminal domain. In situ hybridization data showed that the periostin gene was expressed in the stroma cells of placenta. CONCLUSION: Our study suggests that human periostin may play a role in the pathogenesis of preeclampsia. Although its function remains unclear, the expression of periostin as an adhesion molecule could suggest novel mechanisms in preeclampsia.


Asunto(s)
Moléculas de Adhesión Celular/sangre , Preeclampsia/sangre , Embarazo/sangre , Adulto , Moléculas de Adhesión Celular/metabolismo , Femenino , Humanos , Hibridación in Situ , Mediciones Luminiscentes , Preeclampsia/metabolismo , Embarazo/metabolismo , Valores de Referencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Distribución Tisular
19.
Breast Cancer Res Treat ; 77(3): 245-52, 2003 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-12602924

RESUMEN

Periostin is a recently identified gene that is preferentially expressed in periosteum, indicating a potential role in bone formation and maintenance of structure. We independently identified and isolated periostin from cancer tissue, using the palindromic PCR-driven cDNA Differential Display technique. For the present work, we developed a novel sandwich chemiluminescence assay to detect serum periostin level using newly developed monoclonal and polyclonal antibodies. We investigated serum periostin levels in breast cancer and small cell lung cancer patients, especially in patients with bone metastasis. The study included 58 breast cancer and 44 small cell lung cancer patients. Serum periostin levels were elevated in breast cancer patients presenting with bone metastases (92.0 +/- 28.6 ng/ml) compared to similar breast cancer patients without evidence of bone metastasis (55.0 +/- 16.6 ng/ml, p = 0.04). No correlation was found between the serum periostin level and any other prognostic factors, such as clinical stage and lymph node metastasis in breast cancer. Serum periostin levels thus appear to serve as a marker of bone metastasis from breast cancer. In contrast, serum periostin levels were similar in samples from patients with small cell lung cancer who did or did not have bone metastasis. However, increasing T-stage and N-stage of patients with small cell lung cancer were correlated with higher periostin levels (T4, 126.5 +/- 29.7 ng/ml v.s. T2, 64.9 +/- 16.1 ng/ml, p = 0.03; and T4 v.s. T1, 36.3+/- 7.5 ng/ml, p = 0.01; N3, 108.7 +/- 17.3 ng/ml v.s. N2, 49.7+/- 10.9 ng/ml, p = 0.01). Periostin has a substantial homology with the insect cell adhesion molecule, fasciclin I. Thus, expression of periostin may facilitate tumor cell adhesion to the bone surface. In fact, we found by in situ RNA hybridization, that the periostin gene was highly expressed in the stromal cells immediately surrounding the tumor, but not within the breast cancer cells themselves.


Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Carcinoma de Células Pequeñas/secundario , Moléculas de Adhesión Celular/sangre , Neoplasias Pulmonares/patología , Adulto , Neoplasias Óseas/sangre , Neoplasias de la Mama/sangre , Carcinoma de Células Pequeñas/sangre , Femenino , Humanos , Hibridación in Situ , Mediciones Luminiscentes , Neoplasias Pulmonares/sangre , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Valor Predictivo de las Pruebas
20.
Cytometry A ; 58(2): 147-56, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15057968

RESUMEN

BACKGROUND: Cytomegalovirus (CMV) infection continues to be a major problem for immunocompromised patients. Detection of viral antigens in leukocytes (antigenemia assay) is widely used for the diagnosis of CMV infection and for guiding antiviral therapy. The antigenemia technique, contingent upon the manual microscopic analysis of rare cells, is a laborious task that is subject to human error. In this study, we combine automated microscopy with artificial intelligence for reliable detection of fluorescently labeled CMV-infected cells. METHODS: Cytospin preparations of peripheral blood leukocytes were immunofluorescently labeled for the CMV lower matrix phosphoprotein (pp65) and scanned in the Rare Event Imaging System (REIS), a fully automated image cytometer. The REIS detected potential positive objects and digitally recorded 49 measured cellular features for each identified case. The measurement data of these objects were analyzed by the See5 decision tree (DT) algorithm to ascertain whether they were true-positive detections. RESULTS: The DT was built from the measurement data of 2,047 true- and 2,028 false-positive detections, collected from 32 patient samples. By designating misclassifications of false-negatives three times more costly, the 10-fold cross-validation sensitivity, specificity, and misclassification error of the assay was 94.3%, 56.2%, and 25%, respectively. The method was also validated using an independent test set of 21 patient samples, in which similar results were obtained. CONCLUSIONS: To our knowledge, this study represents the first attempt to improve the accuracy of rare event image cytometry through the implementation of artificial intelligence methodology. Results suggest that cost-sensitive decision tree analysis of digitally measured cellular features vastly improves the performance of rare event image cytometry.


Asunto(s)
Citomegalovirus/aislamiento & purificación , Árboles de Decisión , Técnica del Anticuerpo Fluorescente Indirecta/métodos , Leucocitos/virología , Inteligencia Artificial , Automatización , Células Cultivadas , Técnica del Anticuerpo Fluorescente Indirecta/instrumentación , Humanos , Microscopía Fluorescente , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
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