RESUMEN
BACKGROUND: Most thoracic surgical procedures in the United States are being performed by general surgeons (GSs) without any advanced training. With the recent approval of computed tomography screening for lung malignancy in high-risk populations, the number of thoracic oncologic resections is expected to rise. Previous literature has demonstrated consistently worsened outcomes for patients undergoing thoracic surgical procedure when done by nonthoracic fellowship-trained surgeons. Using the American College of Surgeons National Surgical Quality Improvement Project database, we examined short-term outcomes in patients undergoing video-assisted thoracoscopic surgery (VATS) lobectomy for malignancy. MATERIALS AND METHODS: Data were obtained from the American College of Surgeons National Surgical Quality Improvement Project from 2010-2015. We identified patients who had an International Classification of Disease 9 diagnosis of lung cancer (162) who underwent VATS lobectomy (current procedural terminology 32663). We included only adults (≥18y) and elective cases. We excluded patients who had preoperative diagnosis of sepsis, contaminated wound class, or those patients with missing American Society of Anesthesiologists classification, morbid obesity, functional status, length of stay (LOS), or sex, and race information. We identified two groups by specialty: GS versus cardiothoracic (CT) surgeon. We then performed univariate analysis. We then performed propensity score analysis using a 1:3 ratio of general surgery patients to CT patients. Outcomes of interest included 30-d postoperative mortality, 30-d postoperative morbidity, and LOS. RESULTS: A total of 4105 patients were identified, 607 performed by GSs, 3508 performed by CT surgeons. The mean age for patients who underwent lobectomies by GSs was 68.6 versus 67.8 in the CT surgeon group (P < 0.05). The majority were female (58.09% GS versus 57.74% CT surgeon). There was a statistically significant difference in race between groups; patients were more likely to be African American in the CT surgeon group. Operative time was lower in the GS group as opposed to the CT surgeon group 179 min versus 196 (P < 0.01). Univariate analysis (mortality <0.1 CT surgeon and GS) and 1:3 propensity score matched analysis (0.08 GS% versus 0.08% CT surgeon) failed to demonstrate a significant difference in mortality. There was a statistically significant difference in median LOS between groups (6.2 GS versus 5.1 CT surgeon). Univariate and propensity matched analyses of pneumonia, sepsis, wound infection, deep vein thrombosis, transfusion requirement, myocardial infarction stroke, postoperative renal insufficiency, failure to wean, pulmonary embolism, reintubation, and deep organ space infection all failed to demonstrate a statistically significant difference between our groups of interest. Urinary tract infection was noted to be higher in the GS group operating room 2.29 as compared to the CT surgeon group (P value 0.02). CONCLUSIONS: In this large observational study, we found that VATS lobectomies performed by GS compared to the matched CT surgeon cohort had shorter operative time, and there was no difference in major postoperative morbidity or mortality. However, LOS was higher and there was increased risk of urinary tract infection in the GS compared to matched CT surgeon cohort.
Asunto(s)
Cirugía General/estadística & datos numéricos , Neoplasias Pulmonares/cirugía , Cirujanos/estadística & datos numéricos , Cirugía Torácica Asistida por Video/estadística & datos numéricos , Cirugía Torácica/estadística & datos numéricos , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Estudios RetrospectivosRESUMEN
BACKGROUND: An estimated 38% of US adults are obese. Obesity is associated with socioeconomic disparities and increased rates of comorbidities, and is a known risk factor for development of pancreatic cancer. As a fourth leading cause of death in the United States, pancreatic cancer is commonly treated with a pancreatico-duodenectomy (PD), or Whipple procedure. Data regarding the effects of obesity on post-operative complication rate primarily comes from specialized centers, however the results are mixed. Our aim is to elucidate the effects that obesity has on outcomes after PD for pancreatic head cancer using a national prospectively maintained clinical database. METHOD: The 2010-2015 American College of Surgeons National Surgical Quality Improvement Project (ACS NSQIP) Participant Use Files (PUF) were used as the data source. We identified cases in which PD was performed (CPT code 48150) in the setting of a postoperative diagnosis of pancreatic cancer (ICD9 code 157.0). We excluded cases that had emergency admissions, BMI ≤18.5â¯kg/m2, intraoperative wound classification of III or IV, and disseminated cancer. Cases with missing BMI, preoperative albumin, operative time, LOS data were also excluded. Multiple imputation for missing sex, race, functional status, and ASA classification using chained equations was performed.16 Patients that had BMI ≥30â¯kg/m2 were considered obese, and patients with BMI <30â¯kg/m2 were used as control. RESULTS: 3484 patients underwent pancreaticoduodenectomy for pancreatic cancer. 860 patients were identified as obese. Propensity score analysis was performed matching age, sex, race, functional status, presence of dyspnea, diabetes, hypertension, acute renal failure, dialysis dependence, ascites, steroid use, bleeding disorders, history of chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), weight loss, American Society of Anesthesiologists (ASA) classification, and preoperative albumin levels. After matching, obese patients had higher risk of 30-day postoperative complications compared to control, including organ space wound infections (OR 1.38, 95% CI 1.07-1.79, pâ¯=â¯0.0128), returning to the operating room (OR 1.39, 95% CI 1.01-1.91, pâ¯=â¯0.0461), failure to extubate for greater than 48â¯h (OR 1.60, 95% CI 1.09-2.34, pâ¯=â¯0.0153), death (OR 1.68, 95% CI 1.01-2.78, pâ¯=â¯0.0453), septic shock (OR 2.22, 95% CI 1.46-3.38, pâ¯=â¯0.0002), pulmonary embolism (OR 2.42, 95% CI 1.07-5.45, pâ¯=â¯0.0332), renal insufficiency (OR 2.67, 95% CI 1.33-5.38, pâ¯=â¯0.0058). Sensitivity analysis yielded similar results with the exception of risk for return to the operating room, death, and pulmonary embolism, Pâ¯>â¯.05. CONCLUSION: In this large observational study using a national clinical database, obese patients undergoing PD for head of pancreas cancer had increased risk of postoperative complications and mortality in comparison to controls.
Asunto(s)
Obesidad/epidemiología , Neoplasias Pancreáticas/cirugía , Pancreaticoduodenectomía/efectos adversos , Complicaciones Posoperatorias/epidemiología , Mejoramiento de la Calidad , Medición de Riesgo/métodos , Anciano , Anastomosis Quirúrgica/efectos adversos , Índice de Masa Corporal , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/epidemiología , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
The coding sequences for the transforming (src) protein (p21) of Harvey murine sarcoma virus have been localized to a 1.3 kilobase pair segment near the 5' end of the viral genome. Ligation of the viral terminal repeat DNA to the left end of the src region DNA markedly enhanced the low transforming efficiency of the src region DNA.
Asunto(s)
Transformación Celular Viral , ADN Viral/genética , Virus del Sarcoma Murino/genética , Clonación Molecular , Genes Virales , Secuencias Repetitivas de Ácidos Nucleicos , Transformación Genética , Proteínas Virales/genéticaRESUMEN
Li-Fraumeni syndrome is manifested in a variety of neoplasms that are transmitted in a dominantly inherited pattern. The noncancerous skin fibroblasts of family members exhibit a unique characteristic of being resistant to the killing effect of ionizing radiation. A three- to eightfold elevation in expression of c-myc and an apparent activation of c-raf-1 gene have been observed in these noncancerous skin fibroblasts. These results may provide insight into the heritable defect underlying the familial predisposition to a variety of cancers.
Asunto(s)
Fibroblastos/efectos de la radiación , Síndromes Neoplásicos Hereditarios/genética , Oncogenes/efectos de la radiación , Tolerancia a Radiación , Piel/efectos de la radiación , Animales , Transformación Celular Neoplásica/efectos de la radiación , Células Cultivadas , Humanos , Ratones , Ratones Desnudos , Linaje , Piel/citología , SíndromeRESUMEN
The dystrobrevin-binding protein 1 (DTNBP1) gene is a candidate risk factor for schizophrenia and has been associated with cognitive ability in both patient populations and healthy controls. DTNBP1 encodes dysbindin protein, which is localized to synaptic sites and is reduced in the prefrontal cortex and hippocampus of patients with schizophrenia, indicating a potential role in schizophrenia etiology. Most studies of dysbindin function have focused on the sandy (sdy) mice that lack dysbindin protein and have a wide range of abnormalities. In this study, we examined dysbindin salt and pepper (spp) mice that possess a single point mutation on the Dtnbp1 gene predicted to reduce, but not eliminate, dysbindin expression. By western blot analysis, we found that spp homozygous (spp -/-) mutants had reduced dysbindin and synaptosomal-associated protein 25 (SNAP-25) in the prefrontal cortex, but unaltered levels in hippocampus. Behaviorally, spp mutants performed comparably to controls on a wide range of tasks assessing locomotion, anxiety, spatial recognition and working memory. However, spp -/- mice had selective deficits in tasks measuring novel object recognition and social novelty recognition. Our results indicate that reduced dysbindin and SNAP-25 protein in the prefrontal cortex of spp -/- is associated with selective impairments in recognition processing. These spp mice may prove useful as a novel mouse model to study cognitive deficits linked to dysbindin alterations. Our findings also suggest that aspects of recognition memory may be specifically influenced by DTNBP1 single nucleotide polymorphisms or risk haplotypes in humans and this connection should be further investigated.
Asunto(s)
Disbindina/genética , Disbindina/fisiología , Reconocimiento en Psicología/fisiología , Animales , Conducta Animal , Trastornos del Conocimiento/genética , Modelos Animales de Enfermedad , Femenino , Haplotipos , Hipocampo/metabolismo , Hipocampo/fisiología , Homocigoto , Masculino , Memoria a Corto Plazo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación Puntual , Polimorfismo de Nucleótido Simple/genética , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiología , Esquizofrenia/genética , Proteína 25 Asociada a Sinaptosomas/genética , Proteína 25 Asociada a Sinaptosomas/metabolismoRESUMEN
Lysates derived from the fibroblasts of individuals who are homozygous for normal p53 or heterozygous for the germ-line p53 mutation characteristic of certain Li-Fraumeni cancer-prone families were assessed for p53 function utilizing the binding of p53 protein to a p53-specific consensus oligonucleotide sequence. As expected, control nuclear lysates containing only mutant p53 or no p53 displayed little or no such binding. However, the nuclear lysates from heterozygous fibroblasts containing similar amounts of normal p53 and 245D mutant p53 displayed binding that was significantly below 50% of that seen with homozygous wild-type p53 in normal cell lysates. The nuclear lysates of these heterozygous or homozygous fibroblasts exhibited similar levels of DNA binding to a consensus oligonucleotide specific for the transcription factor, AP-1. These results indicate that mutant p53 has a transdominant effect on the binding of DNA by normal p53. These findings also suggest that p53 complexes formed in vivo that contain mutant p53 are functionally impaired even if normal p53 is also present in the complex. The implications of a trans-dominant effect of mutant p53 on the cancer-prone phenotype of individuals heterozygous for mutated p53 in Li-Fraumeni families is discussed.
Asunto(s)
Genes p53 , Síndrome de Li-Fraumeni/genética , Proteína p53 Supresora de Tumor/biosíntesis , Secuencia de Bases , Línea Celular , Células Cultivadas , Familia , Femenino , Tamización de Portadores Genéticos , Homocigoto , Humanos , Masculino , Datos de Secuencia Molecular , Oligodesoxirribonucleótidos , Osteosarcoma/genética , Piel/metabolismo , Células Tumorales Cultivadas , Neoplasias del Cuello Uterino/genéticaRESUMEN
Seventy-nine esophageal carcinoma patients were studied for genetic abnormalities in the p53 and Rb tumor suppressor genes. Single-strand conformation polymorphism analysis and DNA sequencing were used to detect p53 point mutations, Northern blotting was used to examine abnormal expression of p53 and Rb, and polymerase chain reaction and Southern blotting were used to analyze allelic loss. Twenty-five cases were analyzed by DNA sequencing to detect mutations in p53. Fourteen samples contained mutations within exons 5 through 9 of p53; seven had missense mutations giving rise to single amino acid substitutions. The remaining seven (50%) contained nonsense mutations leading to premature termination, five due to single base pair substitutions, and two that were the result of frameshift mutations. In other human tumors, p53 mutations are predominantly missense mutations, but our data as well as those from other groups show that nonsense mutations are common in human esophageal cancer. All but one of the constitutionally heterozygous samples containing mutations also manifested loss of the normal p53 allele; the one exception without allelic loss contained a silent mutation, which should not have had any affect on the p53 protein product. In addition, Northern blotting analysis revealed abnormalities (altered transcript size or mRNA levels) in 5 of 7 cases involving p53 and in 2 of 7 cases analyzed for Rb. Thirty-four cases were informative for allelic loss studies of both p53 and Rb; of these, 25 (74%) lost heterozygosity of p53, Rb, or both. When point mutations and mRNA expression abnormalities were also considered, 33 of 45 (73%) tumors informative for allelic loss assays of both genes as well as for mRNA or point mutation studies showed one or more abnormalities in p53 or Rb. Our results strongly suggest that a unique profile of molecular alterations involving p53 and Rb characterizes human esophageal cancer and that these specific genetic lesions are important in the development and/or progression of most human esophageal carcinomas.
Asunto(s)
Neoplasias Esofágicas/genética , Genes de Retinoblastoma , Genes p53 , Mutación , ARN Mensajero/análisis , Adenocarcinoma/genética , Secuencia de Bases , Carcinoma de Células Escamosas/genética , Deleción Cromosómica , Humanos , Datos de Secuencia Molecular , ARN Neoplásico/análisisRESUMEN
The identification of germ-line mutations in the p53 gene has provided a situation where comparable amounts of wild-type and mutant p53 co-exist in constitutional cells of certain individuals who are cancer-prone. Here we report the biochemical characteristics of several Li-Fraumeni syndrome associated mutant p53 proteins in order to assess the influence of germ-line mutant p53 on the functions of the wild-type p53. Unlike 248W mutant p53 protein, which was previously shown to have no effect on the wild-type p53 conformation (Milner & Medcalf, 1991; Cell 65, 765-774), germ-line associated mutant p53 proteins with residue 133T, 245D or 258K, converted the wild-type p53 conformation into the mutant conformation. Furthermore, lysates containing cotranslated wild-type p53 and these mutant p53 proteins were significantly impaired for DNA and SV40 large T antigen binding. These observations suggest that at least some germ-line p53 mutants might exhibit dominant effects on wild-type p53 functions and, like other mutant p53 proteins, the phenotype of germ-line mt p53 proteins might be variable depending on the particular mutation.
Asunto(s)
Genes p53 , Síndrome de Li-Fraumeni/genética , Proteína p53 Supresora de Tumor/genética , Secuencia de Bases , Clonación Molecular , Proteínas de Unión al ADN/metabolismo , Genes Dominantes , Humanos , Datos de Secuencia Molecular , Mutación , Oligodesoxirribonucleótidos/química , Unión Proteica , Conformación Proteica , Proteína p53 Supresora de Tumor/inmunología , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Germline transmission of mutant p53 gene in cancer-prone families with Li-Fraumeni syndrome has revealed a new role for p53 in the genetic predisposition to cancer. The studies reported here focus on the analysis of the expression of normal and mutant p53 RNA and protein in germline configuration and demonstrate that normal skin fibroblasts derived from members of a family with Li-Fraumeni syndrome express mutant p53Gly----Asp(245) protein and RNA at levels similar to the wild-type p53. Thus, these fibroblasts represent a unique biological system in which endogenous promoters are utilized for the expression of both mutant and normal p53. We have further extended the earlier observations on the analysis of mutant p53 with a limited number of tumors derived from individuals with Li-Fraumeni syndrome. Tumors arising from two different germ layers in four individuals in a single family clearly exhibited the loss of the wild-type allele and the retention of the mutant allele observed in the normal skin fibroblasts derived from the same individuals. These observations further support the notion that germline p53 mutation plays a key role in the tumorigenesis of individuals with Li-Fraumeni syndrome.
Asunto(s)
Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/metabolismo , Mutación , Proteína p53 Supresora de Tumor/biosíntesis , Proteína p53 Supresora de Tumor/genética , Alelos , Secuencia de Bases , Northern Blotting , Electroforesis en Gel Bidimensional , Fibroblastos/metabolismo , Expresión Génica , Humanos , Datos de Secuencia Molecular , Oligonucleótidos Antisentido/genética , Reacción en Cadena de la Polimerasa , ARN/análisisRESUMEN
Radiation resistant squamous cell carcinoma of the head and neck cell line JSQ-3 carries a mutant form of tumor suppressor gene p53. Treatment of these cells with an adenoviral vector containing wild-type p53 (Av1p53) was able to inhibit their growth in vitro and in vivo while having no effect on normal cells. More significantly, introduction of wtp53 also reduced the radiation-resistance level of this cell line in vitro, in a viral dose-dependent manner. Furthermore, this radiosensitization also carried over to the in vivo situation where the response of JSQ-3 cell-induced mouse xenografts to radiotherapy was markedly enhanced after treatment with Av1p53. Complete, long-term regression of the tumors for up to 162 days was observed when a single dose of Av1p53 was administered in combination with ionizing radiation, demonstrating the effectiveness of this combination of gene therapy and conventional radiotherapy. This sensitization of tumors to radiation therapy by replacement of wtp53 could significantly decrease the rate of recurrence after radiation treatment. Since radiation is one of the most prevalent forms of adjunctive therapy for a variety of cancers, these results have great relevance in moving toward an improved cancer therapy.
Asunto(s)
Carcinoma de Células Escamosas/radioterapia , Genes p53 , Terapia Genética/métodos , Neoplasias de Cabeza y Cuello/radioterapia , Adenoviridae/genética , Animales , Supervivencia Celular/efectos de la radiación , Terapia Combinada , Femenino , Vectores Genéticos , Humanos , Ratones , Ratones Desnudos , Células Tumorales CultivadasRESUMEN
Wild-type (wt) p53 DNA was transfected into the radioresistant human cell line JSQ-3, established from a squamous cell carcinoma of the head and neck (SCCHN), using a transferrin-liposome system, and the ability of the introduced wt p53 to sensitize the transfected JSQ-3 cells to ionizing radiation was examined. Transferrin increased the in vitro transfection efficiency of cationic liposomes up to 70-80% in JSQ-3 cells, representing a 6- to 10-fold increase over liposome transfection alone. The exogenous wt p53 was expressed at high levels in transferrin-liposome-DNA-transfected cells and resulted in the reversion of the radioresistant phenotype of the JSQ-3 cells in a DNA dose-dependent manner. The D10 values were reduced from 6.36 +/- 0.54 Gy to 4.13 +/- 0.06 Gy, a value in the radiosensitive range. In vivo, the intratumoral injection of the transferrin-liposome system resulted in a higher number of transfected tumor cells in the JSQ-3 induced nude mouse xenografts when compared with transfection by liposome alone. The results indicate that the combination of p53 replacement gene transduction, mediated by the relatively safe transferrin-liposome system, and conventional ionizing radiation may provide a more effective treatment for head and neck cancer.
Asunto(s)
Carcinoma de Células Escamosas/radioterapia , Genes p53/genética , Neoplasias de Cabeza y Cuello/radioterapia , Tolerancia a Radiación , Transfección/métodos , Animales , Western Blotting , Carcinoma de Células Escamosas/genética , Portadores de Fármacos , Genes p53/fisiología , Neoplasias de Cabeza y Cuello/genética , Humanos , Técnicas In Vitro , Liposomas , Ratones , Ratones Desnudos , Transfección/genética , Transferrina/administración & dosificación , Trasplante Heterólogo , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The use of cationic liposomes as nonviral vehicles for the delivery of therapeutic molecules is becoming increasingly prevalent in the field of gene therapy. We have previously demonstrated that the use of the transferrin ligand (Tf) to target a cationic liposome delivery system resulted in a significant increase in the transfection efficiency of the complex [Xu, L., Pirollo, K.F., and Chang, E.H. (1997). Hum. Gene Ther. 8, 467-475]. Delivery of wild-type (wt) p53 to a radiation-resistant squamous cell carcinoma of the head and neck (SCCHN) cell line via this ligand-targeted, liposome complex was also able to revert the radiation resistant phenotype of these cells in vitro. Here we optimized the Tf/liposome/DNA ratio of the complex (LipT) for maximum tumor cell targeting, even in the presence of serum. The efficient reestablishment of wtp53 function in these SCCHN tumor cells in vitro, via the LipT complex, restored the apoptotic pathway, resulting in a significant increase in radiation-induced apoptosis that was directly proportional to the level of exogenous wtp53 in the tumor cells. More significantly, intravenous administration of LipT-p53 markedly sensitized established SCCHN nude mouse xenograft tumors to radiotherapy. The combination of systemic LipT-p53 gene therapy and radiation resulted in complete tumor regression and inhibition of their recurrence even 6 months after the end of all treatment. These results indicate that this tumor-specific, ligand-liposome delivery system for p53 gene therapy, when used in concert with conventional radiotherapy, can provide a new and more effective means of cancer treatment.
Asunto(s)
Carcinoma de Células Escamosas/terapia , Genes p53 , Terapia Genética , Neoplasias de Cabeza y Cuello/terapia , Transferrina/administración & dosificación , Animales , Apoptosis , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/radioterapia , Terapia Combinada , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Liposomas , Ratones , Trasplante de NeoplasiasRESUMEN
Poor response to chemotherapy in patients with breast cancer is often associated with overexpression of HER-2/neu. Interference with HER-2 mRNA translation by means of antisense oligonucleotides might improve the efficacy of chemotherapy. To test this hypothesis, eight breast cancer cell lines and a normal human fibroblast cell line were examined for their level of HER-2 expression, their sensitivity to phosphorothioate antisense oligonucleotides (AS HER-2 ODN), and to various chemotherapeutic agents, and the combination of the two. No correlation was found between the intrinsic HER-2 level and either the sensitivity to a particular chemotherapeutic agent alone, or the amount of growth inhibition observed with a specific AS HER-2 ODN concentration. Although sequence specificity and extent of AS HER-2 ODN inhibition of HER-2 synthesis were somewhat higher in the HER-2 overexpressing MDA-MB-453 and SK-BR-3 cells, we found that antisense treatment significantly sensitized all of the breast cancer cells, even MDA-MB-231 and MDA-MB-435 cells, with approximately basal levels of HER-2, to various chemotherapeutic agents. In addition, the combination of AS HER-2 ODN and taxol was shown to synergistically induce apoptosis in MDA-MB-435. These results demonstrate that overexpression of HER-2 would not be a prerequisite for the effective use of AS HER-2 ODN as a combination treatment modality for breast cancer and suggest that the use of AS HER-2 ODN, as part of a combination treatment modality, need not be limited to breast tumors that display elevated levels of HER-2.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Oligonucleótidos Antisentido/farmacología , Receptor ErbB-2/genética , Células Tumorales Cultivadas/efectos de los fármacos , Apoptosis , Western Blotting , Neoplasias de la Mama/metabolismo , División Celular/efectos de los fármacos , Quimioterapia Combinada , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Citometría de Flujo , Humanos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptor ErbB-2/metabolismo , Células Tumorales Cultivadas/metabolismoRESUMEN
Angiogenesis is a requirement for solid tumor growth. Therefore, inhibition of this neovascularization is one mechanism by which restoration of wtp53 function may lead to tumor regression. Here we report that adenoviral vector-mediated wild-type p53 transduction results in growth inhibition of squamous cell carcinoma of the head and neck tumor cells both in vitro and in a xenograft mouse model. This growth inhibition is associated with the down-regulation of the expression of fibroblast growth factor binding protein, a secreted protein required for the activation of angiogenic factor basic FGF. These findings suggest that wtp53-induced tumor regression is due, at least in part, to antiangiogenesis mediated by the downmodulation of fibroblast growth factor binding protein.
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Proteínas Portadoras/metabolismo , Regulación hacia Abajo/fisiología , Neoplasias de Cabeza y Cuello/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Adenoviridae , Animales , Northern Blotting , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Proteínas Portadoras/genética , División Celular/genética , Colágeno/química , Cartilla de ADN/química , Combinación de Medicamentos , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Humanos , Péptidos y Proteínas de Señalización Intercelular , Péptidos y Proteínas de Señalización Intracelular , Laminina/química , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neovascularización Patológica/patología , Proteoglicanos/química , ARN/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Abnormality in the tumor suppressor gene p53 is one of the most common occurrences associated with human neoplasia. Consequently, restoration of wild-type p53 function is seen as a particularly promising approach for cancer gene therapy. In recent years, considerable research effort has centered upon developing and improving non-viral delivery systems as alternatives to viral vectors for gene delivery. These methods include the use of lipoplexes and polyplexes, and even delivery of naked DNA. Optimally effective cancer gene therapy requires treatment of metastatic as well as local disease, and to achieve this end, systemic delivery systems for therapeutic genes will be required. This review will discuss some of the recent advances in ways to improve targeting, transfection efficiency and stability for systemic, non-viral p53 gene therapy.
Asunto(s)
Genes p53 , Terapia Genética/métodos , Animales , Biolística , ADN/administración & dosificación , ADN/genética , Sistemas de Liberación de Medicamentos , Vectores Genéticos , Humanos , Liposomas/administración & dosificación , Neoplasias/genética , Neoplasias/terapia , Polímeros/administración & dosificaciónRESUMEN
Oncogenes and their normal counterparts, proto-oncogenes, are functionally important cellular genes which interact with one another as components of signal transduction pathways leading to cell growth and differentiation. Numerous reports in the literature have also begun to link these genes to the phenomenon of cellular radiation resistance. In this report we examine the radiation resistance level of NIH 3T3 cells transformed by various oncogenes in an attempt to define the intracellular pathway to the radiation-resistant phenotype. The results demonstrate that an analogous signaling pathway is apparently involved in acquisition of radiation resistance. Serine/threonine protein kinase oncogenes such as raf, mos, and PKC play a central role in the pathway. Moreover, specific oncogenes upstream (sis, HER-2, met, trk, and ras) and downstream (ets and myc) of these important signaling mediators can also influence the radiation resistance level of the cells.
Asunto(s)
Oncogenes , Tolerancia a Radiación/genética , Transducción de Señal , Células 3T3 , Animales , Línea Celular Transformada , Supervivencia Celular/efectos de la radiación , Ratones , Proteínas Nucleares/metabolismo , Fenotipo , Factor de Crecimiento Derivado de Plaquetas/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismoRESUMEN
Noncancerous skin fibroblasts from six family members with Li-Fraumeni syndrome, five with cancer of diverse tissue origin and one with a premalignant neoplasm, showed a high frequency of chromatid aberrations, 94 to 119 breaks and 58 to 95 gaps per 100 metaphase cells arrested with colcemid 0.5 to 1.5 h after X irradiation (1.75 x 10(-2) C/kg). This response results from deficient repair of the radiation-induced DNA damage. In contrast, skin fibroblasts from two unrelated normal controls and a spouse showed 19 breaks and 17 to 19 gaps per 100 cells. Whereas all six members of the cancer-prone family had a radioresistant phenotype, only four had an inherited p53 mutation. Fibroblasts from a radioresistant family member showed the same extent of chromatid damage directly (0 to 0.5 h) after G2-phase X irradiation as those from the radiosensitive control spouse. We conclude, therefore, that radiosensitivity, as determined by cell killing in asynchronous populations of skin fibroblasts, is unrelated to chromosomal sensitivity to G2-phase X irradiation. However, the persistence of a high frequency of chromatid breaks and gaps at 0.5 to 1.5 h after G2-phase X irradiation, a manifestation of deficient DNA repair, is associated with proneness to cancer in this family.
Asunto(s)
Aberraciones Cromosómicas , Reparación del ADN , Fase G2/efectos de la radiación , Síndrome de Li-Fraumeni/genética , Tolerancia a Radiación , Células Cultivadas , Daño del ADN , Femenino , Fibroblastos/efectos de la radiación , Humanos , MasculinoRESUMEN
A long-standing goal in gene therapy for cancer is a stable, low toxic, systemic gene delivery system that selectively targets tumor cells, including metastatic disease. Progress has been made toward developing non-viral, pharmaceutical formulations of genes for in vivo human therapy, particularly cationic liposome-mediated gene transfer systems. Ligand-directed tumor targeting of cationic liposome-DNA complexes (lipoplexes) is showing promise for targeted gene delivery and systemic gene therapy. Lipoplexes directed by ligands such as folate, transferrin or anti-transferrin receptor scFv, showed tumor-targeted gene delivery and expression in human breast, prostate, head and neck cancers. The two elements, ligand/receptor and liposome composition, work together to realize the goal of functional tumor targeting of gene therapeutics. The tumor suppressor gene, p53, has been shown to be involved in the control of DNA damage-induced apoptosis. Loss or malfunction of this p53-mediated apoptotic pathway has been proposed as one mechanism by which tumors become resistant to chemotherapy or radiation. The systemically delivered ligand-liposome-p53 gene therapeutics resulted in efficient expression of functional wild-type p53, sensitizing the tumors to chemotherapy and radiotherapy. This is a novel strategy combining current molecular medicine with conventional chemotherapy and radiotherapy for the treatment of cancer. The systemic delivery of normal tumor suppressor gene p53 by a non-viral, tumor-targeted delivery system as a new therapeutic intervention has the potential to critically impact the clinical management of cancer.
Asunto(s)
Antineoplásicos/administración & dosificación , Marcación de Gen , Genes p53/inmunología , Terapia Genética/métodos , Radiofármacos/administración & dosificación , Animales , Humanos , LiposomasRESUMEN
PURPOSE: To assess medical student attitudes toward, and comfort with, taking turns practicing peer physical examinations (PPEs) on fellow classmates. METHOD: A questionnaire with 25 Likert-scaled questions was administered to 164 end-first-year medical students at the University of Minnesota, Minneapolis. Topics assessed included: (1) comfort with various aspects of PPEs; (2) attitudes regarding the professionalism, appropriateness, and perceived value of PPEs; (3) attitudes toward peer breast, genital, and rectal exams; and (4) the effects of age and gender on response. RESULTS: Of the 164 students surveyed, 124 (76%) responded. Almost all (98%) agreed that PPEs are appropriate, valuable, and a comfortable experience. Fewer students were comfortable with performing inguinal examinations and conducting PPEs with students of the opposite gender. Twelve percent of the students expressed difficulty in setting limits with peers, and 48% felt exposed when undressed as an examination model in front of a group of peers. The majority of students were opposed to peer breast, genital, and rectal examinations. Some statistically significant gender differences and age/gender interactions were observed. CONCLUSION: Results suggest that this sample of medical students was very comfortable with PPEs and willing to participate in PPEs, although a few students were uncomfortable with these examinations. No extensive curricular change appears warranted, though steps can be taken to maximize overall student comfort and to accommodate the few students who do not favor PPEs.
Asunto(s)
Actitud , Educación Médica/métodos , Grupo Paritario , Examen Físico , Estudiantes de Medicina/psicología , Adulto , Femenino , Humanos , Masculino , Encuestas y CuestionariosRESUMEN
We examined a human Alu+ mouse tertiary transformant derived from a noncancerous skin fibroblast cell line which exhibits the unique characteristic of being resistant to the killing effects of ionizing radiation. This transformed cell line was found to contain activated human c-raf-1, and demonstrated an increased level of radioresistance indicating the simultaneous transfer of both the transforming and radiation-resistant phenotypes. We have also found a relationship between the presence of activated oncogenes, specifically those with serine/threonine kinase activity and the radioresistant phenotype.