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BACKGROUND: In developed countries, hepatitis E is a porcine zoonosis caused by hepatitis E virus (HEV) genotype 3. In developing countries, hepatitis E is mainly caused by genotype 1, and causes increased mortality in patients with pre-existing chronic liver disease (CLD). AIM: To determine the role of HEV in patients with decompensated CLD. METHODS: Prospective HEV testing of 343 patients with decompensated CLD at three UK centres and Toulouse France, with follow-up for 6 months or death. IgG seroprevalence was compared with 911 controls. RESULTS: 11/343 patients (3.2%) had acute hepatitis E infection, and three died. There were no differences in mortality (27% vs. 26%, OR 1.1, 95% CI 0.28-4.1), age (P = 0.9), bilirubin (P = 0.5), alanine aminotransferase (P = 0.06) albumin (P = 0.5) or international normalised ratio (P = 0.6) in patients with and without hepatitis E infection. Five cases were polymerase chain reaction (PCR) positive (genotype 3). Hepatitis E was more common in Toulouse (7.9%) compared to the UK cohort (1.2%, P = 0.003). HEV IgG seroprevalence was higher in Toulouse (OR 17, 95% CI 9.2-30) and Truro (OR 2.5, 95% CI 1.4-4.6) than in Glasgow, but lower in cases, compared to controls (OR 0.59, 95% CI 0.41-0.86). CONCLUSIONS: Hepatitis E occurs in a minority of patients with decompensated chronic liver disease. The mortality is no different to the mortality in patients without hepatitis E infection. The diagnosis can only be established by a combination of serology and PCR, the yield and utility of which vary by geographical location.
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Doença Hepática Terminal/virologia , Imunoglobulina G/sangue , Adulto , Alanina Transaminase/sangue , Bilirrubina/sangue , Doença Hepática Terminal/epidemiologia , Feminino , França/epidemiologia , Genótipo , Hepatite E/diagnóstico , Vírus da Hepatite E/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Soroepidemiológicos , Reino Unido/epidemiologiaRESUMO
BACKGROUND AND OBJECTIVES: Irradiation of red cell concentrates RCCs) can lead to well-documented elevated extracellular potassium concentrations. Transfusion of these products has the potential, if given as a massive/rapid transfusion, to lead to transient hyperkalemia. A potassium absorption filter (PAF) has recently been developed and has been proven to effectively remove excess K(+) . However, data are lacking on the red cell quality parameters over storage after irradiation. METHODS: Thirty RCCs were pooled and split into 3 groups of 10. All RCCs were irradiated on day 14 and filtered on day 28 (group 1 control), day 15 (group 2) or day 17 (group 3). Pre-irradiation, pre- and post-filtration and day 28 samples were taken for each study. Standard red cell quality parameters were measured over storage at the above time points. RESULTS: Losses for haemoglobin, haematocrit and volume were minimal after filtration with all units containing >40 g Hgb unit(-1). Statistically, significant differences were observed for K(+) and Na(+) levels in groups filtered at either 24 or 72 h post-irradiation, and this was observed directly after filtration and remained by day 28. Filtration had no significant impact on any other parameters measured. CONCLUSIONS: PAF effectively removed supernatant potassium (93%) from all RCC units. Early removal of K(+) at either day 15 or 17 on RCCs subsequently stored to day 28 had no measurable effect on red cell quality, suggesting this may be a useful device to ensure further safety for at-risk immunocompromised patient groups requiring irradiated RCCs.
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Preservação de Sangue , Eritrócitos , Filtração/métodos , Raios gama , Potássio , Eritrócitos/química , Eritrócitos/citologia , Eritrócitos/metabolismo , Feminino , Humanos , Masculino , Potássio/química , Potássio/metabolismo , Sódio/química , Sódio/metabolismoRESUMO
INTRODUCTION: Up to 10% of pregnant women take antidepressants, of which selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed. Using a rodent model, we investigated the reproductive impacts of perinatal SSRI treatment on reproductive cyclicity and function in female offspring. METHODS: Virgin Wistar rats were given oral vehicle (n = 10) or fluoxetine hydrochloride (FLX, 10 mg/kg/d; n = 11) from 2 weeks prior to mating until weaning. Pubertal onset and reproductive cyclicity in offspring were assessed. Blood and ovarian tissues were collected for measures of reproductive function. RESULTS: Perinatal FLX tends to induce irregular reproductive cycles in adult offspring, which most commonly manifest as a prolonged estrus phase (FLX 34% vs control [CON] 10%) relative to CON offspring. The FLX offspring tended to have longer cycles (P = .052), had more secondary follicles (P = .0067), more total follicles (P = .0310), and increased apoptotic ovarian cells (P < .001). Prenatally exposed FLX offspring demonstrated elevated ovarian messenger RNA (mRNA) levels of ERß (P = .008), Cry1 (P = .043), and tryptophan hydroxylase 2 (P = .024), independent of stage of cycle. Ovarian mRNA levels of brain and muscle Arnt-like protein 1 (P = .046) and Pet-1 (P = .021) were increased in FLX offspring a manner that was reproductive cycle stage dependent. CONCLUSIONS: This is the first study to investigate the postnatal effects of maternal perinatal exposure to FLX on adult offspring reproduction. We show that genes that regulate serotonin signaling and action in the ovary are altered in prenatally FLX-exposed offspring, which when coupled with increased expression of components of the core Circadian Locomotor Output Cycles Kaput (CLOCK) gene regulatory loop may suggest an interaction between serotonergic signaling and clock gene signaling pathways leading to the altered reproductive phenotype.
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Fluoxetina/toxicidade , Folículo Ovariano/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Reprodução/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/toxicidade , Fatores Etários , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Estro/efeitos dos fármacos , Feminino , Fluoxetina/administração & dosagem , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Exposição Materna , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Fenótipo , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , DesmameRESUMO
BACKGROUND AND OBJECTIVES: Recently, a glucose- and bicarbonate-containing additive solution termed PAS 5 demonstrated acceptable 7-day platelet storage after >95% plasma replacement with PAS on the day of collection (Day 0). In this study, we examined platelet storage in >95% PAS 5 after manual washing of Day 1 apheresis platelets in plasma collected using either the Amicus or Trima plateletpheresis devices. MATERIAL AND METHODS: Triple platelet donations in plasma were obtained from Amicus (n = 10) and Trima (n = 10) plateletpheresis devices and stored overnight before being centrifuged and manually processed into three units with the following storage media: 100% plasma, >95% PAS 5 or 65% PAS 5/35% plasma. Platelet units were sampled on Days 1, 5 and 7 of storage using a range of tests recommended by the UK guidelines. RESULTS: The majority of in vitro assay results for platelets in PAS 5 were similar to results in paired 100% plasma platelets (controls). The pH of PAS 5 stored platelet units was above the UK recommended guidelines of 7·4 by Day 5. PAS 5 platelets were no more activated than controls as evidenced by comparable soluble P-selectin levels and CD62p and CD42b expression. PAS 5 platelets also exhibited adhesion and aggregation profiles higher than (Day 1) or comparable to (Days 5 and 7) controls as measured by Impact R. CONCLUSION: The 7-day in vitro storage parameters investigated were comparable between >95% PAS 5 and 100% plasma platelets derived from both Amicus and Trima plateletpheresis devices, with the exception that lactose dehydrogenase release rate and pH were significantly higher in PAS 5 units.
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Plaquetas , Preservação de Sangue , Plaquetoferese , Doadores de Sangue , Humanos , Soluções , Reino UnidoRESUMO
BACKGROUND AND OBJECTIVES: Published prevalence figures for hepatitis E virus (HEV) reveal significant regional differences. Several studies have reported virus transmission via blood transfusion. The aim of this study was to establish HEV seroprevalence and investigate a potential HEV RNA presence in Scottish blood donors. MATERIALS AND METHODS: IgG and IgM were determined in individual serum samples. HEV RNA was investigated in plasma mini-pools corresponding to 43 560 individual donations using nested PCR. Samples amenable to reamplification with primers from a different region were considered confirmed positives, sequenced and analysed. RESULTS: A total of 73 of 1559 tested individual sera (4·7%) were IgG positive, none tested positive for IgM. Plasma mini-pool testing revealed an HEV RNA frequency of 1 in 14 520 donations. Three confirmed positives belonged, as expected to genotype 3. CONCLUSIONS: HEV IgG and RNA figures in Scottish blood donors are lower than those published for the rest of the UK, but sufficiently high to prompt further studies on potential transmission rates and effects of HEV infection, especially for immunosuppressed individuals.
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Doadores de Sangue , Vírus da Hepatite E/isolamento & purificação , Adolescente , Adulto , Feminino , Anticorpos Anti-Hepatite/sangue , Vírus da Hepatite E/genética , Vírus da Hepatite E/imunologia , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Escócia , Estudos Soroepidemiológicos , Adulto JovemRESUMO
In this review we discuss existing as well as new approaches to immunotherapy directed against infected or cancerous cells. These approaches traditionally exploit either natural components of immune system (such as cytokines, chemokines, co-stimulatory molecules and adjuvants), or monoclonal antibodies designed to target foreign agents and/or diseased cells through their molecular markers. Additional strategies in development include therapeutic vaccines, oncolytic viruses and T-cell therapies. In addition, we briefly describe a novel strategy called ReDIT (Re-Directed ImmunoTherapy), based on re-orienting the existing long-lasting immune responses (e.g. induced by measles vaccination or natural infection) towards new target molecules on the surface of infected or malignant cells. This can be principally achieved by using bi-functional protein constructs that contain an antigen carrier component and a re-directing component. The antigen carrier component can consist of the ectodomain of the measles hemagglutinin that can be recognized by antibodies and memory cells generated during previous infection or vaccination. The re-directing component consists of the specific virus- or tumor antigen-binding molecule. The fusion constructs are expected to boost existing anti-measles immunity and re-direct it against a new target, engaging the existing anti-measles immunity as an effector mechanism. Thus, ReDIT is a promising novel approach that may represent a valuable addition to immunotherapy of difficult to treat infections and tumors, as it exploits a mechanism distinct from other available therapies.
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Imunoterapia/métodos , Neoplasias/terapia , Viroses/terapia , Animais , Antígenos de Neoplasias/imunologia , Antígenos Virais/imunologia , Antivirais/imunologia , Antivirais/uso terapêutico , Humanos , Neoplasias/imunologia , Viroses/imunologiaRESUMO
The present study compared developmental potential, telomerase activity and transcript levels of X-linked genes (HPRT, MECP2, RPS4X, SLC25A6, XIAP, XIST and ZFX) in bovine somatic cell nuclear transfer (SCNT) embryos reconstructed with cells derived from a freemartin (female with a male co-twin) or from normal female cattle (control). The rates of cleavage, development to blastocyst and hatched blastocyst stage, and the mean numbers of total and inner cell mass cells in the freemartin SCNT embryos were not significantly different from those of control SCNT embryos (p > 0.05). The levels of telomerase activity analyzed by RQ-TRAP in the freemartin SCNT embryos were also similar to those of the normal SCNT embryos. Transcript levels of HPRT, MECP2, RPS4X and XIAP, measured by quantitative real-time RT-PCR, were not significantly different between the control and freemartin SCNT embryos (p > 0.05). However, the transcript levels of SLC25A6, XIST and ZFX were significantly decreased in the freemartin SCNT embryos compared to control SCNT embryos (p < 0.05). Transfer of 71 freemartin SCNT embryos to 22 recipient cows resulted in 4 (18%) pregnancies, which were lost between days 28 and 90 of gestation. Taken together, the present study demonstrates that the transcript levels of several X-linked genes, especially XIST, showed an aberrant pattern in the freemartin SCNT embryos, suggesting aberrant X inactivation in freemartin clones which may affect embryo survival.
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Embrião de Mamíferos/metabolismo , Freemartinismo/genética , Genes Ligados ao Cromossomo X/genética , Técnicas de Transferência Nuclear/veterinária , Inativação do Cromossomo X/genética , Cromossomo X/genética , Animais , Bovinos , Clonagem de Organismos , Transferência Embrionária/veterinária , Desenvolvimento Embrionário , Feminino , Morte Fetal/genética , Morte Fetal/veterinária , Masculino , Gravidez , RNA Longo não Codificante , RNA Mensageiro/análise , RNA não Traduzido/genética , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Telomerase/metabolismoRESUMO
INTRODUCTION: Sentinel lymph node biopsy improves staging of disease, saves the axilla, and significantly reduces the risk of complications. MATERIAL AND METHODS: The authors compare the two groups of surgical treatment of breast cancer patients--after conventional surgery with axillary exenteration with a group of patients with sentinel node biopsy using gamma probe with limited power. RESULTS: In group of 42 patients after axillary exenteration authors observed: hematoma in 2 patients, 1 postoperative bleeding that need for surgical revision, 2 patients had paresthesia and 1 patient had lymphedema, which represents 11.5% of complications. In the group of 54 patients after limited exercise with the use of sentinel biopsy and gamma probe authors reported only one complication--an infected surgical wound seroma in the axilla (1.8% complications). CONCLUSION: Examination of sentinel node biopsy in combination with exact measurement of gamma probe allows friendly operating performance in the axilla and significantly reduces the incidence of postoperative complications.
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Neoplasias da Mama/cirurgia , Biópsia de Linfonodo Sentinela , Adulto , Idoso , Idoso de 80 Anos ou mais , Axila , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Biópsia de Linfonodo Sentinela/efeitos adversosRESUMO
AIM: The authors point to the risk of hypocoagulation by patients with colorectal carcinoma, who use warfarin. MATERIAL AND METHODS: 185 patients with colorectal cancer were examined for plattellets, prothrombin time and D-dimer. RESULTS: Only 64 patients (35%) had haemocoagulation in the standard, 114 patients (61%) were hypercoagulable and only 7 patients (3.7%) were hypocoagulable. The authors present an interesting case report of a patient who used warfarin. This patient has ileos state by sigmoideal cancer, and in parallel a progressive intramural haematoma in the hepatic flexure of the colon. CONCLUSION: Hypocoagulation state with an intramural haematoma of colon may be very dangerous complication for patients with colorectal cancer and ileos state. Very careful choice of surgical strategy is necessary.
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Transtornos da Coagulação Sanguínea/complicações , Neoplasias do Colo Sigmoide/complicações , Idoso , Transtornos da Coagulação Sanguínea/induzido quimicamente , Doenças do Colo/complicações , Hematoma/complicações , Humanos , Masculino , Varfarina/efeitos adversosRESUMO
Several miniaturized high throughput technologies have been developed in the last decade, primarily to study genomic structures and gene expression patterns under various conditions. At the same time, the microarrays, biosensors, integrated microfluidic lab-on-a-chip devices, next generation sequencing or digital PCR are gradually finding their diagnostic applications, although their suitability for specialised diagnostic fields has still to be assessed. In this review we discuss the potential applications of the new technologies to blood testing.
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Transfusão de Sangue/instrumentação , Miniaturização/instrumentação , Técnicas Biossensoriais/instrumentação , Humanos , Técnicas Analíticas Microfluídicas/instrumentação , TecnologiaRESUMO
OBJECTIVES: To establish prevalence and phylogenetic relationship of SEN virus (SENV) D and H in blood donors from Scotland, Czech Republic and Ghana. AIM: To compare the data between three regions with differing prevalence of blood-borne viruses. BACKGROUND: Anelloviruses are a ubiquitous group of viruses without a clear disease association. Although there is little evidence that they are pathogenic per se, they may have the ability to modify ongoing disease processes. They have a high degree of heterogeneity both within populations and across geographic regions. MATERIALS AND METHODS: Three sets of donor samples were analysed by nested polymerase chain reaction (PCR) and hybridisation. A proportion of amplified samples were sequenced and phylogenetic analysis was carried out. RESULTS: The prevalence figures (including mixed D + H infection) were established for SENV D: 1·0, 8·4 and 25·2% and H: 12·5, 34·8 and 61·0% in Scottish, Czech and Ghanaian blood donors, respectively. The compilation of prevalence figures indicates the changing ratio of SENV D/H in west-east direction, most obvious between Western Europe (D/H < 1) and far East Asia (D/H > 1). Phylogenetic analysis grouped the samples mostly in accordance with geographic origin, despite the variability of short sequence analysed. The previously indicated link between SENV prevalence and age was statistically significant in this study, only for SENV H in Czech samples. CONCLUSION: SENV D and H appear to reflect the incidence of other blood-borne viruses in these locations. SENV H prevalence of 45·4% in Ghana represents the highest single-SENV-genotype prevalence described in blood donors to date.
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Doadores de Sangue , Heterogeneidade Genética , Torque teno virus/genética , África , Fatores Etários , Patógenos Transmitidos pelo Sangue , Europa (Continente) , Genótipo , Geografia , Humanos , Filogenia , PrevalênciaRESUMO
Serological screening assays have greatly reduced, but not eliminated, the risk of transmission of viral infections by transfusion of blood and blood products. In addition, the 1999 regulation of the European Agency for the Evaluation of Medicinal Products requiring all plasma for fractionation to have tested negative for hepatitis C virus (HCV) RNA (CPMP/BWP/390/97, 1998) led many blood transfusion services to introduce nucleic acid amplification technology (NAT) to screen blood donations for HCV, and in some services for human immunodeficiency virus (HIV) and hepatitis B virus (HBV). BioMérieux's second-generation system, the NucliSENS easyMAG, was evaluated as a suitable platform for the automated extraction of nucleic acids for use with the existing SNBTS NAT assays. Two nucleic acid extraction protocols were examined, either lysis on the easyMAG (on board) or a 30-min pre-incubation of the sample with lysis buffer at 37 °C (off board). Off board lysis was found to extract nucleic acid more efficiently for both HCV and HIV NAT assays although the improvement was more marked with HIV. The 95% limit of detections (LODs) were 10.11 IU/ml (on board) and 7.21 IU/ml (off board) for HCV and 55.11 IU/ml (on board) and 34.13 (off board) for HIV. Using the more sensitive off board lysis, nucleic acid extraction specificity, robustness and reliability of the easyMAG were examined and over 10,000 Scottish blood donations (in 107 pools of 95 donations) were tested for HCV and HIV in parallel with the existing assay. The results indicate that the easyMAG is a suitable and flexible nucleic acid extraction system, providing high quality nucleic acids and a rapid response alternative to commercial, fully automated, approved blood screening platforms.
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Automação/métodos , Sangue/virologia , HIV-1/isolamento & purificação , Hepacivirus/isolamento & purificação , Ácidos Nucleicos/isolamento & purificação , Manejo de Espécimes/métodos , Virologia/métodos , Doadores de Sangue , Infecções por HIV/diagnóstico , Infecções por HIV/virologia , HIV-1/genética , Hepacivirus/genética , Hepatite C/diagnóstico , Hepatite C/virologia , Humanos , Escócia , Sensibilidade e EspecificidadeRESUMO
Tumor development is a complex process that relies on interaction and communication between a number of cellular compartments. Much of the mass of a solid tumor is comprised of the stroma which is richly invested with extracellular matrix. Within this matrix are a host of matricellular proteins that regulate the expression and function of a myriad of proteins that regulate tumorigenic processes. One of the processes that is vital to tumor growth and progression is angiogenesis, or the formation of new blood vessels from preexisting vasculature. Within the extracellular matrix are structural proteins, a host of proteases, and resident pro- and antiangiogenic factors that control tumor angiogenesis in a tightly regulated fashion. This paper discusses the role that the extracellular matrix and ECM proteins play in the regulation of tumor angiogenesis.
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Despite our incomplete understanding of the function of the type I insulin-like growth factor receptor (IGF-IR) in tumorigenesis, IGF-IR targeting agents have entered clinical trials for the treatment of human cancers. Previously, we have shown that downregulation of IGF-IR transgene in mammary tumors in MTB-IGFIR transengic mice results in tumor regression in a majority of the mice and most of these mice do not develop recurrent mammary tumors. In this study, we examined mammary tissue of mice that did not develop recurrent tumors. Areas of tumor regression were visible macroscopically and microscopically these lesions contained cell debris, individual cells, lipofuscin and doxycycline crystals. Three of the 12 mice also presented with considerable lobuloalveolar development. The re-expression of the IGF-IR transgene in mammary tissue with stably regressed tumors resulted in the rapid re-emergence of mammary tumors, some of which seemed to originate from the regressed mammary lesions. Thus, despite stable tumor regression after IGF-IR downregulation, mammary tissue contained preneoplastic lesions and tumors rapidly re-appear upon re-overexpression of IGF-IR transgene. Therefore, IGF-IR-targeting agents may be effective at regressing mammary tumors expressing IGF-IR, but these agents will not completely eradicate all tumor cells or restore the mammary stromal environment.
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Neoplasias Mamárias Experimentais/genética , Lesões Pré-Cancerosas/genética , Receptor IGF Tipo 1/genética , Transgenes , Animais , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Transgênicos , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Receptor IGF Tipo 1/metabolismoRESUMO
Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer and also one of the most poorly understood. Other health issues that are affecting women with increasing frequency are obesity and diabetes, which are associated with dysglycemia and increased blood glucose. The Warburg Effect describes the ability of fast-growing cancer cells to preferentially metabolize glucose via anaerobic glycolysis rather than oxidative phosphorylation. Recent epidemiological studies have suggested a role for hyperglycemia in the pathogenesis of a number of cancers. If hyperglycemia contributes to tumour growth and progression, then it is intuitive that antihyperglycemic drugs may also have an important antitumour role. Preliminary reports suggest that these drugs not only reduce available plasma glucose, but also have direct effects on cancer cell viability through modification of molecular energy-sensing pathways. This review investigates the effect that hyperglycemia may have on EOC and the potential of antihyperglycemic drugs as therapeutic adjuncts.
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We have previously shown that in utero nicotine exposure causes impaired fertility, follicle immaturity, and ovarian dysfunction in adult female rat offspring. These characteristics overtly resemble the clinical profile of polycystic ovarian syndrome (PCOS) and recent studies have shown that thiazolidinediones such as rosiglitazone improve fertility in women with PCOS but the mechanism is not well defined. Our goal was to examine whether rosiglitazone would (1) ameliorate the altered ovarian physiology that occurs following fetal and neonatal exposure to nicotine and (2) to examine whether this could be due to normalization of ovarian vascularization. At weaning, offspring of nicotine-exposed dams were given either vehicle (NV) or rosiglitazone (3 mg kg(-1) day(-1); NR). Offspring of saline-exposed dams received vehicle (SV). Tissues were collected when the female offspring reached 26 weeks of age. NV animals had reduced granulosa cell proliferation and increased ovarian cell apoptosis. Treatment with rosiglitazone increased proliferation, and decreased apoptosis, compared NV animals. NV animals had decreased ovarian vascularity relative to controls, whereas NR animals had an intermediate level of ovarian vessel density. Moreover, ovaries from NV animals had decreased levels of the pro-angiogenic growth factors vascular endothelial growth factor (VEGF) and endocrine gland-derived VEGF both of which were increased with rosiglitazone treatment. Rosiglitazone reversed some of the nicotine effects in the ovary and increased ovarian vascularization, follicle maturation and improved oocyte competence. Rosiglitazone may be an important treatment option for PCOS and the present study provides a potential mechanism by which rosiglitazone may have beneficial effects on fertility in these patients.
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Fertilidade/efeitos dos fármacos , Nicotina/efeitos adversos , Ovário/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Tiazolidinedionas/farmacologia , Animais , Animais Recém-Nascidos , Vasos Sanguíneos/efeitos dos fármacos , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Feminino , Fertilidade/fisiologia , Hipoglicemiantes/farmacologia , Infertilidade Feminina/fisiopatologia , Exposição Materna/efeitos adversos , Ovário/irrigação sanguínea , Ovário/fisiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos Wistar , RosiglitazonaRESUMO
The type-I insulin-like growth factor receptor (IGF-IR) is frequently overexpressed in breast cancer and therapeutic agents targeting IGF-IR are currently in development. The ultimate success of anti-IGF-IR therapies will depend on the extent to which established tumors remain dependent upon IGF-IR signaling for sustained growth. To investigate the potential benefits and pitfalls of targeting IGF-IR, we used a doxycycline inducible mouse model of IGF-IR initiated breast cancer. We found that downregulation of IGF-IR results in tumor-size-dependent regression to an undetectable state. Partially regressed tumors almost always resumed growth in the absence of doxycycline and a proportion of tumors that regressed to an undetectable state ultimately recurred. This re-emergence of tumor growth in the absence of doxycycline was facilitated by IGF-IR-dependent and IGF-IR-independent mechanisms. Tumor escape from IGF-IR dependence was associated with an epithelial to mesenchymal transition and upregulation of transcriptional repressors of E-cadherin. These results suggest that tumors initiated by IGF-IR have the ability to become independent of this initiating oncogene, and IGF-IR independence is associated with characteristics consistent with an epithelial to mesenchymal transition.
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Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Receptor IGF Tipo 1/metabolismo , Animais , Neoplasias da Mama/genética , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Progressão da Doença , Doxiciclina/farmacologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Camundongos , Camundongos Transgênicos , Receptor IGF Tipo 1/genética , Recidiva , Células-Tronco/citologia , Células-Tronco/metabolismoRESUMO
The aim of our study was to determine human immunodeficiency virus 1 subtypes in Scottish blood donors. We were able to document virus subtypes present in this population over a period of 19 years and examine associated risk factors where available. Subtype B was found to be the predominant cause of human immunodeficiency virus 1 infection in Scottish blood donors with subtype C increasing in this population after 2002. Non-B subtypes were found mainly in heterosexuals but also in all other risk categories with the exception of men having sex with men (MSM). Within Scotland there is an increase in transmission via heterosexual contact and the consequential introduction of non-B subtypes.
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Doadores de Sangue , HIV-1/isolamento & purificação , Feminino , Infecções por HIV/epidemiologia , HIV-1/genética , Humanos , Masculino , Prevalência , Estudos Retrospectivos , Fatores de Risco , Escócia/epidemiologia , Comportamento SexualRESUMO
Approximately 90% of human ovarian tumors result from transformation of ovarian surface epithelial cells. It has been hypothesized that repeated destruction of the epithelial cells during ovulation, followed by proliferation and migration of epithelial cells to restore the ovarian surface, renders these cells susceptible to mutagenic events. One of the proteins found to promote ovarian surface epithelial cell survival and proliferation was the transcription factor, cAMP response element-binding protein (CREB). Thus, the objective of this study was to determine whether CREB was also highly expressed in tumor cells originating from the ovarian epithelium. Using an ovarian cancer tissue array, it was observed that approximately 54% of the epithelial-derived human ovarian tumors displayed moderate or high levels of CREB immunostaining, while none of the normal ovarian samples did. Comparison of CREB levels in a human ovarian tumor cell line to those of a normal ovarian epithelial cell line revealed elevated levels of CREB and phosphorylated CREB in the ovarian tumor cells. To determine whether CREB regulated proliferation and/or apoptosis in the ovarian tumor cell line, CREB expression was suppressed using RNA interference. Decreased CREB expression significantly reduced ovarian tumor cell proliferation, while there was no effect on apoptosis in these cells. Finally, we showed that CREB is highly expressed in an in vivo murine model of ovarian tumorigenesis. Therefore, CREB is frequently overexpressed in ovarian cancer where it appears to promote cell proliferation.
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Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Adenocarcinoma/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Estadiamento de Neoplasias , Neoplasias Ovarianas/genética , Fosforilação , Análise Serial de TecidosRESUMO
NK cells are an important component of the innate immune response to many virus infections. In particular, they play a major role in control of alpha and beta herpesvirus infections in humans and mice and there is evidence for a protective role in Epstein-Barr virus infection. MHV-68 has been widely used to study gammaherpesvirus pathogenesis and provides a tractable means of investigating the role of NK cells in gammaherpesvirus infections. We have shown that, following MHV-68 infection of mice, the NK cell population is expanded and activated and capable of cytotoxic killing in vitro. However, depletion of NK cells prior to MHV-68 infection did not affect viral loads in vivo. To investigate the possibility that MHV-68 was downregulating NK cell activity in vivo and evading the NK cell response, we infected NK cell-depleted mice with the related virus, MHV-76, which lacks a 9.5 kb region of the genome known to be involved in modulating the host immune response. Infection of NK cell-depleted mice with MHV-76 did not result in increased viral loads indicating that genes within this region do not encode products which modulate NK cell activity.