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OBJECTIVES: Understanding the drivers of HIV-1 transmission is of importance for curbing the ongoing epidemic. Phylogenetic methods based on single viral sequences allow us to assess whether two individuals are part of the same viral outbreak, but cannot on their own assess who potentially transmitted the virus. We developed and assessed a molecular epidemiology method with the main aim to screen cohort studies for and to characterize individuals who are 'potential HIV-1 transmitters', in order to understand the drivers of HIV-1 transmission. METHODS: We developed and validated a molecular epidemiology approach using longitudinally sampled viral Sanger sequences to characterize potential HIV-1 transmitters in the Swiss HIV Cohort Study. RESULTS: Our method was able to identify 279 potential HIV-1 transmitters and allowed us to determine the main epidemiological and virological drivers of transmission. We found that the directionality of transmission was consistent with infection times for 72.9% of 85 potential HIV-1 transmissions with accurate infection date estimates. Being a potential HIV-1 transmitter was associated with risk factors including viral load [adjusted odds ratiomultivariable (95% confidence interval): 1.86 (1.49-2.32)], syphilis coinfection [1.52 (1.06-2.19)], and recreational drug use [1.45 (1.06-1.98)]. By contrast for the potential HIV-1 recipients, this association was weaker or even absent [1.18 (0.82-1.72), 0.89 (0.52-1.55) and 1.53 (0.98-2.39), respectively], indicating that inferred directionality of transmission is useful at the population level. CONCLUSIONS: Our results indicate that longitudinally sampled Sanger sequences do not provide sufficient information to identify transmitters with high certainty at the individual level, but that they allow the drivers of transmission at the population level to be characterized.
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Infecciones por VIH , VIH-1 , Secuencia de Bases , Estudios de Cohortes , VIH-1/genética , Humanos , FilogeniaRESUMEN
We present a novel measurement method for the characterization of thermal diodes in a saturated steam atmosphere. A measuring setup has been developed in which two pressure sensors are integrated. Using a developed analytical model, the heat flow, the volume flow, and the cracking pressure are determined from the measured absolute pressures and the pressure difference. The analytical model was verified using a flow through an orifice. We first calculated the volume flow through the orifice, with a diameter of 3 mm, using the Reader-Harris equation and then compared it to experimentally determined values. The experimentally determined values showed a discrepancy of 9%. With the measurement setup, we have characterized a check valve developed for magnetocaloric heat pumps, which has a thermally rectifying behavior. The developed check valve consists of three spring arms, which are radially attached to a valve disk. The heat flow through the check valve in the forward direction is 166 W for water, 239 W for ethanol, and 547 W for methanol at a temperature difference of 1 K. In the reverse direction, the heat flow is -0.03 W at a temperature difference of -1 K. For methanol, this corresponds to a rectification coefficient of more than 18 000.
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BACKGROUND: Administering stereotactic radiotherapy to the surgical cavity and thus omitting postoperative whole brain radiotherapy (WBRT) is a favored strategy in limited metastatic brain disease. Little is known about the impact of regular magnetic resonance imaging follow-up (MRI FU) in such patient cohorts. The aim of this study is to examine the impact of regular MRI FU and to report the oncological outcomes of patients with one to three brain metastases (BMs) treated with stereotactic radiosurgery (SRS) or hypo-fractionated stereotactic radiotherapy (HFSRT) to the surgical cavity. METHODS: We retrospectively analyzed patients who received SRS or HFSRT to the surgical cavity after resection of one to two BMs. Additional, non-resected BMs were managed with SRS alone. Survival was estimated by the Kaplan-Meier method. Prognostic factors were examined with the log-rank test and Cox proportional hazards model. Regular MRI FU was defined as performing a brain MRI 3 months after radiotherapy (RT) and/or performing ≥1 brain MRI per 180 days. Primary endpoint was local control (LC). Secondary endpoints were distant brain control (DBC), overall survival (OS) and the correlation between regular MRI FU and overall survival (OS), symptom-free survival (SFS), deferment of WBRT and WBRT-free survival (WFS). RESULTS: Overall, 75 patients were enrolled. One, 2 and 3 BMs were seen in 63 (84%), 11 (15%) and 1 (1%) patients, respectively. Forty (53%) patients underwent MRI FU 3 months after RT and 38 (51%) patients received ≥1 brain MRI per 180 days. Median OS was 19.4 months (95% CI: 13.2-25.6 months). Actuarial LC, DBC and OS at 1 year were 72% (95% CI: 60-83%), 60% (95% CI: 48-72%) and 66% (95% CI: 53-76%), respectively. A planning target volume > 15 cm3 (p = 0.01), Graded Prognostic Assessment (GPA) score (p = 0.001) and residual tumor after surgery (p = 0.008) were prognostic for decreased OS in multivariate analysis. No significant correlation between MRI FU at 3 months and OS (p = 0.462), SFS (p = 0.536), WFS (p = 0.407) or deferment of WBRT (p = 0.955) was seen. Likewise, performing ≥1 MRI per 180 days had no significant impact on OS (p = 0.954), SFS (p = 0.196), WFS (p = 0.308) or deferment of WBRT (p = 0.268). CONCLUSION: Our results regarding oncological outcomes consist with the current data from the literature. Surprisingly, regular MRI FU did not result in increased OS, SFS, WFS or deferment of WBRT in our cohort consisting mainly of patients with a single and resected BM. Therefore, the impact of regular MRI FU needs prospective evaluation. TRIAL REGISTRATION: Project ID: 2017-00033, retrospectively registered.
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Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/cirugía , Imagen por Resonancia Magnética/métodos , Neoplasias/patología , Neoplasias/cirugía , Radiocirugia/métodos , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Terapia Recuperativa , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVES: Despite the huge success of antiretroviral therapy (ART), there is an ongoing HIV epidemic among men who have sex with men (MSM) in resource-rich countries. Understanding the driving factors underlying this process is important for curbing the epidemic. METHODS: We simulated the HIV epidemic in MSM in Switzerland by stratifying a mathematical model by CD4 count, the care cascade and condom use. The model was parametrised with clinical, epidemiological and behavioural data from the Swiss HIV Cohort Study and surveys in the HIV-negative population. RESULTS: According to our model, 3.4% of the cases that would otherwise have occurred in 2008-2015 were prevented by early initiation of ART. Only 0.6% of the cases were attributable to a change in condom use in the HIV-positive population, as less usage is mainly seen in virally suppressed MSM. Most new infections were attributable to transmission from recently infected undiagnosed individuals. It was estimated that doubling the diagnosis rate would have resulted in 11.8% fewer cases in 2001-2015. Moreover, it was estimated that introducing pre-exposure prophylaxis (PrEP) for 50% of those MSM not using condoms with occasional partners would have resulted in 22.6% fewer cases in 2012-2015. CONCLUSIONS: By combining observational data on the relevant epidemiological and clinical processes with a mathematical model, we showed that the 'test and treat' approach is most effective in reducing the number of new cases. Only a moderate population-level effect was estimated for early initiation of ART and a weak effect for the change in condom use of diagnosed MSM. Protecting HIV-negative individuals who are not using condoms with PrEP was shown to have a major impact.
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Control de Enfermedades Transmisibles/métodos , Transmisión de Enfermedad Infecciosa/prevención & control , Infecciones por VIH/epidemiología , Infecciones por VIH/transmisión , Homosexualidad Masculina , Adulto , Estudios de Cohortes , Simulación por Computador , Infecciones por VIH/prevención & control , Humanos , Masculino , Modelos Teóricos , Suiza/epidemiologíaRESUMEN
BACKGROUND: Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These 'RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown. METHODS: We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry. RESULTS: We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4-18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4. CONCLUSIONS: These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours.
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Síndrome de Costello/genética , Displasia Ectodérmica/genética , Insuficiencia de Crecimiento/genética , Cardiopatías Congénitas/genética , Neoplasias/epidemiología , Síndrome de Noonan/genética , Proteínas ras/genética , Adolescente , Niño , Preescolar , Síndrome de Costello/patología , Displasia Ectodérmica/patología , Facies , Insuficiencia de Crecimiento/patología , Femenino , Mutación de Línea Germinal , Alemania/epidemiología , Cardiopatías Congénitas/patología , Humanos , Lactante , Masculino , Neoplasias/etiología , Neoplasias/patología , Síndrome de Noonan/patología , Sistema de Registros , Factores de Riesgo , Transducción de SeñalAsunto(s)
Enfermedades de los Perros/genética , Mutación Missense , Enfermedades de la Médula Espinal/veterinaria , Superóxido Dismutasa/genética , Animales , Análisis Mutacional de ADN , Perros , Haplotipos , Heterocigoto , Linaje , Enfermedades de la Médula Espinal/genética , Superóxido Dismutasa-1Asunto(s)
Epigénesis Genética/genética , Impresión Genómica/genética , Animales , Diferenciación Celular/genética , Transformación Celular Neoplásica/genética , Cromosomas Humanos X/genética , Cromosomas Humanos Y/genética , Metilación de ADN/genética , Evolución Molecular , Femenino , Expresión Génica/genética , Humanos , Recién Nacido , Masculino , Ratones , Neoplasias/genética , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , ARN no Traducido/genética , Técnicas Reproductivas Asistidas , Gemelos Monocigóticos/genética , Disomía Uniparental/genéticaRESUMEN
BACKGROUND: Trastuzumab (Herceptin) has clinical indication in association with paclitaxel (Taxol) for the treatment of human epidermal growth factor receptor 2 (HER2)-expressing breast cancer. Synergistic interactions have been reported with taxane derivatives in HER2-expressing breast cancer cells. However, no direct comparison of the potential interest in combining trastuzumab with either paclitaxel or docetaxel (Taxotere) has been reported. MATERIALS AND METHODS: The present study was designed to evaluate in a comparative way the interaction of trastuzumab with paclitaxel or docetaxel in HER2-overexpressing human breast cancer cell lines. HER2 expression was documented in MCF-7, MDA-MB453 and SK-BR3 cell lines using immunocytochemistry with purified mouse anti-human monoclonal antibody. Cytotoxicity assays were performed using the sulforhodamine B assay and in vitro interactions between trastuzumab and taxanes were analyzed using the median-effect principle. RESULTS: Trastuzumab cytotoxicity was confirmed to be directly related to HER2 expression level. At the IC(50), the combination of trastuzumab with either paclitaxel or docetaxel led to synergism in all cell lines. However, considering mean values calculated in the IC(30)-IC(70) range of concentrations, trastuzumab interacted additively with docetaxel in SK-BR3 and MDA-MB453 cell lines while additive and synergistic interactions were achieved with paclitaxel in SK-BR3 and MDA-MB453, respectively. On the same basis, trastuzumab yielded synergistic interaction with both taxanes in the MCF-7 cell line. CONCLUSIONS: The present study shows that at least additive interactions are observed when trastuzumab is combined with either paclitaxel or docetaxel in weak to moderate or more than moderate HER2-expressing cells. Some interesting results were achieved in cells displaying weak HER2 expression which could suggest some further potential interest in trastuzumab.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Genes erbB-2/genética , Paclitaxel/análogos & derivados , Taxoides , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Docetaxel , Relación Dosis-Respuesta a Droga , Femenino , Citometría de Flujo , Regulación de la Expresión Génica , Humanos , Inmunohistoquímica , Paclitaxel/administración & dosificación , Probabilidad , Sensibilidad y Especificidad , Estadísticas no Paramétricas , Trastuzumab , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
PURPOSE: To assess the influence of trans-dominant inhibition of poly(ADP-ribosyl)ation on the rejoining kinetics of radiation-induced DNA double-strand breaks (DSB). MATERIALS AND METHODS: Stable transfectants of the SV40-transformed hamster cell line CO60 were used: COM3 cells contain a construct to overexpress the poly(ADP-ribose) polymerase (PARP-1) DNA-binding domain (DBD) when induced by dexamethasone, as well as a construct for the constitutive overexpression of the human glucocorticoid receptor (Hg0). COR3 are control cells containing only the Hg0 plasmid. DSB induction and rejoining in X-irradiated cells was assessed by DNA pulsed-field electrophoresis. RESULTS: DSB induction was identical in both cell lines and independent of the presence of dexamethasone. DSB rejoining kinetics was independent of dexamethasone in COR3 cells and identical to COM3 cells without dexamethasone. However, in COM3 cells treated with dexamethasone to induce PARP-1 DBD overexpression, the fast component of the rejoining kinetic was largely reduced, and residual fragmentation increased concomitant with the increased damage fraction in slow rejoining. CONCLUSIONS: The results indicate that inhibition of cellular PARP-1 does not affect the rate-limiting step of either fast or slow DSB rejoining. Rather, it appears that absence of poly(ADP-ribosyl)ation due to dominant negative PARP-1 expression induces a shift from rapid to slow DSB rejoining and by this mechanism PARP inhibition may increase the risk of repair failures.
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Rotura Cromosómica , Reparación del ADN/efectos de la radiación , ADN/efectos de la radiación , Poli(ADP-Ribosa) Polimerasas/biosíntesis , Animales , Línea Celular , Células/citología , Células/metabolismo , Células/efectos de la radiación , Cricetinae , Fragmentación del ADN/efectos de la radiación , Dexametasona/farmacología , Relación Dosis-Respuesta en la Radiación , Electroforesis en Gel de Agar , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Poli(ADP-Ribosa) Polimerasas/genética , Estructura Terciaria de Proteína/genética , Receptores de Glucocorticoides/biosíntesis , Receptores de Glucocorticoides/genética , TransfecciónRESUMEN
Alamethicin (ALA), a voltage-gated, ion channel-forming peptide mixture from Trichoderma viride, is a potent elicitor of the biosynthesis of volatile compounds in lima bean (Phaseolus lunatus). Unlike elicitation with jasmonic acid or herbivore damage, the blend of substances emitted comprises only the two homoterpenes, 4,11-dimethylnona-1,3,7-triene and 4,8,12-trimethyltrideca-1,3,7,11-tetraene, and methyl salicylate. Inhibition of octadecanoid signaling by aristolochic acid and phenidone as well as mass spectrometric analysis of endogenous jasmonate demonstrate that ALA induces the biosynthesis of volatile compounds principally via the octadecanoid-signaling pathway (20-fold increase of jasmonic acid). ALA also up-regulates salicylate biosynthesis, and the time course of the production of endogenous salicylate correlates well with the appearance of the methyl ester in the gas phase. The massive up-regulation of the SA-pathway (90-fold) interferes with steps in the biosynthetic pathway downstream of 12-oxophytodienoic acid and thereby reduces the pattern of emitted volatiles to compounds previously shown to be induced by early octadecanoids. ALA also induces tendril coiling in various species like Pisum, Lathyrus, and Bryonia, but the response appears to be independent from octadecanoid biosynthesis, because inhibitors of lipoxygenase and phospholipase A(2) do not prevent the coiling reaction.
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Alameticina/farmacología , Ciclopentanos/farmacología , Canales Iónicos/fisiología , Phaseolus/fisiología , Reguladores del Crecimiento de las Plantas/fisiología , Salicilatos/metabolismo , Transducción de Señal/fisiología , Ácidos Grasos Volátiles/biosíntesis , Canales Iónicos/efectos de los fármacos , Cinética , Oxilipinas , Phaseolus/efectos de los fármacos , Hojas de la Planta/efectos de los fármacos , Hojas de la Planta/fisiología , Transducción de Señal/efectos de los fármacosRESUMEN
A tamoxifen-resistant cell line (MCF7TAM) was established from tamoxifen-sensitive MCF-7 human breast cancer cells expressing estrogen receptors. Though the resistant cell line grows in the presence of tamoxifen, estrogen receptors continue to be expressed at similar levels as in the parental cell line. However, estrogen receptors appeared to be altered in the resistant cell line since important discrepancies are observed between results obtained with ligand binding assays and immunoenzymatic assays, tending to show modifications of estrogen receptor ligand binding capacity. The intracellular distribution of tamoxifen in sensitive and resistant cell lines was investigated using fluorescence of eosin-tamoxifen ionic association. Fluorescence emission spectra of eosin, tamoxifen and eosin-tamoxifen complex (lambda(ex)=480 nm) were analyzed and the maximal fluorescence intensity found for the complex (lambda(em)=540 nm) was four times higher than that of eosin alone, while tamoxifen alone did not emit any fluorescence in this spectral range. In MCF-7 cells, tamoxifen was found to be mainly located surrounding the nucleus, although nuclear fluorescence intensity was significantly lower. No highly fluorescent granules were observed in the resistant cell lines as opposed to sensitive cells. Improvement of this fluorescence microscopy methodology could appear of interest, taking into account the complexity of tamoxifen resistance molecular pathways.