Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) study.

Reliable detection of JAK2-V617F is critical for accurate diagnosis of myeloproliferative neoplasms (MPNs); in addition, sensitive mutation-specific assays can be applied to monitor disease response. However, there has been no consistent approach to JAK2-V617F detection, with assays varying markedly in performance, affecting clinical utility. Therefore, we established a network of 12 laboratories from seven countries to systematically evaluate nine different DNA-based quantitative PCR (qPCR) assays, including those in widespread clinical use. Seven quality control rounds involving over 21,500 qPCR reactions were undertaken using centrally distributed cell line dilutions and plasmid controls. The two best-performing assays were tested on normal blood samples (n=100) to evaluate assay specificity, followed by analysis of serial samples from 28 patients transplanted for JAK2-V617F-positive disease. The most sensitive assay, which performed consistently across a range of qPCR platforms, predicted outcome following transplant, with the mutant allele detected a median of 22 weeks (range 6-85 weeks) before relapse. Four of seven patients achieved molecular remission following donor lymphocyte infusion, indicative of a graft vs MPN effect. This study has established a robust, reliable assay for sensitive JAK2-V617F detection, suitable for assessing response in clinical trials, predicting outcome and guiding management of patients undergoing allogeneic transplant.

Fixed low-dose ultrasound-assisted catheter-directed thrombolysis followed by routine stenting of residual stenosis for acute ilio-femoral deep-vein thrombosis.

Patients with ilio-femoral deep-vein thrombosis (DVT) are at high risk of developing the post-thrombotic syndrome (PTS). In comparison to anticoagulation therapy alone, extended venography-guided catheter-directed thrombolysis without routine stenting of venous stenosis in patients with ilio-femoral DVT is associated with an increased risk of bleeding and a moderate reduction of PTS. We performed a prospective single-centre study to investigate safety, patency and incidence of PTS in patients with acute ilio-femoral DVT treated with fixed-dose ultrasound-assisted catheter-directed thrombolysis (USAT; 20 mg rt-PA during 15 hours) followed by routing stenting of venous stenosis, defined as residual luminal narrowing >50%, absent antegrade flow, or presence of collateral flow at the site of suspected stenosis. A total of 87 patients (age 46 ± 21 years, 60% women) were included. At 15 hours, thrombolysis success ≥50% was achieved in 67 (77%) patients. Venous stenting (mean 1.9 ± 1.3 stents) was performed in 70 (80%) patients, with the common iliac vein as the most frequent stenting site (83%). One major (1%; 95% CI, 0-6%) and 6 minor bleedings (7%; 95%CI, 3-14%) occurred. Primary and secondary patency rates at 1 year were 87% (95% CI, 74-94%) and 96% (95% CI, 88-99%), respectively. At three months, 88% (95% CI, 78-94%) of patients were free from PTS according to the Villalta scale, with a similar rate at one year (94%, 95% CI, 81-99%). In conclusion, a fixed-dose USAT regimen followed by routine stenting of underlying venous stenosis in patients with ilio-femoral DVT was associated with a low bleeding rate, high patency rates, and a low incidence of PTS.

Atherogenic dyslipidemia and residual cardiovascular risk in statin-treated patients

BACKGROUND AND PURPOSE Treatment with statins reduces the rate of cardiovascular events in high-risk patients, but residual risk persists. At least part of that risk may be attributable to atherogenic dyslipidemia characterized by low high-density lipoprotein cholesterol (≤40 mg/dL) and high triglycerides (triglycerides≥150 mg/dL). METHODS We studied subjects with stroke or transient ischemic attack in the Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin With Terutroban in Patients With a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM; n=19,100) and Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL; n=4731) trials who were treated with a statin and who had high-density lipoprotein cholesterol and triglycerides measurements 3 months after randomization (n=10,498 and 2900, respectively). The primary outcome measure for this exploratory analysis was the occurrence of major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). We also performed a time-varying analysis to account for all available high-density lipoprotein cholesterol and triglyceride measurements. RESULTS A total of 10% of subjects in PERFORM and 9% in SPARCL had atherogenic dyslipidemia after ≥3 months on start statin therapy. After a follow-up of 2.3 years (PERFORM) and 4.9 years (SPARCL), a major cardiovascular event occurred in 1123 and 485 patients in the 2 trials, respectively. The risk of major cardiovascular events was higher in subjects with versus those without atherogenic dyslipidemia in both PERFORM (hazard ratio, 1.36; 95% confidence interval, 1.14-1.63) and SPARCL (hazard ratio, 1.40; 95% confidence interval, 1.06-1.85). The association was attenuated after multivariable adjustment (hazard ratio, 1.23; 95% confidence interval, 1.03-1.48 in PERFORM and hazard ratio, 1.24; 95% confidence interval, 0.93-1.65 in SPARCL). Time-varying analysis confirmed these findings. CONCLUSIONS The presence of atherogenic dyslipidemia was associated with higher residual cardiovascular risk in PERFORM and SPARCL subjects with stroke or transient ischemic attack receiving statin therapy. Specific therapeutic interventions should now be trialed to address this residual risk.

Minimal residual disease in cancer therapy - Small things make all the difference

Minimal residual disease (MRD) is a major hurdle in the eradication of malignant tumors. Despite the high sensitivity of various cancers to treatment, some residual cancer cells persist and lead to tumor recurrence and treatment failure. Obvious reasons for residual disease include mechanisms of secondary therapy resistance, such as the presence of mutant cells that are insensitive to the drugs, or the presence of cells that become drug resistant due to activation of survival pathways. In addition to such unambiguous resistance modalities, several patients with relapsing tumors do not show refractory disease and respond again when the initial therapy is repeated. These cases cannot be explained by the selection of mutant tumor cells, and the precise mechanisms underlying this clinical drug resistance are ill-defined. In the current review, we put special emphasis on cell-intrinsic and -extrinsic mechanisms that may explain mechanisms of MRD that are independent of secondary therapy resistance. In particular, we show that studying genetically engineered mouse models (GEMMs), which highly resemble the disease in humans, provides a complementary approach to understand MRD. In these animal models, specific mechanisms of secondary resistance can be excluded by targeted genetic modifications. This allows a clear distinction between the selection of cells with stable secondary resistance and mechanisms that result in the survival of residual cells but do not provoke secondary drug resistance. Mechanisms that may explain the latter feature include special biochemical defense properties of cancer stem cells, metabolic peculiarities such as the dependence on autophagy, drug-tolerant persisting cells, intratumoral heterogeneity, secreted factors from the microenvironment, tumor vascularization patterns and immunosurveillance-related factors. We propose in the current review that a common feature of these various mechanisms is cancer cell dormancy. Therefore, dormant cancer cells appear to be an important target in the attempt to eradicate residual cancer cells, and eventually cure patients who repeatedly respond to anticancer therapy but lack complete tumor eradication.

La biomasa residual lignocelulósica como recurso energético renovable en el Oasis Norte de la provincia de Mendoza, Argentina

El objetivo de esta tesina es evaluar la disponibilidad de biomasa residual lignocelulósica, proveniente de la viticultura, olivicultura y fruticultura, en el Oasis Norte de la provincia de Mendoza, como recurso energético renovable. Se utilizan datos del Registro Único de la Tierra para conocer, por distrito, la superficie cultivada de cada especie vegetal. A través de consultas a profesionales locales, recopilación de información y datos de trabajos del ámbito local, nacional e internacional, se identifican coeficientes de disponibilidad de biomasa y las particularidades que condicionan su aprovechamiento. Los datos se procesan con planillas de cálculo y se aplican en la elaboración de mapas y resultados. Por último se comparan los resultados obtenidos con otros provenientes de estudios regionales en la materia. Los resultados arrojan cifras esperadas y comparables con estudios previos. Se dispone entre 86.286 y 440.669 t*año-1 de biomasa lignocelulósica y entre 1.114.160 GJ*año-1 y 5.856.385 GJ*año-1 de energía según los distintos escenarios evaluados. A nivel del Oasis Norte se puede instalar una planta de generación de energía por incineración de esta biomasa de una potencia entre 8,5 MWe a 76,6 MWe según escenarios. La gran variabilidad de los resultados de cada escenario se debe a la diferencia de factores de Relación de Generación de Residuos y Escobajos, poniendo de manifiesto la importancia de fomentar la investigación en este campo.

El otro Sánchez : Naturalismo ortodoxo y decadentismo residual

Habitualmente parangonado o enfrentado con Florencio Sánchez, el hoy olvidado ganador de concursos literarios Otto Miguel Cione consolidó las fórmulas de la narrativa popular de kioscos de la década posterior: ninfómanas, adúlteros, estafadores y vengadoras se cruzaron en sus ficciones con la enfermedad hereditaria y el conflicto de marginalidad del inmigrante. Su oscilación -muy atenta a los intermitentes impulsos de un mercado lector/espectador- entre una "literatura de consolación" y la intervención en los debates culturales, frente al Sánchez que lucha por la imposición de un teatro de tesis naturalista, da cuenta de una disputa en el marco de las "lecturas aceptables" que son auspiciadas desde el teatro y las que escapan a la vigilancia en el abigarrado entorno de la ficción narrativa de las primeras décadas del XX.

El otro Sánchez : Naturalismo ortodoxo y decadentismo residual

Habitualmente parangonado o enfrentado con Florencio Sánchez, el hoy olvidado ganador de concursos literarios Otto Miguel Cione consolidó las fórmulas de la narrativa popular de kioscos de la década posterior: ninfómanas, adúlteros, estafadores y vengadoras se cruzaron en sus ficciones con la enfermedad hereditaria y el conflicto de marginalidad del inmigrante. Su oscilación -muy atenta a los intermitentes impulsos de un mercado lector/espectador- entre una "literatura de consolación" y la intervención en los debates culturales, frente al Sánchez que lucha por la imposición de un teatro de tesis naturalista, da cuenta de una disputa en el marco de las "lecturas aceptables" que son auspiciadas desde el teatro y las que escapan a la vigilancia en el abigarrado entorno de la ficción narrativa de las primeras décadas del XX.

El otro Sánchez : Naturalismo ortodoxo y decadentismo residual

Habitualmente parangonado o enfrentado con Florencio Sánchez, el hoy olvidado ganador de concursos literarios Otto Miguel Cione consolidó las fórmulas de la narrativa popular de kioscos de la década posterior: ninfómanas, adúlteros, estafadores y vengadoras se cruzaron en sus ficciones con la enfermedad hereditaria y el conflicto de marginalidad del inmigrante. Su oscilación -muy atenta a los intermitentes impulsos de un mercado lector/espectador- entre una "literatura de consolación" y la intervención en los debates culturales, frente al Sánchez que lucha por la imposición de un teatro de tesis naturalista, da cuenta de una disputa en el marco de las "lecturas aceptables" que son auspiciadas desde el teatro y las que escapan a la vigilancia en el abigarrado entorno de la ficción narrativa de las primeras décadas del XX.