Gemcitabine and Oxaliplatin in the Treatment of Patients with Immunotherapy-Resistant Advanced Renal Cell Carcinoma: Final Results of a Single-Institution Phase II Study

BACKGROUND. Currently, there is no standard treatment for patients with advanced renal cell carcinoma (RCC) who do not experience a response to first-line immunotherapy. In the current Phase II study, the authors explored the antitumor activity of a combination of gemcitabine and oxaliplatin (L-OHP) in this setting. METHODS. Forty-two patients with RCC who had progressive disease following immunotherapy received gemcitabine (1000 mg/m2 intravenously on Days 1 and 8 every 21 days) and L-OHP (90 mg/m2 intravenously on Day 1 every 21 days) for a minimum of 2 cycles before responses were evaluated. Responses to treatment and toxicity were recorded according to the Response Evaluation Criteria in Solid Tumors and the National Cancer Institute Common Toxicity Criteria, respectively. RESULTS. No complete responses were recorded; however, 6 patients experienced a partial response (14.28%; 95% confidence interval, 5.43-28.5%), 11 patients (26.19%) had temporary stable disease as a best response, and the remaining 25 patients (59.52%) experienced progression despite receiving treatment. The median time to disease progression was 2.5 months (mean, 3.86 months; range, 1.5-11.0 months), whereas the median overall survival was 9.5 months (mean, 10.46 months; range, 4.0-22.5 months). With regard to toxicity, treatment generally was well tolerated, with only one episode of Grade 4 toxicity and expected episodes of Grade 3 toxicity, including myelosuppression and neuropathy. CONCLUSIONS. The current results suggest that the combination of gemcitabine and L-OHP possesses a certain level of activity and an acceptable toxicity profile in patients with immunotherapy-resistant advanced RCC

Distorted cyclotron line profile in Cep X-4 as observed by NuSTAR

We present spectral analysis of NuSTAR and Swift observations of Cep X-4 during its outburst in 2014. We observed the source once during the peak of the outburst and once during the decay, finding good agreement in the spectral shape between the observations. We describe the continuum using a powerlaw with a Fermi-Dirac cutoff at high energies. Cep X-4 has a very strong cyclotron resonant scattering feature (CRSF) around 30 keV. A simple absorption-like line with a Gaussian optical depth or a pseudo-Lorentzian profile both fail to describe the shape of the CRSF accurately, leaving significant deviations at the red side of the line. We characterize this asymmetry with a second absorption feature around 19 keV. The line energy of the CRSF, which is not influenced by the addition of this feature, shows a small but significant positive luminosity dependence. With luminosities between (1-6)e36 erg/s, Cep X-4 is below the theoretical limit where such a correlation is expected. This behavior is similar to Vela X-1 and we discuss parallels between the two systems.Comment: 6 pages, 4 figure, accepted for publication in ApJ letter

ASPETTI DELLA PRODUZIONE DEI PICCOLI RUMINANTI CON IMPATTO SULLA SALUTE UMANA

Negli ultimi anni l’attenzione del consumatore si è sempre più orientata verso le caratteristiche nutrizionali degli alimenti. Queste proprietà sono di grande importanza anche per quanto riguarda le produzioni dei piccoli ruminanti. Il presente lavoro ha lo scopo di riassumere i principali risultati emersi dal progetto di ricerca “Aspetti della produzione dei piccoli ruminanti con particolare impatto sulla salute umana”. Sono stati analizzati mediante i metodi descritti in letteratura: 1) i polimorfismi genetici dei biopeptidi del latte dei piccoli ruminanti; 2) le attività di alcuni enzimi della membrana del globulo di grasso e la frazione lipidica del latte ovino; 3) la qualità nutrizionale del latte e del formaggio ovino in relazione all’intensità di pascolamento; 4) le componenti bioattive di siero e scotta residui alla produzione dei formaggi ovi-caprini; 5) la resistenza genetica alle encefalopatie spongiformi trasmissibili e l’efficienza economica e biologica in razze ovine. I risultati ottenuti evidenziano, da svariati punti di vista, numerose potenzialità legate alle produzioni dei piccoli ruminanti e alle loro ricadute sulla salute umana

Restricción alimenticia en ovinos: Respuesta endocrino metabólica dependiente de las reservas corporales

las respuestas metabólicas a los cambios en el estado corporal podrían depender de la historia metabólica reciente (nivel de alimentación, efecto dinámico) o más antigua (reservas corporales, efecto estático), concepto denominado "memoria metabólica". El objetivo de este trabajo fue estudiar la respuesta endocrino-metabólica a una restricción alimenticia en ovejas con diferente condición corporal (CC) al inicio del experimento. Durante la estación reproductiva, 36 ovejas Rasa Aragonesa fueron separadas en 2 grupos con diferente CC: CC > 2,75 (moderadamente alta, A, 2,9 ± 0,04) y CC < 2,25 (moderadamente baja, B, 2,1 ± 0,04). Durante 20 días, ambos grupos recibieron una dieta para cubrir los requerimientos de mantenimiento de energía y proteína, tras lo cual se asignaron al azar a dos tratamientos nutricionales: 1,5 (control, C) o 0,5 (subnutrición, S) veces los requerimientos de mantenimiento diario, estableciéndose cuatro grupos: altas control (AC, n = 9), altas subnutridas (AS, n = 10), bajas control (BC, n = 9) y bajas subnutridas (BS, n = 8). Se determinó el peso vivo (PV) y los niveles plasmáticos de glucosa, ácidos grasos no esterificados (AGNE), 3-hidroxibutirato (BHB), insulina, leptina y factor de crecimiento similar a la insulina tipo 1 (IGF-I). Los grupos BS y AS perdieron peso, el grupo BC lo ganó y las ovejas AC lo mantuvieron. La concentración plasmática de glucosa fue mayor y los AGNE menor en las ovejas controles. Las ovejas de alta CC presentaron mayores concentraciones de insulina y de IGF-I, y la leptina tendió a ser mayor en estos animales. A su vez, la insulina fue mayor en los animales controles, mientras que las otras hormonas no fueron afectadas por el tratamiento. Los perfiles de glucosa, BHB, insulina e IGF-I estuvieron afectados por la CC inicial y el tratamiento nutricional, como así lo demuestra la interacción significativa entre estos factores y días. Se evidenció un aumento en el momento del celo de las concentraciones de los metabolitos (glucosa y BHB) y de las hormonas metabólicas (insulina e IGF-I). En conclusión, en este estudio se encontró que los perfiles de glucosa, BHB, insulina e IGF-I varían de forma diferente frente a una restricción alimenticia en función del grado de reservas corporales de las ovejas en el momento de iniciarse la restricción alimenticia.Fil: Fernandez Foren, A.. Universidad de la República; UruguayFil: Abecia, José Alfonso. Universidad de Zaragoza; EspañaFil: Vazquez, Maria Isabel. Universidad Nacional de Río Cuarto. Facultad de Agronomía y Veterinaria; Argentina. Universidad Nacional de Rio Cuarto. Facultad de Agronomia y Veterinaria. Instituto de Ciencias Veterinarias. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Cordoba. Instituto de Ciencias Veterinarias.; ArgentinaFil: Forcada Miranda, Fernando. Universidad de Zaragoza; EspañaFil: Sartore, I.. Universidad de la República; UruguayFil: Carriquiry, M.. Universidad de la República; UruguayFil: Meikle, Ana. Universidad de la República; UruguayFil: Sosa Misuraca, Cecilia. Universidad de Zaragoza; Españ

Restricción alimenticia en ovinos: Respuesta endocrino metabólica dependiente de las reservas corporales

las respuestas metabólicas a los cambios en el estado corporal podrían depender de la historia metabólica reciente (nivel de alimentación, efecto dinámico) o más antigua (reservas corporales, efecto estático), concepto denominado "memoria metabólica". El objetivo de este trabajo fue estudiar la respuesta endocrino-metabólica a una restricción alimenticia en ovejas con diferente condición corporal (CC) al inicio del experimento. Durante la estación reproductiva, 36 ovejas Rasa Aragonesa fueron separadas en 2 grupos con diferente CC: CC > 2,75 (moderadamente alta, A, 2,9 ± 0,04) y CC < 2,25 (moderadamente baja, B, 2,1 ± 0,04). Durante 20 días, ambos grupos recibieron una dieta para cubrir los requerimientos de mantenimiento de energía y proteína, tras lo cual se asignaron al azar a dos tratamientos nutricionales: 1,5 (control, C) o 0,5 (subnutrición, S) veces los requerimientos de mantenimiento diario, estableciéndose cuatro grupos: altas control (AC, n = 9), altas subnutridas (AS, n = 10), bajas control (BC, n = 9) y bajas subnutridas (BS, n = 8). Se determinó el peso vivo (PV) y los niveles plasmáticos de glucosa, ácidos grasos no esterificados (AGNE), 3-hidroxibutirato (BHB), insulina, leptina y factor de crecimiento similar a la insulina tipo 1 (IGF-I). Los grupos BS y AS perdieron peso, el grupo BC lo ganó y las ovejas AC lo mantuvieron. La concentración plasmática de glucosa fue mayor y los AGNE menor en las ovejas controles. Las ovejas de alta CC presentaron mayores concentraciones de insulina y de IGF-I, y la leptina tendió a ser mayor en estos animales. A su vez, la insulina fue mayor en los animales controles, mientras que las otras hormonas no fueron afectadas por el tratamiento. Los perfiles de glucosa, BHB, insulina e IGF-I estuvieron afectados por la CC inicial y el tratamiento nutricional, como así lo demuestra la interacción significativa entre estos factores y días. Se evidenció un aumento en el momento del celo de las concentraciones de los metabolitos (glucosa y BHB) y de las hormonas metabólicas (insulina e IGF-I). En conclusión, en este estudio se encontró que los perfiles de glucosa, BHB, insulina e IGF-I varían de forma diferente frente a una restricción alimenticia en función del grado de reservas corporales de las ovejas en el momento de iniciarse la restricción alimenticia.Fil: Fernandez Foren, A.. Universidad de la República; UruguayFil: Abecia, José Alfonso. Universidad de Zaragoza; EspañaFil: Vazquez, Maria Isabel. Universidad Nacional de Río Cuarto. Facultad de Agronomía y Veterinaria; Argentina. Universidad Nacional de Rio Cuarto. Facultad de Agronomia y Veterinaria. Instituto de Ciencias Veterinarias. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Cordoba. Instituto de Ciencias Veterinarias.; ArgentinaFil: Forcada Miranda, Fernando. Universidad de Zaragoza; EspañaFil: Sartore, I.. Universidad de la República; UruguayFil: Carriquiry, M.. Universidad de la República; UruguayFil: Meikle, Ana. Universidad de la República; UruguayFil: Sosa Misuraca, Cecilia. Universidad de Zaragoza; Españ

The OGLE View of Microlensing towards the Magellanic Clouds. IV. OGLE-III SMC Data and Final Conclusions on MACHOs

In this fourth part of the series presenting the Optical Gravitational Lensing Experiment (OGLE) microlensing studies of the dark matter halo compact objects (MACHOs) we describe results of the OGLE-III monitoring of the Small Magellanic Cloud (SMC). Three sound candidates for microlensing events were found and yielded the optical depth tau_SMC-OIII=1.30+-1.01 10^{-7}, consistent with the expected contribution from Galactic disk and SMC self-lensing. We report that event OGLE-SMC-03 is the most likely a thick disk lens candidate, the first of such type found towards the SMC. In this paper we also combined all OGLE Large and Small Magellanic Cloud microlensing results in order to refine the conclusions on MACHOs. All but one of OGLE events are most likely caused by the lensing by known populations of stars, therefore we concluded that there is no need for introducing any special dark matter compact objects in order to explain the observed events rates. Potential black hole event indicates that similar lenses can contribute only about 2 per cent to the total mass of the halo, which is still in agreement with the expected number of such objects.Comment: Accepted for publication in MNRAS. Data available on the OGLE website http://ogle.astrouw.edu.p

Helping someone with problem drinking: Mental health first aid guidelines - a Delphi expert consensus study

Background Alcohol is a leading risk factor for avoidable disease burden. Research suggests that a drinker's social network can play an integral role in addressing hazardous (i.e., high-risk) or problem drinking. Often however, social networks do not have adequate mental health literacy (i.e., knowledge about mental health problems, like problem drinking, or how to treat them). This is a concern as the response that a drinker receives from their social network can have a substantial impact on their willingness to seek help. This paper describes the development of mental health first aid guidelines that inform community members on how to help someone who may have, or may be developing, a drinking problem (i.e., alcohol abuse or dependence). Methods A systematic review of the research and lay literature was conducted to develop a 285-item survey containing strategies on how to help someone who may have, or may be developing, a drinking problem. Two panels of experts (consumers/carers and clinicians) individually rated survey items, using a Delphi process. Surveys were completed online or via postal mail. Participants were 99 consumers, carers and clinicians with experience or expertise in problem drinking from Australia, Canada, Ireland, New Zealand, the United Kingdom, and the United States. Items that reached consensus on importance were retained and written into guidelines. Results The overall response rate across all three rounds was 68.7% (67.6% consumers/carers, 69.2% clinicians), with 184 first aid strategies rated as essential or important by ≥80% of panel members. The endorsed guidelines provide guidance on how to: recognize problem drinking; approach someone if there is concern about their drinking; support the person to change their drinking; respond if they are unwilling to change their drinking; facilitate professional help seeking and respond if professional help is refused; and manage an alcohol-related medical emergency. Conclusion The guidelines provide a consensus-based resource for community members seeking to help someone with a drinking problem. Improving community awareness and understanding of how to identify and support someone with a drinking problem may lead to earlier recognition of problem drinking and greater facilitation of professional help seeking

Calpain 3 is important for muscle regeneration: Evidence from patients with limb girdle muscular dystrophies

<p>Abstract</p> <p>Background</p> <p>Limb girdle muscular dystrophy (LGMD) type 2A is caused by mutations in the CAPN3 gene and complete lack of functional calpain 3 leads to the most severe muscle wasting. Calpain 3 is suggested to be involved in maturation of contractile elements after muscle degeneration. The aim of this study was to investigate how mutations in the four functional domains of calpain 3 affect muscle regeneration.</p> <p>Methods</p> <p>We studied muscle regeneration in 22 patients with LGMD2A with calpain 3 deficiency, in five patients with LGMD2I, with a secondary reduction in calpain 3, and in five patients with Becker muscular dystrophy (BMD) with normal calpain 3 levels. Regeneration was assessed by using the developmental markers neonatal myosin heavy chain (nMHC), vimentin, MyoD and myogenin and counting internally nucleated fibers.</p> <p>Results</p> <p>We found that the recent regeneration as determined by the number of nMHC/vimentin-positive fibers was greatly diminished in severely affected LGMD2A patients compared to similarly affected patients with LGMD2I and BMD. Whorled fibers, a sign of aberrant regeneration, was highly elevated in patients with a complete lack of calpain 3 compared to patients with residual calpain 3. Regeneration is not affected by location of the mutation in the <it>CAPN3 </it>gene.</p> <p>Conclusions</p> <p>Our findings suggest that calpain 3 is needed for the regenerative process probably during sarcomere remodeling as the complete lack of functional calpain 3 leads to the most severe phenotypes.</p