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Abstract In PIVOT IO 001 (NCT03635983), the combination of the investigational interleukin-2 agonist bempegaldesleukin (BEMPEG) with nivolumab (NIVO) had no added clinical benefit over NIVO monotherapy in unresectable/metastatic melanoma. Pre-defined baseline and on-treatment changes in selected biomarkers were analyzed to explore the potential mechanisms underlying the clinical observations. In each treatment arm, higher baseline tumor mutational burden or immune infiltration/inflammation was associated with improved efficacy compared with lower levels. On-treatment peripheral biomarker changes showed that BEMPEG + NIVO increased all immune cell subset counts interrogated, including regulatory T cells. This was followed by attenuation of the increase in CD8 + T cells, conventional CD4 + T cells, and systemic interferon gamma levels at later treatment cycles in the combination arm. Changes in tumor biomarkers were comparable between arms. These biomarker results help provide a better understanding of the mechanism of action of BEMPEG + NIVO and may help contextualize the clinical observations from PIVOT IO 001.

Summary: Background: Prognostic factors for ambulatory oncology patients have been described, including Eastern Cooperative Oncology Group (ECOG), tumor stage and malnutrition. However, there is no firm evidence on which variables best predict mortality in hospitalized patients receiving active systemic treatment. Our main goal was to develop a predictive model for 90-day mortality upon admission. Methods: Between 2020 and 2022, we prospectively collected data from three sites for cancer patients with hospitalizations. Those with metastatic disease receiving systemic therapy in the 6 months before unplanned admission were eligible to this study. The least absolute shrinkage and selection operator (LASSO) method was used to select the most relevant factors to predict 90-day mortality at admission. A multivariable logistic regression was fitted to create the PROgnostic Score for Hospitalized Cancer Patients (PROMISE) score. The score was developed in a single-center training cohort and externally validated. Findings: Of 1658 hospitalized patients, 1009 met eligibility criteria. Baseline demographics, patient and disease characteristics were similar across cohorts. Lung cancer was the most common tumor type in both cohorts. Factors associated with higher 90-day mortality included worse ECOG, stable/progressive disease, low levels of albumin, increased absolute neutrophil count, and high lactate dehydrogenase. The c-index after bootstrap correction was 0.79 (95% CI, 0.75–0.82) and 0.74 (95% CI, 0.68–0.80) in the training and validation cohorts, respectively. A web tool (https://promise.vhio.net/) was developed to facilitate the clinical deployment of the model. Interpretation: The PROMISE tool demonstrated high performance for identifying metastatic cancer patients who are alive 90 days after an unplanned hospitalization. This will facilitate healthcare providers with rational clinical decisions and care planning after discharge. Funding: Merck S.L.U., Spain.

The need for the public to take an active role in scientific research is becoming increasingly important, particularly in health-related research. However, the coexistence and alignment of scientific and citizen interests, needs, knowledge and timing is not straightforward, especially when involving migrant populations. To conduct impactful research, it becomes also essential to consider the perspectives of policymakers, thereby adding a layer of complexity to the processes.In this article we address the experience of a living lab created in a research institution and supported by the city council and a local foundation, in which we developed three experiences of patient and public involvement (PPI): (1) accessing to comprehensive care for people at risk of Chagas disease; (2) strategies towards improving access and quality of mental healthcare services in migrants; (3) promoting healthy and safe school environments in vulnerable urban settings.These three challenges provided an opportunity to delve into diverse strategies for involving key stakeholders, including migrant populations, expert researchers and political actors in health research. This article offers insights into the successes, challenges, and valuable lessons learnt from these endeavours, providing a vision that can be beneficial for future initiatives. Each living lab experience crafted its unique governance system and agenda tailored to specific challenge scenarios, giving rise to diverse methods and study designs.We have found that the management of the cocreation of the research question and the institutional support are key to building robust PPI processes with migrant groups.

Abstract The efficacy of pembrolizumab monotherapy versus chemotherapy increased with increasing programmed death ligand 1 (PD‐L1) expression, as quantified by combined positive score (CPS; PD‐L1 expression on both tumour cells and immune cells) in patients with previously treated metastatic triple‐negative breast cancer (mTNBC) in the phase 3 KEYNOTE‐119 study. This exploratory analysis was conducted to determine whether the expression of PD‐L1 on tumour cells contributes to the predictive value of PD‐L1 CPS in mTNBC. PD‐L1 expression in tumour samples was assessed using PD‐L1 IHC 22C3 pharmDx and quantified using both CPS and tumour proportion score (TPS; PD‐L1 expression on tumour cells alone). Calculated immune cell density (CID) was defined as CPS minus TPS. The ability of each scoring method (CPS, TPS, and CID) to predict clinical outcomes with pembrolizumab was evaluated. With pembrolizumab, the area under the receiver operating characteristic curve was 0.69 (95% CI = 0.58–0.80) for CPS, 0.55 (95% CI = 0.46–0.64) for TPS, and 0.67 (95% CI = 0.56–0.77) for CID. After correction for cutoff prevalence, CPS performed as well as, if not better than, CID with respect to predicting objective response rate, progression‐free survival, and overall survival. Data from this exploratory analysis suggest that, although PD‐L1 expression on immune cells alone is predictive of response to programmed death 1 blockade in mTNBC, adding tumour PD‐L1 expression assessment (i.e. CPS, which combines immune cell and tumour cell PD‐L1 expression) may improve prediction. PD‐L1 CPS thus remains an effective and broadly applicable uniform scoring system for enriching response to programmed death 1 blockade with pembrolizumab in mTNBC as well as other tumour types.

IntroductionAlthough checkpoint inhibitors (CPIs) have improved outcomes for patients with metastatic melanoma, those progressing on CPIs have limited therapeutic options. To address this unmet need and overcome CPI resistance mechanisms, novel immunotherapies, such as T-cell engaging agents, are being developed. The use of these agents has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs), which is challenging to predict preclinically and can lead to neutralization of the drug and loss of efficacy.MethodsTYRP1-TCB (RO7293583; RG6232) is a T-cell engaging bispecific (TCB) antibody that targets tyrosinase-related protein 1 (TYRP1), which is expressed in many melanomas, thereby directing T cells to kill TYRP1-expressing tumor cells. Preclinical studies show TYRP1-TCB to have potent anti-tumor activity. This first-in-human (FIH) phase 1 dose-escalation study characterized the safety, tolerability, maximum tolerated dose/optimal biological dose, and pharmacokinetics (PK) of TYRP1-TCB in patients with metastatic melanoma (NCT04551352).ResultsTwenty participants with cutaneous, uveal, or mucosal TYRP1-positive melanoma received TYRP1-TCB in escalating doses (0.045 to 0.4 mg). All participants experienced ≥1 treatment-related adverse event (TRAE); two participants experienced grade 3 TRAEs. The most common toxicities were grade 1–2 cytokine release syndrome (CRS) and rash. Fractionated dosing mitigated CRS and was associated with lower levels of interleukin-6 and tumor necrosis factor-alpha. Measurement of active drug (dual TYPR1- and CD3-binding) PK rapidly identified loss of active drug exposure in all participants treated with 0.4 mg in a flat dosing schedule for ≥3 cycles. Loss of exposure was associated with development of ADAs towards both the TYRP1 and CD3 domains. A total drug PK assay, measuring free and ADA-bound forms, demonstrated that TYRP1-TCB-ADA immune complexes were present in participant samples, but showed no drug activity in vitro.DiscussionThis study provides important insights into how the use of active drug PK assays, coupled with mechanistic follow-up, can inform and enable ongoing benefit/risk assessment for individuals participating in FIH dose-escalation trials. Translational studies that lead to a better understanding of the underlying biology of cognate T- and B-cell interactions, ultimately resulting in ADA development to novel biotherapeutics, are needed.

The aim of this study was to compare selection indices for important traits in intensive Spanish goat breeds in four economic scenarios, using the Florida as most representative breed of this production system in Spain. For this analysis, we considered the following traits: milk yield (MY), fat plus protein yields (FPY), casein yield (CY), somatic cell score (SCS), reproductive efficiency (RE), litter size (LS), mammary system (MS), final score (FS), body capacity index (BCI), and length of productive life (LPL). We estimated the genetic parameters and EBVs of most of these traits with REML methodology, while LPL was modeled through survival analysis. Four scenarios were proposed, depending on the overall objective for improvement: (1) milk production, (2) milk production and cheese extract, (3) cheese extract, and (4) milk production, cheese extract and sale of animals. Then, within each scenario, three different types of indices were designed using the different primary and secondary objectives/criteria considered suitable to improve the overall objective. The results indicated that selecting only for primary traits yielded the highest genetic response for all the scenarios. Including secondary traits led to positive correlated responses in those traits, but a decrease in the responses in the primary criteria.

Background Programmed cell death receptor-1 (PD-1)-blocking antibodies are approved to treat metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) cases ineligible for curative surgery or radiation. Notwithstanding, some patients experience inadequate responses or severe immune-related adverse events (AEs), indicating the need for improved therapies. Cosibelimab is a high-affinity programmed cell death-ligand 1 (PD-L1)-blocking antibody that activates innate and adaptive immunity by blocking PD-L1 interaction with PD-1 and B7-1 receptors. It is an unmodified immunoglobulin G1 subtype with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Here, we present results of the pivotal study of patients with metastatic CSCC from an open-label, multicenter, multiregional, multicohort, phase 1 trial of cosibelimab.Methods In this trial, participants with metastatic CSCC received cosibelimab 800 mg intravenously every 2 weeks. Primary endpoint was objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, V.1.1. Secondary endpoints included duration of response (DOR) and safety.Results Objective response was observed in 37 of 78 participants (47.4% (95% CI: 36.0% to 59.1%)), with median follow-up of 15.4 months (range: 0.4 to 40.5) as of data cut-off. Median DOR was not reached (range: 1.4+ to 34.1+ months), with response ongoing in 73.0% of participants. Common treatment-emergent AEs (≥15%) were fatigue (26.9%), rash (16.7%), and anemia (15.4%). Eighteen participants (23.1%) experienced immune-related AEs (grade 3: n=2 (2.6%); no grade 4/5). No treatment-related deaths were reported.Conclusions Cosibelimab demonstrated clinically meaningful ORR and DOR and was associated with a manageable safety profile.Trial registration number NCT03212404.

Targeted therapeutic options for NRAS-mutant melanoma are limited. Here, the authors show that under metabolic stress NRAS-mutant melanoma cells activate a BRAF-dependent glycolysis pathway for survival, leading to improve efficacy of sorafenib when combined with glycolysis inhibitors.

Whether intermittent strategies of delivering drugs can improve cancer patients survival is still unclear. Here, the authors reports the results of a randomized phase II clinical trial aimed to compare the efficacy and safety of two dosing regimens (continuous and intermittent) of vemurafenib and cobimetinib combination as first-line treatment of patients with unresectable or metastatic advanced melanoma with BRAFV600 mutation

Background Corticosteroids are the mainstay of treatment for immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI), but the optimal duration of therapy has not been established. Prolonged use of corticosteroids can cause numerous adverse effects and may decrease progression-free survival among patients treated with ICPis. We sought to determine whether a shorter duration of corticosteroids was equally efficacious and safe as compared with a longer duration.Methods We used data from an international multicenter cohort study of patients diagnosed with ICPi-AKI from 29 centers across nine countries. We examined whether a shorter duration of corticosteroids (28 days or less) was associated with a higher rate of recurrent ICPi-AKI or death within 30 days following completion of corticosteroid treatment as compared with a longer duration (29–84 days).Results Of 165 patients treated with corticosteroids, 56 (34%) received a shorter duration of treatment and 109 (66%) received a longer duration. Patients in the shorter versus longer duration groups were similar with respect to baseline and ICPi-AKI characteristics. Five of 56 patients (8.9%) in the shorter duration group and 12 of 109 (11%) in the longer duration group developed recurrent ICPi-AKI or died (p=0.90). Nadir serum creatinine in the first 14, 28, and 90 days following completion of corticosteroid treatment was similar between groups (p=0.40, p=0.56, and p=0.89, respectively).Conclusion A shorter duration of corticosteroids (28 days or less) may be safe for patients with ICPi-AKI. However, the findings may be susceptible to unmeasured confounding and further research from randomized clinical trials is needed.

BackgroundData related to adverse drug reactions (ADRs), specifically immune-related adverse events (irAEs), in long-term treatment with immunotherapy in real-world practice is scarce, as is general information regarding the management of ADRs.ObjectivesTo characterize and describe the incidence of ADRs in patients who began immunotherapy treatment in clinical practice.MethodsIn a prospective observational study cancer patients ≥18 years of age who were treated with a monotherapy regime of PD-1/PD-L1 inhibitors were evaluated. The study period was from November 2017 to June 2019 and patients were followed up until June 2021. Patients were contacted monthly by telephone and their electronic health records were reviewed. Each ADR was graded according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0).ResultsOut of 99 patients, 86 met the inclusion criteria. Most were male (67.4%), with a median age of 66 (interquartile range, IQR: 59–76). The most frequent cancer was non-small cellular lung cancer (46 cases, 53.5%), followed by melanoma (22, 25.6%). A total of 74 patients (86%) were treated with anti-PD-1 drugs and 12 (14%) were treated with anti-PD-L1 drugs. The median treatment durations were 4.9 (IQR: 1.9–17.0) and 5.9 months (IQR: 1.2–12.3), respectively. Sixty-three patients (73%) developed from a total of 156 (44% of the total number of ADR) irADRs, wherein the most frequent were skin disorders (50 cases, 32%, incidence = 30.5 irADRs/100 patients per year [p-y]), gastrointestinal disorders (29, 19%, 17.7 irADRs/100 p-y), musculoskeletal disorders (17, 11%, 10.4 irADRs/100 p-y), and endocrine disorders (14, 9%, 8.6 irADRs/100 p-y). A total of 22 irADRs (14%) had a latency period of ≥12 months. Twelve irADRs (7.7%) were categorized as grade 3–4, and while 2 (1.3%) were categorized as grade 5 (death). Sixty-one irADRs (39.1%) in 36 patients required pharmacological treatment and 47 irADRs (30.1%) in 22 patients required treatment with corticosteriods.ConclusionThe majority of patients treated with anti-PD1/PDL1-based immunotherapy experienced adverse reactions. Although most of these reactions were mild, 11.5% were categorized as grade 3 or above. A high percentage of the reactions were immune-related and occurred throughout the treatment, thereby indicating that early identification and close monitoring is essential.

Background and AimsImmunotherapy with immune checkpoint inhibitors (ICIs) is a pillar of many advanced tumors. However, there is scarce data concerning the rate of viral hepatitis screening in this population or the risk of viral reactivation.MethodsRetrospective–prospective study that includes all patients who began ICIs between January/2019 and December/2020 in a University Hospital. Data on viral hepatitis screening prior to the beginning of ICIs were collected. In subjects lacking information, serological tests were requested prospectively. Among HBsAg, anti-HBc, or anti-HCV positive subjects, reactivation was prospectively assessed.ResultsDuring the 2-year period of study, 595 subjects received ICIs (61.2% male, mean age 63 years). The most prevalent cancers found were 35.5% lung cancer, 12.1% melanoma, and 8.2% head and neck; ICIs schemes were mainly anti-PD1 (65.7%), followed by anti-PD-L1 (19.2%), and combined therapy (13.6%). Prior to immunotherapy, anti-HCV screening was performed in 462 (77.6%) subjects, HBsAg in 462 (77.6%), anti-HBc in 335 (56.3%), and the complete screening in 328 (55.1%). The anti-HBc screening was more frequently ordered among patients treated with concomitant systemic therapy (p = 0.003), especially in the case of chemotherapy (p = 0.015), though HCV screening was more commonly performed in concomitant therapies different from chemotherapy (p = 0.001). Serological tests were completed prospectively in those alive, leading to an overall prevalence for anti-HCV of 3.5%, HBsAg at 1.3%, and anti-HBc of 15.2%. HCV-RNA was detected in 2/19 (both patients with hepatocellular carcinoma), HBV-DNA in 4/7 HBsAg positive, and in 1/75 anti-HBc positive subject. Five out of the 7 HBsAg carriers and 1/75 anti-HBc+ subjects (due to concomitant antiretroviral therapy) received antiviral prophylaxis. Neither cases of HBV reactivation nor changes in HCV viral load were observed.DiscussionHBV and HCV screening prior to immunotherapy is suboptimal. Though the rate of viral hepatitis reactivation seems extremely low, efforts should be made to optimize viral hepatitis screening prior to immunotherapy for the selection of candidates for either antiviral prophylaxis or periodical follow-up.

Genetic parameters of litter size (LS) and number of kids born alive (NBA) were estimated across parities in Florida and Payoya goat breeds using a threshold random regression model (RRM). We analysed the reproductive records for the Florida and Payoya breeds separately, and a total of 130.849 and 67.478 reproductive records from the first to the seventh parities from Florida and Payoya, respectively, were included in the analysis. Random regressions on Legendre polynomials of standardised parity were included for permanent environmental and additive genetic effects. We based our estimation of all the covariance components on Bayesian inference under categorical distribution and considered heterogeneous residual variances in the model. The estimates of heritabilities ranged from null to 0.37 for LS and from 0.02 to 0.20 for NBA, while the repeatability estimates were between 0.008–0.60 and 0.03–0.44 for LS and NBA, respectively. Phenotypic correlations within-trait along parities ranged widely from −0.31 to 0.97, while the genetic correlations within-trait through parities showed a wider range and magnitude of values, from −0.98 to 0.99 for LS and from −0.72 to 0.99 for NBA. The estimates of genetic correlations between LS and NBA in the different parities were positive in the first two parities and negative in the later ones. Due to the noticeable changes in variance and the incomplete genetic correlations, the use of a random regression model to analyse LS and NBA is recommended in goat breeds.HIGHLIGHTS A bivariate threshold random regression model has been used for the first time to estimate genetic parameters of litter size and number of kids born alive across parities in Spanish goat breeds. The evolution of genetic parameters along parities is different between Florida and Payoya that have different production systems, being more intensive in the case of the Florida breed. Estimates of variance were not constant across parities for both traits and breeds. Genetic correlations within-trait across parities were different from unity. Thus, LS and NBA should be treated as different traits in successive parities. Given that the estimates of variance and covariances are not constant across parities for both traits and breeds, the use of RRM is highly recommended.

This study aimed to estimate genetic parameters of reproductive efficiency over a wide age range of females using a random regression model (RRM) in Spanish goat breeds. A total of 138,139 and 64,638 reproductive records from the first to the sixth parities from Florida and Payoya, respectively, were included in the analysis. Random regressions on Legendre polynomials of standardised age were included for permanent environmental and additive genetic effects. Estimation of the covariance components was based on the Bayesian inference using the GIBBS3F90 software. Differences among genetic variance components for reproductive efficiency were observed over the animal’s lifetime. The estimates of heritabilities were moderate, ranging from 0.21 to 0.32 for Florida and from 0.25 to 0.35 for Payoya, while the fractions of phenotypic variance explained by the permanent environmental effect were high, varying between 0.45–0.68 and 0.58–0.71 for Florida and Payoya, respectively. The correlations for permanent environmental effect over age ranged from 0.37 to 0.99, while the genetic correlations between the different ages varied from 0.36 to 0.98 for Florida and from 0.80 to 0.99 for Payoya. The results from this study support the validity of using an RRM to genetically analyse reproductive efficiency in Spanish dairy goats following the changes in variances and the genetic correlations different from unity over the animal’s lifetime. Moreover, reproductive efficiency is a highly heritable trait that is expressed early in a female’s life, and it could be used as a precocious selection criterion to improve female fertility in Spanish dairy goats.Highlights Reproductive efficiency (RE) has been proposed as a trait to improve female fertility in dairy goats. RE was genetically analysed using an RRM over a range of ages in females from the Florida and Payoya breeds raised under different production systems. Variance components for RE were not constant over age, while the genetic correlations between RE in the different ages were different from unity. The use of RRM for RE is therefore justified in both goat breeds.

Background Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer.Methods We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI.Results ICPi-AKI occurred at a median of 16 weeks (IQR 8–32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3–10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI.Conclusions Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.

Cancer immunotherapy based on the use of antibodies targeting the so-called checkpoint inhibitors, such as programmed cell death-1 receptor, its ligand, or CTLA-4, has shown durable clinical benefit and survival improvement in melanoma and other tumors. However, there are some special situations that could be a challenge for clinical management. Persons with chronic infections, such as HIV-1 or viral hepatitis, latent tuberculosis, or a history of solid organ transplantation, could be candidates for cancer immunotherapy, but their management requires a multidisciplinary approach. The Spanish Melanoma Group (GEM) panel in collaboration with experts in virology and immunology from different centers in Spain reviewed the literature and developed evidence-based guidelines for cancer immunotherapy management in patients with chronic infections and immunosuppression. These are the first clinical guidelines for cancer immunotherapy treatment in special challenging populations. Cancer immunotherapy in chronically infected or immunosuppressed patients is feasible but needs a multidisciplinary approach in order to decrease the risk of complications related to the coexistent comorbidities.

A total of 1,031,143 records of daily dairy control test of Spanish Florida goats were used for this study. The database was edited, and only the records of the first three lactations were kept. The final database contained 340,654 daily-test somatic cell counts from 27,749 daughters of 941 males and 16,243 goats. The evolution of this count in the last 14 years was analyzed following French and American international associations’ criteria for the risk of mastitis in goats, and confirmed the slight increase in SCS in the last years and the importance of this problem (50% of dairy control tests show a risk of suffering mastitis). For the genetic analysis, the SCS records were log-transformed to normalize this variable. Two strategies were used for the genetic analysis: a univariate animal model for the SCS assuming that SCS does not vary throughout the parities, and a multi-character animal model, where SCS is not considered as the same character in the different parities. The heritabilities (h2) were higher in the multiple traits models, showings an upward trend from the first to the third parity (h2 between 0.245 to 0.365). The genetic correlations of the same trait, as well as between breeding values (GVs) between different parities, were different from unity. The breeding values (EBVs) obtained for both models were subjected to a PCA: the first eigenvector (λ1) explained most of the variations (between 74% to 90%), while the second λ2 accounted for between 9% to 20% of the variance, which shows that the selection will be proportionally favorable but not equivalent in all parities and that there are some variations in the type of response.

La instalación como vía de expresión híbrida en la que se contempla la utilización del espacio con un sentido de intervención creativa, - arquitectura, pintura, escultura, fotografía, vídeo, performance, danza, dramatización y música- entre otras disciplinas implicadas, proporciona al campo de la terapia un universo sensorial y proposicional que puede tomarse como base conceptual en el proceso terapéutico mediante las artes.Partiendo del análisis sobre aspectos conceptuales y artistas de referencia de la instalación y tomando en consideración aspectos pertenecientes a terapias de expresión artística, se plantean sesiones arteterapéuticas fundamentadas en el uso de la instalación.

Several studies have demonstrated that melanoma-derived extracellular vesicles (EVs) are involved in lymph node metastasis; however, the molecular mechanisms involved are not completely defined. Here, we found that EMILIN-1 is proteolyzed and secreted in small EVs (sEVs) as a novel mechanism to reduce its intracellular levels favoring metastasis in mouse melanoma lymph node metastatic cells. Interestingly, we observed that EMILIN-1 has intrinsic tumor and metastasis suppressive-like properties reducing effective migration, cell viability, primary tumor growth, and metastasis. Overall, our analysis suggests that the inactivation of EMILIN-1 by proteolysis and secretion in sEVs reduce its intrinsic tumor suppressive activities in melanoma favoring tumor progression and metastasis.

El teatro de Fabbri –de corte eminentemente católico y con planteamientos escénicos ciertamente pirandellianos– no entró en conflicto con la férrea censura que imponía el régimen franquista y gozó de la aceptación del público y de la crítica (con alguna excepción). Es importante subrayar que en ningún momento el dramaturgo reconoce que las traducciones o adaptaciones realizadas hayan sido aliadas o adversarias de su éxito, ya que la resonancia internacional le llega a un autor de la mano solo de sus temas.

El estudio se ocupa de la traducción del teatro italiano en el último cuarto del siglo XX en España. El análisis muestra que no se puede hablar de un modelo de traducción exclusivamente vinculado a la tipología textual; en cambio sí se advierte la existencia de traducciones de varios tipos, clases o naturaleza, dependiendo de la finalidad o la situación comunicativa del destinatario, subrayando así la dependencia y el papel central del sistema meta en el proceso de trasvase de la lengua origen a la lengua meta, y ello se muestra tanto en las traducciones como en las versiones o adaptaciones cotejadas.

We studied the effect of the Temperature Humidity Index (THI) (i.e., the average of temperature and relative humidity registered at meteorological stations) closest to the farms taken during the test day (TD), for total daily protein and fat yields (fpy) of the three main Spanish dairy goats. The data were from Florida (11,244 animals and 126,825 TD), Malagueña (12,215 animals and 141,856 TD) and Murciano Granadina (5162 animals and 62,834 TD) breeding programs and were studied by different linear models to estimate the nature of the fpy response throughout the THI and the weeks of lactation (Days in Milk, DIM) trajectories. The results showed an antagonism between THI and DIM, with a marked depression in the fpy level in animals kept in the hot zone of the THI values (THI > 25) compared with those in the cold zone (THI ≤ 16), with a negative impact equivalent to production of 13 to 30 days. We used a Reaction Norm model (RN), including THI and DIM as fixed covariates and a Test Day Model (TDM), to estimate the genetic (co)variance components. The heritability and genetic correlations estimated with RN and TDM showed a decreased pattern along the scale of THI and DIM, with slight differences between breeds, meaning that there was significant genetic variability in the animal’s ability to react to different levels of THI, which is not constant throughout the DIM, showing the existence of genotype-environment interaction. The breeding values (BV) of all animals for each level of THI and DIM were subject to a principal component analysis, and the results showed that 89 to 98% of the variance between the BV was explained by the two first eigenvalues. The standardized BV were weighted with the corresponding eigenvector coefficients to construct an index that showed, in a single indicator, the most complete expression of the existing genetic variability in the animals’ ability to produce fpy along the trajectories of THI and DIM. This new option will make it easier to select animals which are more productive, and with better adaptability to heat stress, as well as enabling us to exploit genetic variations in the form of the response to heat stress to be adapted to different production systems.

The aim of this study was to estimate genetic parameters for several female fertility criteria and to choose the most suitable selection index in Spanish Florida and Payoya goat breeds. In this study, we analyzed as fertility traits, the age at first kidding (AgFiKid), and the interval between the first and second kiddings (Int12Kid), between the second, third, and remaining kiddings (Int3toKid), and between all kiddings (IntAllKid) in 51,123 and 22,049 Florida and Payoya females, respectively. Genetic parameters were estimated by fitting animal models using restricted maximum likelihood (REML) methodology. We proposed six selection indices to compare the genetic responses for all traits included, based on a new selection index theory. The heritability and repeatability estimates of the traits were low, as expected. The genetic correlations among fertility traits covered a wide range of values from 0.07 (AgFiKid-Int12Kid) to 0.71 (Int3toKid-IntAllKid) in Florida and from −0.02 (AgFiKid-Int12Kid) to 0.82 (Int3toKid-IntAllKid) in Payoya. Overall, the results of this study indicate that IntAllKid gives the highest genetic responses in both breeds but is expressed late in a female’s life. However, AgFiKid and Int12Kid could be recommended as early selection criteria for female fertility in both breeds.

El presente artículo plantea “La Caja” como objeto artístico conceptualizado como material didáctico. Tomando como antecedente la Boîte-en-Valise de Marcel Duchamp y las bases del arte conceptual, la caja como objeto artístico plantea, dentro de los procesos de enseñanza-aprendizaje, una herramienta activa que puede llegar a ser contenedora de conceptos. De este modo, el proyecto “Caja de artista” pretende procesar aspectos curriculares desde una óptica abierta, creativa y que promueva la consecución de competencias básicas. Tras un acercamiento a la aparición y desarrollo de la caja como elemento artístico a lo largo del siglo XX, se exponen los resultados de un estudio realizado con estudiantes de Grado en Maestro de Educación Primaria de una Facultad de Magisterio y Ciencias de la Educación de la Comunidad Valenciana. En base a los proyectos realizados en el área de Educación Artística se describe el proceso de creación así como una evaluación sobre diferentes aspectos en el desarrollo del mismo en base a cuestionarios cumplimentados por los estudiantes. Así mismo, se exponen cuestiones referentes a una puesta en práctica llevada a cabo por estudiantes de Grado en aulas de educación primaria de un CEIP de la Comunidad Valenciana. Para finalizar, se analiza un cuestionario lanzado a los profesores del centro educativo implicados con el fin de extraer una serie de consideraciones sobre esta propuesta artística como posible material didáctico.

The aim of this study is to trace the theatrical translations of the work of Ugo Betti (one of the most important Italian dramatists of the 20th century) in the Spanish theaters during the dictatorship of Franco. This task requires attention to the main parameters such as the literary genre (drama), the socio-political context, the profile of the translators or the adaptors, their conception of translation and the target audience. Drama production (translations or adaptations), even if not published, plays a crucial role regarding the reception of a prominent dramatist at a global level.

PurposeNo approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS)-mutant melanoma is currently available.Patients and methodsIn this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic KRAS- or BRAF-mutant non-small-cell lung cancer (escalation arm) or NRAS-mutant melanoma (escalation and expansion arms).ResultsThirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade ≥3 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily.ConclusionNaporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.

The role of systemic immunity in the pathogenesis of cirrhosis is not fully understood. Analysis of transcriptomic profiles in blood is an easy approach to obtain a wide picture of immune response at the systemic level. We studied gene expression profiles in blood from thirty cirrhotic patients and compared them against those of eight healthy volunteers. Most of our patients were male [n = 21, 70%] in their middle ages [57.4 ± 6.8 yr]. Alcohol abuse was the most frequent cause of cirrhosis (n = 22, 73%). Eleven patients had hepatocellular carcinoma (36.7%). Eight patients suffered from hepatitis C virus infection (26.7%). We found a signature constituted by 3402 genes which were differentially expressed in patients compared to controls (2802 over-expressed and 600 under-expressed). Evaluation of this signature evidenced the existence of an active pro-fibrotic transcriptomic program in the cirrhotic patients, involving the [extra-cellular matrix (ECM)-receptor interaction] & [TGF-beta signaling] pathways along with the [Cell adhesion molecules] pathway. This program coexists with alterations in pathways participating in [Glycine, serine and threonine metabolism], [Phenylalanine metabolism], [Tyrosine metabolism], [ABC transporters], [Purine metabolism], [Arachidonic acid metabolism]. In consequence, our results evidence the co-existence in blood of a genomic program mediating pro-fibrotic mechanisms and metabolic alterations in advanced cirrhosis. Monitoring expression levels of the genes involved in these programs could be of interest for predicting / monitoring cirrhosis evolution. These genes could constitute therapeutic targets in this disease.

Irvalec is a marine-derived antitumor agent currently undergoing phase II clinical trials. In vitro, Irvalec induces a rapid loss of membrane integrity in tumor cells, accompanied of a significant Ca(2+) influx, perturbations of membrane conductivity, severe swelling and the formation of giant membranous vesicles. All these effects are not observed in Irvalec-resistant cells, or are significantly delayed by pretreating the cells with Zn(2+). Using fluorescent derivatives of Irvalec it was demonstrated that the compound rapidly interacts with the plasma membrane of tumor cells promoting lipid bilayer restructuration. Also, FRET experiments demonstrated that Irvalec molecules localize in the cell membrane close enough to each other as to suggest that the compound could self-organize, forming supramolecular structures that likely trigger cell death by necrosis through the disruption of membrane integrity.

In PIVOT IO 001 (NCT03635983), the combination of the investigational interleukin-2 agonist bempegaldesleukin (BEMPEG) with nivolumab (NIVO) had no added clinical benefit over NIVO monotherapy in unresectable/metastatic melanoma. Pre-defined baseline and on-treatment changes in selected biomarkers were analyzed to explore the potential mechanisms underlying the clinical observations. In each treatment arm, higher baseline tumor mutational burden or immune infiltration/inflammation was associated with improved efficacy compared with lower levels. On-treatment peripheral biomarker changes showed that BEMPEG + NIVO increased all immune cell subset counts interrogated, including regulatory T cells. This was followed by attenuation of the increase in CD8 + T cells, conventional CD4 + T cells, and systemic interferon gamma levels at later treatment cycles in the combination arm. Changes in tumor biomarkers were comparable between arms. These biomarker results help provide a better understanding of the mechanism of action of BEMPEG + NIVO and may help contextualize the clinical observations from PIVOT IO 001. [ABSTRACT FROM AUTHOR]

Introduction: Although checkpoint inhibitors (CPIs) have improved outcomes for patients with metastatic melanoma, those progressing on CPIs have limited therapeutic options. To address this unmet need and overcome CPI resistance mechanisms, novel immunotherapies, such as T-cell engaging agents, are being developed. The use of these agents has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs), which is challenging to predict preclinically and can lead to neutralization of the drug and loss of efficacy. Methods: TYRP1-TCB (RO7293583; RG6232) is a T-cell engaging bispecific (TCB) antibody that targets tyrosinase-related protein 1 (TYRP1), which is expressed in many melanomas, thereby directing T cells to kill TYRP1-expressing tumor cells. Preclinical studies show TYRP1-TCB to have potent anti-tumor activity. This first-in-human (FIH) phase 1 dose-escalation study characterized the safety, tolerability, maximum tolerated dose/optimal biological dose, and pharmacokinetics (PK) of TYRP1-TCB in patients with metastatic melanoma (NCT04551352). Results: Twenty participants with cutaneous, uveal, or mucosal TYRP1-positive melanoma received TYRP1-TCB in escalating doses (0.045 to 0.4 mg). All participants experienced ≥1 treatment-related adverse event (TRAE); two participants experienced grade 3 TRAEs. The most common toxicities were grade 1-2 cytokine release syndrome (CRS) and rash. Fractionated dosing mitigated CRS and was associated with lower levels of interleukin-6 and tumor necrosis factor-alpha. Measurement of active drug (dual TYPR1- and CD3-binding) PK rapidly identified loss of active drug exposure in all participants treated with 0.4 mg in a flat dosing schedule for ≥3 cycles. Loss of exposure was associated with development of ADAs towards both the TYRP1 and CD3 domains. A total drug PK assay, measuring free and ADA-bound forms, demonstrated that TYRP1-TCB-ADA immune complexes were present in participant samples, but showed no drug activity in vitro. Discussion: This study provides important insights into how the use of active drug PK assays, coupled with mechanistic follow-up, can inform and enable ongoing benefit/risk assessment for individuals participating in FIH dose-escalation trials. Translational studies that lead to a better understanding of the underlying biology of cognate T- and B-cell interactions, ultimately resulting in ADA development to novel biotherapeutics, are needed. [ABSTRACT FROM AUTHOR]