Mismatches between phenotype andenvironment shape fitness at hyperlocalscales

In the era of human-driven climate change, understanding whether behavioural buffering of temperature change is linked with organismal fitness is essential. According to the ‘cost–benefit’ model of thermoregulation, animals that live in environments with high frequencies of favourable thermal microclimates should incur lower thermoregulatory costs, thermoregulate more efficiently and shunt the associated savings in time and energy towards other vital tasks such as feeding, territory defence and mate acquisition, increasing fitness. Here, we explore how thermal landscapes at the scale of individual territories, physiological performance and behaviour interact and shape fitness in the southern rock agama lizard (Agama atra). We integrated laboratory assays of whole organism performance with behavioural observations in the field, fine-scale estimates of environmental temperature, and paternity assignment of offspring to test whether fitness is predicted by territory thermal quality (i.e. the number of hours that operative temperatures in a territory fall within an individual's performance breadth). Male lizards that occupied territories of low thermal quality spent more time behaviourally compensating for sub-optimal temperatures and displayed less. Further, display rate was positively associated with lizard fitness, suggesting that there is an opportunity cost to engaging in thermoregulatory behaviour that will change as climate change progresses.This research was financially and logistically supported by the National Research Foundation (NRF) of South Africa (CPRR no. 98880). K.A. was supported by the NRF Doctoral Scholarship for Full-time Studies. M.L.L. was supported by a United States National Science Foundation Postdoctoral Fellowship in Biology (award number DBI-1402497). S.T. received funding from grant PID2020-117115GA-100 funded by MCIN/AEI/10.13039/501100011033 and by Ramón y Cajal grant RYC2021-03152-I, funded by MCIN/AEI/10.13039/501100011033 and the European Union NextGenerationEU/PRTR.Peer reviewe

The EMA assessment of pembrolizumab as monotherapy for the first-line treatment of adult patients with metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer

On 21 January 2021, the European Commission amended the marketing authorisation granted for pembrolizumab to include the first-line treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) in adults. The recommended dose of pembrolizumab was either 200 mg every 3 weeks or 400 mg every 6 weeks by intravenous infusion. Pembrolizumab was evaluated in a phase III, open-label, multicentre, randomised trial versus standard of care (SOC: FOLFOX6/FOLFIRI alone or in combination with bevacizumab/cetuximab) as first-line treatment of locally confirmed mismatch repair-deficient or microsatellite instability-high stage IV CRC. Subjects randomised to the SOC arm had the option to crossover and receive pembrolizumab once disease progressed. Both progression-free survival (PFS) and overall survival were primary endpoints. Pembrolizumab showed a statistically significant improvement in PFS compared with SOC, with a hazard ratio of 0.60 [95% confidence interval (CI): 0.45-0.80], P = 0.0002. Median PFS was 16.5 (95% CI: 5.4-32.4) versus 8.2 (95% CI: 6.1-10.2) months for the pembrolizumab versus SOC arms, respectively. The most frequent adverse events in patients receiving pembrolizumab were diarrhoea, fatigue, pruritus, nausea, increased aspartate aminotransferase, rash, arthralgia, and hypothyroidism. Having reviewed the data submitted, the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) considered that the benefit–risk balance was positive. This is the first time the CHMP has issued an opinion for a target population defined by DNA repair deficiency biomarkers. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval in the European Union

Behavioral sensitization and cellular responses to psychostimulants are reduced in D2R knockout mice

Repeated cocaine exposure causes long-lasting neuroadaptations that involve alterations in cellular signaling and gene expression mediated by dopamine in different brain regions, such as the striatum. Previous studies have pointed out to the dopamine D1 receptor as one major player in psychostimulants-induced behavioral, cellular, and molecular changes. However, the role of other dopamine receptors has not been fully characterized. Here we used dopamine D2 receptor knockout (D2−/−) mice to explore the role of D2 receptor (D2R) in behavioral sensitization and its associated gene expression after acute and chronic cocaine and amphetamine administration. We also studied the impact of D2R elimination in D1R-mediated responses. We found that cocaine- and amphetamine-induced behavioral sensitization is deficient in D2−/− mice. The expression of dynorphin, primarily regulated by D1R and a marker of direct-pathway striatal neurons, is attenuated in naïve- and in cocaine- or amphetamine-treated D2−/− mice. Moreover, c-Fos expression observed in D2−/− mice was reduced in acutely but not in chronically treated animals. Interestingly, inactivation of D2R increased c-Fos expression in neurons of the striatopallidal pathway. Finally, elimination of D2R blunted the locomotor and striatal c-Fos response to the full D1 agonist SKF81297. In conclusion, D2R is critical for the development of behavioral sensitization and the associated gene expression, after cocaine administration, and it is required for the locomotor responses promoted by D1R activation.Fil: Solís, Oscar. Consejo Superior de Investigaciones Científicas; EspañaFil: García Sanz, Patricia. Consejo Superior de Investigaciones Científicas; EspañaFil: Martín, Ana B.. Consejo Superior de Investigaciones Científicas; EspañaFil: Granado, Noelia Fernanda. Consejo Superior de Investigaciones Científicas; EspañaFil: Sanz Magro, Adrián. Consejo Superior de Investigaciones Científicas; EspañaFil: Podlesniy, Petar. No especifíca;Fil: Trullas, Ramón. No especifíca;Fil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Maldonado, Rafael. Universitat Pompeu Fabra; EspañaFil: Moratalla, Rosario. Consejo Superior de Investigaciones Científicas; Españ

Behavioral sensitization and cellular responses to psychostimulants are reduced in D2R knockout mice

Repeated cocaine exposure causes long-lasting neuroadaptations that involve alterations in cellular signaling and gene expression mediated by dopamine in different brain regions, such as the striatum. Previous studies have pointed out to the dopamine D1 receptor as one major player in psychostimulants-induced behavioral, cellular, and molecular changes. However, the role of other dopamine receptors has not been fully characterized. Here we used dopamine D2 receptor knockout (D2−/−) mice to explore the role of D2 receptor (D2R) in behavioral sensitization and its associated gene expression after acute and chronic cocaine and amphetamine administration. We also studied the impact of D2R elimination in D1R-mediated responses. We found that cocaine- and amphetamine-induced behavioral sensitization is deficient in D2−/− mice. The expression of dynorphin, primarily regulated by D1R and a marker of direct-pathway striatal neurons, is attenuated in naïve- and in cocaine- or amphetamine-treated D2−/− mice. Moreover, c-Fos expression observed in D2−/− mice was reduced in acutely but not in chronically treated animals. Interestingly, inactivation of D2R increased c-Fos expression in neurons of the striatopallidal pathway. Finally, elimination of D2R blunted the locomotor and striatal c-Fos response to the full D1 agonist SKF81297. In conclusion, D2R is critical for the development of behavioral sensitization and the associated gene expression, after cocaine administration, and it is required for the locomotor responses promoted by D1R activation.This work was supported by grants from the Spanish Ministries of Innovation, Science and Universities (SAF2016-78207-R and PCIN2015-098 to R. Moratalla, SAF2017-84060-R-AEI/FEDER-UE to R. Maldonado, and SAF2017-89791-R to P. Podlesniy and R. Trullas) and Health, Social Services and Equality (PNSD 2016/033 and CIBERNED CB06/05/0055 to R. Moratalla and RETICS/RTA, RD16/0017 to R.Maldonado.) and from the Ramón Areces Foundation (172275 and OTR02679) to R. Moratalla and ANPCYT (Agency for the Promotion of Science and Technology, Argentina), PICT 2013 1523 and 2015 3687 and by the University of Buenos Aires (UBACYT 2018) to M.G.M. and the Catalan Government (AGAUR, #ICREA Acadèmia-2015 and #2017-SGR-669) to R. Maldonado

Multidisciplinary consensus on the criteria for fertility preservation in cancer patients

Infertility is one of the main sequelae of cancer and its treatment in both children and adults of reproductive age. It is, therefore, essential that oncologists and haematologists provide adequate information about the risk of infertility and the possibilities for its preservation before starting treatment. Although many international clinical guidelines address this issue, this document is the first Spanish multidisciplinary guideline in paediatric and adult oncological patients. Experts from the Spanish Society of Medical Oncology, the Spanish Fertility Society, the Spanish Society of Haematology and Haemotherapy, the Spanish Society of Paediatric Haematology and Oncology and the Spanish Society of Radiation Oncology have collaborated to develop a multidisciplinary consensus