Atezolizumab plus modified docetaxel, cisplatin, and fluorouracil as first-line treatment for advanced anal cancer (SCARCE C17-02 PRODIGE 60): a randomised, non-comparative, phase 2 study.

BACKGROUND: The modified docetaxel, cisplatin, and fluorouracil (mDCF) regimen has shown efficacy and safety as first-line treatment for advanced squamous cell carcinoma of the anus, making it a standard regimen. Inhibitors of programmed cell death protein 1 and its ligand, such as pembrolizumab, nivolumab, retifanlimab, avelumab, and atezolizumab, have shown some antitumour activity as monotherapy in advanced squamous cell carcinoma of the anus that is refractory to chemotherapy. This phase 2 study evaluated the combination of mDCF and atezolizumab as first-line treatment in advanced squamous cell carcinoma of the anus. METHODS: In this randomised, open-label, non-comparative, phase 2 study, participants from 21 centres (academic, private, and community hospitals and cancer research centres) across France with chemo-naive, metastatic, or unresectable locally advanced recurrent squamous cell carcinoma of the anus, aged 18 years or older, and with an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly allocated (2:1) to receive either atezolizumab (800 mg intravenously every 2 weeks up to 1 year) plus mDCF (eight cycles of 40 mg per m2 docetaxel and 40 mg per m2 cisplatin on day 1 and 1200 mg per m2 per day of fluorouracil for 2 days, every 2 weeks intravenously; group A) or mDCF alone (group B). Randomisation was done centrally using a minimisation technique and was stratified by age (<65 years vs ≥65 years) and disease status. The primary endpoint was investigator-assessed 12-month progression-free survival in the modified intention-to-treat population in group A (35% for the null hypothesis and 50% for the alternative hypothesis). This trial is registered with ClinicalTrials.gov, NCT03519295, and is closed to new participants. FINDINGS: 97 evaluable participants (64 in group A and 33 in group B) were enrolled between July 3, 2018, and Aug 19, 2020. The median follow-up was 26·5 months (95% CI 24·8-28·4). The median age of participants was 64·1 years (IQR 56·2-71·6), and 71 (73%) were female. 12-month progression-free survival was 45% (90% CI 35-55) in group A and 43% (29-58) in group B. In participants with a PD-L1 combined positive score of 5 or greater, 12-month progression-free survival was 70% (95% CI 47-100) in group A and 40% (19-85) in group B (interaction p=0·051) Both groups showed high compliance. Adverse events of grade 3 or higher were observed in 39 (61%) participants in group A and 14 (42%) in group B. The most common grade 3-4 adverse events were neutropenia (nine [14%] participants in group A vs five [15%] in group B), anaemia (nine [14%] vs one [3%]), fatigue (three [5%] vs four [12%]), and diarrhoea (seven [11%] vs one [3%]). Serious adverse events occurred in 16 (25%) participants in group A and four (12%) in group B, and these were mDCF-related in seven (11%) participants in group A and four (12%) in group B. Atezolizumab-related serious adverse events occurred in nine (14%) participants in group A, including grade 2 infusion-related reaction in three (5%), grade 3 infection in two (3%), and grade 2 colitis, grade 3 acute kidney injury, grade 3 sarcoidosis, and a grade 4 platelet count decrease each in one participant (2%). There were no treatment-related deaths. INTERPRETATION: Despite a higher incidence of adverse events, combining atezolizumab with mDCF is feasible, with similar dose intensity in both groups, although the primary efficacy endpoint was not met. The predictive value of a PD-L1 combined positive score of 5 or greater now needs to be confirmed in future studies. FUNDING: GERCOR, Roche.

The olfactory receptor Olfr78 promotes differentiation of enterochromaffin cells in the mouse colon.

The gastrointestinal epithelium constitutes a chemosensory system for microbiota-derived metabolites such as short-chain fatty acids (SCFA). Here, we investigate the spatial distribution of Olfr78, one of the SCFA receptors, in the mouse intestine and study the transcriptome of colon enteroendocrine cells expressing Olfr78. The receptor is predominantly detected in the enterochromaffin and L subtypes in the proximal and distal colon, respectively. Using the Olfr78-GFP and VilCre/Olfr78flox transgenic mouse lines, we show that loss of epithelial Olfr78 results in impaired enterochromaffin cell differentiation, blocking cells in an undefined secretory lineage state. This is accompanied by a reduced defense response to bacteria in colon crypts and slight dysbiosis. Using organoid cultures, we further show that maintenance of enterochromaffin cells involves activation of the Olfr78 receptor via the SCFA ligand acetate. Taken together, our work provides evidence that Olfr78 contributes to colon homeostasis by promoting enterochromaffin cell differentiation.

Adipocyte Glucocorticoid Receptor Activation With High Glucocorticoid Doses Impairs Healthy Adipose Tissue Expansion by Repressing Angiogenesis.

In humans, glucocorticoids (GCs) are commonly prescribed because of their anti-inflammatory and immunosuppressive properties. However, high doses of GCs often lead to side effects, including diabetes and lipodystrophy. We recently reported that adipocyte glucocorticoid receptor (GR)-deficient (AdipoGR-KO) mice under corticosterone (CORT) treatment exhibited a massive adipose tissue (AT) expansion associated with a paradoxical improvement of metabolic health compared with control mice. However, whether GR may control adipose development remains unclear. Here, we show a specific induction of hypoxia-inducible factor 1α (HIF-1α) and proangiogenic vascular endothelial growth factor A (VEGFA) expression in GR-deficient adipocytes of AdipoGR-KO mice compared with control mice, together with an increased adipose vascular network, as assessed by three-dimensional imaging. GR activation reduced HIF-1α recruitment to the Vegfa promoter resulting from Hif-1α downregulation at the transcriptional and posttranslational levels. Importantly, in CORT-treated AdipoGR-KO mice, the blockade of VEGFA by a soluble decoy receptor prevented AT expansion and the healthy metabolic phenotype. Finally, in subcutaneous AT from patients with Cushing syndrome, higher VEGFA expression was associated with a better metabolic profile. Collectively, these results highlight that adipocyte GR negatively controls AT expansion and metabolic health through the downregulation of the major angiogenic effector VEGFA and inhibition of vascular network development.

Blasts with folded nuclei: A histopathologic finding in myeloid leukemia cutis with NPM1 and FLT3 mutations.

Leukemia cutis is a term used to describe cutaneous manifestations of leukemic infiltration of the skin and portends a poor prognosis. Cutaneous involvement by hematopoietic/lymphoid tumors can occur before, concurrently, or after the initial diagnosis. Early involvement of dermatologists and timely biopsies play a crucial role in achieving a prompt diagnosis. Prior reports of acute myeloid leukemia have revealed a strong association between the cup-like nuclear morphology observed in bone marrow specimens and concurrent mutations of NPM1 and FLT3-ITD. In cutaneous tissue sections of leukemia cutis, folded or indented nuclei may represent the "cup-like" counterpart previously described in bone marrow specimens. Recognizing this morphological feature could aid in identifying this molecular subtype of leukemia cutis. In this study, we present a case of leukemia cutis in a 63-year-old female with AML and NPM1 and FLT3-ITD mutations, demonstrating scattered indented/folded nuclei.

GABRA1-Related Disorders: From Genetic to Functional Pathways.

OBJECTIVE: Variants in GABRA1 have been associated with a broad epilepsy spectrum, ranging from genetic generalized epilepsies to developmental and epileptic encephalopathies. However, our understanding of what determines the phenotype severity and best treatment options remains inadequate. We therefore aimed to analyze the electroclinical features and the functional effects of GABRA1 variants to establish genotype-phenotype correlations. METHODS: Genetic and electroclinical data of 27 individuals (22 unrelated and 2 families) harboring 20 different GABRA1 variants were collected and accompanied by functional analysis of 19 variants. RESULTS: Individuals in this cohort could be assigned into different clinical subgroups based on the functional effect of their variant and its structural position within the GABRA1 subunit. A homogenous phenotype with mild cognitive impairment and infantile onset epilepsy (focal seizures, fever sensitivity, and electroencephalographic posterior epileptiform discharges) was described for variants in the extracellular domain and the small transmembrane loops. These variants displayed loss-of-function (LoF) effects, and the patients generally had a favorable outcome. A more severe phenotype was associated with variants in the pore-forming transmembrane helices. These variants displayed either gain-of-function (GoF) or LoF effects. GoF variants were associated with severe early onset neurodevelopmental disorders, including early infantile developmental and epileptic encephalopathy. INTERPRETATION: Our data expand the genetic and phenotypic spectrum of GABRA1 epilepsies and permit delineation of specific subphenotypes for LoF and GoF variants, through the heterogeneity of phenotypes and variants. Generally, variants in the transmembrane helices cause more severe phenotypes, in particular GoF variants. These findings establish the basis for a better understanding of the pathomechanism and a precision medicine approach in GABRA1-related disorders. Further studies in larger populations are needed to provide a conclusive genotype-phenotype correlation. ANN NEUROL 2023.

A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E-Mutated Differentiated Thyroid Cancer.

PURPOSE: To evaluate the efficacy and safety of dabrafenib-trametinib-131I for the treatment of radioactive iodine refractory metastatic differentiated thyroid cancer (DTC) with a BRAF p.V600E mutation. PATIENTS AND METHODS: A prospective phase II trial including patients with RECIST progression within 18 months and no lesion > 3 cm. Following a baseline recombinant human (rh)TSH-stimulated diagnostic whole-body scan (dc1-WBS), dabrafenib and trametinib were given for 42 days. A second rhTSH-stimulated dc WBS (dc2-WBS) was done at day 28 and 131I (5.5 GBq-150 mCi after rhTSH) was administered at day 35. Primary endpoint was the 6-month RECIST objective response rate. In case of partial response (PR) at 6 or 12 months, a second treatment course could be given. Among 24 enrolled patients, 21 were evaluable at 6 months. RESULTS: Abnormal 131I uptake was present on 5%, 65%, and 95% of the dc1-WBS, dc2-WBS, and post-therapy scans, respectively. At 6 months, PR was achieved in 38%, stable disease in 52%, and progressive disease (PD) in 10%. Ten patients received a second treatment course: one complete response and 6 PRs were observed at 6 months. The median progression-free survival (PFS) was not reached. The 12- and 24-month PFS were 82% and 68%, respectively. One death due to PD occurred at 24 months. Adverse events (AE) occurred in 96% of the patients, with 10 grade 3-4 AEs in 7 patients. CONCLUSIONS: Dabrafenib-trametinib is effective in BRAF p.V600E-mutated DTC patients for restoring 131I uptake with PR observed 6 months after 131I administration in 38% of the patients.

Acceptance, efficacy, and safety of COVID-19 vaccination in older patients with cancer.

PURPOSE: The COVID-19 vaccination campaign began in December 2020, in France, and primarily targeted the oldest people. Our study aimed to determine the level of acceptance of vaccination in a population of older patients with cancer. METHODS: From January 2021, we offered vaccination with the BNT162b2 COVID-19 vaccine to all patients 70 years and older referred to our geriatric oncology center in Marseille University Hospital (AP-HM) for geriatric assessment before initiation of an oncological treatment. Objectives were to evaluate acceptance rate of COVID-19 vaccination and to assess vaccine safety, reactogenicity, and efficacy two months after the first dose. RESULTS: Between January 18, 2021 and May 7, 2021, 150 older patients with cancer were offered vaccination after a geriatric assessment. The majority were men (61.3%), with a mean age of 81 years. The two most frequent primary tumors were digestive (29.4%) and thoracic (18%). The vaccine acceptance rate was 82.6% and the complete vaccination rate (2 doses) reached 75.3%. Among the vaccinated patients, 15.9% reported mild side effects after the first dose and 23.4% after the second dose, mostly arm pain and fatigue. COVID-19 cases were observed in 5.1% of vaccinated patients compared with 16.7% in unvaccinated patients. Of the 22 vaccinated patients who agreed to have their serum tested, 15 had antibodies against the spike protein at day 21 after the first dose. CONCLUSION: Our study showed a high acceptance rate of COVID-19 vaccination, with good tolerance in this frail population. These results highlight the benefits of organizing vaccination campaigns at the very beginning of oncological management in older patients. CLINICAL TRIAL REGISTRATION: This study was registered May 23, 2019 in ClinicalTrials.gov (NCT03960593).

Cold atmospheric plasma differentially affects cell renewal and differentiation of stem cells and APC-deficient-derived tumor cells in intestinal organoids.

Cold atmospheric plasma (CAP) treatment has been proposed as a potentially innovative therapeutic tool in the biomedical field, notably for cancer due to its proposed toxic selectivity on cancer cells versus healthy cells. In the present study, we addressed the relevance of three-dimensional organoid technology to investigate the biological effects of CAP on normal epithelial stem cells and tumor cells isolated from mouse small intestine. CAP treatment exerted dose-dependent cytotoxicity on normal organoids and induced major transcriptomic changes associated with the global response to oxidative stress, fetal-like regeneration reprogramming, and apoptosis-mediated cell death. Moreover, we explored the potential selectivity of CAP on tumor-like Apc-deficient versus normal organoids in the same genetic background. Unexpectedly, tumor organoids exhibited higher resistance to CAP treatment, correlating with higher antioxidant activity at baseline as compared to normal organoids. This pilot study suggests that the ex vivo culture system could be a relevant alternative model to further investigate translational medical applications of CAP technology.

Interleukin-6 is an activator of pituitary stem cells upon local damage, a competence quenched in the aging gland.

Stem cells in the adult pituitary are quiescent yet show acute activation upon tissue injury. The molecular mechanisms underlying this reaction are completely unknown. We applied single-cell transcriptomics to start unraveling the acute pituitary stem cell activation process as occurring upon targeted endocrine cell-ablation damage. This stem cell reaction was contrasted with the aging (middle-aged) pituitary, known to have lost damage-repair capacity. Stem cells in the aging pituitary show regressed proliferative activation upon injury and diminished in vitro organoid formation. Single-cell RNA sequencing uncovered interleukin-6 (IL-6) as being up-regulated upon damage, however only in young but not aging pituitary. Administering IL-6 to young mice promptly triggered pituitary stem cell proliferation, while blocking IL-6 or associated signaling pathways inhibited such reaction to damage. By contrast, IL-6 did not generate a pituitary stem cell activation response in aging mice, coinciding with elevated basal IL-6 levels and raised inflammatory state in the aging gland (inflammaging). Intriguingly, in vitro stem cell activation by IL-6 was discerned in organoid culture not only from young but also from aging pituitary, indicating that the aging gland's stem cells retain intrinsic activatability in vivo, likely impeded by the prevailing inflammatory tissue milieu. Importantly, IL-6 supplementation strongly enhanced the growth capability of pituitary stem cell organoids, thereby expanding their potential as an experimental model. Our study identifies IL-6 as a pituitary stem cell activator upon local damage, a competence quenched at aging, concomitant with raised IL-6/inflammatory levels in the older gland. These insights may open the way to interfering with pituitary aging.

Real-world efficacy and safety of pembrolizumab in patients with non-small cell lung cancer: a retrospective observational study.

BACKGROUND: Pembrolizumab, a humanized immunoglobulin monoclonal antibody directed against the programmed cell death 1 receptor, demonstrated robust efficacy and a manageable safety profile across multiple tumor types in clinical trials. AIM: To investigate the efficacy and safety of first-line pembrolizumab for patients with non-small cell lung cancers (NSCLCs) in clinical practice. METHODS: In this observational monocentric retrospective study, 38 patients with PD-L1 >50% were enrolled between November 2017 and November 2018. RESULTS: The global median overall survival was 11.08 months (95% confidence interval [CI], 5.98-not reached) and the global median progression-free survival was 6 months (95% CI, 3-not reached). In the univariate analysis, clinical performance status score and the development of immune-related adverse events were the only 2 clinical factors significantly correlated with overall survival. CONCLUSION: The results of the present study suggest that pembrolizumab seems less effective in the real-life population than in the pivotal clinical trials in patients with NSCLC but remains an effective treatment option for patients with NSCLC. Longer follow-up is needed.

Medical management of adrenocortical carcinoma: Current recommendations, new therapeutic options and future perspectives.

Adrenocortical carcinoma is a rare malignant tumor of poor prognosis, frequently requiring additional treatments after initial surgery. Due to its adrenolytic action, mitotane has become the first-line medical treatment in patients with aggressive adrenocortical carcinoma. Over the last 2years, apart from the classical chemotherapy based on etoposide and platinum salts, several studies reported the use of drugs such as temozolomide, tyrosine kinase inhibitors or immunotherapy, with more or less convincing results. The aim of this review is to give further insights in the use of these drugs, and to describe potential therapeutic perspectives based on recent pangenomic studies, for the future management of these still difficult to treat tumors.

LGR4 deficiency results in delayed puberty through impaired Wnt/ß-catenin signaling.

The initiation of puberty is driven by an upsurge in hypothalamic gonadotropin-releasing hormone (GnRH) secretion. In turn, GnRH secretion upsurge depends on the development of a complex GnRH neuroendocrine network during embryonic life. Although delayed puberty (DP) affects up to 2% of the population, is highly heritable, and is associated with adverse health outcomes, the genes underlying DP remain largely unknown. We aimed to discover regulators by whole-exome sequencing of 160 individuals of 67 multigenerational families in our large, accurately phenotyped DP cohort. LGR4 was the only gene remaining after analysis that was significantly enriched for potentially pathogenic, rare variants in 6 probands. Expression analysis identified specific Lgr4 expression at the site of GnRH neuron development. LGR4 mutant proteins showed impaired Wnt/ß-catenin signaling, owing to defective protein expression, trafficking, and degradation. Mice deficient in Lgr4 had significantly delayed onset of puberty and fewer GnRH neurons compared with WT, whereas lgr4 knockdown in zebrafish embryos prevented formation and migration of GnRH neurons. Further, genetic lineage tracing showed strong Lgr4-mediated Wnt/ß-catenin signaling pathway activation during GnRH neuron development. In conclusion, our results show that LGR4 deficiency impairs Wnt/ß-catenin signaling with observed defects in GnRH neuron development, resulting in a DP phenotype.

LGR5 controls extracellular matrix production by stem cells in the developing intestine.

The Lgr5 receptor is a marker of intestinal stem cells (ISCs) that regulates Wnt/b-catenin signaling. In this study, phenotype analysis of knockin/knockout Lgr5-eGFP-IRES-Cre and Lgr5-DTReGFP embryos reveals that Lgr5 deficiency during Wnt-mediated cytodifferentiation results in amplification of ISCs and early differentiation into Paneth cells, which can be counteracted by in utero treatment with the Wnt inhibitor LGK974. Conditional ablation of Lgr5 postnatally, but not in adults, alters stem cell fate toward the Paneth lineage. Together, these in vivo studies suggest that Lgr5 is part of a feedback loop to adjust the Wnt tone in ISCs. Moreover, transcriptome analyses reveal that Lgr5 controls fetal ISC maturation associated with acquisition of a definitive stable epithelial phenotype, as well as the capacity of ISCs to generate their own extracellular matrix. Finally, using the ex vivo culture system, evidences are provided that Lgr5 antagonizes the Rspondin 2-Wnt-mediated response in ISCs in organoids, revealing a sophisticated regulatory process for Wnt signaling in ISCs.

Progerin Expression Induces Inflammation, Oxidative Stress and Senescence in Human Coronary Endothelial Cells.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder notably characterized by precocious and deadly atherosclerosis. Almost 90% of HGPS patients carry a LMNA p.G608G splice variant that leads to the expression of a permanently farnesylated abnormal form of prelamin-A, referred to as progerin. Endothelial dysfunction is a key determinant of atherosclerosis, notably during aging. Previous studies have shown that progerin accumulates in HGPS patients' endothelial cells but also during vascular physiological aging. However, whether progerin expression in human endothelial cells can recapitulate features of endothelial dysfunction is currently unknown. Herein, we evaluated the direct impact of exogenously expressed progerin and wild-type lamin-A on human endothelial cell function and senescence. Our data demonstrate that progerin, but not wild-type lamin-A, overexpression induces endothelial cell dysfunction, characterized by increased inflammation and oxidative stress together with persistent DNA damage, increased cell cycle arrest protein expression and cellular senescence. Inhibition of progerin prenylation using a pravastatin-zoledronate combination partly prevents these defects. Our data suggest a direct proatherogenic role of progerin in human endothelial cells, which could contribute to HGPS-associated early atherosclerosis and also potentially be involved in physiological endothelial aging participating to age-related cardiometabolic diseases.

HIV antiretroviral drugs, dolutegravir, maraviroc and ritonavir-boosted atazanavir use different pathways to affect inflammation, senescence and insulin sensitivity in human coronary endothelial cells.

OBJECTIVES: Aging HIV-infected antiretroviral-treatment (ART)-controlled patients often present cardiovascular and metabolic comorbidities. Thus, it is mandatory that life-long used ART has no cardiometabolic toxicity. Protease inhibitors have been associated with cardiometabolic risk, integrase-strand-transfer-inhibitors (INSTI) with weight gain and the CCR5 inhibitor maraviroc with improved vascular function. We have previously reported that the INSTI dolutegravir and maraviroc improved, and ritonavir-boosted atazanavir(atazanavir/r) worsened, inflammation and senescence in human coronary artery endothelial cells (HCAEC)s from adult controls. Here, we analyzed the pathways involved in the drugs' effects on inflammation, senescence and also insulin resistance. METHODS: We analyzed the involvement of the anti-inflammatory SIRT-1 pathway in HCAECs. Then, we performed a transcriptomic analysis of the effect of dolutegravir, maraviroc and atazanavir/r and used siRNA-silencing to address ubiquitin-specific-peptidase-18 (USP18) involvement into ART effects. RESULTS: Dolutegravir reduced inflammation by decreasing NFκB activation and IL-6/IL-8/sICAM-1/sVCAM-1 secretion, as did maraviroc with a milder effect. However, when SIRT-1 was inhibited by splitomicin, the drugs anti-inflammatory effects were maintained, indicating that they were SIRT-1-independant. From the transcriptomic analysis we selected USP18, previously shown to decrease inflammation and insulin-resistance. USP18-silencing enhanced basal inflammation and senescence. Maraviroc still inhibited NFκB activation, cytokine/adhesion molecules secretion and senescence but the effects of dolutegravir and atazanavir/r were lost, suggesting that they involved USP18. Otherwise, in HCAECs, dolutegravir improved and atazanavir/r worsened insulin resistance while maraviroc had no effect. In USP18-silenced cells, basal insulin resistance was increased, but dolutegravir and atazanavir/r kept their effect on insulin sensitivity, indicating that USP18 was dispensable. CONCLUSION: USP18 reduced basal inflammation, senescence and insulin resistance in coronary endothelial cells. Dolutegravir and atazanavir/r, but not maraviroc, exerted opposite effects on inflammation and senescence that involved USP18. Otherwise, dolutegravir improved and atazanavir/r worsened insulin resistance independently of USP18. Thus, in endothelial cells, dolutegravir and atazanavir/r oppositely affected pathways leading to inflammation, senescence and insulin resistance.

Génesis sociohistórica de la expresión corporal en Espanã / Social-historical genesis of bodily expression in Spain / Gênese sócio-histórica da expressão corporal na Espanha

Este artículo tiene como objetivo clarificar y ordenar el proceso de institucionalización de la Expresión Corporal en España ante la escasez y fragmentación de investigaciones sobre los aspectos históricos que incidieron en las principales situaciones político-educativas y autores que la han configurado. Para ello, en primer lugar se ha realizado un análisis de documentos científicos y legales para profundizar en nuestro objeto de estudio. En segundo lugar, se han utilizado las entrevistas informales realizadas durante una observación etnográfica no participante y 16 entrevistas semiestructuradas. Como conclusión, la Expresión Corporal en España se encuentra condicionada por la situación histórica y por su sistema educativo. Además, se identifican geográficamente la Expresión Corporal del Noreste y la Expresión Corporal del Centro-Suroeste. A su vez, los autores han sido clasificados en dos generaciones que contribuyeron al proceso de creación, institucionalización y consolidación de la disciplina

Este artigo tem como objetivo esclarecer o processo de institucionalização da Expressão Corporal na Espanha perante a escassez e a fragmentação das investigações sobre aspectos históricos que incidam sobre as principais situações políticas educativas e autores que a configuraram. Para isso, em primeiro lugar realizou-se uma análise de documentos científicos e jurídicos que permitem aprofundar o nosso tema de estudo. Em segundo lugar, recorreu-se às entrevistas informais realizadas durante uma observação etnográfica não participante e 16 entrevistas semiestruturadas. Como conclusão, a Expressão Corporal na Espanha encontra- se condicionada pela situação histórica e pelo seu sistema educativo. Além disso, identificam-se geograficamente a Corporação do Noroeste e a Corporação do Centro-Sudoeste. Por seu turno, os autores foram classificados em duas gerações que contribuíram para o processo de criação, institucionalização e consolidação da disciplina

This article explains and organizes the process of institutionalization of Bodily Expression in Spain considering the absence and fragmentation of research on historical aspects that impacted on the main political and educational situations and the authors that shaped it. To that end, scientific and legal documents were examined in order to elaborate on the object of study. Secondly, the study used informal interviews conducted during non-participant ethnographic observation and 16 semi-structured interviews. It found that Bodily Expression in Spain has been influenced by the country's historical context and educational system. Furthermore, it identified a Bodily Expression of the NorthEast and a Body Expression of the Centre and South-West. its authors were classified into two generations that contributed to the process of creation, institutionalization and consolidation of the discipline

Efficacy of aflibercept with FOLFOX and maintenance with fluoropyrimidine as first­line therapy for metastatic colorectal cancer: GERCOR VELVET phase II study.

Aflibercept in combination with 5­fluorouracil (5­FU)/irinotecan improves overall survival in the second­line therapy of patients with metastatic colorectal cancer (mCRC). In this study, we evaluated the effects of aflibercept in first­line therapy with FOLFOX followed by maintenance with fluoropyrimidine. VELVET was a prospective, single­arm multicenter phase II study (completed). Patients with previously untreated, unresectable, evaluable or measurable mCRC, with an age ≥18 years, and an ECOG performance status of 0­2 received 6 cycles of modified FOLFOX7 (5­FU/folinic acid and oxaliplatin) with aflibercept at 4 mg/kg every 2 weeks followed by maintenance therapy with fluoropyrimidine with aflibercept until disease progression or limiting toxicity. The reintroduction of oxaliplatin was performed at first progression. The primary endpoint was progression­free survival (PFS) at 6 months. From May, 2013 to May, 2014, 49 patients were included and 48 were evaluable for response. In total, 33 patients (67.4%) were alive without progression at 6 months. The Kaplan­Meier survival 6­month and 1­year PFS rates were 79.1 and 36.1%, respectively, and the median PFS was 9.3 months (95% CI, 8.3­12.5). The objective response rate was 59.2% (N=29/49). The most common (≥10%) grade 3­4 adverse events were hypertension (23%), fatigue (15%), neutropenia (12%), neuropathy (12%) and stomatitis (10%). Three (6%) treatment­related deaths occurred: One from stroke, one from pulmonary embolism and one from neutropenic sepsis. On the whole, this study demonstrates the efficacy of aflibercept in combination with an oxaliplatin­based regimen in the first­line therapy of patients with mCRC. A strict monitoring of blood pressure and immediate management of hypertension during therapy is mandatory.

Efficacy and safety of nivolumab in patients with non-small cell lung cancer: a retrospective study in clinical practice.

Nivolumab, a fully human immunoglobulin monoclonal antibody inhibiting the programmed cell death protein-1 receptor, demonstrated robust efficacy and a manageable safety profile across multiple tumor types in clinical trials. The aim of the present study was to investigate the efficacy and safety of nivolumab for pretreated patients with non-small cell lung cancers in clinical practice. In this observational monocentric retrospective study, 98 patients were enrolled between February 2015 and February 2016. The global median overall survival was 6.34 months (95% confidence interval (CI) : 4.11-10.88) and the global median progression free survival was 1.84 months (95% CI: 1.68-2.73). In the univariate analysis, clinical performance status score was the only factor significantly correlated with overall survival. The safety profile of nivolumab is consistent with that described in prior studies, with only 7% undesirable effects requiring the discontinuation of treatment. The results of the present study demonstrate that nivolumab affords clinical efficacy and manageable tolerability in patients with non-small cell lung cancers.

Adipocyte Glucocorticoid Receptor Deficiency Promotes Adipose Tissue Expandability and Improves the Metabolic Profile Under Corticosterone Exposure.

Widely used for their anti-inflammatory and immunosuppressive properties, glucocorticoids are nonetheless responsible for the development of diabetes and lipodystrophy. Despite an increasing number of studies focused on the adipocyte glucocorticoid receptor (GR), its precise role in the molecular mechanisms of these complications has not been elucidated. In keeping with this goal, we generated a conditional adipocyte-specific murine model of GR invalidation (AdipoGR knockout [KO] mice). Interestingly, when administered a corticosterone treatment to mimic hypercorticism conditions, AdipoGR-KO mice exhibited an improved glucose tolerance and insulin sensitivity. This was related to the adipose-specific activation of the insulin-signaling pathway, which contributed to fat mass expansion, as well as a shift toward an anti-inflammatory macrophage polarization in adipose tissue of AdipoGR-KO animals. Moreover, these mice were protected against ectopic lipid accumulation in the liver and displayed an improved lipid profile, contributing to their overall healthier phenotype. Altogether, our results indicate that adipocyte GR is a key factor of adipose tissue expansion and glucose and lipid metabolism control, which should be taken into account in the further design of adipocyte GR-selective modulators.