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En la España del XVIII existía la necesidad, entre los propios españoles, de crear una autoimagen de España que sirviera como respuesta a las heteroimágenes tan negativas proyectadas desde Francia. La narración El sol de Sevilla (1800), de Pablo de Olavide, fue uno de los intentos más destacados por construir esta clase de discurso nacionalista. Aunque no es aún una novela histórica o romántica, se ambienta en la época de los Reyes Católicos y mitifica la idea de España como potencia civilizadora de otras a partir de una religión presentada siempre como sinónimo de paz y fraternidad entre humanos. Una religión que, de hecho, en Francia cada vez se estaba cuestionando más, lo cual el propio Olavide había señalado como causa de toda la barbarie acontecida durante la Revolución Francesa, de la que él mismo había sido víctima.

INTRODUCTION: Breast cancer (BC) is a highly prevalent and heterogeneous disease, entailing different so-called intrinsic subtypes (IS) according to gene expression, namely Luminal A, Luminal B, HER2-Enriched (HER2E) and Basal-like, as well as a normal breast-like group. The HER2E is still a poorly understood entity, which needs further biologic characterization to improve therapeutic management. MATERIAL AND METHODS: Patients (pts) treated at Hospital Clinic (Barcelona, Spain) over 18 years with a diagnosis of metastatic BC, with available matched primary and metastatic tumor samples for gene expression analyses were retrospectively recruited. Using the nCounter® Breast Cancer 360 panel, we studied the expression of 776 genes pertaining to different tumor and immune pathway-related signatures, with a focus on HER2E vs. non-HER2E tumors. Significant changes were considered at a false discovery rate (FDR) < 5%. Main clinicopathological features were also compared. IS changes from primary to metastatic disease were assessed. RESULTS: Ninety-one pts with paired tumor samples were included. Briefly, primary tumors were 67.0% hormone receptor-positive (HR+)/HER2-negative (HER2-), 14.8% were HER2-positive (HER2+) and 18.2% were triple-negative (TNBC). IS distribution in primary tumors was the following: 25 Luminal A (28%), 22 Luminal B (24%), 24 HER2E (26%), 12 Basal-like (13%), and 8 Normal-like (9%). In contrast, IS distribution in metastatic tumors was the following: 13 Luminal A (14%), 22 Luminal B (24%), 34 HER2-E (37%), 16 Basal-like (18%), and 6 Normal-like (7%). The HER2E disease proved to be a relatively stable subtype, with 16 (66.7%) tumors not changing IS in the transition to metastatic disease (p=0.078). Particularly, within HR+/HER2-, HER2+ and TNBC, 8/12 (66.7%), 8/10 (80.0%) and 1/2 (50.0%) tumors remained HER2E. Conversely, an overall significant switch from Luminal to non-Luminal tumors at the metastatic progression was observed (p=0.031), with 14/19 (73.7%) new non-Luminal BC being HER2E. When considering all primary and metastatic tumors, HER2E were observed to be less frequently estrogen receptor (ER) positive than non-HER2E tumors (55.8% vs. 78.7%; p=0.002), with lower mean progesterone receptor (PR) levels (15.3% vs. 25.8%; p=0.027). Compared to the other subtypes (as a group), the PAM50 risk of recurrence score (ROR-P) was higher for HER2E tumors (59.1 vs. 41.7; p < 0.001), which were also more frequently HER2+ (36.5% vs. 5.8%) and less likely HR+/HER2- (50.0% vs. 73.6%) and TNBC (13.5% vs. 20.7%), compared to non-HER2E (p < 0.001). No significant differences in grade, TILs, Ki67 and histotype were observed. Overall, 140/776 genes were significantly downregulated in HER2E vs. non-HER2E tumors, including genes related to cell adhesion, migration, DNA damage repair, apoptosis, estrogen signalling pathway, senescence. Conversely, 178/776 genes were significantly upregulated, including the tyrosine-kinase receptor FGFR4, genes involved in nuclear activity, DNA transcription regulation, MAP-kinase signaling pathways, proliferation, cytokine response, epithelial-to-mesenchymal transition (EMT), cell cycle progression, and immune-related genes such as CD274 (PD-L1 gene). DISCUSSION: A switch towards more aggressive IS from primary to advanced disease was observed, with an increase in HER2E prevalence. HER2E tumors, which tend to maintain their IS at the metastatic disease, showed upregulation of genes related to proliferation, survival and EMT, coherently with their well-known worse prognosis. FGFR4 and CD274 upregulation, along with downregulation of genes involved in DNA damage repair suggest these tumors might benefit from targeted therapeutic approaches. Genomic higher risk was not convoyed by consistent clinicopathological features, except for lower PR levels and HER2 overexpression at IHC. Further characterization according to primary/metastatic and HR status is ongoing. Intrinsic subtype distribution across primary and metastatic breast tumors Citation Format: Francisco Javier Muñoz-Carrillo, Laia Paré, Benedetta Conte, Adela Rodríguez, Patricia Galván, Esther Sanfeliu, Blanca González-Farré, Claudette Falato, Isabel Garcia-Fructuoso, Barbara Adamo, Nuria Chic, Olga Martínez-Sáez, Tomás Pascual, Reinaldo Moreno, Montserrat Muñoz, Fara Brasó-Maristany, Aleix Prat, Francesco Schettini, Maria Vidal. Clinico-Pathological and Molecular Characterization of HER2-Enriched Breast Tumors Independently of HER2 Status [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-23-16.

El inconstante corregido es la única novela publicada por el limeño Pablo de Olavide, cuya originalidad ha sido confirmada en una investigación reciente que abrió nuevas líneas de investigación a fin de acotar la relevancia exacta de este texto en la historia de la literatura. Con este propósito, y aunque su contenido y su trasfondo ya nos sean conocidos, resulta necesario un análisis de la novela desde el punto de vista formal, lo que la erigiría como pionera en un género sin antecedentes en español. Para ello, se ha utilizado la definición de bildungsroman ofrecida por Miguel Salmerón en su trabajo sobre ese género, y se ha comprobado si el texto de Olavide se adecua a las características de ese tipo de narraciones; a su vez, también ha sido comparado con otras novelas de aprendizaje extranjeras, y con otros textos españoles anteriores a los que se les había asignado ese marbete sin total exactitud. Tales comprobaciones nos permiten afirmar que, en efecto, se trata de la primera bildungsroman hispana —y a un mismo tiempo americana— conocida, y una, además, renovadora y novedosa en el panorama internacional.

Ibrutinib is a first-generation inhibitor of Bruton tyrosine kinase (BTK) that is currently approved to treat patients with B-cell malignancies, including Waldenström macroglobulinemia (WM), relapsed/refractory (R/R) mantle cell lymphoma (MCL), R/R marginal zone lymphoma (MZL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Off-target adverse effects, such as atrial fibrillation, hypertension, and bleeding, have been observed and may limit a patient’s tolerance for treatment. Currently, there is no well-established treatment regimen for patients who cannot tolerate ibrutinib. Approaches to address such patients include managing ibrutinib side effects with supportive care or dose reductions, switching to an alternative covalent BTK inhibitor, or abandoning covalent BTK inhibitors for alternative forms of treatment. Here we review the literature and provide guidance on treating ibrutinib-intolerant patients with B-cell malignancies.

Cope's Largescale Spiny Lizards (Sceloporus utiformis) are endemic to the Pacific slope of Mexico. They are oviparous and are known to inhabit tropical and temperate forests from sea level to 1,800 m a.s.l. Here, we expand this range based on the finding, in May 2022, of two individuals of S. utiformis in the southeastern portion of the Sierra de Manantlán, at 2154 m elevation. We also provide data on morphometry and field body and microhabitat temperatures of these organisms. A previous study conducted at the same locality almost three decades ago found the species to be present at much lower elevations, so we hypothesize that this could be a case of upward range shifting due to climate change. Moreover, as few oviparous members of the genus Sceloporus occur above 2,000 m elevation, this record triggers many questions about the ecological implications of oviparity along elevation gradients.

Globally, accelerated aging is taking place alongside increased life expectancy of the population. This poses a challenge to maintaining autonomy and independence as people age but preventing falls and disabilities. Currently, there are few specific technologies on the market that are focused on the rehabilitation and promotion of autonomy in older adults. This study presents the development of a prototype (Myoviber®) of a low-cost, wearable everyday garment, designed to stimulate the lower limbs by the application of focal muscle vibration and incorporating technical textile qualities. The presented approach is proactive and preventive, maintaining functionality for the elderly while integrating electronic technology into an everyday garment. For this, a comprehensive study was carried out that included the design of the leggings through anthropometric analyses, the development of vibration devices at a stable frequency located in the knee extensor muscle and a smart belt with wireless connection, and the optimization of the battery autonomy. The development of the prototype was carried out through the construction of a vibratory device, which was validated with biomechanical evaluations. The results show an increase in the functional capacity of the lower limbs, in relation to motor tasks such as postural balance and gait in older people.

Resumen El presente trabajo pretende realizar un análisis de la novela Efectos del amor propio (c. 1810) empleando un marco teórico más amplio que el utilizado hasta ahora al estudiarla. Así, pues, consideramos que puede ser tipificada como “autoficción”, un tipo de novela en la que se confunden la identidad del personaje principal y la del autor; de igual manera, también está condicionada por una nueva forma de entender la creación artística surgida a principios del XIX, la “teoría expresiva del arte”, aplicable a las obras cuya finalidad principal era el desahogo íntimo del autor. Abstract This paper aims to carry out an analysis of the novel Efectos del amor propio (c. 1810) using a broader theoretical framework than the one that has been used so far to study it. Thus, we consider that it can be typified as “autofiction”, a type of novel in which the identity of the main character and that of the author are mixed up, and which is conditioned by a new way of understanding artistic creation that emerged in the early nineteenth century: the “expressive theory of art”, applicable to works whose main purpose was the intimate venting of the author.

La literatura española del XVIII tomó como referente fundamental la de la antigüedad grecorromana, lo que también pudo repercutir en el género de la novela, en el que José Marchena llevó a cabo una falsificación de Petronio con el título de Fragmentum petronii (1800). Pero la moral epicúrea contenida en el Satiricón, surgida en un contexto pagano, nada tenía que ver con los preceptos católicos de la España de entonces. El presente artículo pretende analizar cómo la literatura latina sirve de base para que Marchena lleve a cabo, en su obra, una apología implícita de la libertad sexual humana. Para poder precisar esto último, se ha contextualizado al autor en el movimiento filosófico conocido como Ilustración radical, caracterizado por el ateísmo y la actitud transgresora, rasgos estos dos últimos que se han considerado, tras nuestro análisis, como imprescindibles para la composición de un texto tan inclinado al progreso. Eighteenth-century Spanish literature took Greco-Roman antiquity as a fundamental reference, which would also influence the development of the genre of the novel, in which José Marchena carried out a forgery of Petronio with the title of Fragmentum Petronii (1800). But the epicurean morality contained in the Satyricon, which emerged in a pagan context, had nothing to do with the Catholic precepts of Spain at the time. This article aims to analyse how Latin literature serves as the basis for Marchena to carry out, in his work, an implicit apology for human sexual freedom. To argue this, the author has been contextualized in the philosophical movement known as radical Enlightenment, characterized by atheism and a transgressive attitude; in our analysis, these two traits have been considered as essential for the composition of such a progressive text.

Se estudian las habilidades sociales y las técnicas de trabajo en equipo en las que se ha de instruir al periodista de datos, un profesional que se encuentra a medio camino entre el periodismo, la documentación y la computación estadística. Los resultados indican que: a) la mayoría de los grados de periodismo contemplan como competencia básica el trabajo en equipo, aunque su enseñanza-aprendizaje no se materializa en ninguna asignatura concreta, ni siquiera como parte del contenido de la disciplina periodismo de datos; b) pese a que los estudiantes de periodismo mantienen una actitud abierta y positiva al trabajo en equipo, estos perciben que el individualismo y la competencia son más frecuentes entre ellos que la colaboración. Por ello, se proponen una serie de claves sobre la enseñanza-aprendizaje en técnicas de trabajo en equipo para formar a los futuros periodistas de datos en el trabajo colaborativo en grupos multidisciplinares.

Purpose:Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas that express higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a presurgical window of opportunity trial to determine the therapeutic effects of mifepristone in patients with breast cancer, based on their high PRA/PRB isoform ratio (MIPRA; NCT02651844).Patients and Methods:Twenty patients with luminal breast carcinomas with PRA/PRB > 1.5 (determined by Western blots), and PR ≥ 50%, naïve from previous treatment, were included for mifepristone treatment (200 mg/day orally; 14 days). Core needle biopsies and surgical samples were formalin fixed for IHC studies, while others were snap-frozen to perform RNA sequencing (RNA-seq), proteomics, and/or Western blot studies. Plasma mifepristone levels were determined using mass spectrometry. The primary endpoint was the comparison of Ki67 expression pretreatment and posttreatment.Results:A 49.62% decrease in Ki67 staining was observed in all surgical specimens compared with baseline (P = 0.0003). Using the prespecified response parameter (30% relative reduction), we identified 14 of 20 responders. Mifepristone induced an increase in tumor-infiltrating lymphocytes; a decrease in hormone receptor and pSer118ER expression; and an increase in calregulin, p21, p15, and activated caspase 3 expression. RNA-seq and proteomic studies identified downregulated pathways related to cell proliferation and upregulated pathways related to immune bioprocesses and extracellular matrix remodeling.Conclusions:Our results support the use of mifepristone in patients with luminal breast cancer with high PRA/PRB ratios. The combined effects of mifepristone and estrogen receptor modulators warrant clinical evaluation to improve endocrine treatment responsiveness in these patients.See related commentary by Ronchi and Brisken, p. 833

Global warming and changes in precipitation regimes resulting from climate change are altering plant water availability and water use efficiency, which compromises key ecosystem services such as vegetation productivity, ecosystem carbon storage, and ecohydrological regulation. The study of plant water sources and leaf-level water use strategies is particularly important for the management and conservation of Mediterranean ecosystems, which are threatened by increasing climatic aridity. We investigated the water use strategies of 66 woody plant species distributed across 10 sites along a steep 600 km aridity gradient in south-eastern and central Iberian Peninsula. We used soil and plant water stable isotopes (δ2H and δ18O) to quantify the proportion of water extracted from different soil layers, as well as leaf stable isotopes (δ13C, δ18O and Δ18Oenrichment above source water) as proxies for water use efficiency and stomatal regulation. Our results indicate that water extraction depth along the soil profile is strongly constrained by plant species size and height. Bayesian models revealed that small and medium size shrubs use a much greater proportion of shallow soil water than large shrubs and trees, a pattern that is remarkably consistently across study sites and species. Mixed models revealed strong associations between leaf δ13C, Δ18Oenrichment and xylem water δ18O across sites, indicating that woody species with tighter stomatal regulation achieve higher water use efficiency and generally extract water from deeper soil layers. This conservative water use strategy is much more common in larger woody species than in smaller ones. Our findings demonstrate the coexistence of sharply contrasting water use strategies in Mediterranean plant communities. Small and mid-size woody species are heavily reliant on shallow soil water and exhibit a highly acquisitive and profligate water use strategy that enables them to take rapid advantage of an ephemeral resource (topsoil water) after rainfall pulses, although they are less efficient in the use of water at leaf level. On the other hand, large shrubs and trees that use more stable deeper water sources exhibit a much more conservative water use strategy.

Delirium is a neuropsychiatric syndrome associated with increased morbidity and mortality in older patients. The aim of this study was to review predictive biomarkers of delirium in older patients to gain insights into the pathophysiology of this syndrome and provide guidance for future studies. Two authors independently and systematically searched MEDLINE, Embase, Cochrane Library, Web of Science and Scopus databases up to August 2021. A total of 32 studies were included. Only 6 studies were eligible for the meta-analysis, pooled results showed a significant increase in some serum biomarkers (C-reactive protein [CRP], tumour necrosis factor alpha [TNF-α] and interleukin-6 [IL-6]) among patients with delirium (odds ratio = 1.88, 95% CI 1.01 to 1.637; I2 = 76.75%). Although current evidence does not favour the use of any particular biomarker, serum CRP, TNF-α, and IL-6 were the most consistent biomarkers of delirium in older patients.

The knob-scaled lizards (family Xenosauridae) comprise a clade of crevice-dwelling North American lizards with a trend towards low body temperature and high rates of water loss, and are often regarded as thermoconformers. However, there are few studies on their thermal ecology, most of them limited to documenting the body temperatures and their relation with environmental temperatures. Here, we documented the field body temperatures (Tb), selected temperatures (Tset), operative temperatures (Te), thermoregulatory effectiveness, and thermal tolerances of 10 individuals of the Newman’s Knob-scaled Lizard, Xenosaurus newmanorum, collected in the fall of 2017 in La Huasteca region of Mexico. Mean Tb was 22.75 °C and mean Tset 25.08 °C (1.64 °C and 3.97 °C above mean Te, respectively). The species had a relatively narrow thermal tolerance range (25.89 °C). Furthermore, based on two different thermoregulatory indexes, we found direct evidence of active thermoregulation in X. newmanorum. This constitutes the first record of active thermoregulation in a xenosaurid from a low-elevation environment and the second record of thermal tolerances. We discuss on the thermal strategies of other species of the genus and pose that active thermoregulation might be more widespread in Xenosaurus than previously thought.

Study design Single center, two-parallel group, blinding feasibility randomized controlled trial. Background Clinical trials of manual therapy interventions for back pain face methodological challenges regarding blinding of assigned interventions. We assessed blinding of participants and outcome assessors in a methodological randomized trial of two manual therapy interventions of the back and explored factors influencing perceptions about intervention assignment. Methods In a doctoral-level Introduction to Epidemiology course on 7–8 November 2022, 24 healthy students were randomly allocated (1:1) to active or control manual therapy interventions. The active manual therapy group (n = 11) received soft tissue mobilization of the lumbar musculature. The control group (n = 13) performed deep breathing exercises while receiving light touch over the thoracic region. The primary outcome was blinding feasibility of study participants immediately after intervention, derived from a 5-point scale and measured by the Bang blinding index (Bang BI), with values ranging from − 1 (opposite guessing) to 1 (complete unblinding), with 0 indicating random guessing (50% correct). Secondary outcomes included blinding feasibility of outcome assessors and factors influencing perceptions about intervention assignment in participants and outcome assessors, explored via thematic analysis. Results 24 participants were analyzed following an intention-to-treat approach. 55% of participants in the active manual therapy group correctly identified their group allocation beyond chance immediately after intervention (Bang BI: 0.55 [95% confidence interval (CI), 0.25 to 0.84]), and 8% did so in the control manual therapy group (0.08 [95% CI, -0.37 to 0.53]). Bang BIs in outcome assessors suggested adequate blinding, with indices of 0.09 (-0.12 to 0.30) and − 0.10 (-0.29 to 0.08) for perceived allocation of active and control manual therapy participants, respectively. Blinding estimates were limited due to imprecision and suboptimal generalizability to real-world clinical settings. Participants and outcome assessors reported varying factors related to perceived intervention arm allocation. Conclusions Our findings suggest that blinding of participants and outcome assessors immediately after a one-time manual therapy intervention is feasible in randomized controlled trial settings. Careful thinking and consideration of blinding in manual therapy intervention trials is warranted and needed. Trial registration: Retrospectively registered at ClinicalTrials.gov ― currently under Protocol Registration and Results System (PRS) review.

RNA-Seq and Proteomics analysis. A and B, Dot plot of relevant enriched pathways from GSEA results (Reactome and Hallmark databases) separating responsive (A) and unresponsive tumors (B). C, Immune cell deconvolution (xcell) in the different tumors analyzed by RNA-Seq. Plots with significant p values analyzed by Wilcoxon test and the T cell CD8+ plot are shown. D, Kegg diagram of the Cell cycle pathway, that may explain mifepristone therapeutics effects. A colored code was used: the first half of the box is colored according to the RNA-Seq data (8 tumors) and the last half of the box is colored according to the proteomic data (n=10 tumors; nuclear fraction).

RNA-Seq Variant calling

Mutations identified in RNA-Seq analysis. The data obtained in RNA-Seq studies were graphed using the Oviz-Bio tool (https://academic.oup.com/nar/article/48/W1/W415/5835823). Only driver breast cancer genes (99) were selected from the Intogene data base (https://www.intogen.org/download) and we found mutations in 19 driver genes after read depth filtering (DP >50). Of note is the missense mutation found in ESR1 in the M070 patient. Left, Percentage of samples with mutations. Color defines the type of mutations.

Evaluation of Ki67 expression in paired samples before and after mifepristone treatment by two independent pathologists, and time elapsed between core needle biopsy and surgery.

Representativeness of Study Participants

Proteomics: Enrichment analysis from heatmap

Purpose:Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas that express higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a presurgical window of opportunity trial to determine the therapeutic effects of mifepristone in patients with breast cancer, based on their high PRA/PRB isoform ratio (MIPRA; NCT02651844).Patients and Methods:Twenty patients with luminal breast carcinomas with PRA/PRB > 1.5 (determined by Western blots), and PR ≥ 50%, naïve from previous treatment, were included for mifepristone treatment (200 mg/day orally; 14 days). Core needle biopsies and surgical samples were formalin fixed for IHC studies, while others were snap-frozen to perform RNA sequencing (RNA-seq), proteomics, and/or Western blot studies. Plasma mifepristone levels were determined using mass spectrometry. The primary endpoint was the comparison of Ki67 expression pretreatment and posttreatment.Results:A 49.62% decrease in Ki67 staining was observed in all surgical specimens compared with baseline (P = 0.0003). Using the prespecified response parameter (30% relative reduction), we identified 14 of 20 responders. Mifepristone induced an increase in tumor-infiltrating lymphocytes; a decrease in hormone receptor and pSer118ER expression; and an increase in calregulin, p21, p15, and activated caspase 3 expression. RNA-seq and proteomic studies identified downregulated pathways related to cell proliferation and upregulated pathways related to immune bioprocesses and extracellular matrix remodeling.Conclusions:Our results support the use of mifepristone in patients with luminal breast cancer with high PRA/PRB ratios. The combined effects of mifepristone and estrogen receptor modulators warrant clinical evaluation to improve endocrine treatment responsiveness in these patients.See related commentary by Ronchi and Brisken, p. 833

A, Library size before and after low count filtering. B, P-value histogram distribution observed in the differential expression analysis. C, Pairwise scatter plots of the first five principal components from the principal component analysis of RNA-Seq data.

RNA-Seq DEG and GSEA

Proteomics: DE and Reactome of Nuc proteins

Proteomics: DE and Reactome of Cyt proteins

Morphological evaluation of CNBs and matched surgical samples; RNA-Seq analysis; Proteomics

Mifepristone plasma levels and mifepristone-related side effects. A, Plasma levels of mifepristone 7 or 14 days after mifepristone treatment. The data from 9-10 patients are shown. Data were analyzed with ANOVA for matched samples (Friedman test). B, Clinical adverse effects grade 1 recorded in mifepristone (MFP)-treated patients. C, Laboratory values. Patients M049, M095 and M140 were treated for diabetes. Patients M009, M019, M023, M042, M049, M062, M070, M077, M090, M095, M105 and M140 were treated for hypertension and patients M009, M019 and M124 were treated for hypothyroidism. Dotted areas represent normal levels. Patients under mifepristone treatment did not interrupt standard medicine care.

Morphological features after mifepristone treatment. A-D, Images illustrating increased stromal tissue (A), thin and scarce collagen fibers, and increased stromal matrix (arrow; B), an area of tissue remodeling (C), and an area of increased differentiation (D) observed in the surgical samples (S) compared to the respective core needle biopsies (CNB). E, Image illustrates an area of necrosis (dotted arrow) together with a differentiated structure (black arrow) in a surgical sample. F, Cells with Alcian blue+ (left), PAS+ (middle) and MUC-1+ (immunohistochemistry; right) vacuoles observed in a mifepristone-treated tumor. Inset: High power field of a differentiated gland/duct.

A, Prevailing PR isoforms before and after mifepristone treatment and their prevailing nuclear (Nuc) or cytosolic (Cyt) localization in western blot studies. *: Prevailing PR isoforms in Western blot studies; #: Distribution of PR in the Nuc or Cyt compartments; CNB: Core needle biopsy, S: Surgical sample. In grey font: Mifepristone unresponsive tumors by Ki67 criteria. B, Representative western blots of CNB and surgical samples from all patients. The upper band is PRB and the lower band PRA, as labeled in the first set.

SUMMARYBiological processes are intrinsically noisy and yet, the result of development –like the species-specific size and shape of organs– is usually remarkably precise. This precision suggests the existence of mechanisms of feedback control that ensure that deviations from a target size are minimized. Still, we have very limited understanding of how these mechanisms operate. Here, we investigate the problem of organ size precision using theDrosophilaeye. The size of the adult eye depends on the rates at which eye progenitor cells grow and differentiate. We first find that the progenitor net growth rate results from the balance between their proliferation and apoptosis, with this latter contributing to determining both final eye size and its variability. In turn, apoptosis of progenitor cells is hampered by Dpp, a BMP2/4 signaling molecule transiently produced by early differentiating retinal cells. Our genetic and computational experiments show how the status of retinal differentiation is communicated to progenitors through the differentiation-dependent production of Dpp which, by adjusting the rate of apoptosis, exerts a feedback control over the net growth of progenitors to reduce final eye size variability.

Despite the development of novel therapies for acute myeloid leukemia (AML), outcomes remain poor for most patients, and therapeutic improvements are an urgent unmet need. Although treatment regimens promoting differentiation have succeeded in the treatment of acute promyelocytic leukemia (APL), their role in other AML subtypes needs to be explored. Here we identified and characterized two lysine (K) deacetylase inhibitors (DACi), CM-444 and CM-1758, exhibiting capacity to promote myeloid differentiation in all AML subtypes at low non-cytotoxic doses unlike other commercial HDACi. Analyzing the acetylome after CM-444 and CM-1758 treatment revealed modulation of non-histone proteins involved in the enhancer–promoter chromatin regulatory complex, including bromodomain proteins (BRDs). This acetylation was essential for enhancing the expression of key transcription factors directly involved in the differentiation therapy induced by CM-444/CM-1758 in AML. In summary, these compounds may represent effective differentiation-based therapeutic agents across AML subtypes with a novel mechanism for treatment of AML.

BACKGROUND: The prognosis of patients with early relapsed or refractory large B-cell lymphoma after the receipt of first-line chemoimmunotherapy is poor.METHODS: In this international, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabtagene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was event-free survival according to blinded central review. Key secondary end points were response and overall survival. Safety was also assessed.RESULTS: A total of 180 patients were randomly assigned to receive axi-cel and 179 to receive standard care. The primary end-point analysis of event-free survival showed that axi-cel therapy was superior to standard care. At a median follow-up of 24.9 months, the median event-free survival was 8.3 months in the axi-cel group and 2.0 months in the standard-care group, and the 24-month event-free survival was 41% and 16%, respectively (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; PCONCLUSIONS: Axi-cel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade toxic effects. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).

Ante los colapsos en los mercados financieros, se han buscado alternativas que diversifiquen el riesgo y sirvan de refugio en los momentos de incertidumbre. Uno de los activos elegido en el mercado estadounidense es el Bitcoin, incluso sobre los activos de refugio más populares como el oro. En este trabajo, se hace un análisis sobre la criptomoneda de mayor impacto (Bitcoin), involucrando el efecto de la pandemia COVID-19 y deducir el comportamiento del mercado de criptomonedas en época de crisis. En particular, se determina la relación que guardan las variables macroeconómicas y si éstas interfieren en el precio de Bitcoin y concluir que los inversionistas podrían confiar en la cripto como un activo para preservar su riqueza en esta pandemia y posiblemente en futuras incertidumbres financieras.