Distribution of PD-L1, TROP2 and HER2- "lowness" in early triple-negative breast cancer: an opportunity for treatment de-escalation.

BACKGROUND: HER2, TROP2 and PD-L1 are novel targets in triple-negative breast cancer (TNBC). The combined expression status of these targets, and whether they can define prognostic subgroups, is currently undefined. METHODS: Immunohistochemistry was used to determine HER2, TROP2 and PD-L1 levels in 459 TNBC cases, that received in the adjuvant/neoadjuvant setting active surveillance, CMF, anthracycline-, anthracycline plus taxane-, or carboplatin-containing regimes. RESULTS: HER2-low patients with PD-L1 > 1 CPS (double-positive, herein "DP") had a mean PFS of 4768 days (95% CI: 4267-5268) versus 3522 days (95% CI: 3184-3861) for non-DP patients (P = 0.002). Regarding the received adjuvant treatment, DP patients (versus non-DP) receiving anthracyclines plus taxanes exhibited a mean PFS time of 4726 (95% CI: 4022-5430) versus 3302 (95% CI: 2818-3785) days (P = 0.039). Finally, 100% of DP patients that received a carboplatin-based regimen were long-term disease-free. CONCLUSIONS: Early HER2-low, PD-L1-positive TNBC patients have a very good prognosis, particularly if treated with anthracycline/taxane- or carboplatin-containing regimes.

Management of Persistent SARS-CoV-2 Infection in Patients with Follicular Lymphoma.

INTRODUCTION: There is no consensus on the management of the coronavirus disease (COVID-19) in patients with secondary immunosuppression due to either an underlying hematological disease or to the effects of immunochemotherapy (ICT). Some of them may present persistent infection with multiple relapses of COVID-19, requiring several admissions. This study evaluated the clinical characteristics and outcomes after treatment of 5 patients with follicular lymphoma (FL), previously treated with ICT, who developed several episodes of COVID-19. METHODS: We analyzed the clinical evolution and response to treatment with antiviral agent, steroids, and convalescent plasma in 5 patients with FL and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persistent infection. Reverse transcriptase polymerase chain reaction tests and peripheral blood immunophenotype were performed for all patients. RESULTS: All patients required hospitalization due to pneumonia with severity criteria and were re-admitted after a median of 22 days (13-42) from the previous discharge. They all showed B-cell depletion by immunophenotyping, and no traces of immunoglobulin antibodies against SARS-CoV-2 were detected in any of the cases. The survival rate was 80%. CONCLUSION: The combination therapy evidenced clinical benefits, demonstrating its capacity to control infection in immunosuppressed FL patients treated with ICT.

"Developing Capabilities". Inclusive Extracurricular Enrichment Programs to Improve the Well-Being of Gifted Adolescents.

The educational inclusion of gifted students requires not only equity but also emotional accessibility and social participation. However, different studies indicate that gifted students constitute a vulnerable group (for example, the incidence of bullying is higher). Psychosocial variables are determinants for the development and expression of giftedness, particularly during adolescence. This study analyzes the impact of an inclusive extracurricular enrichment program for gifted secondary school students on the well-being of adolescents. The program was based on the enrichment model of Renzulli and Reis (2016). The objective was to develop a cluster to facilitate high-achieving learning in collaboration with teachers, administrators, and guidance counselors from their schools as well as university professors and students that would address their emotions and socialization across the board and benefit or involve their peers in their regular classrooms. The intervention took place over two years: eight sessions, one afternoon per week, for five months during each school year. The sample consisted of 47 students from the first and second years of compulsory secondary education (Educación Secundaria Obligatoria - ESO) (age, mean (M) = 12.57, standard deviation (SD) = 0.82) during the first year and 27 students from the first, second, and third years of ESO (age, M = 13.48, SD = 0.94) during the second year; 61.4% were girls. Participants completed a questionnaire before (T1) and (T3) and after (T2) and (T4) each intervention. The results show better outcomes for psychological and subjective well-being, more positive moods, and a significant reduction in school fears. The results from this study indicate the importance of educational screening and support for gifted students to promote their well-being through collaborative enrichment activities.

Emotional Intelligence Profiles and Self-Esteem/Self-Concept: An Analysis of Relationships in Gifted Students.

The psychological well-being of students affects their academic achievement, social relationships and school coexistence and is something that families worry about. This aspect becomes vital when students have atypical development and/or specific needs. Studies on the impact of giftedness on students' self-concept and self-esteem offer mixed results. Emotional Intelligence (EI) is a key factor for their well-being that must be developed by educational institutions. This study analyzes the relationships between emotional intelligence profiles and both self-concept and self-esteem of identified gifted students between 8 and 18 years of age who study in regular Spanish schools and non-identified peers. A total of 118 identified gifted and 122 non-identified subjects participated in the study. The Self-Concept Scale Form 5 (AF5), the Rosenberg Self-Esteem Scale (RSES), and the Trait Meta-Mood Scale-24 (TMMS-24) were administered. Clusters of students were identified on the basis of their scores in the three dimensions of EI. Subsequently, the differences in self-esteem and self-concept according to the student's emotional intelligence profile were analyzed. The results showed a taxonomy of three-cluster profiles in both groups and the existence of differences between profiles of EI in the self-esteem and self-concept dimensions in gifted students, not so in the non-identified group. The results have important implications for education and health professionals, both for the evaluation and for the introduction of adjusted intervention programs in case of vulnerability.

Transient exposure to miR-203 enhances the differentiation capacity of established pluripotent stem cells.

Full differentiation potential along with self-renewal capacity is a major property of pluripotent stem cells (PSCs). However, the differentiation capacity frequently decreases during expansion of PSCs in vitro. We show here that transient exposure to a single microRNA, expressed at early stages during normal development, improves the differentiation capacity of already-established murine and human PSCs. Short exposure to miR-203 in PSCs (miPSCs) induces a transient expression of 2C markers that later results in expanded differentiation potency to multiple lineages, as well as improved efficiency in tetraploid complementation and human-mouse interspecies chimerism assays. Mechanistically, these effects are at least partially mediated by direct repression of de novo DNA methyltransferases Dnmt3a and Dnmt3b, leading to transient and reversible erasure of DNA methylation. These data support the use of transient exposure to miR-203 as a versatile method to reset the epigenetic memory in PSCs, and improve their effectiveness in regenerative medicine.

Antiangiogenics and Hypoxic Response: Role of Fatty Acid Synthase Inhibitors.

One proposed mechanism through which antiangiogenics exert their effect in epithelial malignancies is by improving the status of the aberrant vascular network and secondarily facilitating the delivery of concurrently administrated cytotoxic agents. During this process, known as vascular normalization, the oxygenation of the tumor is usually improved. Many mechanisms of resistance have been proposed to evade the action of this drug class elicited through this mechanism of action. However, a less explored mechanism of action is vascular choking, as increased hypoxia is thought to be associated with the inevitable progression of certain tumor-promotion features. Here we review the available evidence regarding decreased blood flow as a mechanism of action of antiangiogenics at the preclinical and clinical level. Similar to vascular normalization, there are also escape mechanisms against chronic hypoxia generated by treatment with antiangiogenics. Among other compensatory responses, chronic hypoxia is related with the upregulation of lipidic anabolism. Therefore, we focus on how fatty acid synthase, a key player in this response, can be targeted to delay acquired resistance against antiangiogenics, including experimental data from our group. This effect seems to be specific to those cases in which the antiangiogenic treatment induces a hypoxic response, but not in models where the antiangiogenic agent induced normalizing effects. Whether antiangiogenics induce vascular normalization or a hypoxic environment seems to be tractable with a noninvasive PET-tracer: 18F-fluoromisonidazole PET.

Down-regulation of specific miRNAs enhances the expression of the gene Smoothened and contributes to T-cell lymphoblastic lymphoma development.

Inappropriate activation of the GLI/hedgehog (GLI/Hh) signalling occurs in several human cancers, including haematological neoplasms. However, little is known about its relevance in precursor T-cell lymphoblastic lymphomas (T-LBL) development. Moreover, the mechanisms whereby GLI/Hh signalling is activated in haematological malignancies are not fully clear. Here, we show that the gene Smoothened (SMO), the only non-redundant gene of this pathway, is up-regulated in mouse and human T-LBL. Interestingly, down-regulation of micro-RNAs mmu-miR-30a and mmu-miR-141 as well as hsa-miR-193b clearly contributes to enhance the expression of this gene in mouse and human lymphomas and, subsequently, to activate the GLI/Hh signalling. Activation of the GLI/Hh signalling in T-LBL promotes cell survival and proliferation, since inhibition of the pathway using short-hairpin-RNA-mediated SMO knockdown, or cyclopamine as a specific antagonist, significantly reduces these cellular processes. These findings suggest that sustained SMO up-regulation may contribute to T-LBL development and advocate the use of specific SMO inhibitors or microRNAs-based therapies as an attractive possibility to treat an important subset of T-LBL.

The Cdc14B phosphatase displays oncogenic activity mediated by the Ras-Mek signaling pathway.

Cdc14 is a dual-specific phosphatase with relevant functions during mitotic exit in yeast. The relevance of vertebrate Cdc14 phosphatases is not well understood due to the presence of two paralogs, Cdc14A and Cdc14B, and their dispensability for cell cycle progression. Here, we report that overexpression of mammalian Cdc14B, but not Cdc14A, leads to dramatic changes in morphology and malignant transformation of normal murine fibroblasts. Cdc14B disrupts the cytoskeletal F-actin organization with loss of actin stress fibers and vinculin adhesions in a phosphatase-dependent manner. These morphological changes are associated to cellular transformation, as Cdc14B-overexpressing cells display anchorage-independent growth and are able to form tumors in vivo. These alterations are similar to those induced by Ras oncogenes ,and both Cdc14B and H-RasV12 lead to similar changes in the transcriptional profile of transformed cells. Pharmacologic inhibition of the Ras-Mek pathway rescues these defects. These data suggest that Cdc14B, but not Cdc14A, is one of the few phosphatases that display oncogenic activity in mammals and point to the Ras-MAP kinase pathway as a major effector pathway during oncogenic transformation by Cdc14B.

MicroRNAs and the cell cycle.

The control of cell proliferation by microRNAs (miRNAs) is well established and the alteration of these small, non-coding RNAs may contribute to tumor development by perturbing critical cell cycle regulators. Oncogenic miRNAs may facilitate cell cycle entry and progression by targeting CDK inhibitors or transcriptional repressors of the retinoblastoma family. On the other hand, tumor suppressor miRNAs induce cell cycle arrest by downregulating multiple components of the cell cycle machinery. Recent data also suggest that miRNAs act co-ordinately with transcriptional factors involved in cell cycle regulation such as c-MYC, E2F or p53. These miRNAs not only can potentiate the function of these factors but they may also limit the excessive translation of cell cycle proteins upon mitogenic or oncogenic stimuli to protect cells from replicative stress. The implications of these regulatory networks in cell proliferation and human disease are discussed.

Control of cell proliferation pathways by microRNAs.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate a large variety of cellular processes including differentiation, apoptosis and proliferation. Several miRNAs display defective expression patterns in human tumors with the consequent alteration of target oncogene or tumor suppressor genes. Many of these miRNAs modulate the major proliferation pathways through direct interaction with critical regulators such as RAS, PI3K/PTEN or ABL, as well as members of the retinoblastoma pathway, Cyclin-CDK complexes or cell cycle inhibitors of the INK4 or Cip/Kip families. A complex interplay between miRNAs and MYC or E2F family members also exists to modulate cell cycle-dependent transcription during normal or tumoral proliferation. The ability of miRNAs to modulate these proliferation pathways may have relevant implications not only in physiological or developmental processes but also in tumor progression or cancer therapy.

Donación autóloga en una gestante con anticuerpos antieritrocitarios anti-U y anti-He (Henshaw) / Autologous tranfussion in a pregnant with anti-U and anti-He (Henshaw)

No disponible

Occupational rhinoconjunctivitis and food allergy because of aniseed sensitization.

BACKGROUND: Aniseed is a spice frequently used in Mediterranean cooking and, as with other Umbelliferae, it has been involved in clinical allergy. OBJECTIVE: This investigation was undertaken to study the allergens implicated in a case of occupational allergy to aniseed associated with rhinoconjunctivitis and gastrointestinal symptoms. METHODS: Skin prick tests were performed to inhalant allergens, spices used in the patient's workplace (aniseed and cinnamon), and 12 other Umbelliferae spices, birch, and mugwort. A nasal challenge test to aniseed and cinnamon and a double-blind placebo-controlled oral food challenge test to aniseed were also performed. The molecular weights of the allergens were studied by sodium dodecyl sulfate-polyacrylamide gel electrophoresis immunoblotting and cross-reactivity among Umbelliferae species by enzyme immunoassay inhibition. RESULTS: Skin prick tests showed a positive immediate response to aniseed, asparagus, caraway, coriander, cumin, dill, and fennel extracts, and an intense late response to aniseed. Skin prick tests to celery, carrot, birch pollen, and mugwort pollen extracts were negative. Results of a nasal challenge test were positive to aniseed and negative to cinnamon; an aniseed oral food challenge test yielded a positive response. The molecular weights of the main immunoglobulin (Ig)E-binding proteins in aniseed extracts were approximately 48, 42, 39, 37, 34, 33, and 20 kD. Caraway, fennel, cumin, and coriander extracts showed similar IgE-binding patterns. Enzyme immunoassay inhibition studies with the patient's serum revealed cross-reactivity among the IgE components from aniseed, caraway, coriander, fennel, and dill extracts. CONCLUSIONS: We demonstrate the presence of aniseed allergens in a case of occupational rhinoconjunctivitis and food allergy, with molecular weights for this spice that differed from those previously reported.