Branes on Generalized Calibrated Submanifolds

We extend previous results on generalized calibrations to describe supersymmetric branes in supergravity backgrounds with diverse fields turned on, and provide several new classes of examples. As an important application, we show that supersymmetric D-branes in compactifications with field strength fluxes, and on SU(3)-structure spaces, wrap generalized calibrated submanifolds, defined by simple conditions in terms of the underlying globally defined, but non-closed, 2- and 3-forms. We provide examples where the geometric moduli of D-branes (for instance D7-branes in 3-form flux configurations) are lifted by the generalized calibration condition. In addition, we describe supersymmetric D6-branes on generalized calibrated 3-submanifolds of half-flat manifolds, which provide the mirror of B-type D-branes in IIB CY compactifications with 3-form fluxes. Supersymmetric sets of such D-branes carrying no homology charges are mirror to supersymmetric sets of D-branes which are homologically non-trivial, but trivial in K-theory. As an additional application, we describe models with chiral gauge sectors, realized in terms of generalized calibrated brane box configurations of NS- and D5-branes, which are supersymmetric but carry no charges, so that no orientifold planes are required in the compactification.Comment: 40 pages, 3 figures, references adde

Famosa: Evaluation of a multigene panel in patients with suspected HBOC

Background: Objectives: Characterize 1) the frequency of mutations in patients with clinical criteria for HBOC using a 25-gene panel in a Spanish population (FAMOSA study). 2) The psychological impact of these tests and patient''s counseling preferences. Methods: Patients with breast or ovarian cancer who met the NCCN criteria for genetic testing with a) prior testing for BRCA genes with NO mutation identified; or b) recently diagnosed (<6 months) and not genetically tested, were enrolled for multiplex cancer testing (MyRisk 25-gene panel). Participants completed self-questionnaires regarding geneting counseling preferences and three psychological scales (MICRA, CWS, R-IES) at base-line, one week, three and twelve months after results disclosure. Results: From November 14 to February 15, 210 patients were included in the FAMOSA study (109 HBOC). 61 (56%) patients were previously tested for BRCA1/2 gene mutations with conventional techniques; median age: 44y (22-77); gender: 3 males / 106 females; cancer types: breast 95 (87%); ovary 14 (13%). Overall 22 pathogenic variants were identified in 21 patients (19, 3%): 10 BRCA1, 2 BRCA2, 2 PALB2, 3 MUYTH, 1 CDKN2A; 2 ATM, 1 BRAD1, 1 BRIP1. One patient had an unexpected mutation in CDKN2A gene (gluteus sarcoma age 20; bilateral breast ca; ages 45 and 50; father lung ca, age 70; brother melanoma, age 35). Three patients had a significant mutation of a recessive condition in MUYTH. Of 61 patients previously tested negative for HBOC, 1 had a pathogenic variant in BRCA1 and 17/ 19 patients with VUS were classified negative in BRCA genes with MyRisk.Patients are willing to be disclosed all available information from panel testing. Differences were observed among type of results at short and mid-term. Cancer worry was higher in moderate-penetrance carriers than high penetrance carriers. Longer follow up is ongoing. Conclusions: Panel testing in patients with HBOC yielded a 19, 3% mutation rate, increasing the yield of genetic mutations beyond BRCA. Patients are willing to be disclosed all available information from panel testing

Building MSSM Flux Vacua

We construct N=1 and N=0 chiral four-dimensional vacua of flux compactification in Type IIB string theory. These vacua have the common features that they are free of tadpole instabilities (both NSNS and RR) even for models with N=0 supersymmetry. In addition, the dilaton/complex structure moduli are stabilised and the supergravity background metric is warped. We present an example in which the low energy spectrum contains the MSSM spectrum with three generations of chiral matter. In the N=0 models, the background fluxes which stabilise the moduli also induce soft supersymmetry breaking terms in the gauge and chiral sectors of the theory, while satisfying the equation of motion. We also discuss some phenomenological features of these three generation MSSM flux vacua. Our techniques apply to other closed string backgrounds as well and, in fact, also allow to find new N=1 D-brane models which were believed not to exist. Finally, we discuss in detail the consistency conditions of these flux compactifications. Cancellation of K-theory charges puts additional constraints on the consistency of the models, which render some chiral D-brane models in the literature inconsistent.Comment: 33 pages, 1 figure. Minor correction

Chiral 4d string vacua with D-branes and NSNS and RR fluxes

We discuss type IIB orientifolds with D-branes, and NSNS and RR field strength fluxes. The D-brane sectors lead to open string spectra with non-abelian gauge symmetry and charged chiral fermions. The closed string field strengths generate a scalar potential stabilizing most moduli. We describe the construction of N=1 supersymmetric models in the context of orientifolds of IIB theory on T^6/Z_2 x Z_2, containing D9-branes with world-volume magnetic fluxes, and illustrate model building possibilities with several explicit examples. We comment on a T-dual picture with D8-branes on non-Calabi-Yau half-flat geometries, and discuss some of the topological properties of such configurations. We also explore the construction of models with fluxes and with D3-branes at singularities and present a non-supersymmetric 3-family SU(5) model.Comment: latex, 49 pages, 2 figure

AID overexpression leads to aggressive murine CLL and nonimmunoglobulin mutations that mirror human neoplasms

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma

Rationale: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features. Methods: We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro. Results: A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients' liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P=4.67.10(-18)), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. Conclusions: Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients' management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors