Ensembles of endothelial and mural cells promote angiogenesis in prenatal human brain.

Interactions between angiogenesis and neurogenesis regulate embryonic brain development. However, a comprehensive understanding of the stages of vascular cell maturation is lacking, especially in the prenatal human brain. Using fluorescence-activated cell sorting, single-cell transcriptomics, and histological and ultrastructural analyses, we show that an ensemble of endothelial and mural cell subtypes tile the brain vasculature during the second trimester. These vascular cells follow distinct developmental trajectories and utilize diverse signaling mechanisms, including collagen, laminin, and midkine, to facilitate cell-cell communication and maturation. Interestingly, our results reveal that tip cells, a subtype of endothelial cells, are highly enriched near the ventricular zone, the site of active neurogenesis. Consistent with these observations, prenatal vascular cells transplanted into cortical organoids exhibit restricted lineage potential that favors tip cells, promotes neurogenesis, and reduces cellular stress. Together, our results uncover important mechanisms into vascular maturation during this critical period of human brain development.

Endocardial substrate of ventricular tachycardia in an adult patient with congenitally corrected transposition of great arteries without surgical repair.

Congenitally corrected transposition of the great arteries (CCTGA) is a rare congenital heart disease which may present sudden cardiac death presumably due to malignant ventricular tachycardia (VT). In patients with congenital heart disease, knowledge of arrhythmogenic substrate is crucial for planning an ablation procedure. We present the first description of the arrhythmogenic endocardial substrate of a non-iatrogenic scar-related VT in a patient with CCTGA.

Soluble factors in COVID-19 mRNA vaccine-induced myocarditis causes cardiomyoblast hypertrophy and cell injury: a case report.

BACKGROUND: Inflammation affecting the heart and surrounding tissues is a clinical condition recently reported following COVID-19 mRNA vaccination. Assessing trends of these events related to immunization will improve vaccine safety surveillance and best practices for forthcoming vaccine campaigns. However, the causality is unknown, and the mechanisms associated with cardiac myocarditis are not understood. CASE PRESENTATION: After the first dose, we reported an mRNA vaccine-induced perimyocarditis in a young patient with a history of recurrent myocardial inflammation episodes and progressive loss of cardiac performance. We tested this possible inflammatory cytokine-mediated cardiotoxicity after vaccination in the acute phase (ten days), and we found a significant elevation of MCP-1, IL-18, and IL-8 inflammatory mediators. Still, these cytokines decreased considerably at the recovery phase (42 days later). We used the cardiomyoblasts cell line to test the effect of serum on cell viability, observing that serum from the acute phase reduced the cell viability to 75%. We did not detect this toxicity in cells when we tested serum from the patient in the recovery phase. We also tested serum-induced hypertrophy, a phenomenon in myocarditis and heart failure. We found that acute phase-serum has hypertrophy effects, increasing 25% of the treated cardiac cells' surface and significantly increasing B-type natriuretic peptide. However, we did not observe the hypertrophic effect in the recovery phase or sera from healthy controls. CONCLUSION: Our results opened the possibility of the inflammatory cytokines or serum soluble mediators as key factors for vaccine-associated myocarditis. In this regard, identifying anti-inflammatory molecules that reduce inflammatory cytokines could help avoid vaccine-induced myocardial inflammation.

Pediatric chronic urticaria: Clinical and laboratory characteristics and factors linked to remission.

BACKGROUND: Chronic urticaria (CU) is defined as the occurrence of wheals/angioedema for ≥6 consecutive weeks. Until now, guidelines and publications addressing CU have focused mainly on adults. As a result, evidence and guidance in the pediatric population are scarce. METHODS: This study aims to describe clinical and laboratory findings in pediatric CU and to determine factors associated with remission. RESULTS: 185 patients, 54% female, median age at onset of 8.8 years. Angioedema was present in almost half. The most common type of CU was chronic spontaneous urticaria (CSU) in 74%. At least one atopic comorbidity was found in almost a third (35%). In addition, 8% had an autoimmune disorder (exclusively in CSU) and 9% had a psychiatric condition. Basopenia was found in 67% and was more frequently associated with CSU. The basophil activation test (BAT) was positive in 40%. With regard to remission, being of male sex, angioedema absence, the absence of physical triggers, and eosinophil counts >0.51 × 109 /L were associated with shorter CU duration. CONCLUSION: Atopy is a common condition in pediatric CU. CSU is the most common type. Autoimmune comorbidities and basopenia were significantly more common in CSU. In addition, ours is one of the few studies, assessing BAT utility in the pediatric population, being positive in a relevant percentage (40%). BAT positivity was more frequent in CSU. Our results suggest that the absence of angioedema and physical triggers, male sex, and eosinophil counts >0.51 × 109 /L appear to be associated with a better prognosis in terms of remission.

Combining familial hypercholesterolemia and statin genetic studies as a strategy for the implementation of pharmacogenomics. A multidisciplinary approach.

The diagnostic process of familial hypercholesterolemia frequently involves the use of genetic studies. Patients are treated with lipid-lowering drugs, frequently statins. Although pharmacogenomic clinical practice guidelines focusing on genotype-based statin prescription have been published, their use in routine clinical practice remains very modest.We have implemented a new NGS strategy that combines a panel of genes related to familial hypercholesterolemia with genomic regions related to the pharmacogenomics of lipid-lowering drugs described in clinical practice guidelines and in EMA and FDA drug labels. A multidisciplinary team of doctors, biologists, and pharmacists creates a clinical report that provides diagnostic and therapeutic findings using a knowledge management and clinical decision support system, as well as an algorithm for treatment selection.For 12 months, a total of 483 genetic diagnostic studies for familial hypercholesterolemia were carried out, of which 221 (45.8%) requested a complementary pharmacogenomic test. Of these 221 patients, 66.5% were carriers of actionable variants in any of the studied pharmacogenomic pathways: 46.6% of patients in one pathway, 19.0% in two pathways, and 0.9% in three pathways. 45.7% of patients could have a response to atorvastatin different from that of the reference population, 45.7% for simvastatin and lovastatin, 29.0% for fluvastatin, and 6.7% patients for pitavastatin.This implementation approach facilitates the incorporation of pharmacogenomic studies in clinical care practice, it does not add complexity nor additional steps to laboratory processes, and improves the pharmacotherapeutic process of patients.

Local detection of microvessels in IDH-wildtype glioblastoma using relative cerebral blood volume: an imaging marker useful for astrocytoma grade 4 classification.

BACKGROUND: The microvessels area (MVA), derived from microvascular proliferation, is a biomarker useful for high-grade glioma classification. Nevertheless, its measurement is costly, labor-intense, and invasive. Finding radiologic correlations with MVA could provide a complementary non-invasive approach without an extra cost and labor intensity and from the first stage. This study aims to correlate imaging markers, such as relative cerebral blood volume (rCBV), and local MVA in IDH-wildtype glioblastoma, and to propose this imaging marker as useful for astrocytoma grade 4 classification. METHODS: Data from 73 tissue blocks belonging to 17 IDH-wildtype glioblastomas and 7 blocks from 2 IDH-mutant astrocytomas were compiled from the Ivy GAP database. MRI processing and rCBV quantification were carried out using ONCOhabitats methodology. Histologic and MRI co-registration was done manually with experts' supervision, achieving an accuracy of 88.8% of overlay. Spearman's correlation was used to analyze the association between rCBV and microvessel area. Mann-Whitney test was used to study differences of rCBV between blocks with presence or absence of microvessels in IDH-wildtype glioblastoma, as well as to find differences with IDH-mutant astrocytoma samples. RESULTS: Significant positive correlations were found between rCBV and microvessel area in the IDH-wildtype blocks (p < 0.001), as well as significant differences in rCBV were found between blocks with microvascular proliferation and blocks without it (p < 0.0001). In addition, significant differences in rCBV were found between IDH-wildtype glioblastoma and IDH-mutant astrocytoma samples, being 2-2.5 times higher rCBV values in IDH-wildtype glioblastoma samples. CONCLUSIONS: The proposed rCBV marker, calculated from diagnostic MRIs, can detect in IDH-wildtype glioblastoma those regions with microvessels from those without it, and it is significantly correlated with local microvessels area. In addition, the proposed rCBV marker can differentiate the IDH mutation status, providing a complementary non-invasive method for high-grade glioma classification.

Influence of Heat Exchanger Design on the Thermal Performance of a Domestic Wine Cooler Driven by a Magnetic Refrigeration System.

Conventional and not-in-kind refrigerators require heat exchangers for their operation. Yet, most magnetic cooling studies do not take full account of those components despite their importance in defining the cooling capacity and temperature span. To investigate the influence of heat exchanger design parameters on the performance of magnetic refrigerators, a model was developed to integrate the heat exchangers, regenerators and thermal reservoirs. The results were compared with data generated in an apparatus that emulates the conditions of the thermal fluid supplied by the regenerators to a cold heat exchanger positioned inside the cabinet of a retrofitted 130-liter wine cooler. Six tube-fin heat exchangers were evaluated to identify the most suitable geometry (number of tube rows and fin density) for the compact magnetic refrigerator. Numerical simulations described the influence of the heat exchanger on the regenerator performance in terms of the liquid stream effectiveness. For a temperature span of 20°C between the external environment and the refrigerated compartment, the best heat exchanger/fan assembly resulted in a cooling capacity reduction of 37\% and a temperature span increase of 32\%, in comparison with an idealized system. The expected system coefficient of performance (COP) and second-law efficiency were 1.8\% and 13\%, respectively.

Temperature pull-down of a retrofitted wine refrigerator cabinet cooled by a caloric system emulator.

The present study analyzes the time-dependent thermal behavior of a retrofitted wine refrigerator cabinet operated by a caloric system emulator. The presence of a full load of wine bottles enabled the assessment of the thermal stratification inside the cabinet. Further experimental tests have been performed to quantify the overall thermal conductance of the cabinet walls and the thermal conductance of the glass door. A detailed mathematical model was developed to predict the temperature pull down in the refrigerated compartment, considering the interaction between the cabinet air and the wine bottles. In addition to the air and bottle temperatures, a good agreement (lower than 15% relative error) was observed for the cooling capacity. The numerical simulations revealed that the cabinet door was responsible for approximately 60% of the thermal load (even though it corresponded to approximately 20% of the cabinet external area).

Differences between surviving and non-surviving venous thromboembolism COVID-19 patients: a systematic review.

BACKGROUND: To our knowledge, the treatment, outcome, clinical presentation, risk stratification of patients with venous thromboembolism and COVID-19 have not been well characterized. METHODS: We searched for systematic reviews, cohorts, case series, case reports, editor letters, and venous thromboembolism COVID-19 patients' abstracts following PRISMA and PROSPERO statements. We analyzed therapeutic approaches and clinical outcomes of venous thromboembolism COVID-19 patients. Inclusion: COVID-19 patients with venous thromboembolism confirmed by an imaging method (venous doppler ultrasound, ventilation-perfusion lung scan, computed tomography pulmonary angiogram, pulmonary angiography). We assessed and reported the original Pulmonary Embolism Severity Index for each pulmonary embolism patient. In addition, we defined major bleedings according to the International Society of Thrombosis and Haemostasis criteria. RESULTS: We performed a systematic review from August 9 to August 30, 2020. We collected 1,535 papers from PubMed, Scopus, Web of Science, Wiley, and Opengrey. We extracted data from 89 studies that describe 143 patients. Unfractionated and low-molecular-weight heparin was used as parenteral anticoagulation in 85/143 (59%) cases. The Food and Drug Administration-approved alteplase regimen guided the advanced treatment in 39/143 (27%) patients. The mortality was high (21.6%, CI 95% 15.2-29.3). The incidence of major bleeding complications was 1 (0.9%) in the survival group and 1 (3.2%) in the death group. Pulmonary Embolism Severity Index was class I in 11.6% and II in 22.3% in survivors compared to 0% and 6.5% in non-survivors, respectively. Patients who experienced venous thromboembolism events at home were more likely to live than in-hospital events. CONCLUSIONS: We determined a high mortality incidence of pulmonary embolism and a low rate of bleeding. Unfractionated and low-molecular-weight heparin drove parenteral anticoagulation and alteplase the advanced treatment in both groups. The original Pulmonary Embolism Severity Index could be helpful in the risk stratification.

Nasal obstructive disorders impair health-related quality of life in adolescents with persistent allergic rhinitis: A real-life study.

BACKGROUND: We previously reported a higher prevalence of nasal obstructive disorders (NOD) in pediatric patients with persistent allergic rhinitis (PER) not responding to medical treatment. The aim of this study was to determine the impact of NOD on quality of life (QoL) in this population. METHODS: Real-life prospective study including 142 patients (41 children, 6-11 years old and 101 adolescents, 12-17 years old) with moderate and severe PER. After 2 months of medical treatment (intranasal steroids and antihistamines), patients were asked whether their symptoms had improved (yes/no) and classified accordingly in R, responders and NR, non-responders. Nasal symptoms (visual analog scale, VAS), NOD (nasal endoscopy), and QoL (PRQLQ, AdolQRLQ) were also assessed. RESULTS: Sixty-nine adolescents and 24 children were included in the NR group. NR presented worse QoL overall scores in adolescents (3.16±1.1 vs 1.63±0.99; P=.00001) and children (2.19±0.82 vs 1.51±0.77, P=.02). Medical treatment failure was associated with worse outcomes in QoL (adolescents OR: 1.6, P<.0001; children OR: 1.04, P=.036). Female adolescents presented worse QoL scores than males (3.19 vs 2.36, P=.001). The presence of obstructive septal deviation (OR: 1.02, P=.005), obstructive turbinate hyperplasia (OR: 1.03, P=.0006), and coexistence of both (OR=2.06, P=.001) was associated with worse QoL in adolescents. A strong and highly significant correlation was found between nasal symptoms VAS and QoL. CONCLUSION: The presence of NOD, particularly in adolescents, is associated with poor QoL outcomes. Assessment of NOD in pediatric PER should be considered an essential approach to determine the response to treatment and its impact on patient's QoL.

Prospective evaluation of the conversion rate in the receptor status between primary breast cancer and metastasis: results from the GEICAM 2009-03 ConvertHER study.

The objective of this study was to determine the conversion rate of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER) and progesterone receptor (PR) between primary tumors and metastatic lesions in advanced breast cancer. Patients with suspected diagnosis of locally recurrent or metastatic breast cancer, either at first relapse or after successive disease progressions, who had an appropriately preserved sample from a primary tumor and were scheduled for a biopsy of the recurrent lesion, were included. Blinded determinations of receptor status on paired samples were performed by immunohistochemistry and fluorescence in situ hybridization at a central laboratory and compared with those performed locally. Overall, 196 patients were included and 184 patients were considered evaluable. Reasons for non-evaluability included the inability to perform biopsy (n = 4) or biopsy results showing normal tissue (n = 3), benign disease (n = 3) or a second neoplasia (n = 2). Conversion rates determined at local level were higher than those determined centrally (HER2: 16 vs. 3 %, ER: 21 vs. 13 %, PR: 35 vs. 28 %, respectively). There was substantial agreement regarding the expression of HER2 in primary tumors and metastases, and ER at metastases, between local and central laboratories. PR at any site and ER at primary site showed moderate agreement. Oncologists altered their treatment plans in 31 % of patients whose tumor subtype had changed. These results reinforce the recommendation for performing confirmatory biopsies of metastases, not only to avoid misdiagnosis of breast cancer relapse, but also to optimize treatment (clinicaltrials.gov identifier: NCT01377363).

MicroRNA profile in very young women with breast cancer.

BACKGROUND: Breast cancer is rarely diagnosed in very young women (35 years old or younger), and it often presents with distinct clinical-pathological features related to a more aggressive phenotype and worse prognosis when diagnosed at this early age. A pending question is whether breast cancer in very young women arises from the deregulation of different underlying mechanisms, something that will make this disease an entity differentiated from breast cancer diagnosed in older patients. METHODS: We performed a comprehensive study of miRNA expression using miRNA Affymetrix2.0 array on paraffin-embedded tumour tissue of 42 breast cancer patients 35 years old or younger, 17 patients between 45 and 65 years old and 29 older than 65 years. Data were statistically analyzed by t-test and a hierarchical clustering via average linkage method was conducted. Results were validated by qRT-PCR. Putative targeted pathways were obtained using DIANA miRPath online software. RESULTS: The results show a differential and unique miRNA expression profile of 121 miRNAs (p-value <0.05), 96 of those with a FDR-value <0.05. Hierarchical clustering grouped the samples according to their age, but not by subtype nor by tumour characteristics. We were able to validate by qRT-PCR differences in the expression of 6 miRNAs: miR-1228*, miR-3196, miR-1275, miR-92b, miR-139 and miR-1207. Moreover, all of the miRNAs maintained the expression trend. The validated miRNAs pointed out pathways related to cell motility, invasion and proliferation. CONCLUSIONS: The study suggests that breast cancer in very young women appears as a distinct molecular signature. To our knowledge, this is the first time that a validated microRNA profile, distinctive to breast cancer in very young women, has been presented. The miRNA signature may be relevant to open an important field of research in order to elucidate the underlying mechanism in this particular disease, which in a more clinical setting, could potentially help to identify therapeutic targets in this particular set of patients.

Assessing the efficacy of immunotherapy with a glutaraldehyde-modified house dust mite extract in children by monitoring changes in clinical parameters and inflammatory markers in exhaled breath.

INTRODUCTION: The aim of this study was to evaluate the effectiveness of specific immunotherapy (SIT) management with allergoids in children with allergic asthma by monitoring changes in clinical parameters and inflammatory markers in exhaled breath. METHODS: The study population included 43 patients (24 males) of 6-14 years of age, who had allergic asthma and were sensitized to mites. Twenty-three individuals were treated with subcutaneous SIT (PURETHAL® Mites, HAL Allergy) for 8 months, i.e. the SIT group, and 20 were given medication to treat symptoms only, i.e. the control group. Before treatment and after 4 and 8 months, several clinical parameters, the levels of exhaled nitric oxide and the pH of exhaled breath condensate (EBC) were determined. RESULTS: The SIT group presented with an improvement in asthma classification, a reduction in maintenance drug therapy and improved scores on the quality-of-life questionnaire. These changes were not observed in the control group. Both groups presented significant decreases in EBC pH values at 4 and 8 months after treatment compared to at baseline. However, analysis of the variable 'ratio' showed an increase in the EBC pH values after 8 months of treatment in the SIT group compared with the values at 4 months. CONCLUSIONS: SIT with standardized mite extract reduces asthma symptoms in children. A decrease in EBC pH values was observed in both groups, although the SIT group presented a tendency of recovered values after 8 months. Future studies of EBC pH monitoring in the longer term are needed to determine the effectiveness of this marker.

BCAS1 defines a heterogeneous cell population in diffuse gliomas.

Oligodendrocyte precursor markers have become of great interest to identify new diagnostic and therapeutic targets for diffuse gliomas, since state-of-the-art studies point towards immature oligodendrocytes as a possible source of gliomagenesis. Brain enriched myelin associated protein 1 (BCAS1) is a novel marker of immature oligodendrocytes and was proposed to contribute to tumorigenesis in non-central nervous system tumors. However, BCAS1 role in diffuse glioma is still underexplored. This study analyzes the expression of BCAS1 in different tumor samples from patients with diffuse gliomas (17 oligodendrogliomas; 8 astrocytomas; 60 glioblastomas) and uncovers the molecular and ultrastructural features of BCAS1+ cells by immunostaining and electron microscopy. Our results show that BCAS1+ cells exhibit stellate or spherical morphology with similar ultrastructural features. Stellate and spherical cells were detected as isolated cells in all studied gliomas. Nevertheless, only stellate cells were found to be proliferative and formed tightly packed nodules with a highly proliferative rate in oligodendrogliomas. Our findings provide a comprehensive characterization of the BCAS1+ cell population within diffuse gliomas. The observed proliferative capacity and distribution of BCAS1+ stellate cells, particularly in oligodendrogliomas, highlight BCAS1 as an interesting marker, warranting further investigation into its role in tumor malignancy.

Deep learning automatic semantic segmentation of glioblastoma multiforme regions on multimodal magnetic resonance images.

OBJECTIVES: In patients having naïve glioblastoma multiforme (GBM), this study aims to assess the efficacy of Deep Learning algorithms in automating the segmentation of brain magnetic resonance (MR) images to accurately determine 3D masks for 4 distinct regions: enhanced tumor, peritumoral edema, non-enhanced/necrotic tumor, and total tumor. MATERIAL AND METHODS: A 3D U-Net neural network algorithm was developed for semantic segmentation of GBM. The training dataset was manually delineated by a group of expert neuroradiologists on MR images from the Brain Tumor Segmentation Challenge 2021 (BraTS2021) image repository, as ground truth labels for diverse glioma (GBM and low-grade glioma) subregions across four MR sequences (T1w, T1w-contrast enhanced, T2w, and FLAIR) in 1251 patients. The in-house test was performed on 50 GBM patients from our cohort (PerProGlio project). By exploring various hyperparameters, the network's performance was optimized, and the most optimal parameter configuration was identified. The assessment of the optimized network's performance utilized Dice scores, precision, and sensitivity metrics. RESULTS: Our adaptation of the 3D U-net with additional residual blocks demonstrated reliable performance on both the BraTS2021 dataset and the in-house PerProGlio cohort, employing only T1w-ce sequences for enhancement and non-enhanced/necrotic tumor models and T1w-ce + T2w + FLAIR for peritumoral edema and total tumor. The mean Dice scores (training and test) were 0.89 and 0.75; 0.75 and 0.64; 0.79 and 0.71; and 0.60 and 0.55, for total tumor, edema, enhanced tumor, and non-enhanced/necrotic tumor, respectively. CONCLUSIONS: The results underscore the high precision with which our network can effectively segment GBM tumors and their distinct subregions. The level of accuracy achieved agrees with the coefficients recorded in previous GBM studies. In particular, our approach allows model specialization for each of the different tumor subregions employing only those MR sequences that provide value for segmentation.

Proteometabolomics of initial and recurrent glioblastoma highlights an increased immune cell signature with altered lipid metabolism.

BACKGROUND: There is an urgent need to better understand the mechanisms associated with the development, progression, and onset of recurrence after initial surgery in glioblastoma (GBM). The use of integrative phenotype-focused -omics technologies such as proteomics and lipidomics provides an unbiased approach to explore the molecular evolution of the tumor and its associated environment. METHODS: We assembled a cohort of patient-matched initial (iGBM) and recurrent (rGBM) specimens of resected GBM. Proteome and metabolome composition were determined by mass spectrometry-based techniques. We performed neutrophil-GBM cell coculture experiments to evaluate the behavior of rGBM-enriched proteins in the tumor microenvironment. ELISA-based quantitation of candidate proteins was performed to test the association of their plasma concentrations in iGBM with the onset of recurrence. RESULTS: Proteomic profiles reflect increased immune cell infiltration and extracellular matrix reorganization in rGBM. ASAH1, SYMN, and GPNMB were highly enriched proteins in rGBM. Lipidomics indicates the downregulation of ceramides in rGBM. Cell analyses suggest a role for ASAH1 in neutrophils and its localization in extracellular traps. Plasma concentrations of ASAH1 and SYNM show an association with time to recurrence. CONCLUSIONS: We describe the potential importance of ASAH1 in tumor progression and development of rGBM via metabolic rearrangement and showcase the feedback from the tumor microenvironment to plasma proteome profiles. We report the potential of ASAH1 and SYNM as plasma markers of rGBM progression. The published datasets can be considered as a resource for further functional and biomarker studies involving additional -omics technologies.

High ERK protein expression levels correlate with shorter survival in triple-negative breast cancer patients.

The mitogen-activated protein kinase (MAPK) signaling pathway is known to be activated in triple-negative breast cancer (TNBC). Extracellular signal-related kinase (ERK), a member of the MAPK pathway, promotes cell proliferation, angiogenesis, cell differentiation, and cell survival. To assess the prognostic impact of ERK in TNBC patients, relative quantities of ERK (ERK-2 and pMAPK) and direct targets of the ERK pathway (MAPK/ERK kinase 1, phospho-enriched protein in astrocytes [PEA]-15, phosphorylated (p)PEA-15, tuberous sclerosis protein 2, p70S6 kinase, and p27) were measured using reverse-phase protein arrays in tumor tissue from patients with TNBC (n = 97) and non-TNBC (n = 223). Protein levels in patients with TNBC were correlated with clinical and tumor characteristics and outcome. The median age of patients with TNBC was 55 years (range, 27-86 years). Disease stage was I in 21%, II in 60%, and III in 20% of the patients. In a multivariate analysis, among patients with TNBC, those with ERK-2-overexpressing tumors had a lower overall survival rate than those with low ERK-2-expressing tumors (hazard ratio [HR], 2.76; 95% confidence interval [CI], 1.19-6.41). However, high pMAPK levels were associated with a significantly higher relapse-free survival rate (HR, 0.66; 95% CI, 0.46-0.95). In conclusion, ERK-2 and pMAPK are valuable prognostic markers in TNBC. Further studies are justified to elucidate ERK's role in TNBC tumorigenicity and metastasis.

In-depth molecular and phenotypic characterization in a rice insertion line library facilitates gene identification through reverse and forward genetics approaches.

We report here the molecular and phenotypic features of a library of 31,562 insertion lines generated in the model japonica cultivar Nipponbare of rice (Oryza sativa L.), called Oryza Tag Line (OTL). Sixteen thousand eight hundred and fourteen T-DNA and 12,410 Tos17 discrete insertion sites have been characterized in these lines. We estimate that 8686 predicted gene intervals--i.e. one-fourth to one-fifth of the estimated rice nontransposable element gene complement--are interrupted by sequence-indexed T-DNA (6563 genes) and/or Tos17 (2755 genes) inserts. Six hundred and forty-three genes are interrupted by both T-DNA and Tos17 inserts. High quality of the sequence indexation of the T2 seed samples was ascertained by several approaches. Field evaluation under agronomic conditions of 27,832 OTL has revealed that 18.2% exhibit at least one morphophysiological alteration in the T1 progeny plants. Screening 10,000 lines for altered response to inoculation by the fungal pathogen Magnaporthe oryzae allowed to observe 71 lines (0.7%) developing spontaneous lesions simulating disease mutants and 43 lines (0.4%) exhibiting an enhanced disease resistance or susceptibility. We show here that at least 3.5% (four of 114) of these alterations are tagged by the mutagens. The presence of allelic series of sequence-indexed mutations in a gene among OTL that exhibit a convergent phenotype clearly increases the chance of establishing a linkage between alterations and inserts. This convergence approach is illustrated by the identification of the rice ortholog of AtPHO2, the disruption of which causes a lesion-mimic phenotype owing to an over-accumulation of phosphate, in nine lines bearing allelic insertions.

Specific oral desensitization in children with IgE-mediated cow's milk allergy. Evolution in one year.

UNLABELLED: Cow's milk allergy is the most frequent childhood food allergy. Children older than 5 who have not become tolerant have less probabilities of natural tolerance. Specific oral desensitization methods are being investigated in reference centres. The aims of our study were to assess the efficacy of our guideline of specific oral desensitization to cow's milk in children and to know its suitability for anaphylactic children. Both clinical and specific IgE outcomes were evaluated. Eighty-seven children aged 5 to 16 years with a history of cow's milk allergy were included. Prior to desensitization, skin prick test, specific IgE to cow's milk proteins and a double-blind placebo control food challenge were performed in all. Of the 87 patients, 21 had a negative challenge; they were considered tolerant, and they were told to follow a free diet. Of the positive, 44 were anaphylactic and 22 non-anaphylactic. All of them were included. In non-anaphylactic patients, 6 achieved partial and 16 maximum desensitization after 23.1 weeks. In the anaphylactic group, 7 achieved partial and 35 maximum desensitization after 26.4 weeks. Cow's milk-specific IgE levels and casein-specific IgE levels were significantly lower in the tolerant patients at baseline. One year after desensitization, the medium specific cow's milk levels and casein IgE levels had dropped significantly. CONCLUSIONS: Our guideline for specific oral desensitization to cow's milk is efficacious even in patients with anaphylactic reactions to cow's milk and represents a significant life change. Immunological changes in 1 year show a drop in cow's milk protein-specific IgE.