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Members of the Notch family are involved in the development of breast cancer in animal models and in humans. In young transgenic mice, expressing intracellular activated Notch1 (N1(IC)) in mammary cells, we found that CD24(+) CD29(high) progenitor cells had enhanced survival, and were expanded through a cyclin D1-dependent pathway. This expansion positively correlated with the later cyclin D1-dependent formation of basal-like ductal tumors. This expanded population exhibited abnormal differentiation skewed toward the basal cells, showed signs of pre-malignancy (low PTEN/p53 and high c-myc) and contained stem cells with impaired self-renewal in vivo, and more numerous multipotent, ductal-restricted progenitors. Our data suggest that N1(IC) can favor transformation of progenitor cells early in life through a cyclin D1-dependent pathway.

V532 Oph has been found to be a member of the rare, hydrogen-deficient R Coronae Borealis (RCB) stars from new photometric and spectroscopic data reported in this paper. The lightcurve of V532 Oph shows the sudden, deep, irregularly spaced declines characteristic of RCB stars. Its optical spectrum is typical of a warm (T(eff)~7000 K) RCB star, showing weak or absent hydrogen lines, the C2 Swan bands, and no evidence for 13C. In addition, the star shows small pulsations typical of an RCB star and an infrared excess due to circum- stellar dust. It also appears to be significantly reddened by foreground dust. The distance to V532 Oph is estimated to be 5.5-8.7 kpc. These new data show that this star was misclassified as an eclipsing binary in the General Catalog of Variable Stars. The new data presented here for V532 Oph reveal the power of high-quality, high-cadence all-sky photometric surveys, such as ASAS-3, to identify new RCB candidates on the basis of lightcurve data alone, now that they have been collecting data for durations sufficiently long to reveal multiple declines. Despite their small numbers, RCB stars may be of great importance in understanding the late stages of stellar evolution. In particular, their measured isotopic abundances imply that many, if not most, RCB stars are produced by WD mergers, which may be the low-mass counterparts of the more massive mergers thought to produce type Ia supernovae. Therefore, establishing the population of RCB stars in the Galaxy will help constrain the frequency of these WD mergers. Comment: 11 pages, 4 figures, PASP in press

OBJECTIVES: Evaluate the relationship between endothelial activation, malaria complications, and long-term cognitive outcomes in severe malaria survivors. DESIGN: Prospectively cohort study of children with cerebral malaria, severe malarial anemia, or community children. SETTING: Mulago National Referral Hospital in Kampala, Uganda. SUBJECTS: Children 18 months to 12 years old with severe malaria (cerebral malaria, n = 253 or severe malarial anemia, n = 211) or community children (n = 206) were followed for 24 months. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children underwent neurocognitive evaluation at enrollment (community children) or a week following hospital discharge (severe malaria) and 6, 12, and 24 months follow-up. Endothelial activation was assessed at admission on plasma samples (von Willebrand factor, angiopoietin-1 and angiopoietin-2, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, soluble E-Selectin, and P-Selectin). False discovery rate was used to adjust for multiple comparisons. Severe malaria was associated with widespread endothelial activation compared with community children (p < 0.0001 for all markers). Acute kidney injury was independently associated with changes in von Willebrand factor, soluble intercellular adhesion molecule-1, soluble E-Selectin, P-Selectin, and angiopoietin-2 (p < 0.0001 for all). A log(10) increase in angiopoietin-2 was associated with lower cognitive z scores across age groups (children < 5, β −0.42, 95% CI, −0.69 to −0.15, p = 0.002; children ≥ 5, β −0.39, 95% CI, −0.67 to −0.11, p = 0.007) independent of disease severity (coma, number of seizures, acute kidney injury) and sociodemographic factors. Angiopoietin-2 was associated with hemolysis (lactate dehydrogenase, total bilirubin) and inflammation (tumor necrosis factor-α, interleukin-10). In children with cerebral malaria who had a lumbar puncture performed, angiopoietin-2 was associated with blood-brain barrier dysfunction, and markers of neuroinflammation and injury in the cerebrospinal fluid (tumor necrosis factor-α, kynurenic acid, tau). CONCLUSIONS: These data support angiopoietin-2 as a measure of disease severity and a risk factor for long-term cognitive injury in children with severe malaria.

The cardiovascular effects of arginine vasopressin (AVP) administered into a lateral cerebral ventricle or into the cisterna magna were investigated in conscious Long Evans (control) rats and AVP-deficient Brattleboro rats. The effects of subpressor intracerebroventricular and intracisternal doses of AVP on cardiac baroreflex sensitivities were also determined. Intracerebroventricular and intracisternal AVP increased blood pressure of both strains of rat in a dose-dependent manner. The maximum pressor response produced by intracerebroventricular AVP in Long Evans rats was 13 +/- 2/13 +/- 1 mm Hg (systolic/diastolic, n = 6) after 100 ng AVP. The pressor response to the highest intracerebroventricular dose of AVP tested in Brattleboro rats (30 ng) was 46 +/- 13/21 +/- 6 mm Hg (n = 6). Intracerebroventricular AVP caused a tachycardia in Brattleboro rats but had no effect on heart rate of Long Evans rats. At doses greater than 1 ng, the increases in blood pressure produced by intracisternal AVP in both groups of rats were significantly greater than the increases produced by the same doses given intracerebroventricularly. Heart rate fell in a dose-dependent manner after intracisternal AVP in Long Evans rats but not in Brattleboro rats. Cardiac baroreflex sensitivities of Brattleboro rats were not significantly different from those of Long Evans rats and were not modified by intracerebroventricular (0.3 ng) or intracisternal (0.1 ng) AVP. In Long Evans rats, intracisternal AVP (0.3 ng) increased cardiac baroreflex responses to both increases and decreases in pressure. Intracerebroventricular AVP (0.3 ng) increased the sensitivity of the reflex in response to an elevation but not to a reduction in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

The two pillars of rational conformal field theory and rational vertex operator algebras are modularity of characters on the one hand and its interpretation of modules as objects in a modular tensor category on the other one. Overarching these pillars is the Verlinde formula. In this paper we consider the more general class of logarithmic conformal field theories and $C_2$-cofinite vertex operator algebras. We suggest that their modular pillar are trace functions with insertions corresponding to intertwiners of the projective cover of the vacuum, and that the categorical pillar are finite tensor categories $\mathcal C$ which are ribbon and whose double is isomorphic to the Deligne product $\mathcal C\otimes \mathcal C^{opp}$. Overarching these pillars is then a logarithmic variant of Verlinde's formula. Numerical data realizing this are the modular $S$-matrix and modified traces of open Hopf links. The representation categories of $C_2$-cofinite and logarithmic conformal field theories that are fairly well understood are those of the $\mathcal W_p$-triplet algebras and the symplectic fermions. We illustrate the ideas in these examples and especially make the relation between logarithmic Hopf links and modular transformations explicit.

Hyponatraemia is the commonest electrolyte abnormality in hospitalized patients. If the plasma sodium concentration (PNa) declines to ∼ 120 mM in <48 h, brain cell swelling might result in herniation, with devastating consequences. The volume and/or the composition of fluids used for intravenous therapy often contribute to the development of acute hyponatraemia. Our hypothesis is that the traditional calculation of the daily loss of insensible water overestimates this parameter, leading to an excessive daily recommended requirement for water. We offer suggestions to minimize the risk of iatrogenic hyponatraemia.

Abstract Background: The post-HERCULES trial (NCT02878603) evaluated long-term safety and efficacy of caplacizumab in patients with acquired thrombotic thrombocytopenic purpura (aTTP; also known as immune-mediated TTP), and efficacy of repeated use of caplacizumab for aTTP recurrence. Methods: Patients who completed the HERCULES trial were invited to participate in the post-HERCULES study and attend twice-yearly visits for 3 years. In case of aTTP recurrence, patients could receive open-label (OL) caplacizumab with therapeutic plasma exchange (TPE) and immunosuppression (IST). Safety was assessed during the overall study period (intention-to-observe [ITO] population) and during recurrences. TTP-related events (recurrence, mortality, or major thromboembolic events) were assessed in the efficacy ITO population. The ITO population (n=104) included all enrolled patients, grouped by whether they received caplacizumab during HERCULES (randomized or switched to OL after exacerbation). The efficacy ITO population (n=78) included those without aTTP recurrence during HERCULES or prior to the beginning of post-HERCULES. The recurrence population (n=19) included patients with ≥1 recurrence during post-HERCULES; the repeat-use population (n=9) was a subset treated at least twice with caplacizumab (received caplacizumab in HERCULES or treated twice in post-HERCULES). Pharmacodynamics and immunogenicity were assessed in the ITO population. The study was conducted in accordance with the Declaration of Helsinki. Results: Of 104 patients enrolled in post-HERCULES, 75 were treated with caplacizumab along with TPE+IST during HERCULES (caplacizumab group) and 29 were treated with TPE+IST only (placebo group). During the overall post-HERCULES study period, incidence of adverse events (AEs) and serious AEs was similar between the groups. In the ITO population, recurrence occurred in 11/75 patients (15%) in the caplacizumab group and 8/29 patients (28%) in the placebo group. In the efficacy ITO population, TTP-related events occurred in 8% of patients (4/49) randomized to caplacizumab versus 38% (11/29) randomized to placebo (Table 1). Prior rituximab use during HERCULES was similar in both groups (21/49 patients [43%] randomized to caplacizumab and 12/29 [41%] randomized to placebo). Incidence of recurrence by prior rituximab use (with vs without) was 10% (2/21) versus 7% (2/28) among patients randomized to caplacizumab, and 17% (2/12) versus 35% (6/17) among patients randomized to placebo. Of 19 patients with ≥1 recurrence, 13 were treated with caplacizumab and 6/13 received concomitant rituximab. Recurrences were resolved (12/13) or resolving (1/13) for all patients treated with caplacizumab, including 9 patients with repeat caplacizumab use. One patient who did not receive caplacizumab in either HERCULES or post-HERCULES died as an outcome of recurrence. Safety profile of caplacizumab for treatment of recurrence was consistent with that observed in HERCULES (Table 2) . The most common treatment-emergent AEs (TEAEs) with caplacizumab during the first recurrence (n=13) were headache and constipation (n=3 each). In the repeat-use population (n=9), bleeding events were reported in 5/9 patients (56%) for the first recurrence; 2 patients had a serious treatment-related TEAE of genitourinary or gastrointestinal bleeding; 2 patients had treatment-emergent anti-drug antibodies (ADAs) positive in a functional neutralizing antibody assay. No apparent impact of treatment-emergent ADAs on RICO activity or change from baseline in von Willebrand factor antigen concentration was found. Conclusions: The long-term safety profile of patients exposed to caplacizumab together with TPE+IST was similar to those who received IST+TPE only, with no observed increases in recurrence of aTTP. Repeat caplacizumab use was efficacious, with no evidence of safety concerns or boosting of ADA response. Funding: This research was funded by Ablynx, a Sanofi company. Figure 1 Figure 1. Disclosures Scully: Shire: Research Funding; Novartis: Research Funding, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octopharma: Speakers Bureau. de la Rubia: Ablynx/Sanofi: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Bristol Myers Squibb,: Honoraria, Speakers Bureau; Celgene, Takeda, Janssen, Sanofi: Honoraria; Celgene: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations; GSK: Consultancy. Pavenski: Alexion: Honoraria, Research Funding; Bioverativ: Research Funding; Ablynx: Honoraria, Research Funding; Octapharma: Research Funding; Shire: Honoraria. Metjian: Momenta/Johnson & Johnson, Sanofi Aventis, Takeda: Research Funding; Ablynx/Sanofi: Consultancy; Sanofi Aventis, Takeda: Other: Advisory. Knoebl: Ablynx/Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Peyvandi: Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria. Cataland: Alexion: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy, Research Funding; Takeda: Consultancy; Sanofi Genzyme: Consultancy. Coppo: Alexion Pharmaceuticals, Sanofi Aventis, Octapharma AG: Consultancy, Other: Advisory; Alexion Pharmaceuticals, Sandoz, Sanofi Aventis, Takeda: Other: Speakers Bureau; Ablynx/Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kremer Hovinga Strebel: Ablynx/Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Speaker at symposia; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Other: Speaker at symposia; Roche: Other: Speaker at symposia; Siemens: Other: Speaker at symposia. Minkue Mi Edou: Sanofi: Current Employment, Other: May hold shares and/or stock options. de Passos Sousa: Sanofi: Current Employment, Other: May hold shares and/or stock options. Callewaert: Sanofi: Current Employment, Other: May hold shares and/or stock options. Gunawardena: Sanofi: Current Employment, Other: May hold shares and/or stock options. Lin: Sanofi: Current Employment, Other: May hold shares and/or stock options.

Bone and bone marrow are not only anatomically, but also functionally interdependent. In a systematic review, we examined bone health in patients with hematopoietic disorders and demonstrated that an increased hematopoietic cell proliferation, such as in patients with hemolytic anemias, was associated with bone loss, while bone marrow hypocellularity, such as in patients with chronic myelofibrosis (CMF), was associated with bone gain [Steer K et al. J Bone Miner Res 2017]. Since bone mass in CMF increases at the expense of bone marrow, it contributes to patients' morbidity as it is associated with bone pain, and mortality as it may lead to bone marrow failure. A mouse model with a global knockout of the megakaryocyte (MK) lineage specific inhibitory receptor G6b-B was shown to develop myelofibrosis secondary to aberrant platelet production and function [Mazharian A et al Sci Signal 2012]. Moreover, a group of patients with primary myelofibrosis was identified to have loss-of-function mutations in the G6b-B gene [Hofmann I et al Blood 2018]. The objective of this study was to characterize temporal changes in the skeleton of the G6b-B knockout mice. We examined age- and sex-related changes in 4, 8, 16, and 32 week-old G6b-B+/+, G6b-B-/- female and male mice. Starting from 8 weeks-of-age, spleen progressively increased in female G6b-B-/- mice compared to corresponding G6b-B+/+ mice, reaching 2.9-fold increase at 32 weeks (p < 0.001) (Fig.1A). Micro-computed tomography analysis of femur demonstrated that starting at 8 weeks of age female G6b-B-/- mice had a significantly higher proportion of cortical bone and a respectively lower proportion of marrow (Fig.1B). Starting at 16 weeks of age, female G6b-B-/- mice developed trabecula in the medullary cavity normally occupied by the bone marrow, which by 32 weeks led to a 38-fold increase (p < 0.001) in the proportion of bone to tissue volume compared to G6b-B+/+ (Fig.1C,D). At 32-weeks of age, female G6b-B-/- mice also demonstrated a 7-fold increase in BV/TV (p < 0.001) in the region of metaphysis. While some abnormalities were found in male G6b-B-/- mice, they were considerably less severe compared to females. To establish whether the observed bone phenotype is due to MK and platelet functional defects, we performed microcomputed tomography analysis on femurs of 22 week-old G6b-Bfl/fl;Gp1ba-Cre-/- mice with a MK/platelet-specific knockout of G6b-B. Changes in trabecular bone of G6b-Bfl/fl;Gp1ba-Cre-/- mice recapitulated changes of G6b-B-/- mice. However, periosteal perimeter in male G6b-Bfl/fl;Gp1ba-Cre-/- mice was significantly larger, and in female G6b-Bfl/fl;Gp1ba-Cre-/- mice - significantly smaller than in corresponding control mice, while in global G6b-B-/- mice periosteal perimeter was not affected. Female G6b-B-/- mice demonstrated severe splenomegaly as well as progressive osteosclerosis, which was confirmed in G6b-Bfl/fl;Gp1ba-Cre-/- mice, indicating that trabecular bone gain in G6b-B-/- mice is consequent to a MK disfunction. Dramatic sexual dimorphism suggests that sex-related factors play an important role in the development of osteosclerosis. The differences in cortical bone phenotype between the global and conditional knockout of G6b-B suggest the potential role of G6b-B signaling in osteoclasts or osteoblasts. This study demonstrates that MK-associated myelofibrosis is sufficient to induce osteosclerosis of bone marrow, and that sex hormones play an important role either in protecting male mice from osteosclerosis or in exacerbating osteosclerosis in female mice. Disclosures No relevant conflicts of interest to declare.

In the title compound, [Yb(C24H40BN6)2]·C7H8, the Yb atom is coordinated by two tris(3-tert-butyl-5-methylpyrazol-1-yl)hydridoborate [TptBu,Me] ligands. One ligand binds in the κ3mode, throuh three N atoms of the pyrazolyl rings, the other ligand coordinates through two N atoms of the pyrazolyl rings and the H atom attached to the central Bviaan agostic-type interaction through the B—H group of the second TptBu,Meligand, giving an overall distorted octahedral geometry. One of thetert-butyl groups is disordered over two sites, with occupancies of 0.65 and 0.35.