Growth dynamics of plexiform neurofibromas: a retrospective cohort study of 201 patients with neurofibromatosis 1

BACKGROUND: To examine the natural growth dynamics of internal plexiform neurofibromas (PNs) in patients with neurofibromatosis 1 (NF1). METHODS: Two hundred and one NF1 patients underwent whole body MRI (WBMRI). Tumour burden was estimated volumetrically. Non-parametric Spearman’s rho correlation coefficients were used to analyse the relationship of growth rate to tumour volume and age. Chi-squared and Mann–Whitney U tests were used for analysing the association of tumour occurrence with sex or age. Chi-squared tests were used to analyse the association of tumour growth with age group. RESULTS: Seventy-one of 171 patients with serial WBMRI exams had internal PNs (median follow up 2.2 years [1.1 to 4.9 years]). Median whole body tumour volume was 86.4 mL [5.2 to 5878.5 mL]) with a median growth rate of 3.7%/year (−13.4 to 111%/year) that correlated with larger whole body tumour volume (P<0.001) and lower age (P=0.004). No new PNs developed in 273.0 patient-years among patients without tumours. Rate of new tumour development among patients with PNs was 0.6%/year (95% confidence interval 0.02 to 3.4%). Twenty-seven (13.5%) tumours increased significantly and were more frequent among children (P<0.001). Growth rate of tumours was inversely correlated with age (Spearman’s rho=−0.330, P<0.001). Seventy-one (35.5%) tumours had smaller volumes on follow up (median −3.4%/year [−0.07% to −35.9%/year]). CONCLUSION: Children with NF1 and internal PNs are at risk for tumour growth. Most PNs grow slowly or not at all, and some decrease in size. New tumours are infrequent in NF1 patients with PNs and unlikely in patients without PNs

Perceptions of genetic discrimination among people at risk for Huntington’s disease: a cross sectional survey

Objective To assess the nature and prevalence of genetic discrimination experienced by people at risk for Huntington’s disease who had undergone genetic testing or remained untested

Further restrictions on the topology of stationary black holes in five dimensions

We place further restriction on the possible topology of stationary asymptotically flat vacuum black holes in 5 spacetime dimensions. We prove that the horizon manifold can be either a connected sum of Lens spaces and "handles" $S^1 \times S^2$, or the quotient of $S^3$ by certain finite groups of isometries (with no "handles"). The resulting horizon topologies include Prism manifolds and quotients of the Poincare homology sphere. We also show that the topology of the domain of outer communication is a cartesian product of the time direction with a finite connected sum of $\mathbb R^4,S^2 \times S^2$'s and $CP^2$'s, minus the black hole itself. We do not assume the existence of any Killing vector beside the asymptotically timelike one required by definition for stationarity.Comment: LaTex, 22 pages, 9 figure

p21 produces a bioactive secretome that places stressed cells under immunosurveillance

Immune cells identify and destroy damaged cells to prevent them from causing cancer or other pathologies by mechanisms that remain poorly understood. Here, we report that the cell-cycle inhibitor p21 places cells under immunosurveillance to establish a biological timer mechanism that controls cell fate. p21 activates retinoblastoma protein (Rb)-dependent transcription at select gene promoters to generate a complex bioactive secretome, termed p21-activated secretory phenotype (PASP). The PASP includes the chemokine CXCL14, which promptly attracts macrophages. These macrophages disengage if cells normalize p21 within 4 days, but if p21 induction persists, they polarize toward an M1 phenotype and lymphocytes mount a cytotoxic T cell response to eliminate target cells, including preneoplastic cells. Thus, p21 concurrently induces proliferative arrest and immunosurveillance of cells under duress

Optic Nerve Head Quantification in Idiopathic Intracranial Hypertension by Spectral Domain OCT

Objective: To evaluate 3D spectral domain optical coherence tomography (SDOCT) volume scans as a tool for quantification of optic nerve head (ONH) volume as a potential marker for treatment effectiveness and disease progression in idiopathic intracranial hypertension (IIH). Design and Patients: Cross-sectional pilot trial comparing 19 IIH patients and controls matched for gender, age and body mass index. Each participant underwent SDOCT. A custom segmentation algorithm was developed to quantify ONH volume (ONHV) and height (ONHH) in 3D volume scans. Results:Whereas peripapillary retinal nerve fiber layer thickness did not show differences between controls and IIH patients, the newly developed 3D parameters ONHV and ONHH were able to discriminate between controls, treated and untreated patients. Both ONHV and ONHH measures were related to levels of intracranial pressure (ICP). Conclusion: Our findings suggest 3D ONH measures as assessed by SDOCT as potential diagnostic and progression markers in IIH and other disorders with increased ICP. SDOCT may promise a fast and easy diagnostic alternative to repeated lumba

Increased power of mixed models facilitates association mapping of 10 loci for metabolic traits in an isolated population

The potential benefits of using population isolates in genetic mapping, such as reduced genetic, phenotypic and environmental heterogeneity, are offset by the challenges posed by the large amounts of direct and cryptic relatedness in these populations confounding basic assumptions of independence. We have evaluated four representative specialized methods for association testing in the presence of relatedness; (i) within-family (ii) within- and between-family and (iii) mixed-models methods, using simulated traits for 2906 subjects with known genome-wide genotype data from an extremely isolated population, the Island of Kosrae, Federated States of Micronesia. We report that mixed models optimally extract association information from such samples, demonstrating 88% power to rank the true variant as among the top 10 genome-wide with 56% achieving genome-wide significance, a >80% improvement over the other methods, and demonstrate that population isolates have similar power to non-isolate populations for observing variants of known effects. We then used the mixed-model method to reanalyze data for 17 published phenotypes relating to metabolic traits and electrocardiographic measures, along with another 8 previously unreported. We replicate nine genome-wide significant associations with known loci of plasma cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, thyroid stimulating hormone, homocysteine, C-reactive protein and uric acid, with only one detected in the previous analysis of the same traits. Further, we leveraged shared identity-by-descent genetic segments in the region of the uric acid locus to fine-map the signal, refining the known locus by a factor of 4. Finally, we report a novel associations for height (rs17629022, P< 2.1 × 10−8

6D Effective Action of Heterotic Compactification on K3 with nontrivial Gauge Bundles

We compute the six-dimensional effective action of the heterotic string compactified on K3 for the standard embedding and for a class of backgrounds with line bundles and appropriate Yang-Mills fluxes. We compute the couplings of the charged scalars and the bundle moduli as functions of the geometrical K3 moduli from a Kaluza-Klein analysis. We derive the D-term potential and show that in the flux backgrounds U(1) vector multiplets become massive by a Stuckelberg mechanism.Comment: 41 pages, typos corrected, references adde

Heterotic-Type II duality in the hypermultiplet sector

We revisit the duality between heterotic string theory compactified on K3 x T^2 and type IIA compactified on a Calabi-Yau threefold X in the hypermultiplet sector. We derive an explicit map between the field variables of the respective moduli spaces at the level of the classical effective actions. We determine the parametrization of the K3 moduli space consistent with the Ferrara-Sabharwal form. From the expression of the holomorphic prepotential we are led to conjecture that both X and its mirror must be K3 fibrations in order for the type IIA theory to have an heterotic dual. We then focus on the region of the moduli space where the metric is expressed in terms of a prepotential on both sides of the duality. Applying the duality we derive the heterotic hypermultiplet metric for a gauge bundle which is reduced to 24 point-like instantons. This result is confirmed by using the duality between the heterotic theory on T^3 and M-theory on K3. We finally study the hyper-Kaehler metric on the moduli space of an SU(2) bundle on K3.Comment: 27 pages; references added, typos correcte

Neural innervation stimulates splenic TFF2 to arrest myeloid cell expansion and cancer

CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) expand in the spleen during cancer and promote progression through suppression of cytotoxic T cells. An anti-inflammatory reflex arc involving the vagus nerve and memory T cells is necessary for resolution of acute inflammation. Failure of this neural circuit could promote procarcinogenic inflammation and altered tumour immunity. Here we show that splenic TFF2, a secreted anti-inflammatory peptide, is released by vagally modulated memory T cells to suppress the expansion of MDSCs through CXCR4. Splenic denervation interrupts the anti-inflammatory neural arc, resulting in the expansion of MDSCs and colorectal cancer. Deletion of Tff2 recapitulates splenic denervation to promote carcinogenesis. Colorectal carcinogenesis could be suppressed through transgenic overexpression of TFF2, adenoviral transfer of TFF2 or transplantation of TFF2-expressing bone marrow. TFF2 is important to the anti-inflammatory reflex arc and plays an essential role in arresting MDSC proliferation. TFF2 offers a potential approach to prevent and to treat cancer