An investigation of pre-crystalline order, ruling out Pauli crystals and introducing Pauli anti-crystals.

Fluid states of matter can locally exhibit characteristics of the onset of crystalline order. Traditionally this has been theoretically investigated using multipoint correlation functions. However new measurement techniques now allow multiparticle configurations of cold atomic systems to be observed directly. This has led to a search for new techniques to characterize the configurations that are likely to be observed. One of these techniques is the configuration density (CD), which has been used to argue for the formation of "Pauli crystals" by non-interacting electrons in e.g. a harmonic trap. We show here that such Pauli crystals do not exist, but that other other interesting spatial structures can occur in the form of an "anti-Crystal", where the fermions preferentially avoid a lattice of positions surrounding any given fermion. Further, we show that configuration densities must be treated with great care as naive application can lead to the identification of crystalline structures which are artifacts of the method and of no physical significance. We analyze the failure of the CD and suggest methods that might be more suitable for characterizing multiparticle correlations which may signal the onset of crystalline order. In particular, we introduce neighbour counting statistics (NCS), which is the full counting statistics of the particle number in a neighborhood of a given particle. We test this on two dimensional systems with emerging triangular and square crystal structures.

Lactose drives Enterococcus expansion to promote graft-versus-host disease.

Disruption of intestinal microbial communities appears to underlie many human illnesses, but the mechanisms that promote this dysbiosis and its adverse consequences are poorly understood. In patients who received allogeneic hematopoietic cell transplantation (allo-HCT), we describe a high incidence of enterococcal expansion, which was associated with graft-versus-host disease (GVHD) and mortality. We found that Enterococcus also expands in the mouse gastrointestinal tract after allo-HCT and exacerbates disease severity in gnotobiotic models. Enterococcus growth is dependent on the disaccharide lactose, and dietary lactose depletion attenuates Enterococcus outgrowth and reduces the severity of GVHD in mice. Allo-HCT patients carrying lactose-nonabsorber genotypes showed compromised clearance of postantibiotic Enterococcus domination. We report lactose as a common nutrient that drives expansion of a commensal bacterium that exacerbates an intestinal and systemic inflammatory disease.

Braiding and Fusion of Non-Abelian Vortex Anyons.

We have studied topology and dynamics of quantum vortices in spin-2 Bose-Einstein condensates. By computationally modeling controllable braiding and fusion of these vortices, we have demonstrated that certain vortices in such spinor condensates behave as non-Abelian anyons. We identify these anyons as fluxon, chargeon, and dyon quasiparticles. The pertinent anyon models are defined by the quantum double of the underlying discrete non-Abelian symmetry group of the condensate ground state order parameter.

VEGFA links self-renewal and metastasis by inducing Sox2 to repress miR-452, driving Slug.

Cancer stem cells (CSC) appear to have increased metastatic potential, but mechanisms underlying this are poorly defined. Here we show that VEGFA induction of Sox2 promotes EMT and tumor metastasis. In breast lines and primary cancer culture, VEGFA rapidly upregulates SOX2 expression, leading to SNAI2 induction, EMT, increased invasion and metastasis. We show Sox2 downregulates miR-452, which acts as a novel metastasis suppressor to directly target the SNAI2 3'-untranslated region (3'-UTR). VEGFA stimulates Sox2- and Slug-dependent cell invasion. VEGFA increases lung metastasis in vivo, and this is abrogated by miR-452 overexpression. Furthermore, SNAI2 transduction rescues metastasis suppression by miR-452. Thus, in addition to its angiogenic action, VEGFA upregulates Sox2 to drive stem cell expansion, together with miR-452 loss and Slug upregulation, providing a novel mechanism whereby cancer stem cells acquire metastatic potential. Prior work showed EMT transcription factor overexpression upregulates CSC. Present work indicates that stemness and metastasis are a two-way street: Sox2, a major mediator of CSC self-renewal, also governs the metastatic process.

Multiparametric evaluation of preoperative MRI in early stage breast cancer: prognostic impact of peri-tumoral fat

Purpose. Obesity is associated with adverse outcomes in breast cancer patients. Fat-specific cytokines (adipokines) have been proposed as key drivers of breast cancer progression, invasion, and metastasis. We aimed at assessing correlations between peri-tumoral fat, quantified on magnetic resonance imaging (MRI) and pathologic factors potentially impacting therapy recommendations. Methods. We retrospectively reviewed records of 63 patients with early stage breast cancer who underwent preoperative MRI imaging using appropriately weighted series for breast and tumor contouring. Fat volumes were generated through voxel intensity filtering. The peri-tumoral region was defined as the intersection of a 1-cm spherical extension around the tumor and the breast contour. Peri-tumoral fat was defined as the fraction of a fat content in this volume. Surgical pathology records were used to extract clinical data. Statistical analyses were conducted using Pearson and Spearman correlation coefficients. Results. Among reviewed patients, 45 had T1 tumors (1.22 ± 0.85 cm diameter) and 18 had T2 tumors (2.08 ± 1.06 cm). Axillary lymph nodes were dissected in 31 and positive in 17 patients analyzed. Peri-tumoral fat ratio ranged between 25 and 99 %. Peri-tumoral fat ratio significantly correlated with the nodal-positive ratio of positive axillary lymph nodes (r = 0.532). Peri-tumoral fat ratio demonstrated optimally prominent correlation among obese patients upon body mass index categorical stratification. Conclusions. In women with early stage breast cancer, peri-tumoral fat correlates positively with the ratio of pathologically involved axillary nodes. This work highlights a novel method for quantitating peri-tumoral fat content. Preoperative breast MRI may be utilized to predict extent of axillary disease (AU)

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Multiparametric evaluation of preoperative MRI in early stage breast cancer: prognostic impact of peri-tumoral fat.

PURPOSE: Obesity is associated with adverse outcomes in breast cancer patients. Fat-specific cytokines (adipokines) have been proposed as key drivers of breast cancer progression, invasion, and metastasis. We aimed at assessing correlations between peri-tumoral fat, quantified on magnetic resonance imaging (MRI) and pathologic factors potentially impacting therapy recommendations. METHODS: We retrospectively reviewed records of 63 patients with early stage breast cancer who underwent preoperative MRI imaging using appropriately weighted series for breast and tumor contouring. Fat volumes were generated through voxel intensity filtering. The peri-tumoral region was defined as the intersection of a 1-cm spherical extension around the tumor and the breast contour. Peri-tumoral fat was defined as the fraction of a fat content in this volume. Surgical pathology records were used to extract clinical data. Statistical analyses were conducted using Pearson and Spearman correlation coefficients. RESULTS: Among reviewed patients, 45 had T1 tumors (1.22 ± 0.85 cm diameter) and 18 had T2 tumors (2.08 ± 1.06 cm). Axillary lymph nodes were dissected in 31 and positive in 17 patients analyzed. Peri-tumoral fat ratio ranged between 25 and 99 %. Peri-tumoral fat ratio significantly correlated with the nodal-positive ratio of positive axillary lymph nodes (r = 0.532). Peri-tumoral fat ratio demonstrated optimally prominent correlation among obese patients upon body mass index categorical stratification. CONCLUSIONS: In women with early stage breast cancer, peri-tumoral fat correlates positively with the ratio of pathologically involved axillary nodes. This work highlights a novel method for quantitating peri-tumoral fat content. Preoperative breast MRI may be utilized to predict extent of axillary disease.

Targeting of RAGE-ligand signaling impairs breast cancer cell invasion and metastasis.

The receptor for advanced glycation end products (RAGE) is highly expressed in various cancers and is correlated with poorer outcome in breast and other cancers. Here we tested the role of targeting RAGE by multiple approaches in the tumor and tumor microenvironment, to inhibit the metastatic process. We first tested how RAGE impacts tumor cell-intrinsic mechanisms using either RAGE overexpression or knockdown with short hairpin RNAs (shRNAs). RAGE ectopic overexpression in breast cancer cells increased MEK-EMT (MEK-epithelial-to-mesenchymal transition) signaling, transwell invasion and soft agar colony formation, and in vivo promoted lung metastasis independent of tumor growth. RAGE knockdown with multiple independent shRNAs in breast cancer cells led to decreased transwell invasion and soft agar colony formation, without affecting proliferation. In vivo, targeting RAGE shRNA knockdown in human and mouse breast cancer cells, decreased orthotopic tumor growth, reduced tumor angiogenesis and recruitment of inflammatory cells, and markedly decreased metastasis to the lung and liver in multiple xenograft and syngeneic mouse models. To test the non-tumor cell microenvironment role of RAGE, we performed syngeneic studies with orthotopically injected breast cancer cells in wild-type and RAGE-knockout C57BL6 mice. RAGE-knockout mice displayed striking impairment of tumor cell growth compared with wild-type mice, along with decreased mitogen-activated protein kinase signaling, tumor angiogenesis and inflammatory cell recruitment. To test the combined inhibition of RAGE in both tumor cell-intrinsic and non-tumor cells of the microenvironment, we performed in vivo treatment of xenografted tumors with FPS-ZM1 (1 mg/kg, two times per week). Compared with vehicle, FPS-ZM1 inhibited primary tumor growth, inhibited tumor angiogenesis and inflammatory cell recruitment and, most importantly, prevented metastasis to the lung and liver. These data demonstrate that RAGE drives tumor progression and metastasis through distinct tumor cell-intrinsic and -extrinsic mechanisms, and may represent a novel and therapeutically viable approach for treating metastatic cancers.

Cytoplasmic p27 promotes epithelial-mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation.

p27 restrains normal cell growth, but PI3K-dependent C-terminal phosphorylation of p27 at threonine 157 (T157) and T198 promotes cancer cell invasion. Here, we describe an oncogenic feedforward loop in which p27pT157pT198 binds Janus kinase 2 (JAK2) promoting STAT3 (signal transducer and activator of transcription 3) recruitment and activation. STAT3 induces TWIST1 to drive a p27-dependent epithelial-mesenchymal transition (EMT) and further activates AKT contributing to acquisition and maintenance of metastatic potential. p27 knockdown in highly metastatic PI3K-activated cells reduces STAT3 binding to the TWIST1 promoter, TWIST1 promoter activity and TWIST1 expression, reverts EMT and impairs metastasis, whereas activated STAT3 rescues p27 knockdown. Cell cycle-defective phosphomimetic p27T157DT198D (p27CK-DD) activates STAT3 to induce a TWIST1-dependent EMT in human mammary epithelial cells and increases breast and bladder cancer invasion and metastasis. Data support a mechanism in which PI3K-deregulated p27 binds JAK2, to drive STAT3 activation and EMT through STAT3-mediated TWIST1 induction. Furthermore, STAT3, once activated, feeds forward to further activate AKT.

VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2.

Vascular endothelial growth factor-A (VEGF), a potent angiogenic factor, is also implicated in self-renewal in several normal tissue types. VEGF has been shown to drive malignant stem cells but mechanisms thereof and tumor types affected are not fully characterized. Here, we show VEGF promotes breast and lung cancer stem cell (CSC) self-renewal via VEGF receptor-2 (VEGFR-2)/STAT3-mediated upregulation of Myc and Sox2. VEGF increased tumor spheres and aldehyde dehydrogenase activity, both proxies for stem cell function in vitro, in triple-negative breast cancer (TNBC) lines and dissociated primary cancers, and in lung cancer lines. VEGF exposure before injection increased breast cancer-initiating cell abundance in vivo yielding increased orthotopic tumors, and increased metastasis from orthotopic primaries and following tail vein injection without further VEGF treatment. VEGF rapidly stimulated VEGFR-2/JAK2/STAT3 binding and activated STAT3 to bind MYC and SOX2 promoters and induce their expression. VEGFR-2 knockdown or inhibition abrogated VEGF-mediated STAT3 activation, MYC and SOX2 induction and sphere formation. Notably, knockdown of either STAT3, MYC or SOX2 impaired VEGF-upregulation of pSTAT3, MYC and SOX2 expression and sphere formation. Each transcription factor, once upregulated, appears to promote sustained activation of the others, creating a feed-forward loop to drive self-renewal. Thus, in addition to angiogenic effects, VEGF promotes tumor-initiating cell self-renewal through VEGFR-2/STAT3 signaling. Analysis of primary breast and lung cancers (>1300 each) showed high VEGF expression, was prognostic of poor outcome and strongly associated with STAT3 and MYC expression, supporting the link between VEGF and CSC self-renewal. High-VEGF tumors may be most likely to escape anti-angiogenics by upregulating VEGF, driving CSC self-renewal to re-populate post-treatment. Our work highlights the need to better define VEGF-driven cancer subsets and supports further investigation of combined therapeutic blockade of VEGF or VEGFR-2 and JAK2/STAT3.

ERα, SKP2 and E2F-1 form a feed forward loop driving late ERα targets and G1 cell cycle progression.

Estrogen triggers transactivation coupled estrogen receptor α (ERα) proteolysis, but mechanisms thereof remain obscure. Present data link estrogen:ERα-driven transcription with cell cycle progression. Although liganded ERα induces many genes within 1-4 h, gene activation after 6 h is thought to be indirect. Here, we identify SKP2 as a late-acting coactivator that drives ERα targets to promote G1-to-S progression. Data support a model in which estrogen-activated cyclin E-CDK2 binds and phosphorylates ERαS341, to prime ERα-SCF(SKP2) binding via SKP2-L248QTLL252 in late G1. SKP2 activates ERα ubiquitylation and proteolysis. Putative late ERα targets were identified by expression profiling. SKP2 knockdown attenuated E2F-1 and BLM induction. SKP2 overexpression, but not coactivator motif mutant SKP2-L248QTAA252, enhanced estrogen-induced E2F-1 and BLM expression. SKP2 knockdown impaired estrogen-stimulated ERα, SKP2, SRC3 and RNA polymerase II recruitment to E2F-1 and BLM promoters. This work not only identifies these late-activated genes as bona fide ERα targets but describes a novel mechanism for their periodic activation. SKP2 serves as dual ERα E3 ligase/coactivator for late-activated target genes, revealing a novel mechanism whereby ERα/SCF(SKP2) transactivation of E2F-1 feeds forward to drive G1-to-S.

Evaluation of ranks of real space and particle entanglement spectra for large systems.

We devise a way to calculate the dimensions of symmetry sectors appearing in the particle entanglement spectrum (PES) and real space entanglement spectrum (RSES) of multiparticle systems from their real space wave functions. We first note that these ranks in the entanglement spectra equal the dimensions of spaces of wave functions with a number of particles fixed. This also yields equality of the multiplicities in the PES and the RSES. Our technique allows numerical calculations for much larger systems than were previously feasible. For somewhat smaller systems, we can find approximate entanglement energies as well as multiplicities. We illustrate the method with results on the RSES and PES multiplicities for integer quantum Hall states, Laughlin and Jain composite fermion states, and for the Moore-Read state at filling ν = 5/2 for system sizes up to 70 particles.

Competing topological orders in the ν=12/5 quantum Hall state.

We provide numerical evidence that a p(x)-ip(y) paired Bonderson-Slingerland (BS) non-Abelian hierarchy state is a strong candidate for the observed ν=12/5 quantum Hall plateau. We confirm the existence of a gapped incompressible ν=12/5 quantum Hall state with shift S=2 on the sphere, matching that of the BS state. The exact ground state of the Coulomb interaction at S=2 is shown to have a large overlap with the BS trial wave function. Larger overlaps are obtained with BS-type wave functions that are hierarchical descendants of general p(x)-ip(y) weakly paired states at ν=5/2. We perform a finite-size scaling analysis of the ground-state energies for ν=12/5 states at shifts corresponding to the BS (S=2) and 3-clustered Read-Rezayi (S=-2) universality classes. This analysis reveals very tight competition between these two non-Abelian topological orders.

Promotion of cytoplasmic mislocalization of p27 by Helicobacter pylori in gastric cancer.

The cyclin-dependent kinase (CDK) inhibitor p27 has an important role in cell cycle regulation. Reduced expression of p27 is commonly associated with poor prognosis in many malignancies, including gastric cancer. Cytoplasmic p27 mislocalization may be an additional indicator of high-grade tumors and poor prognosis in cancer. As chronic infection by Helicobacter pylori is the most important risk factor for gastric cancer development, we evaluated the effects of H. pylori on p27 expression and localization in gastric cancer cells. Co-culture of gastric cells with H. pylori induced cytoplasmic p27 expression and reduced nuclear p27 expression in vitro. Cytoplasmic p27 expression was associated with and dependent upon phosphorylation of p27 at T157 and T198: wild-type p27 accumulated in the cytoplasm, but non-phosphorylatable mutants affecting T157 or T198 were nuclear in H. pylori-infected cells. These post-translational p27 changes were secondary to activation of cellular phosphoinositide-3 kinase (PI3K) and AKT signaling pathways, and dependent upon a functional H. pylori cag pathogenicity island. We investigated the clinical significance of cytoplasmic p27 mislocalization in 164 cases of resected gastric cancer in tissue microarrays. In 97 cases (59%), cytoplasmic p27 mislocalization was observed, and this was associated with increased mortality in multivariate analysis. These results show that H. pylori infection induces AKT/PI3K-mediated phosphorylation of p27 at T157 and T198 to cause cytoplasmic p27 mislocalization in gastric cancer, and that p27 mislocalization is an adverse prognostic feature in gastric cancer. This is the first demonstration of the translocation of a specific bacterial virulence factor that post-translationally regulates a host cell CDK inhibitor. This is of particular significance, because p27 has both tumor-suppressive and oncogenic activities, depending upon its subcellular localization. Cytoplasmic mislocalization of p27 induced by H. pylori may be an important mechanistic link between H. pylori infection and gastric carcinogenesis.

Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II-IIIc breast cancer.

NOV-002 (a formulation of disodium glutathione disulfide) modulates signaling pathways involved in tumor cell proliferation and metastasis and enhances anti-tumor immune responsiveness in tumor models. The addition of NOV-002 to chemotherapy has been shown to increase anti-tumor efficacy in animal models and some early phase oncology trials. We evaluated the clinical effects of NOV-002 in primary breast cancer, whether adding NOV-002 to standard preoperative chemotherapy increased pathologic complete response rates (pCR) at surgery, and determined whether NOV-002 mitigated hematologic toxicities of chemotherapy and whether levels of myeloid derived suppressor cells (MDSC) were predictive of response. Forty-one women with newly diagnosed stages II-IIIc HER-2 negative breast cancer received doxorubicin-cyclophosphamide followed by docetaxel (AC â†’ T) every 3 weeks and concurrent daily NOV-002 injections. The trial was powered to detect a doubling of pCR rate from 16 to 32% with NOV-002 plus AC â†’ T (α = 0.05, ß = 80%). Weekly complete blood counts were obtained as well as circulating MDSC levels on day 1 of each cycle were quantified. Of 39 patients with 40 evaluable tumors, 15 achieved a pCR (38%), meeting the primary endpoint of the trial. Concurrent NOV-002 resulted in pCR rates for AC â†’ T chemotherapy higher than previously reported. Patients with lower levels of circulating MDSCs at baseline and on the last cycle of chemotherapy had significantly higher probability of a pCR (P = 0.02). Further evaluation of NOV-002 in a randomized study is warranted.

The value of clinical examination in diagnosing pelvic fractures in blunt trauma patients: a brief review.

PURPOSE OF THE STUDY: To evaluate the value of a pelvic X-ray compared to clinical examination in diagnosing pelvic ring fractures, using computed tomography (CT) as the gold standard, in alert [Glasgow Coma Scale (GCS) ≥ 13] adult blunt trauma patients in the emergency room. METHODS: A systematic literature search was performed in PubMed and Embase. The results were screened on their titles and abstracts using in- and exclusion criteria. Subsequently, the selected articles were critically appraised for their relevance and validity. RESULTS: Two studies investigating the diagnostic value of clinical examination and pelvic X-ray compared to CT were identified. Both studies demonstrate higher negative predictive values for clinical examination [0.99 (95% confidence interval [CI] 0.98-1.0) and 1.0 (95% CI 0.99-1.0)] compared to the negative predictive values of pelvic X-ray [0.98 (95% CI 0.93-0.99) and 0.99 (95% CI 0.99-1.0)]. The positive predictive values for clinical examination were low [0.18 (95% CI 0.16-0.23) and 0.35 (95% CI 0.30-0.42)] compared to pelvic X-ray [0.97 (95% CI 0.96-0.98) and 0.97 (95% CI 0.90-0.99)]. CONCLUSIONS: In alert blunt trauma patients, pelvic X-ray only has additional diagnostic value for the detection of pelvic ring fractures if the clinical examination is positive. Pelvic X-ray should not be performed if the clinical examination is negative. In this manner, the expenditure of time, costs, and radiation are optimized.

Theory of topological edges and domain walls.

We investigate domain walls between topologically ordered phases in two spatial dimensions. We present a method which allows for the determination of the superselection sectors of excitations of such walls and which leads to a unified description of the kinematics of a wall and the two phases to either side of it. This incorporates a description of scattering processes at domain walls which can be applied to questions of transport through walls. In addition to the general formalism, we give representative examples including domain walls between the Abelian and non-Abelian topological phases of Kitaev's honeycomb lattice model in a magnetic field, as well as recently proposed domain walls between spin polarized and unpolarized non-Abelian fractional quantum Hall states at different filling fractions.

Topological degeneracy and vortex manipulation in Kitaev's honeycomb model.

The classification of loop symmetries in Kitaev's honeycomb lattice model provides a natural framework to study the Abelian topological degeneracy. We derive a perturbative low-energy effective Hamiltonian that is valid to all orders of the expansion and for all possible toroidal configurations. Using this form we demonstrate at what order the system's topological degeneracy is lifted by finite size effects and note that in the thermodynamic limit it is robust to all orders. Further, we demonstrate that the loop symmetries themselves correspond to the creation, propagation, and annihilation of fermions. We note that these fermions, made from pairs of vortices, can be moved with no additional energy cost.

Decoherence of anyonic charge in interferometry measurements.

We examine interferometric measurements of the topological charge of (non-Abelian) anyons. The target's topological charge is measured from its effect on the interference of probe particles sent through the interferometer. We find that superpositions of distinct anyonic charges a and a' in the target decohere (exponentially in the number of probes particles used) when the probes have nontrivial monodromy with the charges that may be fused with a to give a'.

Probing non-Abelian statistics with quasiparticle interferometry.

We examine interferometric experiments in systems that exhibit non-Abelian braiding statistics, expressing outcomes in terms of the modular S-matrix. In particular, this result applies to fractional quantum Hall interferometry, and we give a detailed treatment of the Read-Rezayi states, providing explicit predictions for the recently observed nu = 12/5 plateau.

p27 deregulation in breast cancer: prognostic significance and implications for therapy.

p27 is a key regulator of G1-to-S phase progression. It prevents premature activation of cyclin E-cdk2 in G1 and promotes the assembly and activation of D-type cyclin-cdks. While the p27 gene is rarely mutated in human cancers, the action of p27 is impaired in breast and other human cancers through accelerated p27 proteolysis, sequestration by cyclin D-cdks, and by p27 mislocalization in tumor cell cytoplasm. Reduced p27 protein is strongly associated with high histopathologic tumor grade, reflecting a lack of tumor differentiation. Loss of p27 is also an indicator of poor patient outcome in a majority of breast cancer studies, including node negative disease. The broad application of p27 in the clinical evaluation of breast cancer prognosis will require a consensus on methods of tumor fixation, staining, and scoring. This review will focus on mechanisms of p27 regulation in normal cells and how deregulation of p27 may arise in breast and other human cancers. The prognostic significance of p27 in human breast cancer and the possible therapeutic implications of these findings will also be reviewed.