The Role of Chemokine Receptor CXCR4 in the Biologic Behavior of Human Soft Tissue Sarcoma

The molecular basis of sarcoma remains poorly understood. However, recent studies have begun to uncover some of the molecular pathways involved in sarcomagenesis. The chemokine receptor CXCR4 has been implicated in sarcoma development and has been found to be a prognostic marker for poor clinical outcome. There is growing evidence that overexpression of CXCR4 plays a significant role in development of metastatic disease, especially in directing tumor cells towards the preferential sites of metastases in sarcoma, lung and bone. Although further investigation is necessary to validate these pathways, there is potential for clinical application, particularly in the use of pharmacologic inhibitors of CXCR4 as means of preventing sarcoma metastasis

Outcome for Patients with Triple-Negative Breast Cancer Is Not Dependent on Race/Ethnicity

Introduction. Triple negative breast cancer (TNBC) is biologically aggressive and is associated with a worse prognosis. To understand the impact of race/ethnicity on outcome for patients with TNBC, confounding factors such as socioeconomic status (SES) need to be controlled. We examined the impact of race/ethnicity on a cohort of patients of low SES who have TNBC. Methods. 786 patients with Stage 0–III breast cancer were evaluated. Of these, 202 patients had TNBC (26%). Primary endpoints were cancer recurrence and death. ZIP code-based income tract and institutional financial data were used to assess SES. Data were analyzed using Kaplan-Meier survival analysis, log-rank tests, Cox Proportional hazard regression, chi square test, and t-tests. A P value ≤0.05 was considered statistically significant. Results. Of the 468 African-Americans (60%) in the database, 138 had TNBC; 64 of 318 Caucasians had TNBC. 80% of patients had an annual income of ≤$20,000. The 5-year overall survival was 77% for African-American women versus 72% for Caucasian women (P = 0.95). On multivariate analysis, race/ethnicity had an impact on disease-free survival (P = 0.027) but not on overall survival (P = 0.98). Conclusion. In a predominantly indigent population, race/ethnicity had no impact on overall survival for patients with triple negative breast cancer

Self-renewal of single mouse hematopoietic stem cells is reduced by JAK2V617F without compromising progenitor cell expansion

Recent descriptions of significant heterogeneity in normal stem cells and cancers have altered our understanding of tumorigenesis, emphasizing the need to understand how single stem cells are subverted to cause tumors. Human myeloproliferative neoplasms (MPNs) are thought to reflect transformation of a hematopoietic stem cell (HSC) and the majority harbor an acquired V617F mutation in the JAK2 tyrosine kinase, making them a paradigm for studying the early stages of tumor establishment and progression. The consequences of activating tyrosine kinase mutations for stem and progenitor cell behavior are unclear. In this article, we identify a distinct cellular mechanism operative in stem cells. By using conditional knock-in mice, we show that the HSC defect resulting from expression of heterozygous human JAK2V617F is both quantitative (reduced HSC numbers) and qualitative (lineage biases and reduced self-renewal per HSC). The defect is intrinsic to individual HSCs and their progeny are skewed toward proliferation and differentiation as evidenced by single cell and transplantation assays. Aged JAK2V617F show a more pronounced defect as assessed by transplantation, but mice that transform reacquire competitive self-renewal ability. Quantitative analysis of HSC-derived clones was used to model the fate choices of normal and JAK2-mutant HSCs and indicates that JAK2V617F reduces self-renewal of individual HSCs but leaves progenitor expansion intact. This conclusion is supported by paired daughter cell analyses, which indicate that JAK2-mutant HSCs more often give rise to two differentiated daughter cells. Together these data suggest that acquisition of JAK2V617F alone is insufficient for clonal expansion and disease progression and causes eventual HSC exhaustion. Moreover, our results show that clonal expansion of progenitor cells provides a window in which collaborating mutations can accumulate to drive disease progression. Characterizing the mechanism(s) of JAK2V617F subclinical clonal expansions and the transition to overt MPNs will illuminate the earliest stages of tumor establishment and subclone competition, fundamentally shifting the way we treat and manage cancers

First cohomology for finite groups of Lie type: simple modules with small dominant weights

Let $k$ be an algebraically closed field of characteristic $p > 0$, and let $G$ be a simple, simply connected algebraic group defined over $\mathbb{F}_p$. Given $r \geq 1$, set $q=p^r$, and let $G(\mathbb{F}_q)$ be the corresponding finite Chevalley group. In this paper we investigate the structure of the first cohomology group $H^1(G(\mathbb{F}_q),L(\lambda))$ where $L(\lambda)$ is the simple $G$-module of highest weight $\lambda$. Under certain very mild conditions on $p$ and $q$, we are able to completely describe the first cohomology group when $\lambda$ is less than or equal to a fundamental dominant weight. In particular, in the cases we consider, we show that the first cohomology group has dimension at most one. Our calculations significantly extend, and provide new proofs for, earlier results of Cline, Parshall, Scott, and Jones, who considered the special case when $\lambda$ is a minimal nonzero dominant weight.Comment: 24 pages, 5 figures, 6 tables. Typos corrected and some proofs streamlined over previous versio

Rational Design of Superhydrophilic/Superoleophobic Surfaces for Oil-Water Separation via Thiol-Acrylate Photopolymerization

We report a simple, rapid, and scalable strategy to fabricate surfaces exhibiting in-air superoleophobic/superhydrophilic wetting via sequential spray deposition and photopolymerization of nanoparticle-laden thiol–acrylate resins comprising both hydrophilic and oleophobic chemical constituents. The combination of spray deposition with nanoparticles provides hierarchical surface morphologies with both micro- and nanoscale roughness. Mapping the wetting behavior as a function of resin composition using high- and low-surface-tension liquid probes enabled facile identification of coatings that exhibit a range of wetting behavior, including superhydrophilic/superoleophilic, superhydrophobic/superoleophobic, and in-air superhydrophilic/superoleophobic wetting. In-air superhydrophilic/superoleophobic wetting was realized by a dynamic rearrangement of the interface to expose a greater fraction of hydrophilic moieties in response to contact with water. We show that these in-air superoleophobic/superhydrophilic coatings deposited onto porous supports enable separation of model oil–water emulsions with separation efficiencies up to 99.9% with 699 L·m–2 h–1 permeate flux when the superhydrophilic/superoleophobic coatings are paired with 0.45 μm nylon membrane supports

A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential

p75 neurotrophin receptor regulates energy balance in obesity

Obesity and metabolic syndrome reflect the dysregulation of molecular pathways that control energy homeostasis. Here, we show that the p75 neurotrophin receptor (p75NTR) controls energy expenditure in obese mice on a high-fat diet (HFD). Despite no changes in food intake, p75NTR-null mice were protected from HFD-induced obesity and remained lean as a result of increased energy expenditure without developing insulin resistance or liver steatosis. p75NTR directly interacts with the catalytic subunit of protein kinase A (PKA) and regulates cAMP signaling in adipocytes, leading to decreased lipolysis and thermogenesis. Adipocyte-specific depletion of p75NTR or transplantation of p75NTR-null white adipose tissue (WAT) into wild-type mice fed a HFD protected against weight gain and insulin resistance. Our results reveal that signaling from p75NTR to cAMP/PKA regulates energy balance and suggest that non-CNS neurotrophin receptor signaling could be a target for treating obesity and the metabolic syndrome

Second cohomology for finite groups of Lie type

Let $G$ be a simple, simply-connected algebraic group defined over $\mathbb{F}_p$. Given a power $q = p^r$ of $p$, let $G(\mathbb{F}_q) \subset G$ be the subgroup of $\mathbb{F}_q$-rational points. Let $L(\lambda)$ be the simple rational $G$-module of highest weight $\lambda$. In this paper we establish sufficient criteria for the restriction map in second cohomology $H^2(G,L(\lambda)) \rightarrow H^2(G(\mathbb{F}_q),L(\lambda))$ to be an isomorphism. In particular, the restriction map is an isomorphism under very mild conditions on $p$ and $q$ provided $\lambda$ is less than or equal to a fundamental dominant weight. Even when the restriction map is not an isomorphism, we are often able to describe $H^2(G(\mathbb{F}_q),L(\lambda))$ in terms of rational cohomology for $G$. We apply our techniques to compute $H^2(G(\mathbb{F}_q),L(\lambda))$ in a wide range of cases, and obtain new examples of nonzero second cohomology for finite groups of Lie type.Comment: 29 pages, GAP code included as an ancillary file. Rewritten to include the adjoint representation in types An, B2, and Cn. Corrections made to Theorem 3.1.3 and subsequent dependent results in Sections 3-4. Additional minor corrections and improvements also implemente

Multi-Player and Multi-Choice Quantum Game

We investigate a multi-player and multi-choice quantum game. We start from two-player and two-choice game and the result is better than its classical version. Then we extend it to N-player and N-choice cases. In the quantum domain, we provide a strategy with which players can always avoid the worst outcome. Also, by changing the value of the parameter of the initial state, the probabilities for players to obtain the best payoff will be much higher that in its classical version.Comment: 4 pages, 1 figur

Resolution of the Distance Ambiguity for Galactic HII Regions

We resolve the kinematic distance ambiguity for 266 inner Galaxy HII regions out of a sample of 291 using existing HI and 13CO sky surveys. Our sample contains all HII regions with measured radio recombination line (RRL) emission over the extent of the 13CO Boston University-Five College Radio Astronomy Observatory Galactic Ring Survey (18 deg, < l < 55 deg. and |b| < 1) and contains ultra compact, compact, and diffuse HII regions. We use two methods for resolving the distance ambiguity for each HII region: HI emission/absorption (HIEA) and HI self-absorption (HISA). We find that the HIEA and HISA methods can resolve the distance ambiguity for 72% and 87% of our sample, respectively. When projected onto the Galactic plane, this large sample appears to reveal aspects of Galactic structure, with spiral arm-like features at Galactocentric radii of 4.5 and 6 kpc, and a lack of HII regions within 3.5 kpc of the Galactic center. Our HII regions are approximately in the ratio of 2 to 1 for far verses near distances. The ratio of far to near distances for ultra-compact HII regions is 2.2 to 1. Compact HII regions are preferentially at the near distance; their ratio of far to near distances is 1.6 to 1. Diffuse HII regions are preferentially at the far distance; their ratio of far to near distances is 3.8 to 1. This implies that the distinction between ultra compact and compact HII regions is due largely to distance, and that the large angular size of diffuse HII regions is not due solely to proximity to the Sun.Comment: Accepted to Ap