Multiple positive solutions to third-order three-point singular semipositone boundary value problem

By using a specially constructed cone and the fixed point index theory, this paper investigates the existence of multiple positive solutions for the third-order three-point singular semipositone BVP: \begin{cases} x'''(t)-\ld f(t,x) =0, &t\in(0,1); [.3pc] x(0)=x'(\eta)=x''(1)=0, & \end{cases} where ${1/2}<\eta<1$, the non-linear term f(t,x):(0,1)\times(0,+\i)\to (-\i,+\i) is continuous and may be singular at $t=0$, $t=1$, and $x=0$, also may be negative for some values of $t$ and $x$, \ld is a positive parameter.Comment: 14 page

A Bayesian adaptive design for dual-agent phase I-II oncology trials integrating efficacy data across stages

Combination of several anticancer treatments has typically been presumed to have enhanced drug activity. Motivated by a real clinical trial, this paper considers phase I-II dose finding designs for dual-agent combinations, where one main objective is to characterize both the toxicity and efficacy profiles. We propose a two-stage Bayesian adaptive design that accommodates a change of patient population in-between. In stage I, we estimate a maximum tolerated dose combination using the escalation with overdose control (EWOC) principle. This is followed by a stage II, conducted in a new yet relevant patient population, to find the most efficacious dose combination. We implement a robust Bayesian hierarchical random-effects model to allow sharing of information on the efficacy across stages, assuming that the related parameters are either exchangeable or nonexchangeable. Under the assumption of exchangeability, a random-effects distribution is specified for the main effects parameters to capture uncertainty about the between-stage differences. The inclusion of nonexchangeability assumption further enables that the stage-specific efficacy parameters have their own priors. The proposed methodology is assessed with an extensive simulation study. Our results suggest a general improvement of the operating characteristics for the efficacy assessment, under a conservative assumption about the exchangeability of the parameters a priori

A Bayesian adaptive design for dual-agent phase I-II cancer clinical trials combining efficacy data across stages

Integrated phase I-II clinical trial designs are efficient approaches to accelerate drug development. In cases where efficacy cannot be ascertained in a short period of time, two-stage approaches are usually employed. When different patient populations are involved across stages, it is worth of discussion about the use of efficacy data collected from both stages. In this paper, we focus on a two-stage design that aims to estimate safe dose combinations with a certain level of efficacy. In stage I, conditional escalation with overdose control (EWOC) is used to allocate successive cohorts of patients. The maximum tolerated dose (MTD) curve is estimated based on a Bayesian dose-toxicity model. In stage II, we consider an adaptive allocation of patients to drug combinations that have a high probability of being efficacious along the obtained MTD curve. A robust Bayesian hierarchical model is proposed to allow sharing of information on the efficacy parameters across stages assuming the related parameters are either exchangeable or nonexchangeable. Under the assumption of exchangeability, a random-effects distribution is specified for the main effects parameters to capture uncertainty about the between-stage differences. The proposed methodology is assessed with extensive simulations motivated by a real phase I-II drug combination trial using continuous doses

Frameshift peptides alter the properties of truncated FUS proteins in ALS-FUS

Mutations in the FUS gene cause a subset of ALS cases (ALS-FUS). The majority of FUS mutations are missense mutations affecting the nuclear localisation signal (NLS) of FUS. In addition, a number of frameshift mutations which result in complete NLS deletion have been described. Patients bearing frameshift mutations usually present with more aggressive disease, characterised by an early onset and rapid progression. Both missense mutations in the NLS coding sequence and complete loss of the NLS are known to result in cytoplasmic mislocalisation of FUS protein. However, in addition to the removal of FUS functional domains, frameshift mutations in most cases lead to the attachment of a “tail” of novel amino acids at the FUS C-terminus – a frameshift peptide. It is not clear whether these peptide tails would affect the properties of truncated FUS proteins. In the current study, we compared intracellular behaviour of disease-associated truncated FUS proteins with and without the corresponding frameshift peptides. We demonstrate that some of these peptides can affect subcellular distribution and/or increase aggregation capacity and stability of the truncated FUS protein. Our study suggests that frameshift peptides can alter the properties of truncated FUS variants which may modulate FUS pathogenicity and contribute to the variability of the disease course in ALS-FUS

Exotic Hadrons Of Minimal Pentaquark (qqqq\Bar{Q}) States

It is shown that the exotic non-qqq hadrons of pentaquark $qqqq\bar{q}$ states can be clearly distinguished from the conventional qqq-baryon resonances or their hybrids if the flavor of $\bar{q}$ is different from any of the other four quarks. We suggest the physical process $p(e,e'K^-)Z(uuud\bar{s})$, which can be investigated at the Thomas Jefferson National Accelerator Facility (JLab), as an ideal process to search for the existence or non-existence of the exotic hadron of minimal pentaquark state $Z(uuud\bar{s})$. (The search for the existence of $Z(uudd\bar{s})$ is also discussed in the paper. We added this sentence after the original published form of this paper.)Comment: 7 latex pages, 1 figur

Association of CYP1B1 Polymorphisms with Breast Cancer: A Case-Control Study in the Han Population in Ningxia Hui Autonomous Region, P. R. China

Studies investigating possible associations between cytochrome P4501B1 (CYP1B1) polymorphisms and breast cancer risk have been inconsistent. We set out to ascertain whether there might be an association between polymorphisms in exon 2 (codon 119, G→T) and exon 3 (codon 432, G→C) of CYP1B1 and breast cancer in a Chinese Han population in the rural region of Ningxia. Using an allele-specific polymerase chain reaction method and direct DNA sequencing, the presence or absence of the two CYP1B1 polymorphisms was investigated. Genotype and allele frequencies were analyzed in breast cancer cases (n = 152) and healthy age-matched controls (n = 156). The odds ratio (OR) of 119G→T or 432G→C in breast cancer cases and controls was 3.3 (95% CI: 1.28 to 8.28) and 2.8 (95% CI: 1.04 to 7.51), respectively. In addition, the OR for people with both polymorphisms (119T and 432C) was 4.69 (95% CI: 1.97 to 11.19). Our results suggest that certain polymorphisms in the CYP1B1 gene might increase risk for breast cancer among Han Chinese, perhaps because they influence the efficiency of CYP1B1 bio-transformation of oestrogens or pro-carcinogens into DNA-reactive electrophiles that may act as cancer-initiating agents

Nanostructured conformal hybrid solar cells: a promising architecture towards complete charge collection and light absorption

We introduce hybrid solar cells with an architecture consisting of an electrodeposited ZnO nanorod array (NRA) coated with a conformal thin layer (&lt; 50 nm) of organic polymer-fullerene blend and a quasi-conformal Ag top contact (Thin/NR). We have compared the performance of Thin/NR cells to conventional hybrid cells in which the same NRAs are completely filled with organic blend (Thick/NR). The Thin/NR design absorbs at least as much light as Thick/NR cells, while charge extraction is significantly enhanced due to the proximity of the electrodes, resulting in a higher current density per unit volume of blend and improved power conversion efficiency. The NRAs need not be periodic or aligned and hence can be made very simply

Cutting Edge: The Heat Shock Protein gp96 Activates Inflammasome-Signaling Platforms in APCs

Several heat shock proteins (HSPs) prime immune responses, which are, in part, a result of activation of APCs. APCs respond to these immunogenic HSPs by upregulating costimulatory molecules and secreting cytokines, including IL-1beta. These HSP-mediated responses are central mediators in pathological conditions ranging from cancer, sterile inflammation associated with trauma, and rheumatoid arthritis. We tested in this study the requirement of inflammasomes in the release of IL-1beta by one immunogenic HSP, gp96. Our results show that murine APCs activate NLRP3 inflammasomes in response to gp96 by K(+) efflux. This is shown to initiate inflammatory conditions in vivo in the absence of additional known inflammasome activators or infection. These results document a novel mechanism by which proteins of endogenous origin, the HSPs, can modulate an inflammatory response following their release from aberrant cells