Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia.

Purpose: RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a phase I study of RG7112 in patients with hematologic malignancies was conducted.

Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) as a prognostic marker for local control in T1-2 N0 breast cancer treated with breast-conserving surgery and radiation therapy (BCS + RT).

Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) expression, involved in the regulation of translation, has been implicated to mediate resistance to chemotherapy and radiation in cancer cells in vitro. The purpose of this study was to evaluate the prognostic significance of IFIT1 protein expression in patients with breast cancer treated with Breast-Conserving Surgery and Radiation Therapy (BCS + RT). A tissue microarray was constructed with specimens from 282 women with node-negative, early-stage (I/II) breast cancer who were treated with BCS + RT.

Nicotine intake and smoking topography in smokers with bipolar disorder.

Objectives: Cigarette smoking behavior in bipolar disorder (BPD), including the effects of mood-stabilizing medications, has not been well characterized.

Methods: We compared serum nicotine, nicotine metabolite levels, and smoking topography in 75 smokers with BPD to 86 control smokers (CON). For some comparisons, an additional control group of 75 smokers with schizophrenia (SCZ) were included.

Growth and translation inhibition through sequence-specific RNA binding by Mycobacterium tuberculosis VapC toxin.

The Mycobacterium tuberculosis genome harbors an unusually large number of toxin-antitoxin (TA) modules. Curiously, over half of these are VapBC (virulence-associated protein) family members. Nonetheless, the cellular target, precise mode of action, and physiological role of the VapC toxins in this important pathogen remain unclear.

Robust segmentation of overlapping cells in histopathology specimens using parallel seed detection and repulsive level set.

Automated image analysis of histopathology specimens could potentially provide support for early detection and improved characterization of breast cancer. Automated segmentation of the cells comprising imaged tissue microarrays (TMAs) is a prerequisite for any subsequent quantitative analysis. Unfortunately, crowding and overlapping of cells present significant challenges for most traditional segmentation algorithms.

Logical Analysis of Data in Structure-Activity Investigation of Polymeric Gene Delivery.

To date semi-empirical or surrogate modeling has demonstrated great success in the prediction of the biologically relevant properties of polymeric materials. For the first time, a correlation between the chemical structures of poly(β-amino esters) and their efficiency in transfecting DNA was established using the novel technique of logical analysis of data (LAD). Linear combination and explicit representation models were introduced and compared in the framework of the present study.

Resource utilization and cost of treatment with anidulafungin or fluconazole for candidaemia and other forms of invasive candidiasis: focus on critically ill patients.

Background: Candidaemia and other forms of invasive candidiasis (C/IC) are serious and costly events for hospitalized patients, particularly those in the ICU. Both fluconazole and the echinocandins are recommended as first-line therapy for C/IC. Resource use and cost considerations are important in selecting appropriate treatment but little information is available on the economic implications of using echinocandins in this setting.

Colorectal cancer screening among primary care patients: does risk affect screening behavior?

Lifestyle factors including smoking, obesity, and diabetes can increase colorectal cancer (CRC) risk. Controversy exists regarding screening rates in individuals at increased CRC risk. To examine the effect of risk on CRC screening in primary care, cross-sectional data collected during January 2006-July 2007 from 720 participants in 24 New Jersey primary care practices were analyzed.

Activity of a C-terminal plant homeodomain (PHD) of Msc1 is essential for function.

Msc1, a member of the Jarid1 family of putative histone demethylases, is required for chromosome stability in fission yeast. Msc1 associates with the Swr1 complex that facilitates deposition of histone H2A.Z into chromatin.

Defective ubiquitin-mediated degradation of antiapoptotic Bfl-1 predisposes to lymphoma.

The antiapoptotic Bcl-2 family member Bfl-1 is up-regulated in many human tumors in which nuclear factor-kappaB (NF-kappaB) is implicated and contributes significantly to tumor cell survival and chemoresistance. We previously found that NF-kappaB induces transcription of bfl-1 and that the Bfl-1 protein is also regulated by ubiquitin-mediated proteasomal degradation. However, the role that dysregulation of Bfl-1 turnover plays in cancer is not known.

Racial differences in adjuvant systemic therapy for early breast cancer among Medicaid beneficiaries.

Black breast cancer patients have shorter survival compared to whites. Lack of optimal treatment may be a potential explanation for this difference. Although racial disparities in surgical and radiation therapy have been studied extensively, there is little information on racial disparities in use of adjuvant systemic therapy.

Quantification of 1-aminopyrene in human urine after a controlled exposure to diesel exhaust.

Diesel exhaust (DE) is a significant source of air pollution that has been linked to respiratory and cardiovascular morbidity and mortality. Many components in DE, such as polycyclic aromatic hydrocarbons, are present in the environment from other sources. 1-Nitropyrene appears to be a more specific marker of DE exposure.

Intensity-modulated radiation therapy for orbital lymphoma.

Purpose: Orbital manifestations of non-Hodgkin's lymphoma (NHL) are rare and accounts for only 1% of all cases of NHL. There have been no reports of treating orbital lymphoma using intensity-modulated radiotherapy (IMRT).

Materials And Methods: Four patients were treated at our institution for orbital lymphoma using IMRT.

Hybrid scoring and classification approaches to predict human pregnane X receptor activators.

Purpose: The human pregnane X receptor (PXR) is a transcriptional regulator of many genes involved in xenobiotic metabolism and excretion. Reliable prediction of high affinity binders with this receptor would be valuable for pharmaceutical drug discovery to predict potential toxicological responses

Materials And Methods: Computational models were developed and validated for a dataset consisting of human PXR (PXR) activators and non-activators. We used support vector machine (SVM) algorithms with molecular descriptors derived from two sources, Shape Signatures and the Molecular Operating Environment (MOE) application software.

Therapeutic starvation and autophagy in prostate cancer: a new paradigm for targeting metabolism in cancer therapy.

Background: Autophagy is a starvation induced cellular process of self-digestion that allows cells to degrade cytoplasmic contents. The understanding of autophagy, as either a mechanism of resistance to therapies that induce metabolic stress, or as a means to cell death, is rapidly expanding and supportive of a new paradigm of therapeutic starvation.

Methods: To determine the effect of therapeutic starvation in prostate cancer, we studied the effect of the prototypical inhibitor of metabolism, 2-deoxy-D-glucose (2DG), in multiple cellular models including a transfected pEGFP-LC3 autophagy reporter construct in PC-3 and LNCaP cells.

The individualization of cancer therapy: the unexpected role of p53.

Our laboratory discovered that p53 can regulate the sensitivity to cancer therapies by affecting three critical aspects of cancer pharmacology: 1). The expression of drug targets; 2). the access of drugs to intracellular targets; and the response to DNA damage.

Resuscitating the microcirculation in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials.

Microcirculatory dysfunction is a critical element of the pathogenesis of severe sepsis and septic shock. In this Bench-to-Bedside review, we present: 1) the central role of the microcirculation in the pathophysiology of sepsis; 2) new translational research techniques of in vivo video microscopy for assessment of microcirculatory flow in human subjects; 3) clinical investigations that reported associations between microcirculatory dysfunction and outcome in septic patients; 4) the potential role of novel agents to "rescue" the microcirculation in sepsis; 5) current challenges facing this emerging field of clinical investigation; and 6) a framework for the design of future clinical trials aimed to determine the impact of novel agents on microcirculatory flow and organ failure in patients with sepsis. We specifically focus this review on the central role and vital importance of the nitric oxide (NO) molecule in maintaining microcirculatory homeostasis and patency, especially when the microcirculation sustains an insult (as with sepsis).

New predictive models for blood-brain barrier permeability of drug-like molecules.

Purpose: The goals of the present study were to apply a generalized regression model and support vector machine (SVM) models with Shape Signatures descriptors, to the domain of blood-brain barrier (BBB) modeling.

Materials And Methods: The Shape Signatures method is a novel computational tool that was used to generate molecular descriptors utilized with the SVM classification technique with various BBB datasets. For comparison purposes we have created a generalized linear regression model with eight MOE descriptors and these same descriptors were also used to create SVM models.

Atrial fibrillation and isolated systolic hypertension: the systolic hypertension in the elderly program and systolic hypertension in the elderly program-extension study.

We performed a post hoc analysis of the Systolic Hypertension in the Elderly Program database to assess the incidence of atrial fibrillation in the elderly hypertensive population, its influence on cardiovascular events, and whether antihypertensive treatment can prevent its onset. The Systolic Hypertension in the Elderly Program was a double-blind placebo-controlled trial in 4736 subjects with isolated systolic hypertension aged >or=60 years. Atrial fibrillation was an exclusion criterion from the trial.

A qualitative analysis of the perception of stigma among Latinos receiving antidepressants.

Objective: This study sought to describe the role of stigma in antidepressant adherence among Latinos.

Methods: The study utilized data generated from six focus groups of Latino outpatients receiving antidepressants (N=30). By using a grounded theory approach, qualitative analysis focused specifically on the role of stigma in antidepressant treatment, as well as salient Latino values.

Inhibition of apoptosis prevents shear-induced detachment of endothelial cells.

Background: Biomaterials placed into the vasculature in man fail to develop an endothelial lining. Attempts to seed endothelial cells (ECs) on prosthetic vascular grafts have failed due to flow-induced detachment. The mechanism of flow-induced detachment of ECs from biomaterials is undefined.

Protease inhibitor associated mutations compromise the efficacy of therapy in human immunodeficiency virus-1 (HIV-1) infected pediatric patients: a cross-sectional study.

Background: Although the introduction of combined therapy with reverse transcriptase and protease inhibitors has resulted in considerable decrease in HIV related mortality; it has also induced the development of multiple drug-resistant HIV-1 variants. The few studies on HIV-1 mutagenesis in HIV infected children have not evaluated the impact of HIV-1 mutations on the clinical, virological and immunological presentation of HIV disease that is fundamental to optimizing the treatment regimens for these patients.

Results: A cross sectional study was conducted to evaluate the impact of treatment regimens and resistance mutation patterns on the clinical, virological, and immunological presentation of HIV disease in 41 children (25 male and 16 female) at the Robert Wood Johnson Pediatric AIDS Program in New Brunswick, New Jersey.

Protection of DNA ends by telomeric 3' G-tail sequences.

The extreme ends of eukaryotic chromosomes contain 3' extensions in the form of single-stranded G-rich repeats, referred to as telomeric 3' G-tails or overhangs. Increasing evidence has suggested that telomeric 3' G-tails can adopt a G-quadruplex conformation both in vitro and in vivo. However, the role of G-quadruplexes on the structure and function of telomeric 3' G-tails remains unclear.