Gestational diabetes status and dietary intake modify maternal and cord blood allostatic load markers.

Introduction: Allostatic load (AL) defines cardiometabolic, inflammatory, and neuroendocrine changes in the body in response to internal and external stressors. It is largely unknown whether gestational diabetes mellitus (GDM) alters maternal and fetal AL, which in turn affects GDM outcomes. Whether dietary intakes and quality can modify AL and thus influence GDM progression is also unknown.

Summary of bi-shRNA/GM-CSF augmented autologous tumor cell immunotherapy (FANG™) in advanced cancer of the liver.

Therapies for advanced hepatocellular carcinoma (HCC) are limited. We carried out a phase I trial of a novel autologous whole-cell tumor cell immunotherapy (FANG™), which incorporates a dual granulocyte macrophage colony-stimulating factor (GM-CSF) expressive/bifunctional small hairpin RNA interference (bi-shRNAi) vector. The bi-shRNAi DNA targets furin, which is a proconvertase of transforming growth factors beta (TGFβ) 1 and 2.

Vertically integrated translational studies of PDX1 as a therapeutic target for pancreatic cancer via a novel bifunctional RNAi platform.

RNA interference (RNAi) represents a powerful, new tool for scientific investigation as well as a promising new form of targeted gene therapy, with applications currently in clinical trials. Bifunctional short hairpin RNA (shRNA) are synthetic RNAi molecules, engineered to utilize multiple endogenous RNAi pathways to specifically silence target genes. Pancreatic and duodenal homeobox 1 (PDX1) is a key regulator of pancreatic development, β-cell differentiation, normal β-cell function and pancreatic cancer.

Assessment of intravenous pbi-shRNA PDX1 nanoparticle (OFHIRNA-PDX1) in yucatan swine.

PDX1 (pancreatic and duodenal homeobox 1) is overexpressed in pancreatic cancer, and its reduction results in tumor regression. Bi-functional pbi-shRNA PDX1 nanoparticle (OFHIRNA-PDX1) utilizes the endogenous micro-RNA biogenesis pathway to effect cleavage- and non-cleavage-dependent degradation of PDX1 mRNA. We have shown that OFHIRNA-PDX1 reduces pancreatic tumor volume in xenograft models.

Immune response and survival of refractory cancer patients who received TGF-β2 antisense/GM-CSF gene modified autologous tumor cell (TAG) vaccine.

TAG vaccine is a novel 'triad vaccine' that involves transfection of autologous tumor with a dual plasmid, TGFβ2 antisense gene and GM-CSF gene. Patients with advanced cancer who failed standard therapy were treated. IFN-γ ELISPOT analysis (Enzyme-Linked Immunospot Assay for Interferon Gamma) using TAG autologous vaccine target cells was performed prior to vaccination and at week 12 after the third vaccination.

Ewing's Sarcoma: Development of RNA Interference-Based Therapy for Advanced Disease.

Ewing's sarcoma tumors are associated with chromosomal translocation between the EWS gene and the ETS transcription factor gene. These unique target sequences provide opportunity for RNA interference(i)-based therapy. A summary of RNAi mechanism and therapeutically designed products including siRNA, shRNA and bi-shRNA are described.

Defining the "normal" postejaculate urinalysis.

Although sperm have been shown to be present in the postejaculate urinalysis (PEU) of both fertile and infertile men, the number of sperm present in the PEU of the general population has never been well defined. The objective of this study was to describe the semen and PEU findings in both the general and infertile population, in order to develop a better appreciation for "normal." Infertile men (n = 77) and control subjects (n = 71) were prospectively recruited.

Phase I trial of "bi-shRNAi(furin)/GMCSF DNA/autologous tumor cell" vaccine (FANG) in advanced cancer.

We performed a phase I trial of FANG vaccine, an autologous tumor-based product incorporating a plasmid encoding granulocyte-macrophage colony-stimulating factor (GMCSF) and a novel bifunctional short hairpin RNAi (bi-shRNAi) targeting furin convertase, thereby downregulating endogenous immunosuppressive transforming growth factors (TGF) β1 and β2. Patients with advanced cancer received up to 12 monthly intradermal injections of FANG vaccine (1 × 10(7) or 2.5 × 10(7) cells/ml injection).

In vivo safety and antitumor efficacy of bifunctional small hairpin RNAs specific for the human Stathmin 1 oncoprotein.

Bifunctional small hairpin RNAs (bi-shRNAs) are functional miRNA/siRNA composites that are optimized for posttranscriptional gene silencing through concurrent mRNA cleavage-dependent and -independent mechanisms (Rao et al., 2010 ). We have generated a novel bi-shRNA using the miR30 scaffold that is highly effective for knockdown of human stathmin (STMN1) mRNA.

Hereditary inclusion body myopathy: single patient response to intravenous dosing of GNE gene lipoplex.

Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult-onset myopathy due to mutations in the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) gene. Affected patients have no therapeutic options. We have previously demonstrated in preclinical testing the ability to safely correct GNE gene function through liposomal delivery of the wild-type GNE gene.

Phase I trial of TGF-beta 2 antisense GM-CSF gene-modified autologous tumor cell (TAG) vaccine.

Purpose: On the basis of the hypothesis that the combined expression of immunostimulatory granulocyte macrophage colony stimulating factor (GM-CSF) and antitumor suppressor TGF-β2 antisense (AS) transgenes can break tolerance and stimulate immune responses to cancer-associated antigens, we constructed an expression plasmid [the tumor-associated glycoprotein (TAG) plasmid] that coexpresses GM-CSF and TGF-β2 AS nucleotide sequences and which was incorporated into an autologous whole-cell vaccine.

Experimental Design: Patients undergoing resection were enrolled. Freshly harvested autologous tumor cells were mechanically and enzymatically disaggregated, then electroporated with the TAG vector.

Enhanced target gene knockdown by a bifunctional shRNA: a novel approach of RNA interference.

RNA interference (RNAi) is a natural cellular regulatory process that inhibits gene expression by transcriptional, post-transcriptional and translational mechanisms. Synthetic approaches that emulate this process (small interfering RNA (siRNA), short hairpin RNA (shRNA)) have been shown to be similarly effective in this regard. We developed a novel 'bifunctional' RNAi strategy, which further optimizes target gene knockdown outcome.

Hereditary inclusion body myopathy: single patient response to GNE gene Lipoplex therapy.

Background: Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult onset myopathy. It is characterized by mutations of the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) gene. Afflicted patients have no therapeutic options.

Hereditary Inclusion Body Myopathy (HIBM2).

Hereditary inclusion body myopathy type 2 (HIBM2) is a myopathy characterized by progressive muscle weakness with early adult onset. The disease is the result of a recessive mutation in the Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase gene (GNE), which results in reduced enzyme function and sialic acid levels. A majority of individuals with HIBM2 are from Iranian-Jewish or Japanese decent, but isolated cases have been identified world wide.

Development and validation of a low-literacy Chronic Obstructive Pulmonary Disease knowledge Questionnaire (COPD-Q).

Objective: The objective of this study was to develop a content valid, understandable, readable, and reliable Chronic Obstructive Pulmonary Disease knowledge Questionnaire (COPD-Q).

Methods: Twenty-one questions were generated as potential items to include in the COPD-Q. Twenty-two content experts provided both qualitative and quantitative assessments of two COPD-Q drafts.

A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors.

A phase I clinical trial was conducted to determine the clinical safety of Telomelysin, a human telomerase reverse transcriptase (hTERT) promoter driven modified oncolytic adenovirus, in patients with advanced solid tumors. A single intratumoral injection (IT) of Telomelysin was administered to three cohorts of patients (1 x 10(10), 1 x 10(11), 1 x 10(12) viral particles). Safety, response and pharmacodynamics were evaluated.

Safety and in vivo expression of a GNE-transgene: a novel treatment approach for hereditary inclusion body myopathy-2.

Hereditary inclusion body myopathy-2 (HIBM2) is an adult-onset, muscular disease caused by mutations in the GNE gene. HIBM2-associated GNE mutations causing hyposialyation have been proposed to contribute to reduced muscle function in patients with HIBM2, though the exact cause of this disease is unknown. In the current studies we examined pre-clinical in vivo toxicity, and expression of the plasmid-based, CMV driven wild-type GNE plasmid vector.

Phase II trial of Belagenpumatucel-L, a TGF-beta2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer (NSCLC) patients.

In a previous dose escalation trial we demonstrated dose related survival correlation to Belagenpumatucel-L. In order to further evaluate safety and response at the previously defined optimal dose and schedule and to gain preliminary evidence on a hypothesis that the level of circulating tumor cells (CTCs) in blood may correlate with the overall survival of patients with stage IV NSCLC, we initiated a phase II trial. Patients received intradermal immunization of 2.

Systemic therapeutic gene delivery for cancer: crafting Paris' arrow.

Tremendous strides have been made in proteogenomics and RNA interference technologies. Hence "personalized" cancer gene therapy has become a foreseeable rather than a predictable reality. Currently, the lack of an optimized, systemic gene delivery vehicle remains a key limiting factor for developing effective treatment applications.

Stathmin 1: a novel therapeutic target for anticancer activity.

Stathmin 1 (STMN1), also known as p17, p18, p19, 19K, metablastin, oncoprotein 18, LAP 18 and Op18, is a 19 kDa cytosolic protein. It was the first discovered member of a family of phylogenetically related microtubule-destabilizing phosphoproteins critically involved in the construction and function of the mitotic spindle. A threshold level of STMN1 is required for orderly progression through mitosis in a variety of cell types.

Preclinical assessment of wt GNE gene plasmid for management of hereditary inclusion body myopathy 2 (HIBM2).

Hereditary Inclusion Body Myopathy (HIBM2) is a chronic progressive skeletal muscle wasting disorder which generally leads to complete disability before the age of 50 years. There is currently no effective therapeutic treatment for HIBM2. Development of this disease is related to expression in family members of an autosomal recessive mutation of the GNE gene, which encodes the bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE/MNK).

A phase I trial of intravenous infusion of ONYX-015 and enbrel in solid tumor patients.

ONYX-015 is an attenuated chimeric human group C adenovirus, which preferentially replicates in and lyses tumor cells that are p53 negative. The purpose of this phase I, dose-escalation study was to determine the safety and feasibility of intravenous infusion with ONYX-015 in combination with enbrel in patients with advanced carcinoma. Enbrel is a recombinant dimer of human tumor-necrosis factor (TNF)-alpha receptor, previously shown to reduce the level of functional TNF.