Entrepreneurship and Criminal Justice Populations: A Social Cognitive Perspective.

A criminal record limits employment opportunities of those released from prison. Entrepreneurship, or starting one's own business venture, has been suggested as a way to overcome the employment barriers of a criminal record, given that many justice-involved persons have entrepreneurship experiences, often through illegal ventures. Sparse research has investigated how legal or illegal business experience translates to legal entrepreneurship attitudes.

Fertility-preserving myeloablative conditioning using single-dose CD117 antibody-drug conjugate in a rhesus gene therapy model.

Hematopoietic stem cell (HSC) gene therapy has curative potential; however, its use is limited by the morbidity and mortality associated with current chemotherapy-based conditioning. Targeted conditioning using antibody-drug conjugates (ADC) holds promise for reduced toxicity in HSC gene therapy. Here we test the ability of an antibody-drug conjugate targeting CD117 (CD117-ADC) to enable engraftment in a non-human primate lentiviral gene therapy model of hemoglobinopathies.

Overall safety of relamorelin in adults with diabetic gastroparesis: Analysis of phase 2a and 2b trial data.

Background: Relamorelin, a pentapeptide ghrelin receptor agonist, accelerated gastric emptying significantly and improved symptoms in adults with diabetic gastroparesis in phase 2 trials.

Aim: To assess the safety and tolerability of relamorelin across phase 2 trials.

Methods: Safety assessments in patients aged 18-75 years (weight, adverse events [AEs] and laboratory tests) from two randomised, double-blind phase 2 trials (NCT01571297, NCT02357420; results published previously) were reviewed descriptively.

Peficitinib, an Oral Janus Kinase Inhibitor, in Moderate-to-severe Ulcerative Colitis: Results From a Randomised, Phase 2 Study.

Background And Aims: Janus kinase [JAK] inhibitors have shown efficacy in ulcerative colitis [UC]. We studied the dose-response, efficacy, and safety of peficitinib, an oral JAK inhibitor, in patients with moderate-to-severe UC.

Methods: In this Phase 2b, dose-ranging trial, we evaluated peficitinib at 25 mg once daily [o.

Metabolic Fate of C-Labeled Polydextrose and Impact on the Gut Microbiome: A Triple-Phase Study in a Colon Simulator.

The present study introduces a novel triple-phase (liquids, solids, and gases) approach, which employed uniformly labeled [U-C] polydextrose (PDX) for the selective profiling of metabolites generated from dietary fiber fermentation in an in vitro colon simulator using human fecal inocula. Employing C NMR spectroscopy, [U-C] PDX metabolism was observed from colonic digest samples. The major C-labeled metabolites generated were acetate, butyrate, propionate, and valerate.

The cell-wall active mannuronan C5-epimerases in the model brown alga Ectocarpus: From gene context to recombinant protein.

Mannuronan C5-epimerases (ManC5-Es) catalyze in brown algae the remodeling of alginate, a major cell-wall component which is involved in many biological functions in these organisms. ManC5-Es are present as large multigenic families in brown algae, likely indicating functional specificities and specializations. ManC5-Es control the distribution pattern of (1-4) linked β-d-mannuronic acid (M) and α-l-guluronic acid (G) residues in alginates, giving rise to widely different polysaccharide compositions and sequences, depending on tissue, season, age, or algal species.

High Throughput Identification and Quantification of Phospholipids in Complex Mixtures.

We present a fully automatic method, autoP, for identification and quantification of lipids in complex lipid mixtures from 1D (31)P and 2D (1)H-(31)P NMR spectra. The (31)P chemical shifts in lipids are highly sensitive to experimental conditions such as pH and temperature, so the present method uses the much more unambiguous (1)H chemical shifts for assignment and (31)P intensities for quantification. By using 2D (1)H-(31)P total correlation spectroscopy (TOCSY) correlation experiments, we demonstrate that approximately 20 different lipids can be automatically and unambiguously assigned and quantified by this automatic method.

Solid-state NMR methods for oriented membrane proteins.

Oriented-sample solid-state NMR represents one of few experimental methods capable of characterising the membrane-bound conformation of proteins in the cell membrane. Since the technique was developed 25 years ago, the technique has been applied to study the structure of helix bundle membrane proteins and antimicrobial peptides, characterise protein-lipid interactions, and derive information on dynamics of the membrane anchoring of membrane proteins. We will review the major developments in various aspects of oriented-sample solid-state NMR, including sample-preparation methods, pulse sequences, theory required to interpret the experiments, perspectives for and guidelines to new experiments, and a number of representative applications.

Pharmacokinetic interaction between etravirine or rilpivirine and telaprevir in healthy volunteers: A randomized, two-way crossover trial.

Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) may require treatment with an HIV non-nucleoside reverse transcriptase inhibitor (NNRTI), for example, rilpivirine or etravirine, and an HCV direct-acting antiviral drug such as telaprevir. In a two-panel, two-way, crossover study, healthy volunteers were randomized to receive etravirine 200 mg twice daily ± telaprevir 750 mg every 8 hours or rilpivirine 25 mg once daily ± telaprevir 750 mg every 8 hours. Pharmacokinetic assessments were conducted for each drug at steady-state when given alone and when coadministered; statistical analyses were least-square means with 90% confidence intervals.

EXPERIENCES OF RECIPIENTS AND LIVING DONORS THE FIRST THREE DAYS AFTER KIDNEY TRANSPLANTATION.

Background: Living donor transplantation is described as a stressful and complex process for both recipients and donors. Few studies have described the experiences of recipients and donors in the first three post-operative days after living kidney transplantation.

Objectives: To explore how recipients and living donors experienced the first three post-operative days after kidney transplantation.

Effects of JNJ-40929837, a leukotriene A4 hydrolase inhibitor, in a bronchial allergen challenge model of asthma.

Unlabelled: Leukotriene B4 (LTB4) is a chemotactic mediator implicated in the pathogenesis of asthma. JNJ-40929837 is an oral inhibitor of LTA4 hydrolase, which catalyzes LTB4 production. We evaluated the effects of JNJ-40929837 in a human bronchial allergen challenge (BAC) model.

Telaprevir twice daily is noninferior to telaprevir every 8 hours for patients with chronic hepatitis C.

Background & Aims: We performed an open-label, multicenter, phase 3 study of the safety and efficacy of twice-daily telaprevir in treatment-naive patients with chronic hepatitis C virus (HCV) genotype 1 infection, including those with cirrhosis.

Methods: Patients were randomly assigned to groups treated with telaprevir 1125 mg twice daily or 750 mg every 8 hours plus peginterferon alfa-2a and ribavirin for 12 weeks; patients were then treated with peginterferon alfa-2a and ribavirin alone for 12 weeks if their level of HCV RNA at week 4 was <25 IU/mL or for 36 weeks if their level was higher. The primary objective was to demonstrate noninferiority of telaprevir twice daily versus every 8 hours in producing a sustained virological response 12 weeks after the end of therapy (SVR12) (based on a -11% lower limit of the 95% lower confidence interval for the difference between groups).

Omitting adjuvant radiotherapy in endometrial cancer increases the rate of locoregional recurrences but has no effect on long-term survival: the Danish Endometrial Cancer Study.

Objectives: In 2 prospective nationwide studies, the Danish Endometrial Cancer Study demonstrated that postoperative radiotherapy (RT) could be omitted in low- and intermediate-risk stage I patients without loss of survival when evaluated after 5 years. In the present study, we evaluated the consequence of this decision on the long-term risk of recurrence and death.

Study Design: From 1998 to 1999, 1166 patients newly diagnosed with uterine carcinoma were included.

Facile synthesis of phosphatidyl saccharides for preparation of anionic nanoliposomes with enhanced stability.

Physical stability during storage and against processing such as dehyration/rehydration are the cornerstone in designing delivery vehicles. In this work, mono-, di- and tri-saccharides were enzymatically conjugated to phosphatidyl group through a facile approach namely phospholipase D (PLD) mediated transphosphatidylation in a biphasic reaction system. The purified products were structurally identified and the connectivities of carbohydrate to phosphatidyl moiety precisely mapped by (1)H, (31)P, (13)C NMR pulse sequences and LC-ESI-FTMS.

A highly sensitive and selective method for the determination of leukotriene B4 (LTB4) in ex vivo stimulated human plasma by ultra fast liquid chromatography-tandem mass spectrometry.

Leukotriene B4 (LTB4) is an important inflammatory component in a number of diseases and has been used as a pharmacodynamic (PD) biomarker. In this report, a highly sensitive and selective ultra fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) method for the determination of LTB4 in plasma from ex vivo stimulated human blood, using leukotriene B4-d4 (LTB4-d4, contains four deuterium atoms at the 6, 7, 14, and 15 positions) as the internal standard (IS), was developed and validated. The chromatographic separation of LTB4 from its three isomers and an unknown interference peak from human plasma was crucial to achieve accurate determination of 0.

Mechanisms of peptide-induced pore formation in lipid bilayers investigated by oriented 31P solid-state NMR spectroscopy.

There is a considerable interest in understanding the function of antimicrobial peptides (AMPs), but the details of their mode of action is not fully understood. This motivates extensive efforts in determining structural and mechanistic parameters for AMP's interaction with lipid membranes. In this study we show that oriented-sample (31)P solid-state NMR spectroscopy can be used to probe the membrane perturbations and disruption by AMPs.

Phospholipase D (PLD) catalyzed synthesis of phosphatidyl-glucose in biphasic reaction system.

Presence of saccharides in glycophospholipids may increase its potential to form supramolecular structures, which are not only stable for an extended period of time as compared to other PLs like phosphatidylcholine, but may also confer an antioxidative property. Most syntheses routes for glycophospholipid involved the usage of toxic chemicals or solvents, complicated steps and low yield. The present work attempted to develop an enzymatic method for the production of glycophospholipids.

Translational evaluation of JNJ-18038683, a 5-hydroxytryptamine type 7 receptor antagonist, on rapid eye movement sleep and in major depressive disorder.

In rodents 5-hydroxytryptamine type 7 (5-HT(7)) receptor blockade has been shown to be effective in models of depression and to increase the latency to rapid eye movement (REM) sleep and decrease REM duration. In the clinic, the REM sleep reduction observed with many antidepressants may serve as a biomarker. We report here the preclinical and clinical evaluation of a 5-HT(7) receptor antagonist, (3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1-(phenylmethyl)pyrazolo[3,4-d]azepine 2-hydroxy-1,2,3-propanetricarboxylate) (JNJ-18038683).

Survival of Danish patients with endometrial cancer in the intermediate-risk group not given postoperative radiotherapy: the Danish Endometrial Cancer Study (DEMCA).

Objectives: In a prospective study during the years 1986 to 1988, the Danish Endometrial Cancer Group (DEMCA) demonstrated that postoperative radiotherapy was unnecessary for low-risk patients with stage I disease. In the present study, we evaluated in a population-based study if radiotherapy could also be omitted for intermediate-risk patients with stage I disease without loss of survival.

Study Design: From 1998 to 1999, 1166 patients newly diagnosed with carcinoma of the uterus were included in this prospective nationwide study.

Long-term-stable ether-lipid vs conventional ester-lipid bicelles in oriented solid-state NMR: altered structural information in studies of antimicrobial peptides.

Recently, ether lipids have been introduced as long-term stable alternatives to the more natural, albeit easier degradable, ester lipids in the preparation of oriented lipid bilayers and bicelles for oriented-sample solid-state NMR spectroscopy. Here we report that ether lipids such as the frequently used 14-O-PC (1,2-di-O-tetradecyl-sn-glycero-3-phosphocholine) may induce significant changes in the structure and dynamics, including altered interaction between peptides and lipids relative to what is observed with the more conventionally used DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) bilayers. Such effects are demonstrated for the antimicrobial peptide novicidin, for which 2D separate-local-field NMR and circular dichroism experiments reveal significant structural/conformational differences for the peptide in the two different lipid systems.

A brief survey of first-in-human studies.

First-in-human (FIH) studies are a critical step in the drug development process and typically aim to characterize a compound's pharmacokinetics, potential effective concentration or dose, and safety or tolerability margins. Although effort continues to enhance the predictive quality of the selection of FIH doses from preclinical data, and little consensus is available on the design and conduct of FIH studies, detailed surveys describing general approaches taken in FIH studies are useful in the optimization of early-phase clinical drug development. Although allometric scaling techniques continue to provide poor predictive estimates for human pharmacokinetic parameters, FIH starting doses are selected with substantial safety factors applied to human equivalent dose, often in excess of regulatory guidelines.

A phase II study of combination chemotherapy in early relapsed epithelial ovarian cancer using gemcitabine and pegylated liposomal doxorubicin.

Objective: Treatment of epithelial ovarian cancer patients relapsing with a short treatment-free interval (TFI) after prior chemotherapy is unsatisfactory. This phase II trial evaluated the activity and feasibility of pegylated liposomal doxorubicin (PLD) plus gemcitabine in this setting.

Methods: Patients who had received prior platinum and paclitaxel with a TFI 0-12 months received PLD 25 mg/m(2)day 1 plus gemcitabine 800 mg/m(2)day 1, 8 every 21 days.

Simultaneous determination of tolbutamide, omeprazole, midazolam and dextromethorphan in human plasma by LC-MS/MS--a high throughput approach to evaluate drug-drug interactions.

Drug-drug interactions involving cytochrome P450 (CYP450s) are an important factor for evaluation of a new chemical entity (NCE) in drug development. To evaluate the potential inhibitory effects of a NCE on the pharmacokinetics of a cocktail of representative probes of CYP enzymes (midazolam for CYP3A4, tolbutamide for CYP2C9, omeprazole for CYP2C19 and dextromethorphan for CYP2D6) and the safety and tolerability of the NCE in the presence of probe substrates, a high throughput liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of tolbutamide, omeprazole, midazolam and dextromethorphan in human plasma using tolbutamide-d(9), midazolam-d(4), (+/-)-omeprazole-d(3), and dextromethorphan-d(3) as the internal standards (ISs). Human plasma samples of 50 microL were extracted by a simple protein-precipitation procedure and analyzed using a high performance liquid chromatography electrospray tandem mass spectrometer system.

Pardaxin permeabilizes vesicles more efficiently by pore formation than by disruption.

Pardaxin is a 33-amino-acid neurotoxin from the Red Sea Moses sole Pardachirus marmoratus, whose mode of action shows remarkable sensitivity to lipid chain length and charge, although the effect of pH is unclear. Here we combine optical spectroscopy and dye release experiments with laser scanning confocal microscopy and natural abundance (13)C solid-state nuclear magnetic resonance to provide a more complete picture of how pardaxin interacts with lipids. The kinetics and efficiency of release of entrapped calcein is highly sensitive to pH.

Divorcing folding from function: how acylation affects the membrane-perturbing properties of an antimicrobial peptide.

Many small cationic peptides, which are unstructured in aqueous solution, have antimicrobial properties. These properties are assumed to be linked to their ability to permeabilize bacterial membranes, accompanied by the transition to an alpha-helical folding state. Here we show that there is no direct link between folding of the antimicrobial peptide Novicidin (Nc) and its membrane permeabilization.