Low-cost 3D printed lenses for brightfield and fluorescence microscopy.

We present the fabrication and implementation of low-cost optical quality 3D printed lenses, and their application as microscope objectives with different prescriptions. The imaging performance of the 3D printed lenses was benchmarked against commercially available optics including a 20 mm focal length 12.7 mm diameter NBK-7 plano-convex lens used as a low magnification objective, and a separate high magnification objective featuring three 6 mm diameter NBK-7 lenses with different positive and negative focal lengths.

Miniaturized structured illumination microscopy using two 3-axis MEMS micromirrors.

We present the development and performance characterisation of a novel structured illumination microscope (SIM) in which the grating pattern is generated using two optical beams controlled via 2 micro-electro-mechanical system (MEMS) three-axis scanning micromirrors. The implementation of MEMS micromirrors to accurately and repeatably control angular, radial and phase positioning delivers flexible control of the fluorescence excitation illumination, with achromatic beam delivery through the same optical path, reduced spatial footprint and cost-efficient integration being further benefits. Our SIM architecture enables the direct implementation of multi-color imaging in a compact and adaptable package.

MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia.

Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown.

Applying the Noninferiority Paradigm to Assess Exposure-Response Similarity and Dose Between Pediatric and Adult Patients.

The use of extrapolation of efficacy in pediatric drug development programs is possible when disease progression and treatment response are similar in adult and pediatric populations. Historically, the exposure-response (E-R) similarity was assessed by visual inspection of 2 E-R curves to support pediatric extrapolation. The aim of this study was to develop a quantitative framework to describe the E-R relationship and the difference in E-R between pediatric and adult patients based on accumulated experience in pediatric drug development programs.

KRAS mutant allele-specific expression knockdown in pancreatic cancer model with systemically delivered bi-shRNA KRAS lipoplex.

The KRAS oncogene, present in over 90% of pancreatic ductal adenocarcinomas, is most frequently the result of one of three gain-of-function substitution mutations of codon 12 glycine. Thus far, RAS mutations have been clinically refractory to both direct and selective inhibition by systemic therapeutics. This report presents the results of pre-clinical assessment of a lipoplex comprising a plasmid-encoded, modular bi-functional shRNA (bi-shRNA), which executes selective and multi-mutant allelic KRASG12mut gene silencing, encased within a fusogenic liposome systemic delivery vehicle.

Organic solute carrier 22 (SLC22) family: Potential for interactions with food, herbal/dietary supplements, endogenous compounds, and drugs.

Many drugs, hormones, components of herbal medicines, environmental pesticides and toxins are Solute Carrier family 22 (SLC22) substrates. The last twenty years has seen great progress in determining SLC22 tissue expression profiles, membrane localization, energetics, substrate profiles and biopharmaceutical significance. However, much still remains to be answered in terms of SLC22 family member's roles in 'normal' physiology as compared to pathophysiological states, as well as in drug interactions that impact pharmacokinetics, efficacy and toxicity.

Preclinical Biodistribution and Safety Evaluation of a pbi-shRNA STMN1 Lipoplex after Subcutaneous Delivery.

Stathmin-1 (STMN1) is a microtubule-destabilizing protein which is overexpressed in cancer. Its overexpression is associated with poor prognosis and also serves as a predictive marker to taxane therapy. We have developed a proprietary bi-functional shRNA (bi-shRNA) platform to execute RNA interference (RNAi)-mediated gene silencing and a liposome-carrier complex to systemically deliver the pbi-shRNA plasmids.

Preclinical Justification of pbi-shRNA EWS/FLI1 Lipoplex (LPX) Treatment for Ewing's Sarcoma.

The EWS/FLI1 fusion gene is well characterized as a driver of Ewing's sarcoma. Bi-shRNA EWS/FLI1 is a functional plasmid DNA construct that transcribes both siRNA and miRNA-like effectors each of which targets the identical type 1 translocation junction region of the EWS/FLI1 transcribed mRNA sequence. Previous preclinical and clinical studies confirm the safety of this RNA interference platform technology and consistently demonstrate designated mRNA and protein target knockdown at greater than 90% efficiency.

Phase 1 Trial of Bi-shRNA STMN1 BIV in Refractory Cancer.

Stathmin1 (STMN1) is a microtubule modulator that is expressed in multiple cancers and correlates with poor survival. We previously demonstrated in vivo safety of bifunctional (bi) shRNA STMN1 bilamellar invaginated vesicle (BIV) and that systemic delivery correlated with antitumor activity. Patients with superficial advanced refractory cancer with no other standard options were entered into trial.

Surgical competency for urethrovesical anastomosis during robot-assisted radical prostatectomy: development and validation of the robotic anastomosis competency evaluation.

Objective: To develop and validate an assessment tool for the performance of urethrovesical anastomosis (UVA).

Methods: A multicenter, prospective, observational study was conducted in 2 phases. Phase 1, development and content validation, used a panel of 5 experienced robotic surgeons to develop a 6-domain scoring system, Robotic Anastomosis Competence Evaluation (RACE), to assess technical skills for performing UVA.

Enterotoxigenic K99+ Escherichia coli attachment to host cell receptors inhibited by recombinant pili protein.

Most enterotoxigenic Escherichia coli (ETEC) isolated from neonatal cattle with diarrhea (enteric colibacillosis) exhibit the colonization factor antigen, K99. The K99 pili are necessary for the bacteria to bind to a receptor, N-glycolylneuraminic acid-GM3 on the host cells in the small intestine where the bacteria multiply and secrete toxins that cause the diarrhea. When the attachment of the ETEC to host cell is inhibited, the bacteria do not accumulate sufficiently in the gut to cause disease.