Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor.

BACKGROUND: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. METHODS: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (change in low density lipoprotein cholesterol). RESULTS: MK-0616 displayed high affinity (Ki = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84-103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple-oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43-85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616. CONCLUSIONS: This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.

Disruption of PAK3 Signaling in Social Interaction Induced cFos Positive Cells Impairs Social Recognition Memory.

P21-activated kinase 3 (PAK3) gene mutations are linked to several neurodevelopmental disorders, but the underlying mechanisms remain unclear. In this study, we used a tetracycline-inducible system to control the expression of a mutant PAK3 (mPAK3) protein in immediate early gene, namely cFos, positive cells to disrupt PAK signaling, specifically in cells activated by social interaction in transgenic mice. We show that the expression of mPAK3-GFP proteins was in cFos-expressing excitatory and inhibitory neurons in various brain regions, such as the cortex and hippocampus, commonly activated during learning and memory. Basal expression of mPAK3-GFP proteins in cFos-positive cells resulted in social recognition memory deficits in the three-chamber social interaction test, without affecting locomotor activity or other forms of memory. The social memory deficit was rescued by doxycycline to halt the mPAK3-GFP transgene expression. In addition, we show that the expression of mPAK3-GFP proteins in a subset of cFos-positive cells, induced by an antecedent short social interaction, termed social pairing, was sufficient to impair social recognition memory. These results indicate that normal PAK signaling in cFos-positive cells activated during social interaction is critical for social memory.

Population Pharmacokinetic Analyses of Ertugliflozin in Select Ethnic Populations.

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, is approved for treatment of type 2 diabetes. Two population pharmacokinetic (PK) analyses were conducted, using data from up to 17 phase 1 to 3 studies, to characterize ertugliflozin PK parameters in select ethnic subgroups: (1) East/Southeast (E/SE) Asian vs non-E/SE Asian subjects; (2) Asian subjects from mainland China vs Asian subjects from the rest of the world and non-Asian subjects. A 2-compartment model with first-order absorption, lag time, and first-order elimination was fitted to the observed data. For the E/SE Asian vs non-E/SE Asian analysis (13 692 PK observations from 2276 subjects), E/SE Asian subjects exhibited a 17% increase in apparent clearance (CL/F) and 148% increase in apparent central volume of distribution (Vc/F) vs non-E/SE Asian subjects. However, individual post hoc CL/F values were similar between groups when body weight differences were considered. For the second analysis (16 018 PK observations from 2620 subjects), compared with non-Asian subjects, CL/F was similar while Vc/F increased by 44% in Asian subjects from mainland China and both CL/F and Vc/F increased in Asian subjects from the rest of the world (8% and 115%, respectively) vs non-Asian subjects. Increases in Vc/F would decrease the ertugliflozin maximum concentration but would not impact area under the concentration-time curve. Therefore, the differences in CL/F (area under the concentration-time curve) and Vc/F were not considered clinically relevant or likely to result in meaningful ethnic differences in the PK of ertugliflozin.

End-to-end application of model-informed drug development for ertugliflozin, a novel sodium-glucose cotransporter 2 inhibitor.

Model-informed drug development (MIDD) is critical in all stages of the drug-development process and almost all regulatory submissions for new agents incorporate some form of modeling and simulation. This review describes the MIDD approaches used in the end-to-end development of ertugliflozin, a sodium-glucose cotransporter 2 inhibitor approved for the treatment of adults with type 2 diabetes mellitus. Approaches included (1) quantitative systems pharmacology modeling to predict dose-response relationships, (2) dose-response modeling and model-based meta-analysis for dose selection and efficacy comparisons, (3) population pharmacokinetics (PKs) modeling to characterize PKs and quantify population variability in PK parameters, (4) regression modeling to evaluate ertugliflozin dose-proportionality and the impact of uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A9 genotype on ertugliflozin PKs, and (5) physiologically-based PK modeling to assess the risk of UGT-mediated drug-drug interactions. These end-to-end MIDD approaches for ertugliflozin facilitated decision making, resulted in time/cost savings, and supported registration and labeling.

Meta-Analysis of Noncompartmental Pharmacokinetic Parameters of Ertugliflozin to Evaluate Dose Proportionality and UGT1A9 Polymorphism Effect on Exposure.

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, is primarily metabolized via glucuronidation by the uridine 5'-diphospho-glucuronosyltransferase (UGT) isoform UGT1A9. This noncompartmental meta-analysis of ertugliflozin pharmacokinetics evaluated the relationship between ertugliflozin exposure and dose, and the effect of UGT1A9 genotype on ertugliflozin exposure. Pharmacokinetic data from 25 phase 1 studies were pooled. Structural models for dose proportionality described the relationship between ertugliflozin area under the plasma concentration-time curve (AUC) or maximum observed plasma concentration (Cmax ) and dose. A structural model for the UGT1A9 genotype described the relationship between ertugliflozin AUC and dose, with genotype information on 3 UGT1A9 polymorphisms (UGT1A9-2152, UGT1A9*3, UGT1A9*1b) evaluated as covariates from the full model. Ertugliflozin AUC and Cmax increased in a dose-proportional manner over the dose range of 0.5-300 mg, and population-predicted AUC and Cmax values for the 5- and 15-mg ertugliflozin tablets administered in the fasted state demonstrated good agreement with the observed data. The largest change in ertugliflozin AUC was in subjects carrying the UGT1A9*3 heterozygous variant, with population-predicted AUC (90% confidence interval) values of 485 ng·h/mL (458 to 510 ng·h/mL) and 1560 ng·h/mL (1480 to 1630 ng·h/mL) for ertugliflozin 5 and 15 mg, respectively, compared with 436 ng·h/mL (418 to 455 ng·h/mL) and 1410 ng·h/mL (1350 to 1480 ng·h/mL), respectively, in wild-type subjects. Overall, the mean effects of the selected UGT1A9 variants on ertugliflozin AUC were within ±10% of the wild type. UGT1A9 genotype did not have any clinically meaningful effects on ertugliflozin exposure in healthy subjects. No ertugliflozin dose adjustment would be required in patients with the UGT1A9 variants assessed in this study.

Population Pharmacokinetic Model for Ertugliflozin in Healthy Subjects and Patients With Type 2 Diabetes Mellitus.

Ertugliflozin is a selective sodium-glucose cotransporter 2 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). A population pharmacokinetic (popPK) model was developed to characterize the pharmacokinetics (PK) of ertugliflozin and quantify the influence of intrinsic (eg, body weight, age, sex, race, estimated glomerular filtration rate [eGFR], T2DM) and extrinsic (eg, food) covariates on the PK parameters of ertugliflozin. The analysis was conducted using data from 15 clinical studies (phases 1-3) enrolling healthy subjects and patients with T2DM, which included 13,691 PK observations from 2276 subjects and was performed using nonlinear mixed-effects modeling. A 2-compartment popPK model with first-order absorption and a lag time and first-order elimination, described the plasma concentration-time profile of ertugliflozin after single and multiple dosing in healthy subjects and in patients with T2DM. Apparent clearance increased with increasing body weight and eGFR, was slightly lower in patients with T2DM and females, and was slightly higher in Asians. Apparent central volume of distribution increased with increasing body weight and was higher in females and Asians. Administration of ertugliflozin with food decreased the absorption rate constant (ka ) and relative bioavailability (F1) compared with fasted. When ertugliflozin was administered without regard to food, estimates of ka and F1 were similar to those for administration with food. The popPK model successfully characterized ertugliflozin exposure in healthy subjects and patients with T2DM. None of the covariates evaluated had a clinically relevant effect on ertugliflozin PK.

Bioequivalence of Metformin in Ertugliflozin/Metformin Fixed-Dose Combination Tablets to Canadian-Sourced Metformin Coadministered With Ertugliflozin Under Fasted and Fed States.

A fixed-dose combination (FDC) product of a selective sodium-glucose cotransporter 2 inhibitor ertugliflozin and immediate-release metformin is approved for type 2 diabetes mellitus in the United States, European Union countries, Canada, and other countries. Two studies were conducted to assess the bioequivalence of metformin in the ertugliflozin/metformin FDC tablets to the corresponding doses of Canadian-sourced metformin (Glucophage) coadministered with ertugliflozin. Both studies were phase 1 randomized, open-label, 2-period, single-dose crossover studies (n = 32) in which healthy subjects received an ertugliflozin/metformin FDC tablet (2.5/500 mg or 7.5/850 mg) and the respective doses of the individual components (ertugliflozin coadministered with Canadian-sourced metformin) under fasted (n = 18) or fed (n = 14) conditions. Blood samples were collected 72 hours postdose to determine metformin concentrations. The 90% confidence intervals were within the bioequivalence acceptance criteria for the adjusted geometric mean ratios (FDC:coadministered) for metformin area under the plasma concentration-time curve from time zero to time t, where t is the last point with a measurable concentration and peak observed plasma concentration for both dose strengths under fasted and fed conditions. All study medications were well tolerated. Bioequivalence was demonstrated for the metformin component of the ertugliflozin/metformin FDC tablets and the corresponding doses of the Canadian-sourced metformin coadministered with ertugliflozin.

Neuroligin 2 regulates absence seizures and behavioral arrests through GABAergic transmission within the thalamocortical circuitry.

Epilepsy and autism spectrum disorders (ASD) are two distinct brain disorders but have a high rate of co-occurrence, suggesting shared pathogenic mechanisms. Neuroligins are cell adhesion molecules important in synaptic function and ASD, but their role in epilepsy remains unknown. In this study, we show that Neuroligin 2 (NLG2) knockout mice exhibit abnormal spike and wave discharges (SWDs) and behavioral arrests characteristic of absence seizures. The anti-absence seizure drug ethosuximide blocks SWDs and rescues behavioral arrests and social memory impairment in the knockout mice. Restoring GABAergic transmission either by optogenetic activation of the thalamic reticular nucleus (nRT) presynaptic terminals or postsynaptic NLG2 expression in the thalamic neurons reduces the SWDs and behavioral arrests in the knockout mice. These results indicate that NLG2-mediated GABAergic transmission at the nRT-thalamic circuit represents a common mechanism underlying both epileptic seizures and ASD.

Coexisting attractors in the context of cross-scale population dynamics: measles in London as a case study.

Patterns of measles infection in large urban populations have long been considered the paradigm of synchronized nonlinear dynamics. Indeed, recurrent epidemics appear approximately mass-action despite underlying heterogeneity. However, using a subset of rich, newly digitized mortality data (1897-1906), we challenge that proposition. We find that sub-regions of London exhibited a mixture of simultaneous annual and biennial dynamics, while the aggregate city-level dynamics appears firmly annual. Using a simple stochastic epidemic model and maximum-likelihood inference methods, we show that we can capture this observed variation in periodicity. We identify agreement between theory and data, indicating that both changes in periodicity and epidemic coupling between regions can follow relatively simple rules; in particular we find local variation in seasonality drives periodicity. Our analysis underlines that multiple attractors can coexist in a strongly mixed population and follow theoretical predictions.

Bioequivalence of Ertugliflozin/Metformin Fixed-Dose Combination Tablets and Coadministration of Respective Strengths of Individual Components.

A fixed-dose combination (FDC) of ertugliflozin, a selective sodium-glucose cotransporter 2 inhibitor, and immediate-release metformin is approved for the treatment of type 2 diabetes mellitus in the United States and European Union. Four open-label, randomized, 2-period, single-dose, crossover studies were conducted under fasted conditions in healthy subjects to demonstrate bioequivalence of the ertugliflozin/metformin FDC tablets and coadministration of the individual components at respective strengths. In each study, 32 or 34 subjects received an ertugliflozin/metformin FDC tablet (2.5 mg/500 mg, 7.5 mg/850 mg, or 7.5 mg/1000 mg) and the respective doses of individual components (ertugliflozin with US- or EU-sourced metformin [Glucophage]). Plasma samples for ertugliflozin and metformin concentrations were collected for 72 hours in each period. For both ertugliflozin and metformin, the 90% confidence intervals for the adjusted geometric mean ratio (FDC : coadministration) for area under the plasma concentration-time profile from time zero extrapolated to infinity and maximum observed plasma concentration were within acceptance criteria for bioequivalence. The majority of adverse events were mild in intensity. The studies demonstrated that each strength of FDC tablet is bioequivalent to respective doses of coadministered individual components, supporting that safety and efficacy can be bridged to the individual components used in phase 3 studies evaluating ertugliflozin in combination with metformin.

Bioequivalence of Ertugliflozin/Sitagliptin Fixed-Dose Combination Tablets and Coadministration of Respective Strengths of Individual Components.

A fixed-dose combination (FDC) tablet of ertugliflozin, a selective inhibitor of sodium-glucose cotransporter 2, and sitagliptin, a dipeptidyl peptidase-4 inhibitor, was developed for the treatment of patients with type 2 diabetes mellitus. Four studies were conducted under fasted conditions to demonstrate bioequivalence of ertugliflozin/sitagliptin FDC tablets and individual components at respective strengths when coadministered in healthy subjects. All studies had open-label, randomized, 2-period, 2-sequence, single-dose crossover designs. In each study 18 or 19 subjects were enrolled and received an ertugliflozin/sitagliptin FDC tablet (5 mg/50 mg, 5 mg/100 mg, 15 mg/50 mg, or 15 mg/100 mg) and corresponding strengths of ertugliflozin and sitagliptin coadministered as individual components. For both ertugliflozin and sitagliptin, the 90%CIs for the ratio (FDC:coadministration) of geometric means for area under the plasma concentration-time profile from time 0 extrapolated to infinite time, and maximum observed plasma concentration, were within acceptance criteria for bioequivalence (80% to 125%). All adverse events were mild in intensity. The 4 studies demonstrated that each strength of FDC tablet is bioequivalent to the respective dose of coadministered individual components. This indicates that the known efficacy and tolerability of ertugliflozin and sitagliptin when coadministered can be translated to the use of a FDC formulation.

A PK/PD study comparing twice-daily to once-daily dosing regimens of ertugliflozin in healthy subjects
.

OBJECTIVE: Ertugliflozin is approved in the US and European Union as a stand-alone product for adults with type 2 diabetes mellitus as once daily (QD) dosing. The approved fixed-dose combination (FDC) of ertugliflozin and immediate-release metformin is dosed twice daily (BID). This study assessed steady-state pharmacokinetics (PK; area under the concentration-time curve over 24 hours (AUC24)) and pharmacodynamics (PD; urinary glucose excretion over 24 hours (UGE24)) for ertugliflozin 5 and 15 mg total daily doses administered BID or QD. MATERIALS AND METHODS: In this open-label, two-cohort, randomized, multiple-dose, crossover study, healthy subjects received ertugliflozin 2.5 mg BID and 5 mg QD (n = 28) or ertugliflozin 7.5 mg BID and 15 mg QD (n = 22) for 6 days. Plasma and urine samples were collected for 24 hour post morning dose on day 6 in each period. RESULTS: The geometric mean ratio (GMR) (90% CI) of ertugliflozin AUC24 was 100.8% (98.8%, 102.8%) for 2.5 mg BID vs. 5 mg QD, and 99.7% (97.1%, 102.5%) for 7.5 mg BID vs. 15 mg QD. GMR (90% CI) of UGE24 for BID vs. QD administration was 110.2% (103.0%, 117.9%) at a total daily dose of 5 mg, and 102.8% (97.7%, 108.1%) at 15 mg. The 90% CIs of the GMR of AUC24 and UGE24 for BID vs. QD dosing were within the acceptance range for equivalence (80 - 125%) and the prespecified criterion for similarity (70 - 143%), respectively. All treatments were well tolerated. CONCLUSION: There are no clinically meaningful differences in steady-state PK or PD between ertugliflozin BID and QD regimens at total daily doses of 5 and 15 mg, supporting BID administration of ertugliflozin as a component of the ertugliflozin/metformin (immediate-release) FDC.

Assessment of the Drug Interaction Potential of Ertugliflozin With Sitagliptin, Metformin, Glimepiride, or Simvastatin in Healthy Subjects.

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor for the treatment of adults with type 2 diabetes mellitus, is expected to be coadministered with sitagliptin, metformin, glimepiride, and/or simvastatin. Four separate open-label, randomized, single-dose, crossover studies were conducted in healthy adults to assess the potential pharmacokinetic interactions between ertugliflozin 15 mg and sitagliptin 100 mg (n = 12), metformin 1000 mg (n = 18), glimepiride 1 mg (n = 18), or simvastatin 40 mg (n = 18). Noncompartmental pharmacokinetic parameters derived from plasma concentration-time data were analyzed using mixed-effects models to assess interactions. Coadministration of sitagliptin, metformin, glimepiride, or simvastatin with ertugliflozin had no effect on area under the plasma concentration-time profile from time 0 to infinity (AUCinf ) or maximum observed plasma concentration (Cmax ) of ertugliflozin (per standard bioequivalence boundaries, 80% to 125%). Similarly, ertugliflozin did not have any impact on AUCinf or Cmax of sitagliptin, metformin, or glimepiride. AUCinf for simvastatin (24%) and simvastatin acid (30%) increased slightly after coadministration with ertugliflozin and was not considered clinically relevant. All treatments were well tolerated. The lack of clinically meaningful pharmacokinetic interactions demonstrates that ertugliflozin can be coadministered safely with sitagliptin, metformin, glimepiride, or simvastatin without any need for dose adjustment.

Effect of Food on the Pharmacokinetics of Ertugliflozin and Its Fixed-Dose Combinations Ertugliflozin/Sitagliptin and Ertugliflozin/Metformin.

Ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, is approved in the United States and European Union for the treatment of type 2 diabetes in adults, both as monotherapy and as part of fixed-dose combination (FDC) therapies with either sitagliptin or immediate-release metformin. The effect of a standard, high-fat breakfast on the pharmacokinetics of the highest strengths of ertugliflozin monotherapy (15 mg), ertugliflozin/sitagliptin FDC (15-/100-mg), and ertugliflozin/metformin FDC (7.5-/1000-mg) tablets was evaluated. In 3 separate open-label, 2-period, 2-sequence, single-dose, crossover studies, 14 healthy subjects per study were randomized to receive either ertugliflozin monotherapy or FDC tablets comprising ertugliflozin and sitagliptin or ertugliflozin and metformin under fasted and fed (or vice versa) conditions. Food did not meaningfully affect the pharmacokinetics of ertugliflozin, sitagliptin, or metformin. For FDCs, the effect of food was consistent with that described for individual components. All treatments were well tolerated. Ertugliflozin and ertugliflozin/sitagliptin FDC tablets can be administered without regard to meals. As metformin is administered with meals because of its gastrointestinal side effects, the ertugliflozin/metformin FDC should also be administered with meals.

Pharmacokinetics of Single-dose Ertugliflozin in Patients With Hepatic Impairment.

PURPOSE: Ertugliflozin, an oral, highly selective inhibitor of the sodium-glucose cotransporter 2, is approved in the United States and the European Union for the treatment of adults with type 2 diabetes mellitus. Hepatic impairment may affect, to varying degrees, the absorption, metabolism, and excretion of drugs and may be associated with a lower plasma protein binding compared with that in healthy individuals. This study was conducted to assess the effect of hepatic impairment on the pharmacokinetic (PK), safety, and tolerability profiles of ertugliflozin after administration of a single, 15-mg oral dose. METHODS: This was a Phase I, open-label, single-dose study in healthy individuals (n = 8) and those with moderate hepatic impairment (n = 8). Eligible participants were men or women aged 18 to 75years with a body mass index of 18.0 to 40.5 kg/m2. Healthy individuals had normal hepatic function; patients with hepatic impairment had a Child-Pugh score of 7 to 9 points (moderate hepatic impairment). Blood samples were collected before dosing and during 96hours after dosing for evaluation of PK parameters. Adverse events were monitored throughout the study. FINDINGS: The adjusted least squares geometric meanratios for total ertugliflozin AUC0-∞ and Cmax inpatients with moderate hepatic impairment comparedwith healthy individuals were 87.4% (90% CI, 68.1%-112.2%) and 78.7% (90% CI, 65.7%-94.2%), respectively. The AUC0-∞ and Cmax for unbound ertugliflozin were also similar between patients with moderate hepatic impairment and healthy individuals. Mean half-life estimates for ertugliflozin were similar (14.6vs 13.8 hours) in patients with moderate hepatic impairment and healthy individuals. The number of participants with all-causality treatment-emergent adverse events was similar for both groups (2 of 8 patients with moderate hepatic impairment and 3 of 8 healthy individuals). IMPLICATIONS: Moderate hepatic impairment had no clinically relevant effect on the PK and safety profiles of ertugliflozin. The results of this study support a recommendation for no dose adjustment of ertugliflozin in patients with mild or moderate hepatic impairment. Ertugliflozin was well tolerated when administered tohealthy individuals and patients with moderate hepatic impairment. ClinicalTrials.gov identifier: NCT02115347.

Novel Application of the Two-Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin.

Ertugliflozin, a sodium glucose cotransporter-2 inhibitor, is approved in the United States for treatment of type 2 diabetes mellitus. A novel two-period study design with 14 C microtracer dosing in each period was used to determine absolute oral bioavailability (F) and fraction absorbed (Fa ) of ertugliflozin. Eight healthy adult men received 100-µg i.v. 14 C-ertugliflozin (400 nCi) dose 1 h after a 15-mg oral unlabeled ertugliflozin dose (period 1), followed by 100 µg 14 C-ertugliflozin orally along with 15 mg oral unlabeled ertugliflozin (period 2). Unlabeled ertugliflozin plasma concentrations were determined using high-performance liquid-chromatography tandem mass spectrometry (HPLC-MS/MS). 14 C-ertugliflozin plasma concentrations were determined using HPLC-accelerator mass spectrometry (AMS) and 14 C urine concentrations were determined using AMS. F ((area under the curve (AUC)p.o. /14 C-AUCi.v. )*(14 C-Dosei.v. /Dosep.o. )) and Fa ((14 C_Total_Urinep.o. /14 C_Total_Urinei.v. )* (14 C-Dosei.v. /14 C-Dosep.o. )) were estimated. Estimates of F and Fa were 105% and 111%, respectively. Oral absorption of ertugliflozin was complete under fasted conditions and F was ∼100%. Ertugliflozin was well tolerated.

Recent advances in spectroelectrochemistry.

The integration of two quite different techniques, conventional electrochemistry and spectroscopy, into spectroelectrochemistry (SEC) provides a complete description of chemically driven electron transfer processes and redox events for different kinds of molecules and nanoparticles. SEC possesses interdisciplinary advantages and can further expand the scopes in the fields of analysis and other applications, emphasizing the hot issues of analytical chemistry, materials science, biophysics, chemical biology, and so on. Considering the past and future development of SEC, a review on the recent progress of SEC is presented and selected examples involving surface-enhanced Raman scattering (SERS), ultraviolet-visible (UV-Vis), near-infrared (NIR), Fourier transform infrared (FTIR), fluorescence, as well as other SEC are summarized to fully demonstrate these techniques. In addition, the optically transparent electrodes and SEC cell design, and the typical applications of SEC in mechanism study, electrochromic device fabrication, sensing and protein study are fully introduced. Finally, the key issues, future perspectives and trends in the development of SEC are also discussed.

Systematic Screening of Chemokines to Identify Candidates to Model and Create Ectopic Lymph Node Structures for Cancer Immunotherapy.

The induction of ectopic lymph node structures (ELNs) holds great promise to augment immunotherapy against multiple cancers including metastatic melanoma, in which ELN formation has been associated with a unique immune-related gene expression signature composed of distinct chemokines. To investigate the therapeutic potential of ELNs induction, preclinical models of ELNs are needed for interrogation of these chemokines. Computational models provide a non-invasive, cost-effective method to investigate leukocyte trafficking in the tumor microenvironment, but parameterizing such models is difficult due to differing assay conditions and contexts among the literature. To better achieve this, we systematically performed microchemotaxis assays on purified immune subsets including human pan-T cells, CD4+ T cells, CD8+ T cells, B cells, and NK cells, with 49 recombinant chemokines using a singular technique, and standardized conditions resulting in a dataset representing 238 assays. We then outline a groundwork computational model that can simulate cellular migration in the tumor microenvironment in response to a chemoattractant gradient created from stromal, lymphoid, or antigen presenting cell interactions. The resulting model can then be parameterized with standardized data, such as the dataset presented here, and demonstrates how a computational approach can help elucidate developing ELNs and their impact on tumor progression.

Meta-analysis of gender differences in efficacy outcomes for HIV-positive subjects in randomized controlled clinical trials of antiretroviral therapy (2000-2008).

Women are often underrepresented in randomized clinical trials (RCT) of HIV-1 drugs. As a result, determining whether women have different virologic outcomes compared to men is not always possible because the gender-related analyses usually lack statistical power. To address this important public health concern, the Food and Drug Administration's (FDA) Division of Antiviral Products (DAVP) created a database including 20,328 HIV-positive subjects from 40 RCTs in 18 New Drug Applications (NDAs) submitted to the FDA between 2000 and 2008. These RCTs were conducted for at least 48 weeks in duration and were used to support approval of new molecular entity, new formulation, or major label change. To delineate potential gender differences in antiretroviral treatment (ART), we evaluated the percentage of subjects with HIV RNA less than 50 copies per milliliter at 48 weeks. Analyses of the database represent the most systematic review of gender-related ART efficacy data to date. Overall, the meta-analyses did not demonstrate statistically or clinically significant gender differences in virologic outcome at week 48. However, the corresponding subgroup analyses appear to show several statistically significant gender differences favoring males.