Utility of physiologically based pharmacokinetic modeling to predict inter-antibody variability in monoclonal antibody pharmacokinetics in mice.

In this investigation, we tested the hypothesis that a physiologically based pharmacokinetic (PBPK) model incorporating measured metrics of off-target binding can largely explain the inter-antibody variability in monoclonal antibody (mAb) pharmacokinetics (PK). A diverse panel of 83 mAbs was evaluated for PK in wild-type mice and subjected to 10 assays to measure major physiochemical attributes. After excluding for target-mediated elimination and immunogenicity, 56 of the remaining mAbs with an eight-fold variability in the area under the curve (: 1.

Development of in silico models to predict viscosity and mouse clearance using a comprehensive analytical data set collected on 83 scaffold-consistent monoclonal antibodies.

Biologic drug discovery pipelines are designed to deliver protein therapeutics that have exquisite functional potency and selectivity while also manifesting biophysical characteristics suitable for manufacturing, storage, and convenient administration to patients. The ability to use computational methods to predict biophysical properties from protein sequence, potentially in combination with high throughput assays, could decrease timelines and increase the success rates for therapeutic developability engineering by eliminating lengthy and expensive cycles of recombinant protein production and testing. To support development of high-quality predictive models for antibody developability, we designed a sequence-diverse panel of 83 effector functionless IgG1 antibodies displaying a range of biophysical properties, produced and formulated each protein under standard platform conditions, and collected a comprehensive package of analytical data, including in vitro assays and in vivo mouse pharmacokinetics.

Ethnic diversity in treatment response for colorectal cancer: proof of concept for radiomics-driven enrichment trials.

Background: Several barriers hamper recruitment of diverse patient populations in multicenter clinical trials which determine efficacy of new systemic cancer therapies.

Purpose: We assessed if quantitative analysis of computed tomography (CT) scans of metastatic colorectal cancer (mCRC) patients using imaging features that predict overall survival (OS) can unravel the association between ethnicity and efficacy.

Methods: We retrospectively analyzed CT images from 1584 mCRC patients in two phase III trials evaluating FOLFOX ± panitumumab (n = 331, 350) and FOLFIRI ± aflibercept (n = 437, 466) collected from August 2006 to March 2013.

Case series: Traumatic ocular lacerations secondary to pressure washers.

Purpose: Numerous causes of ocular lacerations, including, open globe injuries have been extensively reported but to our knowledge this is first time that pressure washers have been reported to be the culprit. Thus, in this case series we describe the uniqueness of ocular findings secondary to high-power pressure washer injuries that are a result of their mechanistic function.

Observations: Here we report a case series of 3 patients who presented in an emergency department with pain and decreased visual acuity following usage of high-pressure washer machines.

Wintertime Nitrous Oxide Emissions in the San Joaquin Valley of California Estimated from Aircraft Observations.

Nitrous oxide (NO) is a long-lived greenhouse gas that also destroys stratospheric ozone. NO emissions are uncertain and characterized by high spatiotemporal variability, making individual observations difficult to upscale, especially in mixed land use source regions like the San Joaquin Valley (SJV) of California. Here, we calculate spatially integrated NO emission rates using nocturnal and convective boundary-layer budgeting methods.

The role of a suburban forest in controlling vertical trace gas and OH reactivity distributions - a case study for the Seoul metropolitan area.

We present trace gas vertical profiles observed by instruments on the NASA DC-8 and at a ground site during the Korea-US air quality study (KORUS) field campaign in May to June 2016. We focus on the region near the Seoul metropolitan area and its surroundings where both anthropogenic and natural emission sources play an important role in local photochemistry. Integrating ground and airborne observations is the major research goal of many atmospheric chemistry field campaigns.

Engineered IL-21 Cytokine Muteins Fused to Anti-PD-1 Antibodies Can Improve CD8+ T Cell Function and Anti-tumor Immunity.

Inhibitors that block the programmed cell death-1 (PD-1) pathway can potentiate endogenous antitumor immunity and have markedly improved cancer survival rates across a broad range of indications. However, these treatments work for only a minority of patients. The efficacy of anti-PD-1 inhibitors may be extended by cytokines, however, the incorporation of cytokines into therapeutic regimens has significant challenges.

Curcumin in Autoimmune and Rheumatic Diseases.

Over recent decades, many clinical trials on curcumin supplementation have been conducted on various autoimmune diseases including osteoarthritis, type 2 diabetes, and ulcerative colitis patients. This review attempts to summarize the highlights from these clinical trials. The efficacy of curcumin either alone or in conjunction with existing treatment was evaluated.

Omega-3 Fatty Acids in Rheumatic Diseases: A Critical Review.

Many clinical trials of omega-3 fatty acids, supplied as fish oil supplements, have been carried out in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), lupus nephritis, and osteoarthritis (OA) over the past 3 decades. This review attempts to summarize the highlights of these studies to evaluate the clinical efficacy for omega-3 fatty acids to be added alongside existing treatment regimens. A total of 20 clinical trials have been carried out in RA, of which 16 exhibited significant improvements in multiple disease clinical outcomes.

Vehicle Emissions as an Important Urban Ammonia Source in the United States and China.

Ammoniated aerosols are important for urban air quality, but emissions of the key precursor NH are not well quantified. Mobile laboratory observations are used to characterize fleet-integrated NH emissions in six cities in the U.S.

Adult Tph2 knockout mice without brain serotonin have moderately elevated spine trabecular bone but moderately low cortical bone thickness.

Disruption of serotonin synthesis in neurons and the periphery by knockout (KO) of mouse genes for tryptophan hydroxylases (peripheral Tph1 and neuronal Tph2) has been claimed to decrease (Tph2 KO) and increase (Tph1 KO) bone mass. In this report, adult male and female Tph2 KO mice were observed to have elevated spine trabecular bone. Female Tph2 KO mice have reduced midshaft femur cortical bone thickness.

Rosmarinic acid and baicalin epigenetically derepress peroxisomal proliferator-activated receptor γ in hepatic stellate cells for their antifibrotic effect.

Unlabelled: Hepatic stellate cells (HSCs) undergo myofibroblastic transdifferentiation (activation) to participate in liver fibrosis and identification of molecular targets for this cell fate regulation is essential for development of efficacious therapeutic modalities for the disease. Peroxisomal proliferator-activated receptor γ (PPARγ) is required for differentiation of HSCs and its epigenetic repression underlies HSC activation. The herbal prescription Yang-Gan-Wan (YGW) prevents liver fibrosis, but its active ingredients and molecular mechanisms are unknown.

Prophylactic intravenous immunoglobulin during autologous haemopoietic stem cell transplantation for multiple myeloma is not associated with reduced infectious complications.

Patients with multiple myeloma undergoing autologous haemopoietic stem cell transplantation (ASCT) are at high risk for infectious complications. Peri-transplant intravenous immunoglobulin (IVIG) has been used with the aim of reducing these risks. Our retrospective, non-randomised study of peri-transplant IVIG use and effect on infectious complications in 266 ASCTs for myeloma from 2000 to 2009 at a major metropolitan referral centre for haematological malignancies found no difference between those receiving peri-transplant IVIG (0.

Hepatoprotective mechanisms of Yan-gan-wan.

Background And Aims: : A herbal prescription, Yan-gan-wan (YGW), has been known to offer hepatoprotective effects in Asian countries for years. This study investigated its mechanisms of action.

Methods: : The effects of YGW on CCl(4) induced liver damage were tested in mice and cultured hepatocytes.