Several antibody-drug conjugates (ADC) showing strong clinical responses in solid tumors target high expression antigens (HER2, TROP2, Nectin-4, and folate receptor alpha/FRa). Highly expressed tumor antigens often have significant low-level expression in normal tissues, resulting in the potential for target-mediated drug disposition (TMDD) and increased clearance. However, ADCs often do not cross-react with normal tissue in animal models used to test efficacy (typically mice), and the impact of ADC binding to normal tissue antigens on tumor response remains unclear. An antibody that cross-reacts with human and murine FRa was generated and tested in an animal model where the antibody/ADC bind both human tumor FRa and mouse FRa in normal tissue. Previous work has demonstrated that a "carrier" dose of unconjugated antibody can improve the tumor penetration of ADCs with high expression target-antigens. A carrier dose was employed to study the impact on cross-reactive ADC clearance, distribution, and efficacy. Co-administration of unconjugated anti-FRa antibody with the ADC-improved efficacy, even in low expression models where co-administration normally lowers efficacy. By reducing target-antigen-mediated clearance in normal tissue, the coadministered antibody increased systemic exposure, improved tumor tissue penetration, reduced target-antigen-mediated uptake in normal tissue, and increased ADC efficacy. However, payload potency and tumor antigen saturation are also critical to efficacy, as shown with reduced efficacy using too high of a carrier dose. The judicious use of higher antibody doses, either through lower DAR or carrier doses, can improve the therapeutic window by increasing efficacy while lowering target-mediated toxicity in normal tissue.

The Ki values for probenecid inhibition of 2ME2 glucuronide formation, when compared to maximum probenecid plasma concentrations anticipated clinically, indicate that probenecid co-administration has the potential to augment systemic plasma levels of 2ME2 after oral dosage in humans.

Recessive mutations in multiple epidermal growth factor‐like domains 10 (MEGF10) underlie a rare congenital muscle disease known as MEGF10 myopathy. MEGF10 and its Drosophila homolog Draper (Drpr) are transmembrane receptors expressed in muscle and glia. Drpr deficiency is known to result in muscle abnormalities in flies. In the current study, flies that ubiquitously overexpress Drpr, or mouse Megf10, display developmental arrest. The phenotype is reproduced with overexpression in muscle, but not in other tissues, and with overexpression during intermediate stages of myogenesis, but not in myoblasts. We find that tubular muscle subtypes are particularly sensitive to Megf10/Drpr overexpression. Complementary genetic analyses show that Megf10/Drpr and Notch may interact to regulate myogenesis. Our findings provide a basis for investigating MEGF10 in muscle development using Drosophila.

Objectives Resveratrol is a naturally occurring antioxidant with therapeutic potential in prevention and treatment of neoplastic disease and other human disorders. However, net clearance of resveratrol in humans is very high, mainly due to glucuronide conjugation. This leads to extensive presystemic extraction and low plasma concentrations after oral dosage. The present study evaluated the effect of probenecid, an inhibitor of glucuronide conjugation, on resveratrol metabolism in vitro. Methods Biotransformation of resveratrol to its 3‐O‐glucuronide and 4′‐O‐glucuronide conjugates was studied in vitro using human liver microsomal preparations. The mechanism and inhibitory potency of probenecid were evaluated based on a mixed competitive‐noncompetitive inhibition model. Key findings Probenecid inhibition of resveratrol 3‐O‐glucuronidation was predominantly noncompetitive, with an inhibition constant (Ki) averaging 3.1 mm. Conclusions The ratio of in vivo maximum concentration of probenecid [I] during usual clinical use to the in vitro Ki value ([I]/Ki) exceeds the boundary value of 0.1, used by regulatory agencies to identify the possibility of clinical drug interactions. This finding, together with the known property of probenecid as an inhibitor of glucuronide conjugation in humans, suggests that probenecid could serve as a pharmacokinetic boosting agent to enhance systemic exposure to resveratrol in humans.

BackgroundsThe number of hip fractures, the most common complication of osteoporosis, has increased rapidly over the past decades. The goal of this study is to estimate the avoidable burden of certain modifiable risk factor of the condition using the Generalized Impact Fraction (GIF) model, which has been suggested and used by epidemiologists to overcome the drawbacks associated with the use of Attributable Fraction index. In addition to preventing a risk factor or the avoidable fraction of burden, this index can also calculate the change in the burden, when a risk factor is altered.MethodsInternational databases were searched through PubMed, CINAHLD, Embase using OVID and Google scholar. National resources were searched through IranDoc, IranMedex, SID and Journal sites. Other resources include abstract books and articles sent to the IOF congress. The following search strategy was used: (“Osteoporotic fracture” OR “Fragility Hip fracture” OR “Calcium” OR “vitamin D” OR “BMI” OR “lean body weight” OR “Physical activity” OR “exercise” OR “Smoke”) AND (“prevalence” OR “incidence” OR “relative risk”) and limited to “humans.”ResultsWith regards to different scenarios already explained in modifying the studied risk factors, the greatest impact in reducing the prevalence of risk factors on osteoporotic hip fractures, was seen in low serum vitamin D levels, low physical activity and low intake of calcium and vitamin D, respectively. According to the fact that interventions for low serum vitamin D and low intake of calcium and vitamin D, are related to each other, it can be concluded that implementing interventions to change these two risk factors, in the easy, moderate and difficult scenarios, would result in approximately a 5%, 11% and 17% decrease in the burden of osteoporotic hip fractures, respectively. The addition of interventions addressing low physical activity in the easy, moderate and difficult scenarios, an 8%, 21% and 35% reduction in the burden of osteoporotic hip fractures would be reported, respectively.ConclusionImproving serum vitamin D levels, recommending the consumption of calcium and vitamin D supplementations and advocating physical activity are the most effective interventions to reduce the risk of osteoporotic hip fractures.