Rapid conjugation of antibodies to toxins to select candidates for the development of anticancer Antibody-Drug conjugates (ADcs)

Antibody-Drug Conjugates (ADCs) developed as a targeted treatment approach to deliver toxins directly to cancer cells are one of the fastest growing classes of oncology therapeutics, with eight ADCs and two immunotoxins approved for clinical use. However, selection of an optimum target and payload combination, to achieve maximal therapeutic efficacy without excessive toxicity, presents a significant challenge. We have developed a platform to facilitate rapid and cost-effective screening of antibody and toxin combinations for activity and safety, based on streptavidin-biotin conjugation. For antibody selection, we evaluated internalization by target cells using streptavidin-linked antibodies conjugated to biotinylated saporin, a toxin unable to cross cell membranes. For payload selection, we biotinylated toxins and conjugated them to antibodies linked to streptavidin to evaluate antitumour activity and pre-clinical safety. As proof of principle, we compared trastuzumab conjugated to emtansine via streptavidin-biotin (Trastuzumab-SB-DM1) to the clinically approved trastuzumab emtansine (T-DM1). We showed comparable potency in reduction of breast cancer cell survival in vitro and in growth restriction of orthotopic breast cancer xenografts in vivo. Our findings indicate efficient generation of functionally active ADCs. This approach can facilitate the study of antibody and payload combinations for selection of promising candidates for future ADC development

An Atlas of Human Regulatory T Helper-like Cells Reveals Features of Th2-like Tregs that Support a Tumorigenic Environment

Regulatory T cells (Tregs) play a pivotal role in maintaining immunological tolerance, but they can also play a detrimental role by preventing antitumor responses. Here, we characterized T helper (Th)-like Treg subsets to further delineate their biological function and tissue distribution, focusing on their possible contribution to disease states. RNA sequencing and functional assays revealed that Th2-like Tregs displayed higher viability and autocrine interleukin-2 (IL-2)-mediated activation than other subsets. Th2-like Tregs were preferentially found in tissues rather than circulation and exhibited the highest migratory capacity toward chemokines enriched at tumor sites. These cellular responses led us to hypothesize that this subset could play a role in maintaining a tumorigenic environment. Concurrently, Th2-like Tregs were enriched specifically in malignant tissues from patients with melanoma and colorectal cancer compared to healthy tissue. Overall, our results suggest that Th2-like Tregs may contribute to a tumorigenic environment due to their increased cell survival, higher migratory capacity, and selective T-effector suppressive ability. Graphical Abstrac

The Effect of a Surface Combat Swimming Training Program on Swimming Performance

In this study the effect of a surface combat swimming (sCS) training program on performance in freestyle swimming and sCS was examined. Forty-five officer cadets were divided into three equivalent groups: a control group (CG), a group that was trained only with a swimsuit and fins (SF), and a group that was trained with combat uniform and equipment (UE). Groups SF and UE followed a 60-min training program with sCS for 4 weeks, 4 times per week. Before and after the training program all groups performed 4×50 and 400-m freestyle swimming, 250-m sCS with a uniform and equipment, 350-m with a swimsuit and fins, and 300-m with a swimsuit. The UE group showed improved performance in 4×50-m (mean±SD 14±9 s) and in 250-m sCS (24±14 s) (p <0.01). Both the SF group and the UE group improved in 300-m sCS, in 350-m sCS and in 400-m freestyle (p <0.05). We conclude that the training adaptations seemed to be specific, not only with regard to the activity performed, but also in terms of the actual conditions of an operation, which also include equipment. © 2021 Georg Thieme Verlag. All rights reserved

The Effect of a Surface Combat Swimming Training Program on Swimming Performance

In this study the effect of a surface combat swimming (sCS) training program on performance in freestyle swimming and sCS was examined. Forty-five officer cadets were divided into three equivalent groups: a control group (CG), a group that was trained only with a swimsuit and fins (SF), and a group that was trained with combat uniform and equipment (UE). Groups SF and UE followed a 60-min training program with sCS for 4 weeks, 4 times per week. Before and after the training program all groups performed 4×50 and 400-m freestyle swimming, 250-m sCS with a uniform and equipment, 350-m with a swimsuit and fins, and 300-m with a swimsuit. The UE group showed improved performance in 4×50-m (mean±SD 14±9 s) and in 250-m sCS (24±14 s) (p <0.01). Both the SF group and the UE group improved in 300-m sCS, in 350-m sCS and in 400-m freestyle (p <0.05). We conclude that the training adaptations seemed to be specific, not only with regard to the activity performed, but also in terms of the actual conditions of an operation, which also include equipment. © 2021 Georg Thieme Verlag. All rights reserved

Production and consumption responses to policy interventions in Tanzania's dairy industry

The study uses a partial equilibrium model of Tanzania’s informal dairy value chain to determine the benefits to milk producers and consumers from three policy interventions proposed in the Tanzania Livestock Modernization Initiative (TLMI). Using aggregate time series data to simulate the model, the study finds that from an individual policy perspective, expanding the national herd would produce the largest benefits for producers and consumers; producers would gain over 550 million shillings annually and consumers would gain about 35 shillings per capita. Comparing the other two interventions, consumers would benefit more from a better regulatory environment than from a reduction in cow prices, while producers would benefit more from a reduction in cow prices than from better regulations. If all policies are implemented simultaneously, even greater benefits would be realised; consumer surplus would increase by 85 shillings annually and producer surplus would increase by over one billion shillings in real terms. The results suggest that policy interventions outlined in the TLMI that address supply constraints are critical to developing the country’s dairy industry