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Antibody–drug conjugates (ADCs) combine the specificity of monoclonal antibodies with the potency of highly cytotoxic agents, potentially reducing the severity of side effects by preferentially targeting their payload to the tumour site. ADCs are being increasingly used in combination with other agents, including as first-line cancer therapies. As the technology to produce these complex therapeutics has matured, many more ADCs have been approved or are in late-phase clinical trials. The diversification of antigenic targets as well as bioactive payloads is rapidly broadening the scope of tumour indications for ADCs. Moreover, novel vector protein formats as well as warheads targeting the tumour microenvironment are expected to improve the intratumour distribution or activation of ADCs, and consequently their anticancer activity for difficult-to-treat tumour types. However, toxicity remains a key issue in the development of these agents, and better understanding and management of ADC-related toxicities will be essential for further optimization. This Review provides a broad overview of the recent advances and challenges in ADC development for cancer treatment.Antibody–drug conjugates (ADCs) combine the specificity of monoclonal antibodies with the potency of cytotoxic agents. The technology to develop these agents has improved in past years, but toxicity remains a key issue. This Review provides a broad overview of the recent advances and challenges in ADC development for cancer treatment.

Bispecific antibodies (bsAbs) enable novel mechanisms of action and/or therapeutic applications that cannot be achieved using conventional IgG-based antibodies. Consequently, development of these molecules has garnered substantial interest in the past decade and, as of the end of 2023, 14 bsAbs have been approved: 11 for the treatment of cancer and 3 for non-oncology indications. bsAbs are available in different formats, address different targets and mediate anticancer function via different molecular mechanisms. Here, we provide an overview of recent developments in the field of bsAbs for cancer therapy. We focus on bsAbs that are approved or in clinical development, including bsAb-mediated dual modulators of signalling pathways, tumour-targeted receptor agonists, bsAb–drug conjugates, bispecific T cell, natural killer cell and innate immune cell engagers, and bispecific checkpoint inhibitors and co-stimulators. Finally, we provide an outlook into next-generation bsAbs in earlier stages of development, including trispecifics, bsAb prodrugs, bsAbs that induce degradation of tumour targets and bsAbs acting as cytokine mimetics.Bispecific antibodies (bsAbs) can mediate therapeutic effects beyond those of natural monospecific antibodies. This Review provides an overview of recent developments in the field of bsAbs for cancer therapy and an outlook into next-generation bsAbs in earlier stages of development.

The asymptotic safety scenario in gravity is accessed within the systematic vertex expansion scheme for functional renormalisation group flows put forward in Christiansen et al. (Phys Lett B 728:114, 2014), Christiansen et al. (Phy Rev D 93:044036, 2016), and implemented in Christiansen et al. (Phys Rev D 92:121501, 2015) for propagators and three-point functions. In the present work this expansion scheme is extended to the dynamical graviton four-point function. For the first time, this provides us with a closed flow equation for the graviton propagator: all vertices and propagators involved are computed from their own flows. In terms of a covariant operator expansion the current approximation gives access to Λ, R, R2 as well as Rμν2 and higher derivative operators. We find a UV fixed point with three attractive and two repulsive directions, thus confirming previous studies on the relevance of the first three operators. In the infrared we find trajectories that correspond to classical general relativity and further show non-classical behaviour in some fluctuation couplings. We also find signatures for the apparent convergence of the systematic vertex expansion. This opens a promising path towards establishing asymptotically safe gravity in terms of apparent convergence.

The term bispecific antibody (bsAb) is used to describe a large family of molecules designed to recognize two different epitopes or antigens. BsAbs come in many formats, ranging from relatively small proteins, merely consisting of two linked antigen-binding fragments, to large immunoglobulin G (IgG)-like molecules with additional domains attached. An attractive bsAb feature is their potential for novel functionalities — that is, activities that do not exist in mixtures of the parental or reference antibodies. In these so-called obligate bsAbs, the physical linkage of the two binding specificities creates a dependency that can be temporal, with binding events occurring sequentially, or spatial, with binding events occurring simultaneously, such as in linking an effector to a target cell. To date, more than 20 different commercialized technology platforms are available for bsAb creation and development, 2 bsAbs are marketed and over 85 are in clinical development. Here, we review the current bsAb landscape from a mechanistic perspective, including a comprehensive overview of the pipeline.Bispecific antibodies — a large family of molecules that are designed to recognize two different epitopes or antigens — come in many formats and can have the potential for novel functionalities that are not provided by mixtures of monoclonal antibodies. This article reviews the current bispecific antibody landscape from a mechanistic perspective, including a comprehensive overview of the pipeline.

In early type 2 diabetes, the strategy of “induction” with short-term intensive insulin therapy followed by “maintenance” with metformin can stabilize pancreatic beta-cell function in some patients but not others. We thus sought to elucidate determinants of sustained stabilization of beta-cell function. In this secondary analysis of ClinicalTrials.Gov NCT02192424, adults with ≤5-years diabetes duration were randomized to 3-weeks induction insulin therapy (glargine/lispro) followed by metformin maintenance either with or without intermittent 2-week courses of insulin every 3-months for 2-years. Sustained stabilization (higher beta-cell function at 2-years than at baseline) was achieved in 55 of 99 participants. Independent predictors of sustained stabilization were the change in beta-cell function during induction and changes in hepatic insulin resistance and alanine aminotransferase during maintenance. Thus, initial reversibility of beta-cell dysfunction during induction and subsequent preservation of hepatic insulin sensitivity during maintenance are associated with sustained stabilization of beta-cell function following short-term insulin and metformin. ClinicalTrials.Gov NCT02192424 In early type 2 diabetes, “induction” with short-term insulin therapy followed by “maintenance” with metformin can stabilize beta-cell function. The authors show that initial reversibility of beta-cell dysfunction followed by preserved hepatic insulin sensitivity determine sustained stabilization.

The development dynamics and self-organization of glandular branched epithelia is of utmost importance for our understanding of diverse processes ranging from normal tissue growth to the growth of cancerous tissues. Using single primary murine pancreatic ductal adenocarcinoma (PDAC) cells embedded in a collagen matrix and adapted media supplementation, we generate organoids that self-organize into highly branched structures displaying a seamless lumen connecting terminal end buds, replicating in vivo PDAC architecture. We identify distinct morphogenesis phases, each characterized by a unique pattern of cell invasion, matrix deformation, protein expression, and respective molecular dependencies. We propose a minimal theoretical model of a branching and proliferating tissue, capturing the dynamics of the first phases. Observing the interaction of morphogenesis, mechanical environment and gene expression in vitro sets a benchmark for the understanding of self-organization processes governing complex organoid structure formation processes and branching morphogenesis. Pancreatic ductal adenocarcinomas (PDAC) exhibit complex morphologies challenging to capture in organoid models. Here, the authors develop PDAC organoids that can recreate branched structures and, with the use of a minimal mathematical model, shed light to pathways and processes directing the dynamics of self-organization and branching morphogenesis.

Managed reef fish in the Atlantic Ocean of the southeastern United States (SEUS) support a multi-billion dollar industry. There is a broad interest in locating and protecting spawning fish from harvest, to enhance productivity and reduce the potential for overfishing. We assessed spatiotemporal cues for spawning for six species from four reef fish families, using data on individual spawning condition collected by over three decades of regional fishery-independent reef fish surveys, combined with a series of predictors derived from bathymetric features. We quantified the size of spawning areas used by reef fish across many years and identified several multispecies spawning locations. We quantitatively identified cues for peak spawning and generated predictive maps for Gray Triggerfish (Balistes capriscus), White Grunt (Haemulon plumierii), Red Snapper (Lutjanus campechanus), Vermilion Snapper (Rhomboplites aurorubens), Black Sea Bass (Centropristis striata), and Scamp (Mycteroperca phenax). For example, Red Snapper peak spawning was predicted in 24.7-29.0°C water prior to the new moon at locations with high curvature in the 24-30 m depth range off northeast Florida during June and July. External validation using scientific and fishery-dependent data collections strongly supported the predictive utility of our models. We identified locations where reconfiguration or expansion of existing marine protected areas would protect spawning reef fish. We recommend increased sampling off southern Florida (south of 27° N), during winter months, and in high-relief, high current habitats to improve our understanding of timing and location of reef fish spawning off the southeastern United States.

BACKGROUND AND AIMS: The knowledge of soil water storage is vital for rational agricultural management, and in soil-plant-water relations. This study was conducted to evaluate the temporal processes of soil water status of a sugarcane field under residue management during the 2011/2012 and 2012/2013 growing seasons in southern Brazil. METHODS: Soil water storage (SWS) and matric potential (Ψ) were monitored in the 0–10 and 10–20 and 40–60 cm layers using time domain reflectometer sensors and tensiometers while precipitation (P) and potential crop evapotranspiration (ET) were obtained using rainguage and daily weather data. RESULTS: There was significant temporal variation of soil water status with soil depths. SWS was lower while matric potential was higher in no mulch treatment than in mulched treatment in both growing seasons. SWS cross-correlated with other variables, however, results were not the same for the different soil depths and treatments. Classical regression of SWS from combinations of log (Ψ), ET and P gave satisfactory results, however state-time analysis was better with higher R²values and incorporated errors. CONCLUSIONS: State-time analysis, combined with state-space could be a useful tool for good predictions of soil water status. Residue mulching influenced soil water status, thus proved to be a sustainable soil management practice.

Introduction: In breast conserving surgery (BCS), 15–40% of patients must undergo a second surgery (re-operation) due to post-surgical cancer-positive margins. Efficient intraoperative assessment of lumpectomy margins can reduce this rate. Classical methods like specimen radiography and ultrasound have limitations. The SHIELD study was conducted to prospectively quantify the reduction of the re-operation rate when the Histolog® Scanner (HLS) confocal microscope is intraoperatively used by surgeons for the margin assessment. Methods: 50 patients undergoing BCS were enrolled and analyzed. Lumpectomy margins were intraoperatively assessed by surgeons with the HLS in addition to standard-of-care techniques. Detected positive margins triggered the excision of additional recuts during the same surgery. Subsequent re-operation and detection rates were compared to historical data and pathology gold standards, respectively. Results: The study population included 32% of patients with pure invasive cancer(s), 18% with pure DCIS and 50% with invasive cancer(s) mixed with DCIS. The overall mean age was 63.56. All population features were statistically similar to the historical control (p > 0.1). Notably, 80.95% sensitivity and 99.53% specificity for breast cancer detection at the margin were intraoperatively achieved by the surgeons using the HLS. The re-operation rate in SHIELD was 10% (5/50) while the historical control was 30% (12/40) corresponding to a 67% reduction (p = 0.016). Notably, 17/21 positive margins were intraoperatively identified with the HLS while 4/21 were detected with standard-of-care techniques. Conclusions: The intraoperative use of the Histolog Scanner confocal microscope provides a significant increase in detection rates of lumpectomy positive margins resulting in a substantial reduction in the re-operation rate, while preserving specimen integrity without impact on histopathology assessment.

In vitro human tissue engineered human blood vessels (TEBV) that exhibit vasoactivity can be used to test human toxicity of pharmaceutical drug candidates prior to pre-clinical animal studies. TEBVs with 400–800 μM diameters were made by embedding human neonatal dermal fibroblasts or human bone marrow-derived mesenchymal stem cells in dense collagen gel. TEBVs were mechanically strong enough to allow endothelialization and perfusion at physiological shear stresses within 3 hours after fabrication. After 1 week of perfusion, TEBVs exhibited endothelial release of nitric oxide, phenylephrine-induced vasoconstriction and acetylcholine-induced vasodilation, all of which were maintained up to 5 weeks in culture. Vasodilation was blocked with the addition of the nitric oxide synthase inhibitor L-N G -Nitroarginine methyl ester (L-NAME). TEBVs elicited reversible activation to acute inflammatory stimulation by TNF-α which had a transient effect upon acetylcholine-induced relaxation and exhibited dose-dependent vasodilation in response to caffeine and theophylline. Treatment of TEBVs with 1 μM lovastatin for three days prior to addition of Tumor necrosis factor – α (TNF-α) blocked the injury response and maintained vasodilation. These results indicate the potential to develop a rapidly-producible, endothelialized TEBV for microphysiological systems capable of producing physiological responses to both pharmaceutical and immunological stimuli.