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Background and objective: Kidney transplant recipients (KTRs) have an increased risk of developing genitourinary cancers, including prostate cancer (PCa), which is expected to become more prevalent due to an aging KTR population. Thus, knowledge of surgical outcomes, including treatment of PCa, within this unique cohort is required. Methods: Data of 62 KTRs undergoing radical prostatectomy (RP) between 2006 and 2023 at nine urologic transplant centers were analyzed. Complications were assessed using the Clavien-Dindo classification. Perioperative outcomes were evaluated, and a follow-up was conducted. Overall survival (OS), biochemical recurrence–free survival (BRFS), and death-censored graft survival were determined via the Kaplan-Meier method and log-rank testing. Key findings and limitations: Overall, 50 open radical retropubic RPs and 12 robot-assisted RPs (RARPs) were included. The intraoperative blood loss was lower after RARP, but operative time was longer. Of the patients, 50% experienced no postoperative complication, and grade ≥3 complications were observed in 14.5%. There was no graft loss related to RP. A histopathologic analysis revealed pN1 in 8.1% and positive surgical margins in 25.8% of the cases. At a median follow-up of 48.5 mo, the median OS was 128 (95% confidence interval [CI] 71.2–184.8) mo, BRFS was 106 (95% CI 55.8; 156.2) mo, and graft survival was 127 (95% CI 66.7–187.3) mo. Limitations include the retrospective design, and variations between groups and centers. Conclusions and clinical implications: Our findings support RP as a feasible and safe treatment option for localized PCa in KTRs with acceptable oncologic outcome. Special care is required in screening and awareness for the risk of understaging. Patient summary: This study analyzed the safety and effectiveness of two prostate cancer surgery methods—open and robot-assisted surgery—in the special group of kidney transplant recipients. Both surgical methods were performed safely with acceptable oncologic outcomes; however, sample size was too small to draw definite conclusions between the two operative methods.

Abstract Exposure to nanoparticles (NPs) is frequently associated with adverse cardiovascular effects. In contrast, NPs in nanomedicine hold great promise for precise lung‐specific drug delivery, especially considering the extensive pulmonary capillary network that facilitates interactions with bloodstream‐suspended particles. Therefore, exact knowledge about effects of engineered NPs within the pulmonary microcirculation are instrumental for future application of this technology in patients. To unravel the real‐time dynamics of intravenously delivered NPs and their effects in the pulmonary microvasculature, we employed intravital microscopy of the mouse lung. Only PEG‐amine‐QDs, but not carboxyl‐QDs triggered rapid neutrophil recruitment in microvessels and their subsequent recruitment to the alveolar space and was linked to cellular degranulation, TNF‐α, and DAMP release into the circulation, particularly eATP. Stimulation of the ATP‐gated receptor P2X7R induced expression of E‐selectin on microvascular endothelium thereby mediating the neutrophilic immune response. Leukocyte integrins LFA‐1 and MAC‐1 facilitated adhesion and decelerated neutrophil crawling on the vascular surface. In summary, this study unravels the complex cascade of neutrophil recruitment during NP‐induced sterile inflammation. Thereby we demonstrate novel adverse effects for NPs in the pulmonary microcirculation and provide critical insights for optimizing NP‐based drug delivery and therapeutic intervention strategies, to ensure their efficacy and safety in clinical applications.

Abstract In this study, we aimed to establish a technique for intraprostatic implantation of prostate cancer (PCa) spheroids and to identify the impact of three-dimensional organization of PCa cells on tumor progression and metastasis in a representative in vivo model. 40,000 LNCaP cells were implanted into the prostate of immunodeficient SCID mice either as single cells (n = 8) or as preformed 3D spheroids (n = 8). For a follow up of 20 weeks, tumor growth was monitored by serum PSA and high-resolution 3D ultrasonography. Eventually, animals were sacrificed and autopsied. The organ dissects were analyzed for the presence of metastases by histology (H&E) and immunohistochemistry (AMACR, AR, Ki-67, CK5, CK8, E-Cadherin, Vimentin). Solid intraprostatic tumors developed in 50% of mice after spheroid implantation and in 50% of mice after implantation of a single cells. Primary tumors of LNCaP spheroids evolved earlier, exhibiting a shorter tumor doubling time whilst developing larger tumor volumes, which was reflected by a higher immunohistochemical expression of Ki-67 and AR, too. Spheroid tumors established lung and lymph node metastases in 75% of mice, in contrast to 50% of mice after single cell implantation. Our technique enables a variety of studies regarding the influence of the tumor microenvironment on PCa progression.

Abstract Weibel Palade bodies (WPB) are lysosome‐related secretory organelles of endothelial cells. Commonly known for their main cargo, the platelet and leukocyte receptors von‐Willebrand factor (VWF) and P‐selectin, WPB play a crucial role in hemostasis and inflammation. Here, the authors identify the glycerophosphodiester phosphodiesterase domain‐containing protein 5 (GDPD5) as a WPB cargo protein and show that GDPD5 is transported to WPB following uptake from the plasma membrane via an unique endocytic transport route. GDPD5 cleaves GPI‐anchored, plasma membrane‐resident proteins within their GPI‐motif, thereby regulating their local activity. The authors identify a novel target of GDPD5 , the complement regulator CD59, and show that it is released from the endothelial surface by GDPD5 following WPB exocytosis. This results in increased deposition of complement components and can enhance local inflammatory and thrombogenic responses. Thus, stimulus‐induced WPB exocytosis can modify the endothelial cell surface by GDPD5‐mediated selective release of a subset of GPI‐anchored proteins.

In vitro culture systems that structurally model human myogenesis and promote PAX7+ myogenic progenitor maturation have not been established. Here we report that human skeletal muscle organoids can be differentiated from induced pluripotent stem cell lines to contain paraxial mesoderm and neuromesodermal progenitors and develop into organized structures reassembling neural plate border and dermomyotome. Culture conditions instigate neural lineage arrest and promote fetal hypaxial myogenesis toward limb axial anatomical identity, with generation of sustainable uncommitted PAX7 myogenic progenitors and fibroadipogenic (PDGFRa+) progenitor populations equivalent to those from the second trimester of human gestation. Single-cell comparison to human fetal and adult myogenic progenitor /satellite cells reveals distinct molecular signatures for non-dividing myogenic progenitors in activated (CD44High/CD98+/MYOD1+) and dormant (PAX7High/FBN1High/SPRY1High) states. Our approach provides a robust 3D in vitro developmental system for investigating muscle tissue morphogenesis and homeostasis.

Background: Robot-assisted partial nephrectomy (RAPN) is a challenging procedure that is influenced by a multitude of factors. Objective: To assess the impact of prior surgical experience on perioperative outcomes in RAPN. Design, setting, and participants: In this retrospective multicenter study, results for 2548 RAPNs performed by 25 surgeons at eight robotic referral centers were analyzed. Perioperative data for all consecutive RAPNs from the start of each individual surgeon’s experience were collected, as well as the number of prior open or laparoscopic kidney surgeries, pelvic surgeries (open, laparoscopic, robotic), and other robotic interventions. Intervention: Transperitoneal or retroperitoneal RAPN. Outcome measurements and statistical analysis: The impact of prior surgical experience on operative time, warm ischemia time (WIT), major complications, and margin, ischemia, complication (MIC) score (negative surgical margins, WIT ≤20 min, no major complications) was assessed via univariate and multivariable regression analyses accounting for age, gender, body mass index (BMI), American Society of Anesthesiologists score, PADUA score, and RAPN experience. Results and limitations: BMI, PADUA score, and surgical experience in RAPN had a strong impact on perioperative outcomes. A plateau effect for the learning curve was not observed. Prior laparoscopic kidney surgery significantly reduced the operative time (p

Neuronal information conductance often involves the transmission of action potentials. The spreading of action potentials along the axonal process of a neuron is based on three physical parameters: the axial resistance of the axon, the axonal insulation by glial membranes, and the positioning of voltage-gated ion channels. In vertebrates, myelin and channel clustering allow fast saltatory conductance. Here, we show that in Drosophila melanogaster voltage-gated sodium and potassium channels, Para and Shal, co-localize and cluster in an area resembling the axon initial segment. The local enrichment of Para but not of Shal localization depends on the presence of peripheral wrapping glial cells. In larvae, relatively low levels of Para channels are needed to allow proper signal transduction and nerves are simply wrapped by glial cells. In adults, the concentration of Para increases and is prominently found at the axon initial segment of motor neurons. Concomitantly, these axon domains are covered by a mesh of glial processes forming a lacunar structure that possibly serves as an ion reservoir. Directly flanking this domain glial processes forming the lacunar area appear to collapse and closely apposed stacks of glial cell processes can be detected, resembling a myelin-like insulation. Thus, Drosophila development may reflect the evolution of myelin which forms in response to increased levels of clustered voltage-gated ion channels.

This review discusses picosecond ultrasonics experiments using ultrashort hard x-ray probe pulses to extract the transient strain response of laser-excited nanoscopic structures from Bragg-peak shifts. This method provides direct, layer-specific, and quantitative information on the picosecond strain response for structures down to few-nm thickness. We model the transient strain using the elastic wave equation and express the driving stress using Grüneisen parameters stating that the laser-induced stress is proportional to energy density changes in the microscopic subsystems of the solid, i.e., electrons, phonons and spins. The laser-driven strain response can thus serve as an ultrafast proxy for local energy-density and temperature changes, but we emphasize the importance of the nanoscale morphology for an accurate interpretation due to the Poisson effect. The presented experimental use cases encompass ultrathin and opaque metal-heterostructures, continuous and granular nanolayers as well as negative thermal expansion materials, that each pose a challenge to established all-optical techniques.

Abstract The plasma membrane of a cell is subject to stresses causing ruptures that must be repaired immediately to preserve membrane integrity and ensure cell survival. Yet, the spatio‐temporal membrane dynamics at the wound site and the source of the membrane required for wound repair are poorly understood. Here, it is shown that early endosomes, previously only known to function in the uptake of extracellular material and its endocytic transport, are involved in plasma membrane repair in human endothelial cells. Using live‐cell imaging and correlative light and electron microscopy, it is demonstrated that membrane injury triggers a previously unknown exocytosis of early endosomes that is induced by Ca2+ entering through the wound. This exocytosis is restricted to the vicinity of the wound site and mediated by the endosomal soluble N‐ethylmaleimide sensitive factor attachment protein receptor (SNARE) VAMP2, which is crucial for efficient membrane repair. Thus, the newly identified Ca2+‐evoked and localized exocytosis of early endosomes supplies the membrane material required for rapid resealing of a damaged plasma membrane, thereby providing the first line of defense against damage in mechanically challenged endothelial cells.

Summary: The extra-embryonic tissues that form the placenta originate from a small population of trophectoderm cells with stem cell properties, positioned at the embryonic pole of the mouse blastocyst. During the implantation stages, the polar trophectoderm rapidly proliferates and transforms into extra-embryonic ectoderm. The current model of trophoblast morphogenesis suggests that tissue folding reshapes the trophoblast during the blastocyst to egg cylinder transition. Instead of through folding, here we found that the tissue scale architecture of the stem cell compartment of the trophoblast lineage is reorganized via inversion of the epithelial polarity axis. Our findings show the developmental significance of polarity inversion and provide a framework for the morphogenetic transitions in the peri-implantation trophoblast.

How pluripotency transcription factors regulate the cellular architecture and energetics has remained largely unknown. Here the authors identify Lima1 as a key effector that mediates the pluripotency control of membrane dynamics and cellular metabolism.

Developmental and regenerative bone formation require the removal of chondrocytes and matrix. Here the authors show that these processes involve mesenchymal stromal cell-derived septoclasts, which disappear after the completion of development but re-emerge during fracture healing.

Abstract Objectives Although biomarkers predicting therapy response in first‐line metastatic renal carcinoma (mRCC) therapy remain to be defined, C‐reactive protein (CRP) kinetics have recently been associated with immunotherapy (IO) response. Here, we aimed to assess the predictive and prognostic power of two contemporary CRP kinetics definitions in a large, real‐world first‐line mRCC cohort. Methods Metastatic renal carcinoma patients treated with IO‐based first‐line therapy within 5 years were retrospectively included in this multicentre study. According to Fukuda et al., patients were defined as ‘CRP flare‐responder’, ‘CRP responder’ and ‘non‐CRP responder’; according to Ishihara et al., patients were defined as ‘normal’, ‘normalised’ and ‘non‐normalised’ based on their early CRP kinetics. Patient and tumor characteristics were compared, and treatment outcome was measured by overall (OS) and progression‐free survival (PFS), including multivariable Cox regression analyses. Results Out of 316 mRCC patients, 227 (72%) were assigned to CRP groups according to Fukuda. Both CRP flare‐ (HR [Hazard ratio]: 0.59) and CRP responders (HR: 0.52) had a longer PFS, but not OS, than non‐CRP responders. According to Ishihara, 276 (87%) patients were assigned to the respective groups, and both normal and normalised patients had a significantly longer PFS and OS, compared with non‐normalised group. Conclusion Different early CRP kinetics may predict therapy response in first‐line mRCC therapy in a large real‐world cohort. However, further research regarding the optimal timing and frequency of measurement is needed.

Current tissue engineering strategies lack materials that promote angiogenesis. Here the authors develop a microfluidic in vitro model in which chemokine-guided endothelial cell sprouting into a tunable hydrogel is followed by the formation of perfusable lumens to determine the material properties that regulate angiogenesis.

Embryonic diapause is a state of dormancy with poorly understood mechanisms of embryo intrinsic regulation. Here, the authors show that murine diapause is a dynamic process, where tissue-scale reorganization of the pluripotent lineage is controlled in an autocrine manner by the Wnt/b-catenin/Esrrb signalling cascade.