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The generation of antibody-drug conjugates with optimal functionality depends on many parameters. These include binder epitope, antibody format, linker composition, conjugation site(s), drug-to-antibody ratio, and conjugation method. The production of matrices that cover all possible parameters is a major challenge in identifying optimal antibody-drug conjugates. To address this bottleneck, we adapted our Format Chain Exchange technology (FORCE), originally established for bispecific antibodies, toward the generation of binder-format-payload matrices (pair-FORCE). Antibody derivatives with exchange-enabled Fc-heterodimers are combined with payload-conjugated Fc donors, and subsequent chain-exchange transfers payloads to antibody derivatives in different formats. The resulting binder-format-conjugate matrices can be generated with cytotoxic payloads, dyes, haptens, and large molecules, resulting in versatile tools for ADC screening campaigns. We show the relevance of pair-FORCE for identifying optimal HER2-targeting antibody-drug conjugates. Analysis of this matrix reveals that the notion of format-defines-function applies not only to bispecific antibodies, but also to antibody-drug conjugates., (© 2024. The Author(s).)

Spondylodiscitis is a rather rare condition with an annual incidence of 1-7 per 100,000. Thus, empirical data on the treatment of this disease are limited. In 2020, the first German guideline for the diagnosis and treatment of spondylodiscitis was published. In a 5-year retrospective analysis, we examined the patient collective, the current diagnosis and treatment strategy, and the effect of Magnetic Resonance Imaging (MRI) diagnostics on therapeutic decisions of a consecutive monocentric cohort of 66 patients without neurological symptoms. The majority of the patients were male (55%) with a mean age of 74 years. Non-operative therapy was found to be associated with short-term treatment success in 54 (82%) of the patients. In 12 patients, who underwent surgical therapy, MRI diagnostics and clinical findings were equally important for the decision to perform a surgery. Patients treated operatively stayed for an average of 33.6 (±12.9) days in the hospital and thus significantly longer than non-operatively treated patients with 22.2 (±8.0) days. The in-house standard of care did not essentially deviate from the guideline's recommendations. Future research should address early detection of the need for surgical therapy, and immediate anti-infective treatment appropriate to the detected pathogen.

Cancer-specific TCF1 + stem-like CD8 + T cells can drive protective anticancer immunity through expansion and effector cell differentiation 1-4 ; however, this response is dysfunctional in tumours. Current cancer immunotherapies 2,5-9 can promote anticancer responses through TCF1 + stem-like CD8 + T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1 + CD8 + T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE 2 ) restricts the proliferative expansion and effector differentiation of TCF1 + CD8 + T cells within tumours, which promotes cancer immune escape. PGE 2 does not affect the priming of TCF1 + CD8 + T cells in draining lymph nodes. PGE 2 acts through EP 2 and EP 4 (EP 2 /EP 4 ) receptor signalling in CD8 + T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1 + tumour-infiltrating CD8 + T lymphocytes (TILs). Ablation of EP 2 /EP 4 signalling in cancer-specific CD8 + T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE 2 -mediated inhibition of TCF1 + TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1 + TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE 2 -EP 2 /EP 4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control., (© 2024. The Author(s).)

Large bone defects of the lower extremities are challenging for both patients and the treating orthopedic surgeons. The treatment is determined by the size and location of the defect; however, patient-specific factors, such as the soft tissue situation and the presence of systemic comorbidities must be taken into consideration in the treatment strategy. Osteodistraction is an excellent technique especially for large bone defects exceeding 3 cm; however, it is time-consuming and required external fixation prior to the development of motorized distraction nails. This article describes the procedure for the treatment of large bone defects of the lower extremities, with its possibilities and limitations, using the novel plate-assisted bone segment transport (PABST) procedure., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The RNA-binding protein PURA has been implicated in the rare, monogenetic, neurodevelopmental disorder PURA Syndrome. PURA binds both DNA and RNA and has been associated with various cellular functions. Only little is known about its main cellular roles and the molecular pathways affected upon PURA depletion. Here, we show that PURA is predominantly located in the cytoplasm, where it binds to thousands of mRNAs. Many of these transcripts change abundance in response to PURA depletion. The encoded proteins suggest a role for PURA in immune responses, mitochondrial function, autophagy and processing (P)-body activity. Intriguingly, reduced PURA levels decrease the expression of the integral P-body components LSM14A and DDX6 and strongly affect P-body formation in human cells. Furthermore, PURA knockdown results in stabilization of P-body-enriched transcripts, whereas other mRNAs are not affected. Hence, reduced PURA levels, as reported in patients with PURA Syndrome, influence the formation and composition of this phase-separated RNA processing machinery. Our study proposes PURA Syndrome as a new model to study the tight connection between P-body-associated RNA regulation and neurodevelopmental disorders., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: While repeated shutdown and lockdown measures helped contain the spread of SARS-CoV-2 during the COVID-19 pandemic, social distancing and self-isolation negatively impacted global mental health in 2020 and 2021. Although suicide rates did reportedly not increase during the first months of the pandemic, long-term data, and data on the quality of serious violent suicide attempts (SVSAs) are not available to date., Materials and Methods: Orthopaedic trauma patient visits to the emergency department (ED), ED trauma team activations, and SVSAs were retrospectively evaluated from January 2019 until May 2021 in four Level-I Trauma Centers in Berlin, Germany. SVSAs were assessed for suicide method, injury pattern and severity, type of treatment, and length of hospital stay., Results: Significantly fewer orthopaedic trauma patients presented to EDs during the pandemic ( n = 70,271) compared to the control ( n = 84,864) period ( p = 0.0017). ED trauma team activation numbers remained unchanged. SVSAs (corrected for seasonality) also remained unchanged during control ( n = 138) and pandemic ( n = 129) periods, and no differences were observed for suicide methods, injury patterns, or length of hospital stay., Conclusion: Our data emphasize that a previously reported rise in psychological stress during the COVID-19 pandemic does not coincide with increased SVSA rates or changes in quality of SVSAs., (Copyright © 2022 Maleitzke, Zocholl, Topp, Dimitrov-Discher, Daus, Reaux, Zocholl, Conze, Kolster, Weber, Fleckenstein, Scheutz Henriksen, Stöckle, Fuchs, Gümbel, Spranger, Ringk and Märdian.)

Background: Architectural division of aseptic and septic operating theatres is a distinct structural feature of surgical departments in Germany. Internationally, hygienists and microbiologists mainly recommend functional separation (i.e. aseptic procedures first) without calling for separate operating floors and rooms. However, patients with severe musculoskeletal infections (e.g. joint empyema, spondylodiscitis, deep implant-associated infections) may benefit from the permanent availability of septic operating capacities without delay caused by an ongoing aseptic surgical program. A systematic literature review on the influence of a structural separation of septic and aseptic operating theatres on process and/or outcome quality has not yet been conducted., Methods: Systematic literature search in PubMed MEDLINE, Ovid Embase, CINAHL and the Cochrane Library, screening of referenced citations, and assessment of grey literature., Results: A total of 572 articles were found through the systematic literature search. No head-to-head studies (neither randomised, quasi-randomised nor observational) were identified which examined the impact of structural separation of septic and aseptic operating theatres on process and/or outcome quality., Conclusions: This review did not identify evidence in favour nor against architectural separation of septic or aseptic operating theatre. Specifically, there is no evidence of a harmful effect of architectural separation. Unless prospective studies, ideally randomised trials, will be available, it is unjustified to call for abolishing established hospital structures. Future investigations must address patient-centered endpoints, surgical site infections, process quality and hospital economy., Systematic Review Registration: PROSPERO (International prospective register of systematic reviews): CRD42018086568.

Hintergrund: Der Verschluss von Wunden mit ausgeprägtem Weichteilschaden stellt eine chirurgische Herausforderung dar und erfordert häufig umfangreiche plastische Operationen sowie freie Lappenplastiken. Die Kombination von Dermisersatzpräparaten und Spalthauttransplantationen ist eine innovative Methode die zur Versorgung von komplexen Verletzungen der Extremitäten angewandt werden kann. Wir haben diese Technik in das Standard-Handwerkszeug bei komplexen Verletzungen der Extremitäten aufgenommen. Die klinischen Ergebnisse von 56 behandelten Patienten werden vorgestellt., Patienten Und Methoden: In 44 Fällen (78,6 %) wurde die beschriebene Methode an Defekten der unteren Extremitäten verwendet, einschließlich sieben Personen (12,5 %), die sich einer Stumpfdeckung nach Amputation unterzogen. Zwölf Defekte (21,4 %) befanden sich an den oberen Extremitäten. In zwei Fällen (3,6 %) wurde die Matriderm(®) -Matrix verwendet, um Nerven von unmittelbar angrenzenden chirurgischen Implantaten zu schützen., Ergebnisse: Bei 41 Patienten (73,2 %) kam es zur Einheilung des Transplantats ohne Komplikationen. Fünfzehn Patienten (26,8 %) zeigten eine gestörte Wundheilung nach Defektverschluss, die unter konservativer Therapie zur Ausheilung gebracht werden konnte. Ein Patient (1,8 %) zeigte ein Transplantatversagen, was eine Revisionsoperation erforderlich machte. Umfangreiche plastische Rekonstruktionen mussten bei keinem Patienten angewandt werden., Schlussfolgerungen: Bei Fällen, in denen ausgedehnte plastische Operationen nicht möglich oder nicht erwünscht sind, ist die Verwendung von Dermisersatzpräparaten in Kombination mit Spalthauttransplantationen eine vielversprechende Alternative zum Wundverschluss bei ausgedehnten Weichteilschäden., (© 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Background: The closure of wounds associated with soft tissue defects is surgically challenging, frequently requiring extensive plastic surgery and free flaps. The combination of dermal skin substitutes and split-thickness skin grafting is an innovative method used to cover such wounds. We incorporated this technique into the standard therapeutic armamentarium for complex injuries to the extremities. Clinical results of 56 patients thus treated are presented., Patients and Methods: In 44 (78.6 %) cases, the method described was used for defects on the lower extremities, including seven (12.5 %) individuals undergoing amputation stump coverage. Twelve (21.4 %) defects were located on the upper extremities. In two (3.6 %) cases, Matriderm(®) matrix was used to protect nerves from adjacent surgical implants., Results: In 41 (73.2 %) patients, the graft healed without any complication. Fifteen (26.8 %) patients displayed impaired wound healing following defect closure and were subsequently managed conservatively. One patient (1.8 %) showed graft failure, leading to revision surgery. None of the patients required extensive plastic surgery., Conclusions: In cases where plastic surgery is unavailable or undesirable, the use of dermal skin substitutes in combination with split-thickness skin grafting represents a promising alternative for covering wounds associated with soft tissue defects., (© 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)