CRISPR/Cas9 editing of NKG2A improves the efficacy of primary CD33-directed chimeric antigen receptor natural killer cells.

Chimeric antigen receptor (CAR)-modified natural killer (NK) cells show antileukemic activity against acute myeloid leukemia (AML) in vivo. However, NK cell-mediated tumor killing is often impaired by the interaction between human leukocyte antigen (HLA)-E and the inhibitory receptor, NKG2A. Here, we describe a strategy that overcomes CAR-NK cell inhibition mediated by the HLA-E-NKG2A immune checkpoint. We generate CD33-specific, AML-targeted CAR-NK cells (CAR33) combined with CRISPR/Cas9-based gene disruption of the NKG2A-encoding KLRC1 gene. Using single-cell multi-omics analyses, we identified transcriptional features of activation and maturation in CAR33-KLRC1ko-NK cells, which are preserved following exposure to AML cells. Moreover, CAR33-KLRC1ko-NK cells demonstrate potent antileukemic killing activity against AML cell lines and primary blasts in vitro and in vivo. We thus conclude that NKG2A-deficient CAR-NK cells have the potential to bypass immune suppression in AML.

Regarding a human costoscapular joint by Prof. Dr. H. von Luschka (1870): A translation.

Knowledge of variant anatomy was important during the time of Dr. Hubert von Luschka (1820-1875) and continues to be of relevance in current practice to prevent medical and surgical errors and to improve patient outcomes. Dr. H. von Luschka described an anatomical variant observed in the left scapula of a 40-year-old male: a connection between the medial superior angle of the scapula, piercing through the serratus posterior muscle to connect via a synovial capsule to the articular surface of the thoracic wall. The clinical relevance of this so-called "Luschka's tubercle" of the shoulder continues to be discussed. This translation is intended to broaden access to this hallmark manuscript to a wide audience of English readers. The introduction places the manuscript in the context of historical and current discussions. Three authors, all proficient in the German and English languages and educated in the anatomy of the shoulder, conducted the translation. The skeletal process that is part of the described joint structure appears similar to what is now called Luschka's tubercle. The full structure, including its connecting parts, are not currently included in anatomical nomenclature. In conclusion, Luschka's text and named tubercle continue to contribute to the discussion of scapulothoracic joint disorders.

Novel pre-clinical mouse models for chronic Graft-versus-Host Disease.

Despite considerable progress in allogeneic hematopoietic cell transplantation (allo-HCT) has been achieved over the past years, chronic Graft-versus-Host Disease (cGvHD) still contributes to high morbidity rates, thus remaining a major hurdle in allo-HCT patients. To understand the complex pathophysiology of cGvHD and to develop refined prophylaxis and treatment strategies, improved pre-clinical models are needed. In this study, we developed two murine cGvHD models, which display high long-term morbidity but low mortality and depict the heterogeneous clinical manifestations of cGvHD seen in patients. We established a haploidentical C57BL/6→B6D2F1 allo-HCT model that uses myeloablative radiation and G-CSF-mobilized splenocytes as stem cell source and a sub-lethally irradiated Xenograft model, which utilizes the transfer of human peripheral blood mononuclear cells (PBMCs) into NOD scid gamma (NSG)-recipients. We characterized both mouse models to exhibit diverse clinical and histopathological signs of human cGvHD as extensive tissue damage, fibrosis/sclerosis, inflammation and B cell infiltration in cGvHD target organs skin, liver, lung and colon and found a decelerated immune cell reconstitution in the late phase after HCT. Our pre-clinical models can help to gain a deeper understanding of the target structures and mechanisms of cGvHD pathology and may enable a more reliable translation of experimental findings into the human setting of allo-HCT.

Translation of Runge's 1873 publication "On the etiology and treatment of writer's cramp": The first description of "tennis elbow".

This publication by Dr Ferdinand Runge is ubiquitously credited as first to describe the symptoms, pathology, and treatment of patients with lateral epicondylosis (tennis elbow). However, the main focus of his work was to provide insight into causes of writer's cramp and treatments for the condition, elegantly illustrated in four case reports. This work, recently cited as unavailable, is written in German. Given the high frequency of citations in the English literature, it was considered useful to translate it into English to widen access to a broader readership. The purpose of this project was briefly to introduce the life and clinical expertise of Dr. Ferdinand Runge and the content of his work, followed by a translation of the entire manuscript into English. The paper was translated by the three authors using a process of sequential consensus. All are proficient in German and English, with clinical expertise in both topics. A brief reflection is provided to place Dr Runge's observations, clinical reasoning, and contemporaneously available treatments in the context of current thinking about lateral epicondylalgia. Dr. Runge shares his expertise, carefully reporting pertinent examination findings for each case, sharing hypotheses about the etiology of writer's cramp, and using the effectiveness of his applied treatment as confirmation. He concludes that careful evaluation of the patient's activities that hindered writing prior to the onset of the writer's cramp is key to managing this ailment. The topics addressed in this classic work are still thought-provoking.

A synopsis on different homologous series of fomocaine derivatives. In vitro interactions with the cytochrome P450 system, toxicity, and local anaesthetic effects in rats--Part 1.

Fomocaine (CAS 56583-43-6) is a basic ether-type local anaesthetic used in dermatological practice for surface anaesthesia. For many years, modifications of the fomocaine molecule have been pursued, e.g. to improve its physicochemical properties and also in view of possible new (systemic) applications, e.g. in the treatment of migraine or as antiarrhythmic. The present paper provides a survey of the investigations undertaken with all the different series of fomocaine derivatives synthesized so far with respect to their in vitro interaction capacity at the cytochrome P450 system, in vivo toxicity (LD50; paresis of the N. ischiadicus) and local anaesthetic effects (conduction anaesthesia at the N. ischiadicus; surface anaesthesia of the cornea) in rats. The main objective of this systematic comparison of the effects of all these substances was to assess possible basic structure-activity relationships.