Exploiting WEE1 Kinase Activity as FUS::DDIT3-Dependent Therapeutic Vulnerability in Myxoid Liposarcoma.

Purpose: The pathognomonic FUS::DDIT3 fusion protein drives myxoid liposarcoma (MLS) tumorigenesis via aberrant transcriptional activation of oncogenic signaling. As FUS::DDIT3 has so far not been pharmacologically tractable to selectively target MLS cells, this study investigated the functional role of the cell cycle regulator WEE1 as novel FUS::DDIT3-dependent therapeutic vulnerability in MLS.

Experimental Design: Immunohistochemical evaluation of the cell cycle regulator WEE1 was performed in a large cohort of MLS specimens.

Surface Treatment Strategies and Their Impact on the Material Behavior and Interfacial Adhesion Strength of Shape Memory Alloy NiTi Wire Integrated in Glass Fiber-Reinforced Polymer Laminate Structures.

Over the past few decades, there has been a growing trend in designing multifunctional materials and integrating various functions into a single component structure without defects. This research addresses the contemporary demand for integrating multiple functions seamlessly into thermoplastic laminate structures. Focusing on NiTi-based shape memory alloys (SMAs), renowned for their potential in introducing functionalities like strain measurement and shape change, this study explores diverse surface treatments for SMA wires.

Superficial fibromas with CTNNB1 mutation.

Superficial fibromas are a group of mesenchymal spindle cell lesions with pathomorphological heterogeneity and diverse molecular backgrounds. In part, they may be indicators of an underlying syndrome. Among the best-known entities of superficial fibromas is Gardner fibroma, a plaque-like benign tumor, which is associated with APC germline mutations and occurs in patients with familial adenomatosis polyposis (Gardner syndrome).

A Custom Panel for Profiling Microglia Gene Expression.

Despite being immune cells of the central nervous system (CNS), microglia contribute to CNS development, maturation, and homeostasis, and microglia dysfunction has been implicated in several neurological disorders. Recent advancements in single-cell studies have uncovered unique microglia-specific gene expression. However, there is a need for a simple yet elegant multiplexed approach to quantifying microglia gene expression.

[Gastrointestinal stromal tumors : Where do we stand?].

For more than 20 years gastrointestinal stromal tumors (GIST) have been a paradigm for a targeted treatment with tyrosine kinase inhibitors. A fundamental prerequisite for a neoadjuvant or adjuvant treatment of localized GIST or an additive treatment of metastatic GIST is the molecular typing of tumors, ideally at the initial diagnosis. In addition, the possibility of a hereditary or syndromic predisposition must be considered because this results in consequences for the treatment and a different follow-up strategy.

Effect of Milling Time and Reinforcement Volume Fraction on Microstructure and Mechanical Properties of SiC-Reinforced AA2017 Composite Powder Produced by High-Energy Ball Milling.

The influence of milling time and volume fraction of reinforcement on the morphology, microstructure, and mechanical behaviors of SiC-reinforced AA2017 composite powder produced by high-energy ball milling (HEBM) was investigated. AA2017 + SiC composite powder with different amounts of SiC particles (5, 10, and 15 vol%) was successfully prepared from gas-atomized AA2017 aluminum alloy powder with a particle size of <100 μm and silicon carbide (SiC) powder particles with an average particle size of <1 μm. An optical microscope (OM), X-ray diffraction (XRD), and scanning electron microscope (SEM) were utilized to characterize the microstructure of the milled composite powder at different milling periods.

Outcome of First-Line Treatment With Pembrolizumab According to KRAS/TP53 Mutational Status for Nonsquamous Programmed Death-Ligand 1-High (≥50%) NSCLC in the German National Network Genomic Medicine Lung Cancer.

Introduction: Programmed death-ligand 1 expression currently represents the only validated predictive biomarker for immune checkpoint inhibition in metastatic NSCLC in the clinical routine, but it has limited value in distinguishing responses. Assessment of KRAS and TP53 mutations (mut) as surrogate for an immunosupportive tumor microenvironment (TME) might help to close this gap.

Methods: A total of 696 consecutive patients with programmed death-ligand 1-high (≥50%), nonsquamous NSCLC, having received molecular testing within the German National Network Genomic Medicine Lung Cancer between 2017 and 2020, with Eastern Cooperative Oncology Group performance status less than or equal to 1 and pembrolizumab as first-line palliative treatment, were included into this retrospective cohort analysis.

Immunohistochemical expression of TROP‑2 (TACSTD2) on the urothelial carcinoma of the urinary bladder and other types of cancer.

In metastatic or locally advanced urothelial carcinoma (UC), therapeutic options have been limited to chemotherapy and immune checkpoint inhibitors. Novel targets and drugs such as antibody drug conjugates have been developed, and enfortumab vedotin targeting nectin-4 and sacituzumab govitecan (SG) targeting trophoblast cell surface antigen 2 (TROP-2), the protein product of the TACSTD2 gene, have been approved. The expression of TROP-2 was investigated within UC and other types of carcinomas, and within the tissue of different healthy organs to understand treatment responses and toxicities.

NKX3.1 immunohistochemistry and methylome profiling in mesenchymal chondrosarcoma: additional diagnostic value for a well-defined disease?

Mesenchymal chondrosarcoma (MCS) is a rare and highly aggressive tumour of soft tissue and bone that is defined by an underlying and highly specific fusion transcript involving HEY1 and NCOA2. Histologically, the tumours show a biphasic appearance consisting of an undifferentiated blue and round cell component as well as islands of highly differentiated cartilage. Particularly in core needle biopsies, the chondromatous component can be missed and the non-specific morphology and immunophenotype of the round cell component can cause diagnostic challenges.

Interdependence of SS18-SSX-driven YAP1 and β-Catenin Activation in Synovial Sarcoma.

Unlabelled: Synovial sarcoma, a rare malignant soft tissue tumor, is characterized by a specific chromosomal translocation t(X;18). The resulting chimeric SS18-SSX fusion protein drives synovial sarcoma pathogenesis by integrating into the BAF complex and dysregulating gene transcription. Because previous functional analyses revealed a connection between SS18-SSX and the activity of the transcriptional coregulators YAP1/TAZ and β-catenin, respectively, this study examined a potential interdependence between these essential effector proteins in synovial sarcoma.

Molecular profiling of EBV associated diffuse large B-cell lymphoma.

Epstein-Barr virus (EBV) associated diffuse large B-cell lymphoma (DLBCL) represents a rare aggressive B-cell lymphoma subtype characterized by an adverse clinical outcome. EBV infection of lymphoma cells has been associated with different lymphoma subtypes while the precise role of EBV in lymphomagenesis and specific molecular characteristics of these lymphomas remain elusive. To further unravel the biology of EBV associated DLBCL, we present a comprehensive molecular analysis of overall 60 primary EBV positive (EBV+) DLBCLs using targeted sequencing of cancer candidate genes (CCGs) and genome-wide determination of recurrent somatic copy number alterations (SCNAs) in 46 cases, respectively.

Recurrent EWSR1::COLCA2 Fusions Define a Novel Sarcoma With Spindle/Round Cell Morphology and Strong Predilection for the Sinonasal Tract.

The last 2 decades have attended a dynamic evolution in the nosology of poorly differentiated sinonasal tract malignancies, with several new molecularly defined entities having been described in addition to delineation of the genetic driver/s of some established older entities. These discoveries, however, mostly concerned epithelial-derived neoplasms (carcinomas). Adamantinoma-like Ewing sarcoma and biphenotypic sinonasal sarcoma are the major representatives of the newly defined mesenchymal categories.

Inhibition of p38 signaling curtails the SARS-CoV-2 induced inflammatory response but retains the IFN-dependent antiviral defense of the lung epithelial barrier.

SARS-CoV-2 is the causative agent of the immune response-driven disease COVID-19 for which new antiviral and anti-inflammatory treatments are urgently needed to reduce recovery time, risk of death and long COVID development. Here, we demonstrate that the immunoregulatory kinase p38 MAPK is activated during viral entry, mediated by the viral spike protein, and drives the harmful virus-induced inflammatory responses. Using primary human lung explants and lung epithelial organoids, we demonstrate that targeting p38 signal transduction with the selective and clinically pre-evaluated inhibitors PH-797804 and VX-702 markedly reduced the expression of the pro-inflammatory cytokines IL6, CXCL8, CXCL10 and TNF-α during infection, while viral replication and the interferon-mediated antiviral response of the lung epithelial barrier were largely maintained.

[Abdominal soft tissue tumors].

Gastrointestinal stromal tumors are the most common mesenchymal tumors in the abdomen and occur in Germany with an incidence of 10 to 15 cases per million inhabitants. Clear identification and characterization are of major importance for the prognosis and therapy of patients. Similarly, they have to be differentiated from other mesenchymal neoplasias such as leiomyomatous, neurogenic, adipocytic, and fibroblastic tumors.

Influencing the Size and Shape of High-Energy Ball Milled Particle Reinforced Aluminum Alloy Powder.

High-energy ball milling represents an efficient process for producing composite powders consisting of ceramic particles dispersed in a metallic matrix. However, collision events, plastic deformations, and cold welding during the milling lead to a flake or block-like shape of the resulting composite powders. Further consolidation of such irregularly shaped powders by powder bed-based additive manufacturing technologies can be challenging because of their low flowability and low bulk density.

SS18-SSX drives CREB activation in synovial sarcoma.

Purpose: Synovial sarcoma (SySa) is a rare soft tissue tumor characterized by a reciprocal t(X;18) translocation. The chimeric SS18-SSX fusion protein represents the major driver of the disease, acting as aberrant transcriptional dysregulator. Oncogenic mechanisms whereby SS18-SSX mediates sarcomagenesis are incompletely understood, and strategies to selectively target SySa cells remain elusive.

Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcoma.

Myxoid liposarcoma (MLS) represents a common subtype of liposarcoma molecularly characterized by a recurrent chromosomal translocation that generates a chimeric FUS-DDIT3 fusion gene. The FUS-DDIT3 oncoprotein has been shown to be crucial in MLS pathogenesis. Acting as a transcriptional dysregulator, FUS-DDIT3 stimulates proliferation and interferes with adipogenic differentiation.

A phase II trial to evaluate the combination of pixantrone and obinutuzumab for patients with relapsed aggressive lymphoma: Final results of the prospective, multicentre GOAL trial.

The prognosis of patients with relapsed diffuse large B-cell lymphoma (DLBCL) remains poor with current options. Here we prospectively evaluated the combination of pixantrone with obinutuzumab for up to six cycles for patients with relapsed or refractory DLBCL. Overall response rate (ORR) was the primary end-point.

Design of a targeted next-generation DNA sequencing panel for pediatric T-cell lymphoblastic lymphoma to unravel biology and optimize treatment.

Low incidence and molecular heterogeneity of pediatric T-cell lymphoblastic lymphoma (T-LBL) require an international, large-scale effort to identify novel clinical biomarkers. The ongoing international clinical trial LBL2018 (NCT04043494) represents an ideal opportunity to implement a common analytic approach. Targeted next-generation sequencing is well-suited for this purpose; however, selection of relevant target genes for T-LBL remains subject of ongoing debates.

Efficacy and safety of efpeglenatide in key patient subgroups from the BALANCE randomized trial, stratified by pre-diabetes status, BMI, and age at baseline.

Introduction: Efpeglenatide is a long-acting glucagon-like peptide-1 receptor agonist being developed to improve glycemic control in type 2 diabetes (T2D). In the BALANCE 205 study (NCT02075281), efpeglenatide significantly reduced body weight versus placebo in patients with obesity, or overweight with comorbidities, and without T2D. These subanalyses explore the efficacy and safety of efpeglenatide in subgroups of patients with pre-diabetes and stratified by body mass index (BMI) or age from the BALANCE study.

Recurrent CTNNB1 mutations in craniofacial osteomas.

Osteoma is a benign bone forming tumor predominantly arising on the surface of craniofacial bones. While the vast majority of osteomas develops sporadically, a small subset of cases is associated with Gardner syndrome, a phenotypic variant of familial adenomatous polyposis caused by mutations in the APC gene resulting in aberrant activation of WNT/β-catenin signaling. In a sequencing analysis on a cohort of sporadic, non-syndromal osteomas, we identified hotspot mutations in the CTNNB1 gene (encoding β-catenin) in 22 of 36 cases (61.