Neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin in women with early HER2-positive breast cancer: the randomized phase 2 ABCSG-52/ATHENE trial.

The role of anthracyclines in the treatment of early breast cancer (EBC) is increasingly being challenged, especially in de-escalation strategies. However, owing to their immunogenic effects, anthracyclines are promising combination partners with immunotherapies. In the randomized phase 2 trial ABCSG-52 (EudraCT no.

CT-based radiomic prognostic vector (RPV) predicts survival and stromal histology in high-grade serous ovarian cancer: an external validation study.

Objectives: In women with high-grade serous ovarian cancer (HGSOC), a CT-based radiomic prognostic vector (RPV) predicted stromal phenotype and survival after primary surgery. The study's purpose was to fully externally validate RPV and its biological correlate.

Materials And Methods: In this retrospective study, ovarian masses on CT scans of HGSOC patients, who underwent primary cytoreductive surgery in an ESGO-certified Center between 2002 and 2017, were segmented for external RPV score calculation and then correlated with overall survival (OS) and progression-free survival (PFS).

Simultaneous multicolor fluorescence imaging using PSF splitting.

We present a way to encode more information in fluorescence imaging by splitting the original point spread function (PSF), which offers broadband operation and compatibility with other PSF engineering modalities and existing analysis tools. We demonstrate the approach using the 'Circulator', an add-on that encodes the fluorophore emission band into the PSF, enabling simultaneous multicolor super-resolution and single-molecule microscopy using essentially the full field of view.

IL-27 Gene Therapy Ameliorates IPEX Syndrome Caused by Germline Mutation of Foxp3 Gene: A Major Role for Induction of IL-10.

Inactivating mutations of Foxp3, the master regulator of regulatory T cell development and function, lead to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in mice and humans. IPEX is a fatal autoimmune disease, with allogeneic stem cell transplant being the only available therapy. In this study, we report that a single dose of adeno-associated virus (AAV)-IL-27 to young mice with naturally occurring Foxp3 mutation (Scurfy mice) substantially ameliorates clinical symptoms, including growth retardation and early fatality.

Heterochiral modifications enhance robustness and function of DNA in living human cells.

Oligonucleotide therapeutics are becoming increasingly important as more are approved by the FDA, both for treatment and vaccination. Similarly, dynamic DNA nanotechnology is a promising technique that can be used to sense exogenous input molecules or endogenous biomarkers and integrate the results of multiple sensing reactions in situ via a programmed cascade of reactions. The combination of these two technologies could be highly impactful in biomedicine by enabling smart oligonucleotide therapeutics that can autonomously sense and respond to a disease state.

IL-27 in combination with anti-PD-1 can be anti-cancer or pro-cancer.

Interleukin-27 (IL-27) is known to play opposing roles in immunology. The present paper considers, specifically, the role IL-27 plays in cancer immunotherapy when combined with immune checkpoint inhibitor anti-PD-1. We first develop a mathematical model for this combination therapy, by a system of Partial Differential Equations, and show agreement with experimental results in mice injected with melanoma cells.

Diagnostic efficacy of C-X-C motif chemokine receptor 4-directed PET/CT in newly diagnosed head and neck squamous cell carcinoma - a head-to-head comparison with [F]FDG.

Background: The aim of this study was to determine the read-out capabilities of the novel C-X-C motif chemokine receptor 4 (CXCR4)-targeting radiotracer [Ga]Ga-PentixaFor compared to the reference radiotracer [F]FDG in untreated individuals with head and neck squamous cell carcinoma (HNSCC).

Material And Methods: 12 patients with histologically confirmed HNSCC were scheduled for [F]FDG and [Ga]Ga-PentixaFor PET/CT. Maximum standardized uptake values (SUV) and target-to-background ratios (TBR) were applied with vena cava superior serving as reference.

CXCR4-Directed Imaging and Endoradiotherapy in Desmoplastic Small Round Cell Tumors.

Desmoplastic small round cell tumor (DSRCT) is a rare, radiosensitive, yet difficult-to-treat sarcoma subtype affecting predominantly male adolescents. Extensive intraperitoneal seeding is common and requires multimodal management. With no standard therapy established, the prognosis remains poor, and new treatment options are needed.

Application of Biophysical Techniques to Cellular and Molecular Oncology.

Dysregulated cellular processes drive malignant transformation, tumor progression, and metastasis, and affect responses to therapies [...

Dendritic cell expression of CD24 contributes to optimal priming of T lymphocytes in lymph nodes.

CD24 is a GPI anchored cell surface glycoprotein whose function as a co-stimulatory molecule has been implicated. However, the function of CD24 on antigen presenting cells during T cell responses is not well understood. Here we show that in the CD24-deficient host, adoptively transferred CD4 T cells undergo inefficient expansion and have accelerated cell death in lymph nodes, which results in insufficient priming of T cells.

CD24 is expressed on FoxP3 regulatory T cells and regulates their function.

CD24 is a glycosyl-phosphatidylinositol (GPI) anchored cell surface glycoprotein with a variety of immunomodulatory functions such as inhibition of thymic generation of autoreactive T cells, regulation of antigen presenting cell functions, and mediation of autoimmunity. Given the autoimmune nature of FoxP3 regulatory T cells and their importance in autoimmune diseases, we hypothesize that CD24 regulates the generation and functions of Treg cells. Through the analysis of the Treg repertoire in two strains of CD24-deficient mice, we found that CD24 does not globally affect the thymic generation of Treg cells.

Listeria toxin promotes phosphorylation of the inflammasome adaptor ASC through Lyn and Syk to exacerbate pathogen expansion.

Inflammasome activation exacerbates infectious disease caused by pathogens such as Listeria monocytogenes, Staphylococcus aureus, and severe acute respiratory syndrome coronavirus 2. Although these pathogens activate host inflammasomes to regulate pathogen expansion, the mechanisms by which pathogen toxins contribute to inflammasome activation remain poorly understood. Here we show that activation of inflammasomes by Listeria infection is promoted by amino acid residue T223 of listeriolysin O (LLO) independently of its pore-forming activity.

Dysregulation of Cytosolic c-di-GMP in Promotes Cellular Non-Canonical Ferroptosis.

Programmed cell death plays an important role in modulating host immune defense and pathogen infection. Ferroptosis is a type of inflammatory cell death induced by intracellular iron-dependent accumulation of toxic lipid peroxides. Although ferroptosis has been associated with cancer and other sterile diseases, very little is known about the role of ferroptosis in modulating host-pathogen interactions.

Mechanisms regulating DMTF1β/γ expression and their functional interplay with DMTF1α.

The cyclin D binding myb‑like transcription factor 1 (DMTF1), a haplo‑insufficient tumor suppressor gene, has 3 alternatively spliced mRNA isoforms encoding DMTF1α, β and γ proteins. Previous studies have indicated a tumor suppressive role of DMTF1α and the oncogenic activity of DMTF1β, while the function of DMTF1γ remains largely undetermined. In the present study, the mechanisms regulating DMTF1 isoform expression were investigated and the functional interplay of DMTF1β and γ with DMTF1α was characterized.

Comparison of PD-L1 protein expression between primary tumors and metastatic lesions in triple negative breast cancers.

Programmed Death Ligand 1 (PD-L1) positivity rates differ between different metastatic sites and the primary tumor. Understanding PD-L1 expression characteristics could guide biopsy procedures and motivate research to better understand site-specific differences in the tumor microenvironment. The purpose of this study was to compare PD-L1 positivity on immune cells and tumor cells in primary and metastatic triple negative breast cancer (TNBC) tumors.

Improved cancer detection in Waldeyer's tonsillar ring by Ga-FAPI PET/CT imaging.

Purpose: In cancer of unknown primary (CUP), positron emission tomography/computed tomography (PET/CT) with the glucose analog [F]FDG represents the standard imaging approach for localization of the malignant primary. Frequently, however, [F]FDG PET/CT cannot precisely distinguish between small occult tumors and chronic inflammation, especially in Waldeyer's tonsillar ring. To improve the accuracy for detecting primary tumors in the Waldeyer's tonsillar ring, the novel PET tracer [Ga]Ga-FAPI-4 for specific imaging of fibroblast activation protein (FAP) expression was used as a more specific target for cancer imaging.

Factors influencing agreement of breast cancer luminal molecular subtype by Ki67 labeling index between core needle biopsy and surgical resection specimens.

Reliable determination of Ki67 labeling index (Ki67-LI) on core needle biopsy (CNB) is essential for determining breast cancer molecular subtype for therapy planning. However, studies on agreement between molecular subtype and Ki67-LI between CNB and surgical resection (SR) specimens are conflicting. The present study analyzed the influence of clinicopathological and sampling-associated factors on agreement.

RTK signaling requires C3ar1/C5ar1 and IL-6R joint signaling to repress dominant PTEN, SOCS1/3 and PHLPP restraint.

How receptor tyrosine kinase (RTK) growth signaling is controlled physiologically is incompletely understood. We have previously provided evidence that the survival and mitotic activities of vascular endothelial cell growth factor receptor-2 (VEGFR2) signaling are dependent on C3a/C5a receptor (C3ar1/C5ar1) and IL-6 receptor (IL-6R)-gp130 joint signaling in a physically interactive platform. Herein, we document that the platelet derived and epidermal growth factor receptors (PDGFR and EGFR) are regulated by the same interconnection and clarify the mechanism underlying the dependence.

Microbial Metabolite Signaling Is Required for Systemic Iron Homeostasis.

Iron is a central micronutrient needed by all living organisms. Competition for iron in the intestinal tract is essential for the maintenance of indigenous microbial populations and for host health. How symbiotic relationships between hosts and native microbes persist during times of iron limitation is unclear.

ASC and NLRP3 maintain innate immune homeostasis in the airway through an inflammasome-independent mechanism.

It is widely accepted that inflammasomes protect the host from microbial pathogens by inducing inflammatory responses through caspase-1 activation. Here, we show that the inflammasome components ASC and NLRP3 are required for resistance to pneumococcal pneumonia, whereas caspase-1 and caspase-11 are dispensable. In the lung of S.

Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome.

The NLRP3 inflammasome can be activated by stimuli that include nigericin, uric acid crystals, amyloid-β fibrils and extracellular ATP. The mitotic kinase NEK7 licenses the assembly and activation of the NLRP3 inflammasome in interphase. Here we report a cryo-electron microscopy structure of inactive human NLRP3 in complex with NEK7, at a resolution of 3.

PD-L1 Expression in Mastocytosis.

Programmed death 1 (PD-1), when activated by its ligands PD-L1 and PD-L2, suppresses active immune cells in normal immune regulation to limit autoimmunity and, in tumors, as a mechanism of immune evasion. PD-L1 expression has been described as both a prognostic and predictive marker in many solid and hematologic neoplasms, as targeted therapies against the PD-1/PD-L1 interaction have gained clinical importance. PD-L1 expression has been assessed in a few studies on mastocytosis.