Monthly Readers' Choice

The antibody drug conjugate (ADC) Trastuzumab deruxtecan (T-DXd) has shown activity in breast cancer with low levels of HER2 expression. The historical/conventional assays for HER2 were designed separate high levels of HER2 from intermediate levels and show no expression in the low range. In this study, we determine the optimal dynamic range for unamplified HER2 detection in breast cancer and then design a quantitative assay to stratify HER2 expression in unamplified cases. Assessment of HER2 protein in the optimal dynamic range will ultimately help select the optimal patients for T-DXd and this work can serve as a model for other assays for ADCs where pathology reads may be less accurate that protein measurements.

Current treatments, which mostly aim to restore bowel habits, are ineffective for intestinal pain in irritable bowel syndrome (IBS). Abnormal gut-derived serotonin metabolism and mucosal neurite outgrowth are linked to visceral hypersensitivity. Enhanced mucosal innervation dependent on 5-HT₇ contributes to hyperalgesia in two IBS-like mouse models. A positive-feedback loop between serotonin and neurotrophin is involved in intensifying nerve fiber elongation. A novel 5-HT₇ receptor antagonist may be administered orally as an intestinal analgesic for IBS-related pain.

Targeting Siglec-15 may be an effective alternative therapy for patients that do not respond to PD-1/PD-L1 inhibition. In this study, the authors show broad expression of this potential immune modulatory target in a wide range of cancer types. These data may inform future clinical development and show potential for future companion diagnostic tests for Siglec-15 therapeutics.

The expression of circRTN4 is significantly enhanced in lupus nephritis. Downregulation of circRTN4 expression alleviates extracellular matrix deposition by targeting the miR-513a-5p/FN axis in cultured human renal mesangial cells and pristane-induced BALB/c mice or MRL/lpr mice. In addition, monocyte circRTN4 participates in mesangial cell dysfunction in an exosome-dependent manner. Exosomal circRTN4 mzytherefore be an effective biomarker for lupus nephritis detection and a novel therapeutic target.

The authors carried out a comparative genetic and histopathological study of 15 patient-derived xenografts (PDX) that were newly established from patients with various types of aggressive non-Hodgkin lymphomas. We have demonstrated that despite keeping the same genetic profiles the PDX models do not recapitulate microenvironmental heterogeneity of the original lymphomas. These findings have implications on the relevance of PDX models in the context of preclinical research.

When skeletal muscles undergo ischemia/reperfusion injury, fibroblast growth factor 21 (FGF21), a stress regulator, is upregulated and reduces Drp1 levels, which consequently alleviates abnormal mitochondrial fission and apoptosis. This work provides new insight into relationship between FGF21 and mitochondria and provides a possible therapeutic target for amelioration of muscle ischemia/reperfusion injury.

This study describes how HOTAIRM1 transferred by alveolar epithelial cell (AEC)-derived Exos promotes proliferation and transdifferentiation of lung fibroblasts. The authors reveal the mechanism by which HOTAIRM1 competitively binds to miR-30d-3p and YY1 to upregulate the expression of HSF1. Furthermore, AEC-Exosomes harboring HOTAIRM1 accelerates interstitial pulmonary fibrosis through disrupting miR-30d-3p-mediated HSF1 inhibition and inducing HSF1.

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with no curative therapy. Liquid-liquid phase separation (LLPS) is a biophysical phenomenon in which a homogeneous mixture of solutions separates into two phases. Recently LLPS has gained attention in ALS research because many ALS-causing proteins undergo LLPS, which eventually contribute to protein aggregates. This review summarizes the molecular mechanisms underlying the LLPS of ALS-causing proteins and discusses strategies to develop therapeutics targeting LLPS.

Siglec-15 is normally expressed by myeloid cells and upregulated in some human cancers and represents a promising new target for immunotherapy. The aim of this study was to develop an immunohistochemical assay for Siglec-15 to be used as a companion diagnostic for future clinical trials. Here, the authors created and validated an assay with a novel recombinant antibody to the cytoplasmic domain of Siglec-15. This study may support development of a companion diagnostic assay to enrich for patients expressing the Siglec-15 target for therapy.

As the coronavirus disease 2019 (COVID-19) pandemic evolves, evidence has implicated the heart as a critical target of injury. We examined purported mechanisms of COVID-19-associated heart damage in 21 COVID-19-positive decedents, compared to clinically matched controls and other etiologies of viral myocarditis in a custom tissue microarray, via immunohistochemistry and in situ hybridization. Collectively, COVID-19-associated cardiac injury was multifactorial, with elevated levels of neutrophil extracellular traps and von Willebrand factor as defining features of direct and indirect viral-associated injury.

Multiplexed ion beam imaging by time-of-flight (MIBI-TOF) uses secondary ion mass spectrometry to image dozens of proteins simultaneously in the same tissue section. The authors undertook a validation study, assessing concordance across serial sections of a tissue microarray that were independently imaged by MIBI-TOF or single-plex immunohistochemistry. They demonstrate that MIBI-TOF can generate consistent and quantitative annotations of clinically relevant cell states in archival human tissue and present a scalable framework for benchmarking multiplexed immunohistochemical approaches.

NORAD, a non-coding RNA activated by DNA damage, is highly expressed in osteosarcoma cells and tissue. The authors show that extracellular vesicles (EVs) derived from bone mesenchymal stem cells (BMSCs) deliver NORAD to osteosarcoma cells to regulate the miR-30c-5p/ Krueppel-like factor 10 axis, thereby accelerating the progression and metastasis of osteosarcoma.

In this study, the technical feasibility and the diagnostic value of SNP array analysis on 171 core needle biopsies (CNB) from soft tissue and bone tumors was evaluated. The analysis succeeded technically in 98% of the cases. The copy number profiles were compatible with the CNB diagnoses in 87% of the cases and was in 77% of the cases representative for the whole lesion.

Bronchopulmonary dysplasia (BPD) is still the most common challenge in preterm neonates. The authors found that reactive oxygen species and sCD146 are increased in preterm peripheral blood samples. They then show that the CD146-HIF-1α axis contributes to alveolarization and propose that CD146 may be a novel candidate in BPD therapy.

As IL-34, a macrophage growth factor, is elevated in RA patients, it is considered a therapeutic target. Unexpectedly, inflammatory arthritis in IL-34 null mice and the newly identified IL-34 receptor, PTPRZ, null mice worsened disease. Through macrophage mediated mechanisms, IL-34 and PTPRZ-dependent events limited apoptotic neutrophil rich synovial inflammation and joint destruction. These findings counter the assumption that IL-34 is harmful in RA, and fuel further studies before designing a therapeutic approach for this illness.

The present study reveals that the hepatitis-B (HBV) antigen HBeAg found in HBV⁺HCC upregulates long non-coding RNA MAPKAPK5_AS1 (MAAS) expression in M2 macrophages by affecting its m6A modification. MAAS is transferred to HBV⁺HCC cells via exosomes, which in turn facilitates their proliferation. This is a novel role for MAAS and further elucidates the mechanism of HBeAg-induced HBV-related HCC development.

Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic skin disease caused by mutations in the gene COL7A1. The authors developed a strategy to investigate the impact of each pathogenic mutation on skin integrity using CRISPR-mediated genome editing in mice in order to create a reliable animal model for the study of this devastating disease.

The authors defined the role of DNA methyltransferase 1 (DNMT1) during heart failure and identified the underlying mechanism. DNMT1 enhances the methylation of the miR-152-3p promoter region. DNMT1 also enhances the expression of the transcription factor ETS1, which further elevates RhoH expression. DNMT1 therefore induces heart failure by inhibiting mitophagy of in H9c2 cells through regulating the miR-152-3p/ETS1/RhoH axis.

SLUG is expressed in the myoepithelial cells of normal salivary glands and is highly upregulated in the neoplastic myoepithelial cells and stromal cells of pleomorphic adenoma (PA). SLUG is less likely to be affected by PLAG1. SLUG is involved in the regulation of epithelial-mesenchymal transition (EMT) marker expression in primary cultured PA cells, indicating that SLUG might be a key transcription factor controlling EMT in PA.

Mammals exhibit epidermal patterning, as seen in mouse tail scales and human skin microtopography. In this article, the authors demonstrate that type XVII collagen (COL17), a niche for epidermal stem cells, modulate epidermal patterning in mice and humans. COL17 further prevents wound-induced epidermal deformation. This study paves the way for elucidating the role of the stem cell niche in tissue pattern formation.

This study reveals that miR-483-5p is upregulated by cisplatin treatment and exacerbates cisplatin-induced acute kidney injury via negative regulation of GPX3 and contributes to tubular cell apoptosis. The authors demonstrate that miR-483-5p is a key upstream mediator regulating acute kidney injury induced by cisplatin and may serve as a new target for diagnosis and therapy.

Gastric cancer possesses great histological and molecular diversity, which creates obstacles for rapid and efficient diagnoses. To overcome the limitations of the classic diagnostic procedure in gastric cancer, the authors established a deep learning system to achieve intelligent tumor differentiation grading and microsatellite instability status recognition using hematoxylin-eosin stained whole slide images from 467 patients. They used the convolutional neural network visualization to demonstrate the key pathological features learned by the system to increase system interpretability.

The authors show that LINC01963 is overexpressed in the PC3-DR cells and that LINC01963 silencing enhances the chemosensitivity of PC3-DR to docetaxel and inhibits tumorigenicity and lung metastasis. Silencing of LINC01963 ireduces TrkB protein levels to enhance the chemosensitivity of cells to docetaxel by competitively binding to miR-216b-5p.