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Our Monthly Top Picks

This Collection highlights the newest top-viewed content from Laboratory Investigation. Updated each month, we hope you enjoy reading this selection of articles. Laboratory Investigation aims to publish high-quality original research in all biomedical disciplines relating to the understanding of human disease and the application of new methods to the diagnosis of disease.

April

The authors used artificial intelligence to estimate gestational age from scanned whole-slide images of placenta. They developed attention and aggregation deep learning methods because of the large volume of data and tissue heterogeneity. This study provides proof-of-concept in unannotated, unknown images with high accuracy.

Article | | Laboratory Investigation

The authors examined late- and early-onset murine retinoblastoma tumors and noted that aggressive tumors uniquely expressed an immune gene expression signature. This led to accumulation of a variety of immune cells, including T-lymphocytes, that was not observed in less aggressive tumors. Gene expression analysis identified the immune signature in human and other murine tumors, and they observed it correlated with less proliferative tumors.

Article | | Laboratory Investigation

Immune cells are involved in skeletal muscle regeneration, but the mechanisms are unclear. In this paper, the authors show that programmed death-1 (PD-1), a key immunosuppressive receptor that is involved in adaptive immune responses, can promote contused skeletal muscle regeneration by regulating Treg cell generation and macrophage polarization.

Article | Open Access | | Laboratory Investigation

The authors show that intraperitoneal injection of tubeimoside I (TBM) alleviates the endothelial dysfunction caused by sepsis. Their results suggest that TBM functions by reducing oxidative stress and apoptosis via SIRT3, an NAD-dependent deacetylase. TBM is therefore a promising new therapeutic agent against sepsis-induced endothelial dysfunction.

Article | | Laboratory Investigation

The authors provide evidence that EZH2 inhibits miR-138 expression by histone methylation of its promoter, which induces cartilage degeneration in osteoarthritis models by upregulating expression of the syndecan proteoglycan SDC1. These results suggest a novel mechanistic strategy for future treatments.

Article | | Laboratory Investigation

The authors extensively defined feline low-grade intestinal T-cell lymphoma on the clinical, laboratory, radiological, histologic and molecular levels and demonstrated it is a relevant model for human T-cell lymphoproliferative disorder of the gastrointestinal tract, a rare and poorly described entity. Based on these findings, the group also proposed a new model of digestive T-cell lymphomagenesis.

Technical Report | | Laboratory Investigation

In this article the authors demonstrate that monomeric C reactive protein (mCRP) increases NOS2, COX2, MMP13, VCAM1, IL-6, IL-8, and LCN2 expression in chondrocytes. mCRP exerts a sustained catabolic effect on chondrocytes, increasing the expression of inflammatory mediators and proteolytic enzymes, which can promote cartilage extracellular matrix breakdown and osteoarthritis development and progression.

Article | | Laboratory Investigation

The m6A modification level of LncRNA FENDRR is elevated in endometrioid endometrial carcinoma (EEC) cells and the abundant m6A modification promotes FENDRR degradation via recruiting the m6A binding protein YTHDF2. Subsequently, the downregulation of FENDRR resulted in the accumulation of SOX4 protein, thus boosting the proliferation of EEC cells

Article | | Laboratory Investigation

March

The breast cancer immune microenvironment was analyzed with the nanoString GeoMx® Digital Spatial Profiler (DSP) in cases from the Carolina Breast Cancer Study. Basal-like breast cancers showed increased expression of markers for regulatory T cells. The results were highly reproducible between whole sections and tissue microarrays.

Technical Report | | Laboratory Investigation

Most current biomedical datasets are rectangular in shape and have few missing data, but the sample sizes are very large. Rigorous analyses of these huge datasets demand considerably more efficient and more accurate machine-learning algorithms to classify outcomes. This paper aims to determine the performance and efficiency of classifying multi-category outcomes of such rectangular data.

Article | | Laboratory Investigation

The authors developed a deep-learning-based ductal carcinoma in situ (DCIS) grading system that achieved performance similar to expert observers. To the best of our knowledge, this is the first automated system for the grading of DCIS that could assist pathologists by providing robust and reproducible second opinions on DCIS grade.

Technical Report | Open Access | | Laboratory Investigation

The findings of the present study demonstrate that inflammasome NLRP3 deficiency did not attenuate, but enhanced hepatocellular steatosis, injury and death, inflammation, and fibrosis, as well as insulin resistance in both liver and adipose tissues. This effect is probably due to an enhanced inflammatory response with elevated monocyte chemotactic protein-1 and M1 microphages.

Article | | Laboratory Investigation

This manuscript describes a methodology to quantify the abnormalities in digital cytology images. This automatic AI-system incorporates deep learning structures, mathematical algorithms, and image processing methods to locate and segment abnormal and suspicious cells. Characterized as more informative, objective, and reproducible, it has the potential to assist clinical practice.

Article | | Laboratory Investigation

Dimethylarginine dimethylamino hydrolase-1 (DDAH-1), as the critical enzyme responsible for asymmetric dimethylarginine (ADMA) degradation, serves as a protective factor for ischemic stroke. DDAH-1 protects ischemia-induced disruption of blood-brain-barrier via regulating ADMA level and preventing tight junction proteins degradation. The supplementation of L-arginine helps restore the function of DDAH-1.

Article | | Laboratory Investigation

February

Data processing and learning has become a spearhead for the advancement of medicine. Computational pathology is burgeoning subspecialty that promises a better-integrated solution to whole-slide images, multi-omics data and clinical informatics as innovative approach for patient care. This review describes clinical perspectives and discusses the statistical methods, clinical applications, potential obstacles, and future directions of computational pathology.

Review Article | | Laboratory Investigation

Tissue cytometry is a promising new microscopy technique that can be used to enumerate and characterize each cell in a tissue. Here the authors describe a complete and accessible pipeline, including methods of sample preparation, microscopy, image analysis, and data analysis for large-scale three-dimensional tissue cytometry of human kidney tissues.

Technical Report | | Laboratory Investigation

Real-time lipid patterns can identify liver tumors and their inter-tumor and intra-tumor heterogeneity. Ceramides and related sphingolipids are a common feature of necrotic tumors and can characterize the tumor phenotype based on metabolic shifts relevant for cell death pathways. Lipid patterns have the potential to improve clinical decision-making in the near future.

Article | | Laboratory Investigation

Using approaches involving chimeric mice and macrophage-adipocyte cocultures, the authors demonstrate that PFKFB3 disruption only in hematopoietic cells exacerbates the severity of diet-induced adipose tissue inflammation and systemic insulin resistance. Mechanistically, macrophage factors generated in response to PFKFB3 disruption act to enhance adipocyte proinflammatory responses and impair adipocyte insulin signaling.

Article | | Laboratory Investigation

The abnormal differentiation of Th17 cells is a vital promoter of immune thrombocytopenia (ITP) progression. In this study, the authors found that miR-199a-5p is downregulated during ITP. Supplementation of extracellular vesicles (EVs) derived from miR-199a-5p-modified ADSCs markedly repress Th17 differentiation by transferring miR-199a-5p to CD4+T cells, thus ameliorating experimental ITP.

Article | | Laboratory Investigation

In this study, the authors reveal that the hypoxic microenvironment stimulates glioma to generate miR-1246- and miR-10b-5p-rich exosomes, which are delivered to normoxic glioma cells to promote their migration and invasion by targeting FRK and TFAP2A respectively. Treatment targeting the exosomes and microRNAs may impair the motility of gliomas, providing a novel direction for the development of antitumor therapy.

Article | | Laboratory Investigation

Recent studies highlight a prominent role of human lung pericytes in lung diseases. However, human lung pericytes usually stop growth within ten passages. This study successfully established an immortalized human lung pericyte cell line, which exhibited sustained proliferation, retained pericyte characteristics and function, is a promising tool for in vitro pericyte studies.

Article | | Laboratory Investigation

Genome-wide association studies have linked Forkhead Box F1 (FOXF1) to Barrett’s esophagus (BE) but functional data are lacking. Using in vitro models and human material, the authors found that FOXF1 promotes columnar phenotype and cell motility in esophageal squamous epithelial cells, which may have a critical role in BE development.

Article | | Laboratory Investigation

PLODs play important roles in cancer progression. In silico analysis of PLOD expression in ovarian cancer was performed. PLOD-enriched pathways and related genes were validated by immunohistochemistry in OvCa tissue blocks and in vivo xenograft murine models. PLODs are generally overexpressed in OvCa and each PLOD may be functionally non-redundant.

Article | | Laboratory Investigation

The authors report the successful assessment of LD-RT-PCR, a cheap, fast, sensitive, specific, and easily upgradable assay for routine detection of theranostic gene translocations and MET exon 14 skipping in thoracic oncology. It appears to be an excellent cost-effective alternative to FISH and to more expensive and complex assays such as RNA-seq.

Technical Report | | Laboratory Investigation

January

Nitric oxide (NO) plays an important role in tumor biology, including the generation and maintenance of cancer stem cells (CSCs) subpopulations. Here the authors show that the inhibition of NO production in estrogen-positive breast cancer not only impact the CSC subpopulation but also enhance the efficacy of hormonal therapy with tamoxifen.

Article | | Laboratory Investigation

Vascular endothelial growth factor secreted by placenta-derived mesenchymal stem cells (PD-MSCs) promotes follicular development and ovarian function after ovariectomy through vascular remodeling. These results provide fundamental data for understanding the therapeutic mechanisms of stem cell therapy based on placenta-derived mesenchymal stem cells PD-MSCs and provide a theoretical foundation for their application for obstetrical and gynecological diseases, including infertility and menopause.

Article | Open Access | | Laboratory Investigation

The authors show that plasminogen activator inhibitor-1 (PAI-1) derived from cancer-associated fibroblasts promotes the invasion of esophageal squamous cell carcinoma (ESCC) cells and the migration of macrophages via lipoprotein receptor-related protein 1 (LRP1). High expression of PAI-1 and/or LRP1 is associated with poor prognosis in patients with ESCC, and the PAI-1/LRP1 axis could be a target of anticancer therapy.

Article | Open Access | | Laboratory Investigation

This study shows that exercise increases adropin levels and inhibits NLRP3 inflammasome activation in mice with diet-induced nonalcoholic steatohepatitis (NASH). Furthermore, adropin suppresses palmitic acid-induced NLRP3 inflammasome activation in hepatocytes and Kupffer cells. These results indicate that exercise may inhibit NLRP3 inflammasome activation via adropin induction, resulting in NASH improvement.

Article | | Laboratory Investigation

Disorders involving injury to tissue stem cells may show unusually devastating clinical consequences. In acute graft-versus-host disease (aGVHD) relatively few cytotoxic immune cells target skin stem cells to produce significant morbidity and mortality. By analogy, SARS-CoV-2 initially homes to pulmonary stem cells that preferentially express the ACE2 receptor, thus potentially incurring similarly robust pathological consequences. As with aGVHD, lung stem cell targeting is a potential co-factor in explaining age-related severity of COVID-19 infection.

Mini Review | | Laboratory Investigation

This study demonstrates that ATF-3 plays a suppressive function in melanoma tumor progression via a significant decrease in expression in metastatic melanoma and correlation with tumor virulence. ATF-3 overexpression significantly inhibits cell growth, migration, and invasion in vitro, and abrogates tumor growth in a human melanoma xenograft mouse model in vivo.

Article | | Laboratory Investigation

This study confirms that the expression of GTSE1 in prostate cancer is significantly increased and negatively correlated with patient prognosis. Furthermore, GTSE1 promotes prostate cancer cell proliferation via the SP1/FOXM1 signaling pathway, which facilitates tumorigenesis and progression. These results suggest that GTSE1 has potential value as a prognostic marker and therapeutic target in prostate cancer.

Article | | Laboratory Investigation

Chronic stress can change hepatic lipid accumulation via elevation of hepatic β-muricholic acid levels in nonalcoholic steatohepatitis mice, disrupting bile acid homeostasis by induction of hepatic Cyp7a1 expression. This study describes a new role βMCA in the liver, indicating its potential usefulness for nonalcohol fatty liver disease therapy.

Article | | Laboratory Investigation

The correlation between SMAD4 mutations and clinico-molecular features in a Chinese non-small cell lung cancer (NSCLC) cohort was studied using next-generation sequencing. Integrated bioinformatics analyses based on public databases were conducted to further investigate the prognostic value of SMAD4. Results showed that SMAD4 alteration was associated with poor survival and resistance to platinum-based chemotherapy, suggesting that SMAD4 alteration might be a predictive marker in NSCLC.

Article | | Laboratory Investigation

This paper reports the optimisation of digital pathology approaches for evaluating drug responses in patient-derived explants at endpoint. The authors compare three image analysis software platforms and find that all three generate comparable data to that of a histomorphometrist. They also demonstrate the power of multi-immunofluorescence staining for monitoring multiple biomarkers simultaneously compared to virtual double staining of sequential sections by immunohistochemistry.

Article | | Laboratory Investigation