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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.

January

The authors show that 13-cis-retinoic acid (13cRA) has an antiproliferative effect in MYCN-amplified neuroblastoma cells. Poly (I:C) synergized with 13cRA enhances anti-apoptotic effects through innate immune signaling and mitochondrial stress response in 13cRA-responsive neuroblastoma cells. In addition, a combination of 13cRA/poly (I:C) induces neural differentiation and inhibits vessel formation, leading to retarded tumor growth.

Article | | Laboratory Investigation

Unlike C57BL/6-KitW-sh/W-sh mice, BALB/c-KitW-sh/W-sh mice exhibit wild-type levels of airway hyperresponsiveness and lung inflammation and remodeling in two models of allergic airway inflammation. By contrast, neither genotype exhibits signs of IgE-dependent passive cutaneous anaphylaxis. Thus, genetic background influences the apparent importance of mast cells in different models of allergic diseases.

Article | | Laboratory Investigation

This work examines the pathogenesis of angiotensin II (Ang-II)-induced muscle wasting. The authors show that Ang II increases NLRP3 inflammasome activation and mitochondrial reactive oxygen species generation. Additionally, PPAR-γ agonist can protect against Ang II-induced muscle wasting by preventing mitochondrial dysfunction (MtD), oxidative stress, and NLRP3 inflammasome activation. Targeting the PPAR-γ/MtD/NLRP3 inflammasome axis may therefore provide a therapeutic approach for muscle wasting.

Article | | Laboratory Investigation

The S100A4/non-muscle myosin II-related signal cascade may contribute to the establishment and maintenance of epithelial mesenchymal transition/cancer stem cell properties, along with changes in cell proliferation and migration capability. These events may be initiated in carcinomatous components in uterine carcinosarcoma and lead to divergent sarcomatous differentiation.

Article | | Laboratory Investigation

The pathological significance of adipophilin (ADP), a primary protein component of lipid droplets, in cancer remains unclear. Here the authors show that high ADP expression in malignant melanoma is significantly associated with high proliferation and poor clinical prognosis. Cell-based assays supported the importance of ADP in tumor proliferation. They propose that ADP is a marker of aggressive melanoma with a lipogenic phenotype.

Article | | Laboratory Investigation

The authors investigated the effects of castration-induced stromal remodeling and subsequent aberrant activation of epithelial–stromal interactions on reconstituted human prostate-like epithelium. They demonstrate that castration-induced stromal remodeling disrupted the reconstituted epithelial structure and induced the appearance of tenascin-C-positive fibroblasts, accompanied by activation of TGF-β signaling. The alteration of prostate stromal structure may be responsible for loss of the basement membrane and epithelial cell polarity.

Article | | Laboratory Investigation

The central nervous system damage in neonatal mice with EV-A71 infection may be caused by activated fetal cerebral astrocytes related to the immune response to the virus, including the disruption of the functioning of the brainstem through increased cytokines and neurotransmitters, rather than the typical cytopathic effect of viral infection.

Article | Open Access | | Laboratory Investigation

This study shows that TRPC5 is an important negative regulator of retinal ganglion cell (RGC) axonal outgrowth and an important regulator of neurite remodeling. The authors hypothesize that TRPC5 senses abnormal intraocular pressure changes and contributes to the death of RGCs in disease. In glaucoma, for example, excessive Ca2+ entry through TRPC5 might induce dendritic and axonal remodeling, which could lead to cell death.

Article | | Laboratory Investigation

Transient receptor potential cation channel subfamily V (TRPV) can be overexpressed in breast cancer. TRPV channels play important roles in breast cancer cell proliferation, migration, and cell death as well as the tumor microenvironment and cancer-associated pain. This review provides an overview of TRPV channels in the context of breast cancer.

Review Article | | Laboratory Investigation

In this study, the authors show that arctigenin (AG) inhibits the inflammatory myeloid phenotype and alleviates heart damage after myocardial infarction. Mechanically, the transcription factor NFAT5 is involved in the cardioprotective effect of AG via the JAK/STAT and NF-κB signaling pathways.

Article | | Laboratory Investigation

December

The expression of the stimulator of interferon genes (STING) in liver tissues is associated with the progression of human nonalcoholic fatty liver disease. Specifically, STING-expressing macrophages, in particular, monocyte-derived macrophages, are positively correlated with the degree of liver inflammation and/or fibrosis progression, which appeared to be mediated by the activation of the STING-TBK1 signaling pathway in macrophage.

Article | | Laboratory Investigation

In the glioma microenvironment, tumor-associated macrophages secrete large amounts of chemokine (C-C motif) ligand 8 CCL8, which contributes to pseudopodia formation of glioblastoma cells and promotes progression of glioma. CCL8 induces invasion and stem-like traits of glioblastoma cells via CCR1/ CCR5-mediated ERK1/2 activation.

Article | | Laboratory Investigation

The hedgehog pathway is pivotal in basal cell carcinoma and medulloblastoma development. Gorlin syndrome-derived, induced pluripotent stem cells (iPSCs) carrying a heterozygous mutation in PTCH1, a hedgehog target gene, exhibited high GLI1 expression and enhanced sensitivity to a hedgehog pathway inhibitor after neural differentiation. These iPSCs can serve as a model for hedgehog pathway-related tumors.

Technical Report | | Laboratory Investigation

The authors evaluated the efficiency of different maternal diet interventions on reducing the risk for offspring nonalcoholic fatty liver disease due to maternal overnutrition. They found that that different maternal diet interventions prime the lipid metabolism differently via changes in lipogenesis and β-oxidation through insulin/AKT signaling and 5′ AMP-activated protein kinase signaling.

Article | | Laboratory Investigation

The authors examined the mechanisms underlying the lineage switch from prostate adenocarcinoma (AdPC) to lethal neuroendocrine prostate cancer (NEPC). They identified SRY-related HMG-box gene 2 (SOX2) as a potential repressor that causes decreased expression of AdPC-specific genes in NEPC. The repressor role of SOX2 is attributed to the marked global hypomethylation of histone H3, which is driven by the activation of lysine-specific demethylase 1 (LSD1).

Article | | Laboratory Investigation

Vascular endothelial growth factor increases the profibrotic activity of atrial fibroblasts by activating the currents through transient receptor potential channels and intermediate-conductance calcium-activated K+ (KCa3.1) channels and by enhancing Ca2+ entry-induced phosphorylated Ca2+/calmodulin-dependent protein kinase II (CaMKII) signaling. These findings suggest a novel strategy targeting atrial myopathy and arrhythmofibrosis.

Article | | Laboratory Investigation

November

The authors reveal that TRPV4, a thermosensitive ion channel, is constitutively active in the brain. They found that local brain temperature is increased at epileptogenic foci, and that hyperthermia lead TRPV4 over-activation and hyper-neuronal activities. Notably, brain cooling treatment drastically suppresses epileptic discharges dependent on the inactivation of TRPV4.

Article | | Laboratory Investigation

Digital image analysis (DIA) of multiplex fluorescence-based immunohistochemistry and visual chromogenic evaluation of CDX2, SOX2, SOX9, E-cadherin, and β-catenin in colorectal cancer are comparable, recognizing prognostic value of CDX2 and negative correlation with SOX2. Membrane staining is best evaluated visually, while DIA enables single-cell coexpression analysis and improves visualization and detection of clinicopathological and biological associations.

Technical Report | Open Access | | Laboratory Investigation

Transient receptor ion channels have emerged as critical channels/receptors in numerous physiological and pathological conditions. In this paper the authors discuss our current understanding of the role of macrophage transient receptor potential channel subfamily V member 4 (TRPV4) in various inflammatory conditions.

Review Article | | Laboratory Investigation

The authors investigated the potential mechanisms of interleukin-33 (IL-33) in the pathogenesis of ulcerative colitis. IL-33 was found to sustain mucosal inflammation by down-regulation of protective ABCG5/8 during recovery from colitis. These results may help to increase understanding regarding the IL-33-mediated pathogenesis of ulcerative colitis and potentially contribute to creation of a novel therapeutic strategy.

Article | | Laboratory Investigation

The two Na+ and water pore-forming claudins, claudin-2 and claudin-15, are reciprocally regulated during human development. This study shows that expression of these claudins is altered in celiac disease, graft-versus-host disease, and common variable immunodeficiency, but that the specific claudin affected differed between children and adults, suggesting distinct contributions to diarrheal pathophysiology.

Article | | Laboratory Investigation

In this paper, the authors found that conditional ablation of Shp2 in mouse K14-positive corneal epithelium (Shp2K14ce-cko) impairs corneal innervation and results in corneal epithelial thinning, which resembles neurotrophic keratopathy. Furthermore, the data indicate that Shp2 signaling plays a pivotal role in corneal epithelial homeostasis.

Article | | Laboratory Investigation

The expression of HIP/PAP and its mouse counterpart, Reg3B, is markedly unregulated in fibrotic livers. Ectopic HIP/PAP potently protects from CCl4- and BDL-induced liver fibrosis in mice. This study shows that downregulation of TGF-βRII expression is one of the important underlying mechanisms for HIP/PAP in suppression of hepatic fibrosis.

Article | | Laboratory Investigation

Polydatin (PD) protects against LPS-induced vascular leakage in multiple organs and this effect is dependent on SIRT3 activation. PD enhances SIRT3-mediated deacetylation of SOD2 and CypD, thus suppressing mitochondrial dysfunction and subsequent endothelial barrier dysfunction. In addition, RAGE is involved in LPS-regulated SIRT3 signaling.

Article | | Laboratory Investigation

October

The paper describes a fully automated numerical analysis for an unbiased quantification of non-alcoholic fatty liver disease (NAFLD) histological features in rodent models. The technique offers a quantitative high-throughput method to rapidly detect NAFLD in large preclinical studies and for accurately monitoring disease evolution.

Technical Report | | Laboratory Investigation

In this study, the authors show that RIP1/RIP3/MLKL-mediated necroptosis is activated in a mouse model of Parkinson’s disease. Blockade of necroptosis through pharmacological intervention by Nec-1 or deletion of RIP3/MLKL gene increased dopamine levels and the number of dopaminergic neurons in mice. Moreover, necroptosis enhanced the expression of pro-inflammatory genes, which may have initiated neuroinflammation and in turn aggravated dopaminergic neuron necroptosis.

Article | | Laboratory Investigation

This study shows a negative regulation of autophagy-related RNA transcripts and the upregulation and downregulation of p62 and LC3-B proteins, respectively, in the central nervous system of scrapie-infected transgenic mice at clinical stage. These findings likely reflect an impairment of the autophagic pathway at the late symptomatic stage of prion infection.

Technical Report | | Laboratory Investigation

Bone marrow mesenchymal stem cells (BMSC) or BMSC-derived exosome transplantation improves rat ovarian function after chemotherapy-induced ovarian failure. Furthermore, transfer of miR-144-5p using BMSC-derived exosomes decreases granulosa cell (GCs) apoptosis via the PTEN pathway. Thus, a cell-free therapeutic strategy may be possible for ovarian failure.

Article | | Laboratory Investigation

The authors investigated global analysis coupled shotgun proteomics and in silico metabolic pathway analyses in malignant lymphoma and normal lymphocytes. Trifunctional protein subunit alfa (HADHA) was detected as a lymphoma-specific protein and a prognostic predictor. In vitro, downregulation of HADHA inhibited cell growth and increase susceptibility of cell death stimuli. Therefore, HADHA may be a potential therapeutic target in refractory malignant lymphoma cases.

Article | | Laboratory Investigation

This study reveals that adhesion molecule ICAM-1 is markedly upregulated in the aorta after angiotensin II infusion. Blockage of soluble ICAM-1 prevents Ang II-induced arterial hypertension and vascular remodeling by reducing macrophage adhesion, suggesting that targeting ICAM-1 may represent a new therapeutic target for hypertension.

Article | | Laboratory Investigation

The role of the prostaglandin E1 receptor EP1 in hypertensive kidney disease remains controversial. EP1 mediates thick ascending limb chloride transport response to prostaglandin E2 and inhibits vasopressin-mediated water transport in the inner medullary collecting duct (IMCD). Though the IMCD transport is unaltered by hypertension, its responsiveness to vasopressin is reduced in diabetes. Moreover, EP1 is protective against glomerular and endothelial injury in hypertensive kidney disease, unlike its harmful role in diabetic kidney disease. This highlights the importance of carefully examining disease state (diabetes vs hypertension) when characterizing underlying disease processes.

Article | | Laboratory Investigation

This study suggests a potential mechanism wherein microRNA-21-5p (miR-21-5p) inhibition downregulates autophagy, migration ability, and LC3B expression via PTEN/AKT signaling in electron beam (EB)-irradiated keloid fibroblasts, effectively preventing local invasion and recurrence. Therefore, miR-21-5p could be a new therapeutic target, to replace EB irradiation, and control keloid relapse.

Article | | Laboratory Investigation