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The authors demonstrate that carnitine palmitoyltransferase 1A (CPT1A) expression is reduced in glioma stem cells (GSCs) in comparison with non-stem tumor cells. CPT1A overexpression promotes mitochondrial fusion and GSC differentiation by increasing the phosphorylation of dynamin-related protein 1 (Drp1) at Ser-637, thus impairing GSC-derived xenograft growth and prolonging survival in tumor-bearing mice. These results suggest that CPT1A could be a molecular target for GSC differentiation therapy.
The authors synthesized formalin-fixed paraffin-embedded (FFPE)-like images (“virtual FFPE”) from frozen (FF) section samples. Five board-certified pathologists evaluated the results in a blinded test. Clinical assessments of disease on the virtual FFPE images showed a higher inter-observer agreement compared to FF images. These findings suggest that virtual FFPE images can increase the quality and speed of histopathologic examinations without adding to cost or effort.
Conventional histological and cytological stains, including hematoxylin & eosin and Papanicolaou, are combined with immunohistochemistry and simultaneously evaluated on the same specimen slide by use of invisible chromogens. Visible and invisible light used to illuminate the specimen are separated and directed to color and monochrome cameras, respectively, providing conventional stain and immunohistochemistry in side-by-side videos on the computer monitor. Alternatively, multispectral imaging of single microscope fields provides archiving and further evaluation utilizing image processing.
Neuroendocrine prostate cancer (NEPC) is an aggressive prostate cancer (PCa) variant. The exact mechanism underlying PCa development remains unclear due to the limited availability of NEPC models. In this review, the authors summarize strategies for NEPC model development and methods for model evaluation; discuss the origin of NEPC and the neuroendocrine transformation mechanism; and propose the challenges associated with research on NEPC. This study provides valuable insights into NEPC development and reveals potential therapeutic targets for NEPC.
Commensal microbe effects on alveolar bone homeostasis have been attributed to the oral microbiota, yet the impact of commensal gut microbes is unknown. Studies performed with segmented filamentous bacteria (SFB) monoassociated mice revealed commensal gut microbes modulate osteoimmune responses and skeletal homeostasis in alveolar bone. This work challenges the current paradigm that alveolar bone health is strictly regulated by oral microbes.
Cell-free DNA (cfDNA) profiling as liquid biopsy is of clinical utility in carcinomas of adult-onset. However, its application in childhood cancers, including brain tumors, has not been as extensively studied. In this article, we review the current status of applying cfDNA analysis for pediatric central nervous system neoplasms. Technical challenges, evidence for utility based on current literature, and potential future developments are discussed.
This study reveals a novel role for the stress-response protein sirtuin 6 (SIRT6) in modulation of glucolipid metabolism disorders in the liver and pancreas under conditions of overnutrution and starvation. The authors show that SIRT6 regulates SREBP1c through the AMPKα-mTORC1 pathway, which and then affects glucolipid metabolic enzymes in an LXR-independent pathway.
Osteosarcoma is a tumour with a highly complex genome, which hampers the identification of driver genes. Using a model of murine mesenchymal stem cells (MSCs) with deficient p15Ink4b, p16Ink4a, or p19Arf that transform earlier compared to wild-type MSCs, the authors demonstrated that loss of p16Ink4a is a driver of osteosarcomagenesis. This can be exploited with a CDK4/CDK6 inhibitor, as osteosarcoma cells showed sensitivity to palbociclib which might be used as a novel therapeutic option.
Under high-glucose conditions, LECs obtain characteristics of mesenchymal cells such as high migratory capacity and invasiveness, which is the foundational basis for DC progression. The authors demonstrated that lncRNA GAS5 facilitates high glucose-induced lens epithelial cell migration and epithelial-to-mesenchymal transition by regulating the miR-204-3p/TGFBR1 axis. This study, therefore, provides novel insights into the pathogenesis of DCs.
The smoothened (SMO) receptor maintains levels of insulin-like growth factor 1 receptor (IGF1R) in several types of cancer cells, and high protein levels of both receptors correlate with poor survival in diffuse large B-cell lymphoma (DLBCL) patients. Loss of SMO favors IGF1R degradation over recycling, and IGF1R-mediated AKT/PI3K signaling, but MAPK is not significantly impaired. The preferential disruption of AKT signaling correlates with a loss of IGF1R and AKT in raft microdomains.
Cholangiocytes are the primary targets of cholangiopathies. This study elucidates the role of miR-200c in maintaining cholangiocyte homeostasis making use of cell culture and mouse models of cholestasis. MiR-200c restrains the proliferative and neuroendocrine-like activation of cholangiocytes by targeting sestrin 1(SESN1) and inhibiting the IL-6/AKT feedback loop to prevent cholestatic liver injury. The findings provide critical mechanistic insights into biliary liver fibrosis and suggest miR-200c may be a novel therapeutic target of cholangiopathies.
Thioredoxin domain containing 5 (TXNDC5) is highly expressed in patients with septic shock. It is also upregulated in mice with lipopolysaccharide (LPS)-induced sepsis and mouse macrophages subjected to LPS stimulation. Txndc5 depletion reduced inflammatory cytokine production and affected recruitment of macrophages and neutrophils in LPS-challenged mice. TXNDC5 inhibition alleviated LPS-induced sepsis by inhibiting the nuclear factor kappa B signaling pathway. These findings suggest that TXNDC5 inhibition may be a therapeutic approach for sepsis.
The authors examined 13 mismatch repair-deficient (MMRD)-associated primary brain tumors to determine molecular characteristics and biological behavior. MMRD occurred after chemotherapy and radiotherapy in two cases. The genetic profile of MMRD glioblastoma was different from that of conventional glioblastoma. Half of the MMRD-gliomas and all Lynch syndrome-associated GBMs were high in microsatellite instability. These tumors had high mutational burdens and tended to have shorter progression-free survival than glioma without MMRD.
Rare tumors, such as mesenchymal chondrosarcoma (MCS) lack effective treatments partly due to unavailability of research models. The authors developed novel in vitro and in vivo MCS models and validated them at the single-cell RNA level. MCS dependencies were identified and coupled with clinically available therapies. Imatinib showed the highest selectivity and cytotoxicity in both models.
An artificial intelligence (AI) model was developed to discriminate between fibroadenomas and phyllodes tumors on core biopsy images. It employed a two-stage architecture comprising a convolutional neural network (CNN) component for feature extraction, and a recurrent neural network (RNN) component for whole-slide classification, with an overall slide-level accuracy of 87.5%.
This study confirms the preservation of EZH2 overexpression in 22 patient-derived orthotopic xenograft models of pediatric brain tumors. The authors demonstrate the activity of an FDA-approved EZH2 inhibitor, tazemetostat, alone and in combination with radiation in a subset of the models, and identifies EZH2-negative cells as potential cause of therapy resistance.