Deep learning for digital pathology is hindered by the extremely high spatial resolution of whole-slide images (WSIs). Most studies have employed patch-based methods, which often require detailed ...annotation of image patches. This typically involves laborious free-hand contouring on WSIs. To alleviate the burden of such contouring and obtain benefits from scaling up training with numerous WSIs, we develop a method for training neural networks on entire WSIs using only slide-level diagnoses. Our method leverages the unified memory mechanism to overcome the memory constraint of compute accelerators. Experiments conducted on a data set of 9662 lung cancer WSIs reveal that the proposed method achieves areas under the receiver operating characteristic curve of 0.9594 and 0.9414 for adenocarcinoma and squamous cell carcinoma classification on the testing set, respectively. Furthermore, the method demonstrates higher classification performance than multiple-instance learning as well as strong localization results for small lesions through class activation mapping.
G protein‐coupled estrogen receptor‐1 (GPER), a member of the G protein‐coupled receptor (GPCR) superfamily, mediates estrogen‐induced proliferation of normal and malignant breast epithelial cells. ...However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non‐BCSCs of three patient‐derived xenografts of ER−/PR+ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER‐mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD‐Ser118 to sustain BCSC characteristics. Transfection with a dominant‐negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs.
What's new?
G protein‐coupled estrogen receptor‐1 (GPER) mediates estrogen‐induced proliferation of normal and malignant breast epithelial cells. However, the role of GPER in breast cancer stem cells (BCSC) biology remains unclear. Here, using patient‐derived xenografts of ER–/PR+ breast cancer, the authors found higher expression of GPER in BCSCs than non‐BCSCs. Moreover, the results indicated that stemness features were sustained via GPER‐mediated PKA/BAD phosphorylation. Stimulation by the GPER ligand tamoxifen enhanced BCSC cell viability and population and BAD phosphorylation. The findings revealed a vital role of GPER‐mediated signaling pathways in BCSC survival, suggesting GPER as a potential therapeutic target for eradicating BCSCs.
Molecular biology applications based on gold nanotechnology have revolutionary impacts, especially in diagnosing and treating molecular and cellular levels. The combination of plasmonic resonance, ...biochemistry, and optoelectronic engineering has increased the detection of molecules and the possibility of atoms. These advantages have brought medical research to the cellular level for application potential. Many research groups are working towards this. The superior analytical properties of gold nanoparticles can not only be used as an effective drug screening instrument for gene sequencing in new drug development but also as an essential tool for detecting physiological functions, such as blood glucose, antigen-antibody analysis, etc. The review introduces the principles of biomedical sensing systems, the principles of nanomaterial analysis applied to biomedicine at home and abroad, and the chemical surface modification of various gold nanoparticles.
Urothelial carcinoma (UC), as one of the malignant tumors, has a high incidence, mortality, and poor survival rate. FGFR3 is one of the frequency mutation genetic events of UC. Recent studies have ...reported that FGFR3 mutations are associated with lower aggressiveness and better prognosis of UC, and small molecule compounds with FGFR3 mutations have been developed and treated. However, they are still limited, especially for wild‐type cells. We used Ingenuity Pathways Analysis (IPA) to analyze the significantly expression of 351 genes (>2‐fold change cutoff value) between FGFR3 wild‐type and mutation/fusion UC cells by FGFR3 inhibitors treatment. Through the predicted canonical pathways, several metabolism‐related events have been regulated, including purine biosynthesis. Focusing on de novo purine biosynthesis, we found that several involved enzymes are upregulated in UC. In addition, we have also observed that several enzymes are inhibited by FGFR3 inhibitors in mutant cells, but not in wild type. We then hypothesized that purine biosynthetic events might confer drug resistance and promote UC tumorigenicity. To verify our observations, we determined the expression level of purine biosynthesis after FGFR3 classification. The results indicate a similar trend in clinical cohorts that overexpression of purine biosynthesis genes in FGFR3 wild‐type. Moreover, combining these genes can be used as an independent prognostic factor (HR=1.41, p=0.026). We further established the overexpression of purine biosynthesis genes in some FGFR3 mutant UC cells. We determined that purine biosynthesis genes cause FGFR3 mutations models to be more prone to mesenchymal and metastatic than controls. Our studies also observed that FGFR3 wild‐type cells promote UC cell radioresistance via purine biosynthesis and further activate the homologous recombination repair mechanism. Combining all evidence, we claim that purine biosynthesis should be focused and regarded as a novel strategy against UC.
Cisplatin is the first-line chemotherapy used against most upper aerodigestive tract carcinomas. In head and neck cancer, sensitivity to cisplatin remains the key issue in treatment response and ...outcome. Genetic heterogeneity and aberrant gene expression may be the intrinsic factors that cause primary cisplatin-resistance.
Combination of the HNSCC gene expression data and the cisplatin sensitivity results from public database. We found that aldo-keto reductase family 1 member C1 (AKR1C1) may be associated with cisplatin sensitivity in HNSCC treatment of naïve cells. We examined the AKR1C1 expression and its correlation with cisplatin IC
and prognosis in patients. The in vitro and in vivo AKR1C1 functions in cisplatin-resistance through overexpression or knockdown assays, respectively. cDNA microarrays were used to identify the upstream regulators that modulate AKR1C1-induced signaling in HNSCC. Finally, we used the cigarette metabolites to promote AKR1C1 expression and ruxolitinib to overcome AKR1C1-induced cisplatin-resistance.
AKR1C1 positively correlates to cisplatin-resistance in HNSCC cells. AKR1C1 is a poor prognostic factor for recurrence and death of HNSCC patients. Silencing of AKR1C1 not only reduced in vitro IC
but also increased in vivo cisplatin responses and vise versa in overexpression cells. Cigarette metabolites also promote AKR1C1 expression. Transcriptome analyses revealed that STAT1 and STAT3 activation enable AKR1C1-induced cisplatin-resistance and can be overcome by ruxolitinib treatment.
AKR1C1 is a crucial regulator for cisplatin-resistance in HNSCC and also poor prognostic marker for patients. Targeting the AKR1C1-STAT axis may provide a new therapeutic strategy to treat patients who are refractory to cisplatin treatment.
Thousand and one kinases (TAOKs) are members of the MAP kinase kinase kinase (MAP3K) family. Three members of this subfamily, TAOK1, 2, and 3, have been identified in mammals. It has been shown that ...TAOK1, 2 and 3 regulate the p38 MAPK and Hippo signaling pathways, while TAOK 1 and 2 modulate the SAPK/JNK cascade. Furthermore, TAOKs are involved in additional interactions with other cellular proteins and all of these pathways modulate vital physiological and pathophysiological responses in cells and tissues. Dysregulation of TAOK-related pathways is implicated in the development of diseases including inflammatory and immune disorders, cancer and drug resistance, and autism and Alzheimer's diseases. This review collates current knowledge concerning the roles of TAOKs in protein-protein interaction, signal transduction, physiological regulation, and pathogenesis and summarizes the recent development of TAOK-specific inhibitors that have the potential to ameliorate TAOKs' effects in pathological situations.
The aldolase family members involved in metabolism and glycolysis are present in three isoforms: ALDOA, ALDOB, and ALDOC. Aldolases are differentially expressed in human tissues, and aberrant ...expression has been observed in several human diseases and cancer types. However, non-enzymatic functions through protein–protein interactions or epigenetic modifications have been reported in recent years. Using high-throughput screening and -omics database integration, aldolase has been validated as an independent clinical prognostic marker of human cancers. Therefore, the aim of this review was to provide potential clinical value from in silico predictions and also summarize well-known signaling axes or phenotypes in various cancer types. Finally, we discuss the role of aldolase in the treatment of human diseases and cancers.
The enzymatic and non-enzymatic functions of glycolysis promote tumor cell growth, cell cycle, and cancer metastasis.
Isoforms of aldolases are abundant in the human body and play roles in glycolysis, fructolysis, and the synthesis of glyceraldehyde and ATP.
The expression of aldolase family members is associated with poor survival rates or multiple clinical parameters in several cancer types.
In silico analysis assesses the clinical value of aldolase family members as prognostic and diagnostic markers of human cancers and diseases.
The non-enzymatic functions of aldolases reveal novel phenotypes or signaling through protein–protein interactions.
An outbreak of respiratory illness proved to be infected by a 2019 novel coronavirus, officially named Coronavirus Disease 2019 (COVID-19), was notified first in Wuhan, China, and has spread rapidly ...in China and to other parts of the world. Herein, we reported the first confirmed case of novel coronavirus pneumonia (NCP) imported from China in Taiwan. This case report revealed a natural course of NCP with self-recovery, which may be a good example in comparison with medical treatments.
Background
The abnormal modification of chondroitin sulfate is one of the leading causes of disease, including cancer progression. During chondroitin sulfate biosynthesis, the CHST11 enzyme plays a ...vital role in its modification, but its role in cancer is not fully understood. Therefore, understanding the relationship between CHST11 and pulmonary‐related diseases through clinically relevant information may be useful for diagnosis or treatment.
Methods
A variety of pulmonary fibrosis clinical gene expression omnibus (GEO) datasets were used to assess the association between CHST11‐related manifestations and fibrosis. Multiple lung cancer‐related databases, including The Cancer Genome Atlas, GEO datasets, UCSC Xena, GEPIA2, Cbioportal and ingenuity pathway analysis were used to evaluate the clinical correlation between CHST11 and lung cancer and potential molecular mechanisms. For drug repurposing prediction, the molecules that correlated with CHST11 were subjected to the LINCS L1000 algorithm. A variety of in vitro assays were performed to evaluate the in‐silico models, including RNA and protein expression, proliferation, migration and invasion.
Results
Clinical analyses indicate that the levels of CHST11 are significantly elevated in cases of pulmonary‐related diseases, including fibrosis and lung cancer. According to multiple lung cancer cohorts, CHST11 is the only member of the carbohydrate sulfotransferase family associated with overall survival for lung adenocarcinomas, and it is highly related to smoking‐induced lung cancer patients. Based on the results of in vitro experiments, CHST11 expression contributes to tumor malignancy and promotes multiple fibrotic activators. Correlation‐based ingenuity pathway analysis indicated that CHST11‐related molecules contributed to pulmonary fibrosis or lung adenocarcinomas via similar upstream stimulators. Based on known molecular regulatory relationships, CHST11 has been associated with the regulation of TGF‐β and INFγ as important molecules contributing to fibrosis and cancer progression. Interestingly, WordCloud analysis revealed that CHST11‐related molecules are involved in regulation primarily by integrin signaling, and these relationships were consistently reflected in the analysis of cell lines and the clinical correlation. A CHST11 signature‐based drug repurposing analysis demonstrated that the CHST11/integrin axis could be targeted by AG‐1478 (Tyrphostin AG 1478), brefeldin A, geldanamycin and importazole.
Conclusions
This study provides the first demonstration that CHST11 may be used as a biomarker for pulmonary fibrosis or lung cancer, and the levels of CHST11 were increased by TGF‐β and INFγ. The molecular simulation analyses demonstrate that the CHST11/integrin axis is a potential therapeutic target for treating lung cancer.
In this study, expression of CHST11 was linked to pulmonary related diseases such as fibrosis and lung cancer progression. It may be possible to provide alternative strategies for pulmonary diseases by targeting CHST11‐related events.
Abstract Distant metastasis and recurrence are the greatest challenges in the clinical management of lung cancer. Despite advances in targeted therapies, high mortality rates persist. Therefore, ...alternative therapeutic interventions are urgently required. Accumulating evidence indicates that normalizing tumor metabolism may be a way to increase therapeutic efficacy and to reduce tumor malignancy. Here, we analyzed integrated transcriptomics data and an shRNA library against glycolytic enzymes and found that elevated Aldolase A expression is highly correlated with metastatic potential and a poor prognosis in patients with non-small cell lung cancer (NSCLC). We validated our in silico findings with an immunohistochemical analysis of clinical samples. Aldolase A silencing significantly suppressed metastatic potential both in vitro and in vivo , whereas the ectopic overexpression of Aldolase A resulted in the opposite phenotype. Furthermore, our microarray and Ingenuity Pathway Analyses (IPA) revealed that Aldolase A-driven lung cancer metastasis was closely linked to hypoxia inducible factor 1 alpha (HIF-1α)-downstream signaling. Importantly, Aldolase A overexpression may promote the release of lactate to block PHD activities and further induce HIF-1α stabilization. Aldolase A and nuclear HIF-1α overexpression levels were positively correlated and were significantly associated with a poorer survival rate in lung cancer patients ( P = 0.008 for Overall Survival, P = 0.021 for Disease-free Survival). Furthermore, MMP9, a downstream target of HIF-1α, was significantly upregulated after ALDOA overexpression. A MMP9 inhibitor significantly inhibited cell invasion and migration in ALDOA-HIF-1α axis-induced lung cancer. In summary, our results reveal the molecular mechanism of Aldolase A in promoting lung cancer metastasis via PHD-mediated stabilization of HIF-1α and the subsequent activation of MMP9. The ALDOA-HIF-1α axis may provide a new therapeutic target for metastatic lung cancer treatment.
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