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Cell migration, which is often impaired under high glucose (HG) conditions, plays a crucial role in the pathogenesis of various diabetic complications. This study investigates the role of mitochondrial aldehyde dehydrogenase (ALDH2) in the HG-induced migratory inhibition. Using fibroblasts sub-cultured in HG medium as a cell model of chronic hyperglycemia, we found that prolonged exposure to HG stress inhibited cell migration via a novel mechanism independent of oxidative stress or cell death. By increasing osmolality, HG induced perinuclear clustering of mitochondria, enhanced focal adhesion maturation, and caused the cells to be less responsive to migratory cues. The pharmacological inhibition of ALDH2 exaggerated this phenomenon, while ALDH2 overexpression protected cells from the migratory impairment caused by HG-induced hyperosmolality. Cells with ALDH2 overexpression exhibited less mature focal adhesions and longer mitochondrial network, suggesting that ALDH2 might preserve mitochondrial integrity to facilitate the focal adhesion turnover during cell migration.

Poly(ADP-ribose) polymerase (PARP) inhibitors selectively cause the failure of DNA single-stranded break (SSB) repair but do not affect double-stranded break (DSB) repair. Furthermore, antitumor activities have been reported for breast cancer, with germline BRCA1/2 mutations. The prevalence of germline BRCA1/2 mutations never exceed one-tenth; beyond BRCA1/2, genes recurrently altered (more than 5%) in the homologous repair pathway are ARID1A, PALB2, and PTEN. Altered homologous recombination repair genes can total up to one-quarter based on different definitions, and the potential of PARP inhibitors will be elucidated when further studies unraveling the impact of individual homologous recombination genes are conducted.

Glycoprotein non-metastatic B (GPNMB) is a transmembrane protein overexpressed in numerous cancers including triple-negative breast cancers (TNBC). It has been linked to promote cancer aggressiveness and implicated as a novel target for GPNMB-expressing cancers. In current study, we aimed to explore the clinical significance of GPNMB in TNBC. Among 759 specimens, immunohistochemistry (IHC) exhibited GPNMB expressions were variable in different subtypes and significantly higher in TNBC. Kaplan–Meier analysis revealed GPNMB overexpression in TNBC was associated with worse prognosis especially distant metastasis ( P  = 0.020, HR = 2.515, CI 1.154–5.480). Multivariate analysis showed GPNMB expression was an independent prognostic factor in terms of recurrence and distant metastasis ( P  = 0.008, HR = 3.22, CI 1.36–7.61; P  = 0.017, HR = 3.08, CI 1.22–7.74). In silico analysis showed high mRNA expression of GPNMB was associated with distant metastasis and GPNMB was overexpressed in TNBC. Furthermore, GPNMB positively correlated with epithelial–mesenchymal transition (EMT) regulators, mesenchymal marker vimentin, MMP and integrins. The protein levels of Twist and MMP2 were upregulated by GPNMB overexpression in TNBC cells. GPNMB-enhanced cell invasion was attenuated by broad spectrum MMP inhibitor (GM 6001) and the selective inhibitor of MMP-2 (ARP100). In summary, GPNMB expression is prevalent in TNBC and may be implicated as a prognostic biomarker in patients with TNBC.

Purpose This study aims to explore the influence of social interaction processes on transactive memory system (TMS) practice, the mediation of knowledge integration to the relationship between TMS and team performance and the moderation of team psychological safety to the relationship among TMS, knowledge intentions and team performance. Design/methodology/approach The authors collected data from a sample of 366 team members from 55 research and development (R&D) teams in Taiwan and conduct the analysis using the partial least squares method. Findings The results of this study indicate that social interaction processes have a positive effect on a TMS; a TMS can foster team performance, but knowledge integration mediates the relationship between the TMS and team performance; and team psychological safety can moderate the relationship between the TMS, knowledge integration and team performance. Originality/value Existing studies not only fail to explore the influence of social interaction processes on a TMS practice but also lack empirical analyses to explore knowledge integration as a mediator and team psychological safety as a moderator. This study fills that gap by developing a model that includes these types of relationships and suggests the importance of the TMS in the context of R&D.

The interplay between copy number variation (CNV) and differential gene expression may be able to shed light on molecular process underlying breast cancer and lead to the discovery of cancer-related genes. In the current study, genes concurrently identified in array comparative genomic hybridization (CGH) and gene expression microarrays were used to derive gene signatures for Han Chinese breast cancers. We performed 23 array CGHs and 81 gene expression microarrays in breast cancer samples from Taiwanese women. Genes with coherent patterns of both CNV and differential gene expression were identified from the 21 samples assayed using both platforms. We used these genes to derive signatures associated with clinical ER and HER2 status and disease-free survival. DISTRIBUTIONS OF SIGNATURE GENES WERE STRONGLY ASSOCIATED WITH CHROMOSOMAL LOCATION: chromosome 16 for ER and 17 for HER2. A breast cancer risk predictive model was built based on the first supervised principal component from 16 genes (RCAN3, MCOLN2, DENND2D, RWDD3, ZMYM6, CAPZA1, GPR18, WARS2, TRIM45, SCRN1, CSNK1E, HBXIP, CSDE1, MRPL20, IKZF1, and COL20A1), and distinct survival patterns were observed between the high- and low-risk groups from the combined dataset of 408 microarrays. The risk score was significantly higher in breast cancer patients with recurrence, metastasis, or mortality than in relapse-free individuals (0.241 versus 0, P<0.001). The concurrent gene risk predictive model remained discriminative across distinct clinical ER and HER2 statuses in subgroup analysis. Prognostic comparisons with published gene expression signatures showed a better discerning ability of concurrent genes, many of which were rarely identifiable if expression data were pre-selected by phenotype correlations or variability of individual genes. We conclude that parallel analysis of CGH and microarray data, in conjunction with known gene expression patterns, can be used to identify biomarkers with prognostic values in breast cancer.

BackgroundThe aim of this study was to investigate the role of IL-17A in the cancer microenvironment and the recurrence of triple negative breast cancer (TNBC).MethodsUsing human TNBC cell lines, the role of IL17-A was investigated by knocked down of IL-17A (ΔIL-17A) and by administration of IL-17A into the culture medium. Cell proliferation assays, migration assays, as well as Western blot analysis and real-time PCR, were used to evaluate IL-17A-related signaling. Three types of 4T1 cells were implanted into BALB/c mice, namely wild type (WT), ΔIL-17A, and WT + neutralizing IL-17 antibody (WT + Ab) cells. Tumor weight, necrosis area, and the number of circulating tumor cells (CTCs) were measured. Immunohistochemistry and Western blotting were used to analyze expression of CD34, CD8, and TGF-β1 as well as anoikis resistance. The Kaplan–Meier’s method was used to correlate IL-17A expression and patient outcome, including disease-free survival (DFS) and overall survival (OS).ResultsOur results demonstrated that IL-17A was able to stimulate the migratory activity, but not the growth rate, of MDA-MB-231/468 cells. In vivo, for the ΔIL-17A group, there was an increase in necrosis area, a decrease in tumor CD34 expression and a reduction in the number of CTCs. Furthermore, in WT + Ab group, there was a decreased in tumor expression of CD34, fewer CD8 ( +) cells, and fewer CTCs, but an increase in expression of TGF-β1 expression. Both of the above were compared to the WT group. Knockdown of IL-17A also decreased anoikis resistance in human TNBC and the murine 4T1 cell lines. Kaplan–Meier analysis disclosed a negative correlation between tumor expression of IL-17A and OS in TNBC patients.ConclusionWe conclude that IL-17A promotes migratory and angiogenic activity in tumors, enhances anoikis resistance, and modulates the immune landscape of the tumor microenvironment such changes favor cancer metastasis.

Background Women with breast cancer are known to suffer from disease and treatment, and the generic measurement tools may underestimate their frailty. A specific instrument comprehensively measuring frailty among women with breast cancer has not yet been developed. This study aims to develop and validate the tool of breast cancer comprehensive frailty scale (BCCFS). Methods A descriptive and explorative study design was used. We collected the data through systematic literature and modified Delphi method. After an initial search and screening process, a total of 33 articles were included for review and consideration in the item design. Ten experts were invited to generate and validate initial items. The validity was assessed using a sample of 205 women with breast cancer in Taiwan. Its validity was then tested using item analysis, exploratory factor analysis, confirmatory factor analysis, criterion-related validity and areas under the receiver-operating characteristic, while its reliability was evaluated through internal consistencies and test-retest analyses. Results A three-factor solution with 16 items was chosen and accounted for approximately 58.57% of the total variance by exploratory factor analysis (KMO = 0.85; Bartlett’s Test of Sphericity: χ2 = 2881.34, p  < 0.001). The factors were interpreted as (1) deterioration of body and mobility, (2) negative emotions, and (3) cognitive impairment. The goodness of fit indices of the confirmatory factor analysis were as follows: chi-square = 234.498 ( p  < 0.01), normed chi-square = 2.322, SRMR = 0.055, RMSEA = 0.08, CFI = 0.930, and LI = 0.917. The Cronbach’s alpha calculated for the BCCFS (16 items) was 0.91 (95% confidence interval: 0.89 to 0.93), and the test-retest reliability coefficient was 0.60. Using the G8 screening tool as a standard indicator of frailty, analysis of receiver operating characteristic curve showed that 31.5 was the best cut point (area under curve = 0. 816, 95% confidence interval: 0.757 to 0.874) with a sensitivity of 63.5% and specificity of 84.4%. Conclusion The instrument exhibited acceptable psychometric properties, proving it to be a valuable tool for evaluating frailty in women with breast cancer. Further assessments of its reliability, validity, and generality from health providers’ views in different contexts and cultures are recommended.

Background The homologous recombination (HR) repair pathway for DNA damage, particularly the BRCA1 and BRCA2 genes, has become a target for cancer therapy, with poly ADP-ribose polymerase (PARP) inhibitors showing significant outcomes in treating germline BRCA1/2 (g BRCA1/2 ) mutated breast cancer. Recent studies suggest that some patients with somatic BRCA1/2 (s BRCA1/2 ) mutation or mutations in HR-related genes other than BRCA1/2 may benefit from PARP inhibitors as well, particularly those with PALB2 mutations. The current analysis aims to evaluate the prevalence of genetic alterations specific to BRCA1 , BRCA2 , and PALB2 in a large cohort of Taiwanese breast cancer patients through tumor-targeted sequencing. Methods A total of 924 consecutive assays from 879 Taiwanese breast cancer patients underwent tumor-targeted sequencing (Thermo Fisher Oncomine Comprehensive Assay v3). We evaluated BRCA1 , BRCA2 , and PALB2 mutational profiles, with variants annotated and curated by the ClinVAR, the Oncomine™ Knowledgebase Reporter, and the OncoKB™. We also conducted reflex germline testing using either whole exome sequencing (WES) or whole genome sequencing (WGS), which is ongoing. Results Among the 879 patients analyzed (924 assays), 130 had positive mutations in BRCA1 (3.1%), BRCA2 (8.6%), and PALB2 (5.2%), with a total of 14.8% having genetic alterations. Co-occurrence was noted between BRCA1/BRCA2 , BRCA1/PALB2, and BRCA2/PALB2 mutations. In BRCA1 -mutated samples, only p.K654fs was observed in three patients, while other variants were observed no more than twice. For BRCA2 , p.N372H was the most common (26 patients), followed by p.S2186fs, p.V2466A, and p.X159_splice (5 times each). For PALB2 , p.I887fs was the most common mutation (30 patients). This study identified 176 amino acid changes; 60.2% (106) were not documented in either ClinVAR or the Oncomine™ Knowledgebase Reporter. Using the OncoKB™ for annotation, 171 (97.2%) were found to have clinical implications. For the result of reflex germline testing, three variants ( BRCA1 c.1969_1970del, BRCA1 c.3629_3630del, BRCA2 c.8755-1G > C) were annotated as Pathogenic/Likely pathogenic (P/LP) variants by ClinVar and as likely loss-of-function or likely oncogenic by OncoKB; while one variant ( PALB2 c.448C > T) was not found in ClinVar but was annotated as likely loss-of-function or likely oncogenic by OncoKB. Conclusion Our study depicted the mutational patterns of BRCA1 , BRCA2 , and PALB2 in Taiwanese breast cancer patients through tumor-only sequencing. This highlights the growing importance of BRCA1/2 and PALB2 alterations in breast cancer susceptibility risk and the treatment of index patients. We also emphasized the need to meticulously annotate variants in cancer-driver genes as well as actionable mutations across multiple databases.

Mammographic screening has contributed to a significant reduction in breast cancer mortality. Several studies have highlighted the correlation between breast density, as detected through mammography, and a higher likelihood of developing breast cancer. A polygenic risk score (PRS) is a numerical score that is calculated based on an individual's genetic information. This study aims to explore the potential roles of PRS as candidate markers for breast cancer development and investigate the genetic profiles associated with clinical characteristics in Asian females with dense breasts. This is a retrospective cohort study integrated breast cancer screening, population genotyping, and cancer registry database. The PRSs of the study cohort were estimated using genotyping data of 77 single nucleotide polymorphisms based on the PGS000001 Catalog. A subgroup analysis was conducted for females without breast symptoms. Breast cancer patients constituted a higher proportion of individuals in PRS Q4 (37.8% vs. 24.8% in controls). Among dense breast patients with no symptoms, the high PRS group (Q4) consistently showed a significantly elevated breast cancer risk compared to the low PRS group (Q1–Q3) in both univariate (OR = 2.25, 95% CI 1.43–3.50, P  < 0.001) and multivariate analyses (OR: 2.23; 95% CI 1.41–3.48, P  < 0.001). The study was extended to predict breast cancer risk using common low-penetrance risk variants in a PRS model, which could be integrated into personalized screening strategies for Taiwanese females with dense breasts without prominent symptoms.

Background The aim of the study was to enhance colorectal cancer prognostication by integrating single nucleotide polymorphism (SNP) and gene expression (GE) microarrays for genomic and transcriptional alteration detection; genes with concurrent gains and losses were used to develop a prognostic signature. Methods The discovery dataset comprised 32 Taiwanese colorectal cancer patients, of which 31 were assayed for GE and copy number variations (CNVs) with Illumina Human HT-12 BeadChip v4.0 and Omni 25 BeadChip v1.1. Concurrent gains and losses were declared if coherent manners were observed between GE and SNP arrays. Concurrent genes were also identified in The Cancer Genome Atlas Project (TCGA) as the secondary discovery dataset ( n  = 345). Results The “universal” concurrent genes, which were the combination of z-transformed correlation coefficients, contained 4022 genes. Candidate genes were evaluated within each of the 10 public domain microarray datasets, and 1655 (2000 probe sets) were prognostic in at least one study. Consensus across all datasets was used to build a risk predictive model, while distinct relapse-free/overall survival patterns between defined risk groups were observed among four out of five training datasets. The predictive accuracy of recurrence, metastasis, or death was between 61 and 86% (cross-validation area under the receiver operating characteristic (ROC) curve: 0.548-0.833) from five independent validation studies. Conclusion The colorectal cancer concurrent gene signature is prognostic in terms of recurrence, metastasis, or mortality among 1746 patients. Genes with coherent patterns between genomic and transcriptional contexts are more likely to provide prognostication for colorectal cancer.