bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from DNA Damage-Binding Complex Recruits HDAC1 to Repress Bcl-2 Transcription in Human Ovarian Cancer Cells
Authors: Zhao Ran , Han Chunhua , Eisenhauer Eric , Kroger John , Zhao Weiqiang , Yu Jianhua , Selvendiran Karuppaiyah , Liu Xingluo , Wani Altaf A. , Wang Qi-En
Published: April 2023

Abstract
Elevated expression of the antiapoptotic factor Bcl-2 is believed to be one of the contributing factors to an increased relapse rate associated with multiple cisplatin-resistant cancers. DNA damage-binding protein complex subunit 2 (DDB2) has recently been revealed to play an important role in sensitizing human ovarian cancer cells to cisplatin-induced apoptosis through the downregulation of Bcl-2, but the underlying molecular mechanism remains poorly defined. Here, it is report that DDB2 functions as a transcriptional repressor for Bcl-2 in combination with DDB1. Quantitative ChIP and EMSA analysis revealed that DDB2 binds to a specific cis-acting element at the 5′-end of Bcl-2 P1 promoter. Overexpression of DDB2 resulted in marked losses of histone H3K9,14 acetylation along the Bcl-2 promoter and enhancer regions, concomitant with a local enrichment of HDAC1 to the Bcl-2 P1 core promoter in ovarian cancer cells. Coimmunoprecipitation and in vitro binding analyses identified a physical interaction between DDB1 and HDAC1, whereas downregulation of HDAC1 significantly enhanced Bcl-2 promoter activity. Finally, in comparison with wild-type DDB2, mutated DDB2, which is unable to repress Bcl-2 transcription, mediates a compromised apoptosis upon cisplatin treatment. Taken together, these data support a model wherein DDB1 and DDB2 cooperate to repress Bcl-2 transcription. DDB2 recognizes and binds to the Bcl-2 P1 promoter, and HDAC1 is recruited through the DDB1 subunit associated with DDB2 to deacetylate histone H3K9,14 across Bcl-2 regulatory regions, resulting in suppressed Bcl-2 transcription.

Implications: Increasing the expression of DDB complex may provide a molecular strategy for cancer therapy. Mol Cancer Res; 12(3); 370–80. ©2013 AACR.
Data from MYC Mediates mRNA Cap Methylation of Canonical Wnt/β-Catenin Signaling Transcripts By Recruiting CDK7 and RNA Methyltransferase
Authors: Posternak Valeriya , Ung Matthew H. , Cheng Chao , Cole Michael D.
Published: April 2023

Abstract
MYC is a pleiotropic transcription factor that activates and represses a wide range of target genes and is frequently deregulated in human tumors. While much is known about the role of MYC in transcriptional activation and repression, MYC can also regulate mRNA cap methylation through a mechanism that has remained poorly understood. Here, it is reported that MYC enhances mRNA cap methylation of transcripts globally, specifically increasing mRNA cap methylation of genes involved in Wnt/β-catenin signaling. Elevated mRNA cap methylation of Wnt signaling transcripts in response to MYC leads to augmented translational capacity, elevated protein levels, and enhanced Wnt signaling activity. Mechanistic evidence indicates that MYC promotes recruitment of RNA methyltransferase (RNMT) to Wnt signaling gene promoters by enhancing phosphorylation of serine 5 on the RNA polymerase II carboxy-terminal domain, mediated in part through an interaction between the TIP60 acetyltransferase complex and TFIIH.

Implications: MYC enhances mRNA cap methylation above and beyond transcriptional induction. Mol Cancer Res; 15(2); 213–24. ©2016 AACR.
Data from VEGFR-1 Pseudogene Expression and Regulatory Function in Human Colorectal Cancer Cells
Authors: Ye Xiangcang , Fan Fan , Bhattacharya Rajat , Bellister Seth , Boulbes Delphine R. , Wang Rui , Xia Ling , Ivan Cristina , Zheng Xiaofeng , Calin George A. , Wang Jing , Lu Xiongbin , Ellis Lee M.
Published: April 2023

Abstract
A large number of pseudogenes have been found to be transcribed in human cancers. However, only a few pseudogenes are functionally characterized. Here, we identified a transcribed pseudogene of VEGFR1, or fms-related tyrosine kinase 1 (FLT1), in human colorectal cancer cells. Interestingly, this pseudogene (designated as FLT1P1) was found to be transcribed bidirectionally and functionally modulated cognate VEGFR1 protein expression in the cells. Mechanistically, expression of FLT1P1 antisense transcript not only inhibited the VEGFR1 expression, but also inhibited non-cognate VEGF-A expression through interaction with miR-520a. Perturbation of FLT1P1 expression by RNA interference (RNAi) markedly inhibited tumor cell proliferation and xenograft tumor growth. This study identifies FLT1P1 antisense as a critical regulator of VEGFR1 and VEGF-A expression in colorectal cancer cells, and highlights its role in regulation of the pathogenesis of colorectal cancer.

Implications: The VEGFR1 pseudogene, FLT1P1, is a novel and functional regulator of VEGF signaling and its targeting could be an alternative strategy to modulate its cognate/target gene expression and downstream activity in cancer. Mol Cancer Res; 13(9); 1274–82. ©2015 AACR.
Data from Impeding Circulating Tumor Cell Reseeding Decelerates Metastatic Progression and Potentiates Chemotherapy
Authors: Qian Chen , Worrede-Mahdi Asurayya , Shen Fei , DiNatale Anthony , Kaur Ramanpreet , Zhang Qiang , Cristofanilli Massimo , Meucci Olimpia , Fatatis Alessandro
Published: April 2023

Abstract
Circulating tumor cells (CTCs) are commonly detected in the systemic blood of patients with cancer with metastatic tumors. However, the mechanisms controlling the viability of cancer cells in blood and length of time spent in circulation, as well as their potential for generating additional tumors are still undefined. Here, it is demonstrated that CX3CR1, a chemokine receptor, drives reseeding of breast CTCs to multiple organs. Antagonizing this receptor dramatically impairs the progression of breast cancer cells in a relevant model of human metastatic disease, by affecting both tumor growth and numerical expansion. Notably, therapeutic targeting of CX3CR1 prolongs CTC permanence in the blood, both promoting their spontaneous demise by apoptosis and counteracting metastatic reseeding. These effects lead to containment of metastatic progression and extended survival. Finally, targeting CX3CR1 improves blood exposure of CTCs to doxorubicin and in combination with docetaxel shows synergistic effects in containing overall tumor burden.
Implications:
The current findings shed light on CTCs reseeding dynamics and support the development of CX3CR1 antagonism as a viable strategy to counteract metastatic progression.
Data from Epigenetic Inactivation and Tumor-Suppressor Behavior of NGFR in Human Colorectal Cancer
Authors: Yang Zuli , Chen Hao , Huo Lijun , Yang Zihuan , Bai Yang , Fan Xinjuan , Ni Beibei , Fang Lekun , Hu Jun , Peng Junsheng , Wang Lei , Wang Jianping
Published: April 2023

Abstract
The nerve growth factor receptor (NGFR/p75) is a potential tumor suppressor, but its role in colorectal cancer is unknown. Here, the hypermethylation status, biologic function, and clinical relevance were determined for p75NGFR in colorectal cancer. The methylation status and expression of p75NGFR were assessed in colorectal cancer cell lines and clinical tissues by bisulfite genomic sequencing (BGS), qRT-PCR, and immunoblot assay. Methylation of p75NGFR was frequently found in colorectal cancer, leading to its silencing or downregulation, and it was effectively restored by a demethylation agent. The overexpression of p75NGFR in multiple colorectal cancer cell model systems significantly inhibited cell proliferation (concomitant with G1-phase arrest), invasion, and colony formation and induced cell apoptosis. In contrast, p75NGFR knockdown significantly promoted proliferative and invasive phenotypes. Importantly, p75NGFR methylation was observed in the majority of primary colorectal cancer specimens and was associated with histologic grade and preoperative serum CA19-9 levels. Multivariate analysis indicated that patients who lack p75NGFR have reduced overall survival (64% vs. 75%, P = 0.028) and disease-free survival (61% vs. 72%, P = 0.034) compared with p75NGFR-positive patients. In conclusion, p75NGFR is predominantly silenced or downregulated in colorectal cancer, and its biologic activities are consistent with it being a relevant tumor suppressor.

Implications: p75NGFR is a candidate tumor suppressor and has independent prognostic potential in colorectal cancer. Mol Cancer Res; 13(1); 107–19. ©2014 AACR.
Data from Oncogenic STRAP Supports Hepatocellular Carcinoma Growth by Enhancing Wnt/β-Catenin Signaling
Authors: Wang Wenhui , Li Shan , Liu Pengyu , Sideras Kostandinos , van de Werken Harmen J.G. , van der Heide Marieke , Cao Wanlu , Lavrijsen Marla , Peppelenbosch Maikel P. , Bruno Marco , Pan Qiuwei , Smits Ron
Published: April 2023

Abstract
Aberrant activation of Wnt/β-catenin signaling plays a key role in the onset and development of hepatocellular carcinomas (HCC), with about half of them acquiring mutations in either CTNNB1 or AXIN1. The serine/threonine kinase receptor-associated protein (STRAP), a scaffold protein, was recently shown to facilitate the aberrant activation of Wnt/β-catenin signaling in colorectal cancers. However, the function of STRAP in HCC remains completely unknown. Here, increased levels of STRAP were observed in human and mouse HCCs. RNA sequencing of STRAP knockout clones generated by gene editing of Huh6 and Huh7 HCC cells revealed a significant reduction in expression of various metabolic and cell-cycle–related transcripts, in line with their general slower growth observed during culture. Importantly, Wnt/β-catenin signaling was impaired in all STRAP knockout/down cell lines tested, regardless of the underlying CTNNB1 or AXIN1 mutation. In accordance with β-catenin's role in (cancer) stem cell maintenance, the expressions of various stem cell markers, such as AXIN2 and LGR5, were reduced and concomitantly differentiation-associated genes were increased. Together, these results show that the increased STRAP protein levels observed in HCC provide growth advantage among others by enhancing Wnt/β-catenin signaling. These observations also identify STRAP as a new player in regulating β-catenin signaling in hepatocellular cancers.
Implications:
Elevated STRAP levels in hepatocellular cancers provide a growth advantage by enhancing Wnt/β-catenin signaling.
Data from Methylation of the HOXA10 Promoter Directs miR-196b-5p–Dependent Cell Proliferation and Invasion of Gastric Cancer Cells
Authors: Shao Linlin , Chen Zheng , Peng Dunfa , Soutto Mohammed , Zhu Shoumin , Bates Andreia , Zhang Shutian , El-Rifai Wael
Published: April 2023

Abstract
The cross-talk between epigenetics and miRNA expression plays an important role in human tumorigenesis. Herein, the regulation and role of miR-196b-5p in gastric cancer was investigated. qRT-PCR demonstrated that miR-196b-5p is significantly overexpressed in human gastric cancer tissues (P < 0.01). In addition, it was determined that HOXA10, a homeobox family member and host gene for miR-196b-5p, is overexpressed and positively correlated with miR-196b-5p expression levels (P < 0.001). Quantitative pyrosequencing methylation analysis demonstrated significantly lower levels of DNA methylation at the HOXA10 promoter in gastric cancer, as compared with nonneoplastic gastric mucosa specimens. 5-Aza-2′-deoxycytidine treatment confirmed that demethylation of HOXA10 promoter induces the expression of HOXA10 and miR-196b-5p in gastric cancer cell model systems. Using the Tff1 knockout mouse model of gastric neoplasia, hypomethylation and overexpression of HOXA10 and miR-196b-5p in gastric tumors was observed, as compared with normal gastric mucosa from Tff1 wild-type mice. Mechanistically, reconstitution of TFF1 in human gastric cancer cells led to an increased HOXA10 promoter methylation with reduced expression of HOXA10 and miR-196b-5p. Functionally, miR-196b-5p reconstitution promoted human gastric cancer cell proliferation and invasion in vitro. In summary, the current data demonstrate overexpression of miR-196b-5p in gastric cancer and suggest that TFF1 plays an important role in suppressing the expression of miR-196b-5p by mediating DNA methylation of the HOXA10 promoter. Loss of TFF1 expression may promote proliferation and invasion of gastric cancer cells through induction of promoter hypomethylation and expression of the HOXA10/miR-196b-5p axis.

Implications: This study indicates that loss of TFF1 promotes the aberrant overexpression of HOXA10 and miR-196b-5p by demethylation of the HOXA10 promoter, which provides a new perspective of TFF1/HOXA10/miR-196b-5p functions in human gastric cancer. Mol Cancer Res; 16(4); 696–706. ©2018 AACR.
Data from Whole-Genome and Transcriptional Analysis of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer Demonstrates Intraclass Heterogeneity
Authors: Aggarwal Rahul R. , Quigley David A. , Huang Jiaoti , Zhang Li , Beer Tomasz M. , Rettig Matthew B. , Reiter Rob E. , Gleave Martin E. , Thomas George V. , Foye Adam , Playdle Denise , Lloyd Paul , Chi Kim N. , Evans Christopher P. , Lara Primo N. , Feng Felix Y. , Alumkal Joshi J. , Small Eric J.
Published: April 2023

Abstract
Therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC) can be accompanied by treatment-emergent small-cell neuroendocrine carcinoma (t-SCNC), a morphologically distinct subtype. We performed integrative whole-genome and -transcriptome analysis of mCRPC tumor biopsies including paired biopsies after progression, and multiple samples from the same individual. t-SCNC was significantly less likely to have amplification of AR or an intergenic AR-enhancer locus, and demonstrated lower expression of AR and its downstream transcriptional targets. Genomic and transcriptional hallmarks of t-SCNC included biallelic loss of RB1, elevated expression levels of CDKN2A and E2F1, and loss of expression of the AR and AR-responsive genes including TMPRSS2 and NKX3-1. We identified three tumors that converted from adenocarcinoma to t-SCNC and demonstrate spatial and temporal intrapatient heterogeneity of metastatic tumors harboring adenocarcinoma, t-SCNC, or mixed expression phenotypes, with implications for treatment strategies in which dual targeting of adenocarcinoma and t-SCNC phenotypes may be necessary.
Implications:
The t-SCNC phenotype is characterized by lack of AR enhancer gain and loss of RB1 function, and demonstrates both interindividual and intraindividual heterogeneity.

Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/6/1235/F1.large.jpg.
Data from ABCC1-Exported Sphingosine-1-phosphate, Produced by Sphingosine Kinase 1, Shortens Survival of Mice and Patients with Breast Cancer
Authors: Yamada Akimitsu , Nagahashi Masayuki , Aoyagi Tomoyoshi , Huang Wei-Ching , Lima Santiago , Hait Nitai C. , Maiti Aparna , Kida Kumiko , Terracina Krista P. , Miyazaki Hiroshi , Ishikawa Takashi , Endo Itaru , Waters Michael R. , Qi Qianya , Yan Li , Milstien Sheldon , Spiegel Sarah , Takabe Kazuaki
Published: April 2023

Abstract
Sphingosine-1-phosphate (S1P), a bioactive sphingolipid mediator, has been implicated in regulation of many processes important for breast cancer progression. Previously, we observed that S1P is exported out of human breast cancer cells by ATP-binding cassette (ABC) transporter ABCC1, but not by ABCB1, both known multidrug resistance proteins that efflux chemotherapeutic agents. However, the pathologic consequences of these events to breast cancer progression and metastasis have not been elucidated. Here, it is demonstrated that high expression of ABCC1, but not ABCB1, is associated with poor prognosis in breast cancer patients. Overexpression of ABCC1, but not ABCB1, in human MCF7 and murine 4T1 breast cancer cells enhanced S1P secretion, proliferation, and migration of breast cancer cells. Implantation of breast cancer cells overexpressing ABCC1, but not ABCB1, into the mammary fat pad markedly enhanced tumor growth, angiogenesis, and lymphangiogenesis with a concomitant increase in lymph node and lung metastases as well as shorter survival of mice. Interestingly, S1P exported via ABCC1 from breast cancer cells upregulated transcription of sphingosine kinase 1 (SPHK1), thus promoting more S1P formation. Finally, patients with breast cancers that express both activated SPHK1 and ABCC1 have significantly shorter disease-free survival. These findings suggest that export of S1P via ABCC1 functions in a malicious feed-forward manner to amplify the S1P axis involved in breast cancer progression and metastasis, which has important implications for prognosis of breast cancer patients and for potential therapeutic targets.

Implication: Multidrug resistant transporter ABCC1 and activation of SPHK1 in breast cancer worsen patient's survival by export of S1P to the tumor microenvironment to enhance key processes involved in cancer progression. Mol Cancer Res; 16(6); 1059–70. ©2018 AACR.
Data from BORIS Expression in Ovarian Cancer Precursor Cells Alters the CTCF Cistrome and Enhances Invasiveness through GALNT14
Authors: Hillman Joanna C. , Pugacheva Elena M. , Barger Carter J. , Sribenja Sirinapa , Rosario Spencer , Albahrani Mustafa , Truskinovsky Alexander M. , Stablewski Aimee , Liu Song , Loukinov Dmitri I. , Zentner Gabriel E. , Lobanenkov Victor V. , Karpf Adam R. , Higgins Michael J.
Published: April 2023

Abstract
High-grade serous carcinoma (HGSC) is the most aggressive and predominant form of epithelial ovarian cancer and the leading cause of gynecologic cancer–related death. We have previously shown that CTCFL (also known as BORIS, Brother of the Regulator of Imprinted Sites) is expressed in most ovarian cancers, and is associated with global and promoter-specific DNA hypomethylation, advanced tumor stage, and poor prognosis. To explore its role in HGSC, we expressed BORIS in human fallopian tube secretory epithelial cells (FTSEC), the presumptive cells of origin for HGSC. BORIS-expressing cells exhibited increased motility and invasion, and BORIS expression was associated with alterations in several cancer-associated gene expression networks, including fatty acid metabolism, TNF signaling, cell migration, and ECM–receptor interactions. Importantly, GALNT14, a glycosyltransferase gene implicated in cancer cell migration and invasion, was highly induced by BORIS, and GALNT14 knockdown significantly abrogated BORIS-induced cell motility and invasion. In addition, in silico analyses provided evidence for BORIS and GALNT14 coexpression in several cancers. Finally, ChIP-seq demonstrated that expression of BORIS was associated with de novo and enhanced binding of CTCF at hundreds of loci, many of which correlated with activation of transcription at target genes, including GALNT14. Taken together, our data indicate that BORIS may promote cell motility and invasion in HGSC via upregulation of GALNT14, and suggests BORIS as a potential therapeutic target in this malignancy.
Implications:
These studies provide evidence that aberrant expression of BORIS may play a role in the progression to HGSC by enhancing the migratory and invasive properties of FTSEC.
Data from Breast Cancer Risk–Associated SNPs in the mTOR Promoter Form De Novo KLF5- and ZEB1-Binding Sites that Influence the Cellular Response to Paclitaxel
Authors: Chen Qiuchen , Deng Xiaolan , Hu Xiaoyun , Guan Shu , He Miao , Wang Yilin , Wei Binbin , Zhang Jing , Zhao Haishan , Yao Weifan , Jin Feng , Liu Yong , Chen Jianjun , Olapade Olufunmilayo I. , Wu Huizhe , Wei Minjie
Published: April 2023

Abstract
ZEB1 (a positive enhancer) and KLF5 (a negative silencer) affect transcription factors and play inherently conserved roles in tumorigenesis and multidrug resistance. In humans, the rs2295080T-allele at the mTOR promoter locus has been associated with human cancer risk; however, the 63 bp spacing of another SNP rs2295079 has not been identified. Here, we discovered, for the first time, that rs2295079 (-78C/G) and rs2295080 (-141G/T) formed linkage haplotypes, with Ht1 (-78C/-141G) and Ht2 (-78G/-141T) being dominant, which were associated with distinct susceptibility to breast cancer, response to paclitaxel, and clinical outcomes in breast cancer. At the cellular level, compared with Ht1, Ht2 exhibits a much stronger effect on promoting mTOR expression, leading to enhanced tumor cell growth and strengthened resistance to PTX treatment. Mechanistically, the -141T allele of Ht2 creates a novel ZEB1-binding site; meanwhile, the -78C allele of Ht1 exists as an emerging KLF5-binding site, which synergistically induces promote/inhibit mTOR expression, cell proliferation, and excretion of cytotoxic drugs through the ZEB1/KLF5–mTOR–CCND1/ABCB1 cascade, thereby affecting the response to paclitaxel treatment in vivo and in vitro. Our results suggest the existence of a ZEB1/KLF5–mTOR–CCND1/ABCB1 axis in human cells that could be involved in paclitaxel response pathways and functionally regulate interindividualized breast cancer susceptibility and prognosis.
Implications:
This study highlights the function of haplotypes of mTOR -78C/-141G and -78G/-141T, in affecting breast cancer susceptibility and paclitaxel response regulated by ZEB1/KLF5–mTOR–CCND1/ABCB1 axis.
Data from Epigenetic Profiling Identifies LIF as a Super-enhancer-Controlled Regulator of Stem Cell–like Properties in Osteosarcoma
Authors: Lu Bing , He Yangyang , He Jincan , Wang Li , Liu Zhenguo , Yang Jiayan , Gao Zhuoxing , Lu Guohao , Zou Changye , Zhao Wei
Published: April 2023

Abstract
Osteosarcoma is an aggressive malignancy with poor prognosis. Super-enhancers (SE) have been highlighted as critical oncogenic elements required for maintaining the cancer cell characteristics. However, the regulatory role of SEs in osteosarcoma properties has not yet been elucidated. In the current study, we found that osteosarcoma cells and clinical specimens shared a significant fraction of SEs. Moreover, leukemia-inhibitory factor (LIF) was identified as an essential factor under the control of osteosarcoma-specific SE. The expression of LIF was positively correlated with the stem cell core factor genes in osteosarcoma. Furthermore, LIF recombinant protein–treated osteosarcoma cells displayed enhanced stem cell–like characteristics, such as increased sphere-forming potential, stimulated self-renewal, upregulated metastasis ability, and increased stemness-related gene expression. Notably, the histone 3 lysine 27 tri-methylation (H3K27me3) demethylase UTX was found as a key activator of LIF transcription in osteosarcoma. The UTX inhibitor, GSK-J4, induced H3K27me3 accumulation and impaired histone 3 lysine 27 acetylation (H3K27ac) at LIF gene locus, leading to LIF signaling pathway inhibition. GSK-J4 treatment resulted in profound defects in stem cell-like characteristics and stemness-related gene activation in osteosarcoma by modulating the H3K27ac of NOTCH1 signaling pathway gene loci. The NOTCH1 inhibitor Crenigacestat (TargetMol, T3633) repressed LIF-mediated activation of the stemness-related genes in osteosarcoma patient-derived primary tissues.
Implications:
This study reveals osteosarcoma SE profiles and uncovers a distinct tumor–stemness epigenetic regulatory mechanism in which an osteosarcoma-specific SE-mediated factor, LIF, promotes osteosarcoma stemness gene activation via NOTCH1 signaling pathway.
Data from SPHK1 Is a Novel Target of Metformin in Ovarian Cancer
Authors: Hart Peter C. , Chiyoda Tatsuyuki , Liu Xiaojing , Weigert Melanie , Curtis Marion , Chiang Chun-Yi , Loth Rachel , Lastra Ricardo , McGregor Stephanie M. , Locasale Jason W. , Lengyel Ernst , Romero Iris L.
Published: April 2023

Abstract
The role of phospholipid signaling in ovarian cancer is poorly understood. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of sphingosine that has been associated with tumor progression through enhanced cell proliferation and motility. Similarly, sphingosine kinases (SPHK), which catalyze the formation of S1P and thus regulate the sphingolipid rheostat, have been reported to promote tumor growth in a variety of cancers. The findings reported here show that exogenous S1P or overexpression of SPHK1 increased proliferation, migration, invasion, and stem-like phenotypes in ovarian cancer cell lines. Likewise, overexpression of SPHK1 markedly enhanced tumor growth in a xenograft model of ovarian cancer, which was associated with elevation of key markers of proliferation and stemness. The diabetes drug, metformin, has been shown to have anticancer effects. Here, we found that ovarian cancer patients taking metformin had significantly reduced serum S1P levels, a finding that was recapitulated when ovarian cancer cells were treated with metformin and analyzed by lipidomics. These findings suggested that in cancer the sphingolipid rheostat may be a novel metabolic target of metformin. In support of this, metformin blocked hypoxia-induced SPHK1, which was associated with inhibited nuclear translocation and transcriptional activity of hypoxia-inducible factors (HIF1α and HIF2α). Further, ovarian cancer cells with high SPHK1 were found to be highly sensitive to the cytotoxic effects of metformin, whereas ovarian cancer cells with low SPHK1 were resistant. Together, the findings reported here show that hypoxia-induced SPHK1 expression and downstream S1P signaling promote ovarian cancer progression and that tumors with high expression of SPHK1 or S1P levels might have increased sensitivity to the cytotoxic effects of metformin.
Implications:
Metformin targets sphingolipid metabolism through inhibiting SPHK1, thereby impeding ovarian cancer cell migration, proliferation, and self-renewal.
Data from Influence of Exogenous Tissue Factor on Estrogen Receptorα Expression in Breast Cancer Cells: Involvement of β1-Integrin, PAR2, and Mitogen-Activated Protein Kinase Activation
Authors: Collier Mary E.W. , Li Chao , Ettelaie Camille
Published: April 2023

Abstract
Increased expression of tissue factor (TF) has been associated with invasive forms of breast cancer. Conversely, the loss of estrogen receptor α (ERα) is associated with increased cell invasiveness. We have examined the influence of exogenous truncated recombinant TF (rTF) on ERα expression and cell invasiveness and investigated the mechanism of rTF signaling. The influence of rTF on ERα expression in MCF-7 and T47D cell lines was investigated using reverse transcription-PCR and ELISA. Cell invasion was measured using Boyden chamber-based invasion assays. Additionally, the interaction of fluorescein-labeled rTF with the surface of MCF-7 cells and particularly with β1-integrin was examined. Treatment of cells with rTF resulted in the down-regulation of ERα mRNA and protein over 24 h, which required β1-integrin and involved the mitogen-activated protein kinase pathway but did not require PAR2 activation. The addition of rTF reduced estradiol-mediated cell proliferation as well as increased cell invasiveness requiring both PAR2 and β1-integrin activation. Fluorescein-labeled rTF was shown to bind to the surface of MCF-7 cells within 5 min and peaked at 15 min. The bound rTF colocalized with cellular β1-integrin and was disrupted in the presence of excess unlabeled rTF and an anti-β1 polyclonal antibody. Finally, affinity purification of β1-integrin using rTF-conjugated agarose showed a requirement for the presence of divalent cations but not factor VIIa. The results indicate that rTF is capable of down-regulating ERα expression in breast cancer cells, resulting in decreases in estrogen-mediated cell proliferation and increased invasiveness. Furthermore, the mechanisms by which rTF induces these changes involve both PAR2 and β1-integrin. (Mol Cancer Res 2008;6(12):1807–18)
Data from Suppression of Anoikis by SKP2 Amplification and Overexpression Promotes Metastasis of Esophageal Squamous Cell Carcinoma
Authors: Wang Xiao-Chun , Wu Yu-Peng , Ye Bo , Lin De-Chen , Feng Yan-Bin , Zhang Zi-Qiang , Xu Xin , Han Ya-Ling , Cai Yan , Dong Jin-Tang , Zhan Qi-Min , Wu Min , Wang Ming-Rong
Published: April 2023

Abstract
The gene of SKP2, located on chromosome 5p13, plays a critical role in cell cycle progression, especially at the G1-S transition, putatively through its control of several cell cycle regulator proteins including p27kip1, p21cip1, p57kip2, p130, cyclin E, and c-Myc. Previous studies in this laboratory revealed that gain of chromosome 5p was often seen in esophageal squamous cell carcinoma (ESCC). In the present study, we examined the amplification status and expression level of SKP2 in ESCC and investigated its clinicopathologic significance. Amplification and elevated expression of SKP2 correlated significantly with tumor stage and positive lymph node metastasis (P < 0.05). The SKP2 protein expression level as determined by immunohistochemical staining showed a significant inverse correlation with p27 protein. In vivo assay showed that inhibition of SKP2 expression also decreased tumor growth and lung metastasis of ESCC cells. At the molecular level, knockdown of SKP2 by RNA interference inhibited cell migration and invasion ability. Knockdown of SKP2 expression sensitized cancer cells to anoikis, and a wobble mutant of SKP2 that is resistant to SKP2 small interfering RNA can rescue this effect. Expression level of pAkt decreased after SKP2 knockdown. Treatment of cells with phosphoinositidyl 3-kinase inhibitor (LY294002) and constitutively activator (insulin-like growth factor I) had significant effects on the anoikis of SKP2 RNA interference cells. These results show for the first time that SKP2 is amplified and overexpressed in ESCC. Elevated expression of SKP2 protected cancer cells from anoikis, and this effect was mediated, at least in part, by the phosphoinositidyl 3-kinase-Akt pathway. (Mol Cancer Res 2009;7(1):12–22)
Data from Cryptotanshinone Activates p38/JNK and Inhibits Erk1/2 Leading to Caspase-Independent Cell Death in Tumor Cells
Authors: Chen Wenxing , Liu Lei , Luo Yan , Odaka Yoshinobu , Awate Sanket , Zhou Hongyu , Shen Tao , Zheng Shizhong , Lu Yin , Huang Shile
Published: April 2023

Abstract
Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, the underlying mechanism is not well understood. Here, we show that CPT induced caspase-independent cell death in human tumor cells (Rh30, DU145, and MCF-7). Besides downregulating antiapoptotic protein expression of survivin and Mcl-1, CPT increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK), and inhibited phosphorylation of extracellular signal–regulated kinases 1/2 (Erk1/2). Inhibition of p38 with SB202190 or JNK with SP600125 attenuated CPT-induced cell death. Similarly, silencing p38 or c-Jun also in part prevented CPT-induced cell death. In contrast, expression of constitutively active mitogen-activated protein kinase kinase 1 (MKK1) conferred resistance to CPT inhibition of Erk1/2 phosphorylation and induction of cell death. Furthermore, we found that all of these were attributed to CPT induction of reactive oxygen species (ROS). This is evidenced by the findings that CPT induced ROS in a concentration- and time-dependent manner; CPT induction of ROS was inhibited by N-acetyl-l-cysteine (NAC), a ROS scavenger; and NAC attenuated CPT activation of p38/JNK, inhibition of Erk1/2, and induction of cell death. The results suggested that CPT induction of ROS activates p38/JNK and inhibits Erk1/2, leading to caspase-independent cell death in tumor cells. Cancer Prev Res; 5(5); 778–87. ©2012 AACR.
Moving Spatially Resolved Multiplexed Protein Profiling toward Clinical Oncology
Authors: Pourmaleki Maryam , Socci Nicholas D. , Hollmann Travis J. , Mellinghoff Ingo K.
Published: April 2023

The shift in cancer therapy from broadly cytotoxic agents toward “personalized” treatments that target specific alterations in each patient's tumor requires diagnostic pathology approaches that are quantitative and biospecimen-friendly. Novel multiplexed antibody-based imaging technologies can measure single-cell expression of over 60 proteins in intact tumor sections and hold promise for clinical oncology.
Interactions between Macrophages and Biofilm during Staphylococcus aureus-Associated Implant Infection: Difficulties and Solutions
Authors: Li Mingzhang , Yu Jinlong , Guo Geyong , Shen Hao
Published: April 2023

Staphylococcus aureus (S. aureus) biofilm is the major cause of failure of implant infection treatment that results in heavy social and economic burden on individuals, families, and communities. Planktonic S. aureus attaches to medical implant surfaces where it proliferates and is wrapped by extracellular polymeric substances, forming a solid and complex biofilm. This provides a stable environment for bacterial growth, infection maintenance, and diffusion and protects the bacteria from antimicrobial agents and the immune system of the host. Macrophages are an important component of the innate immune system and resist pathogen invasion and infection through phagocytosis, antigen presentation, and cytokine secretion. The persistence, spread, or clearance of infection is determined by interplay between macrophages and S. aureus in the implant infection microenvironment. In this review, we discuss the interactions between S. aureus biofilm and macrophages, including the effects of biofilm-related bacteria on the macrophage immune response, roles of myeloid-derived suppressor cells during biofilm infection, regulation of immune cell metabolic patterns by the biofilm environment, and immune evasion strategies adopted by the biofilm against macrophages. Finally, we summarize the current methods that support macrophage-mediated removal of biofilms and emphasize the importance of considering multi-dimensions and factors related to implant-associated infection such as immunity, metabolism, the host, and the pathogen when developing new treatments.
A Markov model of generator performance at the Kainji hydro-power station in Nigeria
Authors: Ale Thomas Olabode , Olufeagba Benjamin Jimi , Oyeleye Mathew Olayinka
Published: April 2023

The Kainji hydropower station is a seven turbo-alternator station that for many years served as the base load supply for the Nigerian power grid. Over 200,000 pieces of data about the performance of the machines were used to estimate values of the failure and repair rates for each machine and a Markov steady-state model of the plant was constructed to determine the probability output of the turbines. This result showed that Kaplan turbine (KT) 12 is prone to failure compared to any other KT unit in the hydropower plant. Also, the clusters of probability that define the system state due to the different output capacities of the units show that the hydropower plant has not performed to its maximum capacity, further evaluation shows that 60% of the KT machine units are operating which is consistent with the observed robustness of the output. The model not only conforms to observations but reasonably provide a means of studying the effects of different actions that may be taken to improve the performance of hydropower plant.
Online detection of interturn short-circuit fault in induction motor based on 5th harmonic current tracking using Vold-Kalman filter
Authors: Mazzoletti Manuel A. , Gentile Francisco R. , Donolo Pablo D. , Bossio Guillermo R.
Published: April 2023

In this paper we propose a strategy for real-time detection of interturn short-circuit faults (ISCF) on three-phase induction motor (IM) by using a Vold-Kalman filter (VKF) algorithm. ISCF produce a thermal stress into the stator winding due to large current that flows through the short-circuited turns. Therefore, incipient fault detection is required in order to avoid catastrophic failures such as phase to phase, or phase to ground faults. The strategy is based on an analytical IM model that includes a ISCF fault in any of the phase windings and considering the h-th harmonic in the voltage supply. Based on equivalent electrical circuits with harmonics in sequence components, we propose a strategy for detection of an ISCF on IM by tracking the 5th harmonic current component using a VKF algorithm. The proposed model is experimentally validated using a three-phase IM with modified stator windings to generate ISCF. Also, the IM is feeded by a programmable voltage source to synthesize distorted voltage supply with the 5th harmonic. The results demonstrated that the positive-sequence magnitude for the 5th harmonic current component is a good indicator of the fault severity once it exceeds a threshold limit value, even under load variations and unbalanced voltages.
A new linear quadratic regulator model to mitigate frequency disturbances in the power system during cyber-attack
Authors: Musleh Uddin Muhammad , Rafiqul Islam Kazi , Monirul Kabir Md.
Published: April 2023

This paper proposes a new model integrating a linear quadratic regulator (LQR) controller to mitigate frequency disturbances in the power system during cyber-attack, called as linear quadratic regulator to mitigate frequency disturbances (LQRMFD). As we know, most of the existing models have a common problem with achieving significant performances in mitigating dynamic response parameters, such as frequency deviation and settling time. However, the key aspect of LQRMFD is to mitigate the above issues with remarkable performance improvements. An uncommon and stable power system model has been considered in LQRMFD first to reach such a goal. A numerical problem has been solved to derive a certain characteristic equation, where the Routh-Hurwitz array criterion is applied for determining the stability of such a power system. After that, a state-space equation is developed from the power system to activate the LQR controller. Thus, achieving diversity and eliminating the redundancy of the power system considered can be obtained in LQRMFD. To evaluate the performance of LQRMFD, a series of experiments was conducted using the MATLAB-Simulink tool. Rigorous comparisons were also made among the results of LQRMFD, self-implemented and existing models. Furthermore, a detailed analysis was reported among those models to find the performance improvement of LQRMFD in percentage.
DC-link voltage balancing and control of qZ-source inverter fed induction motor drive
Authors: Zar Thin , Suan Tial Mai Kai , Naing Tun Lin
Published: April 2023

Poor performance of the motor drive system is caused when the direct current-link (DC-link) capacitor voltages of the inverter are not sufficiently generated. This is mainly because of the various load torque changes and input voltage fluctuation. The qZ-source inverter operates with a fully shoot-through technique. This technique causes mismatching between the upper and lower DC-link capacitor voltages. Without capacitor voltage-balancing function, the desired DC-link capacitor voltages could not be provided or maintained when there are load and speed changes. A Sawtooth carrier-based simple boost triple-sixty-degree (TSD) pulse width modulation (PWM) technique is used to drive the qZ-source T-type inverter because this technique can give a more significant boost DC-link voltage than a traditional simple boost PWM technique. Proportional integral (PI) controller is applied for the DC-link voltage controller to achieve the fast response and less steady-state error. The simulation model was constructed for a 4 kW, 400 V, 1,400 rpm induction motor (IM) drive system used in rolling mill using MATLAB/Simulink with and without voltage balancing function. As a result, DC-link voltages of the qZ-source T-type inverter fed the induction motor drive system could be controlled using a capacitor voltage-balancing function and the output power of the motor from the simulation result is approximately equal to 4 kW.
Reconfigurable negative bit line collapsed supply write-assist for 9T-ST static random access memory cell
Authors: Ganesh Chokkakula , Noorbasha Fazal , Murthy Korlapati Satyanarayana
Published: April 2023

This paper presents a reconfigurable negative bit line collapsed supply (RNBLCS) write driver circuit for the 9T Schmitt trigger-based static random-access memory (SRAM) cell (9T-ST), significantly improving write performance for real-time memory applications. In deep sub-micron technology, increasing device parameter deviations significantly reduce SRAM cells' write-ability. The proposed RNBLCS write-assist driver for 9T-ST SRAM cell has 0.84×, 0.48×, 0.27× optimized write access delay and 1.05×, 1.08×, 1.19× improvement in write static noise margin (WSNM), 1.05×, 1.13×, and 1.39× improvement in write margin (WM), 0.96×, 0.89× and 0.72× minimum write trip-point (WTP) from transient-negative bit line (Tran-NBL), capacitive charge sharing (CCS), and conventional write circuits respectively. The proposed RNBLCS is functionally verified using a synopsys custom compiler with a 16 nm BSIM4 model card for bulk complementary metal-oxide semiconductor (CMOS).
MF-RALU: design of an efficient multi-functional reversible arithmetic and logic unit for processor design on the field programmable gate array platform
Authors: Sanjeevaiah Girija , Gajanan Sangeetha Bhandari
Published: April 2023

Most modern computer applications use reversible logic gates to solve power dissipation issues. This manuscript uses an efficient multi-functional reversible arithmetic and logical unit (MF-RALU) to perform 30 operations. The 32-bit MF-RALU includes arithmetic, logical, complement, shifters, multiplexers, different adders, and multipliers. The multi-bit reversible multiplexers are used to construct the MF-RALU structure. The Reduced instruction set computer (RISC) processor is designed to realize the functionality of the MF-RALU. The MF-RALU can perform its operation in a single clock cycle. The 1-bit RALU is developed and compared with existing approaches with improvements in performance metrics. The 32-bit reversible arithmetic units (RAUs) and reversible logical units (RLUs) are constructed using 1-bit RALU. The MF-RALU and RISC processor are synthesized individually in the Vivado environment using Verilog-HDL and implemented on Artix-7 field programmable gate array (FPGA). The MF-RALU utilizes a <11% chip area and consumes 332 mW total power. The RISC processor utilizes a <3% chip area and works at 483 MHZ frequency by consuming 159 mW of total power on Artix-7 FPGA.
Adiabatic technique based low power synchronous counter design
Authors: Sanadhya Minakshi , Sharma Devendra Kumar , Hameed Chyad Alfilh Raed
Published: April 2023

The performance of integrated circuits is evaluated by their design architecture, which ensures high reliability and optimizes energy. The majority of the system-level architectures consist of sequential circuits. Counters are fundamental blocks in numerous very large-scale integration (VLSI) applications. The T-flip-flop is an important block in synchronous counters, and its high-power consumption impacts the overall effectiveness of the system. This paper calculates the power dissipation (PD), power delay product (PDP), and latency of the presented T flip-flop. To create a 2-bit synchronous counter based on the novel T flip-flops, a performance matrix such as PD, latency, and PDP is analyzed. The analysis is carried out at 100 and 10 MHz frequencies with varying temperatures and operating voltages. It is observed that the presented counter design has a lesser power requirement and PDP compared to the existing counter architectures. The proposed T-flip-flop design at the 45 nm technology node shows an improvement of 30%, 76%, and 85% in latency, PD, and PDP respectively to the 180 nm node at 10 MHz frequency. Similarly, the proposed counter at the 45 nm technology node shows 96% and 97% improvement in power dissipation, delay, and PDP respectively compared to the 180 nm at 10 MHz frequency.
Design and performance analysis of front and back Pi 6 nm gate with high K dielectric passivated high electron mobility transistor
Authors: Gowthami Yadala , Balaji Bukya , Srinivasa Rao Karumuri
Published: April 2023

Advanced high electron mobility transistor (HEMT) with dual front gate, back gate with silicon nitride/aluminum oxide (Si3N4/Al2O3) as passivation layer, has been designed. The dependency on DC characteristics and radio frequency characteristics due to GaN cap layers, multi gate (FG and BG), and high K dielectric material is established. Further compared single gate (SG) passivated HEMT, double gate (DG) passivated HEMT, double gate triple (DGT) tooth passivated HEMT, high K dielectric front Pi gate (FG) and back Pi gate (BG) HEMT. It is observed that there is an increased drain current (Ion) of 5.92 (A/mm), low leakage current (Ioff) 5.54E-13 (A) of transconductance (Gm) of 3.71 (S/mm), drain conductance (Gd) of 1.769 (S/mm), Cutoff frequency (fT) of 743 GHz maximum oscillation frequency (Fmax) 765 GHz, minimum threshold voltage (Vth) of -4.5 V, on resistance (Ron) of 0.40 (Ohms) at Vgs=0 V. These outstanding characteristics and transistor structure of proposed HEMT and materials involved to apply for upcoming generation high-speed GHz frequency applications.
Medical system based on thermal optical system and neural network
Authors: Abd El Gawad Yahia Zakria , Youssef Mohamed I. , Nasser Tarek Mahmoud
Published: April 2023

Military personnel in the training or operational phases always need constant medical examination, but the presence of efficient medical care is difficult to implement in real-time for such cases. A wireless system for thermal tracking of soldiers was proposed, as well as tracking their vital signs in real time. Thermal cameras are used with an optical system designed to increase the accuracy of the thermal images captured as the change in the electro-cardiogram, heart rate, and temperature measurements are measured using a specially designed circuit. The results from both the thermal system and the biometric system are combined and sent to a computer for analysis using a model prepared with neural network technology. The proposed system was tested, and a database was created for 127 males and 110 females during training and rest times. The neural network model achieved a response time of 85 seconds until the release of the final analysis, and the accuracy of the proposed tracking system is 96%. The main contribution of this paper is the design of an integrated portable system for rapid, in-field, real-time military medical diagnostics.
Power transfer control within the framework of vehicle-to-house technology
Authors: Ben Sassi Hicham , Mazzi Yahia , Errahimi Fatima , Es-Sbai Najia
Published: April 2023

The emerging vehicle-to-grid (V2G) technology has gained a lot of praise in the last few years, following its experimental validation in several countries. As a result, this technology is being investigated for standalone houses under the name of vehicle-to-house (V2H). This latter proposes a two-way power transfer between the electric vehicles and isolated houses relying on renewable sources for power supply. In this paper an implementation of the V2H technology is investigated, using the adaptive backstepping control approach for the bidirectional half-bridge and the integral sliding mode control for the DC-DC converter. The robustness of the controller and its capability to respond to the desired performances were tested using different realistic scenarios. The obtained results yielded, a perfect sinusoidal output voltage with a voltage level of 220 V and a frequency of 50 Hz. This is further been validated by a frequency analysis resulting in a THD of 0.25%.