bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring How UK Public Authorities Use Redaction to Protect Personal Information
Authors: Chen Yijun , Kirkham Reuben
Published: March 2024

Document redaction has become increasingly important for individuals and organizations. This article investigates public-sector information redaction practices in order to determine if they adequately protect personal information from accidental disclosure due to redaction errors. Despite the importance of this in respect of data protection, 66.4% of those Public Authorities that responded did not hold formal policies or procedures
at all
. To assess those policies that did exist, we produced a 17-item check list of minimum best practice. Even those with policies and procedures had substantial defects to some degree (with the median performance being 29.4% on our checklist), with policies frequently recommending the use of high-risk redaction methods and overlooking essential practices. This means that these existing practices amount to widespread breaches of data protection law on the ground. To remedy this, we articulate a new set of document redaction standards, which overcome the existing inadequacies in current guidance, as well as make proposals for regulatory reform in this space.
Applied Machine Learning for Information Security
Authors: Samtani Sagar , Raff Edward , Anderson Hyrum
Published: March 2024

Information security has undoubtedly become a critical aspect of modern cybersecurity practices. Over the past half-decade, numerous academic and industry groups have sought to develop machine learning, deep learning, and other areas of artificial intelligence-enabled analytics into information security practices. The Conference on Applied Machine Learning (CAMLIS) is an emerging venue that seeks to gather researchers and practitioners to discuss applied and fundamental research on machine learning for information security applications. In 2021, CAMLIS partnered with
ACM Digital Threats: Research and Practice (DTRAP)
to provide opportunities for authors of accepted CAMLIS papers to submit their research for consideration into
ACM DTRAP
via a Special Issue on Applied Machine Learning for Information Security. This editorial summarizes the results of this Special Issue.
A Differential Evolution Offloading Strategy for Latency and Privacy Sensitive Tasks with Federated Local-edge-cloud Collaboration
Authors: Chen Yishan , Li Wei , Huang Junhong , Gao Honghao , Deng Shuiguang
Published: March 2024

Due to an explosive growth in mobile devices and the rapid evolution of wireless communication technologies, local-edge-cloud computing is becoming an attractive solution for providing a higher-quality service by exploiting the multi-computation power of mobile devices, edge servers and cloud. However, as the tasks are latency and privacy sensitive, highly credible task offloading becomes a crucial problem in a local-edge-cloud orchestrated computing system. In this paper, we study the computation offloading problem for latency and privacy sensitive tasks in a hierarchical local-edge-cloud network by using federated learning method. Our goal is to minimize the operational time of latency-sensitive tasks requested by mobile devices that have data privacy concerns, while each task can be executed under local, edge or cloud computing mode with no need to rely on privacy data. We first build system models to analyze the latency incurred under different computing modes, and then develop a constrained optimization problem to minimize the latency consumed by the federated offloading collaboration. A Hierarchical Federated Averaging method based on Differential Evolution algorithm (HierFAVG-DE) is proposed for solving the problem in-hand, and extensive simulations are conducted to verify the superiority of our approach.
Suitable and Style-Consistent Multi-Texture Recommendation for Cartoon Illustrations
Authors: Wu Huisi , Wang Zhaoze , Li Yifan , Liu Xueting , Lee Tong-Yee
Published: March 2024

Texture plays an important role in cartoon illustrations to display object materials and enrich visual experiences. Unfortunately, manually designing and drawing an appropriate texture is not easy even for proficient artists, let alone novice or amateur people. While there exist tons of textures on the Internet, it is not easy to pick an appropriate one using traditional text-based search engines. Although several texture pickers have been proposed, they still require the users to browse the textures by themselves, which is still labor-intensive and time-consuming. In this article, an automatic texture recommendation system is proposed for recommending multiple textures to replace a set of user-specified regions in a cartoon illustration with visually pleasant look. Two measurements, the suitability measurement and the style-consistency measurement, are proposed to make sure that the recommended textures are suitable for cartoon illustration and at the same time mutually consistent in style. The suitability is measured based on the synthesizability, cartoonity, and region fitness of textures. The style-consistency is predicted using a learning-based solution since it is subjective to judge whether two textures are consistent in style. An optimization problem is formulated and solved via the genetic algorithm. Our method is validated on various cartoon illustrations, and convincing results are obtained.
Electronic Structures of Passive Film Formed on Ti and Cr in a Phosphate Buffer Solution of pH 7
Authors: Kim Seong-Cheol , Tsuchiya Hiroaki , Manaka Tomoyo , Hanawa Takao , Fujimoto Shinji
Published: March 2024

The electronic structures, including the semiconductive properties, of the passive films formed on Cr and Ti in a phosphate buffer solution of pH 7 were evaluated using photoelectrochemical response, electrochemical impedance spectroscopy and X-ray photoelectron spectroscopy (XPS). Based on the results, electronic band structure models of the passive films were proposed: the passive films on Cr consisted of an inner p-type oxide layer with a band gap energy, E
g, of 3.6 eV and an outer p-type hydroxide layer with E
g of 2.5 eV whereas those on Ti consisted of an inner n-type oxide layer with E
g of 3.2 eV and an outer n-type hydroxide layer with E
g of 2.5 eV. The type of semiconductor evaluated for the oxide and hydroxide layers was strongly supported by valence-band XPS, which can provide the energy difference between the Fermi energy of the underlying metal and the highest energy of the valence bands of the oxide and hydroxide layers in the passive films.
Albumin promoter-driven FlpO expression induces efficient genetic recombination in mouse liver
Authors: Zhu Xiaohui , Yang Yan , Feng Dongfeng , Wang Oliver , Chen Jiaxiang , Wang Jiale , Wang Bin , Liu Yang , Edenfield Brandy H. , Haddock Ashley N. , Wang Ying , Patel Tushar , Bi Yan , Ji Baoan
Published: March 2024

A liver-specific Alb-FlpO mouse line was generated. By coupling it with other existing CreERT or Cre lines, the dual recombinase approach can enable sequential gene modifications within the same cell or across various cell types in an organism for liver research through temporal and spatial gene manipulations.
Enabling Workplace and Community Responses to Domestic Abuse: A Mixed Method Systematic Review of Training for Informal Supporters
Authors: Schucan Bird K. , Stokes N. , Rivas C.
Published: March 2024

Alongside formal agencies and specialist services, informal and social networks play a pivotal role in responding to domestic abuse in the community. Friends, relatives, and neighbours are uniquely placed to recognise domestic abuse, respond to victim‐survivors, and refer to wider services. Yet, informal networks may not know how to respond and feel overwhelmed or ill‐equipped to offer support. This mixed method systematic review examined the role of training for equipping and enabling informal supporters to respond to disclosures of abuse. To do so, four bibliographic databases, alongside specialist repositories and websites, were searched for empirical studies of educational programmes tailored towards informal networks. Nine included studies were subject to data extraction and quality appraisal by two members of the review team. A thematic synthesis of qualitative data was undertaken to identify the characteristics of training deemed important by informal supporters. The findings focused on engaging informal supporters in the issue of domestic abuse, training content, materials, and delivery. The themes were translated into ten recommendations and juxtaposed with studies reporting quantitative evidence of effectiveness. The resulting matrix was used to identify five characteristics of successful training for informal supporters. These included training content that covered (a) warning signs and nature of domestic abuse, (b) impacts of abuse, and (c) how to respond/local resources. Tailoring training to the context/audience and the use of nontext formats were also evidenced by included studies. The review highlights the potential of educational programmes for enabling community responses to victim‐survivors. Such interventions offer opportunities for formal agencies to collaborate with informal networks and strengthen the societal‐wide response to domestic abuse.
Mechanism Analysis of the Impact of COVID‐19 on the Whole Process of Aircraft Turnaround Operations
Authors: Tang Xiaowei , Wu Jiaqi , Wu Cheng-Lung , Zhang Shengrun
Published: March 2024

Efficient aircraft turnaround operations at airports are vital to ensure overall air traffic network performance. After the outbreak of COVID‐19, the traditional aircraft ground handling process has changed significantly due to new requirements put forward by the pandemic prevention and control policy. To better understand how COVID‐19 has affected ground handling operations, a discrete‐event simulation model of turnaround is established to analyze the change in the whole turnaround process before and after the pandemic. The critical path of turnaround operations was used to identify the significantly affected subprocesses to which airports should pay attention. For a case study on the two busiest airports in China, the aircraft turnaround time increased by about 18% after COVID‐19. Cabin cleaning, catering, and passenger embarking were the main processes in causing this increase. By evaluating the impact mechanism of COVID‐19 on turnaround operations, the study sheds light on strategic, tactical, and operational approaches for relevant authorities.
Reasonable Treatment Range of Karst Cave Encountered by Super‐Large Diameter Shield Tunnel in Strongly Karst‐Developed Area
Authors: Wang Jiang , Yang Jinwen , Yan Xianglin
Published: March 2024

When a super‐large diameter shield tunnel passes through a strongly karst‐developed area, in order to ensure the stability of the tunnel and economy of karst reinforcement, the reasonable treatment range for a huge number of karst caves needs to be researched. Based on a karst treatment project of a shield tunnel with a diameter of 14.5 m, this paper studies the influence of intrusive fully filled karst caves on the stability of the lining and excavation face by using theoretical calculation. In addition, the safe distance between the tunnel and karst caves outside the tunnel is proposed through numerical simulation, and the corresponding treatment range is obtained. The results show that the bearing capacity of the lining has a certain reserve when the intrusive cave is smaller than a certain size, and the caves filled with plastic or hard plastic clay have sufficient antifracturing ability. Therefore, some small fully filled caves inside the tunnel profile can be left unreinforced. On the other side, the critical safe distance is only 1–2 m for the caves with a size of 3 m, so the outside caves with a size less than 3 m can be left unreinforced in the treatment range farther away from the tunnel. The proposed treatment range is close to similar projects that have been built, indicating that analysis results are reasonable.
Data from Histone Deacetylase 2 Modulates p53 Transcriptional Activities through Regulation of p53-DNA Binding Activity
Authors: Harms Kelly Lynn , Chen Xinbin
Published: March 2024

Abstract
Histone deacetylase (HDAC) inhibitors are emerging as promising cancer therapeutics. HDAC inhibitors have been found to induce cellular activities that are strikingly similar to p53-mediated responses to genotoxic stress. For example, HDAC inhibitors induce cell cycle arrest, apoptosis, and cellular senescence. Because at least 11 HDACs are affected by the current HDAC inhibitors, the HDAC critical for tumor cell survival and proliferation remains unknown. Thus, we sought to characterize the distinct roles of HDACs in the p53 pathway. Through the use of stable MCF7 cell lines which inducibly express short hairpin RNA targeting HDAC2, we found that HDAC2 plays important roles in the p53 pathway. Specifically, we found that knockdown of HDAC2 inhibited cellular proliferation in a dose-dependent manner which was also partly p53-dependent. Furthermore, knockdown of HDAC2 induced cellular senescence. Importantly, we found that knockdown of HDAC2 enhanced p53-dependent trans-repression and trans-activation of a subset of target genes. We found that the enhancement was due to increased p53-DNA binding activity but not alterations in p53 stability or posttranslational modification(s). Thus, for the first time, our data suggest that HDAC inhibitors function through the p53 pathway, at least in part, by activating p53-DNA binding activity. [Cancer Res 2007;67(7):3145–52]
Data from High SEPT9_v1 Expression in Human Breast Cancer Cells Is Associated with Oncogenic Phenotypes
Authors: Gonzalez Maria E. , Peterson Esther A. , Privette Lisa M. , Loffreda-Wren Janice L. , Kalikin Linda M. , Petty Elizabeth M.
Published: March 2024

Abstract
Altered expression of the human septin gene, SEPT9, and its murine homologue, Sept9, has been implicated in neoplasia. However, their role(s) in oncogenesis remains poorly understood. We found amplification of SEPT9 in 67% of breast cancer cells (BCC) when compared with immortalized human mammary epithelial cells (IHMEC) as well as high levels of SEPT9 expression in the majority (61%) of the BCCs studied, unlike IHMECs. Expression profiling of variant SEPT9 transcripts and translated products revealed that high expression of the variant, SEPT9_v1, in contrast to other variants, was widespread in BCCs (55% of the BCCs) but not in IHMECs. High expression of SEPT9_v1 was also observed in primary breast cancer samples by immunohistochemical studies. We subsequently examined the phenotypic consequences of SEPT9_v1 expression in human breast cells. Retroviral expression of SEPT9_v1 in IHMEC cell culture models showed that SEPT9_v1 accelerated growth kinetics, stimulated cell motility, promoted invasion in Matrigel Transwell assays, increased genomic instability with the development of aneuploidy, and stimulated morphologic changes. Significant cytokinesis defects and disruption of tubulin microfilaments were also observed by immunofluorescence when SEPT9_v1 was ectopically expressed in IHMECs. Furthermore, SEPT9_v1 markedly enhanced neoplastic transformation in Hs578T cells, a BCC with no endogenous expression of the SEPT9_v1 isoform. Small interfering RNA–mediated and short hairpin RNA–mediated inhibition of SEPT9_v1 expression in two BCCs with high levels of endogenous SEPT9_v1 expression inhibited neoplastic growth properties of the cells. Taken together, our findings suggest that increased SEPT9_v1 expression contributes to the malignant pathogenesis of some breast tumors. [Cancer Res 2007;67(18):8554–11]
Data from Chemotherapeutic Agents Up-regulate the Cytomegalovirus Promoter: Implications for Bioluminescence Imaging of Tumor Response to Therapy
Authors: Svensson Robert U. , Barnes J. Matthew , Rokhlin Oskar W. , Cohen Michael B. , Henry Michael D.
Published: March 2024

Abstract
Bioluminescence imaging is widely used to evaluate tumor growth and response to therapy in living animals. In cells expressing luciferase under the control of a constitutive promoter, light output in part depends on viable cell number, so that changes in bioluminescence intensity may be correlated with changes in viable tumor mass over time. We have found that treatment of cancer cell lines expressing luciferase under control of the cytomegalovirus (CMV) promoter with staurosporine, doxorubicin, and paclitaxel results in a transient increase in bioluminescence, which is positively correlated with apoptosis and inversely correlated with cell viability. In contrast, similar treatment of cell lines expressing luciferase under control of the SV40 promoter did not exhibit this result. We found that low doses of staurosporine induced bioluminescence in CMV- but not SV40-driven luciferase cell lines, whereas high doses elicited induction in both, indicating promoter-dependent and promoter-independent mechanisms of bioluminescence induction. The promoter-dependent increase in bioluminescence intensity from CMV-driven luciferase is a result of induction of luciferase mRNA and protein expression. We extended these findings in vivo; doxorubicin treatment resulted in a transient induction in bioluminescence when normalized to tumor volume in CMV- but not SV40-driven luciferase-expressing xenografts. We found that inhibition of the p38 mitogen-activated protein kinase pathway blocked bioluminescence induction by doxorubicin, paclitaxel, and staurosporine in CMV-driven luciferase-expressing cells. These findings have important implications when using bioluminescence to monitor the efficacy of anticancer therapy and underscore the complex regulation of the CMV promoter, which is widely used for high-level protein expression in mammalian cells. [Cancer Res 2007;67(21):10445–54]
Data from The Nucleolin Targeting Aptamer AS1411 Destabilizes Bcl-2 Messenger RNA in Human Breast Cancer Cells
Authors: Soundararajan Sridharan , Chen Weiwei , Spicer Eleanor K. , Courtenay-Luck Nigel , Fernandes Daniel J.
Published: March 2024

Abstract
We sought to determine whether nucleolin, a bcl-2 mRNA-binding protein, has a role in the regulation of bcl-2 mRNA stability in MCF-7 and MDA-MB-231 breast cancer cells. Furthermore, we examined the efficacy of the aptamer AS1411 in targeting nucleolin and inducing bcl-2 mRNA instability and cytotoxicity in these cells. AS1411 at 5 μmol/L inhibited the growth of MCF-7 and MDA-MB-231 cells, whereas 20 μmol/L AS1411 had no effect on the growth rate or viability of normal MCF-10A mammary epithelial cells. This selectivity of AS1411 was related to a greater uptake of AS1411 into the cytoplasm of MCF-7 cells compared with MCF-10A cells and to a 4-fold higher level of cytoplasmic nucleolin in MCF-7 cells. Stable siRNA knockdown of nucleolin in MCF-7 cells reduced nucleolin and bcl-2 protein levels and decreased the half-life of bcl-2 mRNA from 11 to 5 hours. Similarly, AS1411 (10 μmol/L) decreased the half-life of bcl-2 mRNA in MCF-7 and MDA-MB-231 cells to 1.0 and 1.2 hours, respectively. In contrast, AS1411 had no effect on the stability of bcl-2 mRNA in normal MCF-10A cells. AS1411 also inhibited the binding of nucleolin to the instability element AU-rich element 1 of bcl-2 mRNA in a cell-free system and in MCF-7 cells. Together, the results suggest that AS1411 acts as a molecular decoy by competing with bcl-2 mRNA for binding to cytoplasmic nucleolin in these breast cancer cell lines. This interferes with the stabilization of bcl-2 mRNA by nucleolin and may be one mechanism by which AS1411 induces tumor cell death. [Cancer Res 2008;68(7):2358–65]
Data from Class III β-Tubulin Mediates Sensitivity to Chemotherapeutic Drugs in Non–Small Cell Lung Cancer
Authors: Gan Pei Pei , Pasquier Eddy , Kavallaris Maria
Published: March 2024

Abstract
First line therapy for non–small cell lung carcinoma (NSCLC) commonly includes combination therapy with a tubulin-binding agent (TBA) and a DNA-damaging agent. TBAs suppress microtubule dynamics by binding to the β-tubulin subunit of α/β-tubulin, inducing mitotic arrest and apoptosis. Up-regulation of class III β-tubulin (βIII-tubulin) has been implicated in clinical resistance in NSCLC, ovarian and breast tumors treated in combination with a TBA and DNA-damaging agent. To investigate the functional significance of βIII-tubulin in resistance to both these classes of agents, small interfering RNA (siRNA) was used to silence the expression of this isotype in two NSCLC cell lines, NCI-H460 and Calu-6. Reverse transcription-PCR and immunoblotting showed that βIII-siRNA potently inhibited the expression of βIII-tubulin, without affecting the expression of other major β-tubulin isotypes. Clonogenic assays showed that βIII-siRNA cells were significantly more sensitive to TBAs, paclitaxel, vincristine, and vinorelbine, and for the first time, DNA-damaging agents, cisplatin, doxorubicin, and etoposide compared with controls. Cell cycle analysis of H460 βIII-siRNA cells showed reduced accumulation at the G2-M boundary and an increase in the sub-G1 population in response to TBA treatment compared with control cells. Importantly, βIII-siRNA cells displayed a significant dose-dependent increase in Annexin V staining when treated with either paclitaxel or cisplatin, compared with controls. These findings have revealed a novel role for βIII-tubulin in mediating response to both TBA and DNA-damaging agent therapy and may have important implications for improving the targeting and treatment of drug-refractory NSCLC. [Cancer Res 2007;67(19):9356–63]
Data from Cathepsin E Prevents Tumor Growth and Metastasis by Catalyzing the Proteolytic Release of Soluble TRAIL from Tumor Cell Surface
Authors: Kawakubo Tomoyo , Okamoto Kuniaki , Iwata Jun-ichi , Shin Masashi , Okamoto Yoshiko , Yasukochi Atsushi , Nakayama Keiichi I. , Kadowaki Tomoko , Tsukuba Takayuki , Yamamoto Kenji
Published: March 2024

Abstract
The aspartic proteinase cathepsin E is expressed predominantly in cells of the immune system and highly secreted by activated phagocytes, and deficiency of cathepsin E in mice results in a phenotype affecting immune responses. However, because physiologic substrates for cathepsin E have not yet been identified, the relevance of these observations to the physiologic functions of this protein remains speculative. Here, we show that cathepsin E specifically induces growth arrest and apoptosis in human prostate carcinoma tumor cell lines without affecting normal cells by catalyzing the proteolytic release of soluble tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) from the cell surface. The antitumor activity of cathepsin E was corroborated by in vivo studies with mice bearing human and mouse tumor transplants. Administration of purified cathepsin E into human tumor xenografts in nude mice dose-dependently induced apoptosis in the tumor cells to inhibit tumor growth. The growth, viability, and metastasis of mouse B16 melanoma cells were also more profound in cathepsin E–deficient mice compared with those in the syngeneic wild-type and transgenic mice overexpressing cathepsin E. Taken together, the number of apoptotic tumor cells, as well as tumor-infiltrating activated macrophages, was apparently reduced in cathepsin E–deficient mice compared with those in the other two groups, implying the positive correlation of endogenous cathepsin E levels with the extent of tumor suppression in vivo. These results thus indicate that cathepsin E plays a substantial role in host defense against tumor cells through TRAIL-dependent apoptosis and/or tumor-associated macrophage-mediated cytotoxicity. [Cancer Res 2007;67(22):10869–78]
Data from Nuclear Factor-κB, an Unappreciated Tumor Suppressor
Authors: Chen Fei , Castranova Vince
Published: March 2024

Abstract
The notion that nuclear factor-κB (NF-κB) is a tumor-promoting transcription factor has become a widely accepted dogma in biology. However, recent findings suggest an inhibitory role for NF-κB in carcinogenesis and tumorigenesis. Although the tumor suppressor–like effect of NF-κB remains to be rigorously established by further studies using cellular and animal models, these latest findings warrant caution with respect to blockage of NF-κB activation as a broad strategy in treating cancers. [Cancer Res 2007;67(23):11093–8]
Data from Retinoblastoma Function Is Essential for Establishing Lung Epithelial Quiescence after Injury
Authors: Mason-Richie Nicole A. , Mistry Meenakshi J. , Gettler Caitlin A. , Elayyadi Asmaa , Wikenheiser-Brokamp Kathryn A.
Published: March 2024

Abstract
The retinoblastoma gene product (RB) regulates cell cycle, quiescence, and survival in a cell type–dependent and environment-dependent manner. RB function is critical in the pulmonary epithelium, as evidenced by nearly universal RB inactivation in lung cancer and increased lung cancer risk in persons with germline RB gene mutations. Lung carcinomas occur in the context of epithelial remodeling induced by cytotoxic damage. Whereas the role of RB in development and normal organ homeostasis has been extensively studied, RB function in the context of cellular injury and repair has remained largely unexplored. In the current studies, the RB gene was selectively deleted in the respiratory epithelium of the mouse. Although RB was not required for establishing or maintaining quiescence during lung homeostasis, RB was essential for establishing quiescence during epithelial repair after injury. Notably, aberrant cell cycle progression was sustained for 9 months after injury in RB-deficient lungs. Prenatal and postnatal RB ablation had similar effects, providing evidence that timing of RB loss was not critical to the outcome and that the injury-induced phenotype was not secondary to compensatory alterations occurring during development. These data show that RB is essential for repair of the respiratory epithelium after cytotoxic damage and support a critical unique role for RB in the context of epithelial remodeling after injury. Because human cancers are associated with chronic cellular damage, these findings have important new implications for RB-mediated tumor suppression. [Cancer Res 2008;68(11):4068–76]
Data from Molecular Signature of MT1-MMP: Transactivation of the Downstream Universal Gene Network in Cancer
Authors: Rozanov Dmitri V. , Savinov Alexei Y. , Williams Roy , Liu Kang , Golubkov Vladislav S. , Krajewski Stan , Strongin Alex Y.
Published: March 2024

Abstract
Invasion-promoting MT1-MMP is directly linked to tumorigenesis and metastasis. Our studies led us to identify those genes, the expression of which is universally linked to MT1-MMP in multiple tumor types. Genome-wide expression profiling of MT1-MMP–overexpressing versus MT1-MMP–silenced cancer cells and a further data mining analysis of the preexisting expression database of 190 human tumors of 14 cancer types led us to identify 11 genes, the expression of which correlated firmly and universally with that of MT1-MMP (P < 0.00001). These genes included regulators of energy metabolism (NNT), trafficking and membrane fusion (SLCO2A1 and ANXA7), signaling and transcription (NR3C1, JAG1, PI3Kδ, and CK2α), chromatin rearrangement (SMARCA1), cell division (STK38/NDR1), apoptosis (DAPK1), and mRNA splicing (SNRPB2). Our subsequent extensive analysis of cultured cells, tumor xenografts, and cancer patient biopsies supported our data mining. Our results suggest that transcriptional reprogramming of the specific downstream genes, which themselves are associated with tumorigenesis, represents a distinctive “molecular signature” of the proteolytically active MT1-MMP. We suggest that the transactivation activity of MT1-MMP contributes to the promigratory cell phenotype, which is induced by this tumorigenic proteinase. The activated downstream gene network then begins functioning in unison with MT1-MMP to rework the signaling, transport, cell division, energy metabolism, and other critical cell functions and to commit the cell to migration, invasion, and, consequently, tumorigenesis. [Cancer Res 2008;68(11):4086–96]
Data from A Small Molecule Disruptor of Rb/Raf-1 Interaction Inhibits Cell Proliferation, Angiogenesis, and Growth of Human Tumor Xenografts in Nude Mice
Authors: Kinkade Rebecca , Dasgupta Piyali , Carie Adam , Pernazza Daniele , Carless Melanie , Pillai Smitha , Lawrence Nicholas , Sebti Said M. , Chellappan Srikumar
Published: March 2024

Abstract
Although it is well established that cyclin-dependent kinases phosphorylate and inactivate Rb, the Raf-1 kinase physically interacts with Rb and initiates the phosphorylation cascade early in the cell cycle. We have identified an orally active small molecule, Rb/Raf-1 disruptor 251 (RRD-251), that potently and selectively disrupts the Rb/Raf-1 but not Rb/E2F, Rb/prohibitin, Rb/cyclin E, and Rb/HDAC binding. The selective inhibition of Rb/Raf-1 binding suppressed the ability of Rb to recruit Raf-1 to proliferative promoters and inhibited E2F1-dependent transcriptional activity. RRD-251 inhibited anchorage-dependent and anchorage-independent growth of human cancer cells and knockdown of Rb with short hairpin RNA or forced expression of E2F1 rescued cells from RRD-251–mediated growth arrest. P.o. treatment of mice resulted in significant tumor growth suppression only in tumors with functional Rb, and this was accompanied by inhibition of angiogenesis, inhibition of proliferation, decreased phosphorylated Rb levels, and inhibition of Rb/Raf-1 but not Rb/E2F1 binding in vivo. Thus, selective targeting of Rb/Raf-1 interaction seems to be a promising approach for developing novel chemotherapeutic agents. [Cancer Res 2008;68(10):3810–8]
Data from Defective Transcription/Repair Factor IIH Recruitment to Specific UV Lesions in Trichothiodystrophy Syndrome
Authors: Chiganças Vanessa , Lima-Bessa Keronninn M. , Stary Anne , Menck Carlos F.M. , Sarasin Alain
Published: March 2024

Abstract
Most trichothiodystrophy (TTD) patients present mutations in the xeroderma pigmentosum D (XPD) gene, coding for a subunit of the transcription/repair factor IIH (TFIIH) complex involved in nucleotide excision repair (NER) and transcription. After UV irradiation, most TTD/XPD patients are more severely affected in the NER of cyclobutane pyrimidine dimers (CPD) than of 6-4-photoproducts (6-4PP). The reasons for this differential DNA repair defect are unknown. Here we report the first study of NER in response to CPDs or 6-4PPs separately analyzed in primary fibroblasts. This was done by using heterologous photorepair; recombinant adenovirus vectors carrying photolyases enzymes that repair CPD or 6-4PP specifically by using the energy of light were introduced in different cell lines. The data presented here reveal that some TTD/XPD mutations affect the recruitment of TFIIH specifically to CPDs, but not to 6-4PPs. This deficiency is further confirmed by the inability of TTD/XPD cells to recruit, specifically for CPDs, NER factors that arrive in a TFIIH-dependent manner later in the NER pathway. For 6-4PPs, we show that TFIIH complexes carrying an NH2-terminal XPD mutated protein are also deficient in recruitment of NER proteins downstream of TFIIH. Treatment with the histone deacetylase inhibitor trichostatin A allows the recovery of TFIIH recruitment to CPDs in the studied TTD cells and, for COOH-terminal XPD mutations, increases the repair synthesis and survival after UV, suggesting that this defect can be partially related with accessibility of DNA damage in closed chromatin regions. [Cancer Res 2008;68(15):6074–83]
Data from Cancer Immunotherapy Targeting the High Molecular Weight Melanoma-Associated Antigen Protein Results in a Broad Antitumor Response and Reduction of Pericytes in the Tumor Vasculature
Authors: Maciag Paulo Cesar , Seavey Matthew M. , Pan Zhen-Kun , Ferrone Soldano , Paterson Yvonne
Published: March 2024

Abstract
The high molecular weight melanoma-associated antigen (HMW-MAA), also known as melanoma chondroitin sulfate proteoglycan, has been used as a target for the immunotherapy of melanoma. This antigen is expressed on the cell surface and has a restricted distribution in normal tissues. Besides its expression in a broad range of transformed cells, this antigen is also found in pericytes, which are important for tumor angiogenesis. We generated a recombinant Listeria monocytogenes (Lm-LLO-HMW-MAA-C) that expresses and secretes a fragment of HMW-MAA (residues 2,160–2,258) fused to the first 441 residues of the listeriolysin O (LLO) protein. Immunization with Lm-LLO-HMW-MAA-C was able to impede the tumor growth of early established B16F10-HMW-MAA tumors in mice and both CD4+ and CD8+ T cells were required for therapeutic efficacy. Immune responses to a known HLA-A2 epitope present in the HMW-MAA2160-2258 fragment was detected in the HLA-A2/Kb transgenic mice immunized with Lm-LLO-HMW-MAA-C. Surprisingly, this vaccine also significantly impaired the in vivo growth of other tumorigenic cell lines, such as melanoma, renal carcinoma, and breast tumors, which were not engineered to express HMW-MAA. One hypothesis is that the vaccine could be targeting pericytes, which are important for tumor angiogenesis. In a breast tumor model, immunization with Lm-LLO-HMW-MAA-C caused CD8+ T-cell infiltration in the tumor stroma and a significant decrease in the number of pericytes in the tumor blood vessels. In conclusion, a Lm-based vaccine against HMW-MAA can trigger cell-mediated immune responses to this antigen that can target not only tumor cells but also pericytes in the tumor vasculature. [Cancer Res 2008;68(19):8066–75]
Data from Mechanism of In vitro Pancreatic Cancer Cell Growth Inhibition by Melanoma Differentiation–Associated Gene-7/Interleukin-24 and Perillyl Alcohol
Authors: Lebedeva Irina V. , Su Zhao-zhong , Vozhilla Nichollaq , Chatman Lejuan , Sarkar Devanand , Dent Paul , Athar Mohammad , Fisher Paul B.
Published: March 2024

Abstract
The death rate for pancreatic cancer approximates the number of new cases each year, and when diagnosed, current therapeutic regimens provide little benefit in extending patient survival. These dire statistics necessitate the development of enhanced single or combinatorial therapies to decrease the pathogenesis of this invariably fatal disease. Melanoma differentiation–associated gene-7/interleukin-24 (mda-7/IL-24) is a potent cancer gene therapeutic because of its broad-spectrum cancer-specific apoptosis-inducing properties as well as its multipronged indirect antitumor activities. However, pancreatic cancer cells show inherent resistance to mda-7/IL-24 that is caused by a block of translation of mda-7/IL-24 mRNA in these tumor cells. We now reveal that a dietary agent perillyl alcohol (POH) in combination with Ad.mda-7 efficiently reverses the mda-7/IL-24 “protein translational block” by inducing reactive oxygen species, thereby resulting in mda-7/IL-24 protein production, growth suppression, and apoptosis. Pharmacologic inhibitor and small interfering RNA studies identify xanthine oxidase as a major source of superoxide radical production causing these toxic effects. Because both POH and Ad.mda-7 are being evaluated in clinical trials, combining a dietary agent and a virally delivered therapeutic cytokine provides an innovative approach for potentially treating human pancreatic cancer. [Cancer Res 2008;68(18):7439–47]
Data from An Integrative Genomic and Proteomic Analysis of PIK3CA, PTEN, and AKT Mutations in Breast Cancer
Authors: Stemke-Hale Katherine , Gonzalez-Angulo Ana Maria , Lluch Ana , Neve Richard M. , Kuo Wen-Lin , Davies Michael , Carey Mark , Hu Zhi , Guan Yinghui , Sahin Aysegul , Symmans W. Fraser , Pusztai Lajos , Nolden Laura K. , Horlings Hugo , Berns Katrien , Hung Mien-Chie , van de Vijver Marc J. , Valero Vicente , Gray Joe W. , Bernards René , Mills Gordon B. , Hennessy Bryan T.
Published: March 2024

Abstract
Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy–based sequencing and reverse-phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT, and PTEN mutations and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor–positive (34.5%) and HER2-positive (22.7%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor–positive cancers. Unlike AKT1 mutations that were absent from cell lines, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant effect on outcome after adjuvant tamoxifen therapy in 157 hormone receptor–positive breast cancer patients. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines. PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss rendered cells significantly more sensitive to growth inhibition by the PI3K inhibitor LY294002 than did PIK3CA mutations. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration present may have implications for the selection of PI3K-targeted therapies in hormone receptor–positive breast cancer. [Cancer Res 2008;68(15):6084–91]
Data from Use of a Cryptic Splice Site for the Expression of Huntingtin Interacting Protein 1 in Select Normal and Neoplastic Tissues
Authors: Graves Chiron W. , Philips Steven T. , Bradley Sarah V. , Oravecz-Wilson Katherine I. , Li Lina , Gauvin Alice , Ross Theodora S.
Published: March 2024

Abstract
Huntingtin interacting protein 1 (HIP1) is a 116-kDa endocytic protein, which is necessary for the maintenance of several tissues in vivo as its deficiency leads to degenerative adult phenotypes. HIP1 deficiency also inhibits prostate tumor progression in mice. To better understand how deficiency of HIP1 leads to such phenotypes, we analyzed tumorigenic potential in mice homozygous for a Hip1 mutant allele, designated Hip1Δ3-5, which is predicted to result in a frame-shifted, nonsense mutation in the NH2 terminus of HIP1. In contrast to our previous studies using the Hip1 null allele, an inhibition of tumorigenesis was not observed as a result of the homozygosity of the nonsense Δ3-5 allele. To further examine the contrasting results from the prior Hip1 mutant mice, we cultured tumor cells from homozygous Δ3-5 allele–bearing mice and discovered the presence of a 110-kDa form of HIP1 in tumor cells. Upon sequencing of Hip1 DNA and message from these tumors, we determined that this 110-kDa form of HIP1 is the product of splicing of a cryptic U12-type AT-AC intron. This event results in the insertion of an AG dinucleotide between exons 2 and 6 and restoration of the reading frame. Remarkably, this mutant protein retains its capacity to bind lipids, clathrin, AP2, and epidermal growth factor receptor providing a possible explanation for why tumorigenesis was not altered after this knockout mutation. Our data show how knowledge of the transcript that is produced by a knockout allele can lead to discovery of novel types of molecular compensation at the level of splicing. [Cancer Res 2008;68(4):1064–73]
Data from Abnormal DNA Methylation of CD133 in Colorectal and Glioblastoma Tumors
Authors: Yi Joo Mi , Tsai Hsing-Chen , Glöckner Sabine C. , Lin Steven , Ohm Joyce E. , Easwaran Hari , James C. David , Costello Joseph F. , Riggins Gregory , Eberhart Charles G. , Laterra John , Vescovi Angelo L. , Ahuja Nita , Herman James G. , Schuebel Kornel E. , Baylin Stephen B.
Published: March 2024

Abstract
Much recent effort has focused on identifying and characterizing cellular markers that distinguish tumor propagating cells (TPC) from more differentiated progeny. We report here an unusual promoter DNA methylation pattern for one such marker, the cell surface antigen CD133 (Prominin 1). This protein has been extensively used to enrich putative cancer propagating stem-like cell populations in epithelial tumors and, especially, glioblastomas. We find that, within individual cell lines of cultured colon cancers and glioblastomas, the promoter CpG island of CD133 is DNA methylated, primarily, in cells with absent or low expression of the marker protein, whereas lack of such methylation is evident in purely CD133+ cells. Differential histone modification marks of active versus repressed genes accompany these DNA methylation changes. This heterogeneous CpG island DNA methylation status in the tumors is unusual in that other DNA hypermethylated genes tested in such cultures preserve their methylation patterns between separated CD133+ and CD133− cell populations. Furthermore, the CD133 DNA methylation seems to constitute an abnormal promoter signature because it is not found in normal brain and colon but only in cultured and primary tumors. Thus, the DNA methylation is imposed on the transition between the active versus repressed transcription state for CD133 only in tumors. Our findings provide additional insight for the dynamics of aberrant DNA methylation associated with aberrant gene silencing in human tumors. [Cancer Res 2008;68(19):8094–103]
Data from Tissue Inhibitor of Metalloproteinase-3 via Oncolytic Herpesvirus Inhibits Tumor Growth and Vascular Progenitors
Authors: Mahller Yonatan Y. , Vaikunth Sachin S. , Ripberger Maria C. , Baird William H. , Saeki Yoshinaga , Cancelas Jose A. , Crombleholme Timothy M. , Cripe Timothy P.
Published: March 2024

Abstract
Malignant solid tumors remain a significant clinical challenge, necessitating innovative therapeutic approaches. Oncolytic viral therapy is a nonmutagenic, biological anticancer therapeutic shown to be effective against human cancer in early studies. Because matrix metalloproteinases (MMP) play important roles in the pathogenesis and progression of cancer, we sought to determine if “arming” an oncolytic herpes simplex virus (oHSV) with an MMP-antagonizing transgene would increase virus-mediated antitumor efficacy. We generated oHSVs that express human tissue inhibitor of metalloproteinases 3 (TIMP3) or firefly luciferase and designated them rQT3 and rQLuc, respectively. We evaluated the antitumor efficacy of these viruses against neuroblastoma and malignant peripheral nerve sheath tumor (MPNST) xenografts. Relative to rQLuc, rQT3-infected primary human MPNST and neuroblastoma cells exhibited equivalent virus replication but increased cytotoxicity and reduced MMP activity. In vivo, rQT3-treated tumors showed delayed tumor growth, increased peak levels of infectious virus, immature collagen extracellular matrix, and reduced tumor vascular density. Remarkably, rQT3 treatment reduced circulating endothelial progenitors, suggesting virus-mediated antivasculogenesis. We conclude that rQT3 enhanced antitumor efficacy through multiple mechanisms, including direct cytotoxicity, elevated virus titer, and reduced tumor neovascularization. These findings support the further development of combined TIMP-3 and oncolytic virotherapy for cancer. [Cancer Res 2008;68(4):1170–9]
Data from RhoC Promotes Metastasis via Activation of the Pyk2 Pathway in Prostate Cancer
Authors: Iiizumi Megumi , Bandyopadhyay Sucharita , Pai Sudha K. , Watabe Misako , Hirota Shigeru , Hosobe Sadahiro , Tsukada Taisei , Miura Kunio , Saito Ken , Furuta Eiji , Liu Wen , Xing Fei , Okuda Hiroshi , Kobayashi Aya , Watabe Kounosuke
Published: March 2024

Abstract
RhoC is a member of the Ras-homologous family of genes which have been implicated in tumorigenesis and tumor progression. However, the exact role of RhoC is controversial and is yet to be clarified. We have examined the effect of RhoC on prostate tumor cells and found that RhoC had no effect on cell proliferation in vitro or on tumor growth in mice. However, RhoC significantly enhanced the metastatic ability of the tumor cells in these animals, suggesting that RhoC affects only the metastasis but not the growth of prostate tumor cells. The results of our immunohistochemical analyses on tumor specimens from 63 patients with prostate cancer indicate that RhoC expression had no significant correlation with Gleason grade. However, the expression of RhoC showed significant positive correlation with both lymph node and distant metastasis, and it was inversely correlated with patient survival. We also found that RhoC significantly augmented the invasion and motility of prostate tumor cells by activating matrix metalloproteinases 2 and 9 (MMP2 and MMP9) in vitro. The results of our antibody array analysis for signal molecules revealed that RhoC significantly activated kinases including mitogen-activated protein kinase (MAPK), focal adhesion kinase (FAK), Akt, and Pyk2. Inhibition of Pyk2 kinase blocked the RhoC-dependent activation of FAK, MAPK, and Akt, followed by the suppression of MMP2 and MMP9. Inhibitors of both MAPK and Akt also significantly blocked the activities of these MMPs. Therefore, our results indicate that RhoC promotes tumor metastasis in prostate cancer by sequential activation of Pyk2, FAK, MAPK, and Akt followed by the up-regulation of MMP2 and MMP9, which results in the stimulation of invasiveness of tumor cells. [Cancer Res 2008;68(18):7613–20]
Data from A Notch1 Ectodomain Construct Inhibits Endothelial Notch Signaling, Tumor Growth, and Angiogenesis
Authors: Funahashi Yasuhiro , Hernandez Sonia L. , Das Indranil , Ahn Audrey , Huang Jianzhong , Vorontchikhina Marina , Sharma Anshula , Kanamaru Emi , Borisenko Valeriya , DeSilva Dinuka M. , Suzuki Akihiko , Wang Xing , Shawber Carrie J. , Kandel Jessica J. , Yamashiro Darrell J. , Kitajewski Jan
Published: March 2024

Abstract
Notch signaling is required for vascular development and tumor angiogenesis. Although inhibition of the Notch ligand Delta-like 4 can restrict tumor growth and disrupt neovasculature, the effect of inhibiting Notch receptor function on angiogenesis has yet to be defined. In this study, we generated a soluble form of the Notch1 receptor (Notch1 decoy) and assessed its effect on angiogenesis in vitro and in vivo. Notch1 decoy expression reduced signaling stimulated by the binding of three distinct Notch ligands to Notch1 and inhibited morphogenesis of endothelial cells overexpressing Notch4. Thus, Notch1 decoy functioned as an antagonist of ligand-dependent Notch signaling. In mice, Notch1 decoy also inhibited vascular endothelial growth factor–induced angiogenesis in skin, establishing a role for Notch receptor function in this process. We tested the effects of Notch1 decoy on tumor angiogenesis using two models: mouse mammary Mm5MT cells overexpressing fibroblast growth factor 4 (Mm5MT-FGF4) and NGP human neuroblastoma cells. Exogenously expressed FGF4 induced Notch ligand expression in Mm5MT cells and xenografts. Notch1 decoy expression did not affect tumorigenicity of Mm5MT-FGF4 cells in vitro but restricted Mm5MT-FGF4 xenograft growth in mice while markedly impairing neoangiogenesis. Similarly, Notch1 decoy expression did not affect NGP cells in vitro but disrupted vessels and decreased tumor viability in vivo. These results strongly suggest that Notch receptor signaling is required for tumor neoangiogenesis and provides a new target for tumor therapy. [Cancer Res 2008;68(12):4727–35]