bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between body mass index and burnout among nurses in China: a cross-sectional study
Authors: Miao Liangzhuang , Niu Xiaogui , Huang Minxiang , Cao Gaofang , Fu Chang
Published: March 2024

Objectives

Body mass index (BMI) can affect an individual’s health. The night shift is a characteristic of the nursing profession, which is associated with an abnormal BMI. However, few studies have investigated the association between BMI and burnout in Chinese nurses. This study examined the association between BMI and burnout among Chinese nurses.

Methods

A total of 1863 nurses from 12 tertiary hospitals in Shandong Province of China were selected. BMI was calculated as body weight divided by height squared. The Maslach Burnout Service Inventory General Survey (MBI-GS) was used to measure the level of burnout among nurses. Ordinal logistic regression was used to analyse the association between BMI and burnout.

Results

In this study, the prevalence of normal BMI, underweight, overweight, and obesity was 69.2%, 7.5%, 18.2%, and 5.2%, respectively. The prevalence of high emotional exhaustion, high cynicism, and low personal accomplishment among nurses was 26.1%, 38.7%, and 35.6%, respectively. Nurses who were obese were more likely to have high levels of emotional exhaustion (OR=1.493, 95% CI: 1.011 to 2.206) and cynicism (OR=1.511, 95% CI: 1.014 to 2.253), and nurses who were underweight were more likely to have high levels of cynicism (OR=1.593, 95% CI: 1.137 to 2.232) compared with those who were normal weight.

Conclusions

Obesity was positively associated with emotional exhaustion and cynicism, and being underweight was only positively associated with cynicism among Chinese nurses. Hospital administrators should consider BMI when taking effective measures to reduce burnout among nurses.
Portable devices for diagnosis and monitoring of glaucoma: a scoping review protocol
Authors: Garba Farouk , Kyari Fatima , Nolan Winifred , Burton Matthew J , Gordon Iris , Evans Jennifer R , Hu Victor H
Published: March 2024

Introduction

Glaucoma is the leading cause of irreversible blindness in the world. The need to diagnose glaucoma early in its natural history before extensive sight loss occurs cannot be overemphasised. However, glaucoma is largely asymptomatic in the early stages of the disease making it complex to diagnose clinically and requires the support of technology. The objective of this scoping review is to determine the nature and extent of the evidence for use of portable devices in the diagnosis of glaucoma.

Methods

We will consider studies conducted in all healthcare settings using portable devices for the detection of all type of adult glaucoma. We will also include any systematic reviews or scoping reviews, which relate to this topic. Searches will be conducted in MEDLINE, Embase, CENTRAL on the Cochrane Library and Global Health databases, from their inception to the present. Reference lists from publications identified in the searches will also be reviewed. Two authors will independently screen titles and abstracts, followed by full-text screening to assess studies for inclusion. Any disagreements will be discussed and resolved with a third author. Tables accompanied by narrative descriptions will be employed to discuss results and show how it relates to review questions.

Ethics and dissemination

Ethical approval is not required in this review. Only published and publicly accessible data will be used. We will publish our findings in an open-access, peer-reviewed journal and develop an accessible summary of results and recommendations.
Willingness to purchase institutionalised elderly services and influencing factors among Chinese older adults: a nationwide cross-sectional study
Authors: Zhu Rui , Hou Wenjie , Wang Lingmeng , Zhang Chenchen , Guo Xing , Luo Dan , Wang Fuzhi
Published: March 2024

Objectives

In view of the serious ageing of China’s population and the low desire of elderly people to purchase institutionalised elderly care services, we explored the willingness of Chinese elderly people to purchase institutionalised elderly care services and its influencing factors.

Design

This was a cross-sectional study. Three multivariate logistic regression analysis models of the willingness of elderly people to purchase institutionalised elderly care services were established (model 1: ‘reluctance – willingness’; model 2: ‘reluctance – hesitation’; and model 3: ‘hesitation – willingness’) to explore the factors that influence elderly people’s willingness to purchase institutionalised elderly care services.

Setting

This study was based on the 2022 Psychology and Behaviour Investigation of Chinese Residents database.

Participants

Research data from 4123 older adults who met the requirements of this study were screened from the database.

Results

Of the 4123 respondents, roughly equal numbers had negative and positive attitudes towards purchasing institutionalised senior care services (1125, 27.3% vs 1079, 26.2%, respectively), and 1919 (46.5%) had hesitant attitudes. The analysis of model 1 showed that medical insurance participation, the number of children and siblings, chronic diseases and per capita monthly household income had an influential effect on the willingness of elderly people to purchase institutional care. In model 2, we found that factors such as per capita monthly household income and anxiety led to hesitancy among older adults to purchase institutionalised senior care services. In model 3, we further found that social support and health literacy led to a shift from hesitation to willingness to purchase institutionalised elderly care services.

Conclusion

The number of children, number of siblings, per capita monthly income of the family, medical insurance participation, health status, health literacy and social support were found to be the main factors influencing the purchase of institutionalised care by elderly individuals.
Overloaded transnidal pressure gradient as the hemodynamic mechanism leading to arteriovenous malformation rupture: a quantitative analysis using intravascular pressure monitoring and color-coded digital subtraction angiography
Authors: Zhang Yukun , Chen Yu , Li Ruinan , Ma Li , Han Heze , Li Zhipeng , Zhang Haibin , Yuan Kexin , Zhao Yang , Jin Weitao , Chen Pingting , Zhou Wanting , Ye Xun , Li Youxiang , Wang Shuo , Chen Xiaolin , Zhao Yuanli
Published: March 2024

Background

The hemodynamics of brain arteriovenous malformations (AVMs) may have implications for hemorrhage. This study aimed to explore the hemodynamics of ruptured AVMs by direct microcatheter intravascular pressure monitoring (MIPM) and indirect quantitative digital subtraction angiography (QDSA).

Methods

We recruited patients with AVMs at a tertiary neurosurgery center from October 2020 to March 2023. In terms of MIPM, we preoperatively super-selected a predominant feeding artery and main draining vein through angiography to measure intravascular pressure before embolization. In processing of QDSA, we adopted previously standardized procedure for quantitative hemodynamics analysis of pre-embolization digital subtraction angiography (DSA), encompassing main feeding artery, nidus, and the main draining vein. Subsequently, we investigated the correlation between AVM rupture and intravascular pressure from MIPM, as well as hemodynamic parameters derived from QDSA. Additionally, we explored the interrelationships between hemodynamic indicators in both dimensions.

Results

After strict screening of patients, our study included 10 AVMs (six ruptured and four unruptured). We found that higher transnidal pressure gradient (TPG) (53.00±6.36 vs 39.25±8.96 mmHg, p=0.042), higher feeding artery pressure (FAP) (72.83±5.46 vs 65.00±6.48 mmHg, p=0.031) and higher stasis index of nidus (3.54±0.73 vs 2.43±0.70, p=0.043) were significantly correlated with AVM rupture. In analysis of interrelationships between hemodynamic indicators in both dimensions, a strongly positive correlation (r=0.681, p=0.030) existed between TPG and stasis index of nidus.

Conclusions

TPG and FAP from MIPM platform and nidus stasis index from QDSA platform were correlated with AVM rupture, and both were positively correlated, suggesting that higher pressure load within nidus may be the central mechanism leading to AVM rupture.
Psychological safety in the perioperative environment: a cost-consequence analysis
Authors: Cladis Franklyn P , Hudson Mark , Goh Joel
Published: March 2024

Introduction

Psychologically unsafe healthcare environments can lead to high levels of staff turnover, and unwanted financial burden. In this study, we investigate the hypothesis that lower levels of psychological safety are associated with higher levels of turnover, within an anaesthesiology department and we estimate the cost attributable to low psychological safety, driven by turnover costs.

Methods

Psychological safety was measured in one academic department. The psychological safety score was correlated with ‘intention to leave’ using linear regression and Pearson correlation and a cost-consequence analysis was performed.

Results

One hundred and thirty-eight physician anaesthesiologists (MDs) and 282 certified registered nurse anaesthetists (CRNAs) were surveyed. The response rate was 67.4% (93/138) for MDs and 60.6% (171/282) for CRNAs. There was an inverse relationship between psychological safety and turnover intent for both MDs (Pearson correlation −0.373, p value <0.0002) and CRNAs (Pearson correlation −0.486, p value <0.0002). The OR of intent to turn over in the presence of low psychological safety was 6.86 (95% CI 1.38 to 34.05) for MDs and 8.93 (95% CI 4.27 to 18.68) for CRNAs. The cost-consequence analysis demonstrated the cost of low psychological safety related to turnover per year was $337, 428 for MDs and $14, 024, 279 for CRNAs. Reducing low psychological safety in CRNAs from 31.6% to 20% reduces the potential cost of low psychological to $8 876 126.03.

Conclusion

There is a cost relationship between low psychological safety and turnover. Low psychological safety in an academic anaesthesiology department may result in staff turnover, and potentially high financial costs.
Cancer centre information and support services and patient needs: participatory action research study
Authors: Driessen Helen P A , Busschbach Jan J V , Elfrink Erna J , van der Rijt Carin C D , Paardekooper Gabriël M R M , den Hollander Corine J , Kranenburg Leonieke W
Published: March 2024

Objectives

Clear information and supportive care are necessary for oncology patients and their relatives to manage the disease (trajectory). Centres for information and support aim to address their needs by offering informal and non-medical formal services. This study evaluated whether the centres’ services offered meet the needs of its visitors, and whether there is interest for these among oncology patients treated at affiliated hospitals.

Methods

In this participatory action research, interviews were conducted among visitors of two centres (Patient Information Center Oncology (PATIO) and IntermeZZo) and among patients treated at the affiliated hospitals. Visitors were interviewed to share their experiences regarding the centres’ services offered. Patients from the hospitals were interviewed about their interest in such support. Data were collected during three different periods and adjustments were made to the centres’ services between measurements.

Results

111 (PATIO) and 123 visitors (IntermeZZo) were interviewed, and 189 and 149 patients at the respective hospitals. Reasons to visit PATIO/IntermeZZo were to relax (93.1%), seek professional advice (54.6%) and meet peers (36.3%). Visitors indicated that the visits met their needs (99.1%), citing the accessible support and the expertise in oncology. 20% of patients interviewed at the hospitals expressed interest in visiting PATIO/IntermeZZo. The majority of patients (89.6%) considered these centres an integral part of their treatment process. These findings were stable over time.

Conclusions

Patients and their relatives highly value the services of hospital-affiliated centres for information and support. Future research should address how such centres best be integrated in the Dutch healthcare system.
Anomalous spin precession systematic effects in the search for a muon EDM using the frozen-spin technique
Authors: Cavoto G. , Chakraborty R. , Doinaki A. , Dutsov C. , Giovannozzi M. , Hume T. , Kirch K. , Michielsen K. , Morvaj L. , Papa A. , Renga F. , Sakurai M. , Schmidt-Wellenburg P.
Published: March 2024

At the Paul Scherrer Institut (PSI), we are developing a high-precision apparatus with the aim of searching for the muon electric dipole moment (EDM) with unprecedented sensitivity. The underpinning principle of this experiment is the frozen-spin technique, a method that suppresses the spin precession due to the anomalous magnetic moment, thereby enhancing the signal-to-noise ratio for EDM signals. This increased sensitivity enables measurements that would be difficult to achieve with conventional $$g - 2$$

g
-
2

muon storage rings. Given the availability of the $${125}\,{\textrm{MeV}/\textit{c}}$$

125

MeV
/
c

muon beam at PSI, the anticipated statistical sensitivity for the EDM after a year of data collection is $${6\times 10^{-23}}\,{e\!\cdot \!\textrm{cm}}.$$

6
×

10

-
23

e

·

cm

.

To achieve this goal, it is imperative to do a detailed analysis of any potential spurious effects that could mimic EDM signals. In this study, we present a quantitative methodology to evaluate the systematic effects that might arise in the context of the frozen-spin technique utilised within a compact storage ring. Our approach involves the analytical derivation of equations governing the motion of the muon spin in the electromagnetic (EM) fields intrinsic to the experimental setup, validated through numerical simulations. We also illustrate a method to calculate the cumulative geometric (Berry’s) phase. This work complements ongoing experimental efforts to detect a muon EDM at PSI and contributes to a broader understanding of spin-precession systematic effects.
Accelerating AdS black holes in gravity’s rainbow
Authors: Panah B. Eslam , Zare S. , Hassanabadi H.
Published: March 2024

Motivated by the effect of the energy of moving particles in C-metric, we first obtain exact accelerating black hole solutions in gravity’s rainbow. Then, we study the effects of gravity’s rainbow and C-metric parameters on the Ricci and Kretschmann scalars, and also the asymptotical behavior of this solution. Next, we indicate how different parameters of the obtained accelerating black holes in gravity’s rainbow affect thermodynamics quantities (such as the Hawking temperature, and entropy) and the local stability (by evaluating the heat capacity). In the following, we extract the geodesic equations to determine the effects of various parameters on photon trajectory in the vicinity of this black hole, as well as obtain the radius of the photon sphere and the corresponding critical impact parameter to gain insight into AdS black hole physics by adding the gravity’s rainbow to C-metric.
Exploring the Impact of an IoT-based Game on the Experience of Visitors at a Natural Science Museum
Authors: Balducci Fabrizio , Buono Paolo , Desolda Giuseppe , Lanzilotti Rosa , Piccinno Antonio , Costabile Maria Francesca
Published: March 2024

The use of Internet of Things (IoT) technology to improve access to cultural heritage sites and enhance visitor engagement has become increasingly popular. Nevertheless, there is a lack of studies evaluating the actual benefits of such technology on visitors’ experiences, which is crucial to improve the IoT adoption in this field. To address this issue, we present an exploratory study we performed to understand whether and how an IoT-based game affects the experience of museum visitors. The game is played after a traditional guided tour; it was created following a meta-design approach to enable domain experts, such as museum professional guides, to adapt the game to specific visitors and/or situations. The study involved a total of 18 participants who took a guided tour of the Museum of Natural Sciences of the University of Bari and played the game afterward. Both quantitative and qualitative data were collected. The study results show that playing the IoT-based game positively affects the experience of visitors and, in particular, their emotions. Visitor workload was also found to be greater than that of a guided tour, but this had no negative impact on visitor experience. The study findings have implications for the design and development of future IoT games to enhance engagement and to improve the experience of visitors at cultural heritage sites.
Review—Different Electrochemical Method Employed for Biomarkers Detection in Colorectal Cancer
Authors: Hu Beibei , Zhao Danya , Li Lanying , Li Xiaomeng , Ma Lijie , Jing Yongshuai , Li Zhongqiu , Sun Shiguo
Published: March 2024

Colorectal cancer is a common tumor that kills tens of thousands of people each year. Colorectal cancer was divided into two groups: primary colorectal cancer and metastatic colorectal cancer, the latter of which requires complicated treatment. The methods of early diagnosis of colorectal cancer include colorectal laparoscopy, tissue section, and B-ultrasonography. Although these methods produce desirable results, the pain of the process is limited by the need for professional instruction. As more and more biomarkers for colorectal cancer are being discovered, electrochemistry has received a lot of attention due to its advantages of being cost-effective, non-invasive, and highly sensitive. Colorectal cancer biomarkers are divided into nucleic acid, protein, and metabolite three categories, of which protein biomarkers are the most common. There are CEA, CA153, CA199, AFP, IL-6, CDH-17, IL-13Rα2, E-Cadherin, FGFR4, etc. This paper reviews various electrochemical platforms for biomarker detection of colorectal cancer. This review will pave the way for the establishment of new electrochemical platforms for screening various colorectal cancer biomarkers.
Regulating the Wnt/β‐catenin Signaling Pathway Promotes Repigmentation in Vitiligo Using Fire Needle Therapy
Authors: Xu Yan-Li , Sun Guang-Mei , Zhang Jin-Mei , Ma Yu-Han , Li Guang-Zhi , Zhang Lu , Cheng Fang , Zhang Bao-Xiang
Published: March 2024

Background. Vitiligo is a dermatological disorder characterized by the depletion of melanocytes. The key to its treatment lies in the promotion of melanin regeneration. The Wnt/β‐catenin signalling pathway assumes a pivotal role in this regenerative process. Fire needle therapy (FNT), a traditional Chinese medical technique, has emerged as a promising intervention. Methods. We analyzed gene expression associated with the Wnt/β‐catenin signalling pathway in both normal skin and the lesions of patients with vitiligo in the Gene Expression Omnibus database (GEO database). Furthermore, we evaluated the gene expression of this pathway and assessed the effects of FNT on pigmentation and its influence on the Wnt/β‐catenin signalling pathway in a vitiligo mouse model. Results. Compared to that of the normal skin, the mRNA levels of WNT10A, WNT10B, WNT2, WNT2B, WNT3, WNT3A, WNT4, WNT5B, WNT7B, and LEF1 displayed significant decreases in the lesions of patients with vitiligo. Moreover, vitiligo mouse skin lesions improved following FNT, and the number of melanocytes and melanin levels increased. In addition, posttreatment, genes associated with the Wnt/β‐catenin signalling pathway were revealed to be upregulated. Conclusion. FNT may play an important role in promoting pigmentation in vitiligo through modulation of the Wnt/β‐catenin signalling pathway. This adds to the growing body of literature supporting the use of FNT to treat vitiligo. This, in turn, may inform clinical practice and improve patient outcomes.
Data from Differing Src Signaling Levels Have Distinct Outcomes in Drosophila
Authors: Vidal Marcos , Warner Stephen , Read Renee , Cagan Ross L.
Published: March 2024

Abstract
High levels of Src activity are found in a broad spectrum of cancers. The roles of Src and its negative regulator Csk have been extensively studied, although results have often proved contradictory or the relevance to whole organisms is unclear. In Drosophila, overexpression of either Src orthologue resulted in apoptotic cell death, but paradoxically, reducing dCsk activity led to over-proliferation and tissue overgrowth. Here, we show that in Drosophila epithelia in situ, the levels of Src signaling determine the cellular outcome of Src activation. Apoptotic cell death was triggered specifically at high Src signaling levels; lower levels directed antiapoptotic signals while promoting proliferation. Furthermore, our data indicate that expression of kinase-dead Src isoforms do not necessarily act as dominant-negative factors, but can instead increase Src pathway activity, most likely by titrating Csk activity away from endogenous Src. The importance of Src activity levels was emphasized when we examined oncogenic cooperation between Src and Ras: malignant overgrowth was observed specifically when high Src signaling levels were achieved. We propose a model in which low levels of Src signaling promote survival and proliferation during early stages of tumorigenesis, whereas strong Src signaling, coupled with antiapoptotic signals, directs invasive migration and metastasis during advanced tumor stages. [Cancer Res 2007;67(21):10278–85]
Data from Therapeutic Efficacy of ABT-737, a Selective Inhibitor of BCL-2, in Small Cell Lung Cancer
Authors: Hann Christine L. , Daniel Vincent C. , Sugar Elizabeth A. , Dobromilskaya Irina , Murphy Sara C. , Cope Leslie , Lin Xue , Hierman Jared S. , Wilburn Daniel L. , Watkins D. Neil , Rudin Charles M.
Published: March 2024

Abstract
Bcl-2 is a central regulator of cell survival that is overexpressed in the majority of small cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. We compared primary SCLC xenografts prepared from de novo human tumors with standard cell line–based xenografts in the evaluation of a novel and highly potent small molecule inhibitor of Bcl-2, ABT-737. ABT-737 induced dramatic regressions in tumors derived from some SCLC cell lines. In contrast, only one of three primary xenograft SCLC tumors showed significant growth inhibition with ABT-737. Explanations for this apparent dichotomy may include relatively low expression of Bcl-2 in the primary xenografts or inherent differences in the model systems. The addition of etoposide to ABT-737 in the primary xenografts resulted in significant decreases in tumor growth, underscoring the clinical potential of ABT-737 in combination therapy. To identify factors that may contribute to resistance to ABT-737 and related inhibitors, we isolated resistant derivatives of an initially sensitive cell line–based xenograft. Acquired resistance in this model was associated with decreases in the expression of the primary target Bcl-2, of proapoptotic partners of Bcl-2 (Bax and Bim), and of Bcl-2:Bim heterodimers. Expression profiling reveals 85 candidate genes demonstrating consistent changes in gene expression with acquired resistance. Taken together, these data have specific implications for the clinical development of Bcl-2 inhibitors for SCLC and broader implications for the testing of novel anticancer strategies in relevant preclinical models. [Cancer Res 2008;68(7):2321–8]
Data from Knock-in of Oncogenic Kras Does Not Transform Mouse Somatic Cells But Triggers a Transcriptional Response that Classifies Human Cancers
Authors: Arena Sabrina , Isella Claudio , Martini Miriam , de Marco Ario , Medico Enzo , Bardelli Alberto
Published: March 2024

Abstract
KRAS mutations are present at a high frequency in human cancers. The development of therapies targeting mutated KRAS requires cellular and animal preclinical models. We exploited adeno-associated virus–mediated homologous recombination to insert the Kras G12D allele in the genome of mouse somatic cells. Heterozygous mutant cells displayed a constitutively active Kras protein, marked morphologic changes, increased proliferation and motility but were not transformed. On the contrary, mouse cells in which we overexpressed the corresponding Kras cDNA were readily transformed. The levels of Kras activation in knock-in cells were comparable with those present in human cancer cells carrying the corresponding mutation. Kras-mutated cells were compared with their wild-type counterparts by gene expression profiling, leading to the definition of a “mutated Kras-KI signature” of 345 genes. This signature was capable of classifying mouse and human cancers according to their KRAS mutational status, with an accuracy similar to or better than published Ras signatures. The isogenic cells that we have developed recapitulate the oncogenic activation of KRAS occurring in cancer and represent new models for studying Kras-mediated transformation. Our results have implications for the identification of human tumors in which the oncogenic KRAS transcriptional response is activated and suggest new strategies to build mouse models of tumor progression. [Cancer Res 2007;67(18):8468–76]
Data from A Role for Glial Cell–Derived Neurotrophic Factor–Induced Expression by Inflammatory Cytokines and RET/GFRα1 Receptor Up-regulation in Breast Cancer
Authors: Esseghir Selma , Todd S. Katrina , Hunt Toby , Poulsom Richard , Plaza-Menacho Ivan , Reis-Filho Jorge S. , Isacke Clare M.
Published: March 2024

Abstract
By screening a tissue microarray of invasive breast tumors, we have shown that the receptor tyrosine kinase RET (REarranged during Transfection) and its coreceptor GFRα1 (GDNF receptor family α-1) are overexpressed in a subset of estrogen receptor–positive tumors. Germ line–activating oncogenic mutations in RET allow this receptor to signal independently of GFRα1 and its ligand glial cell–derived neurotrophic factor (GDNF) to promote a spectrum of endocrine neoplasias. However, it is not known whether tumor progression can also be driven by receptor overexpression and whether expression of GDNF, as has been suggested for other neurotrophic factors, is regulated in response to the inflammatory microenvironment surrounding many epithelial cancers. Here, we show that GDNF stimulation of RET+/GFRα1+ MCF7 breast cancer cells in vitro enhanced cell proliferation and survival, and promoted cell scattering. Moreover, in tumor xenografts, GDNF expression was found to be up-regulated on the infiltrating endogenous fibroblasts and to a lesser extent by the tumor cells themselves. Finally, the inflammatory cytokines tumor necrosis factor-α and interleukin-1β, which are involved in tumor promotion and development, were found to act synergistically to up-regulate GDNF expression in both fibroblasts and tumor cells. These data indicate that GDNF can act as an important component of the inflammatory response in breast cancers and that its effects are mediated by both paracrine and autocrine stimulation of tumor cells via signaling through the RET and GFRα1 receptors. [Cancer Res 2007;67(24):11732–41]
Data from A Transgenic Mouse Model of Plasma Cell Malignancy Shows Phenotypic, Cytogenetic, and Gene Expression Heterogeneity Similar to Human Multiple Myeloma
Authors: Boylan Kristin L.M. , Gosse Mary A. , Staggs Sarah E. , Janz Siegfried , Grindle Suzanne , Kansas Geoffrey S. , Van Ness Brian G.
Published: March 2024

Abstract
Multiple myeloma is an incurable plasma cell malignancy for which existing animal models are limited. We have previously shown that the targeted expression of the transgenes c-Myc and Bcl-XL in murine plasma cells produces malignancy that displays features of human myeloma, such as localization of tumor cells to the bone marrow and lytic bone lesions. We have isolated and characterized in vitro cultures and adoptive transfers of tumors from Bcl-xl/Myc transgenic mice. Tumors have a plasmablastic morphology and variable expression of CD138, CD45, CD38, and CD19. Spectral karyotyping analysis of metaphase chromosomes from primary tumor cell cultures shows that the Bcl-xl/Myc tumors contain a variety of chromosomal abnormalities, including trisomies, translocations, and deletions. The most frequently aberrant chromosomes are 12 and 16. Three sites for recurring translocations were also identified on chromosomes 4D, 12F, and 16C. Gene expression profiling was used to identify differences in gene expression between tumor cells and normal plasma cells (NPC) and to cluster the tumors into two groups (tumor groups C and D), with distinct gene expression profiles. Four hundred and ninety-five genes were significantly different between both tumor groups and NPCs, whereas 124 genes were uniquely different from NPCs in tumor group C and 204 genes were uniquely different from NPCs in tumor group D. Similar to human myeloma, the cyclin D genes are differentially dysregulated in the mouse tumor groups. These data suggest the Bcl-xl/Myc tumors are similar to a subset of plasmablastic human myelomas and provide insight into the specific genes and pathways underlying the human disease. [Cancer Res 2007;67(9):4069–78]
Data from DNA Protein Kinase–Dependent G2 Checkpoint Revealed following Knockdown of Ataxia-Telangiectasia Mutated in Human Mammary Epithelial Cells
Authors: Arlander Sonnet J.H. , Greene Bryan T. , Innes Cynthia L. , Paules Richard S.
Published: March 2024

Abstract
Members of the phosphatidylinositol 3-kinase–related kinase family, in particular the ataxia-telangiectasia mutated (ATM) kinase and the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs), regulate cellular responses to DNA double-strand breaks. Increased sensitivity to ionizing radiation (IR) in DNA-PKcs– or ATM-deficient cells emphasizes their important roles in maintaining genome stability. Furthermore, combined knockout of both kinases is synthetically lethal, suggesting functional complementarity. In the current study, using human mammary epithelial cells with ATM levels stably knocked down by >90%, we observed an IR-induced G2 checkpoint that was only slightly attenuated. In marked contrast, this G2 checkpoint was significantly attenuated with either DNA-PK inhibitor treatment or RNA interference knockdown of DNA-PKcs, the catalytic subunit of DNA-PK, indicating that DNA-PK contributes to the G2 checkpoint in these cells. Furthermore, in agreement with the checkpoint attenuation, DNA-PK inhibition in ATM-knockdown cells resulted in reduced signaling of the checkpoint kinase CHK1 as evidenced by reduced CHK1 phosphorylation. Taken together, these results show a DNA-PK–dependent component to the IR-induced G2 checkpoint, in addition to the well-defined ATM-dependent component. This may have important implications for chemotherapeutic strategies for breast cancers. [Cancer Res 2008;68(1):89–97]
Data from CD133+ and CD133− Glioblastoma-Derived Cancer Stem Cells Show Differential Growth Characteristics and Molecular Profiles
Authors: Beier Dagmar , Hau Peter , Proescholdt Martin , Lohmeier Annette , Wischhusen Jörg , Oefner Peter J. , Aigner Ludwig , Brawanski Alexander , Bogdahn Ulrich , Beier Christoph P.
Published: March 2024

Abstract
Although glioblastomas show the same histologic phenotype, biological hallmarks such as growth and differentiation properties vary considerably between individual cases. To investigate whether different subtypes of glioblastomas might originate from different cells of origin, we cultured tumor cells from 22 glioblastomas under medium conditions favoring the growth of neural and cancer stem cells (CSC). Secondary glioblastoma (n = 7)–derived cells did not show any growth in the medium used, suggesting the absence of neural stem cell–like tumor cells. In contrast, 11/15 primary glioblastomas contained a significant CD133+ subpopulation that displayed neurosphere-like, nonadherent growth and asymmetrical cell divisions yielding cells expressing markers characteristic for all three neural lineages. Four of 15 cell lines derived from primary glioblastomas grew adherently in vitro and were driven by CD133− tumor cells that fulfilled stem cell criteria. Both subtypes were similarly tumorigenic in nude mice in vivo. Clinically, CD133− glioblastomas were characterized by a lower proliferation index, whereas glial fibrillary acidic protein staining was similar. GeneArray analysis revealed 117 genes to be differentially expressed by these two subtypes. Together, our data provide first evidence that CD133+ CSC maintain only a subset of primary glioblastomas. The remainder stems from previously unknown CD133− tumor cells with apparent stem cell–like properties but distinct molecular profiles and growth characteristics in vitro and in vivo. [Cancer Res 2007;67(9):4010–5]
Data from Tumor Necrosis Factor α Mediates Homogeneous Distribution of Liposomes in Murine Melanoma that Contributes to a Better Tumor Response
Authors: Seynhaeve Ann L.B. , Hoving Saske , Schipper Debby , Vermeulen Cindy E. , aan de Wiel-Ambagtsheer Gisela , van Tiel Sandra T. , Eggermont Alexander M.M. , ten Hagen Timo L.M.
Published: March 2024

Abstract
Successful treatment of solid tumors with chemotherapeutics requires that adequate levels reach the tumor cells. Tumor vascular normalization has been proposed to enhance drug delivery and improve tumor response to chemotherapy. Differently, augmenting leakage of the tumor-associated vasculature, and as such enhance vascular abnormality, may improve tumor response as well. In the present study, we show that addition of low-dose tumor necrosis factor α (TNF) to systemic injections with pegylated long circulating liposomes augmented the tumor accumulation of these liposomes 5- to 6-fold, which strongly correlated with enhanced tumor response. Using intravital microscopy, we could study the liposomal distribution inside the tumor in more detail. Especially 100 nm liposomes effectively extravasate in the surrounding tumor tissue in the presence of TNF and this occurred without any effect on tumor vascular density, branching, and diameter. Next to that, we observed in living animals that tumor cells take up the liposomes intact, followed by intracellular degradation. To our knowledge, this is an unprecedented observation. Taken together, TNF renders more tumor vessels permeable, leading to a more homogeneous distribution of the liposomes throughout the tumor, which is crucial for an optimal tumor response. We conclude that delivery of nanoparticulate drug formulations to solid tumor benefits from augmenting the vascular leakage through vascular manipulation with vasoactive drugs like TNF. [Cancer Res 2007;67(19):9455–62]
Data from Inhibition of Multiple Vascular Endothelial Growth Factor Receptors (VEGFR) Blocks Lymph Node Metastases but Inhibition of VEGFR-2 Is Sufficient to Sensitize Tumor Cells to Platinum-Based Chemotherapeutics
Authors: Sini Patrizia , Samarzija Ivana , Baffert Fabienne , Littlewood-Evans Amanda , Schnell Christian , Theuer Andreas , Christian Sven , Boos Anja , Hess-Stumpp Holger , Foekens John A. , Setyono-Han Buddy , Wood Jeanette , Hynes Nancy E.
Published: March 2024

Abstract
Vascular endothelial growth factor receptors (VEGFR) have important roles in cancer, affecting blood and lymphatic vessel functionality as well as tumor cells themselves. We compared the efficacy of a VEGFR tyrosine kinase inhibitor, PTK787/ZK222584 (PTK/ZK), which targets the three VEGFRs, with blocking antibodies directed against VEGFR-2 (DC101) or VEGF-A (Pab85618) in a metastatic melanoma model. Although all inhibitors exerted comparable effects on primary tumor growth, only PTK/ZK significantly reduced lymph node metastasis formation. A comparable decrease in lymphatic vessel density following blockade of VEGFR-2 (DC101) or the three VEGFRs (PTK/ZK) was observed in the metastases. However, the functionality of lymphatics surrounding the primary tumor was more significantly disrupted by PTK/ZK, indicating the importance of multiple VEGFRs in the metastatic process. The antimetastatic properties of PTK/ZK were confirmed in a breast carcinoma model. B16/BL6 tumor cells express VEGF ligands and their receptors. Blockade of a VEGFR-1 autocrine loop with PTK/ZK inhibited tumor cell migration. Furthermore, the tumor cells also showed enhanced sensitivity to platinum-based chemotherapy in combination with PTK/ZK, indicating that autocrine VEGFRs are promoting tumor cell migration and survival. In summary, our results suggest that, in addition to blocking angiogenesis, combined inhibition of the three VEGFRs may more efficiently target other aspects of tumor pathophysiology, including lymphatic vessel functionality, tumor cell dissemination, survival pathways, and response to chemotherapeutic compounds. [Cancer Res 2008;68(5):1581–92]
Data from p53 Loss Synergizes with Estrogen and Papillomaviral Oncogenes to Induce Cervical and Breast Cancers
Authors: Shai Anny , Pitot Henry C. , Lambert Paul F.
Published: March 2024

Abstract
Whereas the tumor suppressor p53 gene is frequently mutated in most human cancers, this is not the case in human papillomavirus (HPV)-associated cancers, presumably because the viral E6 oncoprotein inactivates the p53 protein. The ability of E6 to transform cells in tissue culture and induce cancers in mice correlates in part with its ability to inactivate p53. In this study, we compared the expression of the HPV16 E6 oncogene to the conditional genetic disruption of p53 in the context of a mouse model for cervical cancer in which estrogen is a critical cofactor. Nearly all of the K14Crep53f/f mice treated with estrogen developed cervical cancer, a stark contrast to its complete absence in like-treated K14E6WTp53f/f mice, indicating that HPV16 E6 must only partially inactivate p53. p53-independent activities of E6 also contributed to carcinogenesis, but in the female reproductive tract, these activities were manifested only in the presence of the HPV16 E7 oncogene. Interestingly, treatment of K14Crep53f/f mice with estrogen also resulted in mammary tumors after only a short latency, many of which were positive for estrogen receptor α. The majority of these mammary tumors were of mixed cell types, suggestive of their originating from a multipotent progenitor. Furthermore, a subset of mammary tumors arising in the estrogen-treated, p53-deficient mammary glands exhibited evidence of an epithelial to mesenchymal transition. These data show the importance of the synergy between estrogen and p53 insufficiency in determining basic properties of carcinogenesis in hormone-responsive tissues, such as the breast and the reproductive tract. [Cancer Res 2008;68(8):2622–31]
Data from Ability of Mature Dendritic Cells to Interact with Regulatory T Cells Is Imprinted during Maturation
Authors: Muthuswamy Ravikumar , Urban Julie , Lee Je-Jung , Reinhart Todd A. , Bartlett David , Kalinski Pawel
Published: March 2024

Abstract
Preferential activation of regulatory T (Treg) cells limits autoimmune tissue damage during chronic immune responses but can also facilitate tumor growth. Here, we show that tissue-produced inflammatory mediators prime maturing dendritic cells (DC) for the differential ability of attracting anti-inflammatory Treg cells. Our data show that prostaglandin E2 (PGE2), a factor overproduced in chronic inflammation and cancer, induces stable Treg-attracting properties in maturing DC, mediated by CCL22. The elevated production of CCL22 by PGE2-matured DC persists after the removal of PGE2 and is further elevated after secondary stimulation of DC in a neutral environment. This PGE2-induced overproduction of CCL22 and the resulting attraction of FOXP3+ Tregs are counteracted by IFNα, a mediator of acute inflammation, which also restores the ability of the PGE2-exposed DC to secrete the Th1-attracting chemokines: CXCL9, CXCL10, CXCL11, and CCL5. In accordance with these observations, different DCs clinically used as cancer vaccines show different Treg-recruiting abilities, with PGE2-matured DC, but not type 1–polarized DC, generated in the presence of type I and type II IFNs, showing high Treg-attracting activity. The current data, showing that the ability of mature DC to interact with Treg cells is predetermined at the stage of DC maturation, pave the way to preferentially target the regulatory versus proinflammatory T cells in autoimmunity and transplantation, as opposed to intracellular infections and cancer. [Cancer Res 2008;68(14):5972–8]
Data from NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and Metastasis
Authors: Eccles Suzanne A. , Massey Andy , Raynaud Florence I. , Sharp Swee Y. , Box Gary , Valenti Melanie , Patterson Lisa , de Haven Brandon Alexis , Gowan Sharon , Boxall Frances , Aherne Wynne , Rowlands Martin , Hayes Angela , Martins Vanessa , Urban Frederique , Boxall Kathy , Prodromou Chrisostomos , Pearl Laurence , James Karen , Matthews Thomas P. , Cheung Kwai-Ming , Kalusa Andrew , Jones Keith , McDonald Edward , Barril Xavier , Brough Paul A. , Cansfield Julie E. , Dymock Brian , Drysdale Martin J. , Finch Harry , Howes Rob , Hubbard Roderick E. , Surgenor Alan , Webb Paul , Wood Mike , Wright Lisa , Workman Paul
Published: March 2024

Abstract
We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (Kd = 1.7 nmol/L) and proliferation of human tumor cells with GI50 values of approximately 2 to 40 nmol/L, inducing G1-G2 arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI50. This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1α, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro, WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials. [Cancer Res 2008;68(8):2850–60]
Data from Androgen Receptor and Invasion in Prostate Cancer
Authors: Hara Takahito , Miyazaki Hideyo , Lee Aram , Tran Chau P. , Reiter Robert E.
Published: March 2024

Abstract
Activation of androgen receptor (AR) stimulates the growth of not only androgen-dependent but also of androgen-refractory prostate cancer. However, neither the role of AR in invasion/metastasis nor the relationship between invasiveness and androgen-refractory status has been established. In this study, we used the androgen-dependent prostate cancer cell line MDA PCa 2b, derived from a human bone metastasis, to generate an invasive subline (MDA-I) using a Matrigel chamber. MDA-I cells expressed higher levels of AR and prostate-specific antigen than their less invasive parental cells. Blocking AR function or removal of androgen suppressed the invasion of MDA-I cells, whereas stimulating AR increased invasion. In addition, forced AR overexpression increased the invasiveness of MDA PCa 2b cells. Next, we showed that an androgen-refractory subline (MDA-hr) of MDA PCa 2b cells also expressed higher levels of AR and were more invasive than their parental androgen-dependent cells. Blocking AR function suppressed the invasiveness of MDA-hr cells. Gelatin zymography indicated that matrix metalloproteinase 2 (MMP-2) and MMP-9 activities were regulated by AR signaling and closely correlated with the invasiveness of the androgen-dependent and androgen-refractory prostate cancer cells. These data suggest that AR promotes the invasiveness of both androgen-dependent and androgen-refractory prostate cancer and that a more invasive phenotype might develop through AR activation during cancer progression. These findings potentially support the use of adjuvant hormonal therapy and the future development of more potent androgen blockade therapy. [Cancer Res 2008;68(4):1128–35]
Data from Differential Cellular Internalization of Anti-CD19 and -CD22 Immunotoxins Results in Different Cytotoxic Activity
Authors: Du Xing , Beers Richard , FitzGerald David J. , Pastan Ira
Published: March 2024

Abstract
B-cell malignancies routinely express surface antigens CD19 and CD22. Immunotoxins against both antigens have been evaluated, and the immunotoxins targeting CD22 are more active. To understand this disparity in cytotoxicity and guide the screening of therapeutic targets, we compared two immunotoxins, FMC63(Fv)-PE38–targeting CD19 and RFB4(Fv)-PE38 (BL22)–targeting CD22. Six lymphoma cell lines have 4- to 9-fold more binding sites per cell for CD19 than for CD22, but BL22 is 4- to 140-fold more active than FMC63(Fv)-PE38, although they have a similar cell binding affinity (Kd, ∼7 nmol/L). In 1 hour, large amounts of BL22 are internalized (2- to 3-fold more than the number of CD22 molecules on the cell surface), whereas only 5.2% to 16.6% of surface-bound FMC63(Fv)-PE38 is internalized. The intracellular reservoir of CD22 decreases greatly after immunotoxin internalization, indicating that it contributes to the uptake of BL22. Treatment of cells with cycloheximide does not reduce the internalization of BL22. Both internalized immunotoxins are located in the same vesicles. Our results show that the rapid internalization of large amounts of BL22 bound to CD22 makes CD22 a better therapeutic target than CD19 for immunotoxins and probably for other immunoconjugates that act inside cells. [Cancer Res 2008;68(15):6300–5]