bluuebunny/crossref_metadata_2025_split huggingface dataset:
Semaphorin 7A Promotes Macrophage-Mediated Lymphatic Remodeling during Postpartum Mammary Gland Involution and in Breast Cancer
Authors: Elder Alan M. , Tamburini Beth A.J. , Crump Lyndsey S. , Black Sarah A. , Wessells Veronica M. , Schedin Pepper J. , Borges Virginia F. , Lyons Traci R. 
Published: September 2018

AbstractPostpartum mammary gland involution is a tissue remodeling event that occurs in all mammals in the absence of nursing or after weaning to return the gland to the pre-pregnant state. The tissue microenvironment created by involution has proven to be tumor promotional. Here we report that the GPI-linked protein semaphorin 7A (SEMA7A) is expressed on mammary epithelial cells during involution and use preclinical models to demonstrate that tumors induced during involution express high levels of SEMA7A. Overexpression of SEMA7A promoted the presence of myeloid-derived podoplanin (PDPN)-expressing cells in the tumor microenvironment and during involution. SEMA7A drove the expression of PDPN in macrophages, which led to integrin- and PDPN-dependent motility and adherence to lymphatic endothelial cells to promote lymphangiogenesis. In support of this mechanism, mammary tissue from SEMA7A-knockout mice exhibited decreased myeloid-derived PDPN-expressing cells, PDPN-expressing endothelial cells, and lymphatic vessel density. Furthermore, coexpression of SEMA7A, PDPN, and macrophage marker CD68 predicted for decreased distant metastasis-free survival in a cohort of over 600 cases of breast cancer as well as in ovarian, lung, and gastric cancers. Together, our results indicate that SEMA7A may orchestrate macrophage-mediated lymphatic vessel remodeling, which in turn drives metastasis in breast cancer.Signficance: SEMA7A, which is expressed on mammary cells during glandular involution, alters macrophage biology and lymphangiogenesis to drive breast cancer metastasis. Cancer Res; 78(22); 6473–85. ©2018 AACR.
Cyclin F-Dependent Degradation of RBPJ Inhibits IDH1R132H-Mediated Tumorigenesis
Authors: Deshmukh Ruhi S. , Sharma Shalakha , Das Sanjeev 
Published: September 2018

Abstract
Cyclin F is a substrate recognition subunit of Skp1-Cul1-F-box protein (SCF) E3 ubiquitin ligase complex. Although there have been reports describing the role of cyclin F in the genotoxic stress response, its function under conditions of altered metabolic homeostasis remain unexplored. Here we report that cyclin F is induced upon metabolic stress in a FOXO1-dependent manner. Under metabolic stress conditions, cyclin F mediated polyubiquitylation of RBPJ at Lys315, leading to its proteasomal degradation. RBPJ regulated the expression of IDH1, which is often mutated to an oncogenic form IDH1R132H in cancers. Thus, metabolic stress–induced cyclin F attenuated the oncogenic functions of IDH1R132H in an RBPJ-dependent manner. Studies in mouse tumor models indicated that abrogation of cyclin F expression facilitates IDH1R132H-mediated tumorigenesis and metastasis. In addition, increased IDH1R132H levels correlated with reduced cyclin F levels in increasing grades of glioma. These findings highlight a novel aspect of cyclin F functions in inhibiting tumorigenesis and provide mechanistic insights into regulation of IDH1R132H.
Significance: These findings reveal mechanistic insights into the key role of the cyclin F-RBPJ axis in response to metabolic stress in cancer cells. Cancer Res; 78(22); 6386–98. ©2018 AACR.
An ATM/TRIM37/NEMO Axis Counteracts Genotoxicity by Activating Nuclear-to-Cytoplasmic NF-κB Signaling
Authors: Wu Geyan , Song Libing , Zhu Jinrong , Hu Yameng , Cao Lixue , Tan Zhanyao , Zhang Shuxia , Li Ziwen , Li Jun 
Published: September 2018

Abstract
Blocking genotoxic stress-induced NF-κB activation would substantially enhance the anticancer efficiency of genotoxic chemotherapy. Unlike the well-established classical NF-κB pathway, the genotoxic agents-induced “nuclear-to-cytoplasmic” NF-κB pathway is initiated from the nucleus and transferred to the cytoplasm. However, the mechanism linking nuclear DNA damage signaling to cytoplasmic IKK activation remains unclear. Here, we report that TRIM37, a novel E3 ligase, plays a vital role in genotoxic activation of NF-κB via monoubiquitination of NEMO at K309 in the nucleus, consequently resulting in nuclear export of NEMO and IKK/NF-κB activation. Clinically, TRIM37 levels correlated positively with levels of activated NF-κB and expression of Bcl-xl and XIAP in esophageal cancer specimens, which also associated positively with clinical stage and tumor-node-metastasis classification and associated inversely with overall and relapse-free survival in patients with esophageal cancer. Overexpression of TRIM37 conferred resistance to the DNA-damaging anticancer drug cisplatin in vitro and in vivo through activation of the NF-κB pathway. Genotoxic stress-activated ATM kinase directly interacted with and phosphorylated TRIM37 in the cytoplasm, which induced translocation of TRIM37 into the nucleus, where it formed a complex with NEMO and TRAF6 via a TRAF6-binding motif (TBM). Importantly, blocking the ATM/TRIM37/NEMO axis via cell-penetrating TAT-TBM peptide abrogated genotoxic agent-induced NEMO monoubiquitination and NF-κB activity, resulting in hypersensitivity of cancer cells to genotoxic drugs. Collectively, our results unveil a pivotal role for TRIM37 in genotoxic stress and shed light on mechanisms of inducible chemotherapy resistance in cancer.
Significance: In response to genotoxic stress, TRIM37 activates NF-κB signaling via monoubiquitination of NEMO, which subsequently promotes cisplatin chemoresistance and tumor relapse in cancer. Cancer Res; 78(22); 6399–412. ©2018 AACR.
Harnessing Androgen Receptor Pathway Activation for Targeted Alpha Particle Radioimmunotherapy of Breast Cancer
Authors: Thorek Daniel L.J. , Ku Anson T. , Mitsiades Nicholas , Veach Darren , Watson Philip A. , Metha Dipti , Strand Sven-Erik , Sharma Sai Kiran , Lewis Jason S. , Abou Diane S. , Lilja Hans G. , Larson Steven M. , McDevitt Michael R. , Ulmert David 
Published: September 2018

Abstract

Purpose:
The impact of androgen receptor (AR) activity in breast cancer biology is unclear. We characterized and tested a novel therapy to an AR-governed target in breast cancer.
Experimental Design: We evaluated the expression of prototypical AR gene products human kallikrein 2 (hK2) and PSA in breast cancer models. We screened 13 well-characterized breast cancer cell lines for hK2 and PSA production upon in vitro hormone stimulation by testosterone [dihydrotestosterone (DHT)]. AR-positive lines were further evaluated by exposure to estrogen (17β-Estradiol) and the synthetic progestin D-Norgestrel. We then evaluated an anti-hK2–targeted radiotherapy platform (hu11B6), labeled with alpha (α)-particle emitting Actinium-225, to specifically treat AR-expressing breast cancer xenografts under hormone stimulation.

Results:
D-Norgestrel and DHT activated the AR pathway, while 17β-Estradiol did not. Competitive binding for AR protein showed similar affinity between DHT and D-Norgestrel, indicating direct AR–ligand interaction. In vivo production of hK2 was sufficient to achieve site-specific delivery of therapeutic radionuclide to tumor tissue at &gt;20-fold over background muscle uptake; effecting long-term local tumor control.

Conclusions:
[225Ac]hu11B6 targeted radiotherapy was potentiated by DHT and by D-Norgestrel in murine xenograft models of breast cancer. AR activity in breast cancer correlates with kallikrein-related peptidase-2 and can be activated by D-Norgestrel, a common contraceptive, and AR induction can be harnessed for hK2-targeted breast cancer α-emitter radiotherapy.
Carbonic Anhydrase XII Inhibitors Overcome P-Glycoprotein–Mediated Resistance to Temozolomide in Glioblastoma
Authors: Salaroglio Iris C. , Mujumdar Prashant , Annovazzi Laura , Kopecka Joanna , Mellai Marta , Schiffer Davide , Poulsen Sally-Ann , Riganti Chiara 
Published: September 2018

Abstract
The role of carbonic anhydrase XII (CAXII) in the chemoresistance of glioblastoma is unexplored. We found CAXII and P-glycoprotein (Pgp) coexpressed in neurospheres derived from 3 of 3 patients with different genetic backgrounds and low response to temozolomide (time to recurrence: 6–9 months). CAXII was necessary for the Pgp efflux of temozolomide and second-line chemotherapeutic drugs, determining chemoresistance in neurospheres. Psammaplin C, a potent inhibitor of CAXII, resensitized primary neurospheres to temozolomide by reducing temozolomide efflux via Pgp. This effect was independent of other known temozolomide resistance factors present in the patients. The overall survival in orthotopic patient-derived xenografts of temozolomide-resistant neurospheres, codosed with Psammaplin C and temozolomide, was significantly increased over temozolomide-treated (P &lt; 0.05) and untreated animals (P &lt; 0.02), without detectable signs of systemic toxicity. We propose that a CAXII inhibitor in combination with temozolomide may provide a new and effective approach to reverse chemoresistance in glioblastoma stem cells. This novel mechanism of action, via the interaction of CAXII and Pgp, ultimately blocks the efflux function of Pgp to improve glioblastoma patient outcomes.
Chimeric Antigen Receptor-T Cells with 4-1BB Co-Stimulatory Domain Present a Superior Treatment Outcome than Those with CD28 Domain Based on Bioinformatics
Authors: Zhong Qi , Zhu Yang-min , Zheng Li-ling , Shen Hui-juan , Ou Rui-ming , Liu Zhi , She Yan-ling , Chen Rui , Li Cheng , Huang Jing , Yao Meng-dong , Zhang Qing , Liu Shuang 
Published: September 2018

<b><i>Background:</i></b> The second-generation CD19-chimeric antigen receptor (CAR)-T co-stimulatory domain that is commonly used in clinical practice is CD28 or 4-1BB. Previous studies have shown that the persistence of CAR-T in the 4-1BB co-stimulatory domain appears to be longer. <b><i>Methods:</i></b> The expression profile data of GSE65856 were obtained from GEO database. After data preprocessing, the differentially expressed genes (DEGs) between the mock CAR versus CD19-28z CAR T cells and mock CAR versus CD19-BBz CAR T cells were identified using the limma package. Subsequently, functional enrichment analysis of DEGs was performed using the DAVID tool. Then, the protein-protein international (PPI) network of these DEGs was visualized by Cytoscape, and the miRNA-target gene-disease regulatory networks were predicted using Webgestal. <b><i>Results:</i></b> A total of 18 common DEGs, 6 CD19-28z specific DEGs and 206 CD19-BBz specific DEGs were identified. Among CD19-28z specific DEGs, down-regulated PAX5 might be an important node in the PPI network and could be targeted by miR-496. In CD19-BBz group, JUN was a hub node in the PPI network and involved in the regulations of miR520D – early growth response gene 3 (EGR3)-JUN and mi-R489-AT-rich interaction domain 5A (ARID5A)-JUN networks. <b><i>Conclusion:</i></b> The 4-1BB co-stimulatory domain might play in important role in the treatment of CAR-T via miR-520D-EGR3-JUN and miR489-ARID5A-JUN regulation network, while CD28 had a negative effect on CAR-T treatment.
Attenuation of Remifentanil-Induced Hyperalgesia by Betulinic Acid Associates with Inhibiting Oxidative Stress and Inflammation in Spinal Dorsal Horn
Authors: Lv Chang-Cheng , Xia Man-Li , Shu Shu-Juan , Chen Fei , Jiang Li-Shan 
Published: September 2018

Remifentanil-induced hyperalgesia (RIH) is known to be associated with oxidative stress and inflammation. Betulinic acid (BA) was reported to reduce visceral pain owing to its anti-oxidative and anti-inflammatory potential. Here, we ­explored whether BA can attenuate RIH through inhibiting oxidative stress and inflammation in spinal dorsal horn. Sprague-Dawley rats were randomly divided into 4 groups: Control, Incision, RIH, and RIH pre-treated with BA. After pretreated with BA (25 mg/kg, i.g.) for 7 days, rats were subcutaneously infused with remifentanil (40 μg/kg) for 30 min during right plantar incision surgery to induce RIH. The paw withdrawal mechanical threshold (PWMT), paw withdrawal thermal latency (PWTL), spinal oxidative stress and inflammatory mediators were determined. Intraoperative remifentanil infusion induced postoperative hyperalgesia, as evidenced by the significant decrease in PWMT and PWTL (<i>p</i> &#x3c; 0.01), and the significant increase in oxidative stress and inflammation evidenced by up-regulations of malondialdehyde, 3-nitrotyrosine, interleukin-1β and tumour necrosis factor-α (<i>p</i> &#x3c; 0.01) in spinal dorsal horn and matrix metalloproteinase-9 (MMP-9) activity (<i>p</i> &#x3c; 0.01) in dorsal root ganglion, as well as a decrease in manganese superoxide ­dismutase activity (<i>p</i> &#x3c; 0.01) compared with control and ­incision groups. All these results mentioned above were markedly reversed by pre-treatment with BA (<i>p</i> &#x3c; 0.01) compared with RIH group. These findings demonstrated that BA can effectively attenuate RIH, which associates with potentially inhibiting oxidative stress and subsequently down-regulating MMP-9-related pro-inflammatory cyokines in spinal dorsal horn.
Liver Resection for Hepatic Metastases from Soft Tissue Sarcoma: A Nationwide Study
Authors: Grimme Frederike A.B. , Seesing Maarten F.J. , van Hillegersberg Richard , van Coevorden Frits , de Jong Koert P. , Nagtegaal Iris D. , Verhoef Cornelis , de Wilt Johannes H.W. ,   On behalf of the Dutch Liver Surgery Working Group
Published: September 2018

<b><i>Background:</i></b> This study aims to evaluate the feasibility and safety of resection of sarcoma liver metastases, and to identify possible prognostic factors for long-term survival. <b><i>Methods:</i></b> All patients who underwent resection of liver metastases of sarcoma in the Netherlands from 1998 to 2014 were included. Study data was retrospectively collected from patient files. Survival rates were calculated using Kaplan-Meier survival analysis. <b><i>Results:</i></b> Some 38 patients treated in 16 hospitals were included (15 male, 23 female). The median age was 57 years (37–80 years). The most common histological subtype was leiomyosarcoma (63%). The predominant site of primary tumour was the abdomen (59%). R0 resection was achieved in 16 patients. Mortality was 3 and 16% of included patients had 1 or more complications. The median follow-up period was 18 months (range 1–161). After liver resection, 1-, 3-, and 5-year survival were 88, 54, and 42% respectively. Median overall survival was 46 months (1–161 months). One- and three-year progression-free survival (PFS) after liver resection were 54 and 19% respectively. Median PFS was 16 months (1–61 months). <b><i>Conclusions:</i></b> Liver surgery for sarcoma metastases is safe and leads to a relatively good survival. The choice for surgical treatment should always be discussed in a multidisciplinary sarcoma and liver team.
A Legal Concept in Motion: The ‘Spreader of Corruption’ (sā‘ī bi’l-fesād) from Qarakhanid to Ottoman Jurisprudence
Authors: Aykan Yavuz 
Published: September 2018

AbstractThis article traces the genealogies of the legal concept ‘spreader of corruption’. Although some scholars working on Ottoman law consider this concept to be part of the Ottoman ḳānūn tradition, the history of its adaptation by Ottoman jurists actually dates back to the Qarakhanid period (eleventh century CE). It acquired its legal meaning as a result of jurisprudential debates among Ḥanafī jurists in the context of political turmoil and violent factionalism among madhhabs. Later, Seljuq and Golden Horde legal-textual traditions served as conduit for Ottoman jurists to adapt the concept in order to apply it to a variety of criminal acts. This article explores how the ‘spreader of corruption’ concept was reinterpreted over the centuries and how it contributed to the enforcement of law in the Ottoman context.
Dynamics and Predictability of El Niño–Southern Oscillation: An Australian Perspective on Progress and Challenges
Authors: Santoso Agus , Hendon Harry , Watkins Andrew , Power Scott , Dommenget Dietmar , England Matthew H. , Frankcombe Leela , Holbrook Neil J. , Holmes Ryan , Hope Pandora , Lim Eun-Pa , Luo Jing-Jia , McGregor Shayne , Neske Sonja , Nguyen Hanh , Pepler Acacia , Rashid Harun , Gupta Alex Sen , Taschetto Andréa S. , Wang Guomin , Abellán Esteban , Sullivan Arnold , Huguenin Maurice F. , Gamble Felicity , Delage Francois 
Published: September 2018

AbstractEl Niño and La Niña, the warm and cold phases of El Niño–Southern Oscillation (ENSO), cause significant year-to-year disruptions in global climate, including in the atmosphere, oceans, and cryosphere. Australia is one of the countries where its climate, including droughts and flooding rains, is highly sensitive to the temporal and spatial variations of ENSO. The dramatic impacts of ENSO on the environment, society, health, and economies worldwide make the application of reliable ENSO predictions a powerful way to manage risks and resources. An improved understanding of ENSO dynamics in a changing climate has the potential to lead to more accurate and reliable ENSO predictions by facilitating improved forecast systems. This motivated an Australian national workshop on ENSO dynamics and prediction that was held in Sydney, Australia, in November 2017. This workshop followed the aftermath of the 2015/16 extreme El Niño, which exhibited different characteristics to previous extreme El Niños and whose early evolution since 2014 was challenging to predict. This essay summarizes the collective workshop perspective on recent progress and challenges in understanding ENSO dynamics and predictability and improving forecast systems. While this essay discusses key issues from an Australian perspective, many of the same issues are important for other ENSO-affected countries and for the international ENSO research community.
Perceptions of Rural African American Adults About the Role of Family in Understanding and Addressing Risk Factors for Cardiovascular Disease
Authors: Ellis Katrina R. , Young Tiffany L. , Carthron Dana , Simms Marcia , McFarlin Shirley , Davis Kia L. , Dave Guarav , Corbie-Smith Giselle , Cené Crystal 
Published: September 2018

Purpose: African Americans (AAs) in rural south and southeast regions of the United States have among the highest prevalence of cardiovascular disease (CVD) in the country. The purpose of this qualitative, exploratory study is to understand family influences on CVD-related knowledge and health-related behaviors among rural AA adults. Design: Qualitative descriptive study design using a community-based participatory research approach. Setting: Two rural North Carolina counties. Participants: Eligible participants were AA adults (at least 21 years of age), who self-reported either CVD diagnosis or selected CVD risk factor(s) for themselves or for an adult family member (N = 37). Method: Directed content analysis of semistructured interviews by community and academic partners. Results: Family health history and familial norms and preferences influenced participants’ CVD-related knowledge, beliefs, and health-related behaviors. Participants reported their families were helpful for increasing motivation for and overcoming barriers to healthy behaviors, including hard-to-access community resources and physical challenges. Conversely, and to a lesser extent, participants also reported that family members hindered or had little influence (positive or negative) on their engagement in healthy behaviors. Conclusion: Family played an important role in helping individuals overcome personal and community-related challenges. Efforts to reduce CVD burden among rural AAs should seek to understand the family-related facilitators, barriers, and processes associated with CVD knowledge and risk-reduction behaviors.
Expectations and needs of relatives of critically ill patients in the emergency department
Authors: Ocak Umut , Avsarogullari Levent 
Published: September 2018

Background:The care of critically ill patients is a strong indicator of service quality provided in the emergency department. Since families are the major social support sources, assessing the family members’ needs may reduce their anxiety and depression owing to the acute situation of their loved ones while improving the patients’ recovery.Objective:We aimed to evaluate the expectations and needs of relatives of critically ill patients to formulate solutions to improve the quality of emergency department service.Methods:We conducted a prospective, cross-sectional survey of 873 relatives of nontraumatic, critically ill patients who completed the Turkish version of the Critical Care Family Needs Inventory in the emergency department of a university hospital in Turkey. The needs statements were evaluated under five subheadings: meaning, proximity, communication, comfort, and support.Results:In total, 249 (28.5%) participants were females and 624 (71.5%) were males (mean age, 41.79 years). The “meaning” category was given the highest priority, followed by “communication,” with average points of 3.75 and 3.57, respectively. The most important needs were being informed regularly about the patient’s condition and being assured that the patient is under the best possible care, whereas personal, physical, and emotional needs were the least important.Conclusion:Relatives of critically ill patients primarily focus on the quality of patients’ care. Creating a positive rapport based on trust and providing a healthcare environment where the expectations and needs of relatives are met should be prioritized by emergency department physicians, nurses, and other staff while caring for critically ill patients.
Financial impact from in-office dispensing of oral chemotherapy
Authors: Howard Anna , Kerr Julia , McLain Monica , Modlin Jessie 
Published: September 2018

Background Oral chemotherapy agents are being prescribed more frequently in many cancer types. In-office dispensing of oral chemotherapy agents has demonstrated clinical benefits and also shown financial benefit to third-party payers. A previous publication estimated over $200,000 in cost savings annually from in-office dispensing solely from medications returned to stock for credit. However, pharmacists in the in-office setting perform many other interventions that may affect financial outcomes. Objective Assess financial impact of oral chemotherapy in-office dispensing by a clinic-based oral chemotherapy program serving five outpatient cancer centers in Southern Idaho. Outcomes include calculated monetary waste and cost avoidance of oral chemotherapy prescriptions from in-office dispensing and mail-order pharmacies. Methods Prescriptions received by the clinic-based oral chemotherapy program for filling through in-office dispensing and mail-order pharmacies were monitored for monetary waste and cost avoidance events from December 2016 through May 2017. Information was collected on the number of returned medications, therapy discontinuations, and dose adjustments. Monetary outcomes were calculated using average wholesale price. Results During the six-month evaluation, prescriptions filled through in-office dispensing had a total cost avoidance of $1,020,193 ( n = 154) and total waste of $154,985 ( n = 36) resulting in an estimated net cost avoidance annually of $1,730,416. Prescriptions filled through mail-order had a total cost avoidance of $20,497 ( n = 4) and a total waste of $80,394 ( n = 15) resulting in an estimated $119,794 net annual waste. Conclusions In-office dispensing of oral chemotherapy provided significant cost savings to third-party payers compared to mail-order pharmacy dispensing. Continued evaluation may help further justify the importance and value of in-office dispensing.