bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Proliferative Activity of Mammary Epithelial Cells in Normal Tissue Predicts Breast Cancer Risk in Premenopausal Women
Authors: Huh Sung Jin , Oh Hannah , Peterson Michael A. , Almendro Vanessa , Hu Rong , Bowden Michaela , Lis Rosina L. , Cotter Maura B. , Loda Massimo , Barry William T. , Polyak Kornelia , Tamimi Rulla M. 
Published: March 2016

Abstract
The frequency and proliferative activity of tissue-specific stem and progenitor cells are suggested to correlate with cancer risk. In this study, we investigated the association between breast cancer risk and the frequency of mammary epithelial cells expressing p27, estrogen receptor (ER), and Ki67 in normal breast tissue. We performed a nested case–control study of 302 women (69 breast cancer cases, 233 controls) who had been initially diagnosed with benign breast disease according to the Nurses' Health Studies. Immunofluorescence for p27, ER, and Ki67 was performed on tissue microarrays constructed from benign biopsies containing normal mammary epithelium and scored by computational image analysis. We found that the frequency of Ki67+ cells was positively associated with breast cancer risk among premenopausal women [OR = 10.1, 95% confidence interval (CI) = 2.12–48.0]. Conversely, the frequency of ER+ or p27+ cells was inversely, but not significantly, associated with subsequent breast cancer risk (ER+: OR = 0.70, 95% CI, 0.33–1.50; p27+: OR = 0.89, 95% CI, 0.45–1.75). Notably, high Ki67+/low p27+ and high Ki67+/low ER+ cell frequencies were significantly associated with a 5-fold higher risk of breast cancer compared with low Ki67+/low p27+ and low Ki67+/low ER+ cell frequencies, respectively, among premenopausal women (Ki67hi/p27lo: OR = 5.08, 95% CI, 1.43–18.1; Ki67hi/ERlo: OR = 4.68, 95% CI, 1.63–13.5). Taken together, our data suggest that the fraction of actively cycling cells in normal breast tissue may represent a marker for breast cancer risk assessment, which may therefore impact the frequency of screening procedures in at-risk women. Cancer Res; 76(7); 1926–34. ©2016 AACR.
Shift Work, Chronotype, and Melatonin Patterns among Female Hospital Employees on Day and Night Shifts
Authors: Leung Michael , Tranmer Joan , Hung Eleanor , Korsiak Jill , Day Andrew G. , Aronson Kristan J. 
Published: March 2016

AbstractBackground: Shift work-related carcinogenesis is hypothesized to be mediated by melatonin; however, few studies have considered the potential effect modification of this underlying pathway by chronotype or specific aspects of shift work such as the number of consecutive nights in a rotation. In this study, we examined melatonin patterns in relation to shift status, stratified by chronotype and number of consecutive night shifts, and cumulative lifetime exposure to shift work.Methods: Melatonin patterns of 261 female personnel (147 fixed-day and 114 on rotations, including nights) at Kingston General Hospital were analyzed using cosinor analysis. Urine samples were collected from all voids over a 48-hour specimen collection period for measurement of 6-sulfatoxymelatonin concentrations using the Buhlmann ELISA Kit. Chronotypes were assessed using mid-sleep time (MSF) derived from the Munich Chronotype Questionnaire (MCTQ). Sociodemographic, health, and occupational information were collected by questionnaire.Results: Rotational shift nurses working nights had a lower mesor and an earlier time of peak melatonin production compared to day-only workers. More pronounced differences in mesor and acrophase were seen among later chronotypes, and shift workers working ≥3 consecutive nights. Among nurses, cumulative shift work was associated with a reduction in mesor.Conclusion: These results suggest that evening-types and/or shift workers working ≥3 consecutive nights are more susceptible to adverse light-at-night effects, whereas long-term shift work may also chronically reduce melatonin levels.Impact: Cumulative and current exposure to shift work, including nights, affects level and timing of melatonin production, which may be related to carcinogenesis and cancer risk. Cancer Epidemiol Biomarkers Prev; 25(5); 830–8. ©2016 AACR.
Expression Profile of BCL-2, BCL-XL, and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in Multiple Myeloma Models
Authors: Punnoose Elizabeth A. , Leverson Joel D. , Peale Franklin , Boghaert Erwin R. , Belmont Lisa D. , Tan Nguyen , Young Amy , Mitten Michael , Ingalla Ellen , Darbonne Walter C. , Oleksijew Anatol , Tapang Paul , Yue Peng , Oeh Jason , Lee Leslie , Maiga Sophie , Fairbrother Wayne J. , Amiot Martine , Souers Andrew J. , Sampath Deepak 
Published: March 2016

Abstract
BCL-2 family proteins dictate survival of human multiple myeloma cells, making them attractive drug targets. Indeed, multiple myeloma cells are sensitive to antagonists that selectively target prosurvival proteins such as BCL-2/BCL-XL (ABT-737 and ABT-263/navitoclax) or BCL-2 only (ABT-199/GDC-0199/venetoclax). Resistance to these three drugs is mediated by expression of MCL-1. However, given the selectivity profile of venetoclax it is unclear whether coexpression of BCL-XL also affects antitumor responses to venetoclax in multiple myeloma. In multiple myeloma cell lines (n = 21), BCL-2 is expressed but sensitivity to venetoclax correlated with high BCL-2 and low BCL-XL or MCL-1 expression. Multiple myeloma cells that coexpress BCL-2 and BCL-XL were resistant to venetoclax but sensitive to a BCL-XL–selective inhibitor (A-1155463). Multiple myeloma xenograft models that coexpressed BCL-XL or MCL-1 with BCL-2 were also resistant to venetoclax. Resistance to venetoclax was mitigated by cotreatment with bortezomib in xenografts that coexpressed BCL-2 and MCL-1 due to upregulation of NOXA, a proapoptotic factor that neutralizes MCL-1. In contrast, xenografts that expressed BCL-XL, MCL-1, and BCL-2 were more sensitive to the combination of bortezomib with a BCL-XL selective inhibitor (A-1331852) but not with venetoclax cotreatment when compared with monotherapies. IHC of multiple myeloma patient bone marrow biopsies and aspirates (n = 95) revealed high levels of BCL-2 and BCL-XL in 62% and 43% of evaluable samples, respectively, while 34% were characterized as BCL-2High/BCL-XLLow. In addition to MCL-1, our data suggest that BCL-XL may also be a potential resistance factor to venetoclax monotherapy and in combination with bortezomib. Mol Cancer Ther; 15(5); 1132–44. ©2016 AACR.
BRD4 Regulates EZH2 Transcription through Upregulation of C-MYC and Represents a Novel Therapeutic Target in Bladder Cancer
Authors: Wu Xinchao , Liu Dong , Tao Dan , Xiang Wei , Xiao Xingyuan , Wang Miao , Wang Liang , Luo Gang , Li Yawei , Zeng Fuqing , Jiang Guosong 
Published: March 2016

Abstract
People who develop bladder cancer frequently succumb to the intractable disease. Current treatment strategies are limited presumably due to the underlying molecular complexity and insufficient comprehension. Therefore, exploration of new therapeutic targets in bladder cancer remains necessary. Here, we identify that bromodomain-4 protein (BRD4), an important epigenome reader of bromodomain and extraterminal domain (BET) family member, is a key upstream regulator of enhancer of zeste homologue 2 (EZH2), and represents a novel therapeutic target in bladder cancer. We found that BRD4 was significantly overexpressed in bladder cancer cells and tissues. Inhibition of BRD4 decreased bladder cancer cell proliferation concomitantly with the accumulation of cell apoptosis in vitro and suppressed tumor growth in vivo. We further found that suppression of BRD4 decreased the mRNA and protein levels of EZH2, which was reversed by ectopic expression of C-MYC. In particular, individual silencing of BRD4 using shRNA or the BET inhibitor JQ1 strikingly diminished the recruitment of C-MYC to EZH2 promoter in bladder cancer. Briefly, our research reveals that BRD4 positively regulates EZH2 transcription through upregulation of C-MYC, and is a novel promising target for pharmacologic treatment in transcriptional program intervention against this intractable disease. Mol Cancer Ther; 15(5); 1029–42. ©2016 AACR.
Elevated Translation Initiation Factor eIF4E Is an Attractive Therapeutic Target in Multiple Myeloma
Authors: Li Shirong , Fu Jing , Lu Caisheng , Mapara Markus Y. , Raza Shahzad , Hengst Ulrich , Lentzsch Suzanne 
Published: March 2016

Abstract
eIF4E is the key regulator of protein translation and critical for translation. The oncogenic potential of tumorigenesis, which is highly contingent on cap-dependent eIF4E, also arises from the critical role in the nuclear export and cytosolic translation of oncogenic transcripts. Inhibition of Exportin1 (XPO1), which is the major nuclear export protein for eIF4E-bound oncoprotein mRNAs, results in decreased tumor cell growth in vitro and in vivo, suggesting that eIF4E is critical in multiple myeloma. Indeed, we found that eIF4E is overexpressed in myeloma cell lines and primary myeloma cells compared with normal plasma cells. Although stable overexpression of eIF4E in multiple myeloma cells significantly increases tumorigenesis, knockdown of eIF4E impairs multiple myeloma tumor progression in a human xenograft mouse model. Using a tet-on–inducible eIF4E-knockdown system, eIF4E downregulation blocks multiple myeloma tumor growth in vivo, correlating with decreased eIF4E expression. Further overexpression and knockdown of eIF4E revealed that eIF4E regulates translation of mRNAs with highly complex 5′-untranslated regions, such as c-MYC and C/EBPβ, and subsequently proliferation in multiple myeloma cells, but not in nonmalignant bone marrow stromal cells. Because many transcription factors that are critical for multiple myeloma proliferation exhibit a higher dependency on protein translation, eIF4E is an ideal and selective tool to target multiple myeloma cell growth. Mol Cancer Ther; 15(4); 711–9. ©2016 AACR.
Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance
Authors: Heinrich Anne-Kathrin , Lucas Henrike , Schindler Lucie , Chytil Petr , Etrych Tomáš , Mäder Karsten , Mueller Thomas 
Published: March 2016

Abstract
The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA–doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA–doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging–based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998–1007. ©2016 AACR.
Use of antipsychotics and risk of venous thromboembolism in postmenopausal women
Authors: Liou Jun-Ting , Huang Yun-Wen , Lin Chen , Wu Gwo-Jang , Chu Che-Li , Yeh Chin-Bin , Wang Yun-Han , Wang Meng-Ting 
Published: March 2016

SummaryDespite continued uncertainty of venous thromboembolism (VTE) caused from antipsychotic agents, this safety issue has not been examined in postmenopausal women, a population with high usages of antipsychotics and at high risk for VTE. We assessed whether antipsychotic use was associated with an increased VTE risk in women after menopause. We conducted a nested case-control study of all Taiwanese women aged ≥ 50 years (n = 316,132) using a nationwide healthcare claims database between 2000 and 2011. All newly diagnosed VTE patients treated with an anticoagulant or thrombectomy surgery were identified as cases (n = 2,520) and individually matched to select controls (n = 24,223) by cohort entry date, age, cancer diagnosis and major surgery procedure. The odds ratios (ORs) and 95 % confidence interval (CI) of VTE associated with antipsychotics were estimated by multivariate conditional logistic regressions. Current use of antipsychotics was associated with a 1.90-fold (95 % CI = 1.64–2.19) increased VTE risk compared with nonuse in postmenopausal women. The VTE risk existed in a dose-dependent fashion (test for trend, p<0.001), with a more than quadrupled risk for high-dose antipsychotics (adjusted OR = 4.60; 95 % CI = 2.88–7.33). Current parenteral administration of antipsychotics also led to a 3.46-fold increased risk (95 % CI = 2.39–5.00). Conversely, there was no increased VTE risk when antipsychotics were discontinued for > 30 days. In conclusion, current use of antipsychotics is significantly associated with a dose-dependent increased risk of VTE in postmenopausal women, especially for those currently taking high-dose or receiving parenteral antipsychotics.
miRNA Targeting of Oxysterol-Binding Protein-Like 6 Regulates Cholesterol Trafficking and Efflux
Authors: Ouimet Mireille , Hennessy Elizabeth J. , van Solingen Coen , Koelwyn Graeme J. , Hussein Maryem A. , Ramkhelawon Bhama , Rayner Katey J. , Temel Ryan E. , Perisic Ljubica , Hedin Ulf , Maegdefessel Lars , Garabedian Michael J. , Holdt Lesca M. , Teupser Daniel , Moore Kathryn J. 
Published: March 2016

Objective—
Cholesterol homeostasis is fundamental to human health and is, thus, tightly regulated. MicroRNAs exert potent effects on biological pathways, including cholesterol metabolism, by repressing genes with related functions. We reasoned that this mode of pathway regulation could be exploited to identify novel genes involved in cholesterol homeostasis.

Approach and Results—

Here, we identify oxysterol-binding protein-like 6 (
OSBPL6
) as a novel target of 2 miRNA hubs regulating cholesterol homeostasis: miR-33 and miR-27b. Characterization of
OSBPL6
revealed that it is transcriptionally regulated in macrophages and hepatocytes by liver X receptor and in response to cholesterol loading and in mice and nonhuman primates by Western diet feeding.
OSBPL6
encodes the OSBPL-related protein 6 (ORP6), which contains dual membrane- and endoplasmic reticulum–targeting motifs. Subcellular localization studies showed that ORP6 is associated with the endolysosomal network and endoplasmic reticulum, suggesting a role for ORP6 in cholesterol trafficking between these compartments. Accordingly, knockdown of
OSBPL6
results in aberrant clustering of endosomes and promotes the accumulation of free cholesterol in these structures, resulting in reduced cholesterol esterification at the endoplasmic reticulum. Conversely, ORP6 overexpression enhances cholesterol trafficking and efflux in macrophages and hepatocytes. Moreover, we show that hepatic expression of
OSBPL6
is positively correlated with plasma levels of high-density lipoprotein cholesterol in a cohort of 200 healthy individuals, whereas its expression is reduced in human atherosclerotic plaques.

Conclusions—
These studies identify ORP6 as a novel regulator of cholesterol trafficking that is part of the miR-33 and miR-27b target gene networks that contribute to the maintenance of cholesterol homeostasis.
Cortical Integration of Contextual Information across Objects
Authors: Livne Tomer , Bar Moshe 
Published: March 2016

AbstractRecognizing objects in the environment and understanding our surroundings often depends on context: the presence of other objects and knowledge about their relations with each other. Such contextual information activates a set of medial lobe brain regions, the parahippocampal cortex and the retrosplenial complex. Both regions are more activated by single objects with a unique contextual association than by objects not associated with any specific context. Similarly they are more activated by spatially coherent arrangements of objects when those are consistent with their known spatial relations. The current study tested how context in multiple-object displays is represented in these regions in the absence of relevant spatial information. Using an fMRI slow-event-related design, we show that the precuneus (a subpart of the retrosplenial complex) is more activated by simultaneously presented contextually related objects than by unrelated objects. This suggests that the representation of context in this region is cumulative, representing integrated information across objects in the display. We discuss these findings in relation to processing of visual information and relate them to previous findings of contextual effects in perception.
Sex Differences in the Incidence of Anterior Cruciate Ligament, Medial Collateral Ligament, and Meniscal Injuries in Collegiate and High School Sports
Authors: Stanley Laura E. , Kerr Zachary Y. , Dompier Thomas P. , Padua Darin A. 
Published: March 2016

Background: Previous research has noted sex-based differences in anterior cruciate ligament (ACL) injury rates in young athletes, while little is known about medial collateral ligament (MCL) and meniscal injury rates in this population. The objective of this study was to compare injury rates for traumatic knee injuries (ie, ACL, MCL, and meniscal injuries) in collegiate and high school (HS) varsity student-athletes across multiple sports. Hypothesis: Knee injury rates vary by sex and across different sports and levels of competition. Study Design: Descriptive epidemiology study. Methods: Injury and athlete-exposure data were utilized from the National Athletic Treatment, Injury and Outcomes Network (NATION) and National Collegiate Athletic Association (NCAA) Injury Surveillance Program (ISP) during the 2009-2010 to 2013-2014 academic years. Analyses focused on ACL, MCL, and meniscal injuries. Injury rates and injury rate ratios (IRRs) with 95% CIs were calculated for basketball, ice hockey, lacrosse, soccer, and baseball/softball. Results: The ACL injury rate was higher for female than male athletes at the collegiate (IRR, 2.49; 95% CI, 1.81-3.41) and HS (IRR, 2.30; 95% CI, 1.67-3.18) levels. At the collegiate level, the highest ACL IRR comparing female to male athletes was reported in softball/baseball (IRR, 6.61; 95% CI, 1.48-29.55). At the HS level, the highest ACL IRR was reported in basketball (IRR, 3.68; 95% CI, 1.91-7.10). The MCL injury rate was higher for female than male athletes at the HS level (IRR, 2.11; 95% CI, 1.25-3.56) but lower for female than male athletes at the collegiate level (IRR, 0.73; 95% CI, 0.59-0.92). The meniscal injury rate was lower for female than male athletes at the HS level (IRR, 0.47; 95% CI, 0.31-0.71), while no differences by sex were seen at the collegiate level (IRR, 1.35; 95% CI, 0.90-2.02). Conclusion: Knee injury rates varied by sex across 5 different sports in the HS and collegiate settings. Female athletes sustained ACL injuries at a higher rate than male athletes at both the HS and collegiate levels in these 5 sports; however, there was not a distinct sex disparity in MCL and meniscal injuries. Future studies should examine the rates of concomitant and recurrent injuries to inform injury prevention and rehabilitation programs.
Clinical outcomes of remote asynchronous telerehabilitation are equivalent to traditional therapy following total knee arthroplasty: A randomized control study
Authors: Bini SA , Mahajan J 
Published: March 2016

Introduction Successful post-operative telerehabilitation following total knee replacement (TKR) has been documented using synchronous (real-time) video. Bandwidth and the need for expensive hardware are cited as barriers to implementation. Web-based asynchronous visual platforms promise to address these problems but have not been evaluated. We performed a randomized control study comparing an asynchronous video-based software platform to in-person outpatient physical therapy visits following TKR. Materials and methods Fifty-one patients were randomized to either the intervention group, using an asynchronous video application on a mobile device, or the traditional group undergoing outpatient physical therapy. Outcome data were collected using validated instruments prior to surgery and at a minimum three-month follow-up. Results Twenty-nine patients completed the study. There were no statistically significant differences in any clinical outcome between groups. The satisfaction with care was equivalent between groups. Overall utilization of hospital-based resources was 60% less than for the traditional group. Discussion We report that clinical outcomes following asynchronous telerehabilitation administered over the web and through a hand-held device were not inferior to those achieved with traditional care. Outpatient resource utilization was lower. Patient satisfaction was high for both groups. The results suggest that asynchronous telerehabilitation may be a more practical alternative to real-time video visits and are clinically equivalent to the in-person care model.
The assessment of developmental trauma in children and adolescents: A systematic review
Authors: Denton Ruth , Frogley Catherine , Jackson Sue , John Mary , Querstret Dawn 
Published: March 2016

Background: The assessment of children and young people with history of complex developmental trauma presents a significant challenge to services. Traditional diagnostic categories such as post-traumatic stress disorder (PTSD) are argued to be of limited value, and while the proposed ‘Developmental Trauma Disorder’ definition attempts to address this debate, associated assessment tools have yet to be developed. This review builds on a previous review of assessment measures, undertaken in 2005. Aim: To identify trauma assessment tools developed or evaluated since 2004 and determine which are developmentally appropriate for children or adolescents with histories of complex trauma. Method: A systematic search of electronic databases was conducted with explicit inclusion and exclusion criteria. Results: A total of 35 papers were identified evaluating 29 measures assessing general functioning and mental health ( N = 10), PTSD ( N = 7) and trauma symptomatology outside, or in addition to, PTSD ( N = 11). Studies were evaluated on sample quality, trauma/adversity type, as well as demographic and psychometric data. Distinction was made between measures validated for children (0–12 years) and adolescents (12–18 years). Conclusion: Few instruments could be recommended for immediate use as many required further validation. The Assessment Checklist questionnaires, designed with a developmental and attachment focus, were the most promising tools.