bluuebunny/crossref_metadata_2025_split huggingface dataset:
Environmental Tobacco Smoke Exposure and Survival Following Breast Cancer
Authors: Parada Humberto , Bradshaw Patrick T. , Engel Lawrence S. , Conway Kathleen , Steck Susan E. , Teitelbaum Susan L. , Neugut Alfred I. , Santella Regina M. , Gammon Marilie D. 
Published: October 2016

Abstract
Background: Environmental tobacco smoke (ETS) exposure is hypothesized to influence survival after breast cancer, but few studies have examined this association.
Methods: A population-based cohort of women (N = 1,508) diagnosed with first primary invasive or in situ breast cancer in 1996 to 1997 was interviewed shortly after diagnosis and again approximately 5 years later to assess ETS exposure, and women were followed for more than 18 years using the National Death Index; 597 deaths (237 associated with breast cancer) were identified. Multivariable Cox regression was used to estimate adjusted HRs and 95% confidence intervals (CI) for mortality among women with breast cancer as related to at-diagnosis and at-/postdiagnosis changes in ETS exposure.
Results: There was little or no association between at-diagnosis ETS exposure and all-cause (HR = 1.04; 95% CI, 0.78–1.40) or breast cancer–specific (HR = 0.98; 95% CI, 0.63–1.52) mortality. Mortality was elevated among women who reported cessation in postdiagnosis ETS exposure up to 1 year before the follow-up assessment, for all-cause (HR = 1.81; 95% CI, 0.87–3.74) and breast cancer mortality (HR = 1.89; 95% CI, 0.68–5.24); however, estimates were imprecise.
Conclusions: We found little evidence of an association between at-diagnosis ETS exposure and mortality after breast cancer. Postdiagnosis cessation of ETS exposure was positively associated with mortality, although we could not rule out chance and reverse causation as possible explanations.
Impact: Exposure to ETS does not appear to influence mortality after breast cancer. Cancer Epidemiol Biomarkers Prev; 26(2); 278–80. ©2016 AACR.
Dedifferentiation of Glioma Cells to Glioma Stem-like Cells By Therapeutic Stress-induced HIF Signaling in the Recurrent GBM Model
Authors: Lee Gina , Auffinger Brenda , Guo Donna , Hasan Tanwir , Deheeger Marc , Tobias Alex L. , Kim Jeong Yeon , Atashi Fatemeh , Zhang Lingjiao , Lesniak Maciej S. , James C. David , Ahmed Atique U. 
Published: October 2016

AbstractIncreasing evidence exposes a subpopulation of cancer cells, known as cancer stem cells (CSCs), to be critical for the progression of several human malignancies, including glioblastoma multiforme. CSCs are highly tumorigenic, capable of self-renewal, and resistant to conventional therapies, and thus considered to be one of the key contributors to disease recurrence. To elucidate the poorly understood evolutionary path of tumor recurrence and the role of CSCs in this process, we developed patient-derived xenograft glioblastoma recurrent models induced by anti-glioma chemotherapy, temozolomide. In this model, we observed a significant phenotypic shift towards an undifferentiated population. We confirmed these findings in vitro as sorted CD133-negative populations cultured in differentiation-forcing media were found to acquire CD133 expression following chemotherapy treatment. To investigate this phenotypic switch at the single-cell level, glioma stem cell (GSC)-specific promoter-based reporter systems were engineered to track changes in the GSC population in real time. We observed the active phenotypic and functional switch of single non-stem glioma cells to a stem-like state and that temozolomide therapy significantly increased the rate of single-cell conversions. Importantly, we showed the therapy-induced hypoxia-inducible factors (HIF) 1α and HIF2α play key roles in allowing non-stem glioma cells to acquire stem-like traits, as the expression of both HIFs increase upon temozolomide therapy and knockdown of HIFs expression inhibits the interconversion between non-stem glioma cells and GSCs post-therapy. On the basis of our results, we propose that anti-glioma chemotherapy promotes the accumulation of HIFs in the glioblastoma multiforme cells that induces the formation of therapy-resistant GSCs responsible for recurrence. Mol Cancer Ther; 15(12); 3064–76. ©2016 AACR.
Mitochondrial Targeting of Metformin Enhances Its Activity against Pancreatic Cancer
Authors: Boukalova Stepana , Stursa Jan , Werner Lukas , Ezrova Zuzana , Cerny Jiri , Bezawork-Geleta Ayenachew , Pecinova Alena , Dong Lanfeng , Drahota Zdenek , Neuzil Jiri 
Published: October 2016

AbstractPancreatic cancer is one of the hardest-to-treat types of neoplastic diseases. Metformin, a widely prescribed drug against type 2 diabetes mellitus, is being trialed as an agent against pancreatic cancer, although its efficacy is low. With the idea of delivering metformin to its molecular target, the mitochondrial complex I (CI), we tagged the agent with the mitochondrial vector, triphenylphosphonium group. Mitochondrially targeted metformin (MitoMet) was found to kill a panel of pancreatic cancer cells three to four orders of magnitude more efficiently than found for the parental compound. Respiration assessment documented CI as the molecular target for MitoMet, which was corroborated by molecular modeling. MitoMet also efficiently suppressed pancreatic tumors in three mouse models. We propose that the novel mitochondrially targeted agent is clinically highly intriguing, and it has a potential to greatly improve the bleak prospects of patients with pancreatic cancer. Mol Cancer Ther; 15(12); 2875–86. ©2016 AACR.
Reactivation of p53 by MDM2 Inhibitor MI-77301 for the Treatment of Endocrine-Resistant Breast Cancer
Authors: Lu Jianfeng , McEachern Donna , Li Shunqiang , Ellis Matthew J. , Wang Shaomeng 
Published: October 2016

Abstract
Endocrine therapy has been highly effective for the treatment of estrogen receptor–positive breast cancer, but endocrine resistance develops in a significant proportion of patients. In an effort to develop novel therapeutic strategies for the treatment of endocrine-resistant breast cancer, we have evaluated a potent and specific MDM2–p53 interaction inhibitor, MI-77301, which has been advanced into clinical development, for its therapeutic potential and mechanism of action in vitro and in vivo in WHIM9 and WHIM18 patient-derived xenograft (PDX) models. Both WHIM9 and WHIM18 PDX models exhibit estradiol-independent tumor growth and are resistant to fulvestrant, a highly effective and selective estrogen receptor degrader (SERD). MI-77301 activates wild-type p53 in WHIM9 and WHIM18 cells in vitro and in xenograft tumor tissues in vivo, and it effectively induces upregulation of p21 and cell-cycle arrest in vitro in both models. Although fulvestrant fails to inhibit tumor growth in either of the xenograft models, MI-77301 is highly effective in inhibition of tumor growth at a well-tolerated dose schedule. This study provides a preclinical rationale for evaluation of MI-77301 or other MDM2 inhibitors as a new therapeutic strategy for the treatment of endocrine-resistant breast cancer retaining wild-type p53. Mol Cancer Ther; 15(12); 2887–93. ©2016 AACR.
The BRAF Inhibitor Vemurafenib Activates Mitochondrial Metabolism and Inhibits Hyperpolarized Pyruvate–Lactate Exchange in BRAF-Mutant Human Melanoma Cells
Authors: Delgado-Goni Teresa , Miniotis Maria Falck , Wantuch Slawomir , Parkes Harold G. , Marais Richard , Workman Paul , Leach Martin O. , Beloueche-Babari Mounia 
Published: October 2016

AbstractUnderstanding the impact of BRAF signaling inhibition in human melanoma on key disease mechanisms is important for developing biomarkers of therapeutic response and combination strategies to improve long-term disease control. This work investigates the downstream metabolic consequences of BRAF inhibition with vemurafenib, the molecular and biochemical processes that underpin them, their significance for antineoplastic activity, and potential as noninvasive imaging response biomarkers. 1H NMR spectroscopy showed that vemurafenib decreases the glycolytic activity of BRAF-mutant (WM266.4 and SKMEL28) but not BRAFWT (CHL-1 and D04) human melanoma cells. In WM266.4 cells, this was associated with increased acetate, glycine, and myo-inositol levels and decreased fatty acyl signals, while the bioenergetic status was maintained. 13C NMR metabolic flux analysis of treated WM266.4 cells revealed inhibition of de novo lactate synthesis and glucose utilization, associated with increased oxidative and anaplerotic pyruvate carboxylase mitochondrial metabolism and decreased lipid synthesis. This metabolic shift was associated with depletion of hexokinase 2, acyl-CoA dehydrogenase 9, 3-phosphoglycerate dehydrogenase, and monocarboxylate transporters (MCT) 1 and 4 in BRAF-mutant but not BRAFWT cells and, interestingly, decreased BRAF-mutant cell dependency on glucose and glutamine for growth. Further, the reduction in MCT1 expression observed led to inhibition of hyperpolarized 13C-pyruvate–lactate exchange, a parameter that is translatable to in vivo imaging studies, in live WM266.4 cells. In conclusion, our data provide new insights into the molecular and metabolic consequences of BRAF inhibition in BRAF-driven human melanoma cells that may have potential for combinatorial therapeutic targeting as well as noninvasive imaging of response. Mol Cancer Ther; 15(12); 2987–99. ©2016 AACR.
Targeting Binding Function-3 of the Androgen Receptor Blocks Its Co-Chaperone Interactions, Nuclear Translocation, and Activation
Authors: Lallous Nada , Leblanc Eric , Munuganti Ravi S.N. , Hassona Mohamed D.H. , Nakouzi Nader Al , Awrey Shannon , Morin Helene , Roshan-Moniri Mani , Singh Kriti , Lawn Sam , Yamazaki Takeshi , Adomat Hans H. , Andre Christophe , Daugaard Mads , Young Robert N. , Guns Emma S. Tomlinson , Rennie Paul S. , Cherkasov Artem 
Published: October 2016

Abstract
The development of new antiandrogens, such as enzalutamide, or androgen synthesis inhibitors like abiraterone has improved patient outcomes in the treatment of advanced prostate cancer. However, due to the development of drug resistance and tumor cell survival, a majority of these patients progress to the refractory state of castration-resistant prostate cancer (CRPC). Thus, newer therapeutic agents and a better understanding of their mode of action are needed for treating these CRPC patients. We demonstrated previously that targeting the Binding Function 3 (BF3) pocket of the androgen receptor (AR) has great potential for treating patients with CRPC. Here, we explore the functional activity of this site by using an advanced BF3-specific small molecule (VPC-13566) that was previously reported to effectively inhibit AR transcriptional activity and to displace the BAG1L peptide from the BF3 pocket. We show that VPC-13566 inhibits the growth of various prostate cancer cell lines, including an enzalutamide-resistant cell line, and reduces the growth of AR-dependent prostate cancer xenograft tumors in mice. Importantly, we have used this AR-BF3 binder as a chemical probe and identified a co-chaperone, small glutamine-rich tetratricopeptide repeat (TPR)-containing protein alpha (SGTA), as an important AR-BF3 interacting partner. Furthermore, we used this AR-BF3–directed small molecule to demonstrate that inhibition of AR activity through the BF3 functionality can block translocation of the receptor into the nucleus. These findings suggest that targeting the BF3 site has potential clinical importance, especially in the treatment of CRPC and provide novel insights on the functional role of the BF3 pocket. Mol Cancer Ther; 15(12); 2936–45. ©2016 AACR.
Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells
Authors: Mukhtar Eiman , Adhami Vaqar Mustafa , Siddiqui Imtiaz Ahmad , Verma Ajit Kumar , Mukhtar Hasan 
Published: October 2016

Abstract
Although treatment of prostate cancer has improved over the past several years, taxanes, such as cabazitaxel, remain the only form of effective chemotherapy that improves survival in patients with metastatic castration–resistant prostate cancer. However, the effectiveness of this class of drugs has been associated with various side effects and drug resistance. We previously reported that fisetin, a hydroxyflavone, is a microtubule-stabilizing agent and inhibits prostate cancer cell proliferation, migration, and invasion and suggested its use as an adjuvant for treatment of prostate and other cancer types. In this study, we investigated the effect of fisetin in combination with cabazitaxel with the objective to achieve maximum therapeutic benefit, reduce dose and toxicity, and minimize or delay the induction of drug resistance and metastasis. Our data show for the first time that a combination of fisetin (20 μmol/L) enhances cabazitaxel (5 nmol/L) and synergistically reduces 22Rν1, PC-3M-luc-6, and C4-2 cell viability and metastatic properties with minimal adverse effects on normal prostate epithelial cells. In addition, the combination of fisetin with cabazitaxel was associated with inhibition of proliferation and enhancement of apoptosis. Furthermore, combination treatment resulted in the inhibition of tumor growth, invasion, and metastasis when assessed in two in vivo xenograft mouse models. These results provide evidence that fisetin may have therapeutic benefit for patients with advanced prostate cancer through enhancing the efficacy of cabazitaxel under both androgen-dependent and androgen-independent conditions. This study underscores the benefit of the combination of fisetin with cabazitaxel for the treatment of advanced and resistant prostate cancer and possibly other cancer types. Mol Cancer Ther; 15(12); 2863–74. ©2016 AACR.
Genomics of Ovarian Cancer Progression Reveals Diverse Metastatic Trajectories Including Intraepithelial Metastasis to the Fallopian Tube
Authors: Eckert Mark A. , Pan Shawn , Hernandez Kyle M. , Loth Rachel M. , Andrade Jorge , Volchenboum Samuel L. , Faber Pieter , Montag Anthony , Lastra Ricardo , Peter Marcus E. , Yamada S. Diane , Lengyel Ernst 
Published: October 2016

AbstractAccumulating evidence has supported the fallopian tube rather than the ovary as the origin for high-grade serous ovarian cancer (HGSOC). To understand the relationship between putative precursor lesions and metastatic tumors, we performed whole-exome sequencing on specimens from eight HGSOC patient progression series consisting of serous tubal intraepithelial carcinomas (STIC), invasive fallopian tube lesions, invasive ovarian lesions, and omental metastases. Integration of copy number and somatic mutations revealed patient-specific patterns with similar mutational signatures and copy-number variation profiles across all anatomic sites, suggesting that genomic instability is an early event in HGSOC. Phylogenetic analyses supported STIC as precursor lesions in half of our patient cohort, but also identified STIC as metastases in 2 patients. Ex vivo assays revealed that HGSOC spheroids can implant in the fallopian tube epithelium and mimic STIC lesions. That STIC may represent metastases calls into question the assumption that STIC are always indicative of primary fallopian tube cancers.Significance: We find that the putative precursor lesions for HGSOC, STIC, possess most of the genomic aberrations present in advanced cancers. In addition, a proportion of STIC represent intraepithelial metastases to the fallopian tube rather than the origin of HGSOC. Cancer Discov; 6(12); 1342–51. ©2016 AACR.See related commentary by Swisher et al., p. 1309.This article is highlighted in the In This Issue feature, p. 1293
Malnutrition Identified by the Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition Consensus Criteria and Other Bedside Tools Is Highly Prevalent in a Sample of Individuals Undergoing Treatment for Head and Neck Cancer
Authors: Mulasi Urvashi , Vock David M. , Kuchnia Adam J. , Jha Gautam , Fujioka Naomi , Rudrapatna Venkatesh , Patel Manish R. , Teigen Levi , Earthman Carrie P. 
Published: October 2016

AbstractBackground: Using the Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition (Academy/ASPEN) Consensus malnutrition definition, we estimated malnutrition prevalence in a sample of individuals with head and neck cancer (HNC) and compared it with the Patient‐Generated Subjective Global Assessment (PG‐SGA). We also investigated the utility of the 50‐kHz phase angle (PA) and 200‐kHz/5‐kHz impedance ratio (IR) to identify malnutrition.Materials and Methods: Nineteen individuals (18 males, 1 female) scheduled to undergo chemoradiotherapy were seen at 5 time points during and up to 3 months after treatment completion. Multiple‐frequency bioelectrical impedance analysis, PG‐SGA, nutrition‐focused physical examination, anthropometry, dietary intake, and handgrip strength data were collected.Results: Using the Consensus, 67% were found to be malnourished before treatment initiation; these criteria diagnosed malnutrition with overall good sensitivity (94%) and moderate specificity (43%) compared with PG‐SGA. Over all pooled observations, “malnourished” (by Consensus but not PG‐SGA category) had a lower mean PA (5.2 vs 5.9;P= .03) and higher IR (0.82 vs 0.79;P= .03) than “well‐nourished” categorizations, although the clinical relevance of these findings is unclear. PA and IR were correlated with higher PG‐SGA score (r= −0.35,r= 0.36;P< .01) and handgrip strength (r= 0.48,r= −0.47;P< .01).Conclusion: The Academy/ASPEN Consensus and the PG‐SGA were in good agreement. It is unclear whether PA and IR can be used as surrogate markers of nutrition status or muscle loss.
Extracorporeal membrane oxygenation support for life-threatening acute severe status asthmaticus
Authors: Di Lascio Gabriella , Prifti Edvin , Messai Elmi , Peris Adriano , Harmelin Guy , Xhaxho Roland , Fico Albana , Sani Guido , Bonacchi Massimo 
Published: October 2016

Introduction: Status asthmaticus is a life-threatening condition characterized by progressive respiratory failure due to asthma that is unresponsive to standard therapeutic measures. We used extracorporeal membrane oxygenation (ECMO) to treat patients with near-fatal status asthamticus who did not respond to aggressive medical therapies and mechanical ventilation under controlled permissive hypercapnia. Materials and methods: Between January 2011 and October 2015, we treated 16 adult patients with status asthmaticus (8 women, 8 men, mean age: 50.5±10.6years) with veno-venous ECMO (13 patients) or veno-arterial (3 patients). Patients failed to respond to conventional therapies despite receiving the most aggressive therapies, including maximal medical treatments, mechanical ventilation under controlled permissive hypercapnia and general anesthetics. Results: Mean time spent on ECMO was 300±11.8 hours (range 36–384 hours). PaO2, PaCO2 and pH showed significant improvement promptly after ECMO initiation p=0.014, 0.001 and <0.001, respectively, and such values remained significantly improved after ECMO, p=0.004 and 0.001 and <0.001, respectively. The mean time of ventilation after decannulation until extubation was 175±145.66 hours and the median time to intensive care unit discharge after decannulation was 234±110.30 hours. All 16 patients survived without neurological sequelae. Conclusions: ECMO could provide adjunctive pulmonary support for intubated asthmatic patients who remain severely acidotic and hypercarbic despite aggressive conventional therapy. ECMO should be considered as an early treatment in patients with status asthmaticus whose gas exchange cannot be satisfactorily maintained by conventional therapy for providing adequate gas change and preventing lung injury from the ventilation.
Managing risk during care transitions when approaching end of life: A qualitative study of patients’ and health care professionals’ decision making
Authors: Coombs Maureen A , Parker Roses , de Vries Kay 
Published: October 2016

Background: Increasing importance is being placed on the coordination of services at the end of life. Aim: To describe decision-making processes that influence transitions in care when approaching the end of life. Design: Qualitative study using field observations and longitudinal semi-structured interviews. Setting/participants: Field observations were undertaken in three sites: a residential care home, a medical assessment unit and a general medical unit in New Zealand. The Supportive and Palliative Care Indicators Tool was used to identify participants with advanced and progressive illness. Patients and family members were interviewed on recruitment and 3–4 months later. Four weeks of fieldwork were conducted in each site. A total of 40 interviews were conducted: 29 initial interviews and 11 follow-up interviews. Thematic analysis was undertaken. Findings: Managing risk was an important factor that influenced transitions in care. Patients and health care staff held different perspectives on how such risks were managed. At home, patients tolerated increasing risk and used specific support measures to manage often escalating health and social problems. In contrast, decisions about discharge in hospital were driven by hospital staff who were risk-adverse. Availability of community and carer services supported risk management while a perceived need for early discharge decision making in hospital and making ‘safe’ discharge options informed hospital discharge decisions. Conclusion: While managing risk is an important factor during care transitions, patients should be able to make choices on how to live with risk at the end of life. This requires reconsideration of transitional care and current discharge planning processes at the end of life.
Epidemiological Patterns of Ankle Sprains in Youth, High School, and College Football
Authors: Clifton Daniel R. , Koldenhoven Rachel M. , Hertel Jay , Onate James A. , Dompier Thomas P. , Kerr Zachary Y. 
Published: October 2016

Background: Variations in ankle injury rates and distributions among competition levels are unclear, but such data may help inform strategies to prevent ankle sprains during American football. Purpose: To describe the epidemiological patterns of ankle sprains in youth, high school (HS), and collegiate American football. Study Design: Descriptive epidemiological study. Methods: Data regarding youth, HS, and college football athletes were collected from 3 injury surveillance programs: (1) the Youth Football Safety Study (YFSS), (2) the National Athletic Treatment, Injury and Outcomes Network (NATION), and (3) the National Collegiate Athletic Association (NCAA) Injury Surveillance Program (ISP). During the 2012-2014 seasons, the YFSS, NATION, and NCAA ISP included 310, 184, and 71 football team-seasons, respectively. Athletic trainers (ATs) attended each practice and game and reported injuries and athlete-exposures (AEs) via their preferred injury documentation application. Ankle sprain rates for each type of ankle sprain were calculated overall, by event type (ie, practices and games), and specifically for severe injuries (ie, participation restriction time >21 days) and recurrent injuries (as defined by ATs). Rate ratios (RRs) were used to compare ankle sprain rates by competition level and event type. Injury proportion ratios (IPRs) were used to compare differences in severity, surgical needs, recurrence, injury mechanism, and injury activity by competition level. RRs and IPRs with 95% confidence intervals excluding 1.00 were considered statistically significant. Results: A total of 124, 897, and 643 ankle sprains were reported in youth, HS, and college football, respectively. This led to respective rates of 0.59, 0.73, and 1.19 sprains per 1000 AEs. The ankle sprain rate in college football was higher than the rates in HS (RR = 1.64; 95% CI, 1.48-1.82) and youth (RR = 2.01; 95% CI, 1.65-2.43) football. The proportion of ankle sprains that were recurrent in youth football was higher than the proportions in HS (IPR = 2.73; 95% CI, 1.68-4.50) and college (IPR = 2.19; 95% CI, 1.33-3.61) football. Conclusion: Ankle sprain rates were highest in college athletes. However, level-specific variations in ankle sprain severity and recurrence may highlight the need to develop level-specific policies and prevention strategies to reduce injury incidence.