bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Association of Modifiable Breast Cancer Risk Factors and Somatic Genomic Alterations in Breast Tumors: The Cancer Genome Atlas Network
Authors: Heng Yujing J. , Hankinson Susan E. , Wang Jun , Alexandrov Ludmil B. , Ambrosone Christine B. , de Andrade Victor P. , Brufsky Adam M. , Couch Fergus J. , King Tari A. , Modugno Francesmary , Vachon Celine M. , Eliassen A. Heather , Tamimi Rulla M. , Kraft Peter 
Published: January 2020

Abstract

Background:
The link between modifiable breast cancer risk factors and tumor genomic alterations remains largely unexplored. We evaluated the association of prediagnostic body mass index (BMI), cigarette smoking, and alcohol consumption with somatic copy number variation (SCNV), total somatic mutation burden (TSMB), seven single base substitution (SBS) signatures (SBS1, SBS2, SBS3, SBS5, SBS13, SBS29, and SBS30), and nine driver mutations (CDH1, GATA3, KMT2C, MAP2K4, MAP3K1, NCOR1, PIK3CA, RUNX1, and TP53) in a subset of The Cancer Genome Atlas (TCGA).

Methods:
Clinical and genomic data were retrieved from the TCGA database. Risk factor information was collected from four TCGA sites (n = 219 women), including BMI (1 year before diagnosis), cigarette smoking (smokers/nonsmokers), and alcohol consumption (current drinkers/nondrinkers). Multivariable regression analyses were conducted in all tumors and stratified according to estrogen receptor (ER) status.

Results:
Increasing BMI was associated with increasing SCNV in all women (P = 0.039) and among women with ER− tumors (P = 0.031). Smokers had higher SCNV and TSMB versus nonsmokers (P &lt; 0.05 all women). Alcohol drinkers had higher SCNV versus nondrinkers (P &lt; 0.05 all women and among women with ER+ tumors). SBS3 (defective homologous recombination-based repair) was exclusively found in alcohol drinkers with ER− disease. GATA3 mutation was more likely to occur in women with higher BMI. No association was significant after multiple testing correction.

Conclusions:
This study provides preliminary evidence that BMI, cigarette smoking, and alcohol consumption can influence breast tumor biology, in particular, DNA alterations.

Impact:
This study demonstrates a link between modifiable breast cancer risk factors and tumor genomic alterations.
Cannabinoids Promote Progression of HPV-Positive Head and Neck Squamous Cell Carcinoma via p38 MAPK Activation
Authors: Liu Chao , Sadat Sayed H. , Ebisumoto Koji , Sakai Akihiro , Panuganti Bharat A. , Ren Shuling , Goto Yusuke , Haft Sunny , Fukusumi Takahito , Ando Mizuo , Saito Yuki , Guo Theresa , Tamayo Pablo , Yeerna Huwate , Kim William , Hubbard Jacqueline , Sharabi Andrew B. , Gutkind J. Silvio , Califano Joseph A. 
Published: January 2020

Abstract

Purpose:
Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) is associated with daily marijuana use and is also increasing in parallel with increased marijuana use in the United States. Our study is designed to define the interaction between cannabinoids and HPV-positive HNSCC.

Experimental Design:
The expression of cannabinoid receptors CNR1 and CNR2 was analyzed using The Cancer Genome Atlas (TCGA) HNSCC data. We used agonists, antagonists, siRNAs, or shRNA-based models to explore the roles of CNR1 and CNR2 in HPV-positive HNSCC cell lines and animal models. Cannabinoid downstream pathways involved were determined by Western blotting and analyzed in a primary HPV HNSCC cohort with single-sample gene set enrichment analysis (ssGSEA) and the OncoGenome Positioning System (Onco-GPS).

Results:
In TCGA cohort, the expression of CNR1 and CNR2 was elevated in HPV-positive HNSCC compared with HPV-negative HNSCC, and knockdown of CNR1/CNR2 expression inhibited proliferation in HPV-positive HNSCC cell lines. Specific CNR1 and CNR2 activation as well as nonselective cannabinoid receptor activation in cell lines and animal models promoted cell growth, migration, and inhibited apoptosis through p38 MAPK pathway activation. CNR1/CNR2 antagonists suppressed cell proliferation and migration and induced apoptosis. Using whole-genome expression analysis in a primary HPV HNSCC cohort, we identified specific p38 MAPK pathway activation signature in tumors from HPV HNSCC patients with objective measurement of concurrent cannabinoid exposure.

Conclusions:
Cannabinoids can promote progression of HPV-positive HNSCC through p38 MAPK pathway activation.
Investigating PSMA-Targeted Radioligand Therapy Efficacy as a Function of Cellular PSMA Levels and Intratumoral PSMA Heterogeneity
Authors: Current Kyle , Meyer Catherine , Magyar Clara E. , Mona Christine E. , Almajano Joel , Slavik Roger , Stuparu Andreea D. , Cheng Chloe , Dawson David W. , Radu Caius G. , Czernin Johannes , Lueckerath Katharina 
Published: January 2020

Abstract

Purpose:
Prostate-specific membrane antigen (PSMA) targeting radioligands deliver radiation to PSMA-expressing cells. However, the relationship between PSMA levels and intralesion heterogeneity of PSMA expression, and cytotoxic radiation by radioligand therapy (RLT) is unknown. Here we investigate RLT efficacy as function of PSMA levels/cell, and the fraction of PSMA+ cells in a tumor.

Experimental Design:
RM1 cells expressing different levels of PSMA (PSMA−, PSMA+, PSMA++, PSMA+++; study 1) or a mix of PSMA+ and PSMA− RM1 (study 2, 4) or PC-3/PC-3-PIP (study 3) cells at various ratios were injected into mice. Mice received 177Lu- (studies 1–3) or 225Ac- (study 4) PSMA617. Tumor growth was monitored. Two days post-RLT, tumors were resected in a subset of mice. Radioligand uptake and DNA damage were quantified.

Results:
177Lu-PSMA617 efficacy increased with increasing PSMA levels (study 1) and fractions of PSMA positive cells (studies 2, 3) in both, the RM1 and PC-3-PIP models. In tumors resected 2 days post-RLT, PSMA expression correlated with 177Lu-PSMA617 uptake and the degree of DNA damage. Compared with 177Lu-PSMA617, 225Ac-PSMA617 improved overall antitumor effectiveness and tended to enhance the differences in therapeutic efficacy between experimental groups.

Conclusions:
In the current models, both the degree of PSMA expression and the fraction of PSMA+ cells correlate with 177Lu-/225Ac-PSMA617 tumor uptake and DNA damage, and thus, RLT efficacy. Low or heterogeneous PSMA expression represents a resistance mechanism to RLT.
See related commentary by Ravi Kumar and Hofman, p. 2774
Diverse AR Gene Rearrangements Mediate Resistance to Androgen Receptor Inhibitors in Metastatic Prostate Cancer
Authors: Li Yingming , Yang Rendong , Henzler Christine M. , Ho Yeung , Passow Courtney , Auch Benjamin , Carreira Suzanne , Nava Rodrigues Daniel , Bertan Claudia , Hwang Tae Hyun , Quigley David A. , Dang Ha X. , Morrissey Colm , Fraser Michael , Plymate Stephen R. , Maher Christopher A. , Feng Felix Y. , de Bono Johann S. , Dehm Scott M. 
Published: January 2020

Abstract

Purpose:
Prostate cancer is the second leading cause of male cancer deaths. Castration-resistant prostate cancer (CRPC) is a lethal stage of the disease that emerges when endocrine therapies are no longer effective at suppressing activity of the androgen receptor (AR) transcription factor. The purpose of this study was to identify genomic mechanisms that contribute to the development and progression of CRPC.

Experimental Design:
We used whole-genome and targeted DNA-sequencing approaches to identify mechanisms underlying CRPC in an aggregate cohort of 272 prostate cancer patients. We analyzed structural rearrangements at the genome-wide level and carried out a detailed structural rearrangement analysis of the AR locus. We used genome engineering to perform experimental modeling of AR gene rearrangements and long-read RNA sequencing to analyze effects on expression of AR and truncated AR variants (AR-V).

Results:
AR was among the most frequently rearranged genes in CRPC tumors. AR gene rearrangements promoted expression of diverse AR-V species. AR gene rearrangements occurring in the context of AR amplification correlated with AR overexpression. Cell lines with experimentally derived AR gene rearrangements displayed high expression of tumor-specific AR-Vs and were resistant to endocrine therapies, including the AR antagonist enzalutamide.

Conclusions:
AR gene rearrangements are an important mechanism of resistance to endocrine therapies in CRPC.
Targeting RICTOR Sensitizes SMAD4-Negative Colon Cancer to Irinotecan
Authors: Wong Chen Khuan , Lambert Arthur W. , Ozturk Sait , Papageorgis Panagiotis , Lopez Delia , Shen Ning , Sen Zaina , Abdolmaleky Hamid M. , Győrffy Balázs , Feng Hui , Thiagalingam Sam 
Published: January 2020

Abstract

Deciphering molecular targets to enhance sensitivity to chemotherapy is becoming a priority for effectively treating cancers. Loss of function mutations of SMAD4 in colon cancer are associated with metastatic progression and resistance to 5-fluorouracil (5-FU), the most extensively used drug of almost all chemotherapy combinations used in the treatment of metastatic colon cancer. Here, we report that SMAD4 deficiency also confers resistance to irinotecan, another common chemotherapeutic frequently used alone or in combination with 5-FU against colon cancer. Mechanistically, we find that SMAD4 interacts with and inhibits RICTOR, a component of the mTORC2 complex, resulting in suppression of downstream effector phosphorylation of AKT at Serine 473. In silico meta-analysis of publicly available gene expression datasets derived from tumors indicates that lower levels of SMAD4 or higher levels of RICTOR/AKT, irrespective of the SMAD4 status, correlate with poor survival, suggesting them as strong prognostic biomarkers and targets for therapeutic intervention. Moreover, we find that overexpression of SMAD4 or depletion of RICTOR suppresses AKT signaling and increases sensitivity to irinotecan in SMAD4-deficient colon cancer cells. Consistent with these observations, pharmacologic inhibition of AKT sensitizes SMAD4-negative colon cancer cells to irinotecan in vitro and in vivo. Overall, our study suggests that hyperactivation of the mTORC2 pathway is a therapeutic vulnerability that could be exploited to sensitize SMAD4-negative colon cancer to irinotecan.

Implications:
Hyperactivation of the mTORC2 pathway in SMAD4-negative colon cancer provides a mechanistic rationale for targeted inhibition of mTORC2 or AKT as a distinctive combinatorial therapeutic opportunity with chemotherapy for colon cancer.
Simulation of Atmospheric Motion Vectors for an Observing System Simulation Experiment
Authors: Errico Ronald M. , Carvalho David , Privé Nikki C. , Sienkiewicz Meta 
Published: January 2020

AbstractAn algorithm to simulate locations of atmospheric motion vectors for use in observing system simulation experiments is described and demonstrated. It is intended to obviate likely deficiencies in nature run data if used to produce images for feature tracking. The algorithm employs probabilistic functions that are tuned based on distributions of real observations and histograms of nature run fields. For distinct observation types, the algorithm produces geographical and vertical distributions, time-mean counts, and typical spacings of simulated locations that are, at least qualitatively, similar to those of real observations and are associated with nature run cloud and water vapor fields. It thus appears suitable for generating realistic atmospheric motion vectors for use in observing system simulation experiments.
Impact of Doppler Radar Wind Observations on Australian High-Resolution Numerical Weather Prediction
Authors: Rennie Susan , Rikus Lawrence , Eizenberg Nathan , Steinle Peter , Krysta Monika 
Published: January 2020

Abstract
The impact of Doppler radar wind observations on forecasts from a developmental, high-resolution numerical weather prediction (NWP) system is assessed. The new 1.5-km limited-area model will be Australia’s first such operational NWP system to include data assimilation. During development, the assimilation of radar wind observations was trialed over a 2-month period to approve the initial inclusion of these observations. Three trials were run: the first with no radar data, the second with radial wind observations from precipitation echoes, and the third with radial winds from both precipitation and insect echoes. The forecasts were verified against surface observations from automatic weather stations, against rainfall accumulations using fractions skill scores, and against satellite cloud observations. These methods encompassed verification across a range of vertical levels. Additionally, a case study was examined more closely. Overall results showed little statistical difference in skill between the trials, and the net impact was neutral. While the new observations clearly affected the forecast, the objective and subjective analyses showed a neutral impact on the forecast overall. As a first step, this result is satisfactory for the operational implementation. In future, upgrades to the radar network will start to reduce the observation error, and further improvements to the data assimilation are planned, which may be expected to improve the impact.
Trade War: Likely Impact on India
Authors: Misra Rekha , Choudhry Sonam 
Published: January 2020

The global financial crisis triggered the built up of domestic pressure in some countries to introduce protectionist measures against imports. The present discussion regarding the ‘trade war’ and ‘de-globalisation’ intensified after both the US and China escalated the tariff rates on imports originating in the US and China. This study evaluates the potential economic effects of the substantial tariff hikes by these two major economies on Brazil, Russia, India, China and South Africa, particularly for India. The study adds to the existing literature on the trade war by examining potential impact on India’s exports, that is, both direct and indirect losses as well as benefits arising due to the trade war using the economic model based on the trend in trade flows, similarity index and supply chain networks using World Input-Output tables. The study uses the Vector Error Correction Model to empirically evaluate the pass-through of the tariff hike on Indian exports using bilateral real effective exchange rate (REER)-consumer price index and REER-product price index. The study finds that the US–China trade tussle may provide some opportunities in short to medium run for India as gains through trade deflection would be higher than the losses due to trade reduction. However, in the long-run, further escalation of tariffs will have negative impact at the global level. JEL Codes: F1, F62, F68
Lit environments that promote health and well-being
Authors: van Creveld Karen , Mansfield Kevin 
Published: January 2020

The beneficial effects of light on human non-image forming processes are subject to much research interest and are outlined in this article. Known mechanisms of impact include those on the circadian timing system, the arousal system and the affective system. An indication is made that it is important to consider the characteristics of the light field not just the light source when making recommendations concerning light of certain spectral quality. What types of light field are people exposed to on a regular basis and can these lit environments be considered beneficial? How much do these lit scenes differ in terms of spectral composition, as well as in light distribution patterns and illuminance levels, from those conditions that are currently suggested for optimising occupant health and wellbeing? A representative set of natural and built lit environments were identified ranging from seascapes/landscapes to an urban square and various interior architectural environments. A photometric and colorimetric snapshot was measured during the midday hours, to replicate the visual field as viewed from the perspective of the observer. The measured spectral irradiance of light received at the cornea was converted into derived lighting metrics that are the subject of current recommendation: relative sensitivity curve ( V λ), vertical/horizontal illuminance ratio ( Ev/Eh), cylindrical illuminance ( Ec) and circadian stimulus. The data were analysed to demonstrate that the indications are that more natural lit environments are expected to be beneficial. Discussion follows about the relative importance of spectral composition, intensity and light distribution within the visual field and how these might combine to optimise our health and wellbeing. Practical application: Architectural and engineering designers are being encouraged to devise environments that promote human health and wellbeing. New lighting metrics are being suggested and this article seeks to indicate how effective these metrics are in their ability to characterise these lit environments.
Outcomes and Incidence of Complications Following Endoscopic Gastrocnemius Recession: A Systematic Review
Authors: Brandão Roberto A. , So Eric , Steriovski James , Hyer Christopher F. , Prissel Mark A. 
Published: January 2020

Introduction: Equinus contracture of the ankle can lead to a multitude of foot and ankle pathologies. The gastrocnemius recession has been used to address equinus deformity via various methods, including either an open or an endoscopic approach. Open techniques require increased intraoperative time and complication risks of sural nerve injury, wound complications, and poor cosmesis. Resultantly, the aim of the current study is to review the complications and outcomes of the endoscopic gastrocnemius recession. Methods: A systematic review of electronic databases was performed. The authors compiled data from retrospective and prospective patient studies including general patient demographics, outcomes, qualitative scoring measures, complications, and surgical technique. Results: Eleven studies met our inclusion criteria. A total of 697 feet in 627 patients were included in the current systematic review. The weighted mean age was 45.3 years and weighted mean follow-up was 18.4 months. The most common indication for an endoscopic gastrocnemius recession was equinus contracture. The weighted mean preoperative ankle range of motion was −2.3° and the weighted postoperative ankle range of motion was 10.9°. The most common complications included plantarflexion weakness of the ankle at 3.5%, a sural nerve injury of 3.0% and wound complication rate was 1.0% with no deep infection. The overall complication rate was 7.5%. Conclusion: The endoscopic gastrocnemius recession is a valuable surgical tool in the treatment of ankle equinus. The endoscopic approach has satisfactory outcomes including low incidence of plantarflexion weakness and sural neuritis. Patients should be counseled on these risks preoperatively. Compared with previously reported systematic review of the open technique, the endoscopic approach has a lower overall incidence of complications. Prospective clinical trials comparing open and endoscopic techniques are warranted. Levels of Evidence: Level IV
Trends in Mental Well-Being of Non-Hispanic White Children of Midlife Parents With Low Education
Authors: Bhandari Neeraj 
Published: January 2020

Background: It is unknown whether recent increase in mortality and morbidity linked to mental despair (eg, suicide, opioid addiction, alcoholism) in midlife non-Hispanic whites (NHWs) was accompanied by declines in mental well-being of NHW children. The author examined aggregate trends in the mental well-being of NHW children between 2003 and 2018. Methods: The author used linear (unadjusted) regression to generate estimates of long period (ie, between 2003-2005 and 2016-2018) and annual change in mental well-being and self-assessed health from the National Health Interview Survey data on 68 057 NHW children (aged 4-17 years). Results: The NHW children showed no significant change in any of the tracked indicators (composite Strength and Difficulties Questionnaire [SDQ] 5-item score: long period: −0.03, 95% confidence interval [CI]: −0.09 to 0.02, annual: −0.00, 95% CI: −0.01 to 0.00; severe impairment in mental function: long period: 0.01, 95% CI: 0.00 to 0.02; subjective perception of overall health: long period: −0.01, 95% CI: −0.01 to −0.00). The author did not detect any gradient of worsening SDQ scores with parental midlife status and low parental education. However, the trends in SDQ scores in NHW children were slightly worse than those for children of other major race/ethnic groups, Conclusion: The author did not find evidence of worsening mental distress in NHW children overall or whose parents were in their midlives and less educated.
Multidisciplinary Integrated Pharmacotherapy Curriculum in a Doctor of Pharmacy Program: Educators’ Perceptions, Views, and Perspectives
Authors: Alrasheedy Alian A 
Published: January 2020

Background: In pharmacy education, an integrated curriculum in which the full spectrum of foundational and pharmaceutical sciences is integrated with pharmacotherapy and clinical pharmacy is considered relatively new. At Unaizah College of Pharmacy (UCP), Qassim University, Saudi Arabia, a 6-year PharmD program was developed with a multidisciplinary integrated pharmacotherapy curriculum. The integrated pharmacotherapy curriculum represents approximately half of the didactic curriculum. Objective: The aim of this study was to evaluate the perceptions, the views, and experiences of academic faculty members regarding the impact and implementation of the multidisciplinary integrated pharmacotherapy curriculum in the PharmD program. Methods: A cross-sectional study was conducted with all pharmacy faculty members involved in the integrated curriculum. The data-capturing technique in this study was a Web-based survey. In addition, the survey included an open-ended section in which the participants were encouraged to provide comments/feedback and share their experiences about the integrated curriculum. Results: The majority of participants (96.88%, n = 31) believed that the integrated curriculum is well suited for developing problem-solving skills needed in pharmacy practice. Similarly, 93.76% (n = 30) believed that the integrated curriculum results in better student learning experiences. Of the participants, 81.26% (n = 26) believed it results in a better understanding and application of pharmaceutical sciences in practice compared with traditional courses. Moreover, 71.88% (n = 23) considered that the required depth and breadth of the content related to their disciplines is achievable with this model. Of all participants, 96.88% (n = 31) believed that the successful implementation of this integrated curriculum needs strong collaboration, effective communication, good coordination between all departments, and a flexible, fully customizable, and effective e-learning system. Moreover, all participants believed that full integration requires careful design and implementation to ensure no overlapping or marginalization of topics/disciplines. In this study, 62.51% (n = 20) believed that the fully integrated curriculum results in a relatively higher workload compared with traditional courses. Conclusions: The majority of faculty members had positive perceptions regarding the multidisciplinary integrated pharmacotherapy curriculum. Moreover, the majority had positive views and experiences regarding the implementation of this integrated curriculum. The study identified several factors that helped in the successful implementation of this curriculum. Moreover, several challenges have been identified, including more investment in time and effort to implement this fully integrated curriculum.