bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small-Molecule Sigma1 Modulator Induces Autophagic Degradation of PD-L1
Authors: Maher Christina M. , Thomas Jeffrey D. , Haas Derick A. , Longen Charles G. , Oyer Halley M. , Tong Jane Y. , Kim Felix J. 
Published: November 2017

Abstract
Emerging evidence suggests that Sigma1 (SIGMAR1, also known as sigma-1 receptor) is a unique ligand-regulated integral membrane scaffolding protein that contributes to cellular protein and lipid homeostasis. Previously, we demonstrated that some small-molecule modulators of Sigma1 alter endoplasmic reticulum (ER)–associated protein homeostasis pathways in cancer cells, including the unfolded protein response and autophagy. Programmed death-ligand 1 (PD-L1) is a type I integral membrane glycoprotein that is cotranslationally inserted into the ER and is processed and transported through the secretory pathway. Once at the surface of cancer cells, PD-L1 acts as a T-cell inhibitory checkpoint molecule and suppresses antitumor immunity. Here, we demonstrate that in Sigma1-expressing triple-negative breast and androgen-independent prostate cancer cells, PD-L1 protein levels were suppressed by RNAi knockdown of Sigma1 and by small-molecule inhibition of Sigma1. Sigma1-mediated action was confirmed by pharmacologic competition between Sigma1-selective inhibitor and activator ligands. When administered alone, the Sigma1 inhibitor decreased cell surface PD-L1 expression and suppressed functional interaction of PD-1 and PD-L1 in a coculture of T cells and cancer cells. Conversely, the Sigma1 activator increased PD-L1 cell surface expression, demonstrating the ability to positively and negatively modulate Sigma1 associated PD-L1 processing. We discovered that the Sigma1 inhibitor induced degradation of PD-L1 via autophagy, by a mechanism distinct from bulk macroautophagy or general ER stress–associated autophagy. Finally, the Sigma1 inhibitor suppressed IFNγ-induced PD-L1. Our data demonstrate that small-molecule Sigma1 modulators can be used to regulate PD-L1 in cancer cells and trigger its degradation by selective autophagy.
Implications: Sigma1 modulators sequester and eliminate PD-L1 by autophagy, thus preventing functional PD-L1 expression at the cell surface. This posits Sigma1 modulators as novel therapeutic agents in PD-L1/PD-1 blockade strategies that regulate the tumor immune microenvironment.
Visual Overview: http://mcr.aacrjournals.org/content/molcanres/16/2/243/F1.large.jpg. Mol Cancer Res; 16(2); 243–55. ©2017 AACR.
Loss of Uracil DNA Glycosylase Selectively Resensitizes p53-Mutant and -Deficient Cells to 5-FdU
Authors: Yan Yan , Qing Yulan , Pink John J. , Gerson Stanton L. 
Published: November 2017

Abstract
Thymidylate synthase (TS) inhibitors including fluoropyrimidines [e.g., 5-Fluorouracil (5-FU) and 5-Fluorodeoxyuridine (5-FdU, floxuridine)] and antifolates (e.g., pemetrexed) are widely used against solid tumors. Previously, we reported that shRNA-mediated knockdown (KD) of uracil DNA glycosylase (UDG) sensitized cancer cells to 5-FdU. Because p53 has also been shown as a critical determinant of the sensitivity to TS inhibitors, we further interrogated 5-FdU cytotoxicity after UDG depletion with regard to p53 status. By analyzing a panel of human cancer cells with known p53 status, it was determined that p53-mutated or -deficient cells are highly resistant to 5-FdU. UDG depletion resensitizes 5-FdU in p53-mutant and -deficient cells, whereas p53 wild-type (WT) cells are not affected under similar conditions. Utilizing paired HCT116 p53 WT and p53 knockout (KO) cells, it was shown that loss of p53 improves cell survival after 5-FdU, and UDG depletion only significantly sensitizes p53 KO cells. This sensitization can also be recapitulated by UDG depletion in cells with p53 KD by shRNAs. In addition, sensitization is also observed with pemetrexed in p53 KO cells, but not with 5-FU, most likely due to RNA incorporation. Importantly, in p53 WT cells, the apoptosis pathway induced by 5-FdU is activated independent of UDG status. However, in p53 KO cells, apoptosis is compromised in UDG-expressing cells, but dramatically elevated in UDG-depleted cells. Collectively, these results provide evidence that loss of UDG catalyzes significant cell death signals only in cancer cells mutant or deficient in p53.
Implications: This study reveals that UDG depletion restores sensitivity to TS inhibitors and has chemotherapeutic potential in the context of mutant or deficient p53. Mol Cancer Res; 16(2); 212–21. ©2017 AACR.
Adipocytes Sequester and Metabolize the Chemotherapeutic Daunorubicin
Authors: Sheng Xia , Parmentier Jean-Hugues , Tucci Jonathan , Pei Hua , Cortez-Toledo Omar , Dieli-Conwright Christina M. , Oberley Matthew J. , Neely Michael , Orgel Etan , Louie Stan G. , Mittelman Steven D. 
Published: November 2017

Abstract
Obesity is associated with poorer outcome for many cancers. Previously, we observed that adipocytes protect acute lymphoblastic leukemia (ALL) cells from the anthracycline, daunorubicin. In this study, it is determined whether adipocytes clear daunorubicin from the tumor microenvironment (TME). Intracellular daunorubicin concentrations were evaluated using fluorescence. Daunorubicin and its largely inactive metabolite, daunorubicinol, were analytically measured in media, cells, and tissues using liquid chromatography/mass spectrometry (LC/MS). Expression of daunorubicin-metabolizing enzymes, aldo-keto reductases (AKR1A1, AKR1B1, AKR1C1, AKR1C2, AKR1C3, and AKR7A2) and carbonyl reductases (CBR1, CBR3), in human adipose tissue, were queried using public databases and directly measured by quantitative PCR (qPCR) and immunoblot. Adipose tissue AKR activity was measured by colorimetric assay. Adipocytes absorbed and efficiently metabolized daunorubicin to daunorubicinol, reducing its antileukemia effect in the local microenvironment. Murine studies confirmed adipose tissue conversion of daunorubicin to daunorubicinol in vivo. Adipocytes expressed high levels of AKR and CBR isoenzymes that deactivate anthracyclines. Indeed, adipocyte protein levels of AKR1C1, AKR1C2, and AKR1C3 are higher than all other human noncancerous cell types. To our knowledge, this is the first demonstration that adipocytes metabolize and inactivate a therapeutic drug. Adipocyte-mediated daunorubicin metabolism reduces active drug concentration in the TME. These results could be clinically important for adipocyte-rich cancer microenvironments such as omentum, breast, and marrow. As AKR and CBR enzymes metabolize several drugs, and can be expressed at higher levels in obese individuals, this proof-of-principle finding has important implications across many diseases.
Implications: Adipocyte absorption and metabolism of chemotherapies can reduce cytotoxicity in cancer microenvironments, potentially contributing to poorer survival outcomes. Mol Cancer Res; 15(12); 1704–13. ©2017 AACR.
FBXO31 Suppresses Gastric Cancer EMT by Targeting Snail1 for Proteasomal Degradation
Authors: Zou Shuiyan , Ma Cunying , Yang Fenghua , Xu Xia , Jia Jihui , Liu Zhifang 
Published: November 2017

Abstract
The F-box protein FBXO31, a component of the Skp1/Cul1/F-box (SCF) E3 ubiquitin ligase complex, plays an important regulatory role in neuronal development, stress response, and tumorigenesis. Our recent report indicates that FBXO31 functions as a tumor suppressor in gastric cancer, and the loss of FBXO31 protein is associated with a higher malignant phenotype and poorer prognosis. However, little is known about the underlying mechanism. In this study, FBXO31 inhibits gastric cancer progression by suppressing the epithelial–mesenchymal transition (EMT). FBXO31 overexpression decreases, whereas its inhibition increases, the protein level of the EMT transcription factor Snail1 (SNAI1), respectively. Further evidence demonstrates that FBXO31 interacts with Snail1 and mediates the ubiquitin- and proteasome-dependent degradation of Snail1 in gastric cancer. The F-box domain of FBXO31 and the phosphorylation of Snail1 are necessary for the molecular interaction between FBXO31 and Snail1. Mouse modeling experiments reveal that FBXO31 overexpression inhibits in vivo colonization of gastric cancer cells. Furthermore, a highly significant negative correlation between FBXO31 and Snail1 is validated in human gastric cancer clinical specimens. Taken together, these findings identify Snail1 as a new target protein of FBXO31 in gastric cancer and substantiate a novel regulatory role of FBXO31 on gastric cancer progression and metastasis.
Implication: These findings demonstrate that FBXO31 exerts the tumor-inhibitory role in gastric cancer by ubiquitin-mediated degradation of Snail1, which represents a viable strategy of FBXO31 activators in the prevention and therapy of gastric cancer. Mol Cancer Res; 16(2); 286–95. ©2017 AACR.
Value of Intraoperative Parathyroid Hormone Assay during Parathyroidectomy in Dialysis and Renal Transplant Patients with Secondary and Tertiary Hyperparathyroidism
Authors: El-Husseini Amr , Wang Kevin , Edon Annick , Saxon David , Lima Florence , Sloan David , Sawaya B. Peter 
Published: November 2017

<b><i>Background:</i></b> In dialysis and renal transplant patients with secondary and tertiary hyperparathyroidism (HPT), the value of intraoperative parathyroid hormone (ioPTH) during parathyroidectomy (PTX) and its association with long-term PTH levels are unknown. The present study aims at evaluating the relationship of ioPTH with long-term PTH levels post-PTX in dialysis and renal transplant patients in a single-center study. <b><i>Methods:</i></b> The ioPTH was measured in 57 dialysis patients (33 females and 24 males) and 18 renal transplant recipients (12 males and 6 females) who underwent PTX from 2005 to 2015 for refractory HPT. Near-total PTX was performed in 56 patients and total PTX with autotransplantation in 20 patients. The PTH monitoring included 3 samples: pre-intubation, 10- and 20-min (pre-ioPTH, 10-ioPTH, and 20-ioPTH) post parathyroid gland excision. Patients were followed up for up to 5 years. <b><i>Results:</i></b> In the dialysis group, the median (25th–75th percentile) pre-, 10-, and 20-ioPTH levels were 1,447 pg/mL (938–2,176), 143 pg/mL (78–244) and 112 pg/mL (59–153) respectively. In the renal transplant group, pre-, 10-, and 20-ioPTH levels were 273 pg/mL (180–403), 42 pg/mL (25–72), and 34 pg/mL (23–45) respectively. All patients in the transplant group had a functional kidney transplant at the time of PTX with a median serum creatinine of 1.3 mg/dL (1.2–1.7) and estimated glomerular filtration rate of 55 mL/min (40–60). The median time between renal transplant and PTX surgeries was 22 months (7–81). The last median follow-up PTH level was 66 pg/mL (15–201) in the dialysis group and 54 pg/mL (17–72) in the transplant group (<i>p</i> = 0.438). The mean time for last PTH post-PTX was 2.3 ± 2.0 years. In both groups, there was no significant difference between 20-ioPTH and any-time post-PTX PTH levels (<i>p</i> = 0.6 and <i>p</i> = 0.9). Nineteen patients (25%) were readmitted within 90 days because of hypocalcemia. One patient in the dialysis group was readmitted for post-PTX hematoma evacuation. No patient required repeat PTX because of recurrent HPT that was refractory to medical therapy. Only one dialysis patient required repeat PTX because the first procedure failed. <b><i>Conclusions:</i></b> The 20-ioPTH is a good indicator of long-term PTH levels in dialysis and renal transplant patients. Hypocalcemia is a common complication, particularly in dialysis patients, and it is the main reason for readmission after PTX. Hypoparathyroidism is a potential concern after PTX in dialysis patients.
Evaluation of the Pleiotropic Effects of Statins
Authors: Labos Christopher , Brophy James M. , Smith George Davey , Sniderman Allan D. , Thanassoulis George 
Published: November 2017

Objective—
To reanalyze data from recent randomized trials of statins to assess whether the benefits and risks of statins are mediated primarily via their LDL-C (low-density lipoprotein cholesterol) lowering effects or via other mechanisms.

Approach and Results—

We adapted Egger regression, a technique frequently used in Mendelian randomization studies to detect genetic pleiotropy, to reanalyze the available randomized control trial data of statin therapy. For cardiovascular end points, each 1 mmol/L change in LDL-C with statin therapy was associated with a hazard ratio of 0.77 (95% confidence interval, 0.71–0.84) with an intercept that was indistinguishable from zero (intercept, −0.0032; [95% confidence interval, −0.090 to 0.084];
P
=0.94), indicating no pleiotropy. For incident diabetes mellitus, a 1 mmol/L change in LDL-C with statin therapy was associated with a hazard ratio of 1.07 (95% confidence interval, 0.99–1.16) and an intercept nondistinguishable from zero (intercept, −0.015; [95% confidence interval, −0.30 to 0.27];
P
=0.91), again indicating no pleiotropy.

Conclusions—
Our reanalysis of the randomized control trial data using Egger regression adds to the existing evidence that the cardiovascular benefits of statins and their association with incident diabetes mellitus are mediated primarily, if not entirely, via their LDL-C lowering properties rather than by any pleiotropic effects.
Demand Fluctuation and Supply Chain Integration: Case Studies of Japanese Firms
Authors: Kobayashi Mizuki , Tomino Takahiro , Shintaku Junjiro , Park YoungWon 
Published: November 2017

Abstract
Current Japanese oems utilize both make-to-stock (mts) and make-to-order (mto) to cope with demand fluctuation. In this article, we study how leading manufacturing firms utilize mts and mto by observing two case studies, Toyota’s and Omron’s operations in China. Production and delivery of component suppliers are based on the advance notification from their manufacturers. For this, most automotive firms integrate marketing channels internally, however, most healthcare firms do not. Consequently, it is difficult to forecast and control demand accurately like automotive firms. In this sense, for healthcare firms, it is a tremendous challenge to respond to demand fluctuation through integration with external marketing agencies. We show both companies strategies to mix mts and mto along with integrating internal and external parties.
Architectural Strategy in Complex and Large Products: A Case of Shipbuilding Industry in Japan and Korea
Authors: Mukai Yuichiro 
Published: November 2017

AbstractProducts tend to be more complex or integral when constraints become stricter. Such product design and production require coordination-intensity. From an evolutionary view, many Japanese companies have high levels of organization with multi-skilled labors, so are good at coordination-intensive products. However, they do not always have competitiveness in this field. Only a few researchers have approached this issue, so this article will examine it by using a case study of shipbuilding as a complex and large product industry. Here, the concepts of complexity and largeness are distinctive. From design information view of artifacts, complexity relates to design information, largeness relates to medium. Shipbuilding is an advanced industry facing environmental and safety constraints. Moreover, it has encountered several periods of crisis and recovery. From this analysis using the complexity and largeness axis, many Japanese firms have a competitive advantage in the simple-small category, while Korean firms succeed in the complex-large category. It is a result of an architectural strategy for survival.
Impact of Sea Surface Temperature Forcing on Weeks 3 and 4 Forecast Skill in the NCEP Global Ensemble Forecasting System
Authors: Zhu Yuejian , Zhou Xiaqiong , Peña Malaquias , Li Wei , Melhauser Christopher , Hou Dingchen 
Published: November 2017

Abstract
The Global Ensemble Forecasting System (GEFS) is being extended from 16 to 35 days to cover the subseasonal period, bridging weather and seasonal forecasts. In this study, the impact of SST forcing on the extended-range land-only global 2-m temperature, continental United States (CONUS) accumulated precipitation, and MJO skill are explored with version 11 of the GEFS (GEFSv11) under various SST forcing configurations. The configurations consist of 1) the operational GEFS 90-day e-folding time of the observed real-time global SST (RTG-SST) anomaly relaxed to climatology, 2) an optimal AMIP configuration using the observed daily RTG-SST analysis, 3) a two-tier approach using the CFSv2-predicted daily SST, and 4) a two-tier approach using bias-corrected CFSv2-predicted SST, updated every 24 h. The experimental period covers the fall of 2013 and the winter of 2013/14. The results indicate that there are small differences in the ranked probability skill scores (RPSSs) between the various SST forcing experiments. The improvements in forecast skill of the Northern Hemisphere 2-m temperature and precipitation for weeks 3 and 4 are marginal, especially for North America. The bias-corrected CFSv2-predicted SST experiment generally delivers superior performance with statistically significant improvement in spatially and temporally aggregated 2-m temperature RPSSs over North America. Improved representation of the SST forcing (AMIP) increased the forecast skill for MJO indices up through week 2, but there is no significant improvement of the MJO forecast skill for weeks 3 and 4. These results are obtained over a short period with weak MJO activity and are also subject to internal model weaknesses in representing the MJO. Additional studies covering longer periods with upgraded model physics are warranted.
Social Resilience to Climate-Related Disasters in Ancient Societies: A Test of Two Hypotheses
Authors: Peregrine Peter N. 
Published: November 2017

AbstractCurrent literature on disaster response argues that societies providing greater local participation in decision-making and that have more community coordination and governance organizations are more resilient to climate-related disasters. In contrast, recent research in psychology has argued that societies with tighter social norms and greater enforcement of those norms are more resilient. This paper tests whether one or both of these seemingly competing perspectives can be empirically supported through an examination of the diachronic impact of climate-related disasters on ancient societies. A cross-cultural research design and a sample of 33 archaeologically known societies bracketing 22 catastrophic climate-related disasters are used to test two hypotheses about resilience to climate-related disasters. The paper finds that societies allowing greater political participation appear to provide greater resilience to catastrophic climate-related disasters, generally supporting the predominant perspective in contemporary disaster response.
Draw-and-write technique elicits children’s perceptions of health in the USA and Guatemala
Authors: Renslow Jillian , Maupin Jonathan 
Published: November 2017

Objective: Using the draw-and-write methodology, this study examined cross-cultural similarities and differences in children’s perceptions of health. Design: Cross-sectional design. Setting: One public elementary school in the USA and in Guatemala. Method: The total sample included 161 children 9–10 years of age, 80 in the USA and 81 in Guatemala. Children in each setting were asked to draw-and-write responses to two prompts regarding things that make someone healthy/unhealthy. Responses were coded for the presence of themes for each topic, and statistical tests were performed to test for significant differences by gender and country. Results: Food is central to children’s perceptions of healthy and unhealthy in both locations, as over 90% of children overall depicted food items for both topics. Fruit, in particular, constitutes the majority of depictions for healthy items in both countries, followed by vegetables. In terms of differences, children in the USA were more likely to depict drinking water and exercise as things that make someone healthy and fast food as being unhealthy. Guatemalan children, in contrast, were more likely to depict hygiene and the environment as both healthy and unhealthy. Conclusion: There are more cross-cultural similarities than differences in children’s perceptions of health. While similarities derive from the centrality of food in perceptions of health, differences in perceptions of health emerge from unique national health conditions and initiatives, local socio-ecological contexts and school curricula.
The Influence of Personality Traits on Households’ Financial Risk Tolerance and Financial Behaviour
Authors: Pinjisakikool Teerapong 
Published: November 2017

Using a large sample that can represent the Dutch population, this article mainly studies the determinants of financial risk tolerance. I propose that the big five personality traits are the potential factors that can explain differences in financial risk tolerance among individuals. Furthermore, this article examines the effect of personality traits on the actual financial behaviour of households through financial risk tolerance. I find that all the big five personality traits including extraversion, agreeableness, conscientiousness, emotional stability and intellect significantly predict financial risk tolerance. Additionally, these personality traits as instrumental variables can also indirectly predict the financial behaviour of households. JEL: D10, D14, D19
Susceptibility of iodine concentration map of dual-energy contrast-enhanced digital mammography for quantitative and tumor enhancement assessment
Authors: Hwang Yi-Shuan , Cheung Yun-Chung , Lin Yu-Ying , Hsu Hsiao-Lan , Tsai Hui-Yu 
Published: November 2017

Background Dual-energy (DE) contrast-enhanced digital mammography (DE-CEDM) provides additional information on tumor angiogenesis. Purpose To investigate the susceptibility of reconstructing color-coded iodine concentration maps on the basis of quantitative calibrations of the iodine concentration and contrast-to-noise ratio (CNR) in DE-CEDM applications. Material and Methods A custom-made phantom filled with iodine concentrations in the range of 0.1–10 mg/cm2 was used in calibrations. All DE images were acquired using the GE Senographe Essential system. From DE subtraction images, the image contrast and CNR were obtained, and the quantitative relationship between these two metrics and the iodine concentration at each phantom thickness was investigated. The quantitative CNR calibration curves were applied to reconstruct color-coded iodine maps on a pixel-by-pixel basis. Results Both the mean contrast and mean CNR increased linearly with the iodine concentration. The iodine concentration estimated from the iodine map reconstructed from quantitative CNR calibrations was highly consistent with the desired iodine concentration (R2 = 0.989), and smaller relative errors (in the range of 3.0–19.5%) were observed with iodine concentrations not less than 1 mg/cm2. Conclusion An iodine concentration map could be reconstructed based on the linear relationship between the CNR and iodine concentration. From the color-coded iodine concentration map, the contrast medium enhancement phenomenon could be further estimated quantitatively, and tumor enhancement patterns could be easily observed.