bluuebunny/crossref_metadata_2025_split huggingface dataset:
TPMT and NUDT15 Variants Predict Discontinuation of Azathioprine for Myelotoxicity in Patients with Inflammatory Disease: Real‐World Clinical Results
Authors: Dickson Alyson L. , Daniel Laura L. , Zanussi Jacy , Dale Plummer W. , Wei Wei‐Qi , Liu Ge , Reese Tyler , Anandi Prathima , Birdwell Kelly A. , Kawai Vivian , Cox Nancy J. , Dupont William D. , Hung Adriana M. , Feng QiPing , Stein C. Michael , Chung Cecilia P. 
Published: September 2021

Azathioprine is used frequently to treat several inflammatory conditions. However, treatment is limited by adverse events—in particular, myelotoxicity. Thiopurine‐S‐methyltransferase (TPMT) and nudix hydrolase‐15 (NUDT15) are enzymes involved in azathioprine metabolism; variants in the genes encoding these enzymes increase the risk for azathioprine myelotoxicity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has recommended dose adjustments based on the results of TPMT and NUDT15 genotyping. However, little is known about the importance of this genetic information in routine clinical care. We hypothesized that in patients with inflammatory diseases, TPMT and NUDT15 genotype data predict the risk of discontinuing azathioprine due to myelotoxicity. This was a retrospective cohort study in 1,403 new adult azathioprine users for the management of inflammatory conditions for whom we had genetic information and clinical data. Among patients who discontinued azathioprine, we adjudicated the reason(s). Genotyping was performed using the Illumina Infinium Expanded Multi‐Ethnic Genotyping Array plus custom content. We used CPIC guidelines to determine TPMT and NUDT15 metabolizer status; patients were grouped as either: (i) poor/intermediate, or (ii) normal/indeterminate metabolizers. We classified 110 patients as poor/intermediate, and 1,293 patients as normal/indeterminate metabolizers. Poor/intermediate status was associated with a higher risk for azathioprine discontinuation due to myelotoxicity compared to normal/indeterminate metabolizers (hazard ratio (HR) = 2.90, 95% confidence interval (CI): 1.58–5.31, P = 0.001). This association remained significant after adjustment for race, age at initiation, sex, primary indication, and initial daily dose of azathioprine (adjusted HR (aHR) = 2.67, 95% CI: 1.44–4.94, P = 0.002). In conclusion, TPMT and NUDT15 metabolizer status predicts discontinuation due to myelotoxicity for patients taking azathioprine for inflammatory conditions.
Evaluating patient acceptability and bowel preparation efficacy of sodium picosulfate‐magnesium citrate for colonoscopy
Authors: Shimada Masaaki , Hirashima Noboru , Iwase Hiroaki , Saito Masashi , Kondo Hisashi , Urata Noboru , Unita Satoshi , Kondo Takashi , Tanaka Daiki , Tsunekawa Takuya , Nakamura Sumie , Nishikura Miho , Miyazawa Kaori , Fukuhara Kiyoko , Fujishiro Mitsuhiro 
Published: September 2021

AbstractObjectiveTo evaluate patient acceptability and bowel preparation efficacy of sodium picosulfate‐magnesium citrate (PICOPREP) for colonoscopy.MethodsA questionnaire survey regarding the patient acceptability of bowel preparation agent PICOPREP was administered to 54 patients, and its efficacy was evaluated using the Ottawa Bowel Preparation Scale (OBPS).ResultsEighteen (33.3%) participants reported that PICOPREP is very easy to drink, 30 (55.5%) easy, four (7.4%) acceptable, one (1.9%) difficult, and one (1.9%) very difficult. The flavor was very good as reported by eight (14.8%) participants, good by 25 (46.3%), neutral by 20 (37.0%), bad by one (1.9%), and very bad by none. The number of patients who requested PICOPREP was 42 (77.7%), indicating its high acceptability. Evaluation of the OBPS score showed that the rectosigmoid colon had significantly better polyethylene glycol (PEG) scores than PICOPREP, but the entire colon did not show a significant difference between PICOPREP and PEG scores (1.09 ± 0.65 vs. 1.17 ± 0.76, p = 0.632 in the right colon; 0.48 ± 0.52 vs. 0.72 ± 0.66, p = 0.079 in the mid colon, 0.93 ± 0.49 vs. 0.63 ± 0.52, p = 0.012 in the rectosigmoid colon, and 3.28 ± 1.70 vs. 3.20 ± 1.90, p = 0.836 in the entire colon).ConclusionPICOPREP is considered as one of the important options due to its good patient acceptability and high efficacy similar to PEG.
Demographic risk assessment for a harvested species threatened by climate change: polar bears in the Chukchi Sea
Authors: Regehr Eric V. , Runge Michael C. , Von Duyke Andrew , Wilson Ryan R. , Polasek Lori , Rode Karyn D. , Hostetter Nathan J. , Converse Sarah J. 
Published: September 2021

AbstractClimate change threatens global biodiversity. Many species vulnerable to climate change are important to humans for nutritional, cultural, and economic reasons. Polar bearsUrsus maritimusare threatened by sea‐ice loss and represent a subsistence resource for Indigenous people. We applied a novel population modeling‐management framework that is based on species life history and accounts for habitat loss to evaluate subsistence harvest for the Chukchi Sea (CS) polar bear subpopulation. Harvest strategies followed a state‐dependent approach under which new data were used to update the harvest on a predetermined management interval. We found that a harvest strategy with a starting total harvest rate of 2.7% (˜85 bears/yr at current abundance), a 2:1 male‐to‐female ratio, and a 10‐yr management interval would likely maintain subpopulation abundance above maximum net productivity level for the next 35 yr (approximately three polar bear generations), our primary criterion for sustainability. Plausible bounds on starting total harvest rate were 1.7–3.9%, where the range reflects uncertainty due to sampling variation, environmental variation, model selection, and differing levels of risk tolerance. The risk of undesired demographic outcomes (e.g., overharvest) was positively related to harvest rate, management interval, and projected declines in environmental carrying capacity; and negatively related to precision in population data. Results reflect several lines of evidence that the CS subpopulation has been productive in recent years, although it is uncertain how long this will last as sea‐ice loss continues. Our methods provide a template for balancing trade‐offs among protection, use, research investment, and other factors. Demographic risk assessment and state‐dependent management will become increasingly important for harvested species, like polar bears, that exhibit spatiotemporal variation in their response to climate change.
Advances in the synthesis and applications of raspberry ketone: A review
Authors: Guo Hui , Chang Sha , Jia Lili , Wang Zuoyao , Zhang Qian , Zhang Guobao 
Published: September 2021

AbstractRecent advances in the synthesis and applications of raspberry ketone are reviewed in this paper. Different routes to this material including chemical and biotechnological synthetic methods and extraction from natural sources are compared, and the applications of the ketone in flavour and fragrance, pharmaceuticals and in food and tobacco processing are discussed. Synthesis from petrochemical raw materials has the advantages of ready availability of ingredients and well‐understood synthetic steps, but direct synthesis from petrochemicals will eventually be replaced because of low yields and hazardous results to environment. The ketone can be made from natural raw materials, and the methods are promising if their disadvantages such as limited availability and complex, multi‐step reactions and harsh reaction conditions can be overcome. Biotechnological preparation methods have the advantages of reaction specificity, mild reaction conditions, but are limited in applicability because of complications associated with their synthetic and purification procedures at present. With the development of biotechnology, biotechnological preparation methods of the ketone may be the most important route in the future. Direct extraction of the ketone from natural raw materials is possible, but the cost is very high. From the view of syntheses and applications, the research perspectives of raspberry ketone are outlined in the end of this paper, which are the development of green and effective synthetic methods for raspberry ketone from natural raw materials and the preparation and application of raspberry ketone by biotechnological preparation methods.
The zinc finger and BTB domain containing protein ZBTB20 regulates plasma triglyceride metabolism by repressing lipoprotein lipase gene transcription in hepatocytes
Authors: Li Hao , Liu Gan , Wan Xiaoqing , Zhou Luting , Qin Zhen‐Bang , Ma Xian‐Hua , Su Kai , Liu Ya‐Jin , Yuan Jinghao , Wei Chun‐Chun , Ren An‐Jing , Chen Yu‐Xia , Young Stephen G. , Zhang Hai , Xie Zhifang , Zhang Weiping J. 
Published: September 2021

Abstract

Background and Aims
Lipoprotein lipase (LPL) is responsible for the lipolytic processing of triglyceride‐rich lipoproteins, the deficiency of which causes severe hypertriglyceridemia. Liver LPL expression is high in suckling rodents but relatively low at adulthood. However, the regulatory mechanism and functional significance of liver LPL expression are incompletely understood. We have established the zinc finger protein ZBTB20 as a critical factor for hepatic lipogenesis. Here, we evaluated the role of ZBTB20 in regulating liver Lpl gene transcription and plasma triglyceride metabolism.

Approach and Results
Hepatocyte‐specific inactivation of ZBTB20 in mice led to a remarkable increase in LPL expression at the mRNA and protein levels in adult liver, in which LPL protein was mainly localized onto sinusoidal epithelial cells and Kupffer cells. As a result, the LPL activity in postheparin plasma was substantially increased, and postprandial plasma triglyceride clearance was significantly enhanced, whereas plasma triglyceride levels were decreased. The dysregulated liver LPL expression and low plasma triglyceride levels in ZBTB20‐deficient mice were normalized by inactivating hepatic LPL expression. ZBTB20 deficiency protected the mice against high‐fat diet–induced hyperlipidemia without causing excessive triglyceride accumulation in the liver. Chromatin immunoprecipitation and gel‐shift assay studies revealed that ZBTB20 binds to the LPL promoter in the liver. A luciferase reporter assay revealed that ZBTB20 inhibits the transcriptional activity of LPL promoter. The regulation of LPL expression by ZBTB20 is liver‐specific under physiological conditions.

Conclusions
Liver ZBTB20 serves as a key regulator of LPL expression and plasma triglyceride metabolism and could be a therapeutic target for hypertriglyceridemia.
Integration of glucose and cardiolipin anabolism confers radiation resistance of HCC
Authors: Fang Yuan , Zhan Yizhi , Xie Yuwen , Du Shisuo , Chen Yuhan , Zeng Zhaochong , Zhang Yaowei , Chen Keli , Wang Yongjia , Liang Li , Ding Yi , Wu Dehua 
Published: September 2021

Abstract

Background and Aims
Poor response to ionizing radiation (IR) due to resistance remains a clinical challenge. Altered metabolism represents a defining characteristic of nearly all types of cancers. However, how radioresistance is linked to metabolic reprogramming remains elusive in hepatocellular carcinoma (HCC).

Approach and Results
Baseline radiation responsiveness of different HCC cells were identified and cells with acquired radio‐resistance were generated. By performing proteomics, metabolomics, metabolic flux, and other functional studies, we depicted a metabolic phenotype that mediates radiation resistance in HCC, whereby increased glucose flux leads to glucose addiction in radioresistant HCC cells and a corresponding increase in glycerophospholipids biosynthesis to enhance the levels of cardiolipin. Accumulation of cardiolipin dampens the effectiveness of IR by inhibiting cytochrome c release to initiate apoptosis. Mechanistically, mammalian target of rapamycin complex 1 (mTORC1) signaling‐mediated translational control of hypoxia inducible factor‐1α (HIF‐1α) and sterol regulatory element‐binding protein‐1 (SREBP1) remodels such metabolic cascade. Targeting mTORC1 or glucose to cardiolipin synthesis, in combination with IR, strongly diminishes tumor burden. Finally, activation of glucose metabolism predicts poor response to radiotherapy in cancer patients.

Conclusions
We demonstrate a link between radiation resistance and metabolic integration and suggest that metabolically dismantling the radioresistant features of tumors may provide potential combination approaches for radiotherapy in HCC.
MSI2 expression in adrenocortical carcinoma: Association with unfavorable prognosis and correlation with steroid and immune‐related pathways
Authors: Veronez Luciana C. , das Chagas Pablo F. , Corrêa Carolina A. P. , Baroni Mirella , da Silva Keteryne R. , Nagano Luis F. , Borges Kleiton S. , Queiroz Rosane G. P. , Tone Luiz G. , Scrideli Carlos A. 
Published: September 2021

AbstractAdrenocortical carcinoma (ACC) is a rare, but highly aggressive cancer of the adrenal cortex with a generally poor prognosis. Despite being rare, completely resected ACCs present a high risk of recurrence. Musashi‐2 (MSI2) has recently been recognized as a potential prognostic biomarker and therapeutic target in many cancers. However, no studies have evaluated the clinical significance of MSI2 expression in ACC. Here, we addressed MSI2 expression and its association with ACC prognosis and clinicopathological parameters. MSI2 expression was analyzed in TCGA, GSE12368, GSE33371, and GSE49278 ACC datasets; and its correlation with other genes and immune cell infiltration were investigated by using the R2: Genomics Analysis and Visualization Platform and TIMER databases, respectively. Enrichment analysis was performed with the DAVID Functional Annotation Tool. Kaplan–Meier curves, log‐rank tests, and Cox regression analyses were used to explore the prognostic role of MSI2 in ACC. Our findings demonstrated the potential value of MSI2 overexpression as an independent predictor of poor prognosis in patients with completely resected ACC (hazard ratio 6.715, 95% confidence interval 1.266 – 35.620, p =.025). In addition, MSI2 overexpression was associated with characteristics of unfavorable prognosis, such as cortisol excess (p = .002), recurrence (p =.003), and death (p =.015); positively correlated with genes related to steroid biosynthesis (p < .05); and negatively correlated with immune‐related pathways (p < .05). Our findings demonstrate that MSI2 has value as a prognostic marker for completely resected ACC and reinforce the investigation of its role as a possible therapeutic target for patients with ACC.
Theories, laws, and models in evo‐devo
Authors: Richardson Michael K. 
Published: September 2021

AbstractEvolutionary developmental biology (evo‐devo) is the study of the evolution of developmental mechanisms. Here, I review some of the theories, models, and laws in evo‐devo, past and present. Nineteenth‐century evo‐devo was dominated by recapitulation theory and archetypes. It also gave us germ layer theory, the vertebral theory of the skull, floral organs as modified leaves, and the “inverted invertebrate” theory, among others. Newer theories and models include the frameshift theory, the genetic toolkit for development, the ABC model of flower development, the developmental hourglass, the zootype, Urbilateria, and the hox code. Some of these new theories show the influence of archetypes and recapitulation. Interestingly, recent studies support the old “primordial leaf,” “inverted invertebrate,” and “segmented head” theories. Furthermore, von Baer's first three laws may now need to be rehabilitated, and the hourglass model modified, in view of what Abzhanov has pointed out about the maternal‐zygotic transition. There are many supposed “laws” of evo‐devo but I argue that these are merely generalizations about trends in particular lineages. I argue that the “body plan” is an archetype, and is often used in such a way that it lacks any scientific meaning. Looking to the future, one challenge for evo‐devo will be to develop new theories and models to accommodate the wealth of new data from high‐throughput sequencing, including single‐cell sequencing. One step in this direction is the use of sophisticated in silico analyses, as in the “transcriptomic hourglass” models.
Post‐treatment clinical course following botulinum toxin injection therapy for adductor spasmodic dysphonia: Analysis of data from a placebo‐controlled, randomized, double‐blinded clinical trial in Japan
Authors: Hirose Kahori , Asano Kento , Sakaguchi Masahiko , Nagao Asuka , Nakahira Maya , Doi Nao , Kobayashi Taisuke , Hyodo Masamitsu 
Published: September 2021

AbstractObjectiveBotulinum toxin (BT) therapy is a first‐line treatment for spasmodic dysphonia (SD). However, a detailed chronological course and clinical factors that affect the therapeutic effect have been vague. In this study, we analyzed the data from our placebo‐controlled, randomized, double‐blinded parallel‐group comparison/open‐label clinical trial of BT (Botox) to clarify these.MethodsA total of 22 patients with abductor SD (ADSD) were enrolled. The female‐to‐male ratio was 20:2 with a mean age of 40.0 ± 10.3 years and a median duration of symptoms of 7.5 years. The therapeutic effect was evaluated based on the change in the number of aberrant morae (phonemes), GRBAS scale, Voice Handicap Index (VHI), and Visual Analogue Scale (VAS).ResultsThe change in the number of aberrant morae peaked at 2 weeks and lasted for 12 weeks in the BT group with significance (P < .01) compared to the placebo group. Objective improvement (number of aberrant morae and [S] element in GRBAS) preceded subjective improvement (VHI and VAS). The change in number of aberrant morae and VHI showed a significant correlation (P < .01). The changes in the number of aberrant morae, VHI, and VAS in younger subjects were greater than in older subjects. Patients who presented with post‐treatment breathy hoarseness or dysphagia showed better therapeutic effects.ConclusionsBT therapy was effective for ADSD based on both objective and subjective assessments. Improvements in subjective parameters were delayed compared to objective measures due to post‐treatment breathy hoarseness. However, this adverse event was believed to reflect the treatment effect.Level of Evidence1b.
Metal transporter Slc30a1 controls pharyngeal neural crest differentiation via the zinc‐Snai2‐Jag1 cascade
Authors: Xia Zhidan , Bi Xinying , Yang Sisi , Yang Xiu , Song Zijun , Wei Jiayu , Xu Pengfei , Rink Lothar , Min Junxia , Wang Fudi 
Published: September 2021

AbstractThe pharyngeal arch (PA) is a neural crest (NC)‐derived organ that is transiently developed during embryogenesis and is required for the subsequent development of various tissues. However, the role of zinc during PA differentiation from NC progenitor cells is unknown. Here, we found that the metal transporters Slc30a1a and Slc30a1b mediate zinc homeostasis during PA differentiation. Slc30a1‐deficient zebrafish develop zinc accumulation in NC cells, with increased expression of stemness markers and PA dorsal genes, and SMART‐seq analyses revealed that the genes snai2 and jag1b may serve as downstream targets. Furthermore, functional studies showed that knocking down either snai2 or jag1b rescues PA development in Slc30a1‐deficient zebrafish. Notably, we identified the double zinc‐finger domain in the transcription factor Snai2 as a zinc‐responsive element that regulates jag1b expression. Our findings indicate that the Slc30a1/zinc‐snai2‐jag1b axis is an essential regulatory network controlling PA differentiation, shedding new light on the function of zinc homeostasis in maintaining NC cell stemness and multipotency in vertebrates.
The relationship between multisite peripheral joint pain and physical activity levels in older adults: A cross‐sectional survey
Authors: Smith Robert D. , McHugh Gretl A. , Quicke Jonathan G. , Finney Andrew , Lewis Martyn , Dziedzic Krysia S. , Healey Emma L. 
Published: September 2021

AbstractIntroductionResearch on levels of physical activity (PA) in those with peripheral joint pain have only focused on single sites, in the knee or hips. This study investigated the levels of PA in adults with single‐site and multisite peripheral joint pain compared to adults with no joint pain.MethodsAnalysis of a cross‐sectional population survey mailed to adults aged ≥45 years (n = 28,443) was conducted. Respondents reported any peripheral joint pain in the last 12 months in either the hands, hips, knees or feet; PA levels were self‐reported using the short telephone activity rating scale. The association between PA levels, peripheral joint pain and outcomes of health status (physical and mental component scores, using SF‐12) pain intensity (10‐point scale) and health‐related quality of life (HRQoL) (EQ‐5D) were investigated using analysis of variance and ordinal regressions.ResultsCompared to those with no joint pain, all pain groups reported lower levels of PA: joint pain in one site (odds ratio = 0.91, 95% CI: 0.83–0.99); two sites (0.74, 0.67–0.81), three sites (0.65, 0.59–0.72) and four sites (0.47, 0.42–0.53). Across all joint pain groups, levels of PA were associated with pain intensity, physical health status, mental health status and HRQoL.DiscussionAdults with more sites of peripheral joint pain were more likely to report lower levels of PA. Those with more sites of pain and lower levels of PA reported poorer outcomes. Health care providers should be aware that those with multisite joint pain are most likely to have low levels of PA.
Indicators of motherhood? Sacral preauricular extensions and notches in identified skeletal collections
Authors: Pany‐Kucera Doris , Spannagl‐Steiner Michaela , Desideri Jocelyne , Rebay‐Salisbury Katharina 
Published: September 2021

AbstractThe sacral preauricular extension (SPE) and sacral preauricular notch (SPN) are morphological changes at the ventral apex of the sacrum. We recently specified their shapes and appearances and suggested a scoring system based on prehistoric Austrian skeletal assemblages. We hypothesized that these specific pelvic changes relate to past pregnancies and parturitions, a hypothesis that we now tested on a subsample of individuals from the Simon Identified Skeletal collection in Geneva (n = 62) and the Christ Church, Spitalfields collection in London (n = 27) linked to historical information on deliveries. We found SPE and SPN in low frequencies and only in female individuals with at least two children in both collections, and a significant association between the emergence of SPE and first births by 25 years. SPN was found only in two females in the Simon collection, but both with a very high number of recorded parturitions including twin births. Based on these results, we are confident in our assumption that at least SPE, and possibly also SPN, result from increased compression forces at the sacroiliac joint, and especially at the ventrosuperior margin, in recurring (complicated) birth events, the interaction of enhanced pelvic joint mobility that is highest up to age 25, and postural changes related to weight gain during pregnancy. Pelvic shape, dimensions, body proportions, biomechanical issues and hormonal levels may also play a role in their emergence.