bluuebunny/crossref_metadata_2025 huggingface dataset:
Palindromic Rheumatism: Just a Pre-rheumatoid Stage or Something Else?
Authors: Sanmartí Raimon , Frade-Sosa Beatriz , Morlà Rosa , Castellanos-Moreira Raul , Cabrera-Villalba Sonia , Ramirez Julio , Salvador Georgina , Haro Isabel , Cañete Juan D.
Published: March 2021

Palindromic rheumatism (PR), a unique clinical entity, has a characteristic clinical presentation with a relapsing/remitting course. It is established that most patients with PR evolve to chronic disease, of which rheumatoid arthritis (RA) is by far the most common. The relationship between PR and RA is unclear, with similarities and differences between the two, and not all patients evolve to RA in the long-term. Therefore, PR is clearly a pre-RA stage for most, but not all, patients. Autoimmunity plays a substantial role in PR, with the same characteristic autoantibody profile observed in RA, although with some differences in the immune response repertoire. Autoinflammation may also be relevant in some cases of PR. Prognostic factors for RA progression are identified but their exact predictive value is not clear. There are several unmet needs in PR, such as the diagnostic criteria and clinical case definition, the pathogenic mechanisms involved in the unusual clinical course, and the evolution to RA, and our understanding of the therapeutic strategy that could best avoid progression to persistent and potentially destructive arthritis.
Inactivation Effect of Violet and Blue Light on ESKAPE Pathogens and Closely Related Non-pathogenic Bacterial Species – A Promising Tool Against Antibiotic-Sensitive and Antibiotic-Resistant Microorganisms
Authors: Hoenes Katharina , Bauer Richard , Meurle Tobias , Spellerberg Barbara , Hessling Martin
Published: March 2021

Graphical Abstract
DNA Metabarcoding Reveals Broad Presence of Plant Pathogenic Oomycetes in Soil From Internationally Traded Plants
Authors: Rossmann Simeon , Lysøe Erik , Skogen Monica , Talgø Venche , Brurberg May Bente
Published: March 2021

Plants with roots and soil clumps transported over long distances in plant trading can harbor plant pathogenic oomycetes, facilitating disease outbreaks that threaten ecosystems, biodiversity, and food security. Tools to detect the presence of such oomycetes with a sufficiently high throughput and broad scope are currently not part of international phytosanitary testing regimes. In this work, DNA metabarcoding targeting the internal transcribed spacer (ITS) region was employed to broadly detect and identify oomycetes present in soil from internationally shipped plants. This method was compared to traditional isolation-based detection and identification after an enrichment step. DNA metabarcoding showed widespread presence of potentially plant pathogenic Phytophthora and Pythium species in internationally transported rhizospheric soil with Pythium being the overall most abundant genus observed. Baiting, a commonly employed enrichment method for Phytophthora species, led to an increase of golden-brown algae in the soil samples, but did not increase the relative or absolute abundance of potentially plant pathogenic oomycetes. Metabarcoding of rhizospheric soil yielded DNA sequences corresponding to oomycete isolates obtained after enrichment and identified them correctly but did not always detect the isolated oomycetes in the same samples. This work provides a proof of concept and outlines necessary improvements for the use of environmental DNA (eDNA) and metabarcoding as a standalone phytosanitary assessment tool for broad detection and identification of plant pathogenic oomycetes.
Identification of a Novel Protein-Based Signature to Improve Prognosis Prediction in Renal Clear Cell Carcinoma
Authors: Chu Guangdi , Xu Ting , Zhu Guanqun , Liu Shuaihong , Niu Haitao , Zhang Mingxin
Published: March 2021

Background

Clear cell renal cell carcinoma (ccRCC) is one of the most common types of malignant adult kidney cancer, and its incidence and mortality are not optimistic. It is well known that tumor-related protein markers play an important role in cancer detection, prognosis prediction, or treatment selection, such as carcinoembryonic antigen (CEA), programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4), so a comprehensive analysis was performed in this study to explore the prognostic value of protein expression in patients with ccRCC.

Materials and Methods

Protein expression data were obtained from The Cancer Proteome Atlas (TCPA), and clinical information were downloaded from The Cancer Genome Atlas (TCGA). We selected 445 patients with complete information and then separated them into a training set and testing set. We performed univariate, least absolute shrinkage and selection operator (LASSO) Cox analyses to find prognosis-related proteins (PRPs) and constructed a protein signature. Then, we used stratified analysis to fully verify the prognostic significance of the prognostic-related protein signature score (PRPscore). Besides, we also explored the differences in immunotherapy response and immune cell infiltration level in high and low score groups. The consensus clustering analysis was also performed to identify potential cancer subgroups.

Results

From the training set, a total of 233 PRPs were selected, and a seven-protein signature was constructed, including ACC1, AR, MAPK, PDK1, PEA15, SYK, and BRAF. Based on the PRPscore, patients could be divided into two groups with significantly different overall survival rates. Univariate and multivariate Cox regression analyses proved that this signature was an independent prognostic factor for patients (P < 0.001). Moreover, the signature showed a high ability to distinguish prognostic outcomes among subgroups, and the low score group had a better prognosis (P < 0.001) and better immunotherapy response (P = 0.003) than the high score group.

Conclusion

We constructed a novel protein signature with robust predictive power and high clinical value. This will help to guide the disease management and individualized treatment of ccRCC patients.
Cholesterol, Atherosclerosis, and APOE in Vascular Contributions to Cognitive Impairment and Dementia (VCID): Potential Mechanisms and Therapy
Authors: Duong Michael Tran , Nasrallah Ilya M. , Wolk David A. , Chang Catherine C. Y. , Chang Ta-Yuan
Published: March 2021

Vascular contributions to cognitive impairment and dementia (VCID) are a common cause of cognitive decline, yet limited therapies exist. This cerebrovascular disease results in neurodegeneration via acute, chronic, local, and systemic mechanisms. The etiology of VCID is complex, with a significant impact from atherosclerosis. Risk factors including hypercholesterolemia and hypertension promote intracranial atherosclerotic disease and carotid artery stenosis (CAS), which disrupt cerebral blood flow and trigger ischemic strokes and VCID. Apolipoprotein E (APOE) is a cholesterol and phospholipid carrier present in plasma and various tissues. APOE is implicated in dyslipidemia and Alzheimer disease (AD); however, its connection with VCID is less understood. Few experimental models for VCID exist, so much of the present information has been drawn from clinical studies. Here, we review the literature with a focus on the clinical aspects of atherosclerotic cerebrovascular disease and build a working model for the pathogenesis of VCID. We describe potential intermediate steps in this model, linking cholesterol, atherosclerosis, and APOE with VCID. APOE4 is a minor isoform of APOE that promotes lipid dyshomeostasis in astrocytes and microglia, leading to chronic neuroinflammation. APOE4 disturbs lipid homeostasis in macrophages and smooth muscle cells, thus exacerbating systemic inflammation and promoting atherosclerotic plaque formation. Additionally, APOE4 may contribute to stromal activation of endothelial cells and pericytes that disturb the blood-brain barrier (BBB). These and other risk factors together lead to chronic inflammation, atherosclerosis, VCID, and neurodegeneration. Finally, we discuss potential cholesterol metabolism based approaches for future VCID treatment.
Fatty Acid-Binding Protein 3 Expression in the Brain and Skin in Human Synucleinopathies
Authors: Oizumi Hideki , Yamasaki Kenshi , Suzuki Hiroyoshi , Hasegawa Takafumi , Sugimura Yoko , Baba Toru , Fukunaga Kohji , Takeda Atsushi
Published: March 2021

Parkinson’s disease (PD) and multiple system atrophy are types of adult-onset neurodegenerative disorders named synucleinopathies, which are characterized by prominent intracellular α-synuclein (αSyn) aggregates. We have previously found that αSyn aggregates and the vulnerability of dopaminergic neurons in the mouse brain are partly associated with the expression of fatty acid-binding protein 3 (FABP3, heart FABP). However, it remains to be elucidated whether FABP3 accumulation is associated with αSyn aggregates in human tissues. Here, we histologically studied FABP3 expression in human tissues obtained from patients with synucleinopathies, patients with Alzheimer disease (AD) and controls. We found that (1) a variety of neurons expressed the FABP3 protein in human brain tissues, (2) FABP3 was colocalized with αSyn aggregates in the brains of individuals with synucleinopathies but not with amyloid β or p-tau aggregates in the brains of individuals with AD, and (3) FABP3 was not present in p-αSyn deposits in biopsied skin tissues from individuals with PD. These findings suggest that FABP3 expression is associated with αSyn aggregation in synucleinopathies and provide new insights into the involvement of FABP3 in synucleinopathies.
Overview of MR Image Segmentation Strategies in Neuromuscular Disorders
Authors: Ogier Augustin C. , Hostin Marc-Adrien , Bellemare Marc-Emmanuel , Bendahan David
Published: March 2021

Neuromuscular disorders are rare diseases for which few therapeutic strategies currently exist. Assessment of therapeutic strategies efficiency is limited by the lack of biomarkers sensitive to the slow progression of neuromuscular diseases (NMD). Magnetic resonance imaging (MRI) has emerged as a tool of choice for the development of qualitative scores for the study of NMD. The recent emergence of quantitative MRI has enabled to provide quantitative biomarkers more sensitive to the evaluation of pathological changes in muscle tissue. However, in order to extract these biomarkers from specific regions of interest, muscle segmentation is mandatory. The time-consuming aspect of manual segmentation has limited the evaluation of these biomarkers on large cohorts. In recent years, several methods have been proposed to make the segmentation step automatic or semi-automatic. The purpose of this study was to review these methods and discuss their reliability, reproducibility, and limitations in the context of NMD. A particular attention has been paid to recent deep learning methods, as they have emerged as an effective method of image segmentation in many other clinical contexts.
Clinical Variability of SYNJ1-Associated Early-Onset Parkinsonism
Authors: Lesage Suzanne , Mangone Graziella , Tesson Christelle , Bertrand Hélène , Benmahdjoub Mustapha , Kesraoui Selma , Arezki Mohamed , Singleton Andrew , Corvol Jean-Christophe , Brice Alexis
Published: March 2021

Autosomal recessive early-onset parkinsonism is clinically and genetically heterogeneous. Mutations of three genes,PRKN, PINK1, andDJ-1cause pure phenotypes usually characterized by levodopa-responsive Parkinson's disease. By contrast, mutations of other genes, includingATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, VPS13C, andPTRHD1, cause rarer, more severe diseases with a poor response to levodopa, generally with additional atypical features. We performed data mining on a gene panel or whole-exome sequencing in 460 index cases with early-onset (≤ 40 years) Parkinson's disease, including 57 with autosomal recessive disease and 403 isolated cases. We identified two isolated cases carrying biallelic mutations ofSYNJ1(double-heterozygous p.D791fs/p.Y232H and homozygous p. Y832C mutations) and two siblings with the recurrent homozygous p.R258Q mutation. All four variants were absent or rare in the Genome Aggregation Database, were predicted to be deleterious onin silicoanalysis and were found to be highly conserved between species. The patient with both the previously unknown p.D791fs and p.Y232H mutations presented with dystonia-parkinsonism accompanied by a frontal syndrome and oculomotor disturbances at the age of 39. In addition, two siblings from an Algerian consanguineous family carried the homozygous p.R258Q mutation and presented generalized tonic-clonic seizures during childhood, with severe intellectual disability, followed by progressive parkinsonism during their teens. By contrast, the isolated patient with the homozygous p. Y832C mutation, diagnosed at the age of 20, had typical parkinsonism, with no atypical symptoms and slow disease progression. Our findings expand the mutational spectrum and phenotypic profile ofSYNJ1-related parkinsonism.
Absence of Nonlinear Coupling Between Electric Vestibular Stimulation and Evoked Forces During Standing Balance
Authors: Hannan Kelci B. , Todd Makina K. , Pearson Nicole J. , Forbes Patrick A. , Dakin Christopher J.
Published: March 2021

The vestibular system encodes motion and orientation of the head in space and is essential for negotiating in and interacting with the world. Recently, random waveform electric vestibular stimulation has become an increasingly common means of probing the vestibular system. However, many of the methods used to analyze the behavioral response to this type of stimulation assume a linear relationship between frequencies in the stimulus and its associated response. Here we examine this stimulus-response frequency linearity to determine the validity of this assumption. Forty-five university-aged subjects stood on a force-plate for 4 min while receiving vestibular stimulation. To determine the linearity of the stimulus-response relationship we calculated the cross-frequency power coupling between a 0 and 25 Hz bandwidth limited white noise stimulus and induced postural responses, as measured using the horizontal forces acting at the feet. Ultimately, we found that, on average, the postural response to a random stimulus is linear across stimulation frequencies. This result supports the use of analysis methods that depend on the assumption of stimulus-response frequency linearity, such as coherence and gain, which are commonly used to analyze the body’s response to random waveform electric stimuli.
Global Signal Topography of the Human Brain: A Novel Framework of Functional Connectivity for Psychological and Pathological Investigations
Authors: Ao Yujia , Ouyang Yujie , Yang Chengxiao , Wang Yifeng
Published: March 2021

The global signal (GS), which was once regarded as a nuisance of functional magnetic resonance imaging, has been proven to convey valuable neural information. This raised the following question: what is a GS represented in local brain regions? In order to answer this question, the GS topography was developed to measure the correlation between global and local signals. It was observed that the GS topography has an intrinsic structure characterized by higher GS correlation in sensory cortices and lower GS correlation in higher-order cortices. The GS topography could be modulated by individual factors, attention-demanding tasks, and conscious states. Furthermore, abnormal GS topography has been uncovered in patients with schizophrenia, major depressive disorder, bipolar disorder, and epilepsy. These findings provide a novel insight into understanding how the GS and local brain signals coactivate to organize information in the human brain under various brain states. Future directions were further discussed, including the local-global confusion embedded in the GS correlation, the integration of spatial information conveyed by the GS, and temporal information recruited by the connection analysis. Overall, a unified psychopathological framework is needed for understanding the GS topography.
Respiratory Tract Infections and Antibiotic Resistance: A Protective Role for Vitamin D?
Authors: Derbyshire Emma J. , Calder Philip C.
Published: March 2021

Upper and lower respiratory tract infections are among the most common infections globally, and in the United Kingdom, they account for about half of all oral antibiotics prescribed. Antibiotic overuse and the emergence of “superbugs” that are resistant to their effects is a global problem that is becoming a serious concern. Considering this, the potential role of immunonutrition as a “prehabilitation” in helping to tackle bacterial infections and reduce over-reliance on antibiotic usage is gaining interest. This narrative mini-review summarizes current knowledge on the roles of certain nutrients in helping to modulate immune function, with particular focus on vitamin D. Vitamin D supplementation appears to reduce the risk of acute respiratory tract infections and thus could have a valuable role to play in reducing over-reliance on antibiotics. Investment in high-quality trials is needed to further explore this field.
The Survival Benefits of Surgical Resection and Adjuvant Therapy for Patients With Brainstem Glioma
Authors: Liu Zhuoyi , Feng Songshan , Li Jing , Cao Hui , Huang Jun , Fan Fan , Cheng Li , Liu Zhixiong , Cheng Quan
Published: March 2021

Purpose

The role of surgical resection in the treatment of brainstem glioma (BSG) is poorly understood. For pediatric low-grade (LGBSG) group, several monocentric small-scale retrospective studies reported contradictory conclusions. And there was no clinical study focused on surgical resection for adult or pediatric high-grade (HG) patient groups. This study aims to illustrate whether surgical resection and adjuvant therapy provide survival benefits for patients with histologically confirmed BSG.

Patients and Methods

This retrospective cohort study included 529 patients with histologically confirmed BSG in Surveillance Epidemiology and End Results (SEER) database from 2006-2015. Patients were divided into four groups by age and World Health Organization (WHO) grade. Kaplan-Meier curves of CSS were plotted by different treatment options to compare the survival probability. Univariate and multivariable analyses were then conducted to determine the prognosis effects of surgical resection and adjuvant therapy on cancer specific survival (CSS). All analyses were done in four different groups separately.

Results

The final sample included 529 patients. The entire study population was divided into groups of pediatric LG (n=236, 44.6%), pediatric HG (n=37, 7.0%), adult LG (n=204, 38.6%) and adult HG (n=52, 9.8%). 52.7% (n=144) of pediatric patients had pilocytic astrocytoma and 45.3% (n=116) of adult patients had ependymoma. Pediatric LGBSG group had the highest gross total resection (GTR) rate (61.4%) and 5-year CSS rate (88.6%). Kaplan-Meier curves of pediatric LGBSG group revealed that patients treated with GTR had significantly better survival probability (P=0.033). Multivariable analysis identified GTR as independently significant predictor for prolonged CSS in pediatric LGBSG group (HR0.29, 95%CI 0.11-0.78, P=0.015); Surgical resection showed no relation to CSS in other patient groups. Kaplan-Meier curves of adult HGBSG group showed that patients treated with both RT and CT in adult HGBSG group had the best survival probability (P=0.02). However, multivariable analysis showed the combination of radiotherapy (RT) and chemotherapy (CT) was not significantly related to better CSS in adult HGBSG group (HR0.35, 95%CI 0.11-1.09, P=0.070). Adjuvant therapy didn’t associate with better CSS in other patient groups.

Conclusion

Pediatric LGBSG group had the highest GTR rate and the most favorable clinical outcome. GTR can provide significant survival benefits for pediatric LGBSG group.
Understanding the Immune-Stroma Microenvironment in B Cell Malignancies for Effective Immunotherapy
Authors: Apollonio Benedetta , Ioannou Nikolaos , Papazoglou Despoina , Ramsay Alan G.
Published: March 2021

Cancers, including lymphomas, develop in complex tissue environments where malignant cells actively promote the creation of a pro-tumoral niche that suppresses effective anti-tumor effector T cell responses. Research is revealing that the tumor microenvironment (TME) differs between different types of lymphoma, covering inflamed environments, as exemplified by Hodgkin lymphoma, to non-inflamed TMEs as seen in chronic lymphocytic leukemia (CLL) or diffuse-large B-cell lymphoma (DLBCL). In this review we consider how T cells and interferon-driven inflammatory signaling contribute to the regulation of anti-tumor immune responses, as well as sensitivity to anti-PD-1 immune checkpoint blockade immunotherapy. We discuss tumor intrinsic and extrinsic mechanisms critical to anti-tumor immune responses, as well as sensitivity to immunotherapies, before adding an additional layer of complexity within the TME: the immunoregulatory role of non-hematopoietic stromal cells that co-evolve with tumors. Studying the intricate interactions between the immune-stroma lymphoma TME should help to design next-generation immunotherapies and combination treatment strategies to overcome complex TME-driven immune suppression.
Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs
Authors: Ma Li , Li Haoyang , Wang Dongpo , Hu Ying , Yu Mengjun , Zhang Quan , Qin Na , Zhang Xinyong , Li Xi , Zhang Hui , Wu Yuhua , Lv Jialin , Yang Xinjie , Yu Ruoying , Zhang Shucai , Wang Jinghui
Published: March 2021

Purpose

Circulating cell-free DNA (cfDNA) level has been demonstrated to be associated with efficacy in first generation EGFR TKIs in non-small cell lung cancer (NSCLC). However, the role of dynamic cfDNA analysis using next-generation sequencing (NGS) in patients with subsequent third-generation EGFR TKIs remains unclear.

Methods

From 2016 to 2019, 81 NSCLC patients with EGFR T790M mutation either in tissue or plasma who received third-generation EGFR TKIs treatment were enrolled. CfDNA were sequenced by NGS with a 425-gene panel. The association of clinical characteristics, pretreatment, dynamic cfDNA and T790M level with outcomes in patients treated with the third-generation TKIs were analyzed.

Results

In univariate analysis, the median PFS of patients with undetectable cfDNA level during treatment was significantly longer than those with detectable cfDNA (16.97 vs. 6.10 months; HR 0.2109; P < 0.0001). The median PFS of patients with undetectable T790M level during treatment was significantly longer than those with detectable T790M (14.1 vs. 4.4 months; HR 0.2192; P < 0.001). Cox hazard proportion model showed that cfDNA clearance was an independent predictor for longer PFS (HR 0.3085; P < 0.001) and longer OS (HR 0.499; P = 0.034). The most common resistant mutations of the third-generation TKIs were EGFR C797S (24%). CDK6 CNV, GRIN2A, BRCA2, EGFR D761N, EGFR Q791H, EGFR V843I, and ERBB4 mutation genes may possibly be new resistant mechanisms.

Conclusions

Patients with undetectable cfDNA during the third-generation EGFR TKI treatment have superior clinical outcomes, and dynamic cfDNA analysis by NGS is valuable to explore potential resistant mechanisms.
Augmented Reality Navigation for Stereoscopic Laparoscopic Anatomical Hepatectomy of Primary Liver Cancer: Preliminary Experience
Authors: Zhang Weiqi , Zhu Wen , Yang Jian , Xiang Nan , Zeng Ning , Hu Haoyu , Jia Fucang , Fang Chihua
Published: March 2021

Background

Accurate determination of intrahepatic anatomy remains challenging for laparoscopic anatomical hepatectomy (LAH). Laparoscopic augmented reality navigation (LARN) is expected to facilitate LAH of primary liver cancer (PLC) by identifying the exact location of tumors and vessels. The study was to evaluate the safety and effectiveness of our independently developed LARN system in LAH of PLC.

Methods

From May 2018 to July 2020, the study included 85 PLC patients who underwent three-dimensional (3D) LAH. According to whether LARN was performed during the operation, the patients were divided into the intraoperative navigation (IN) group and the non-intraoperative navigation (NIN) group. We compared the preoperative data, perioperative results and postoperative complications between the two groups, and introduced our preliminary experience of this novel technology in LAH.

Results

There were 44 and 41 PLC patients in the IN group and the NIN group, respectively. No significant differences were found in preoperative characteristics and any of the resection-related complications between the two groups (All P > 0.05). Compared with the NIN group, the IN group had significantly less operative bleeding (P = 0.002), lower delta Hb% (P = 0.039), lower blood transfusion rate (P < 0.001), and reduced postoperative hospital stay (P = 0.003). For the IN group, the successful fusion of simulated surgical planning and operative scene helped to determine the extent of resection.

Conclusions

The LARN contributed to the identification of important anatomical structures during LAH of PLC. It reduced vascular injury and accelerated postoperative recovery, showing a potential application prospects in liver surgery.
Insulin Resistance and Pellino-1 Mediated Decrease in the Activities of Vasodilator Signaling Contributes to Sunitinib-Induced Hypertension
Authors: Liu Yang , Tang Liang-Liang , Liang Chen , Wu Ming-Ming , Zhang Zhi-Ren
Published: March 2021

Antiangiogenic tyrosine kinases inhibitors induce hypertension, which may increase the incidents of cardiovascular complications and limit their use. However, the mechanisms by which usage of TKIs results in hypertension have not been fully understood. Here, we report the potential mechanisms of how sunitinib, a widely used TKI, induces hypertension. Male SD rats were randomly divided into control group and sunitinib-administrated group. We show that sunitinib administration for seven days caused a significant increase in artery blood pressure, along with glycerolipid metabolism abnormalities including decreased food intake and low body weight, hypoglycemia, hyperinsulinemia. Sunitinib administration also resulted in a significant increase in the levels of insulin autoantibody (IAA), cyclic adenosine monophosphate and free fatty acid in serum; whereas, sunitinib administration had no effects on serum glucagon levels. Sunitinib led to the decreased insulin sensitivity as determined by insulin tolerance test (ITT) and glucose tolerance test (GTT), reflecting insulin resistance occurred in sunitinib-treated rats. The results obtained from wire myograph assay in the mesenteric arteries show that endothelium-dependent relaxation, but not endothelium-independent relaxation, was impaired by sunitinib. Furthermore, western blot analysis revealed that the expressions levels of phosphorylated IRS-1, Pellino-1, AKT and eNOS were significantly attenuated by sunitinib in rat mesenteric artery tissues and in the sunitinib-treated primary cultured mesenteric artery endothelial cells. The levels of serum and endothelium-derived nitric oxide were also significantly decreased by sunitinib. Moreover, sunitinib-induced decrease in the expression levels of phosphorylated AKT and eNOS was further reduced by knocking down of Pellino-1 in MAECs. Our results suggest that sunitinib causes vascular dysfunction and hypertension, which are associated with insulin resistance- and Pellino-1-mediated inhibition of AKT/eNOS/NO signaling. Our results may provide a rational for preventing and/or treating sunitinib-induced endothelial dysfunction and hypertension.
The Tubulin Inhibitor VERU-111 in Combination With Vemurafenib Provides an Effective Treatment of Vemurafenib-Resistant A375 Melanoma
Authors: Cui Hongmei , Wang Qinghui , Miller Duane D. , Li Wei
Published: March 2021

Melanoma is one of the deadliest skin cancers having a five-year survival rate around 15–20%. An overactivated MAPK/AKT pathway is well-established in BRAF mutant melanoma. Vemurafenib (Vem) was the first FDA-approved BRAF inhibitor and gained great clinical success in treating late-stage melanoma. However, most patients develop acquired resistance to Vem within 6–9 months. Therefore, developing a new treatment strategy to overcome Vem-resistance is highly significant. Our previous study reported that the combination of a tubulin inhibitor ABI-274 with Vem showed a significant synergistic effect to sensitize Vem-resistant melanoma both in vitro and in vivo. In the present study, we unveiled that VERU-111, an orally bioavailable inhibitor of α and β tubulin that is under clinical development, is highly potent against Vem-resistant melanoma cells. The combination of Vem and VERU-111 resulted in a dramatically enhanced inhibitory effect on cancer cells in vitro and Vem-resistant melanoma tumor growth in vivo compared with single-agent treatment. Further molecular signaling analyses demonstrated that in addition to ERK/AKT pathway, Skp2 E3 ligase also plays a critical role in Vem-resistant mechanisms. Knockout of Skp2 diminished oncogene AKT expression and contributed to the synergistic inhibitory effect of Vem and VERU-111. Our results indicate a treatment combination of VERU-111 and Vem holds a great promise to overcome Vem-resistance for melanoma patients harboring BRAF (V600E) mutation.
The Genetics of Response to and Side Effects of Lithium Treatment in Bipolar Disorder: Future Research Perspectives
Authors: Senner Fanny , Kohshour Mojtaba Oraki , Abdalla Safa , Papiol Sergi , Schulze Thomas G.
Published: March 2021

Although the mood stabilizer lithium is a first-line treatment in bipolar disorder, a substantial number of patients do not benefit from it and experience side effects. No clinical tool is available for predicting lithium response or the occurrence of side effects in everyday clinical practice. Multiple genetic research efforts have been performed in this field because lithium response and side effects are considered to be multifactorial endophenotypes. Available results from linkage and segregation, candidate-gene, and genome-wide association studies indicate a role of genetic factors in determining response and side effects. For example, candidate-gene studies often report GSK3β, brain-derived neurotrophic factor, and SLC6A4 as being involved in lithium response, and the latest genome-wide association study found a genome-wide significant association of treatment response with a locus on chromosome 21 coding for two long non-coding RNAs. Although research results are promising, they are limited mainly by a lack of replicability and, despite the collaboration of consortia, insufficient sample sizes. The need for larger sample sizes and “multi-omics” approaches is apparent, and such approaches are crucial for choosing the best treatment options for patients with bipolar disorder. In this article, we delineate the mechanisms of action of lithium and summarize the results of genetic research on lithium response and side effects.
The History of Lentil (Lens culinaris subsp. culinaris) Domestication and Spread as Revealed by Genotyping-by-Sequencing of Wild and Landrace Accessions
Authors: Liber Marta , Duarte Isabel , Maia Ana Teresa , Oliveira Hugo R.
Published: March 2021

Protein-rich legumes accompanied carbohydrate-rich cereals since the beginning of agriculture and yet their domestication history is not as well understood. Lentil (Lens culinarisMedik. subsp.culinaris) was first cultivated in Southwest Asia (SWA) 8000–10,000 years ago but archeological evidence is unclear as to how many times it may have been independently domesticated, in which SWA region(s) this may have happened, and whether wild species within theLensgenus have contributed to the cultivated gene pool. In this study, we combined genotyping-by-sequencing (GBS) of 190 accessions from wild (67) and domesticated (123) lentils from the Old World with archeological information to explore the evolutionary history, domestication, and diffusion of lentils to different environments. GBS led to the discovery of 87,647 single-nucleotide polymorphisms (SNPs), which allowed us to infer the phylogeny of genusLens. We confirmed previous studies proposing four groups within it. The only gene flow detected was between cultivated varieties and their progenitor (L. culinarissubsp.orientalis) albeit at very low levels. Nevertheless, a few putative hybrids or naturalized cultivars were identified. Within cultivated lentil, we found three geographic groups. Phylogenetics, population structure, and archeological data coincide in a scenario of protracted domestication of lentils, with two domesticated gene pools emerging in SWA. Admixed varieties are found throughout their range, suggesting a relaxed selection process. A small number of alleles involved in domestication and adaptation to climatic variables were identified. Both novel mutation and selection on standing variation are presumed to have played a role in adaptation of lentils to different environments. The results presented have implications for understanding the process of plant domestication (past), the distribution of genetic diversity in germplasm collections (present), and targeting genes in breeding programs (future).
NAC Candidate Gene Marker for bgm-1 and Interaction With QTL for Resistance to Bean Golden Yellow Mosaic Virus in Common Bean
Authors: Soler-Garzón Alvaro , Oladzad Atena , Beaver James , Beebe Stephen , Lee Rian , Lobaton Juan David , Macea Eliana , McClean Phillip , Raatz Bodo , Rosas Juan Carlos , Song Qijian , Miklas Phillip N.
Published: March 2021

Genetic resistance is the primary means for control of Bean golden yellow mosaic virus (BGYMV) in common bean (Phaseolus vulgaris L.). Breeding for resistance is difficult because of sporadic and uneven infection across field nurseries. We sought to facilitate breeding for BGYMV resistance by improving marker-assisted selection (MAS) for the recessive bgm-1 gene and identifying and developing MAS for quantitative trait loci (QTL) conditioning resistance. Genetic linkage mapping in two recombinant inbred line populations and genome-wide association study (GWAS) in a large breeding population and two diversity panels revealed a candidate gene for bgm-1 and three QTL BGY4.1, BGY7.1, and BGY8.1 on independent chromosomes. A mutation (5 bp deletion) in a NAC (No Apical Meristem) domain transcriptional regulator superfamily protein gene Phvul.003G027100 on chromosome Pv03 corresponded with the recessive bgm-1 resistance allele. The five bp deletion in exon 2 starting at 20 bp (Pv03: 2,601,582) is expected to cause a stop codon at codon 23 (Pv03: 2,601,625), disrupting further translation of the gene. A Tm-shift assay marker named PvNAC1 was developed to track bgm-1. PvNAC1 corresponded with bgm-1 across ∼1,000 lines which trace bgm-1 back to a single landrace “Garrapato” from Mexico. BGY8.1 has no effect on its own but exhibited a major effect when combined with bgm-1. BGY4.1 and BGY7.1 acted additively, and they enhanced the level of resistance when combined with bgm-1. Tm-shift assay markers were generated for MAS of the QTL, but their effectiveness requires further validation.
Dinitroaniline Herbicide Resistance and Mechanisms in Weeds
Authors: Chen Jinyi , Yu Qin , Patterson Eric , Sayer Chad , Powles Stephen
Published: March 2021

Dinitroanilines are microtubule inhibitors, targeting tubulin proteins in plants and protists. Dinitroaniline herbicides, such as trifluralin, pendimethalin and oryzalin, have been used as pre-emergence herbicides for weed control for decades. With widespread resistance to post-emergence herbicides in weeds, the use of pre-emergence herbicides such as dinitroanilines has increased, in part, due to relatively slow evolution of resistance in weeds to these herbicides. Target-site resistance (TSR) to dinitroaniline herbicides due to point mutations in α-tubulin genes has been confirmed in a few weedy plant species (e.g.,Eleusine indica,Setaria viridis, and recently inLolium rigidum). Of particular interest is the resistance mutation Arg-243-Met identified from dinitroaniline-resistantL. rigidumthat causes helical growth when plants are homozygous for the mutation. The recessive nature of the TSR, plus possible fitness cost for some resistance mutations, likely slows resistance evolution. Furthermore, non-target-site resistance (NTSR) to dinitroanilines has been rarely reported and only confirmed inLolium rigidumdue to enhanced herbicide metabolism (metabolic resistance). A cytochrome P450 gene (CYP81A10) has been recently identified inL. rigidumthat confers resistance to trifluralin. Moreover, TSR and NTSR have been shown to co-exist in the same weedy species, population, and plant. The implication of knowledge and information on TSR and NTSR in management of dinitroaniline resistance is discussed.
Intellectual Capital and Financial Performance: Comparison With Financial and Pharmaceutical Industries in Vietnam
Authors: Zhang Xiao-Bing , Duc Tran Phuong , Burgos Mutuc Eugene , Tsai Fu-Sheng
Published: March 2021

This study investigates the impacts of intellectual capital through Value-Added Intellectual Capital (VAIC) and its components: human capital efficiency (HCE) and structural capital efficiency (SCE) on financial performance in terms of return on assets (ROA) and return on equity (ROE). In addition, this study compares the effects between firms from financial and pharmaceutical industries. A total of 149 Vietnamese firms comprising of 108 financial firms and 41 pharmaceutical firms were examined. Based on the findings, VAIC and HCE show beneficial impacts on both financial performance measures, ROA, and ROE. However, SCE shows adverse and beneficial implications on ROA and ROE, respectively. In terms of industry comparison, VAIC has positive effects on ROA and ROE among the firms from financial industry, whereas it has no effect in the firms from pharmaceutical industry. The effect of HCE on ROA is stronger in the firms from financial industry than firms from pharmaceutical industry while the effect of HCE on ROE is stronger in the firms from pharmaceutical industry than firms from financial industry. The effect of SCE on ROA is stronger in the pharmaceutical firms than financial firms while the effect of SCE on ROE is stronger in the financial firms than pharmaceutical firms. Lastly, the implications of the importance of knowledge-based resources on value creation were elaborated.
Can the Brain Build Probability Distributions?
Authors: Lindskog Marcus , Nyström Pär , Gredebäck Gustaf
Published: March 2021

How humans efficiently operate in a world with massive amounts of data that need to be processed, stored, and recalled has long been an unsettled question. Our physical and social environment needs to be represented in a structured way, which could be achieved by reducing input to latent variables in the form of probability distributions, as proposed by influential, probabilistic accounts of cognition and perception. However, few studies have investigated the neural processes underlying the brain’s potential ability to represent a probability distribution’s complex, global features. Here, we presented participants with a sequence of tones that formed a normal or a bimodal distribution. Using a novel, single-trial EEG analysis, we demonstrate a neural response that indexes the likelihood of an item, given previously presented items, and corresponds to the experienced tones’ distribution. Our results indicate that the adult human brain can build a representation of the complex, global pattern of a probability distribution and offer a novel tool for an in-depth understanding of related neural mechanics.
Locus of Control and Negative Cognitive Styles in Adolescence as Risk Factors for Depression Onset in Young Adulthood: Findings From a Prospective Birth Cohort Study
Authors: Costantini Ilaria , Kwong Alex S. F. , Smith Daniel , Lewcock Melanie , Lawlor Deborah A. , Moran Paul , Tilling Kate , Golding Jean , Pearson Rebecca M.
Published: March 2021

Whilst previous observational studies have linked negative thought processes such as an external locus of control and holding negative cognitive styles with depression, the directionality of these associations and the potential role that these factors play in the transition to adulthood and parenthood has not yet been investigated. This study examined the association between locus of control and negative cognitive styles in adolescence and probable depression in young adulthood and whether parenthood moderated these associations. Using a UK prospective population-based birth cohort study: the Avon Longitudinal Study of Parents and Children (ALSPAC), we examined the association between external locus of control and negative cognitive styles in adolescence with odds of depression in 4,301 young adults using logistic regression models unadjusted and adjusted for potential confounding factors. Interaction terms were employed to examine whether parenthood (i.e., having become a parent or not) moderated these associations. Over 20% of young adults in our sample were at or above the clinical threshold indicating probable depression. For each standard deviation (SD) increase in external locus of control in adolescence, there was a 19% (95% CI: 8–32%) higher odds of having probable depression in young adulthood, after adjusting for various confounding factors including baseline mood and different demographic and life events variables. Similarly, for each SD increase in negative cognitive styles in adolescence, there was a 29% (95% CI: 16–44%) higher odds of having probable depression in the adjusted model. We found little evidence that parenthood status moderated the relationship between external locus of control or negative cognitive styles in adolescence and probable depression following adjustment for confounding factors. Effect estimates were comparable when performed in the complete case dataset. These findings suggest that having an external locus of control and holding negative cognitive styles in mid- to late adolescence is associated with an increased likelihood of probable depression in young adulthood.
Factors Associated With Mental Suffering in the Brazilian Population: A Multilevel Analysis
Authors: Bezerra Héllyda de Souza , Alves Roberta Machado , Souza Talita Araujo de , Medeiros Arthur de Almeida , Barbosa Isabelle Ribeiro
Published: March 2021

Purpose: To analyze how individual characteristics and the social context are associated with mental distress symptoms in the Brazilian population.

Method: A multilevel cross-sectional study with data from the 2013 National Health Survey. There were two dependent variables: (a) decreased vital energy and somatic symptoms, (b) the presence of depressive thoughts. The independent variables were biological characteristics, education and income, habits and lifestyle, and context variables. Bivariate analysis was performed, and Prevalence Ratios calculated in a Poisson Regression (95% CI). A multilevel Poisson Regression was performed to verify the effect of individual and contextual variables.

Results: Regarding depressive thoughts, young and middle-aged individuals, low education, women, absence of partner, smokers or former smokers, and absence of health insurance were the categories at highest risk; belonging to classes D-E and living in states with lower expected years of schooling proved to be protective factors. Similar results were found for the second outcome.

Conclusions: Symptoms of mental distress were associated with the individual characteristics and contextual aspects of the federation unit. These findings indicate the importance of strengthening psychosocial care aimed at vulnerable groups.
More Hype Than Substance? A Meta-Analysis on Job and Task Rotation
Authors: Mlekus Lisa , Maier Günter W.
Published: March 2021

Although there exist numerous publications on job and task rotation from various disciplines, there is no consistent evidence of their effectiveness. Drawing on theories from industrial and organizational psychology, knowledge management, ergonomics, and management science, we meta-analytically investigated relationships between job/task rotation and employee attitudes, learning and development, psychological and physical health, and organizational performance. Due to a conceptual overlap and frequent confusion of terminology, we analyzed the design of the rotation (job rotation vs. task rotation) as a possible moderator. The three-level meta-analysis on 56 studies (N= 284,086) showed that rotation was significantly associated with job satisfaction (r= 0.27), organizational commitment (r= 0.16), career success (r= 0.31), labor flexibility (r= 0.32), general psychological health (r= 0.20), stress/burnout (r= −0.13), individual performance (r= 0.13), and productivity (r= 0.13). Positive relationships between rotation and physical health could only be found when rotation was compared to high-intensity work. Task rotation yielded stronger relationships with attitudinal outcomes, job rotation with learning and development, psychological health, and organizational performance outcomes. Further moderator analyses showed that individualism decreased relationships between task rotation and attitudes, and correlations with organizational performance and physical health were stronger for subjective measures. The findings indicate that many expectations toward job and task rotation are not fully supported.
Social Sharing of Emotions and Communal Appraisal as Mediators Between the Intensity of Trauma and Social Well-Being in People Affected by the 27F, 2010 Earthquake in the Biobío Region, Chile
Authors: Reyes-Valenzuela Carlos , Villagrán Loreto , Alzugaray Carolina , Cova Félix , Méndez Jaime
Published: March 2021

The psychosocial impacts of natural disasters are associated with the triggering of negative and positive responses in the affected population; also, such effects are expressed in an individual and collective sphere. This can be seen in several reactions and behaviors that can vary from the development of individual disorders to impacts on interpersonal relationships, cohesion, communication, and participation of the affected communities, among others. The present work addressed the psychosocial impacts of the consequences of natural disasters considering individual effects via the impact of trauma and community effects, through the perception of social well-being, the valuation of the community and the social exchange of emotions. The aim of this study was to assess the relationship between individual reactions (i.e., intensity of trauma) and the evaluation of social and collective circumstances (i.e., social well-being) after the earthquake of 27F 2010 in Chile, through collective-type intervention variables not used in previous studies (i.e., social sharing of emotions and community appraisal). For this purpose, a descriptive,ex postfacto correlational and cross-sectional methodology was carried on, with the participation of 487 people affected by the 2010 earthquake, 331 women (68%) and 156 men (32%), between 18 and 58 years old (M= 21.09;SD= 5.45), from the provinces of Ñuble and Biobío, VIII region, Chile. The measurement was carried out 4 years after the earthquake and the results show that greater individual than collective involvements were found, mainly in the coastal zone of the region. The mediation analysis showed that the relationship between the intensity of the trauma and social well-being occurs through a route that considers social sharing of emotions and community appraisal. These results indicate that the overcoming of individual affectations to achieve social well-being occurs when in the immediate post-disaster phases the affected communities activate shared emotional and cognitive processes, which allow them to jointly face subsequent threats and abrupt changes.