bluuebunny/crossref_metadata_2025 huggingface dataset:
CRISPR/Cas9‐based genome engineering: A new breakthrough in the genetic manipulation of filamentous fungi
Authors: Ullah Mati , Xia Lin , Xie Shangxian , Sun Su
Published: November 2020

Filamentous fungi have several industrial, environmental, and medical applications. However, they are rarely utilized owing to the limited availability of full‐genome sequences and genetic manipulation tools. Since the recent discovery of the full‐genome sequences for certain industrially important filamentous fungi, CRISPR/Cas9 technology has drawn attention for the efficient development of engineered strains of filamentous fungi. CRISPR/Cas9 genome editing has been successfully applied to diverse filamentous fungi. In this review, we briefly discuss the use of common genetic transformation techniques as well as CRISPR/Cas9‐based systems in filamentous fungi. Furthermore, we describe potential limitations and challenges in the practical application of genome engineering of filamentous fungi. Finally, we provide suggestions and highlight future research prospects in the area.
Resistance to cognitive biases: Longitudinal trajectories and associations with cognitive abilities and academic achievement across development
Authors: Toplak Maggie E. , Flora David B.
Published: November 2020

Cognitive failures on several reasoning and judgment tasks can be explained by miserly information processing tendencies. These tasks have been examined in child and youth samples, and we extend this work by examining the developmental trajectory of performance on these cognitive bias tasks and their association with other markers of cognitive sophistication. A longitudinal design was used to examine the development of resistance to cognitive biases in a sample of 204 typically developing children and youth. These youth were 8–14 years of age at first assessment and were assessed at three measurement occasions separated by 3 years. Resistance to cognitive biases as represented by performance on five reasoning and judgment tasks, including ratio bias, belief‐bias syllogisms, attribute framing problems, base‐rate sensitivity, and temporal discounting. The developmental trajectory of resistance to cognitive biases was examined. We also estimated associations between trajectories of resistance to cognitive biases and measures of cognitive abilities, actively open‐minded thinking, and superstitious thinking to examine how individual differences in other measures of cognitive sophistication were associated with the development of resistance to cognitive biases. Cognitive ability measures included intelligence (verbal and nonverbal) and executive function tasks (interference control and set‐shifting). Growth modeling results showed that resistance to cognitive biases increased linearly from 8 to 15 years of age, followed by a flat mean trajectory up to age 20. Cognitive ability, actively open‐minded thinking, and superstitious thinking predicted individual differences in resistance to cognitive biases, but not changes in resistance to cognitive biases. Performance on resistance to cognitive biases tasks was positively correlated with self‐ and parent‐reported academic achievement.
Flow injection–chemiluminescence determination of cetirizine dihydrochloride in pharmaceuticals using tris(2,2′‐bipyridyl)ruthenium (II)–Ag(III) complex reaction
Authors: Moazzam Muhammad , Asghar Muhammad , Yaqoob Mohammed , Ali Samar , Nabi Abdul
Published: November 2020

A simple and sensitive flow injection–chemiluminescence (FI–CL) method was developed for determination of cetirizine dihydrochloride (CTZH) in pharmaceuticals. The method is primarily based on the enhancement effect of CTZH on the tris(2,2′‐bipyridyl)ruthenium (II)–diperiodatoargentate (III) ([Ru(bpy)3]2+–Ag(III) complex) CL system in an acidic medium. The optimum investigated variables of the CL reaction were: [Ru(bpy)3]2+, 50 × 10−6 mol/L; sulfuric acid, 1.0 × 10−3 mol/L; Ag(III) complex, 100 × 10−6 mol/L; potassium hydroxide, 1.0 × 10−3 mol/L; flow rate, 3.0 ml/min and sample loop volume, 300 μl. The detection and quantification limits were 2.0 × 10−4 and 5.0 × 10−4 mg/L (S/N of 3 and 10) respectively with a linear calibration range of 5.0 × 10−4 to 7.5 mg/L (R2 = 0.9999, n = 11), injection throughput of 110/h and the relative standard deviations of 1.5–3.5% over the range studied. The methodology was successfully applied to determine CTZH in different pharmaceutical samples and validated with a high‐performance liquid chromatography method, and resulted in the recovery of 94.6–108.6%. The probable CL reaction mechanism is described in brief.
Plasma D‐dimer predicts poor outcome and mortality after spontaneous intracerebral hemorrhage
Authors: Zhou Qi , Zhang Daming , Chen Xin , Yang Zhao , Liu Zhihui , Wei Baixing , Jin Mei , Feng Kairu , Guo Chunmei , Sun Junying , Chen Sheng , Zhang Ruijia , Piao Xiai , Gareev Ilgiz , Sun Zhenying , Wang Xiaoxiong , Li Lili , Zhao Shiguang , Yang Guang
Published: November 2020

Background

The elevation of plasma D‐dimer levels may predict a higher risk of thrombosis and play a role in the pathological process of patients after spontaneous intracerebral hemorrhage (ICH). However, its function in predicting the prognosis of ICH has not been verified on large cases.

Patients and Methods

Retrospective cohort study of 1,332 consecutive patients with spontaneous ICH at an academic medical center was conducted. Functional outcome at three months after ICH was dichotomized using the modified Rankin Scale (0–2 versus 3–6). D‐dimer level in blood was analyzed within 1 hr of admission. An ICH outcome score combining D‐dimer level for evaluating poor functional outcome and mortality was tested.

Results

The proportion of patients with poor functional outcome and mortality at three months was significantly higher in patients with elevated D‐dimer level (p < .001). Multivariable analysis demonstrated that elevated D‐dimer level was an independent predictor of poor functional outcome (odds ratio 1.486, 95% confidence interval 1.086–2.060, p = .014) and mortality (odds ratio 2.015, 95% confidence interval 1.186–3.423, p = .01). An increasing ICH outcome score combining D‐dimer level was associated with increased poor functional outcome and mortality.

Conclusions

Elevated plasma D‐dimer level after spontaneous ICH is associated with poor functional outcome and mortality. The study suggests that elevated D‐dimer level has a predictive value for outcome and mortality in patients with spontaneous ICH.
Inhibition of the activin receptor signaling pathway: A novel intervention against osteosarcoma
Authors: Meier Daniela , Lodberg Andreas , Gvozdenovic Ana , Pellegrini Giovanni , Neklyudova Olga , Born Walter , Fuchs Bruno , Eijken Marco , M. Botter Sander
Published: November 2020

Osteosarcoma is a cancer of pathological bone remodeling with high mortality and severe comorbidity. New therapies are urgently needed. Activin A, a member of the transforming growth factor β (TGFβ) superfamily, has been suggested to stimulate proliferation and invasion of osteosarcoma cells in vitro, thus representing a potential therapeutic target. In this study, inhibition of the activin receptor signaling pathway was explored as a therapy for osteosarcoma. In a murine intratibial osteosarcoma xenograft model, two types of inhibitors were tested: (a) a soluble activin type IIA decoy receptor (ActRIIA‐mFc), or (b) a modified variant of follistatin (FSTΔHBS‐hFc), either alone or in combination with a bisphosphonate. Both inhibitors reduced primary tumor development by nearly 50% compared to vehicle treatment. When ActRIIA‐mFc was combined with bisphosphonate, the effect on tumor size became even more pronounced (78% reduction vs. vehicle). Moreover, FSTΔHBS‐hFc increased body weight in the face of tumor progression (14% increase vs. vehicle), and ActRIIA‐mFc reduced the number of lung metastases when combined with bisphosphonate. The present study demonstrates a novel approach to treating osteosarcoma and encourages further investigation of inhibition of the activin receptor signaling pathway as an intervention against the disease.
The state of renal sympathetic denervation for the management of patients with hypertension: A systematic review and meta‐analysis
Authors: Syed Moinuddin , Osman Mohammed , Alhamoud Hani , Saleem Maryam , Munir Muhamad Bilal , Kheiri Babikir , Balla Sudarshan , Kawsara Akram , Daggubati Ramesh
Published: November 2020

Background

Sympathetic nervous system plays a central role in the development and persistence of essential hypertension. In recent years renal sympathetic denervation (RSD) has emerged as a promising option for the treatment of patients with hypertension.

Methods

We conducted a literature search of PubMed, EMBASE, Cochrane library and Clinicaltrials.gov from inception through April 20, 2020. Outcomes of interest were change in 24‐hour ambulatory systolic (ASBP) or diastolic blood pressure (ADBP) and change in office systolic (OSBP) or diastolic blood pressure (ODBP). We pooled data from randomized controlled trials (RCTS) comparing RSD to sham procedures in the management of hypertension using the random effect model.

Results

A total of 1,363 patients from eight studies were included in the current meta‐analysis. The mean age of the included patients was 56 ± 2.6 years, 29% were women and the median duration of maximum follow up was 6‐month (range 3–12 month). There was more reduction favoring RSD in ASBP (Weighted mean difference [WMD] ‐3.55; 95% CI ‐4.91 – −2.19, p < .001, I2 = 0%), ADBP (WMD ‐1.87; 95% CI ‐3.07 – −0.66, p = .002, I2 = 43%), OSBP (WMD ‐5.5; 95% CI ‐7.59 – −3.40, p < .001, I2 = 7%) and ODBP (WMD ‐3.20; 95% CI ‐4.47 – −1.94, p < .001, I2 = 14%).

Conclusion

The use of RSD for the management of hypertension resulted in effective reduction in the ambulatory and office blood pressure compared to sham procedure. Adequately powered RCTs of RSD are needed to confirm safety, reproducibility and assess the impact on clinical outcomes.
Reconstruction of intraoral oncologic surgical defects with Integra® bilayer wound matrix
Authors: Srivastava Akanksha , Maniakas Anastasios , Myers Jeffrey , Chambers Mark S. , Cardoso Richard
Published: November 2020

Utilization of biologic skin substitutes for the management of soft tissue defects as an alternative to autologous skin grafts has expanded over the past 2 decades. The purpose of this case series study was to report our experience with Integra® bilayer wound matrix for reconstruction of intraoral oncologic defects. Case records of 6 patients with intraoral oncologic defects reconstructed with Integra® bilayer wound matrix were retrospectively reviewed. The surgical defect location, size, and time to removal of surgical splint varied. Clinically, normal oral epithelialization was noted for all patients. One patient demonstrated a small area of dehiscence and bone exposure after adjuvant radiation therapy which resolved with minimal intervention. Integra bilayer wound matrix is a viable and versatile option for reconstruction of intraoral oncologic surgical defects. Further exploration of wound healing with Integra® matrix, surgical techniques, and cost‐effectiveness is advocated.
Influence of Power‐to‐Fuel Plant Flexibility Towards Power and Plant Utilization and Intermediate Hydrogen Buffer Size
Authors: Pfeifer Peter , Biffar Linus , Timm Friedemann , Böltken Tim
Published: November 2020

Conversion of intermittent renewable energy into synthetic fuels and chemicals is required to secure long‐distance transport and feedstock for chemical industry. Due to the fluctuating energy generation, process intensification and feed flexibility are essential. This contribution investigates the importance of feed flexibility on the buffer size with applying a 20:80 scenario of wind/solar energy generation. The degree of power and plant utilization are calculated. With the capability to accept a lower load bound of 17 % after only 10 min, a minimum tank capacity of only 1.3 h is calculated to avoid a fuel plant stop throughout a calendar year. Additional tank capacity for peak power compensation in the range of ∼10 h is beneficial for the utilization degree of power and under the prerequisite of a load‐flexible fuel plant.
Clinical impact of complete atrioventricular block in patients with ST‐segment elevation myocardial infarction
Authors: Kawamura Yosuke , Yokoyama Hiroaki , Kitayama Kazutaka , Miura Naotake , Hamadate Misato , Nagawa Daiki , Nozaka Masashi , Nakata Masamichi , Nishizaki Fumie , Hanada Kenji , Yokota Takashi , Yamada Masahiro , Higuma Takumi , Tomita Hirofumi
Published: November 2020

Complete atrioventricular block (CAVB) is a common complication of ST‐segment elevation myocardial infarction (STEMI). Although STEMI patients complicated with CAVB had a higher mortality in the thrombolytic era, little is known about the impact of CAVB on STEMI patients who underwent primary percutaneous coronary intervention (PCI). The study aimed at evaluating the clinical impact of CAVB on STEMI patients in the primary PCI era. We consecutively enrolled 1295 STEMI patients undergoing primary PCI within 24 hours from onset. Patients were divided into two groups according to the infarct location: anterior STEMI (n = 640) and nonanterior STEMI (n = 655). The outcomes were all‐cause death and major adverse cardiocerebrovascular events (MACCE) with a median follow‐up period of 3.8 (1.7–6.6) years. Eighty‐one patients (6.3%) developed CAVB. The incidence of CAVB was lower in anterior STEMI patients than in nonanterior STEMI (1.7% vs 10.7%, p < .05). Anterior STEMI patients with CAVB had a higher incidence of all‐cause deaths (82% vs 20%, p < .05) and MACCE (82% vs 25%, p < .05) than those without CAVB. Although higher incidence of all‐cause deaths was found more in nonanterior STEMI patients with CAVB compared with those without CAVB (30% vs 18%, p < .05), there was no significant difference in the incidence of MACCE (24% vs 19%). Multivariate analysis showed that CAVB was an independent predictor for all‐cause mortality and MACCE in anterior STEMI patients, but not in nonanterior STEMI. CAVB is rare in anterior STEMI patients, but remains a poor prognostic complication even in the primary PCI era.
Benchmark Data Sets of Boron Cluster Dihydrogen Bonding for the Validation of Approximate Computational Methods
Authors: Fanfrlík Jindřich , Pecina Adam , Řezáč Jan , Lepšík Martin , Sárosi Menyhárt B. , Hnyk Drahomír , Hobza Pavel
Published: November 2020

The success of approximate computational methods, such as molecular mechanics, or dispersion‐corrected density functional theory, in the description of non‐covalent interactions relies on accurate parameterizations. Benchmark data sets are thus required. This area is well developed for organic molecules and biomolecules but practically non‐existent for boron clusters, which have been gaining in importance in modern drug as well as material design. To fill this gap, we have introduced two data sets featuring the most common non‐covalent interaction of boron clusters, the dihydrogen bond, and calculated reference interaction energies at the “golden standard” CCSD(T)/CBS level. The boron clusters studied interact with formamide, methanol, water and methane at various distances and in two geometrical arrangements. The performance of the tested approximate methods is variable and recommendations for further use are given.
Trauma and healing in the underserved populations of homelessness and corrections: Forgiveness Therapy as an added component to intervention
Authors: Song Mary Jacqueline , Yu Lifan , Enright Robert D.
Published: November 2020

The purpose of this article is to begin applying the principles of the psychology of forgiveness to people who are without homes and people who are in prisons. A review of the literature shows trauma for both groups. When the trauma is caused by unjust treatment by others, then excessive anger can result, compromising one's psychological and physical health. We review the interventions that have been offered for those without homes and the imprisoned to examine which existing programmes address such anger. Forgiveness Therapy, although untried in these two settings, may be one beneficial approach for substantially reducing unhealthy anger. Forgiveness interventions have shown a cause‐and‐effect relationship between learning to forgive and overcoming psychological compromise such as strong resentment and clinical levels of anxiety and depression. The literature review here suggests that forgiveness therapy for those without homes and the imprisoned may be a new and important consideration for ameliorating anger and aiding in a changed life pattern.
Clinical Characteristics and Outcome of Drug‐Induced Liver Injury in the Older Patients: From the Young‐Old to the Oldest‐Old
Authors: Weersink Rianne A. , Alvarez‐Alvarez Ismael , Medina‐Cáliz Inmaculada , Sanabria‐Cabrera Judith , Robles‐Díaz Mercedes , Ortega‐Alonso Aida , García‐Cortés Miren , Bonilla Elvira , Niu Hao , Soriano German , Jimenez‐Perez Miguel , Hallal Hacibe , Blanco Sonia , Kaplowitz Neil , Lucena M. Isabel , Andrade Raúl J.
Published: November 2020

Older patients with hepatotoxicity have been scarcely studied in idiosyncratic drug‐induced liver injury (DILI) cohorts. We sought the distinctive characteristics of DILI in older patients across age groups. A total of 882 DILI patients included in the Spanish DILI Registry (33% ≥ 65 years) were categorized according to age: “young” (< 65 years); “young‐old” (65–74 years); “middle‐old” (75–84 years); and “oldest‐old” (≥ 85 years). All elderly groups had an increasingly higher comorbidity burden (P < 0.001) and polypharmacy (P < 0.001). There was a relationship between jaundice and hospitalization (P < 0.001), and both were more prevalent in the older age groups, especially in the oldest‐old (88% and 69%, respectively), and the DILI episode was more severe (P = 0.029). The proportion of females decreased across age groups from the young to the middle‐old, yet in the oldest‐old there was a distinct female predominance. Pattern of liver injury shifted towards cholestatic with increasing age among top culprit drugs amoxicillin‐clavulanate, atorvastatin, levofloxacin, ibuprofen, and ticlopidine. The best cutoff point for increased odds of cholestatic DILI was 65 years. Older patients had increased non–liver‐related mortality (P = 0.030) as shown by the predictive capacity of the Model for End‐Stage Liver Disease score (odds ratio (OR) = 1.116; P < 0.001), and comorbidity burden (OR = 4.188; P = 0.001) in the 6‐month mortality. Older patients with DILI exhibited an increasingly predominant cholestatic phenotype across a range of culprit drugs, other than amoxicillin‐clavulanate, with increased non–liver‐related mortality and require a different approach to predict outcome. The oldest DILI patients exhibited a particular phenotype with more severe DILI episodes and need to be considered when stratifying older DILI populations.
Potential regional declines in species richness of tomato pollinators in North America under climate change
Authors: Carrasco Luis , Papeş Monica , Lochner Ellie N. , Ruiz Brandyn C. , Williams Abigail G. , Wiggins Gregory J.
Published: November 2020

About 70% of the world's main crops depend on insect pollination. Climate change is already affecting the abundance and distribution of insects, which could cause geographical mismatches between crops and their pollinators. Crops that rely primarily on wild pollinators (e.g., crops that cannot be effectively pollinated by commercial colonies of honey bees) could be particularly in jeopardy. However, limited information on plant–pollinator associations and pollinator distributions complicate the assessment of climate change impacts on specific crops. To study the potential impacts of climate change on pollination of a specific crop in North America, we use the case of open‐field tomato crops, which rely on buzz pollinators (species that use vibration to release pollen, such as bumble bees) to increase their production. We aimed to (1) assess potential changes in buzz pollinator distribution and richness, and (2) evaluate the overlap between areas with high densities of tomato crops and high potential decrease in richness. We used baseline (1961–1990) climate and future (2050s and 2080s) climatic projections in ecological niche models fitted with occurrences of wild bees, documented in the literature as pollinators of tomatoes, to estimate the baseline and future potential distribution of suitable climatic conditions of targeted species and to create maps of richness change across North America. We obtained reliable models for 15 species and found important potential decreases in the distribution of some pollinators (e.g., Lasioglossum pectorale and Augochlorella aurata). We observed geographical discrepancies in the projected change in species richness across North America, detecting important declines in the eastern United States (up to 11 species decrease for 2050s). After overlapping the maps of species richness change with a tomato crop map for the United States, we found spatial correspondence between richness declines and areas with high concentration of tomato crops. Disparities in the effects of climate change on the potential future distribution of different wild pollinators and geographical variation in richness highlight the importance of crop‐specific studies. Our study also emphasizes the challenges of compiling and modeling crop‐specific pollinator data and the need to improve our understanding of current distribution of pollinators and their community dynamics under climate change.
A virtual issue highlighting eating disorders in people of black/African and Indigenous heritage
Authors: Mikhail Megan E. , Klump Kelly L.
Published: November 2020

While eating disorders affect people from all racial/ethnic backgrounds, research has traditionally focused on eating disorders in white populations. In this virtual issue, we present a collection of 14 articles previously published in the International Journal of Eating Disorders highlighting eating disorders in people of black/African and Indigenous heritage. Featured articles examine the prevalence and presentation of disordered eating in black and Indigenous populations; access to care and treatment experiences for black and Indigenous people; and environmental stressors, such as acculturative stress and discrimination, that may contribute to disordered eating in these populations. Future directions for inclusive research with people of black/African and Indigenous heritage are discussed, including reporting participant demographics, examining differences in risk factors and treatment outcomes across race/ethnicity, and partnering with black and Indigenous communities to produce culturally sensitive research attuned to the needs and priorities of these populations.
Species interactions across trophic levels mediate rainfall effects on dryland vegetation dynamics
Authors: Farías Ariel A. , Armas Cristina , Gaxiola Aurora , Cea Alex P. , Luis Cortés Jose , López Ramiro P. , Casanoves Fernando , Holmgren Milena , Meserve Peter L. , Gutiérrez Julio R. , Kelt Douglas A.
Published: November 2020

Arid ecosystems are strongly limited by water availability, and precipitation plays a major role in the dynamics of all species in arid regions, as well as the ecosystem processes that occur there. However, understanding how biotic interactions mediate long‐term responses of dryland ecosystems to rainfall remains very fragmented. We report on a unique large‐scale field experiment spanning 25 yr and three trophic levels (plants, small mammal herbivores, predators) in a dryland ecosystem in the northern Chilean Mediterranean Region where we assessed how biotic interactions influence the long‐term plant community responses to precipitation. As the most persistent ecological changes in dryland systems may result from changes in the structure, cover, and composition of the perennial vegetation, we emphasized the interplay between bottom‐up and top‐down controls of perennial plants in our analyses. Rainfall was the primary factor affecting the dynamics of, and interactions among, plants and small mammals. Ephemeral plant cover dynamics closely tracked short‐term annual rainfall, but seemed unaffected by top‐down controls (herbivory). In contrast, the response of the perennial plant cover to precipitation was mediated by (1) a complex interplay between subtle top‐down (herbivory) controls that become more apparent in the long‐term, (2) competition with ephemeral plants during wet years, and (3) an indirect effect of predators on subdominant shrubs and perennial herbs. This long‐term field experiment highlights how climate‐induced responses of arid perennial vegetation are influenced by interactions across trophic levels and temporal scales. In the face of global change, understanding how multi‐trophic controls mediate dryland vegetation responses to climate is essential to properly managing the conservation of biodiversity in arid systems.
Structural and compositional heterogeneity influences the thermal environment across multiple scales
Authors: Londe David W. , Dwayne Elmore R. , Davis Craig A. , Fuhlendorf Samuel D. , Luttbeg Barney , Hovick Torre J.
Published: November 2020

Heterogeneity has a critical influence on biodiversity and ecosystem processes. While the influence of heterogeneity on species diversity and abundance is well documented, how heterogeneity influences the distribution and arrangement of necessary resources across a landscape is still unclear. Heterogeneity in vegetation structure and composition is often cited as an important factor in the near‐ground thermal environment; however, because of a paucity of comparative studies across landscapes that differ in their degree of vegetation heterogeneity, researchers lack knowledge of the underlying mechanisms that influence variation in the thermal environment. Particularly, we do not have a clear understanding of the relative contribution of structural and compositional vegetation heterogeneity to thermal patterns. Therefore, we assessed the thermal environment in nine grassland landscapes that differed in their degree of structural and compositional heterogeneity. At the landscape level, we used a variance partitioning approach with linear mixed models to measure the link between four metrics of vegetation heterogeneity and temperature variability. At the microsite level, we used piecewise structural equation models to assess the fine‐scale drivers of temperature in these landscapes and develop a causal model describing the relationship between vegetation variables and temperature. We found that temperature variance at the landscape scale was strongly related to the diversity of plant functional groups, heterogeneity in plant species composition, and variation in vegetation height. At finer scales, species richness, vegetation height, and overhead obstruction were the best predictors of temperature once weather was accounted for. Vegetation composition variables indirectly influenced fine‐scale temperature variation through their effects on vegetation structure. These results suggest that scale has a strong influence on the observed relationship between temperature variance and different metrics of vegetation heterogeneity. Our results provide support for the role of landscape heterogeneity in shaping the thermal landscape and offer insights into the possible impacts of habitat homogenization on the thermal environment.
4‐1BB costimulation promotes bystander activation of human CD8 T cells
Authors: Reithofer Manuel , Rosskopf Sandra , Leitner Judith , Battin Claire , Bohle Barbara , Steinberger Peter , Jahn‐Schmid Beatrice
Published: November 2020

Costimulatory signals potently promote T‐cell proliferation and effector function. Agonistic antibodies targeting costimulatory receptors of the TNFR family, such as 4‐1BB and CD27, have entered clinical trials in cancer patients. Currently there is limited information how costimulatory signals regulate antigen‐specific but also bystander activation of human CD8 T cells.

Engineered antigen presenting cells (eAPC) efficiently presenting several common viral epitopes on HLA‐A2 in combination with MHC class I tetramer staining were used to investigate the impact of costimulatory signals on human CD8 T‐cell responses. CD28 costimulation potently augmented the percentage and number of antigen‐reactive CD8 T cells, whereas eAPC expressing 4‐1BB‐ligand induced bystander proliferation of CD8 T cells and massive expansion of NK cells. Moreover, the 4‐1BB agonist urelumab similarly induced bystander proliferation of CD8 T cells and NK cells in a dose‐dependent manner. However, the promotion of bystander CD8 T‐cell responses is not a general attribute of costimulatory TNF receptor superfamily (TNFRSF) members, since CD27 signals enhanced antigen‐specific CD8 T cells responses without promoting significant bystander activation.

Thus, the differential effects of costimulatory signals on the activation of human bystander CD8 T cells should be taken into account when costimulatory pathways are harnessed for cancer immunotherapy.
Use of Postregistration Monitoring Data to Evaluate the Ecotoxicological Risks of Pesticides to Surface Waters: A Case Study with Chlorpyrifos in the Iberian Peninsula
Authors: Rico Andreu , Dafouz Raquel , Vighi Marco , Rodríguez-Gil José Luis , Daam Michiel A.
Published: November 2020

Chemical monitoring data sets such as those provided by the implementation of the Water Framework Directive (WFD) offer opportunities to evaluate the ecological risks of pesticides under large spatiotemporal scales and to evaluate the protectiveness of the current prospective risk-assessment framework. As a case study, we used the monitoring data set for the insecticide chlorpyrifos to perform a probabilistic risk assessment for Iberian surface-water ecosystems. The specific objectives of the study were 1) to assess the occurrence of chlorpyrifos in relation to different agricultural production land uses, 2) to assess the spatiotemporal variation in the exceedance of the European WFD short- and long-term environmental quality standards (maximum allowable concentration environmental quality standard [MAC-EQS] and annual average [AA] EQS), and 3) to perform a probabilistic risk assessment for freshwater invertebrates. A database that contains chlorpyrifos concentrations from 14 600 surface water samples taken between 2012 and 2017 in the Iberian Peninsula (Spain and Portugal) was analyzed, and chlorpyrifos was detected in 21% of these samples. The MAC-EQS was exceeded in 2% of the cases, whereas the AA-EQS was exceeded in 18% of the cases. The majority of the exceedances took place in the littoral areas of the eastern and southeastern parts of the Iberian Peninsula, particularly in areas with dominant citrus production during late spring, late summer, and autumn. The present study indicates unacceptable risks posed by chlorpyrifos to Iberian surface waters over the study period, although it was approved for use in Europe. The present study supports the need to perform further postregistration monitoring assessments with other pesticides following similar approaches, which can help to identify possible pesticide-misuse practices and improvements of the prospective risk-assessment framework. Environ Toxicol Chem 2021;40:500–512. © 2020 SETAC
Occurrence and Fate of Bisphenol A and its Congeners in Two Wastewater Treatment Plants and Receiving Surface Waters in Romania
Authors: Chiriac Florentina L. , Paun Iuliana , Pirvu Florinela , Pascu Luoana F. , Galaon Toma
Published: November 2020

The present study investigated the distribution and environmental fate of Bisphenol A (BPA), the 4-hydroxyacetophenone (4-HAP) metabolite, and 5 other bisphenol congeners in 2 municipal wastewater treatment plants (WWTPs) and their receiving rivers in Romania. Accordingly, a new, highly sensitive and accurate solid-phase extraction–liquid chromatography–electrospray ionization–tandem mass spectrometry method was developed and validated. This technique generated low limit of quantitation values: below 2.3 ng/L for surface water and less than 2.4 and 2.7 ng/L for WWTP effluent and influent water. The sum of detected analytes in wastewater was between 1337 and 16 118 ng/L for influent samples and between 15 and 96 ng/L for effluent samples. In surface water, the total of all compounds was somewhere between 34 and 240 ng/L. The highest concentration observed was for BPA in all 3 types of analyzed water (up to 9140 ng/L for influent, as high as 75 ng/L for effluent, and a maximum of 135 ng/L in surface waters). All analyzed samples were free of bisphenols B, C, and F. For all analytes detected in surface water, the concentration values were higher than those determined in the effluent samples, which may be caused by intrinsic contamination of the 2 rivers (Danube and Jiu Rivers). Values of environmental risk coefficients, calculated for both effluents and surface waters, indicated a low ecological risk or no ecological risk for 3 types of organisms (algae, daphnia, and fish). Human risk assessment calculation suggests no risk to human health as a result of the presence of BPA in either of the 2 rivers. Environ Toxicol Chem 2021;40:435–446. © 2020 SETAC
The role of exosomes in liquid biopsy for cancer diagnosis and prognosis prediction
Authors: Li Shiyu , Yi Ming , Dong Bing , Tan Ximin , Luo Suxia , Wu Kongming
Published: November 2020

Liquid biopsy is a revolutionary strategy in cancer diagnosis and prognosis prediction, which is used to analyze cancer cells or cancer‐derived products through biofluids such as blood, urine and so on. Exosomes play a crucial role in mediating cell communication. A growing number of studies have reported that exosomes are involved in tumorigenesis, tumor growth, metastasis and drug resistance by delivering cargos including nucleic acids and protein. Thus, exosomes, as a new type of liquid biopsy, have the potential to be diagnostic or prognostic biomarkers. Herein, we elaborate on the current methods and introduce novel techniques for exosome isolation and characterization. Moreover, we elucidate the advantages of exosomes compared to other biological components in liquid biopsy and summarize the different exosomal biomarkers in cancer diagnosis and prognosis prediction.
Preexisting morbidity profile of women newly diagnosed with breast cancer in sub‐Saharan Africa: African Breast Cancer—Disparities in Outcomes study
Authors: Ayeni Oluwatosin A. , Norris Shane A. , Joffe Maureen , Cubasch Herbert , Galukande Moses , Zietsman Annelle , Parham Groesbeck , Adisa Charles , Anele Angelica , Schüz Joachim , Anderson Benjamin O. , Foerster Milena , dos Santos Silva Isabel , McCormack Valerie A.
Published: November 2020

The presence of preexisting morbidities poses a challenge to cancer patient care. There is little information on the profile and prevalence of multi‐morbidities in breast cancer patients across middle income countries (MIC) to lower income countries (LIC) in sub‐Saharan Africa (SSA). The African Breast Cancer–Disparities in Outcomes (ABC‐DO) breast cancer cohort spans upper MICs South Africa and Namibia, lower MICs Zambia and Nigeria and LIC Uganda. At cancer diagnosis, seven morbidities were assessed: obesity, hypertension, diabetes, asthma/chronic obstructive pulmonary disease, heart disease, tuberculosis and HIV. Logistic regression models were used to assess determinants of morbidities and the influence of morbidities on advanced stage (stage III/IV) breast cancer diagnosis. Among 2189 women, morbidity prevalence was the highest for obesity (35%, country‐specific range 15‐57%), hypertension (32%, 15‐51%) and HIV (16%, 2‐26%) then for diabetes (7%, 4%‐10%), asthma (4%, 2%‐10%), tuberculosis (4%, 0%‐8%) and heart disease (3%, 1%‐7%). Obesity and hypertension were more common in upper MICs and in higher socioeconomic groups. Overall, 27% of women had at least two preexisting morbidities. Older women were more likely to have obesity (odds ratio: 1.09 per 10 years, 95% CI 1.01‐1.18), hypertension (1.98, 1.81‐2.17), diabetes (1.51, 1.32‐1.74) and heart disease (1.69, 1.37‐2.09) and were less likely to be HIV positive (0.64, 0.58‐0.71). Multi‐morbidity was not associated with stage at diagnosis, with the exception of earlier stage in obese and hypertensive women. Breast cancer patients in higher income countries and higher social groups in SSA face the additional burden of preexisting non‐communicable diseases, particularly obesity and hypertension, exacerbated by HIV in Southern/Eastern Africa.
Experiences in the prevention and screening of cervical cancer within Thailand
Authors: Kengsakul Malika , Laowahutanont Piyawat , Wilailak Sarikapan
Published: November 2020

Cervical cancer is the third most common cancer among Thai women, after breast and colon cancer, with an age‐standardized incidence rate (ASR) of 11.7/100 000 women each year, as of 2015. Over decades, comprehensive national cervical cancer screening programs, research, and the HPV vaccination policy have gradually helped decrease the incidence of cervical cancer in Thailand. In 2017, the Thai Ministry of Public Health signed a memorandum of understanding with the Royal Thai College of Obstetricians and Gynecologists to eliminate invasive cervical cancer from Thailand. This is a tremendous challenge for Thailand as a whole. The present paper reviews and discusses the experiences in the prevention and screening of cervical cancer in Thailand.
Vitamin D Receptor Mediates a Myriad of Biological Actions Dependent on Its 1,25‐Dihydroxyvitamin D Ligand: Distinct Regulatory Themes Revealed by Induction of Klotho and Fibroblast Growth Factor‐23
Authors: Haussler Mark R , Livingston Sarah , Sabir Zhela L , Haussler Carol A , Jurutka Peter W
Published: November 2020

The hormonal vitamin D metabolite, 1,25‐dihydroxyvitamin D [1,25(OH)2D], produced in kidney, acts in numerous end organs via the nuclear vitamin D receptor (VDR) to trigger molecular events that orchestrate bone mineral homeostasis. VDR is a ligand‐controlled transcription factor that obligatorily heterodimerizes with retinoid X receptor (RXR) to target vitamin D responsive elements (VDREs) in the vicinity of vitamin D‐regulated genes. Circulating 1,25(OH)2D concentrations are governed by PTH, an inducer of renal D‐hormone biosynthesis catalyzed by CYP27B1 that functions as the key player in a calcemic endocrine circuit, and by fibroblast growth factor‐23 (FGF23), a repressor of the CYP27B1 renal enzyme, creating a hypophosphatemic endocrine loop. 1,25(OH)2D/VDR–RXR acts in kidney to induce Klotho (a phosphaturic coreceptor for FGF23) to correct hyperphosphatemia, NPT2a/c to correct hypophosphatemia, and TRPV5 and CaBP28k to enhance calcium reabsorption. 1,25(OH)2D‐liganded VDR–RXR functions in osteoblasts/osteocytes by augmenting RANK‐ligand expression to paracrine signal osteoclastic bone resorption, while simultaneously inducing FGF23, SPP1, BGLP, LRP5, ANK1, ENPP1, and TNAP, and conversely repressing RUNX2 and PHEX expression, effecting localized control of mineralization to sculpt the skeleton. Herein, we document the history of 1,25(OH)2D/VDR and summarize recent advances in characterizing their physiology, biochemistry, and mechanism of action by highlighting two examples of 1,25(OH)2D/VDR molecular function. The first is VDR‐mediated primary induction of Klotho mRNA by 1,25(OH)2D in kidney via a mechanism initiated by the docking of liganded VDR–RXR on a VDRE at −35 kb in the mouse Klotho gene. In contrast, the secondary induction of FGF23 by 1,25(OH)2D in bone is proposed to involve rapid nongenomic action of 1,25(OH)2D/VDR to acutely activate PI3K, in turn signaling the induction of MZF1, a transcription factor that, in cooperation with c‐ets1‐P, binds to an enhancer element centered at −263 bp in the promoter‐proximal region of the mouse fgf23 gene. Chronically, 1,25(OH)2D‐induced osteopontin apparently potentiates MZF1. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Piezo1 Inactivation in Chondrocytes Impairs Trabecular Bone Formation
Authors: Hendrickx Gretl , Fischer Verena , Liedert Astrid , von Kroge Simon , Haffner-Luntzer Melanie , Brylka Laura , Pawlus Eva , Schweizer Michaela , Yorgan Timur , Baranowsky Anke , Rolvien Tim , Neven Mona , Schumacher Udo , Beech David J , Amling Michael , Ignatius Anita , Schinke Thorsten
Published: November 2020

The skeleton is a dynamic tissue continuously adapting to mechanical stimuli. Although matrix-embedded osteocytes are considered as the key mechanoresponsive bone cells, all other skeletal cell types are principally exposed to macroenvironmental and microenvironmental mechanical influences that could potentially affect their activities. It was recently reported that Piezo1, one of the two mechanically activated ion channels of the Piezo family, functions as a mechanosensor in osteoblasts and osteocytes. Here we show that Piezo1 additionally plays a critical role in the process of endochondral bone formation. More specifically, by targeted deletion of Piezo1 or Piezo2 in either osteoblast (Runx2Cre) or osteoclast lineage cells (Lyz2Cre), we observed severe osteoporosis with numerous spontaneous fractures specifically in Piezo1Runx2Cre mice. This phenotype developed at an early postnatal stage and primarily affected the formation of the secondary spongiosa. The presumptive Piezo1Runx2Cre osteoblasts in this region displayed an unusual flattened appearance and were positive for type X collagen. Moreover, transcriptome analyses of primary osteoblasts identified an unexpected induction of chondrocyte-related genes in Piezo1Runx2Cre cultures. Because Runx2 is not only expressed in osteoblast progenitor cells, but also in prehypertrophic chondrocytes, these data suggested that Piezo1 functions in growth plate chondrocytes to ensure trabecular bone formation in the process of endochondral ossification. To confirm this hypothesis, we generated mice with Piezo1 deletion in chondrocytes (Col2a1Cre). These mice essentially recapitulated the phenotype of Piezo1Runx2Cre animals, because they displayed early-onset osteoporosis with multiple fractures, as well as impaired formation of the secondary spongiosa with abnormal osteoblast morphology. Our data identify a previously unrecognized key function of Piezo1 in endochondral ossification, which, together with its role in bone remodeling, suggests that Piezo1 represents an attractive target for the treatment of skeletal disorders. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Treatment With Tocilizumab for Patients With COVID‐19 Infections: A Case‐Series Study
Authors: Mo Yoonsun , Adarkwah Obed , Zeibeq John , Pinelis Evgeny , Orsini Jose , Gasperino James
Published: November 2020

Tocilizumab (TCZ), a humanized monoclonal antibody targeting the interleukin‐6 receptor, holds the potential for treating coronavirus disease 2019 (COVID‐19) patients, particularly those at high risk of cytokine storm syndrome. However, data regarding the clinical impact of treatment with TCZ in patients with COVID‐19 are limited. This study was conducted to evaluate the safety and effectiveness of TCZ as an adjunct therapy for the treatment of severe COVID‐19 infection. This was a retrospective observational chart review of confirmed COVID‐19 patients who received TCZ, along with other COVID‐19 therapies. The outcomes of interest included changes in vital signs such as temperature and laboratory biomarkers, duration of mechanical ventilation, adverse events possibly associated with TCZ, and intensive care unit and hospital lengths of stay. This study included 38 patients with an average age of 63 years (IQR, 48‐70 years). The average dose of TCZ given was 519 ± 61 mg. Median C‐reactive protein significantly decreased following TCZ administration (189.9 vs 54.8 mg/L, P = .003). Nineteen of all febrile patients before the initiation of TCZ (73%) became fever free on the fourth day of TCZ treatment. Following TCZ treatment, 11 patients developed infections because of multidrug‐resistant bacteria, and elevated liver transaminases were observed in 6 patients. The preliminary findings of this study suggested TCZ appeared to ameliorate COVID‐19‐related cytokine storm syndrome. However, large randomized, controlled trials are needed to investigate whether treatment with TCZ is associated with better outcomes in COVID‐19.
Measuring (biological) materials mechanics with atomic force microscopy. 2. Influence of the loading rate and applied force (colloidal particles)
Authors: Weber Andreas , Zbiral Barbara , Iturri Jagoba , Benitez Rafael , Toca‐Herrera José L.
Published: November 2020

Atomic force microscopy (AFM) is the most often used tool to study the mechanical properties of eukaryotic cells. Due to their complex assembly, cells show viscoelastic properties. When performing experiments, one has to consider the influence of both loading rate and maximum load on the measured mechanical properties. Here, we employed colloidal particles of various sizes (from 2 to 20 μm diameter) to perform force spectroscopy measurements on endothelial cells at loading rates varying from 0.1 to 50 μm/s, and maximum loads ranging from 1 to 25 nN. We were able to determine the non‐linear dependence of cell viscoelastic properties on the loading rate which followed a weak power law. In addition, we show that previous loading at high forces leads to a stiffening of cells. Based on these results we discuss a road map for determining cell mechanical properties using AFM. Finally, this work provides an experimental framework for cell mechanical measurements using force‐cycle experiments.
Surgery versus external beam radiotherapy for hepatocellular carcinoma involving the inferior vena cava or right atrium: A systematic review and meta‐analysis
Authors: Lee Han Ah , Park Sunmin , Seo Yeon Seok , Yoon Won Sup , Shin In‐Soo , Rim Chai Hong
Published: November 2020

We investigated the efficacy and safety of surgery and external beam radiotherapy (EBRT), in patients with hepatocellular carcinoma (HCC) involving the inferior vena cava (IVC) and/or right atrium (RA) through a comparative meta‐analysis. A systematic search of PubMed, MEDLINE, EMBASE, and the Cochrane library was performed for entries until July 2020. Eighteen studies with 22 cohorts were included, encompassing 755 patients. The pooled median overall survival (OS) and 1‐ and 2‐year OS rates were 14.2 months, 55.6%, and 27.4%, respectively. The pooled median OS in the surgery and EBRT arms were 15.3 and 11.7 months, respectively. The pooled 1‐year OS rate in the surgery arm was significantly higher than that in the EBRT arm (62.4%, 95% CI: 53.8%‐70.3% vs 48.8%, 95% CI: 40.9‐56.8, respectively; P = .023), while the 2‐year OS rates were similar (27.5%, 95% CI: 19.7%‐37.1% vs 26.9%, 95% CI: 20.7‐34.2, respectively; P = .913). In the surgical arm, the perioperative mortality and grade ≥3 complication rates were 0%‐7.6% and 3.9%‐67%, respectively. Grade ≥3 complications and radiation‐induced liver disease were rarely observed in the EBRT arm. Surgery could be an effective local modality for achieving the best survival rate, though it requires efforts to minimize morbidities and careful patient selection. EBRT, as a noninvasive modality, is a valid palliative option, especially for high‐risk patients with a shorter life expectancy.