bluuebunny/crossref_metadata_2025 huggingface dataset:
Affordability of Healthy and Sustainable Diets in Nigeria
Authors: Mekonnen Daniel A. , Akerele Dare , Achterbosch Thom , de Lange Thijs , Talsma Elise F.
Published: September 2021

This study examines the cost and affordability of healthy diets in Nigeria. Using the 2015/16 and 2018/19 waves of Nigeria General Household Surveys, we find that, generally, the least-cost options to meet dietary recommendations for vegetables, dairy, and protein-rich foods are more expensive to meet than that of other food groups. Despite improvements during the survey years, the challenges of affordability of healthy diets appear more pronounced in rural than urban, among poorest household groups, and in northern than southern Nigeria. Results suggest that it will be more expensive to meet the dietary recommendation for dairy foods if priority will be given for food systems sustainability over concerns for food preferences of the households. It will however be cheaper to achieve dietary recommendations for vegetables, fruits and starchy staples even when households give more consideration to food systems sustainability than tastes and preferences in their choice of healthy foods. Relative affordability of protein-rich foods are less affected by whether (or not) tastes/preferences or food systems sustainability drives healthy food choices. Key implication is that interventions targeting on affordability of healthy diets should give greater attention to the poorest of the poor, to rural than urban, and to northern than southern Nigeria. Implications relevant for research, policy, and other actors that focus on transformation of the food systems toward achieving healthier diets in a sustainable food systems are discussed.
Postoperative Adjuvant Radiotherapy Can Delay the Recurrence of Desmoid Tumors After R0 Resection in Certain Subgroups
Authors: Yang Tielong , Liu Haotian , Liao Zhichao , Zhang Chao , Xiang Lijie , Yang Jilong
Published: September 2021

Background: When patients with desmoid tumors (DTs) present uncontrolled clinical symptoms, surgery is an effective treatment, but the high postoperative recurrence rate is a major problem. The significance of adjuvant radiotherapy has been debated for many years, and the significance of aggressive surgery has not been reported.

Methods: Medical records for DT patients were collected. KM analysis and the Mann–Whitney U-test were performed to evaluate the role of radiotherapy and aggressive surgery in the entire cohort and different subgroups.

Results: Of 385 DT patients, 267 patients with R0 resection were included in the final analysis. A total of 53 patients (19.85%) experienced recurrence. Although radiotherapy showed no significant effect on recurrence-free survival (RFS) or time to recurrence (TTR) in the entire cohort, radiotherapy delayed recurrence in the age ≤ 30 years old subgroup (TTR = 35 months with surgery plus radiotherapy, TTR = 11 months with surgery alone; p = 0.014) and the tumor diameter >5 cm subgroup (TTR = 26 months with surgery plus radiotherapy, TTR = 11 months with surgery alone; p = 0.02) among patients with a single tumor. Aggressive surgery improved RFS in the tumor diameter >5 cm subgroup (p = 0.049) but not the entire cohort.

Conclusions: Although radiotherapy cannot improve RFS, it can delay recurrence in the age ≤ 30 years old subgroup and the tumor diameter >5 cm subgroup among patients with a single tumor. For patients with large invasive tumors and multiple involved sites, aggressive surgery could be selected to achieve complete tumor resection to improve RFS.
Effects of Adding Eubiotic Lignocellulose on the Growth Performance, Laying Performance, Gut Microbiota, and Short-Chain Fatty Acids of Two Breeds of Hens
Authors: Sun Baosheng , Hou Linyue , Yang Yu
Published: September 2021

Eubiotic lignocellulose is a new and useful dietary fiber source for chickens. However, few studies have been undertaken on the impacts of its use as a supplement in different chicken breeds. In this experiment, 108 Chinese native breed Bian hens (BH) and 108 commercial breed ISA Brown hens (IBH) were chosen. They were randomly divided into three groups, and 0, 2, or 4% eubiotic lignocellulose was added to their feed during the growing periods (9–20 weeks), respectively. We aimed to observe the impacts of adding eubiotic lignocellulose on the growth and laying performance, gut microbiota, and short-chain fatty acid (SCFA) of two breeds of hens. In this study, the addition of eubiotic lignocellulose had no significant effect on the growth performance and gut microbial diversity in the two breeds of chickens (P > 0.05). Compared with the control group, adding 4% eubiotic lignocellulose significantly increased the cecum weight, laying performance (P < 0.05), but had no significant effect on the SCFA of BH (P > 0.05); however, adding 4% significantly inhibited the intestinal development, laying performance, butyrate concentration, and SCFA content of IBH (P < 0.05). Moreover, the relative abundances of the fiber-degrading bacteria Alloprevotella and butyrate-producing bacteria Fusobacterium in the 4% group of BH were significantly higher than those in the 4% group of IBH (P < 0.05), resulting in the concentration of butyrate was significantly higher than those in it (P < 0.05). Combining these results suggests that the tolerance of BH to a high level of eubiotic lignocellulose is greater than that of IBH and adding 2-4% eubiotic lignocellulose is appropriate for BH, while 0–2% eubiotic lignocellulose is appropriate for IBH.
How Are Rural Youths’ Agricultural Skills? Empirical Results and Implications in Southwest China
Authors: Zhu Yuanyuan , Wang Yukuan , Fu Bin , Liu Qin , Li Ming , Yan Kun
Published: September 2021

Global agriculture is facing an aging workforce and successor crisis, while the degradation of rural youths’ agricultural skills, which is indeed a concrete manifestation of young agricultural labor loss, has received little attention. Based on data from 1902 questionnaires in rural Southwest China, this study draws on a qualitative and quantitative analysis of the degradation of their skills to deepen the insights into the relationship between rural youth and agriculture. We found that rural youth have much lower agricultural skills than rural middle-aged and elderly residents, and their agricultural skills vary depending on gender, age, and occupation. Rural young non-agricultural workers’ large proportion among rural youth and low skills are the main sources of the reduction in rural youths’ skills. According to ordered logistic regression analysis, rural young non-agricultural workers who are older, have less education per person in their household, and have a larger cultivated land size have higher skills. As for rural students, 65.44% of the rural students have no skills, age and family’s agricultural income are significant positive influencing factors of their agricultural skills, and female youth have higher agricultural skills. The results provide references for policymakers to formulate targeted policies to cultivate rural young agricultural successors.
Birth Weight and Nutrient Restriction Affect Jejunal Enzyme Activity and Gene Markers for Nutrient Transport and Intestinal Function in Piglets
Authors: Wellington Michael O. , Rodrigues Lucas A. , Li Qiao , Dong Bingqi , Panisson Josiane C. , Yang Chengbo , Columbus Daniel A.
Published: September 2021

Significant variation in the birth weight of piglets has arisen due to increased sow prolificacy. Intestinal development and function may be affected by birth weight. Low birth weight (LBW) pigs may also have reduced feed intake, leading to further impairment of intestinal development. The objective of this study was to examine the intestinal development pattern of LBW and normal birth weight (NBW) piglets with normal nutrition (NN) or restricted nutrition (RN) in the pre-weaning period. Jejunal intestinal samples were analyzed for target gene expression and enzyme activity at d 28 (weaning) and d 56 (post-weaning). At d 28, excitatory amino acid transporter (EAAC1) and sodium-dependent neutral amino acid transporter (B0AT1) were downregulated in LBW compared to NBW pigs (p < 0.05). On d 56, B0AT1 and ASCT2 (glutamine transporter) were downregulated in RN compared to NN pigs (p < 0.05), regardless of birth weight. Peptide transporter 1 (PepT1) expression was downregulated in LBW compared to NBW pigs at 28 d (p < 0.05), with no effects of treatments at 56 d. Sodium-glucose transporter-1 (SGLT1) was upregulated in NBW-NN compared to LBW-NN pigs (p < 0.05) at 28 d. Alkaline phosphatase (ALP) was upregulated in LBW-RN at d 28. At d 56, claudin-3 (CLDN-3) and Zonular occludin-1 (ZO-1) were upregulated in NN compared to RN pigs (p < 0.05). There were no treatment effects on ALP, maltase, or sucrase activity at 28 d. However, at 56 d, ALP was upregulated in NBW-NN pigs while sucrase activity was upregulated in NN pigs (p < 0.05). The results demonstrate differences in jejunal gene expression associated with birth weight, with reduced gene expression of amino acid transporters (PepT1, EAAC1, B0AT1) in LBW compared to NBW pigs (p < 0.05). While neonatal nutrient restriction had minimal effects at 28 d and d 56 for tight junction protein transcript abundance, neutral amino acid transporter abundance was upregulated in NN pigs compared to RN piglets (p < 0.05).
Combined Use of 3D and HSI for the Classification of Printed Circuit Board Components
Authors: Polat Songuel , Tremeau Alain , Boochs Frank
Published: September 2021

Successful recycling of electronic waste requires accurate separation of materials such as plastics, PCBs and electronic components on PCBs (capacitors, transistors, etc.). This article therefore proposes a vision approach based on a combination of 3D and HSI data, relying on the mutual support of the datasets to compensate existing weaknesses when using single 3D- and HSI-Sensors. The combined dataset serves as a basis for the extraction of geometric and spectral features. The classification is performed and evaluated based on these extracted features which are exploited through rules. The efficiency of the proposed approach is demonstrated using real electronic waste and leads to convincing results with an overall accuracy (OA) of 98.24%. To illustrate that the addition of 3D data has added value, a comparison is also performed with an SVM classification based only on hyperspectral data.
Modified Endoscopic-Assisted Approach for Removal of Ectopic Third Molar in the Maxillary Sinus
Authors: Seo Mi-Hyun , Lee Ju-Young , Frimpong Paul , Eo Mi-Young , Kim Soung-Min
Published: September 2021

This case series describes an alternative approach for removing ectopically erupted tooth in the maxillary sinus using an improved endoscopic approach known as modified endoscopic-assisted sinus surgery (MESS). We reviewed medical charts and radiographs of patients who underwent surgical removal of an ectopic tooth in the maxillary sinus using MESS. The surgical technique consisted of creating a bony window in the maxillary sinus wall with a pre-adapted microplate, which was repositioned after the tooth was removed. For all the patients included in this study, there were no postoperative complications clinically and radiographically. At the time of microplate removal, satisfactory bone regeneration was observed around the bony window margins of the maxillary sinus wall. MESS is an effective technique that modifies and integrates the techniques of the conventional Caldwell-Luc procedure (CLP) and functional endoscopic sinus surgery (FESS) and can be used to remove ectopic tooth in the maxillary sinus by avoiding the risk of postoperative sinus-related complications.
Pyrolysis of Mixed Plastic Waste: II. Artificial Neural Networks Prediction and Sensitivity Analysis
Authors: Dubdub Ibrahim , Al-Yaari Mohammed
Published: September 2021

In this work, an artificial neural network (ANN) model was efficiently developed to predict the pyrolysis of mixed plastics, including pure polystyrene (PS), polypropylene (PP), low-density polyethylene (LDPE), and high-density polyethylene (HDPE), at a heating rate of 60 K/min using thermogravimetric analysis (TGA) data. The data of seventeen experimental tests of polymer mixtures with different compositions were used. A feed-forward back-propagation model, with 15 and 10 neurons in two hidden layers and TANSIG-TANSIG transfer functions, was constructed to predict the weight left percent during the pyrolysis of the mixed polymer samples. The model input variables include the composition of each polymer (PS, PP, LDPE, and HDPE), and temperature. The results showed an excellent agreement between the experimental and the predicted weight left percent values, where the correlation coefficient (R) is greater than 0.9999. In addition, to validate the proposed model, a highly efficient performance was found when the proposed model was simulated using new input data. Furthermore, a sensitivity analysis was performed using Pearson correlation to find the uncertainties associated with the relationship between the output and the input parameters. Temperature was found to be the most sensitive input parameter.
Increasing Resilience of Production Systems by Integrated Design
Authors: Ihlenfeldt Steffen , Wunderlich Tim , Süße Marian , Hellmich Arvid , Schenke Christer-Clifford , Wenzel Ken , Mater Sarah
Published: September 2021

The paper presents a framework for considering resilience as an integrated aspect in the design of manufacturing systems. The framework comprises methods for the assessment of resilience, supply chain and production planning, flexible execution and control as well as modular and skill-based methods for automation systems. A basic classification of risk categories and their impacts on manufacturing environments is given so that a concept of reconfigurable and robust production systems can be derived. Based on this, main characteristics and concepts of resilience are applied to manufacturing systems. As a lever of increased resilience on business and supply chain level, options for synchronized production planning are presented in a discrete event simulation. Furthermore, a concept to increase resilience on the level of business process execution is investigated, allowing manufacturing tasks to be rescheduled during runtime using a declarative approach to amend conventional business process models.
Quantifying the Potential Contribution of Urban Forest to PM2.5 Removal in the City of Shanghai, China
Authors: Zhang Biao , Xie Zixia , She Xinlu , Gao Jixi
Published: September 2021

Climate change and air pollution pose multiple health threats to humans through complex and interacting pathways, whereas urban vegetation can improve air quality by influencing pollutant deposition and dispersion. This study estimated the amount of PM2.5 removal by the urban forest in the city of Shanghai by using remote sensing data of vegetation and a model approach. We also identified its potential contribution of urban forest presence in relation to human population and particulate matter concentration. Results show that the urban forest in Shanghai reached 46,161 ha in 2017, and could capture 874 t of PM2.5 with an average of 18.94 kg/ha. There are significant spatial heterogeneities in the role of different forest communities and administrative districts in removing PM2.5. Although PM2.5 removal was relatively harmonized with the human population distribution in terms of space, approximately 57.41% of the urban forest presented low coupling between removal capacity and PM2.5 concentration. Therefore, we propose to plant more trees with high removal capacity of PM2.5 in the western areas of Shanghai, and increase vertical planting in bridge pillars and building walls to compensate the insufficient amount of urban forest in the center area.
The Amyloid Region of Hfq Riboregulator Promotes DsrA:rpoS RNAs Annealing
Authors: Turbant Florian , Wu Pengzhi , Wien Frank , Arluison Véronique
Published: September 2021

Hfq is a bacterial RNA chaperone which promotes the pairing of small noncoding RNAs to target mRNAs, allowing post-transcriptional regulation. This RNA annealing activity has been attributed for years to the N-terminal region of the protein that forms a toroidal structure with a typical Sm-fold. Nevertheless, many Hfqs, including that of Escherichia coli, have a C-terminal region with unclear functions. Here we use a biophysical approach, Synchrotron Radiation Circular Dichroism (SRCD), to probe the interaction of the E. coli Hfq C-terminal amyloid region with RNA and its effect on RNA annealing. This C-terminal region of Hfq, which has been described to be dispensable for sRNA:mRNA annealing, has an unexpected and significant effect on this activity. The functional consequences of this novel property of the amyloid region of Hfq in relation to physiological stress are discussed.
Neuropathic Pain: Biomolecular Intervention and Imaging via Targeting Microglia Activation
Authors: Ji Aijun , Xu Jinbin
Published: September 2021

Many diseases, including cancer, can lead to neuropathic pain (NP). NP is one of the accompanying symptoms of suffering in many conditions and the life quality of NP patient is seriously affected. Due to complex causes, the effects of clinical treatments have been very unsatisfactory. Many experts have found that neuron-microglia interaction plays an essential role in NP occurrence and development. Therefore, the activation of microglia, related inflammatory mediators and molecular and cellular signaling pathways have become the focus of NP research. With the help of modern functional imaging technology, advanced pre-and clinical studies have been carried out and NP interventions have been attempted by using the different pharmaceuticals and the extracted active components of various traditional herbal medicines. In this communication, we review the mechanism of microglia on NP formation and treatment and molecular imaging technology’s role in the clinical diagnosis and evaluation of NP therapies.
The Histaminergic System in Neuropsychiatric Disorders
Authors: Cheng Li , Liu Jiaying , Chen Zhong
Published: September 2021

Histamine does not only modulate the immune response and inflammation, but also acts as a neurotransmitter in the mammalian brain. The histaminergic system plays a significant role in the maintenance of wakefulness, appetite regulation, cognition and arousal, which are severely affected in neuropsychiatric disorders. In this review, we first briefly describe the distribution of histaminergic neurons, histamine receptors and their intracellular pathways. Next, we comprehensively summarize recent experimental and clinical findings on the precise role of histaminergic system in neuropsychiatric disorders, including cell-type role and its circuit bases in narcolepsy, schizophrenia, Alzheimer’s disease, Tourette’s syndrome and Parkinson’s disease. Finally, we provide some perspectives on future research to illustrate the curative role of the histaminergic system in neuropsychiatric disorders.
Biomediators in Polycystic Ovary Syndrome and Cardiovascular Risk
Authors: Pandurevic Srdan , Macut Djuro , Fanelli Flaminia , Pagotto Uberto , Gambineri Alessandra
Published: September 2021

Polycystic ovary syndrome (PCOS) is extremely heterogeneous in terms of clinical manifestations. The variability of the syndrome’s phenotype is derived from the genetic and molecular heterogeneity, with a great deal of environmental factors that may have long-term health consequences, such as metabolic and cardiovascular (CV) diseases. There is no doubt that women with PCOS suffer from metabolic complications more than their age-matched counterparts in the general population and at an earlier age. Obesity, low steroid hormone-binding globulin (SHBG), hyperandrogenemia, insulin resistance, and compensatory hyperinsulinemia are biomediators and early predictors of metabolic complications in PCOS. Doubts remain about the real risk of CV diseases in PCOS and the molecular mechanisms at the basis of CV complications. Based on that assumption, this review will present the available evidence on the potential implications of some biomediators, in particular, hyperandrogenism, estrogen-progesterone imbalance, insulin resistance, and low SHBG, in the processes leading to CV disease in PCOS, with the final aim to propose a more accurate CV risk assessment.
Sphingolipid Profile during Cotton Fiber Growth Revealed That a Phytoceramide Containing Hydroxylated and Saturated VLCFA Is Important for Fiber Cell Elongation
Authors: Chen Qian , Xu Fan , Wang Li , Suo Xiaodong , Wang Qiaoling , Meng Qian , Huang Li , Ma Caixia , Li Guiming , Luo Ming
Published: September 2021

Cotton fiber is a single-celled seed trichrome that arises from the epidermis of the ovule’s outer integument. The fiber cell displays high polar expansion and thickens but not is disrupted by cell division. Therefore, it is an ideal model for studying the growth and development of plant cells. Sphingolipids are important components of membranes and are also active molecules in cells. However, the sphingolipid profile during fiber growth and the differences in sphingolipid metabolism at different developmental stages are still unclear. In this study, we detected that there were 6 classes and 95 molecular species of sphingolipids in cotton fibers by ultrahigh performance liquid chromatography-MS/MS (UHPLC-MS/MS). Among these, the phytoceramides (PhytoCer) contained the most molecular species, and the PhytoCer content was highest, while that of sphingosine-1-phosphate (S1P) was the lowest. The content of PhytoCer, phytoceramides with hydroxylated fatty acyls (PhytoCer-OHFA), phyto-glucosylceramides (Phyto-GluCer), and glycosyl-inositol-phospho-ceramides (GIPC) was higher than that of other classes in fiber cells. With the development of fiber cells, phytosphingosine-1-phosphate (t-S1P) and PhytoCer changed greatly. The sphingolipid molecular species Ceramide (Cer) d18:1/26:1, PhytoCer t18:1/26:0, PhytoCer t18:0/26:0, PhytoCer t18:1/h20:0, PhytoCer t18:1/h26:0, PhytoCer t18:0/h26:0, and GIPC t18:0/h16:0 were significantly enriched in 10-DPA fiber cells while Cer d18:1/20:0, Cer d18:1/22:0, and GIPC t18:0/h18:0 were significantly enriched in 20-DPA fiber cells, indicating that unsaturated PhytoCer containing hydroxylated and saturated very long chain fatty acids (VLCFA) play some role in fiber cell elongation. Consistent with the content analysis results, the related genes involved in long chain base (LCB) hydroxylation and unsaturation as well as VLCFA synthesis and hydroxylation were highly expressed in rapidly elongating fiber cells. Furthermore, the exogenous application of a potent inhibitor of serine palmitoyltransferase, myriocin, severely blocked fiber cell elongation, and the exogenous application of sphingosine antagonized the inhibition of myriocin for fiber elongation. Taking these points together, we concluded that sphingolipids play crucial roles in fiber cell elongation and SCW deposition. This provides a new perspective for further studies on the regulatory mechanism of the growth and development of cotton fiber cells.
Primary Progressive Aphasia: Use of Graphical Markers for an Early and Differential Diagnosis
Authors: Plonka Alexandra , Mouton Aurélie , Macoir Joël , Tran Thi-Mai , Derremaux Alexandre , Robert Philippe , Manera Valeria , Gros Auriane
Published: September 2021

Primary progressive aphasia (PPA) brings together neurodegenerative pathologies whose main characteristic is to start with a progressive language disorder. PPA diagnosis is often delayed in non-specialised clinical settings. With the technologies’ development, new writing parameters can be extracted, such as the writing pressure on a touch pad. Despite some studies having highlighted differences between patients with typical Alzheimer’s disease (AD) and healthy controls, writing parameters in PPAs are understudied. The objective was to verify if the writing pressure in different linguistic and non-linguistic tasks can differentiate patients with PPA from patients with AD and healthy subjects. Patients with PPA (n = 32), patients with AD (n = 22) and healthy controls (n = 26) were included in this study. They performed a set of handwriting tasks on an iPad® digital tablet, including linguistic, cognitive non-linguistic, and non-cognitive non-linguistic tasks. Average and maximum writing pressures were extracted for each task. We found significant differences in writing pressure, between healthy controls and patients with PPA, and between patients with PPA and AD. However, the classification of performances was dependent on the nature of the tasks. These results suggest that measuring writing pressure in graphical tasks may improve the early diagnosis of PPA, and the differential diagnosis between PPA and AD.
Comparison of Different Procedures for Progressive Collapse Analysis of RC Flat Slab Structures under Corner Column Loss Scenario
Authors: Dmitriev Andrey , Lalin Vladimir
Published: September 2021

Progressive collapse is the failure of the whole structure caused by local damage, which leads to significant economic and human losses. Therefore, structures should be designed to sustain local failures and resist subsequent nonproportional damage. This paper compared four procedures for a progressive collapse analysis of two RC structures subjected to a corner column loss scenario. The study is mainly based on the methods outlined in the current Russian standard (linear static (LS) pulldown, nonlinear static (ND) pulldown, and nonlinear dynamic), but also includes LS and NS pushdown procedures suggested by the American guidelines and linear dynamic procedure. We developed detailed finite element models for ANSYS Mechanical and ANSYS/LS-DYNA simulations, explicitly including concrete and reinforcement elements. We applied the Continuous Surface Cap Model (MAT_CSCM) to account for the physical nonlinearity of concrete. We also validated results obtained following these procedures against known experimental data. Simulations using linear static pulldown and linear dynamic procedures lead to 50–70% lower results than the experimental because they do not account for the nonlinear behavior of concrete and reinforcement. Displacements obtained from the NS pulldown method exceed the test data by 10–400%. It is found that correct results for both RC structures can only be found using a nonlinear dynamic procedure, and the mismatch with the test data do not exceed 7%. Compared to static pulldown methods, LS and NS pushdown methods are more accurate and differ from the experiment by 28% and 14%, respectively. This relative accuracy is provided by more correct load multipliers depending on the structure type.
Parametric Investigation on the Effectiveness of FRM-Retrofitting in Masonry Buttressed Arches
Authors: Chisari Corrado , Cacace Daniela , De Matteis Gianfranco
Published: September 2021

Buttressed arches represent some of the most vulnerable elements in historical masonry buildings under seismic actions. Given their structural, architectural and often artistic importance, it is paramount to investigate effective retrofitting measures which satisfy reversibility and compatibility requirements for historical heritage. Among these, Fibre-Reinforced Mortar (FRM), characterised by enhanced ductility, has recently emerged in the scientific literature. In this paper, a numerical investigation aimed at exploring the effectiveness of this seismic retrofitting technique, when applied at intrados or extrados of various typologies of buttressed arches, is presented. An automatic tool for limit analysis is described and validated against a nonlinear Discrete Macro-Element modelling approach. This precedes an extensive parametric analysis, which has highlighted the effect of various geometrical features of the system on both collapse mechanism and maximum acceleration in the unreinforced configuration, and the high increase in seismic capacity provided by the retrofitting. This is particularly remarkable in case of local mechanism, i.e., wholly within the arch, in which case the FRM may be responsible of an overall shifting to a semi-global failure type.
Targeting Autophagy Triggers Apoptosis and Complements the Action of Venetoclax in Chronic Lymphocytic Leukemia Cells
Authors: Avsec Damjan , Jakoš Djordjevič Alma Tana , Kandušer Maša , Podgornik Helena , Škerget Matevž , Mlinarič-Raščan Irena
Published: September 2021

Continuous treatment of patients with chronic lymphocytic leukemia (CLL) with venetoclax, an antagonist of the anti-apoptotic protein Bcl-2, can result in resistance, which highlights the need for novel targets to trigger cell death in CLL. Venetoclax also induces autophagy by perturbing the Bcl-2/Beclin-1 complex, so autophagy might represent a target in CLL. Diverse autophagy inhibitors were assessed for cytotoxic activities against patient-derived CLL cells. The AMPK inhibitor dorsomorphin, the ULK1/2 inhibitor MRT68921, and the autophagosome–lysosome fusion inhibitor chloroquine demonstrated concentration-dependent and time-dependent cytotoxicity against CLL cells, even in those from hard-to-treat patients who carried del(11q) and del(17p). Dorsomorphin and MRT68921 but not chloroquine triggered caspase-dependent cell death. According to the metabolic activities of CLL cells and PBMCs following treatments with 10 µM dorsomorphin (13% vs. 84%), 10 µM MRT68921 (7% vs. 78%), and 25 µM chloroquine (41% vs. 107%), these autophagy inhibitors are selective toward CLL cells. In these CLL cells, venetoclax induced autophagy, and addition of dorsomorphin, MRT68921, or chloroquine showed potent synergistic cytotoxicities. Additionally, MRT68921 alone induced G2 arrest, but when combined with venetoclax, it triggered caspase-dependent cytotoxicity. These data provide the rationale to target autophagy and for autophagy inhibitors as potential treatments for patients with CLL.
Extracorporeal Shock Wave Enhances the Cisplatin Efficacy by Improving Tissue Infiltration and Cellular Uptake in an Upper Urinary Tract Cancer Animal and Human-Derived Organoid Model
Authors: Luo Hao-Lun , Liu Hui-Ying , Chang Yin-Lun , Su Yu-Li , Huang Chun-Chieh , Lin Xin-Jie , Chuang Yao-Chi
Published: September 2021

Upper urinary tract urothelial carcinoma (UTUC) is a relatively rare cancer with a poor prognosis if diagnosed at an advanced stage. Although cisplatin-based chemotherapy is a common treatment strategy, it has a limited response rate. Shock wave lithotripsy is a common treatment for upper urinary tract stones. Low-energy shock waves (LESWs) temporarily increase tissue permeability and enhance drug penetration to the targeted tissue. However, no study has investigated the efficacy of the combination of shock wave lithotripsy and chemotherapy in UTUC. Hence, in this study, we aimed to identify the potential application of the combination of LESW and chemotherapy in UTUC. We evaluated the synergistic effects of LESW and cisplatin in vitro, in vivo, and in patient-derived organoid (PDO) models. Compared with cisplatin alone, the combination treatment caused more significant tumour suppression in vitro and in animal models, without increased toxicity. Histological examination showed that compared with animals treated with cisplatin alone, those who received the combination treatment showed more deteriorated cell arrangement and cell oedema. Moreover, LESW improved the cytotoxicity of cisplatin in the preclinical PDO model of UTUC. Thus, LESW combined with cisplatin is a potential new antitumour strategy for improving the treatment response in locally advanced UTUC.
Cellular Plasticity: A Route to Senescence Exit and Tumorigenesis
Authors: De Blander Hadrien , Morel Anne-Pierre , Senaratne Aruni P. , Ouzounova Maria , Puisieux Alain
Published: September 2021

Senescence is a dynamic, multistep program that results in permanent cell cycle arrest and is triggered by developmental or environmental, oncogenic or therapy-induced stress signals. Senescence is considered as a tumor suppressor mechanism that prevents the risk of neoplastic transformation by restricting the proliferation of damaged cells. Cells undergoing senescence sustain important morphological changes, chromatin remodeling and metabolic reprogramming, and secrete pro-inflammatory factors termed senescence-associated secretory phenotype (SASP). SASP activation is required for the clearance of senescent cells by innate immunity. Therefore, escape from senescence and the associated immune editing would be a prerequisite for tumor initiation and progression as well as therapeutic resistance. One of the possible mechanisms for overcoming senescence could be the acquisition of cellular plasticity resulting from the accumulation of genomic alterations and genetic and epigenetic reprogramming. The modified composition of the SASP produced by these reprogrammed cancer cells would create a permissive environment, allowing their immune evasion. Additionally, the SASP produced by cancer cells could enhance the cellular plasticity of neighboring cells, thus hindering their recognition by the immune system. Here, we propose a comprehensive review of the literature, highlighting the role of cellular plasticity in the pro-tumoral activity of senescence in normal cells and in the cancer context.
PD-L1 Dependent Immunogenic Landscape in Hot Lung Adenocarcinomas Identified by Transcriptome Analysis
Authors: Kirfel Jutta , Kümpers Christiane Charlotte , Fähnrich Anke , Heidel Carsten , Jokic Mladen , Vlasic Ignacija , Marwitz Sebastian , Goldmann Torsten , Pasternack Helen , Bohnet Sabine , Jonigk Danny , Kühnel Mark P. , Offermann Anne , Busch Hauke , Perner Sven
Published: September 2021

Background: Lung cancer is the most frequent cause of cancer-related deaths worldwide. The clinical development of immune checkpoint blockade has dramatically changed the treatment paradigm for patients with lung cancer. Yet, an improved understanding of PD-1/PD-L1 checkpoint blockade-responsive biology is warranted. Methods: We aimed to identify the landscape of immune cell infiltration in primary lung adenocarcinoma (LUAD) in the context of tumoral PD-L1 expression and the extent of immune infiltration (“hot” vs. “cold” phenotype). The study comprises LUAD cases (n = 138) with “hot” (≥150 lymphocytes/HPF) and “cold” (<150 lymphocytes/HPF) tumor immune phenotype and positive (>50%) and negative (<1%) tumor PD-L1 expression, respectively. Tumor samples were immunohistochemically analyzed for expression of PD-L1, CD4, and CD8, and further investigated by transcriptome analysis. Results: Gene set enrichment analysis defined complement, IL-JAK-STAT signaling, KRAS signaling, inflammatory response, TNF-alpha signaling, interferon-gamma response, interferon-alpha response, and allograft rejection as significantly upregulated pathways in the PD-L1-positive hot subgroup. Additionally, we demonstrated that STAT1 is upregulated in the PD-L1-positive hot subgroup and KIT in the PD-L1-negative hot subgroup. Conclusion: The presented study illustrates novel aspects of PD-L1 regulation, with potential biological relevance, as well as relevance for immunotherapy response stratification.
Cyano- and Ketone-Containing Selenoesters as Multi-Target Compounds against Resistant Cancers
Authors: Szemerédi Nikoletta , Dobiasová Simona , Salardón-Jiménez Noemi , Kincses Annamária , Nové Márta , Habibullah Giyaullah , Sevilla-Hernández Clotilde , Benito-Lama Miguel , Alonso-Martínez Francisco-Javier , Viktorová Jitka , Spengler Gabriella , Domínguez-Álvarez Enrique
Published: September 2021

Fifteen selenocompounds, comprising of eight ketone-containing selenoesters (K1–K8, also known as oxoselenoesters) and seven cyano-containing selenoesters (N1–N7, known also as cyanoselenoesters), have been designed, synthesized, and evaluated as novel anticancer agents. These compounds are derivatives of previously reported active selenoesters and were prepared following a three-step one-pot synthetic route. The following evaluations were performed in their biological assessment: cytotoxicity determination, selectivity towards cancer cells in respect to non-cancer cells, checkerboard combination assay, ABCB1 inhibition and inhibition of ABCB1 ATPase activity, apoptosis induction, and wound healing assay. As key results, all the compounds showed cytotoxicity against cancer cells at low micromolar concentrations, with cyanoselenoesters being strongly selective. All of the oxoselenoesters, except K4, were potent ABCB1 inhibitors, and two of them, namely K5 and K6, enhanced the activity of doxorubicin in a synergistic manner. The majority of these ketone derivatives modulated the ATPase activity, showed wound healing activity, and induced apoptosis, with K3 being the most potent, with a potency close to that of the reference compound. To summarize, these novel derivatives have promising multi-target activity, and are worthy to be studied more in-depth in future works to gain a greater understanding of their potential applications against cancer.
Therapeutic Targeting of Acute Myeloid Leukemia by Gemtuzumab Ozogamicin
Authors: Gottardi Michele , Simonetti Giorgia , Sperotto Alessandra , Nappi Davide , Ghelli Luserna di Rorà Andrea , Padella Antonella , Norata Marianna , Giannini Maria Benedetta , Musuraca Gerardo , Lanza Francesco , Cerchione Claudio , Martinelli Giovanni
Published: September 2021

Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by genetic and clinical heterogeneity and high mortality. Despite the recent introduction of novel pharmaceutical agents in hemato-oncology, few advancements have been made in AML for decades. In the last years, the therapeutic options have rapidly changed, with the approval of innovative compounds that provide new opportunities, together with new challenges for clinicians: among them, on 1 September, 2017 the Food and Drug Administration granted approval for Gemtuzumab Ozogamicin (GO) in combination with daunorubicin and cytarabine for the treatment of adult patients affected by newly diagnosed CD33+ AML. Benefits of GO-based regimens were also reported in the pre- and post-transplantation settings. Moreover, several biomarkers of GO response have been suggested, including expression of CD33 and multidrug resistance genes, cytogenetic and molecular profiles, minimal residual disease and stemness signatures. Among them, elevated CD33 expression on blast cells and non-adverse cytogenetic or molecular risk represent largely validated predictors of good response.
Combination of a 15-SNP Polygenic Risk Score and Classical Risk Factors for the Prediction of Breast Cancer Risk in Cypriot Women
Authors: Yiangou Kristia , Kyriacou Kyriacos , Kakouri Eleni , Marcou Yiola , Panayiotidis Mihalis I. , Loizidou Maria A. , Hadjisavvas Andreas , Michailidou Kyriaki
Published: September 2021

The PRS combines multiplicatively the effects of common low-risk single nucleotide polymorphisms (SNPs) and has the potential to be used for the estimation of an individual’s risk for a trait or disease. PRS has been successfully implemented for the prediction of breast cancer risk. The combination of PRS with classical breast cancer risk factors provides a more comprehensive risk estimation and could, thus, improve risk stratification and personalized preventative strategies. In this study, we assessed the predictive performance of the combined effect of PRS15 with classical breast-cancer risk factors in Cypriot women using 1109 cases and 1177 controls from the MASTOS study. The PRS15 was significantly associated with an increased breast cancer risk in Cypriot women OR (95% CI) 1.66 (1.25–2.19). The integrated risk model obtained an AUC (95% CI) 0.70 (0.67–0.72) and had the ability to stratify women according to their disease status at the extreme deciles. These results provide evidence that the combination of PRS with classical risk factors may be used in the future for the stratification of Cypriot women based on their disease risk, and support its potential clinical utility for targeted preventative actions and population screening.
The Reality of Lung Cancer Paradox: The Impact of Body Mass Index on Long-Term Survival of Resected Lung Cancer. A French Nationwide Analysis from the Epithor Database
Authors: Alifano Marco , Daffré Elisa , Iannelli Antonio , Brouchet Laurent , Falcoz Pierre Emmanuel , Le Pimpec Barthes Françoise , Bernard Alain , Pages Pierre Benoit , Thomas Pascal Alexandre , Dahan Marcel , Porcher Raphael
Published: September 2021

Obesity could have a protective effect in patients with lung cancer. We assessed the prognostic role of preoperative BMI on survival in patients who underwent lung resection for NSCLC. A total of 54,631 consecutive patients with resectable lung cancer within a 15-year period were extracted from Epithor (the French Society of Thoracic and Cardiovascular Surgery database). Patient subgroups were defined according to body mass index (BMI): underweight (BMI < 18.5 kg/m2), normal weight (18.5 ≤ BMI < 25 kg/m2), overweight (25 ≤ BMI < 30 kg/m2), and obese (BMI ≥ 30 kg/m2). Underweight was associated with lower survival (unadjusted HRs 1.24 (1.16–1.33)) compared to normal weight, whereas overweight and obesity were associated with improved survival (0.95 (0.92–0.98) and 0.88 (0.84–0.92), respectively). The impact of BMI was confirmed when stratifying for sex or Charlson comorbidities index (CCI). Among patients with obesity, a higher BMI was associated with improved survival. After adjusting for period of study, age, sex, WHO performance status, CCI, side of tumor, extent of resection, histologic type, and stage of disease, the HRs for underweight, overweight, and obesity were 1.51 (1.41–1.63), 0.84 (0.81–0.87), and 0.80 (0.76–0.84), respectively. BMI is a strong and independent predictor of survival in patients undergoing surgery for NSCLC.
Understanding the Radiobiology of Vestibular Schwannomas to Overcome Radiation Resistance
Authors: Thielhelm Torin P. , Goncalves Stefania , Welford Scott M. , Mellon Eric A. , Cohen Erin R. , Nourbakhsh Aida , Fernandez-Valle Cristina , Telischi Fred , Ivan Michael E. , Dinh Christine T.
Published: September 2021

Vestibular schwannomas (VS) are benign tumors arising from cranial nerve VIII that account for 8–10% of all intracranial tumors and are the most common tumors of the cerebellopontine angle. These tumors are typically managed with observation, radiation therapy, or microsurgical resection. Of the VS that are irradiated, there is a subset of tumors that are radioresistant and continue to grow; the mechanisms behind this phenomenon are not fully understood. In this review, the authors summarize how radiation causes cellular and DNA injury that can activate (1) checkpoints in the cell cycle to initiate cell cycle arrest and DNA repair and (2) key events that lead to cell death. In addition, we discuss the current knowledge of VS radiobiology and how it may contribute to clinical outcomes. A better understanding of VS radiobiology can help optimize existing treatment protocols and lead to new therapies to overcome radioresistance.
EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 1)
Authors: Zanelli Magda , Sanguedolce Francesca , Palicelli Andrea , Zizzo Maurizio , Martino Giovanni , Caprera Cecilia , Fragliasso Valentina , Soriano Alessandra , Valle Luca , Ricci Stefano , Cavazza Alberto , Merli Francesco , Pileri Stefano A. , Ascani Stefano
Published: September 2021

EBV is the most common persistent virus in humans. The interaction of EBV with B lymphocytes, which are considered the virus reservoir, is at the base of the life-long latent infection. Under circumstances of immunosuppression, the balance between virus and host immune system is altered and hence, EBV-associated lymphoid proliferations may originate. These disorders encompass several entities, ranging from self-limited diseases with indolent behavior to aggressive lymphomas. The virus may infect not only B-cells, but even T- and NK-cells. The occurrence of different types of lymphoid disorders depends on both the type of infected cells and the state of host immunity. EBV-driven lymphoproliferative lesions can rarely occur in the gastrointestinal tract and may be missed even by expert pathologists due to both the uncommon site of presentation and the frequent overlapping morphology and immunophenotypic features shared by different entities. The aim of this review is to provide a comprehensive overview of the current knowledge of EBV-associated lymphoproliferative disorders, arising within the gastrointestinal tract. The review is divided in three parts. In this part, the available data on EBV biology, EBV-positive mucocutaneous ulcer, EBV-positive diffuse large B-cell lymphoma, not otherwise specified and classic Hodgkin lymphoma are discussed.
3D Model of the Early Melanoma Microenvironment Captures Macrophage Transition into a Tumor-Promoting Phenotype
Authors: Pizzurro Gabriela A. , Liu Chang , Bridges Kathryn , Alexander Amanda F. , Huang Alice , Baskaran Janani P. , Ramseier Julie , Bosenberg Marcus W. , Mak Michael , Miller-Jensen Kathryn
Published: September 2021

Tumor immune response is shaped by the tumor microenvironment (TME), which often evolves to be immunosuppressive, promoting disease progression and metastasis. An important example is melanoma tumors, which display high numbers of tumor-associated macrophages (TAMs) that are immunosuppressive but also have the potential to restore anti-tumor activity. However, to therapeutically target TAMs, there is a need to understand the early events that shape their tumor-promoting profile. To address this, we built and optimized 3D in vitro co-culture systems, composed of a collagen-I matrix scaffolding murine bone-marrow-derived macrophages (BMDMs), YUMM1.7 melanoma cells, and fibroblasts to recreate the early melanoma TME and study how interactions with fibroblasts and tumor cells modulate macrophage immune activity. We monitored BMDM behavior and interactions through time-lapse imaging and characterized their activation and secretion. We found that stromal cells induced a rapid functional activation, with increased motility and response from BMDMs. Over the course of seven days, BMDMs acquired a phenotype and secretion profile that resembled melanoma TAMs in established tumors. Overall, the direct cell–cell interactions with the stromal components in a 3D environment shape BMDM transition to a TAM-like immunosuppressive state. Our systems will enable future studies of changes in macrophage–stromal cross-talk in the melanoma TME.
Liquid Biopsy from Bile-Circulating Tumor DNA in Patients with Biliary Tract Cancer
Authors: Han Jin-Yi , Ahn Keun Soo , Kim Tae-Seok , Kim Yong Hoon , Cho Kwang Bum , Shin Dong Woo , Baek Won-Ki , Suh Seong-Il , Jang Byeong-Churl , Kang Koo Jeong
Published: September 2021

Although liquid biopsy of blood is useful for cancer diagnosis and prediction of prognosis, diagnostic and prognostic value of ctDNA in bile fluid for BTCs are not clear yet. To determine whether liquid biopsy for circulating tumor DNA (ctDNA) can replace tissue biopsy when assessing somatic mutations in biliary tract cancers (BTCs). Bile samples were obtained from 42 patients with BTC. Matched formalin-fixed paraffin-embedded (FFPE) samples were obtained from 20 of these patients and matched plasma samples from 16 of them. Droplet digital PCR (ddPCR) was used for detection KRAS somatic mutation. KRAS mutations were identified in the bile ctDNA of 20 of 42 (48%) patients. Patients with mutant KRAS showed significantly worse survival than those with wild-type KRAS (2-year survival rates: 0% vs. 55.5%, respectively; p = 0.018). There was 80.0% mutational concordance between the paired bile ctDNA and FFPE samples, and 42.9% between the plasma and FFPE samples. On transcriptomic sequencing of one set of paired bile and FFPE samples, expression level of KRAS-associated signaling oncogenes in the bile and tissue samples showed a strong positive correlation (r = 0.991, p < 0.001). Liquid biopsy of bile reliably detect mutational variants within the bile ctDNA of BTC patients. These results suggest that bile is an effective biopsy fluid for ctDNA analysis.