bluuebunny/crossref_metadata_2025 huggingface dataset:
Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions
Authors: Kok Ken , Zwiers Kimberley C. , Boot Rolf G. , Overkleeft Hermen S. , Aerts Johannes M. F. G. , Artola Marta
Published: February 2021

Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by the deficiency of α-galactosidase A (α-GalA) and the consequent accumulation of toxic metabolites such as globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3). Early diagnosis and appropriate timely treatment of FD patients are crucial to prevent tissue damage and organ failure which no treatment can reverse. LSDs might profit from four main therapeutic strategies, but hitherto there is no cure. Among the therapeutic possibilities are intravenous administered enzyme replacement therapy (ERT), oral pharmacological chaperone therapy (PCT) or enzyme stabilizers, substrate reduction therapy (SRT) and the more recent gene/RNA therapy. Unfortunately, FD patients can only benefit from ERT and, since 2016, PCT, both always combined with supportive adjunctive and preventive therapies to clinically manage FD-related chronic renal, cardiac and neurological complications. Gene therapy for FD is currently studied and further strategies such as substrate reduction therapy (SRT) and novel PCTs are under investigation. In this review, we discuss the molecular basis of FD, the pathophysiology and diagnostic procedures, together with the current treatments and potential therapeutic avenues that FD patients could benefit from in the future.
Chemical and Bioinformatics Analyses of the Anti-Leishmanial and Anti-Oxidant Activities of Hemp Essential Oil
Authors: Menghini Luigi , Ferrante Claudio , Carradori Simone , D’Antonio Marianna , Orlando Giustino , Cairone Francesco , Cesa Stefania , Filippi Antonello , Fraschetti Caterina , Zengin Gokhan , Ak Gunes , Tacchini Massimo , Iqbal Kashif
Published: February 2021

Industrial hemp is a multiuse crop that has been widely cultivated to produce fibers and nutrients. The capability of the essential oil (EO) from inflorescences as antimicrobial agent has been reported. However, literature data are still lacking about the hemp EO antiprotozoal efficacy in vivo. The present study aims to unravel this concern through the evaluation of the efficacy of hemp EOs (2.5 mL/kg, intraperitoneally) of three different cultivars, namely Futura 75, Carmagnola selezionata and Eletta campana, in mice intraperitoneally infected with Leishmania tropica. A detailed description of EO composition and targets-components analysis is reported. Myrcene, α-pinene and E-caryophyllene were the main components of the EOs, as indicated by the gas-chromatographic analysis. However, a prominent position in the scenario of the theoretical interactions underlying the bio-pharmacological activity was also occupied by selina-3,7(11)-diene, which displayed affinities in the micromolar range (5.4–28.9) towards proliferator-activated receptor α, cannabinoid CB2 receptor and acetylcholinesterase. The content of this compound was higher in Futura 75 and Eletta campana, in accordance with their higher scavenging/reducing properties and efficacy against the tissue wound, induced by L. tropica. Overall, the present study recommends hemp female inflorescences, as sources of biomolecules with potential pharmacological applications, especially towards infective diseases.
Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma
Authors: Thakur Gitika , Kumar Raj , Kim Saet-Byul , Lee Sang-Yeob , Lee Sung-Lim , Rho Gyu-Jin
Published: February 2021

One of the most severe and devastating cancer is pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the major pancreatic exocrine cancer with a poor prognosis and growing prevalence. It is the most deadly disease, with an overall five-year survival rate of 6% to 10%. According to various reports, it has been demonstrated that pancreatic cancer stem cells (PCSCs) are the main factor responsible for the tumor development, proliferation, resistance to anti-cancer drugs, and recurrence of tumors after surgery. PCSCs have encouraged new therapeutic methods to be explored that can specifically target cancer cells. Furthermore, stem cells, especially mesenchymal stem cells (MSCs), are known as influential anti-cancer agents as they function through anti-inflammatory, paracrine, cytokines, and chemokine′s action. The properties of MSCs, such as migration to the site of infection and host immune cell activation by its secretome, seem to control the microenvironment of the pancreatic tumor. MSCs secretome exhibits similar therapeutic advantages as a conventional cell-based therapy. Moreover, the potential for drug delivery could be enhanced by engineered MSCs to increase drug bioactivity and absorption at the tumor site. In this review, we have discussed available therapeutic strategies, treatment hurdles, and the role of different factors such as PCSCs, cysteine, GPCR, PKM2, signaling pathways, immunotherapy, and NK-based therapy in pancreatic cancer.
STAT3 Signalling via the IL-6ST/gp130 Cytokine Receptor Promotes Epithelial Integrity and Intestinal Barrier Function during DSS-Induced Colitis
Authors: Pang Lokman , Huynh Jennifer , Alorro Mariah G. , Li Xia , Ernst Matthias , Chand Ashwini L.
Published: February 2021

The intestinal epithelium provides a barrier against commensal and pathogenic microorganisms. Barrier dysfunction promotes chronic inflammation, which can drive the pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Although the Signal Transducer and Activator of Transcription-3 (STAT3) is overexpressed in both intestinal epithelial cells and immune cells in IBD patients, the role of the interleukin (IL)-6 family of cytokines through the shared IL-6ST/gp130 receptor and its associated STAT3 signalling in intestinal barrier integrity is unclear. We therefore investigated the role of STAT3 in retaining epithelial barrier integrity using dextran sulfate sodium (DSS)-induced colitis in two genetically modified mouse models, to either reduce STAT1/3 activation in response to IL-6 family cytokines with a truncated gp130∆STAT allele (GP130∆STAT/+), or by inducing short hairpin-mediated knockdown of Stat3 (shStat3). Here, we show that mice with reduced STAT3 activity are highly susceptible to DSS-induced colitis. Mechanistically, the IL-6/gp130/STAT3 signalling cascade orchestrates intestinal barrier function by modulating cytokine secretion and promoting epithelial integrity to maintain a defence against bacteria. Our study also identifies a crucial role of STAT3 in controlling intestinal permeability through tight junction proteins. Thus, therapeutically targeting the IL-6/gp130/STAT3 signalling axis to promote barrier function may serve as a treatment strategy for IBD patients.
Chiral Dualism as a Unifying Principle in Molecular Biophysics
Authors: Malyshko Ekaterina V. , Semenova Ekaterina V. , Bagrova Olga E. , Murtazina Alina R. , Tverdislov Vsevolod A.
Published: February 2021

The origin and potential role of chiral asymmetry remain one of the most exciting issues in biology. In this paper we review the chirality of biological macromolecules, starting at the level of single molecules and continuing to the level of supramolecular assemblies. We discuss the physical and chemical consequences of the presence of chirality and their role in the self-organization and formation of structural hierarchies in cells. Homochirality may serve as an essential factor that invokes mechanisms required to control the formation of discrete structural hierarchies in macromolecules and macromolecular assemblies. Symmetry is of fundamental importance not only for all molecular biology as a systemic factor of its organization but also for pharmacology, as well as a systemic factor of drug stereospecificity.
An All-in-One Solid State Thin-Layer Potentiometric Sensor and Biosensor Based on Three-Dimensional Origami Paper Microfluidics
Authors: Pesaran Shiva , Rafatmah Elmira , Hemmateenejad Bahram
Published: February 2021

An origami three-dimensional design of a paper-based potentiometric sensor is described. In its simplest form, this electrochemical paper-based analytical device (ePAD) is made from three small parts of the paper. Paper layers are folded on each other for the integration of a solid contact ion selective electrode (here a carbon-paste composite electrode) and a solid-state pseudo-reference electrode (here writing pencil 6B on the paper), which are in contact with a hydrophilic channel fabricated on the middle part (third part) of the paper. In this case, the pseudo-reference and working electrodes are connected to the two sides of the hydrophilic channel and hence the distance between them is as low as the width of paper. The unmodified carbon paste electrode (UCPE) and modification with the crown ether benzo15-crown-5 (B15C5) represented a very high sensitivity to Cu (II) and Cd2+ ions, respectively. The sensor responded to H2O2 using MnO2-doped carbon paste electrode (CPE). Furthermore, a biosensor was achieved by the addition of glucose oxidase to the MnO2-doped CPE and hence made it selective to glucose with ultra-sensitivity. In addition to very high sensitivity, our device benefits from consuming a very low volume of sample (10.0 µL) and automatic sampling without need for sampling devices.
Simple Yeast-Direct Catalytic Fuel Cell Bio-Device: Analytical Results and Energetic Properties
Authors: Tomassetti Mauro , Dell’Aglio Emanuele , Castrucci Mauro , Sammartino Maria Pia , Campanella Luigi , Di Natale Corrado
Published: February 2021

This paper reports the analytical detection and energetic properties of a glucose-fed Direct Catalytic Fuel Cell (DCFC) operated in association with yeast cells (Saccharomyces Cerevisiae). The cell was tested in a potentiostatic mode, and the operating conditions were optimized to maximize the current produced by a given concentration of glucose. Results indicate that the DCFC is characterized by a glucose detection limit of the order to 21 mmol L−1. The cell was used to estimate the “pool” of carbohydrate content in commercial soft drinks. Furthermore, the use of different carbohydrates, such as fructose and sucrose, has been shown to result in a good current yield.
Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: Current Evidence and Future Perspectives
Authors: McGrowder Donovan A. , Miller Fabian , Vaz Kurt , Nwokocha Chukwuemeka , Wilson-Clarke Cameil , Anderson-Cross Melisa , Brown Jabari , Anderson-Jackson Lennox , Williams Lowen , Latore Lyndon , Thompson Rory , Alexander-Lindo Ruby
Published: February 2021

Alzheimer’s disease is a progressive, clinically heterogeneous, and particularly complex neurodegenerative disease characterized by a decline in cognition. Over the last two decades, there has been significant growth in the investigation of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease. This review presents current evidence from many clinical neurochemical studies, with findings that attest to the efficacy of existing core CSF biomarkers such as total tau, phosphorylated tau, and amyloid-β (Aβ42), which diagnose Alzheimer’s disease in the early and dementia stages of the disorder. The heterogeneity of the pathophysiology of the late-onset disease warrants the growth of the Alzheimer’s disease CSF biomarker toolbox; more biomarkers showing other aspects of the disease mechanism are needed. This review focuses on new biomarkers that track Alzheimer’s disease pathology, such as those that assess neuronal injury (VILIP-1 and neurofilament light), neuroinflammation (sTREM2, YKL-40, osteopontin, GFAP, progranulin, and MCP-1), synaptic dysfunction (SNAP-25 and GAP-43), vascular dysregulation (hFABP), as well as CSF α-synuclein levels and TDP-43 pathology. Some of these biomarkers are promising candidates as they are specific and predict future rates of cognitive decline. Findings from the combinations of subclasses of new Alzheimer’s disease biomarkers that improve their diagnostic efficacy in detecting associated pathological changes are also presented.
Development of the Spanish Version of Sniffin’s Sticks Olfactory Identification Test: Normative Data and Validity of Parallel Measures
Authors: Delgado-Losada María , Bouhaben Jaime , Delgado-Lima Alice
Published: February 2021

The Sniffin’ Sticks Olfactory Identification Test is a tool for measurement of olfactory performance developed in Germany and validated in several countries. This research aims to develop the Spanish version of the Sniffin’ Sticks Olfactory Identification Test and obtain normative values for the Spanish population. The parameters are free recall and subjective intensity of odorants are included. The influence of possible demographic covariates such as sex, age, smoking, or educational level are analyzed, and the items that best discriminate are studied. In addition, the internal structure validity of the blue and purple versions is studied as a parallel measure, and a cultural adaptation of the purple version is carried out. For this, three independent samples of normosmic healthy volunteers were studied. To obtain normative values, the sample was of 417 participants (18–89 years). For the internal structure validity study of both versions, the sample was 226 (18–70 years), and for familiarity of the purple version, the sample was 75 participants (21–79 years). Results indicated that men and women and smokers and non-smokers perform equally. However, differences were found as age progresses, being more pronounced after 60 years old in all three measurements of the identification test. This research also provides the items that best discriminate in the blue version and a cultural adaptation for the purple version. In conclusion, the Sniffin’ Sticks Odor Identification Test is a suitable tool for olfactory assessment in the Spanish population. The instrument has been expanded with two new scores, and normative data as a function of age are provided. Its parallel version also seems appropriate for testing, as items have been culturally adapted and evidence of internal structure validity for both versions is reported.
Gamma-Range Auditory Steady-State Responses and Cognitive Performance: A Systematic Review
Authors: Parciauskaite Vykinta , Bjekic Jovana , Griskova-Bulanova Inga
Published: February 2021

The auditory steady-state response (ASSR) is a result of entrainment of the brain’s oscillatory activity to the frequency and phase of temporally modulated stimuli. Gamma-range ASSRs are utilized to observe the dysfunctions of brain-synchronization abilities in neuropsychiatric and developmental disorders with cognitive symptoms. However, the link between gamma-range ASSRs and cognitive functioning is not clear. We systematically reviewed existing findings on the associations between gamma-range ASSRs and cognitive functions in patients with neuropsychiatric or developmental disorders and healthy subjects. The literature search yielded 1597 articles. After excluding duplicates and assessing eligibility, 22 articles were included. In healthy participants, the gamma-range ASSR was related to cognitive flexibility and reasoning as measured by complex tasks and behavioral indicators of processing speed. In patients with schizophrenia, the studies that reported correlations found a higher ASSR to be accompanied by better performance on short-term memory tasks, long-term/semantic memory, and simple speeded tasks. The main findings indicate that individual differences in the gamma-range ASSR reflect the level of attentional control and the ability to temporary store and manipulate the information, which are necessary for a wide range of complex cognitive activities, including language, in both healthy and impaired populations.
Eye Fixation-Related Potentials during Visual Search on Acquaintance and Newly-Learned Faces
Authors: Lee Seungji , Lee Doyoung , Gil Hyunjae , Oakley Ian , Cho Yang Seok , Kim Sung-Phil
Published: February 2021

Searching familiar faces in the crowd may involve stimulus-driven attention by emotional significance, together with goal-directed attention due to task-relevant needs. The present study investigated the effect of familiarity on attentional processes by exploring eye fixation-related potentials (EFRPs) and eye gazes when humans searched for, among other distracting faces, either an acquaintance’s face or a newly-learned face. Task performance and gaze behavior were indistinguishable for identifying either faces. However, from the EFRP analysis, after a P300 component for successful search of target faces, we found greater deflections of right parietal late positive potentials in response to newly-learned faces than acquaintance’s faces, indicating more involvement of goal-directed attention in processing newly-learned faces. In addition, we found greater occipital negativity elicited by acquaintance’s faces, reflecting emotional responses to significant stimuli. These results may suggest that finding a familiar face in the crowd would involve lower goal-directed attention and elicit more emotional responses.
The Sleep Impact on Activity Diary (SIAD): A Novel Assessment of Daytime Functioning in Insomnia
Authors: Bickley Kelsey , Lovato Nicole , Lack Leon
Published: February 2021

Daytime impairments feature in the diagnostic criteria for insomnia disorder yet are rarely assessed comprehensively in clinical practice and tend to focus on mood and subjective assessment of cognitive competence. In order to gain more information about the engagement in daily activities we developed the Sleep Impact on Activity Diary (SIAD). This initial investigation included 22 insomnia patients (15 females, aged 49.9 years, SD = 17.6) and 19 normal sleeper controls (13 females, aged 30.9 years, SD = 8.9). For 14 consecutive evenings, participants rated how their prior night-time sleep impacted their participation in 12 common daytime activities (e.g., work, self-care, leisure). They also rated how much effort each activity required (Range: 0–4). Overall, insomnia patients participated in only one fewer activity type per day (M = 7.48, SD = 1.34) than controls (M = 8.39, SD = 1.43) (p = 0.041, d = 0.66). More noteworthy, they reported that sleep negatively affected their participation more than controls (M = 1.56, SD = 0.92 versus M = 0.23, SD = 0.35; p = < 0.001, d = 1.90), and that activities required more effort (M = 1.58, SD = 0.64 versus M = 0.81, SD = 0.76; p = 0.001, d = 1.10). This pilot study with the SIAD suggests that, compared to good sleepers, insomnia patients participate in somewhat fewer activities but that their activities require considerably more effort and are adversely affected by their sleep. The SIAD tool promises to provide a more comprehensive picture of the everyday impact of insomnia. It remains to be validated on a much larger sample in a clinical treatment study.
Risk Factors of the First-Time Stroke in the Southwest of Saudi Arabia: A Case-Control Study
Authors: Alhazzani Adel , Mahfouz Ahmed , Abolyazid Ahmed , Awadalla Nabil
Published: February 2021

Worldwide, stroke is the second leading cause of death and a frequent cause of permanent disability. The objective was to identify the first-time stroke modifiable risk factors in the Aseer region, southwest Saudi Arabia. In a multicenter hospital-based case-control study design, all first stroke patients admitted to hospitals in the Aseer region were included consecutively over one year. Age, sex, and geographical residence-matched controls were selected and included in a ratio of 1:1. Data collected included altitude (low or high), nationality, marital status, educational level, family history of stroke, history of diabetes mellitus, history of systemic hypertension, high cholesterol level, current smoking, obesity, and regular exercise practice. The study included 1249 first-time stroke patients and 1249 age, sex, and residence-matched controls. Hypertension, diabetes mellitus, obesity, and high cholesterol were significantly highly prevalent among cases (57.7%, 49.4%, 42.0%, 29.4%, respectively) compared to controls (31.8%, 25.9%, 30.8%, 12.1%, respectively). Practicing regular exercise was significantly highly prevalent among controls (29.9%) compared to cases (13.1%). Multivariable logistic regression analysis revealed that systemic hypertension (adjusted odds ratio (aOR) = 2.12, 95%CI: 1.74–2.57), diabetes mellitus (aOR = 1.73, 95%CI: 1.41–2.21), obesity (aOR = 1.95, 95%CI: 1.61–2.28) and high cholesterol (aOR = 1.64, 95%CI: 1.28–2.10) were significant risk factors, while regular exercise practice was a significant protective factor (aOR = 0.12, 95%CI: 0.05–0.26) for stroke. Hypertension, diabetes mellitus, obesity, and high cholesterol are major risk factors for stroke in the Aseer region of southwest Saudi Arabia. The protective role of regular physical activity in reducing the risk of stroke is evident. The observed higher prevalence of potentially modifiable risk factors among stroke cases encourages an urgent need to develop and implement a national program to control these factors.
Sentence Recall in Latent and Anomic Aphasia: An Exploratory Study of Semantics and Syntax
Authors: Salis Christos , Martin Nadine , Reinert Laura
Published: February 2021

We investigated whether semantic plausibility and syntactic complexity affect immediate sentence recall in people with latent and anomic aphasia. To date, these factors have not been explored in these types of aphasia. As with previous studies of sentence recall, we measured accuracy of verbatim recall and uniquely real-time speech measures. The results showed that accuracy did not distinguish performance between latent aphasia and neurotypical controls. However, some of the real-time speech measures distinguished performance between people with latent aphasia and neurotypical controls. There was some evidence, though not pervasive, that semantic plausibility and syntactic complexity influenced recall performance. There were no interactions between semantic plausibility and syntactic complexity. The speed of preparation of responses was slower in latent aphasia than controls; it was also slower in anomic aphasia than both latent and control groups. It appears that processing speed as indexed by temporal speech measures may be differentially compromised in latent and anomic aphasia. However, semantic plausibility and syntactic complexity did not show clear patterns of performance among the groups. Notwithstanding the absence of interactions, we advance an explanation based on conceptual short-term memory as to why semantically implausible sentences are typically more erroneous and possibly also slower in recall.
Construction Waste Audit in the Framework of Sustainable Waste Management in Construction Projects—Case Study
Authors: Spišáková Marcela , Mésároš Peter , Mandičák Tomáš
Published: February 2021

The issue of sustainability has long been the subject of interest in architecture engineering and the construction sector. All three aspects of sustainability—economic, environmental, and social—can be affected through appropriate construction waste management. Construction and demolition waste (CDW) is one of the largest worldwide waste streams, therefore, it is given great attention by all stakeholders (investors, contractors, authorities, etc.). Research studies show that one of the main barriers to insufficient CDW recovery is inadequate policies and legal frameworks to manage CDW. It is also one of European Union’s (EU) environmental priorities. The aim of the article was to confirm the economic potential of construction and demolition waste audit processing through a case study. A pre-demolition waste audit was processed for an unused shopping center building in the town Snina in Slovakia. Subsequently, a comparison of economic parameters (waste disposal costs and transport costs) of the recommended CDW management was performed. This comparison confirmed the economic benefits of environmentally friendly construction waste management methods according to the waste audit results, which would also increase the sustainability of construction projects. Additionally, the cost parameters of selected waste disposal methods could be another dimension of building information modeling.
A Modified 2 Tier Chemotherapy Response Score (CRS) and Other Histopathologic Features for Predicting Outcomes of Patients with Advanced Extrauterine High-Grade Serous Carcinoma after Neoadjuvant Chemotherapy
Authors: Zhong Yanping , Liu Jinsong , Li Xiaoran , Westin Shannon N. , Malpica Anais , Lawson Barrett C. , Lee Sanghoon , Fellman Bryan M. , Coleman Robert L. , Sood Anil K. , Fleming Nicole D.
Published: February 2021

Background: The impact of chemotherapy response score (CRS) on prognosis has varied among studies. We addressed the prognostic significance of CRS and the prognostic value of previously undescribed histologic features using a cohort of 245 patients. Methods: Retrospective study in patients with advanced extrauterine high-grade serous carcinomas treated with neoadjuvant chemotherapy followed by interval tumor reductive surgery from 1990 to 2018 in our hospital. Gynecologic pathologists assessed tumor CRS and other histologic features. Clinical information was collected, and multivariate analyses were conducted. Results: A modified 2 tier CRS (CRS 1/2 versus CRS 3) was significantly associated, independent of scoring site (omental versus adnexal), with overall survival (OS) (omentum, p = 0.018; adnexa, p = 0.042; entire cohort, p = 0.002) and progression-free survival (PFS) (p = 0.021, p = 0.035, and p = 0.001, respectively). On multivariate survival analysis, 2 tier CRS, oncocytic change, inflammation, and desmoplasia were significant for OS (p = 0.034, p = 0.020, p = 0.007, and p = 0.010, respectively). Likewise, 2 tier CRS, inflammation, and desmoplasia were significant for PFS (p = 0.012, p = 0.003, p = 0.011, respectively). Conclusions: The modified 2 tier CRS was significantly associated with survival, independent of scoring site. Additional histologic features including oncocytic change, inflammation, and desmoplasia can also predict patient outcomes.
Tackling HLA Deficiencies Head on with Oncolytic Viruses
Authors: Fisher Kerry , Hazini Ahmet , Seymour Leonard W.
Published: February 2021

Dysregulation of HLA (human leukocyte antigen) function is increasingly recognized as a common escape mechanism for cancers subject to the pressures exerted by immunosurveillance or immunotherapeutic interventions. Oncolytic viruses have the potential to counter this resistance by upregulating HLA expression or encouraging an HLA-independent immunological responses. However, to achieve the best therapeutic outcomes, a prospective understanding of the HLA phenotype of cancer patients is required to match them to the characteristics of different oncolytic strategies. Here, we consider the spectrum of immune competence observed in clinical disease and discuss how it can be best addressed using this novel and powerful treatment approach.
The Distinctive Serum Metabolomes of Gastric, Esophageal and Colorectal Cancers
Authors: Ren Zhenxing , Rajani Cynthia , Jia Wei
Published: February 2021

Three of the most lethal cancers in the world are the gastrointestinal cancers—gastric (GC), esophageal (EC) and colorectal cancer (CRC)—which are ranked as third, sixth and fourth in cancer deaths globally. Early detection of these cancers is difficult, and a quest is currently on to find non-invasive screening tests to detect these cancers. The reprogramming of energy metabolism is a hallmark of cancer, notably, an increased dependence on aerobic glycolysis which is often referred to as the Warburg effect. This metabolic change results in a unique metabolic profile that distinguishes cancer cells from normal cells. Serum metabolomics analyses allow one to measure the end products of both host and microbiota metabolism present at the time of sample collection. It is a non-invasive procedure requiring only blood collection which encourages greater patient compliance to have more frequent screenings for cancer. In the following review we will examine some of the most current serum metabolomics studies in order to compare their results and test a hypothesis that different tumors, notably, from EC, GC and CRC, have distinguishing serum metabolite profiles.
SILAC-Based Quantitative Proteomic Analysis of Oxaliplatin-Resistant Pancreatic Cancer Cells
Authors: Kim Young Eun , Kim Eun-Kyung , Song Min-Jeong , Kim Tae-Young , Jang Ho Hee , Kang Dukjin
Published: February 2021

Oxaliplatin is a commonly used chemotherapeutic drug for the treatment of pancreatic cancer. Understanding the cellular mechanisms of oxaliplatin resistance is important for developing new strategies to overcome drug resistance in pancreatic cancer. In this study, we performed a stable isotope labelling by amino acids in cell culture (SILAC)-based quantitative proteomics analysis of oxaliplatin-resistant and sensitive pancreatic cancer PANC-1 cells. We identified 107 proteins whose expression levels changed (thresholds of 2-fold changes and p-value ≤ 0.05) between oxaliplatin-resistant and sensitive cells, which were involved in multiple biological processes, including DNA repair, cell cycle process, and type I interferon signaling pathway. Notably, myristoylated alanine-rich C-kinase substrate (MARCKS) and Wntless homolog protein (WLS) were upregulated in oxaliplatin-resistant cells compared to sensitive cells, as confirmed by qRT-PCR and Western blot analysis. We further demonstrated the activation of AKT and β-catenin signaling (downstream targets of MARCKS and WLS, respectively) in oxaliplatin-resistant PANC-1 cells. Additionally, we show that the siRNA-mediated suppression of both MARCKS and WLS enhanced oxaliplatin sensitivity in oxaliplatin-resistant PANC-1 cells. Taken together, our results provide insights into multiple mechanisms of oxaliplatin resistance in pancreatic cancer cells and reveal that MARCKS and WLS might be involved in the oxaliplatin resistance.
Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer
Authors: Werle Silke D. , Schwab Julian D. , Tatura Marina , Kirchhoff Sandra , Szekely Robin , Diels Ramona , Ikonomi Nensi , Sipos Bence , Sperveslage Jan , Gress Thomas M. , Buchholz Malte , Kestler Hans A.
Published: February 2021

Cofilin-1 (CFL1) overexpression in pancreatic cancer correlates with high invasiveness and shorter survival. Besides a well-documented role in actin remodeling, additional cellular functions of CFL1 remain poorly understood. Here, we unraveled molecular tumor-promoting functions of CFL1 in pancreatic cancer. For this purpose, we first show that a knockdown of CFL1 results in reduced growth and proliferation rates in vitro and in vivo, while apoptosis is not induced. By mechanistic modeling we were able to predict the underlying regulation. Model simulations indicate that an imbalance in actin remodeling induces overexpression and activation of CFL1 by acting on transcription factor 7-like 2 (TCF7L2) and aurora kinase A (AURKA). Moreover, we could predict that CFL1 impacts proliferation and apoptosis via the signal transducer and activator of transcription 3 (STAT3). These initial model-based regulations could be substantiated by studying protein levels in pancreatic cancer cell lines and human datasets. Finally, we identified the surface protein CD44 as a promising therapeutic target for pancreatic cancer patients with high CFL1 expression.
Blocking Migration of Polymorphonuclear Myeloid-Derived Suppressor Cells Inhibits Mouse Melanoma Progression
Authors: Groth Christopher , Arpinati Ludovica , Shaul Merav E. , Winkler Nina , Diester Klara , Gengenbacher Nicolas , Weber Rebekka , Arkhypov Ihor , Lasser Samantha , Petrova Vera , Augustin Hellmut G. , Altevogt Peter , Utikal Jochen , Fridlender Zvi G. , Umansky Viktor
Published: February 2021

Background: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms. Furthermore, we inhibited PMN-MDSC migration in vivo to determine its effect on tumor progression. Methods: Using the RET transgenic melanoma mouse model, we investigated the immunosuppressive function of MDSC subsets and chemokine receptor expression on these cells. The effect of CXCR2 inhibition on PMN-MDSC migration and tumor progression was studied in RET transgenic mice and in C57BL/6 mice after surgical resection of primary melanomas. Results: Immunosuppressive capacity of intratumoral M- and PMN-MDSC was comparable in melanoma bearing mice. Anti-CXCR2 therapy prolonged survival of these mice and decreased the occurrence of distant metastasis. Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells. Conclusions: We provide evidence for the tumor−promoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice.
Circulating Cell-Free DNA in Breast Cancer: Searching for Hidden Information towards Precision Medicine
Authors: Panagopoulou Maria , Esteller Manel , Chatzaki Ekaterini
Published: February 2021

Breast cancer (BC) is a leading cause of death between women. Mortality is significantly raised due to drug resistance and metastasis, while personalized treatment options are obstructed by the limitations of conventional biopsy follow-up. Lately, research is focusing on circulating biomarkers as minimally invasive choices for diagnosis, prognosis and treatment monitoring. Circulating cell-free DNA (ccfDNA) is a promising liquid biopsy biomaterial of great potential as it is thought to mirror the tumor’s lifespan; however, its clinical exploitation is burdened mainly by gaps in knowledge of its biology and specific characteristics. The current review aims to gather latest findings about the nature of ccfDNA and its multiple molecular and biological characteristics in breast cancer, covering basic and translational research and giving insights about its validity in a clinical setting.
Mouse Preclinical Cancer Immunotherapy Modeling Involving Anti-PD-1 Therapies Reveals the Need to Use Mouse Reagents to Mirror Clinical Paradigms
Authors: Monjazeb Arta M. , Wang Ziming , Vick Logan V. , Dunai Cordelia , Minnar Christine , Khuat Lam T. , Murphy William J.
Published: February 2021

Immune checkpoint inhibition (ICI) has emerged as one of the most powerful tools to reverse cancer induced immune suppression. Monoclonal antibodies (mAbs) targeting programmed cell death 1/programmed cell death ligand 1(PD-1/PD-L1) are FDA-approved and their clinical use is rapidly expanding. As opposed to the clinical paradigm, which can result in significant responses and toxicities, it has been difficult to reproduce these effects preclinically using mouse models. In large part, this is due to models, which employ rapidly growing ex vivo cultured transplantable tumor cell lines engrafted into young naïve inbred laboratory mice. However, another issue concerns the use and repeated application of xenogeneic reagents in mice (i.e., rat or hamster mAbs directed against mouse antigens at variance with clinical use of human or humanized mAbs). Building on our previous studies demonstrating that repeated administration of commonly used xenogeneic anti-PD-1 mAbs derived from both rat and hamster can induce fatal hypersensitivity in some tumor-bearing mice, we sought to compare these result with the effects of a mouse anti-mouse PD-1 mAb. Application of a murine anti-mouse PD-1 (clone: MuDX400) did not result in lethal anaphylaxis in the 4T1 tumor model. It also displayed superior antitumor effects in this and other tumor models, as it did not induce neutralizing antibody responses against the anti-PD-1 mAb, such as were observed when using xenogeneic anti-PD1 mAbs. These results demonstrate that more accurate preclinical modeling necessitates the use of mouse reagents mirroring the clinical scenario to ascertain long-term effects or toxicities, while avoiding xenogeneic responses, which do not occur clinically. Furthermore, these studies suggest a direct mechanism, whereby preclinical murine studies have often failed to recapitulate the clinical efficacy and toxicity of single agent checkpoint inhibition.
The Underlying Biology and Therapeutic Vulnerabilities of Leptomeningeal Metastases in Adult Solid Cancers
Authors: Dankner Matthew , Lam Stephanie , Degenhard Theresa , Garzia Livia , Guiot Marie-Christine , Petrecca Kevin , Siegel Peter M.
Published: February 2021

Metastasis to the central nervous system occurs in approximately 20% of patients with advanced solid cancers such as lung cancer, breast cancer, and melanoma. While central nervous system metastases most commonly form in the brain parenchyma, metastatic cancer cells may also reside in the subarachnoid space surrounding the brain and spinal cord to form tumors called leptomeningeal metastases. Leptomeningeal metastasis involves cancer cells that reach the subarachnoid space and proliferate in the cerebrospinal fluid compartment within the leptomeninges, a sequela associated with a myriad of symptoms and poor prognosis. Cancer cells exposed to cerebrospinal fluid in the leptomeninges must contend with a unique microenvironment from those that establish within the brain or other organs. Leptomeningeal lesions provide a formidable clinical challenge due to their often-diffuse infiltration within the subarachnoid space. The molecular mechanisms that promote the establishment of leptomeningeal metastases have begun to be elucidated, demonstrating that it is a biological entity distinct from parenchymal brain metastases and is associated with specific molecular drivers. In this review, we outline the current state of knowledge pertaining to the diagnosis, treatment, and molecular underpinnings of leptomeningeal metastasis.
Molecular Classification and Tumor Microenvironment Characterization of Gallbladder Cancer by Comprehensive Genomic and Transcriptomic Analysis
Authors: Ebata Nobutaka , Fujita Masashi , Sasagawa Shota , Maejima Kazuhiro , Okawa Yuki , Hatanaka Yutaka , Mitsuhashi Tomoko , Oosawa-Tatsuguchi Ayako , Tanaka Hiroko , Miyano Satoru , Nakamura Toru , Hirano Satoshi , Nakagawa Hidewaki
Published: February 2021

Gallbladder cancer (GBC), a rare but lethal disease, is often diagnosed at advanced stages. So far, molecular characterization of GBC is insufficient, and a comprehensive molecular portrait is warranted to uncover new targets and classify GBC. We performed a transcriptome analysis of both coding and non-coding RNAs from 36 GBC fresh-frozen samples. The results were integrated with those of comprehensive mutation profiling based on whole-genome or exome sequencing. The clustering analysis of RNA-seq data facilitated the classification of GBCs into two subclasses, characterized by high or low expression levels of TME (tumor microenvironment) genes. A correlation was observed between gene expression and pathological immunostaining. TME-rich tumors showed significantly poor prognosis and higher recurrence rate than TME-poor tumors. TME-rich tumors showed overexpression of genes involved in epithelial-to-mesenchymal transition (EMT) and inflammation or immune suppression, which was validated by immunostaining. One non-coding RNA, miR125B1, exhibited elevated expression in stroma-rich tumors, and miR125B1 knockout in GBC cell lines decreased its invasion ability and altered the EMT pathway. Mutation profiles revealed TP53 (47%) as the most commonly mutated gene, followed by ELF3 (13%) and ARID1A (11%). Mutations of ARID1A, ERBB3, and the genes related to the TGF-β signaling pathway were enriched in TME-rich tumors. This comprehensive analysis demonstrated that TME, EMT, and TGF-β pathway alterations are the main drivers of GBC and provides a new classification of GBCs that may be useful for therapeutic decision-making.
Physiological Biomarkers Assessed by Low-Tech Exercise Tests Predict Complications and Overall Survival in Patients Undergoing Pneumonectomy Due to Lung Cancer
Authors: Marjanski Tomasz , Wnuk Damian , Dziedzic Robert , Ostrowski Marcin , Sawicka Wioletta , Marjanska Ewa , Rzyman Witold
Published: February 2021

Due to its debilitating character pneumonectomy this is last-resort procedure. Preoperative results of the 6-min walking test (6MWT) help to identify high risk of postoperative complications and increased mortality in patients undergoing lobectomy for lung cancer. The aim of the study was to validate the value of 500 m in 6MWT as an indicator, which differentiates risk of complications in patients undergoing pneumonectomy. 125 patients who underwent pneumonectomy at Thoracic Surgery Department between 2009 and 2018. On the day preceding the surgery, patients underwent 6MWT. The patients were in median age of 63 years. The cut-off value of 500 m identified patients with increased 90-day mortality [17.9% vs. 3.5%, odds ratio (OR) 6.271, 95% confidence interval (CI) 1.528–25.739], first-year mortality (30.7% vs. 11.6%, OR 3.378, 95% CI 1.310–8.709), and overall survival (p = 0.02). Patients who covered a distance ≤ 500 m had an increased risk of atrial fibrillation (35.9% vs. 16.3%, OR 2.880, 95% CI 1.207–6.870) and cardiac complications (38.4% vs. 19.8%, OR 2.537, 95% CI 1.100–5.849). Patients unable to reach 500 m in 6MWT are in a high risk of postoperative death after pneumonectomy, what may be a result of increased frequency of postoperative cardiac complications. Poor result of 6MWT is a predictor of worse overall survival.
Neuroblastoma Invasion Strategies Are Regulated by the Extracellular Matrix
Authors: Gavin Cian , Geerts Nele , Cavanagh Brenton , Haynes Meagan , Reynolds C. Patrick , Loessner Daniela , Ewald Andrew J. , Piskareva Olga
Published: February 2021

Neuroblastoma is a paediatric malignancy of the developing sympathetic nervous system. About half of the patients have metastatic disease at the time of diagnosis and a survival rate of less than 50%. Our understanding of the cellular processes promoting neuroblastoma metastases will be facilitated by the development of appropriate experimental models. In this study, we aimed to explore the invasion of neuroblastoma cells and organoids from patient-derived xenografts (PDXs) grown embedded in 3D extracellular matrix (ECM) hydrogels by time-lapse microscopy and quantitative image analysis. We found that the ECM composition influenced the growth, viability and local invasion of organoids. The ECM compositions induced distinct cell behaviours, with Matrigel being the preferred substratum for local organoid invasion. Organoid invasion was cell line- and PDX-dependent. We identified six distinct phenotypes in PDX-derived organoids. In contrast, NB cell lines were more phenotypically restricted in their invasion strategies, as organoids isolated from cell line-derived xenografts displayed a broader range of phenotypes compared to clonal cell line clusters. The addition of FBS and bFGF induced more aggressive cell behaviour and a broader range of phenotypes. In contrast, the repression of the prognostic neuroblastoma marker, MYCN, resulted in less aggressive cell behaviour. The combination of PDX organoids, real-time imaging and the novel 3D culture assays developed herein will enable rapid progress in elucidating the molecular mechanisms that control neuroblastoma invasion.
Transfer Learning in Breast Cancer Diagnoses via Ultrasound Imaging
Authors: Ayana Gelan , Dese Kokeb , Choe Se-woon
Published: February 2021

Transfer learning is a machine learning approach that reuses a learning method developed for a task as the starting point for a model on a target task. The goal of transfer learning is to improve performance of target learners by transferring the knowledge contained in other (but related) source domains. As a result, the need for large numbers of target-domain data is lowered for constructing target learners. Due to this immense property, transfer learning techniques are frequently used in ultrasound breast cancer image analyses. In this review, we focus on transfer learning methods applied on ultrasound breast image classification and detection from the perspective of transfer learning approaches, pre-processing, pre-training models, and convolutional neural network (CNN) models. Finally, comparison of different works is carried out, and challenges—as well as outlooks—are discussed.
Toll-Like Receptor 7 Mediates Inflammation Resolution and Inhibition of Angiogenesis in Non-Small Cell Lung Cancer
Authors: Liotti Federica , Marotta Maria , Sorriento Daniela , Pone Emanuela , Morra Francesco , Melillo Rosa Marina , Prevete Nella
Published: February 2021

Pattern recognition receptors (PRR) promote inflammation but also its resolution. We demonstrated that a specific PRR—formyl peptide receptor 1 (FPR1)—sustains an inflammation resolution response with anti-angiogenic and antitumor potential in gastric cancer. Since toll-like receptor 7 (TLR7) is crucial in the physiologic resolution of airway inflammation, we asked whether it could be responsible for pro-resolving and anti-angiogenic responses in non-small cell lung cancer (NSCLC). TLR7 correlated directly with pro-resolving and inversely with angiogenic mediators in NSCLC patients, as revealed by a publicly available RNAseq analysis. In NSCLC cells, depletion of TLR7 caused an upregulation of angiogenic mediators and a stronger vasculogenic response of endothelial cells compared to controls, assessed by qPCR, ELISA, protein array, and endothelial cell responses. TLR7 activation induced the opposite effects. TLR7 silencing reduced, while its activation increased, the pro-resolving potential of NSCLC cells, evaluated by qPCR, flow cytometry, and EIA. The increased angiogenic potential of TLR7-silenced NSCLC cells is due to the lack of pro-resolving mediators. MAPK and STAT3 signaling are responsible for these activities, as demonstrated through Western blotting and inhibitors. Our data indicate that TLR7 sustains a pro-resolving signaling in lung cancer that inhibits angiogenesis. This opens new possibilities to be exploited for cancer treatment.
Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular Carcinoma
Authors: Ridder Dirk Andreas , Schindeldecker Mario , Weinmann Arndt , Berndt Kristina , Urbansky Lana , Witzel Hagen Roland , Heinrich Stefan , Roth Wilfried , Straub Beate Katharina
Published: February 2021

Patients with hepatocellular carcinoma (HCC) have a highly variable clinical course. Therefore, there is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Recently, it has been demonstrated that dysregulation of the urea cycle (UC) is a common phenomenon in multiple types of cancer. Upon UC dysregulation, nitrogen is diverted toward the multifunctional enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), and increases pyrimidine synthesis. In this study, we investigated the role of CAD and carbamoyl-phosphate synthetase 1 (CPS1), a rate-limiting enzyme of the UC highly expressed in hepatocytes, in HCC. We created a tissue microarray to analyze expression of both enzymes by immunohistochemistry in a large and well-characterized overall cohort of 871 HCCs of 561 patients that underwent surgery. CAD was induced in recurrent HCCs, and high expression predicted shorter overall survival. CPS1 was downregulated in HCC and further reduced in recurrent tumors and distant metastases. Additionally, low CPS1 was associated with short overall survival. A combined score of both enzymes was an independent prognostic marker in a multivariate Cox regression model (HR = 1.37, 95% confidence interval 1.06–1.75, p = 0.014). Inhibition of pyrimidine synthesis may represent a novel therapeutic strategy for HCC.