bluuebunny/crossref_metadata_2025 huggingface dataset:
Growth Kinetics of Probiotic Lactobacillus Strains in the Alternative, Cost-Efficient Semi-Solid Fermentation Medium
Authors: Śliżewska Katarzyna , Chlebicz-Wójcik Agnieszka
Published: November 2020

The growing need for Lactobacillus bacteria usage in industry and the expending probiotic market led to a search for new cost-efficient fermentation media from which a high yield of these bacteria could be obtained. The following study aimed to elaborate cultivation medium, for Lactobacillus spp. growth, which main components would be wheat, maize, barley, and rye flours. The optimal temperature for Lactobacillus growth in new semi-solid fermentation (SSF) medium, water content, and pH of the medium were analyzed by the plate count method. It was established, that the highest bacteria counts were obtained from cultures conducted in the SSF medium with flours to water ratio of 1:1.5 with a natural pH of 6.0 at 37 °C. Subsequently, the growth kinetics of analyzed strains, in both MRS and the SSF media, were studied. The newly designed media contributed to the increased duration of selected Lactobacillus strains lag phase, which varied from 1.98 to 5.64; nevertheless, the maximum growth rate of the strains was two times higher in the SSF medium rather than in MRS, which also resulted in shorter generation time. The developed medium has the potential to become a new cost-efficient fermentation medium for Lactobacillus spp.
Sensing of Proteins by ICD Response of Iron(II) Clathrochelates Functionalized by Carboxyalkylsulfide Groups
Authors: Losytskyy Mykhaylo , Chornenka Nina , Vakarov Serhii , Meier-Menches Samuel , Gerner Christopher , Potocki Slawomir , Arion Vladimir , Gumienna-Kontecka Elzbieta , Voloshin Yan , Kovalska Vladyslava
Published: November 2020

Recognition of elements of protein tertiary structure is crucial for biotechnological and biomedical tasks; this makes the development of optical sensors for certain protein surface elements important. Herein, we demonstrated the ability of iron(II) clathrochelates (1–3) functionalized with mono-, di- and hexa-carboxyalkylsulfide to induce selective circular dichroism (CD) response upon binding to globular proteins. Thus, inherently CD-silent clathrochelates revealed selective inducing of CD spectra when binding to human serum albumin (HSA) (1, 2), beta-lactoglobuline (2) and bovine serum albumin (BSA) (3). Hence, functionalization of iron(II) clathrochelates with the carboxyalkylsulfide group appears to be a promising tool for the design of CD-probes sensitive to certain surface elements of proteins tertiary structure. Additionally, interaction of 1–3 with proteins was also studied by isothermal titration calorimetry, protein fluorescence quenching, electrospray ionization mass spectrometry (ESI-MS) and computer simulations. Formation of both 1:1 and 1:2 assemblies of HSA with 1–3 was evidenced by ESI-MS. A protein fluorescence quenching study suggests that 3 binds with both BSA and HSA via the sites close to Trp residues. Molecular docking calculations indicate that for both BSA and HSA, binding of 3 to Site I and to an “additional site” is more favorable energetically than binding to Site II.
Phytomediated Photo-Induced Green Synthesis of Silver Nanoparticles Using Matricaria chamomilla L. and Its Catalytic Activity against Rhodamine B
Authors: Alshehri Abdulmohsen Ali , Malik Maqsood Ahmad
Published: November 2020

The bio-fabrication of silver nanoparticles (AgNPs) was carried out through the facile green route, using the aqueous extract of Matricaria chamomilla L. Herein, we have developed a cost-efficient, ecofriendly, and photo-induced method for the biomolecule-assisted synthesis of AgNPs using an aqueous extract of Matricaria chamomilla L. as a bio-reducing and capping/stabilizing agent. The biomolecule-capped AgNPs were confirmed from the surface plasmon resonance (SPR) band at λmax = 450 nm using a UV–visible spectrometer. The stability of the AgNPs was confirmed by recording the UV–visible spectra for a more extended period, and no precipitation was observed in the sol. The morphology and structure of photo-induced biomolecule-capped AgNPs were characterized by different microscopic and spectroscopy techniques such as TEM, SEM, EDX, XRD, and FTIR analysis. The role of phytochemicals as reducing and stabilizing agents was confirmed by comparative FTIR analysis of the AgNPs and pure Matricaria chamomilla L. aqueous extract. The obtained result shows that the AgNPs are mostly spherical morphology with an average size of about 26 nm. Furthermore, the thermal stability of biomolecule-capped AgNPs was examined by TGA-DTG analysis that showed a weight loss of approximately 36.63% up to 800 °C. Moreover, the potential photocatalytic activity of photo-induced AgNPs against Rhodamine B (RB) was examined in the presence of UV light irradiation. The catalyst reusability, the effect of catalyst dosage and initial dye concentration, and the effect of the temperature and pH of the reaction medium were also assessed.
BODIPY Dyes as Probes and Sensors to Study Amyloid-β-Related Processes
Authors: Dzyuba Sergei V.
Published: November 2020

Amyloid formation plays a major role in a number of neurodegenerative diseases, including Alzheimer’s disease. Amyloid-β peptides (Aβ) are one of the primary markers associated with this pathology. Aβ aggregates exhibit a diverse range of morphologies with distinct pathological activities. Recognition of the Aβ aggregates by using small molecule-based probes and sensors should not only enhance understanding of the underlying mechanisms of amyloid formation, but also facilitate the development of therapeutic strategies to interfere with amyloid neurotoxicity. BODIPY (boron dipyrrin) dyes are among the most versatile small molecule fluorophores. BODIPY scaffolds could be functionalized to tune their photophysical properties to the desired ranges as well as to adapt these dyes to various types of conditions and environments. Thus, BODIPY dyes could be viewed as unique platforms for the design of probes and sensors that are capable of detecting and tracking structural changes of various Aβ aggregates. This review summarizes currently available examples of BODIPY dyes that have been used to investigate conformational changes of Aβ peptides, self-assembly processes of Aβ, as well as Aβ interactions with various molecules.
Religious Coping, Hopelessness, and Suicide Ideation in Subjects with First-Episode Major Depression: An Exploratory Study in the Real World Clinical Practice
Authors: De Berardis Domenico , Olivieri Luigi , Rapini Gabriella , Serroni Nicola , Fornaro Michele , Valchera Alessandro , Carano Alessandro , Vellante Federica , Bustini Massimiliano , Serafini Gianluca , Pompili Maurizio , Ventriglio Antonio , Perna Giampaolo , Fraticelli Silvia , Martinotti Giovanni , Di Giannantonio Massimo
Published: November 2020

Background. This study aimed to evaluate the potential relationships between religious coping, hopelessness, and suicide ideation in adult outpatients with the first episode of major depressive disorder (MDD). Methods. Ninety-four adult outpatients with MDD were assessed through the Hamilton Depression Rating Scale (HAM-D), the Beck Hopelessness Scale (BHS), and the Scale of Suicide Ideation (SSI). Religious coping was assessed with the Italian version of the Brief RCOPE scale, consisting of seven positive coping items (PosCop) and seven negative coping items (NegCop). Results. The results showed that the Brief RCOPE PosCop scale exhibited a strong inverse correlation with HAM-D, BHS, and SSI, whereas HAM-D and BHS were positively correlated with SSI. Brief RCOPE NegCop scores were positively correlated only with SSI. Regression analysis with SSI as the dependent variable showed that higher Brief RCOPE PosCop scores were associated with lower suicide ideation, whereas higher HAM-D and BHS scores were associated with higher suicide ideation. Conclusion. Positive religious coping may be a protective factor against the development of suicide ideation, perhaps counteracting the severity of depressive symptoms and hopelessness. The evaluation of religious coping should be performed in all subjects with MDD in everyday clinical practice. However, this study was preliminary, and limitations must be considered.
Amino Acid Levels as Potential Biomarker of Elderly Patients with Dementia
Authors: Socha Edyta , Kośliński Piotr , Koba Marcin , Mądra-Gackowska Katarzyna , Kędziora-Kornatowska Kornelia , Gackowski Marcin , Daghir-Wojtkowiak Emilia
Published: November 2020

Dementia is a clinical syndrome characterized by cognitive impairment, in which there is disturbance of multiple higher cortical functions. The primary risk factor of dementia is old age, and due to significant changes in the worldwide demographic structure, the prevalence of cognitive impairment is increasing dramatically with aging populations in most countries. Alzheimer’s disease is the predominant and leading cause of dementia. The aim of this study was to evaluate the modifications of amino acids that characterize the initial stages of dementia to help our understanding of the complex and multifactorial pathogenesis of neurodegenerative disorders. A total of 123 participants were divided into two groups: healthy elderly subjects and patients with mild or moderate dementia. The results of this study indicate that the serum levels of three amino acids were changed significantly in patients with dementia, in relation to the subjects without dementia. In particular, we observed differences in concentrations for serine, arginine and isoleucine (all of them were significantly increased in patients with dementia, compared with the control group). Our results suggest that the metabolisms of some amino acids seem be changed in patients with dementia. We conclude that amino acid profiling might be helpful for the better understanding of biochemical and metabolic changes related to the pathogenesis and progression of dementia. However, considering the multifactorial, heterogenous and complex nature of this disease, validation with a greater study sample in further research is required.
Detecting the Potential for Consciousness in Unresponsive Patients Using the Perturbational Complexity Index
Authors: Sinitsyn Dmitry O. , Poydasheva Alexandra G. , Bakulin Ilya S. , Legostaeva Liudmila A. , Iazeva Elizaveta G. , Sergeev Dmitry V. , Sergeeva Anastasia N. , Kremneva Elena I. , Morozova Sofya N. , Lagoda Dmitry Yu. , Casarotto Silvia , Comanducci Angela , Ryabinkina Yulia V. , Suponeva Natalia A. , Piradov Michael A.
Published: November 2020

The difficulties of behavioral evaluation of prolonged disorders of consciousness (DOC) motivate the development of brain-based diagnostic approaches. The perturbational complexity index (PCI), which measures the complexity of electroencephalographic (EEG) responses to transcranial magnetic stimulation (TMS), showed a remarkable sensitivity in detecting minimal signs of consciousness in previous studies. Here, we tested the reliability of PCI in an independently collected sample of 24 severely brain-injured patients, including 11 unresponsive wakefulness syndrome (UWS), 12 minimally conscious state (MCS) patients, and 1 emergence from MCS patient. We found that the individual maximum PCI value across stimulation sites fell within the consciousness range (i.e., was higher than PCI*, which is an empirical cutoff previously validated on a benchmark population) in 11 MCS patients, yielding a sensitivity of 92% that surpassed qualitative evaluation of resting EEG. Most UWS patients (n = 7, 64%) showed a slow and stereotypical TMS-EEG response, associated with low-complexity PCI values (i.e., ≤PCI*). Four UWS patients (36%) provided high-complexity PCI values, which might suggest a covert capacity for consciousness. In conclusion, this study successfully replicated the performance of PCI in discriminating between UWS and MCS patients, further motivating the application of TMS-EEG in the workflow of DOC evaluation.
Improving City Vitality through Urban Heat Reduction with Green Infrastructure and Design Solutions: A Systematic Literature Review
Authors: Elliott Helen , Eon Christine , Breadsell Jessica
Published: November 2020

Cities are prone to excess heat, manifesting as urban heat islands (UHIs). UHIs impose a heat penalty upon urban inhabitants that jeopardizes human health and amplifies the escalating effects of background temperature rises and heatwaves, presenting barriers to participation in city life that diminish interaction and activity. This review paper investigates how green infrastructure, passive design and urban planning strategies—herein termed as green infrastructure and design solutions (GIDS)—can be used to cool the urban environment and improve city vitality. A systematic literature review has been undertaken connecting UHIs, city vitality and GIDS to find evidence of how qualities and conditions fundamental to the vitality of the city are diminished by heat, and ways in which these qualities and conditions may be improved through GIDS. This review reveals that comfortable thermal conditions underpin public health and foster activity—a prerequisite for a vital city—and that reducing environmental barriers to participation in urban life enhances physical and mental health as well as activity. This review finds that GIDS manage urban energy flows to reduce the development of excess urban heat and thus improve the environmental quality of urban spaces. Furthermore, it finds that the most equitable approach to urban cooling is one that reduces the intensity of the meso-scale UHI that affects all urban inhabitants. Subsequently, a cooler urban fabric based on GIDS is proposed. A cohesive approach to the widespread adoption of GIDS shows potential to produce a cooler urban fabric that is human-centered in its function and aesthetic to enhance participation in public life and stimulate life on the streets. Four spatial scales are presented in which a combination of GIDS may be collectively implemented to reduce the meso-scale UHI, including the urban, intra-urban, building and body scales. This approach considers the interacting nature of GIDS applied within contrasting urban landscapes, and aims to produce cooler urban conditions, better walking environments, and ecosystem co-benefits to stimulate participation in physical activity and public life to underpin public health, productivity and livelihoods, thereby inducing city vitality.
Multi-Omics and Informatics Analysis of FFPE Tissues Derived from Melanoma Patients with Long/Short Responses to Anti-PD1 Therapy Reveals Pathways of Response
Authors: Garg Saurabh K. , Welsh Eric A. , Fang Bin , Hernandez Yuliana I. , Rose Trevor , Gray Jhanelle , Koomen John M. , Berglund Anders , Mulé James J. , Markowitz Joseph
Published: November 2020

Anti-PD-1 based immune therapies are thought to be dependent on antigen processing and presentation mechanisms. To characterize the immune-dependent mechanisms that predispose stage III/IV melanoma patients to respond to anti-PD-1 therapies, we performed a multi-omics study consisting of expression proteomics and targeted immune-oncology-based mRNA sequencing. Formalin-fixed paraffin-embedded tissue samples were obtained from stage III/IV patients with melanoma prior to anti-PD-1 therapy. The patients were first stratified into poor and good responders based on whether their tumors had or had not progressed while on anti-PD-1 therapy for 1 year. We identified 263 protein/gene candidates that displayed differential expression, of which 223 were identified via proteomics and 40 via targeted-mRNA analyses. The downstream analyses of expression profiles using MetaCore software demonstrated an enrichment of immune system pathways involved in antigen processing/presentation and cytokine production/signaling. Pathway analyses showed interferon (IFN)-γ-mediated signaling via NF-κB and JAK/STAT pathways to affect immune processes in a cell-specific manner and to interact with the inducible nitric oxide synthase. We review these findings within the context of available literature on the efficacy of anti-PD-1 therapy. The comparison of good and poor responders, using efficacy of PD-1-based therapy at 1 year, elucidated the role of antigen presentation in mediating response or resistance to anti-PD-1 blockade.
A Four-Inflow Construction to Ensure Thermal Stability and Uniformity during Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Rats
Authors: Löke Daan R. , Helderman Roxan F. C. P. A. , Sijbrands Jan , Rodermond Hans M. , Tanis Pieter J. , Franken Nicolaas A. P. , Oei Arlene L. , Kok H. Petra , Crezee Johannes
Published: November 2020

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) is used for treating peritoneal metastases of various origins. Present HIPEC protocols have rarely been validated for relevant parameters such as optimal agent, duration and perfusate temperature. In vitro experiments are not completely representative of clinical circumstances. Therefore, a good preclinical in vivo HIPEC model is needed in which temperature distributions can be well-controlled and are stable throughout treatments. Methods: We designed a setup able to generate and maintain a homogeneous flow during a 90-min HIPEC procedure using our in-house developed treatment planning tools and computer aided design (CAD) techniques. Twelve rats were treated with heated phosphate-buffered saline (PBS) using two catheter setups (one vs. four- inflows) and extensive thermometry. Simulated and measured thermal distribution and core temperatures were evaluated for the different setups. Results: Overall, the four-inflow resulted in more stable and more homogeneous thermal distributions than the one-inflow, with lower standard deviations (0.79 °C vs. 1.41 °C at the outflow, respectively) and less thermal losses. The average thermal loss was 0.4 °C lower for rats treated with the four-inflow setup. Rat core temperatures were kept stable using occasional tail cooling, and rarely exceeded 39 °C. Conclusion: Increasing the number of inflow catheters from one to four resulted in increased flow and temperature homogeneity and stability. Tail cooling is an adequate technique to prevent rats from overheating during 90-min treatments. This validated design can improve accuracy in future in vivo experiments investigating the impact of relevant parameters on the efficacy of different HIPEC protocols.
MiR-215-5p Reduces Liver Metastasis in an Experimental Model of Colorectal Cancer through Regulation of ECM-Receptor Interactions and Focal Adhesion
Authors: Machackova Tana , Vychytilova-Faltejskova Petra , Souckova Kamila , Trachtova Karolina , Brchnelova Dominika , Svoboda Marek , Kiss Igor , Prochazka Vladimir , Kala Zdenek , Slaby Ondrej
Published: November 2020

Background: Growing evidence suggests that miR-215-5p is a tumor suppressor in colorectal cancer (CRC); however, its role in metastasis remains unclear. This study evaluates the effects of miR-215 overexpression on the metastatic potential of CRC. Methods: CRC cell lines were stably transfected with miR-215-5p and used for in vitro and in vivo functional analyses. Next-generation sequencing and RT-qPCR were performed to study changes on the mRNA level. Results: Overexpression of miR-215-5p significantly reduced the clonogenic potential, migration, and invasiveness of CRC cells in vitro and tumor weight and volume, and liver metastasis in vivo. Transcriptome analysis revealed mRNAs regulated by miR-215-5p and RT-qPCR confirmed results for seven selected genes. Significantly elevated levels of CTNNBIP1 were also observed in patients’ primary tumors and liver metastases compared to adjacent tissues, indicating its direct regulation by miR-215-5p. Gene Ontology and KEGG pathway analysis identified cellular processes and pathways associated with miR-215-5p deregulation. Conclusions: MiR-215-5p suppresses the metastatic potential of CRC cells through the regulation of divergent molecular pathways, including extracellular-matrix-receptor interaction and focal adhesion. Although the specific targets of miR-215-5p contributing to the formation of distant metastases must be further elucidated, this miRNA could serve as a promising target for CRC patients’ future therapeutic strategies.
A Novel Pipeline for Drug Repurposing for Bladder Cancer Based on Patients’ Omics Signatures
Authors: Mokou Marika , Lygirou Vasiliki , Angelioudaki Ioanna , Paschalidis Nikolaos , Stroggilos Rafael , Frantzi Maria , Latosinska Agnieszka , Bamias Aristotelis , Hoffmann Michèle J. , Mischak Harald , Vlahou Antonia
Published: November 2020

Multi-omics signatures of patients with bladder cancer (BC) can guide the identification of known de-risked therapeutic compounds through drug repurposing, an approach not extensively explored yet. In this study, we target drug repurposing in the context of BC, driven by tissue omics signatures. To identify compounds that can reverse aggressive high-risk Non-Muscle Invasive BC (NMIBC) to less aggressive low-risk molecular subtypes, the next generation Connectivity Map (CMap) was employed using as input previously published proteomics and transcriptomics respective signatures. Among the identified compounds, the ATP-competitive inhibitor of mTOR, WYE-354, showed a consistently very high score for reversing the aggressive BC molecular signatures. WYE-354 impact was assessed in a panel of eight multi-origin BC cell lines and included impaired colony growth and proliferation rate without any impact on apoptosis. Overall, with this study we introduce a promising pipeline for the repurposing of drugs for BC treatment, based on patients’ omics signatures.
SNP-SNP Interaction in Genes Encoding PD-1/PD-L1 Axis as a Potential Risk Factor for Clear Cell Renal Cell Carcinoma
Authors: Wagner Marta , Tupikowski Krzysztof , Jasek Monika , Tomkiewicz Anna , Witkowicz Agata , Ptaszkowski Kuba , Karpinski Pawel , Zdrojowy Romuald , Halon Agnieszka , Karabon Lidia
Published: November 2020

PD-1/PD-L1 axis plays an important role in maintaining homeostasis and prevention from autoimmunity; however, in the tumor microenvironment, PD-1/PD-L1 interaction is responsible for the evasion of immune surveillance by tumor cells. We therefore hypothesized that single nucleotide polymorphisms (SNPs) in genes encoding PD-1 and PD-L1 molecules are associated with the development and outcome of renal cell carcinoma (RCC). Here we genotyped nine polymorphisms: five of PDCD1: rs36084323G>A, rs11568821G>A, rs2227981C>T, rs10204525G>A, rs7421861T>C and four of PD-L1: rs822335C>T, rs4143815G>C, rs4742098A>G, rs10815225G>C in 237 RCC patients (including 208 with clear cell RCC (ccRCC)) and 256 controls, with application of allelic discrimination method with use of TaqMan Assays. Interestingly, we found the SNP-SNP interaction between rs10815225 and rs7421861 polymorphisms associated with ccRCC risk. The rs7421861 TC genotype decreased the risk of ccRCC development compared to TT and CC genotypes in the group of rs10815225 GC + CC individuals (OR = 0.21, CI95% = 0.08; 0.54). While possessing of rs10815225 GC or CC genotype increased susceptibility to ccRCC when compared to rs10815225 GG genotype in individuals with rs7421861 TT or CC genotype (OR = 2.40, CI95% = 1.25; 4.61). In conclusion, genetic variants in PDCD1 and PD-L1 genes, especially taken together as SNP-SNP interactions, can be considered to be ccRCC risk factors.
Iron Dysregulation in Human Cancer: Altered Metabolism, Biomarkers for Diagnosis, Prognosis, Monitoring and Rationale for Therapy
Authors: Lelièvre Pierre , Sancey Lucie , Coll Jean-Luc , Deniaud Aurélien , Busser Benoit
Published: November 2020

Iron (Fe) is a trace element that plays essential roles in various biological processes such as DNA synthesis and repair, as well as cellular energy production and oxygen transport, and it is currently widely recognized that iron homeostasis is dysregulated in many cancers. Indeed, several iron homeostasis proteins may be responsible for malignant tumor initiation, proliferation, and for the metastatic spread of tumors. A large number of studies demonstrated the potential clinical value of utilizing these deregulated proteins as prognostic and/or predictive biomarkers of malignancy and/or response to anticancer treatments. Additionally, the iron present in cancer cells and the importance of iron in ferroptosis cell death signaling pathways prompted the development of therapeutic strategies against advanced stage or resistant cancers. In this review, we select relevant and promising studies in the field of iron metabolism in cancer research and clinical oncology. Besides this, we discuss some co-existing discrepant findings. We also present and discuss the latest lines of research related to targeting iron, or its regulatory pathways, as potential promising anticancer strategies for human therapy. Iron chelators, such as deferoxamine or iron-oxide-based nanoparticles, which are already tested in clinical trials, alone or in combination with chemotherapy, are also reported.
Magnetic Particles for CTC Enrichment
Authors: Liu Peng , Jonkheijm Pascal , Terstappen Leon W. M. M. , Stevens Michiel
Published: November 2020

Here, we review the characteristics and synthesis of magnetic nanoparticles (MNPs) and place these in the context of their usage in the immunomagnetic enrichment of Circulating Tumor Cells (CTCs). The importance of the different characteristics is explained, the need for a very specific enrichment is emphasized and different (commercial) magnetic separation techniques are shown. As the specificity of an MNP is in a large part dependent on the antibody coated onto the particle, different strategies in the coupling of specific antibodies as well as an overview of the available antibodies is given.
Visfatin Enhances Breast Cancer Progression through CXCL1 Induction in Tumor-Associated Macrophages
Authors: Wang Yen-Yun , Chen Huan-Da , Lo Steven , Chen Yuk-Kwan , Huang Yu-Ci , Hu Stephen Chu-Sung , Hsieh Ya-Ching , Hung Amos C. , Hou Ming-Feng , Yuan Shyng-Shiou F.
Published: November 2020

Visfatin, an adipocytokine highly expressed in breast tumor tissues, is associated with breast cancer progression. Recent studies showed that adipocytokines mediate tumor development through adipocytokine tumor-stromal interactions in the tumor microenvironment. This study focused on the interaction between one key stromal constituent—tumor-associated macrophages—and visfatin. Pretreatment of THP-1 and peripheral blood mononuclear cells (PBMCs) with recombinant visfatin resulted in M2-polarization determined by CD163 and CD206 expression. Indirect co-culture with visfatin-treated THP-1 (V-THP-1) promoted the viability, migration, tumorsphere formation, EMT, and stemness of breast cancer cells. Cytokine array identified an increased CXCL1 secretion in V-THP-1 conditioned medium and recombinant CXCL1 enhanced cell migration and invasion, which were abrogated by the CXCL1-neutralizing antibody. Additionally, visfatin induced pERK in THP-1 cells and clinical samples confirmed a positive CXCL1/pERK correlation. In an orthotopic mouse model, the tumor bioluminescent signal of luciferase-expressing MDA-MB-231 (Luc-MDA-MB-231) cells co-cultured with V-THP-1 and the expression of proliferation marker Ki67 were significantly higher than that co-cultured with THP-1. Furthermore, tail vein-injected Luc-MDA-MB-231 pretreated with V-PBMCs conditioned medium metastasized to lungs more frequently compared to control, and this was reversed by CXCL1 blocking antibody. In summary, this study demonstrated that visfatin enhanced breast cancer progression via pERK/CXCL1 induction in macrophages.
Application of Artificial Intelligence Technology in Oncology: Towards the Establishment of Precision Medicine
Authors: Hamamoto Ryuji , Suvarna Kruthi , Yamada Masayoshi , Kobayashi Kazuma , Shinkai Norio , Miyake Mototaka , Takahashi Masamichi , Jinnai Shunichi , Shimoyama Ryo , Sakai Akira , Takasawa Ken , Bolatkan Amina , Shozu Kanto , Dozen Ai , Machino Hidenori , Takahashi Satoshi , Asada Ken , Komatsu Masaaki , Sese Jun , Kaneko Syuzo
Published: November 2020

In recent years, advances in artificial intelligence (AI) technology have led to the rapid clinical implementation of devices with AI technology in the medical field. More than 60 AI-equipped medical devices have already been approved by the Food and Drug Administration (FDA) in the United States, and the active introduction of AI technology is considered to be an inevitable trend in the future of medicine. In the field of oncology, clinical applications of medical devices using AI technology are already underway, mainly in radiology, and AI technology is expected to be positioned as an important core technology. In particular, “precision medicine,” a medical treatment that selects the most appropriate treatment for each patient based on a vast amount of medical data such as genome information, has become a worldwide trend; AI technology is expected to be utilized in the process of extracting truly useful information from a large amount of medical data and applying it to diagnosis and treatment. In this review, we would like to introduce the history of AI technology and the current state of medical AI, especially in the oncology field, as well as discuss the possibilities and challenges of AI technology in the medical field.
First Line Systemic Treatment for MALT Lymphoma—Do We Still Need Chemotherapy? Real World Data from the Medical University Vienna
Authors: Kiesewetter Barbara , Simonitsch-Klupp Ingrid , Mayerhoefer Marius E. , Dolak Werner , Lukas Julius , Raderer Markus
Published: November 2020

There is no clear therapeutic algorithm for mucosa-associated lymphoid tissue (MALT) lymphoma beyond Helicobacter pylori eradication and while chemotherapy-based regimens are standard for MALT lymphoma patients in need of systemic treatment, it appears of interest to also investigate chemotherapy-free strategies. We have retrospectively assessed MALT lymphoma patients undergoing upfront systemic treatment, classified either as chemotherapy (=classical cytostatic agents +/− rituximab) or immunotherapy (=immunomodulatory agents or single anti-CD20 antibodies) at the Medical University Vienna 1999–2019. The primary endpoint was progression-free survival (PFS). In total, 159 patients were identified with a median follow-up of 67 months. The majority of patients had extragastric disease (80%), but we also identified 32 patients (20%) with Helicobacter pylori negative or disseminated gastric lymphoma. Regarding the type of first line treatment and outcome, 46% (74/159) received a chemotherapy-based regimen and 54% (85/159) immunotherapy including IMiDs lenalidomide/thalidomide (37%), anti-CD20-anitbodies rituximab/ofatumumab (27%), macrolides clarithromycin/azithromycin (27%) and proteasome inhibitor bortezomib (9%). Median PFS was 76 months (95%CI 50–102), and while the overall response (90% vs. 68%, p < 0.01) and the complete remission rate (75% vs. 43%, p < 0.01) was significantly higher for chemotherapy, there was no difference in PFS between chemotherapy (median 81 months, 95%CI 47–116) and immunotherapy (76 months, 95%CI 50–103, p = 0.57), suggesting comparable long-term outcomes. To conclude, our data show higher response rates with chemo- compared to immunotherapy, but this did not translate into a superior PFS. Given the biological background of MALT lymphoma, and the favorable toxicity profile of novel immunomodulatory treatments, this should be further investigated.
Animal Safety, Toxicology, and Pharmacokinetic Studies According to the ICH S9 Guideline for a Novel Fusion Protein tTF-NGR Targeting Procoagulatory Activity into Tumor Vasculature: Are Results Predictive for Humans?
Authors: Berdel Wolfgang E. , Harrach Saliha , Brand Caroline , Brömmel Kathrin , Berdel Andrew F. , Hintelmann Heike , Schliemann Christoph , Schwöppe Christian
Published: November 2020

Background: CD-13 targeted tissue factor tTF-NGR is a fusion protein selectively inducing occlusion of tumor vasculature with resulting tumor infarction. Mechanistic and pharmacodynamic studies have shown broad anti-tumor therapeutic effects in xenograft models. Methods: After successful Good Manufacturing Practice (GMP) production and before translation into clinical phase I, ICH S9 (S6) guideline-conforming animal safety, toxicology, and pharmacokinetic (PK) studies were requested by the federal drug authority in accordance with European and US regulations. Results: These studies were performed in mice, rats, guinea pigs, and beagle dogs. Results of the recently completed clinical phase I trial in end-stage cancer patients showed only limited predictive value of these non-clinical studies for patient tolerability and safety in phase I. Conclusions: Although this experience cannot be generalized, alternative pathways with seamless clinical phase 0 microdosing—phase I dose escalation studies are endorsed for anticancer drug development and translation into the clinic.
Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma in Asia Frequently Shows SETD2 Alterations
Authors: Tomita Sakura , Kikuti Yara Yukie , Carreras Joaquim , Sakai Rika , Takata Katsuyoshi , Yoshino Tadashi , Bea Silvia , Campo Elias , Missiaglia Edoardo , Bouilly Justine , Letourneau Audrey , de Leval Laurence , Nakamura Naoya
Published: November 2020

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare primary T-cell lymphoma of the digestive tract derived from intraepithelial lymphocytes and characterized by an aggressive clinical course. In this study, nine cases of Japanese MEITL were analyzed by targeted Next Generation Sequencing (NGS) and immunohistochemistry and were integrated with previously reported whole-genome copy number microarray-based assay data. The highlight of our findings is that all cases showed alterations of the tumor suppressor gene SETD2 by mutations and/or loss of the corresponding 3p21 locus. We also demonstrated that all cases showed mutations in one or more genes of JAK/STAT pathway. Therefore, the combination of epigenetic deregulation and cell signaling activation represent major oncogenic events in the pathogenesis of MEITL in Asian MEITL, similar to Western MEITL.
Hürthle Cells on Fine-Needle Aspiration Cytology Are Important for Risk Assessment of Focally PET/CT FDG Avid Thyroid Nodules
Authors: Poller David N. , Megadmi Hakim , Ward Matthew J. A. , Trimboli Pierpaolo
Published: November 2020

This study assesses the role of [18F] FDG PET/CT, fine needle aspiration (FNA) cytology and ultrasound in the 1–2% of patients with focally positive thyroid nodules on FDG PET/CT. All FDG PET/CT scans with focally increased thyroid FDG PET/CT uptake performed over 37 months in one institution were matched to patients undergoing thyroid FNA. Diffuse FDG PET/CT uptake patients were excluded. A total of 47 patients showed focally increased thyroid uptake. Consistent with previous studies, 18 (38.2%) patients had malignancy—12 primary thyroid carcinoma, 1 parathyroid carcinoma, 3 metastatic carcinoma to the thyroid and 2 lymphoma. A total of 15 (31.9%) lesions categorized as non-malignant contained Hürthle cells/oncocytes. A total of 14 lesions (29.8%) had focally increased FDG PET/CT uptake with no specific cytological or histopathological cause identified. No focally PET avid Hürthle cell/oncocytic lesions were found to be malignant. Exclusion of oncocytic lesions increased the calculated risk of malignancy (ROM) of focally PET avid nodules from 38% to 68%. It may be useful to exclude focally FDG PET/CT avid Hürthle cell/oncocytic lesions, typically reported as follicular neoplasm or suspicious for a follicular neoplasm, Hürthle cell type (Oncocytic) type, RCPath Thy 3F: Bethesda IV or sometimes Thy 3a: Bethesda III FNAs) from ROM calculations. Oncocytic focally PET/CT FDG avid lesions appear of comparatively lower risk of malignancy and require investigation or operation but these lesions should be readily identified by FNA cytology on diagnostic work up of focally PET avid thyroid nodules.
MiR-378a-3p Is Critical for Burkitt Lymphoma Cell Growth
Authors: Niu Fubiao , Dzikiewicz-Krawczyk Agnieszka , Koerts Jasper , de Jong Debora , Wijenberg Laura , Fernandez Hernandez Margot , Slezak-Prochazka Izabella , Winkle Melanie , Kooistra Wierd , van der Sluis Tineke , Rutgers Bea , Terpstra Miente Martijn , Kok Klaas , Kluiver Joost , van den Berg Anke
Published: November 2020

MicroRNAs (miRNAs) are small RNA molecules with important gene regulatory roles in normal and pathophysiological cellular processes. Burkitt lymphoma (BL) is an MYC-driven lymphoma of germinal center B (GC-B) cell origin. To gain further knowledge on the role of miRNAs in the pathogenesis of BL, we performed small RNA sequencing in BL cell lines and normal GC-B cells. This revealed 26 miRNAs with significantly different expression levels. For five miRNAs, the differential expression pattern was confirmed in primary BL tissues compared to GC-B cells. MiR-378a-3p was upregulated in BL, and its inhibition reduced the growth of multiple BL cell lines. RNA immunoprecipitation of Argonaute 2 followed by microarray analysis (Ago2-RIP-Chip) upon inhibition and ectopic overexpression of miR-378a-3p revealed 63 and 20 putative miR-378a-3p targets, respectively. Effective targeting by miR-378a-3p was confirmed by luciferase reporter assays for MAX Network Transcriptional Repressor (MNT), Forkhead Box P1 (FOXP1), Interleukin 1 Receptor Associated Kinase 4 (IRAK4), and lncRNA Just Proximal To XIST (JPX), and by Western blot for IRAK4 and MNT. Overexpression of IRAK4 and MNT phenocopied the effect of miR-378a-3p inhibition. In summary, we identified miR-378a-3p as a miRNA with an oncogenic role in BL and identified IRAK4 and MNT as miR-378a-3p target genes that are involved in its growth regulatory role.
Serum-Derived Exosomal MicroRNA Profiles Can Predict Poor Survival Outcomes in Patients with Extranodal Natural Killer/T-Cell Lymphoma
Authors: Ryu Kyung Ju , Lee Ji Young , Choi Myung Eun , Yoon Sang Eun , Cho Junhun , Ko Young Hyeh , Shim Joon Ho , Kim Won Seog , Park Chaehwa , Kim Seok Jin
Published: November 2020

Exosomes containing microRNAs (miRNAs) might have utility as biomarkers to predict the risk of treatment failure in extranodal NK/T-cell lymphoma (ENKTL) because exosomal cargo miRNAs could reflect tumor aggressiveness. We analyzed the exosomal miRNAs of patients in favorable (n = 22) and poor outcome (n = 23) groups in a training cohort. Then, using the Nanostring nCounter® microRNA array, we compared them with miRNAs identified in human NK/T lymphoma (NKTL) cell line-derived exosomes to develop exosomal miRNA profiles. We validated the prognostic value of serum exosomal miRNA profiles with an independent cohort (n = 85) and analyzed their association with treatment resistance using etoposide-resistant cell lines. A comparison of the top 20 upregulated miRNAs in the training cohort with poor outcomes with 16 miRNAs that were upregulated in both NKTL cell lines, identified five candidate miRNAs (miR-320e, miR-4454, miR-222-3p, miR-21-5p, and miR-25-3p). Among these, increased levels of exosomal miR-4454, miR-21-5p, and miR-320e were associated with poor overall survival in the validation cohort. Increased levels were also found in relapsed patients post-treatment. These three miRNAs were overexpressed in NKTL cell lines that were resistant to etoposide. Furthermore, transfection of NKTL cell lines with miR-21-5p and miR-320e induced an increase in expression of the proinflammatory cytokines such as macrophage inflammatory protein 1 alpha. These studies show that serum levels of exosomal miR-21-5p, miR-320e, and miR-4454 are increased in ENKTL patients with poor prognosis. Upregulation of these exosomal miRNAs in treatment-resistant cell lines suggests they have a role as biomarkers for the identification of ENKTL patients at high risk of treatment failure.
Maintenance of Energy Homeostasis during Calorically Restricted Ketogenic Diet and Fasting-MR-Spectroscopic Insights from the ERGO2 Trial
Authors: Wenger Katharina J. , Wagner Marlies , Harter Patrick N. , Franz Kea , Bojunga Jörg , Fokas Emmanouil , Imhoff Detlef , Rödel Claus , Rieger Johannes , Hattingen Elke , Steinbach Joachim P. , Pilatus Ulrich , Voss Martin
Published: November 2020

Background: The ERGO2 (Ernaehrungsumstellung bei Patienten mit Rezidiv eines Glioblastoms) MR-spectroscopic imaging (MRSI) subtrial investigated metabolism in patients randomized to calorically restricted ketogenic diet/intermittent fasting (crKD-IF) versus standard diet (SD) in addition to re-irradiation (RT) for recurrent malignant glioma. Intracerebral concentrations of ketone bodies (KB), intracellular pH (pHi), and adenosine triphosphate (ATP) were non-invasively determined. Methods: 50 patients were randomized (1:1): Group A keeping a crKD-IF for nine days, and Group B a SD. RT was performed on day 4–8. Twenty-three patients received an extended MRSI-protocol (1H decoupled 31P MRSI with 3D chemical shift imaging (CSI) and 2D 1H point-resolved spectroscopy (PRESS)) at a 3T scanner at baseline and on day 6. Voxels were selected from the area of recurrent tumor and contralateral hemisphere. Spectra were analyzed with LCModel, adding simulated signals of 3-hydroxybutyrate (βOHB), acetone (Acn) and acetoacetate (AcAc) to the standard basis set. Results: Acn was the only reliably MRSI-detectable KB within tumor tissue and/or normal appearing white matter (NAWM). It was detected in 4/11 patients in Group A and in 0/8 patients in Group B. MRSI results showed no significant depletion of ATP in tumor tissue of patients at day 6 during crKD-IF, even though there were a significant difference in ketone serum levels between Group A and B at day 6 and a decline in fasting glucose in Group A from baseline to day 6. The tumor specific alkaline pHi was maintained. Conclusions: Our metabolic findings suggest that tumor cells maintain energy homeostasis even with reduced serum glucose levels and may generate additional ATP through other sources.
Flow Simulations Including Iron Nanoparticle Nucleation, Growth and Evaporation for Floating Catalyst CNT Production
Authors: Gökstorp Filip K. A. , Juniper Matthew P.
Published: November 2020

We use a computational fluid dynamics model coupled with a particle dynamics model to simulate how catalyst nanoparticles nucleate, grow and evaporate over the length of a floating catalyst reactor. We focus on the influence of the flowrate in the reactor and the ferrocene mass fraction on the production of the catalyst nanoparticles. In the downstream region of the reactor, where the majority of CNT growth occurs, we find that, as either the flowrate or the ferrocene mass fraction increases, the particle mass fraction profile changes, with the mass fraction peak shifting away from the centreline. This displacement away from the centreline of the mass fraction peak may explain why the CNTs form a hollow, sock-like, aerogel at the downstream end of the reactor.
Expression and Signaling of β-Adrenoceptor Subtypes in the Diabetic Heart
Authors: Erdogan Betul R. , Michel Martin C. , Arioglu-Inan Ebru
Published: November 2020

Diabetes is a chronic, endocrine disorder that effects millions of people worldwide. Cardiovascular complications are the major cause of diabetes-related morbidity and mortality. Cardiac β1- and β2-adrenoceptor (AR) stimulation mediates positive inotropy and chronotropy, whereas β3-AR mediates negative inotropic effect. Changes in β-AR responsiveness are thought to be an important factor that contributes to the diabetic cardiac dysfunction. Diabetes related changes in β-AR expression, signaling, and β-AR mediated cardiac function have been studied by several investigators for many years. In the present review, we have screened PubMed database to obtain relevant articles on this topic. Our search has ended up with wide range of different findings about the effect of diabetes on β-AR mediated changes both in molecular and functional level. Considering these inconsistent findings, the effect of diabetes on cardiac β-AR still remains to be clarified.
BRAF: A Two-Faced Janus
Authors: Pisapia Pasquale , Pepe Francesco , Iaccarino Antonino , Sgariglia Roberta , Nacchio Mariantonia , Russo Gianluca , Gragnano Gianluca , Malapelle Umberto , Troncone Giancarlo
Published: November 2020

Gain-of-function of V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) is one of the most frequent oncogenic mutations in numerous cancers, including thyroid papillary carcinoma, melanoma, colon, and lung carcinomas, and to a lesser extent, ovarian and glioblastoma multiforme. This mutation aberrantly activates the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway, thereby eliciting metastatic processes. The relevance of BRAF mutations stems from its prognostic value and, equally important, from its relevant therapeutic utility as an actionable target for personalized treatment. Here, we discuss the double facets of BRAF. In particular, we argue the need to implement diagnostic molecular algorithms that are able to detect this biomarker in order to streamline and refine diagnostic and therapeutic decisions.
Two-Dimensional As/BlueP van der Waals Hetero-Structure as a Promising Photocatalyst for Water Splitting: A DFT Study
Authors: Liu Xinyi , Jiang Bei , Liu Yanxin , Liu Lei , Xia Tian , Zhang Xin , Ye Cong , Yu Yunjin , Wang Bin
Published: November 2020

Constructing van der Waals (vdW) hetero-structure by stacking different two-dimensional (2D) materials has become an effective method for designing new-type and high-quality electronic and optoelectronic nano-devices. In this work, we designed a 2D As/BlueP vdW hetero-structure by stacking monolayer arsenene (As) and monolayer blue phosphorous (BlueP) vertically, which were recently implemented in experiments, and investigated its structural, electronic, and photocatalytic water splitting properties by using the standard first principles calculation method with HSE06 hybrid exchange-correlation functional. Numerical results show that the As/BlueP vdW hetero-structure is structural robust, even at room temperature. It presents semi-conducting behavior, and the conduction band minimum (CBM) and the valence band maximum (VBM) are dominated by BlueP and As, respectively. The typical type-II band alignment predicts the potential application of the hetero-structure in highly efficient optoelectronics and solar energy conversion. Moreover, the CBM and the VBM straddle the redox potentials of water in acid environment, predicting the possibility of the As/BlueP hetero-structure as a 2D photocatalyst for water splitting. When an in-plane strain is applied, the band edges and, further, the optoelectronic properties of the hetero-structure can be effectively tuned. Especially, when tensile strain is equal to 4.5%, the optical absorption spectrum is effectively broadened in a visible light region, which will largely improve its photocatalytic efficiency, although the pH value of the solution range reduction. This work provides theoretical evidence that the As/BlueP hetero-structure has potential application as a 2D photocatalyst in water splitting.
Enhanced Conversion Efficiency of a-Si:H Thin-Film Solar Cell Using ZnO Nanorods
Authors: Lai Fang-I , Yang Jui-Fu , Hsu Yu-Chao , Kuo Shou-Yi
Published: November 2020

The surface reflectivity of a material will vary as light passes through interfaces with different refractive indices. Therefore, the optical loss and reflection of an optical-electronic component can be reduced by fabricating nanostructures on its surface. In the case of a solar cell, the presence of nanostructures can deliver many different advantages, such as decreasing the surface reflectivity, enhancing the light trapping, and increasing the efficiency of the carrier collection by providing a shorter diffusion distance for the photogenerated minority carriers. In this study, an approximately 50-nm thick seed layer was first prepared using spin coating. Zinc oxide nanorods (ZnO-NRs) were then grown using a chemical solution method (CSM). The ZnO-NRs were approximately 2 μm in height and 100 nm in diameter. After applying them to amorphous silicon (a-Si:H) solar cells, the short-circuit current density increased from 8.03 to 9.24 mA/cm2, and the photovoltaic conversion efficiency increased by 11.24%.