bluuebunny/crossref_metadata_2025 huggingface dataset:
PD-L1 as a Prognostic Factor in Early-Stage Colon Carcinoma within the Immunohistochemical Molecular Subtype Classification
Authors: Azcue Pablo , Encío Ignacio , Guerrero Setas David , Suarez Alecha Javier , Galbete Arkaitz , Mercado María , Vera Ruth , Gomez-Dorronsoro Maria Luisa
Published: April 2021

Background. There is a patent need to better characterize early-stage colorectal cancer (CRC) patients. PD-1 ligand (PD-L1) expression has been proposed as a prognostic factor but yields mixed results in different settings. The Consensus Molecular Subtype (CMS) classification has yet to be integrated into clinical practice. We sought to evaluate the prognostic value of PD-L1 expression overall and within CMS in early-stage colon cancer patients, in the hope of assisting treatment choice in this setting. Methods. Tissue-microarrays were constructed from tumor samples of 162 stage II/III CRC patients. They underwent automatic immunohistochemical staining for PD-L1 and the proposed CMS panel. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Results. PD-L1 expression was significantly and independently associated with better prognosis (HR = 0.46 (0.26–0.82), p = 0.009) and was mostly seen in immune cells of the tumor-related stroma. CMS4 five-folds the risk of mortalitycompared with CMS1 (HR = 5.58 (1.36, 22.0), p = 0.034). In the subgroup CMS2/CMS3 analysis, PD-L1 expression significantly differentiated individuals with better OS (p = 0.004) and DFS (p < 0.001). Conclusions. Our study suggests that PD-L1 expression is an independent prognostic factor in patients with stage II/III colon cancer. Additionally, it successfully differentiates patients with better prognosis in the CMS2/CMS3 group and may prove significant for the clinical relevance of the CMS classification.
Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review)
Authors: Peiffert Mathilde , Cugnet-Anceau Christine , Dalle Stephane , Chikh Karim , Assaad Souad , Disse Emmanuel , Raverot Gérald , Borson-Chazot Françoise , Abeillon-du Payrat Juliette
Published: April 2021

Thyrotoxicosis is an adverse event associated with immune checkpoint inhibitors (ICPis) that occurs in 0.6 to 3.2% of treated patients, depending on ICPi class. Presentation usually consists of a biphasic thyroiditis with transient thyrotoxicosis and secondary hypothyroidism. ICPi-induced Graves’ disease (GD), due to the stimulating activity of TSH-receptor autoantibodies (TRAb), is extremely rare. The aim of this retrospective study was to describe the characteristics and evolution of GD during ICPi therapy. Five among 243 patients followed for ICPi-induced thyrotoxicosis showed TRAb positivity (2% of the cohort). GD occurred quickly after initiation of ICPis; its course was typical for two patients, with prolonged requirement for antithyroid drug treatment (ATD). The three other patients experienced biphasic thyroiditis with secondary hypothyroidism requiring long-term substitution. Three other patients had a diagnosis of GD before starting ICPis; they evolved toward hypothyroidism with early cessation of ATD and long-term substitution treatment during ICPi treatment. None developed significant Graves’ orbitopathy. ICPi treatment was not interrupted for thyroid dysfunction. In conclusion, GD is a rare, immune-related adverse event of ICPis with an unusual course and frequent evolution to biphasic thyroiditis. In the case of ICPi-induced thyrotoxicosis in the presence of TRAb, observing the spontaneous evolution and performing a scintigraphy are useful before starting ATD treatment. Pre-existing GD is not exacerbated by ICPis and tends to evolve towards hypothyroidism. ICPi treatment can be maintained with adequate biochemical surveillance.
The New Serum-Free OptiPASS® Medium in Cold and Oxygen-Free Conditions: An Innovative Conservation Method for the Preservation of MDA-MB-231 Triple Negative Breast Cancer Spheroids
Authors: Goisnard Antoine , Dubois Clémence , Daumar Pierre , Aubel Corinne , Depresle Marie , Gauthier Jean , Vidalinc Bernard , Penault-Llorca Frédérique , Mounetou Emmanuelle , Bamdad Mahchid
Published: April 2021

Cancer spheroids are very effective preclinical models to improve anticancer drug screening. In order to optimize and extend the use of spheroid models, these works were focused on the development of a new storage concept to maintain these models in the longer term using the Triple-Negative Breast Cancer MDA-MB-231 spheroid models. The results highlight that the combination of a temperature of 4 °C and oxygen-free conditions allowed the spheroid characteristics of OptiPASS® serum-free culture medium to preserve the spheroid characteristics during 3-, 5- or 7-day-long storage. Indeed, after storage they were returned to normal culture conditions, with recovered spheroids presenting similar growth rates (recovery = 96.2%), viability (Live/Dead® profiles) and metabolic activities (recovery = 90.4%) compared to nonstored control spheroids. Likewise, both recovered spheroids (after storage) and nonstored controls presented the same response profiles as two conventional drugs, i.e., epirubicin and cisplatin, and two anti-PARP1 targeted drugs—i.e., olaparib and veliparib. This new original storage concept seems to induce a temporary stop in spheroid growth while maintaining their principal characteristics for further use. In this way, this innovative and simple storage concept may instigate future biological sample preservation strategies.
Comparison of Four Ultrasonography-Based Risk Stratification Systems in Thyroid Nodules with Nondiagnostic/Unsatisfactory Cytology: A Real-World Study
Authors: Lee You-Bin , Oh Young-Lyun , Shin Jung-Hee , Kim Sun-Wook , Chung Jae-Hoon , Min Yong-Ki , Hahn Soo-Yeon , Kim Tae-Hyuk
Published: April 2021

We compared American Thyroid Association (ATA) guidelines, Korean (K)-Thyroid Imaging, Reporting and Data Systems (TIRADS), EU-TIRADS, and American College of Radiology (ACR) TIRADS in diagnosing malignancy for thyroid nodules with nondiagnostic/unsatisfactory cytology. Among 1143 nondiagnostic/unsatisfactory aspirations from April 2011 to March 2016, malignancy was detected in 39 of 89 excised nodules. The minimum malignancy rate was 7.82% in EU-TIRADS 5 and 1.87–3.00% in EU-TIRADS 3–4. In the other systems, the minimum malignancy rate was 14.29–16.19% in category 5 and ≤3% in the remaining categories. Although the EU-TIRADS category ≥ 5 exhibited the highest positive likelihood ratio (LR) of only 2.214, category ≥ 5 in the other systems yielded the highest positive LR of >5. Receiver operating characteristic (ROC) curves of all systems to predict malignancy were located statistically above the diagonal nondiscrimination line (P for ROC curve: EU-TIRADS, 0.0022; all others, 0.0001). The areas under the ROC curve (AUCs) were not significantly different among the four systems. The ATA guidelines, K-TIRADS, and ACR TIRADS may be useful to guide management for nondiagnostic/unsatisfactory nodules. The EU-TIRADS, although also useful, exhibited inferior performance in predicting malignancy for nondiagnostic/unsatisfactory nodules in Korea, an iodine-sufficient area.
Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC
Authors: Dong Yawen , Wong Jeffrey Sum Lung , Sugimura Ryohichi , Lam Ka-On , Li Bryan , Kwok Gerry Gin Wai , Leung Roland , Chiu Joanne Wing Yan , Cheung Tan To , Yau Thomas
Published: April 2021

Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 with alternative agents, chiefly cytotoxic T-lymphocyte antigen-4 (CTLA-4) ICIs or agents targeting other oncogenic pathways such as the vascular endothelial growth factor (VEGF) pathway and the c-MET pathway, has, in addition to the benefit of directly targeting alterative oncogenic pathways, in vitro evidence of synergism through altering the genomic and function signatures of T cells and expression of immune checkpoints. Several trials have been completed or are underway evaluating such combinations. Finally, studies utilizing transcriptomics and organoids are underway to establish biomarkers to predict ICI response. This review aims to discuss the biological rationale and clinical advances in ICI-based combinations in HCCs, as well as the progress and prospects of the search for the aforementioned biomarkers in ICI treatment of HCC.
Excluding Lung Tissue from the PTV during Internal Mammary Irradiation. A Safe Technique for OAR-Sparing?
Authors: Borm Kai J. , Hofmann Christopher , Düsberg Mathias , Oechsner Markus , Dapper Hendrik , Devecka Michal , Combs Stephanie E.
Published: April 2021

The current study aims to determine whether exclusion of lung tissue from planning treatment volume (PTV) is a valid organ at risk (OAR)-sparing technique during internal mammary irradiation (IMNI). Twenty patients with left-sided breast cancer undergoing adjuvant radiotherapy including IMNI after mastectomy or lumpectomy with daily ConeBeam CT (CBCT; median n = 28) were enrolled in the current study. The daily dose distribution of the patients was estimated by recalculating treatment plans on CBCT-scans based on a standard PTV (PTV margin: 5mm-STD) and a modified PTV, which excluded overlapping lung tissue (ExLung). Using 3D-deformable dose accumulation, the dose coverage in the target volume was estimated in dependence of the PTV-margins. The estimated delivered dose in the IMN-CTV was significantly lower for the ExLung PTV compared to the STD PTV: ExLung: V95%: 76.6 ± 22.9%; V90%: 89.6 ± 13.2%, STD: V95%: 95.6 ± 7.4%; V90%: 99.1 ± 2.7%. Daily CBCT imaging cannot sufficiently compensate the anatomic changes and intrafraction movement throughout the treatment. Therefore, to ensure adequate delivery of the prescribed dose to the IMN-CTV, exclusion of lung tissue from the PTV to spare the OARs is not recommended.
A Novel Thienopyrimidine Analog, TPH104, Mediates Immunogenic Cell Death in Triple-Negative Breast Cancer Cells
Authors: Tukaramrao Diwakar Bastihalli , Malla Saloni , Saraiya Siddharth , Hanely Ross Allen , Ray Aniruddha , Kumari Shikha , Raman Dayanidhi , Tiwari Amit K.
Published: April 2021

Enhancing the tumor immunogenic microenvironment has been suggested to circumvent triple-negative breast cancer (TNBC) resistance and increase the efficacy of conventional chemotherapy. Here, we report a novel chemotherapeutic compound, TPH104, which induces immunogenic cell death in the TNBC cell line MDA-MB-231, by increasing the stimulatory capacity of dendritic cells (DCs), with an IC50 value of 140 nM. TPH104 (5 µM) significantly increased ATP levels in the supernatant and mobilized intracellular calreticulin to the plasma membrane in MDA-MB-231 cells, compared to cells incubated with the vehicle. Incubating MDA-MB-231 cells for 12 h with TPH104 (1–5 µM) significantly increased TNF-α mRNA levels. The supernatants of dying MDAMB-231 cells incubated with TPH104 increased mouse bone marrow-derived DC maturation, the expression of MHC-II and CD86 and the mRNA expression of TNF-α, IL-6 and IL-12. Overall, these results indicate that TPH104 induces immunogenic cell death in TNBC cells, in part, by activating DCs.
CAR-T in Cancer Treatment: Develop in Self-Optimization, Win-Win in Cooperation
Authors: Guo Feifei , Cui Jiuwei
Published: April 2021

Despite remarkable achievements in the treatment of hematologic malignancies, chimeric antigen receptor (CAR)-T cell therapy still faces many obstacles. The limited antitumor activity and persistence of infused CAR-T cells, especially in solid tumors, are the main limiting factors for CAR-T therapy. Moreover, clinical security and accessibility are important unmet needs for the application of CAR-T therapy. In view of these challenges, many potentially effective solutions have been proposed and confirmed. Both the independent and combined strategies of CAR-T therapy have exhibited good application prospects. Thus, in this review, we have discussed the cutting-edge breakthroughs in CAR-T therapy for cancer treatment, with the aim of providing a reference for addressing the current challenges.
Lag Time between Onset of First Symptom and Treatment of Retinoblastoma: An International Collaborative Study of 692 Patients from 10 Countries
Authors: Kaliki Swathi , Ji Xunda , Zou Yihua , Rashid Riffat , Sultana Sadia , Taju Sherief Sadik , Cassoux Nathalie , Y. Diaz Coronado Rosdali , Luis Garcia Leon Juan , López Arturo Manuel Zapata , Polyakov Vladimir G. , Ushakova Tatiana L. , Rani Roy Soma , Ahmad Alia , Al Harby Lamis , Reddy M. Ashwin , Sagoo Mandeep S. , L. Berry Jesse , Kim Jonathan , Polski Ashley , Astbury Nicholas J. , Bascaran Covadonga , Blum Sharon , Bowman Richard , Burton Matthew J. , Foster Allen , Gomel Nir , Keren-Froim Naama , Madgar Shiran , W. Stacey Andrew , M. Steinberg David , Mohamed Ashik , Zondervan Marcia , Fabian Ido Didi
Published: April 2021

Background: The relationship between lag time and outcomes in retinoblastoma (RB) is unclear. In this study, we aimed to study the effect of lag time between onset of symptoms and diagnosis of retinoblastoma (RB) in countries based on their national-income and analyse its effect on the outcomes. Methods: We performed a prospective study of 692 patients from 11 RB centres in 10 countries from 1 January 2019 to 31 December 2019. Results: The following factors were significantly different among different countries based on national-income level: age at diagnosis of RB (p = 0.001), distance from home to nearest primary healthcare centre (p = 0.03) and mean lag time between detection of first symptom to visit to RB treatment centre (p = 0.0007). After adjusting for country income, increased lag time between onset of symptoms and diagnosis of RB was associated with higher chances of an advanced tumour at presentation (p < 0.001), higher chances of high-risk histopathology features (p = 0.003), regional lymph node metastasis (p < 0.001), systemic metastasis (p < 0.001) and death (p < 0.001). Conclusions: There is a significant difference in the lag time between onset of signs and symptoms and referral to an RB treatment centre among countries based on national income resulting in significant differences in the presenting features and clinical outcomes.
Prostate Cancer Mortality Associated with Aggregate Polymorphisms in Androgen-Regulating Genes: The Atherosclerosis Risk in the Communities (ARIC) Study
Authors: Prizment Anna E. , McSweeney Sean , Pankratz Nathan , Joshu Corinne E. , Hwang Justin H. , Platz Elizabeth A. , Ryan Charles J.
Published: April 2021

Genetic variations in androgen metabolism may influence prostate cancer (PC) prognosis. Clinical studies consistently linked PC prognosis with four single nucleotide polymorphisms (SNPs) in the critical androgen-regulating genes: 3-beta-hydroxysteroid dehydrogenase (HSD3B1) rs1047303, 5-alpha-reductase 2 (SRD5A2) rs523349, and solute carrier organic ion (SLCO2B1) rs1789693 and rs12422149. We tested the association of four androgen-regulating SNPs, individually and combined, with PC-specific mortality in the ARIC population-based prospective cohort. Men diagnosed with PC (N = 622; 79% White, 21% Black) were followed for death (N = 350) including PC death (N = 74). Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95%CI adjusting for center, age, stage, and grade at diagnosis using separate hazards for races. A priori genetic risk score (GRS) was created as the unweighted sum of risk alleles in the four pre-selected SNPs. The gain-of-function rs1047303C allele was associated PC-specific mortality among men with metastatic PC at diagnosis (HR = 4.89 per risk allele, p = 0.01). Higher GRS was associated with PC-specific mortality (per risk allele: HR = 1.26, p = 0.03). We confirmed that the gain-of-function allele in HSD3B1 rs1047303 is associated with greater PC mortality in men with metastatic disease. Additionally, our findings suggest a cumulative effect of androgen-regulating genes on PC-specific mortality; however, further validation is required.
Implementation of Double Immune Checkpoint Blockade Increases Response Rate to Induction Chemotherapy in Head and Neck Cancer
Authors: Semrau Sabine , Gostian Antoniu-Oreste , Traxdorf Maximilian , Eckstein Markus , Rutzner Sandra , von der Grün Jens , Illmer Thomas , Hautmann Matthias , Klautke Gunther , Laban Simon , Brunner Thomas , Tamaskovics Bálint , Frey Benjamin , Zhou Jian-Guo , Geppert Carol-Immanuel , Hartmann Arndt , Balermpas Panagiotis , Budach Wilfried , Gaipl Udo , Iro Heinrich , Fietkau Rainer , Hecht Markus
Published: April 2021

To determine whether a single dose of double immune checkpoint blockade (induction chemoimmunotherapy (ICIT)) adds benefit to induction single-cycle platinum doublet (induction chemotherapy (IC)) in locally advanced head and neck squamous cell carcinoma (HNSCC), patients treated with cisplatin 30 mg/m2 d1-3 and docetaxel 75 mg/m2 d1 combined with durvalumab 1500 mg fixed dose d5 and tremelimumab 75 mg fixed dose d5 (ICIT) within the CheckRad-CD8 trial were compared with a retrospective cohort receiving the same chemotherapy (IC) without immunotherapy. The endpoint of this analysis was the complete response rate (CR). A total of 53 patients were treated with ICIT and 104 patients with IC only. CR rates were 60.3% for ICIT and 40.3% for IC (p = 0.018). In the total population (n = 157), the most important predictor to achieve a CR was treatment type (OR: 2.21 for ICIT vs. IC; p = 0.038, multivariate analysis). The most diverse effects in CR rates between ICIT and IC were observed in younger (age ≤ 60) patients with HPV-positive OPSCCs (82% vs. 33%, p = 0.176), while there was no difference in older patients without HPV-positive OPSCCs (53% vs. 48%). The analysis provides initial evidence that ICIT could result in higher CR rates than IC. Young patients with HPV-positive OPSCCs may have the greatest benefit from additional immune checkpoint inhibitors.
The Current Landscape of Clinical Trials for Systemic Treatment of HCC
Authors: Foerster Friedrich , Galle Peter Robert
Published: April 2021

The clinical development of systemic treatments for hepatocellular carcinoma (HCC) has gained significant momentum in recent years. After the unexpected failure of the phase 3 trials testing the PD1-inhibitors nivolumab and pembrolizumab as monotherapy in advanced HCC, a multitude of trials employing different agents in various combinations and at different disease stages have been initiated. The first positive results reported for the combination of atezolizumab and bevacizumab, as the first line treatment of advanced HCC, will bring lasting change to the management of HCC and has increased the odds of success for alternative combination therapies. This review article seeks to provide clarity on the complex and evolving landscape of clinical trials on systemic treatments of HCC. It covers current trials which test various systemic treatments (i) in the first and second line in advanced HCC, (ii) in intermediate HCC, (iii) as adjuvant as well as (iv) neoadjuvant strategies, and (v) including immune interventions other than immune checkpoint inhibition.
Systematic Review and Network Meta-Analysis of Anaplastic Lymphoma Kinase (ALK) Inhibitors for Treatment-Naïve ALK-Positive Lung Cancer
Authors: Chuang Cheng-Hao , Chen Hsiao-Ling , Chang Hsiu-Mei , Tsai Yu-Chen , Wu Kuan-Li , Chen I-Hua , Chen Kung-Chao , Lee Jui-Ying , Chang Yong-Chieh , Chen Chin-Ling , Tu Yu-Kang , Hung Jen-Yu , Yang Chih-Jen , Chong Inn-Wen
Published: April 2021

Several anaplastic lymphoma kinase inhibitors (ALKIs) have demonstrated excellent efficacy on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and also better adverse effect (AE) profiles compared to cytotoxic chemotherapy in advanced stage anaplastic lymphoma kinase (ALK) rearrangement-positive non-small cell lung cancer (NSCLC) in phase III randomized clinical trials (RCTs). We conducted this systematic review and network meta-analysis to provide a ranking of ALKIs for treatment-naïve ALK-positive patients in terms of PFS, ORR, and AEs. In addition, a sub-group analysis of treatment benefits in patients with baseline brain metastasis was also conducted. Contrast-based analysis was performed for multiple treatment comparisons with the restricted maximum likelihood approach. Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being the best (Prbest) reference. All next-generation ALKIs were superior to crizotinib in PFS but lorlatinib and brigatinib had increased AEs. The probability of lorlatinib being ranked first among all treatment arms was highest (SUCRA = 93.3%, Prbest = 71.8%), although there were no significant differences in pairwise comparisons with high- (600 mg twice daily) and low- (300 mg twice daily) dose alectinib. In subgroup analysis of patients with baseline brain metastasis, low-dose alectinib had the best PFS (SUCRA = 87.3%, Prbest = 74.9%). Lorlatinib was associated with the best ranking for ORR (SUCRA = 90.3%, Prbest = 71.3%), although there were no significant differences in pairwise comparisons with the other ALKIs. In addition, low-dose alectinib had the best safety performance (SUCRA = 99.4%, Prbest = 97.9%). Lorlatinib and low-dose alectinib had the best PFS and ORR in the overall population and baseline brain metastasis subgroup, respectively. Low-dose alectinib had the lowest AE risk among the available ALKIs. Further head-to-head large-scale phase III RCTs are needed to verify our conclusions.
Distal Pancreatectomy with Celiac Axis Resection: Systematic Review and Meta-Analysis
Authors: Nigri Giuseppe , Petrucciani Niccolò , Belloni Elena , Lucarini Alessio , Aurello Paolo , D’Angelo Francesco , di Saverio Salomone , Fancellu Alessandro , Ramacciato Giovanni
Published: April 2021

Background: Major vascular invasion represents one of the most frequent reasons to consider pancreatic adenocarcinomas unresectable, although in the last decades, demolitive surgeries such as distal pancreatectomy with celiac axis resection (DP-CAR) have become a therapeutical option. Methods: A meta-analysis of studies comparing DP-CAR and standard DP in patients with pancreatic adenocarcinoma was conducted. Moreover, a systematic review of studies analyzing oncological, postoperative and survival outcomes of DP-CAR was conducted. Results: Twenty-four articles were selected for the systematic review, whereas eleven were selected for the meta-analysis, for a total of 1077 patients. Survival outcomes between the two groups were similar in terms of 1 year overall survival (OS) (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.34 to 1.31, p = 0.24). Patients who received DP-CAR were more likely to have T4 tumors (OR 28.45, 95% CI 10.46 to 77.37, p < 0.00001) and positive margins (R+) (OR 2.28, 95% CI 1.24 to 4.17, p = 0.008). Overall complications (OR, 1.72, 95% CI, 1.15 to 2.58, p = 0.008) were more frequent in the DP-CAR group, whereas rates of pancreatic fistula (OR 1.16, 95% CI 0.81 to 1.65, p = 0.41) were similar. Conclusions: DP-CAR was not associated with higher mortality compared to standard DP; however, overall morbidity was higher. Celiac axis involvement should no longer be considered a strict contraindication to surgery in patients with locally advanced pancreatic adenocarcinoma. Considering the different baseline tumor characteristics, DP-CAR may need to be compared with palliative therapies instead of standard DP.
Precision Oncology Beyond Genomics: The Future Is Here—It Is Just Not Evenly Distributed
Authors: Pfohl Ulrike , Pflaume Alina , Regenbrecht Manuela , Finkler Sabine , Graf Adelmann Quirin , Reinhard Christoph , Regenbrecht Christian , Wedeken Lena
Published: April 2021

Cancer is a multifactorial disease with increasing incidence. There are more than 100 different cancer types, defined by location, cell of origin, and genomic alterations that influence oncogenesis and therapeutic response. This heterogeneity between tumors of different patients and also the heterogeneity within the same patient’s tumor pose an enormous challenge to cancer treatment. In this review, we explore tumor heterogeneity on the longitudinal and the latitudinal axis, reviewing current and future approaches to study this heterogeneity and their potential to support oncologists in tailoring a patient’s treatment regimen. We highlight how the ideal of precision oncology is reaching far beyond the knowledge of genetic variants to inform clinical practice and discuss the technologies and strategies already available to improve our understanding and management of heterogeneity in cancer treatment. We will focus on integrating multi-omics technologies with suitable in vitro models and their proficiency in mimicking endogenous tumor heterogeneity.
Dendritic Cells: Neglected Modulators of Peripheral Immune Responses and Neuroinflammation in Mood Disorders?
Authors: Leite Dantas Rafael , Freff Jana , Ambrée Oliver , Beins Eva C. , Forstner Andreas J. , Dannlowski Udo , Baune Bernhard T. , Scheu Stefanie , Alferink Judith
Published: April 2021

Affective disorders (AD) including major depressive disorder (MDD) and bipolar disorder (BD) are common mood disorders associated with increased disability and poor health outcomes. Altered immune responses characterized by increased serum levels of pro-inflammatory cytokines and neuroinflammation are common findings in patients with AD and in corresponding animal models. Dendritic cells (DCs) represent a heterogeneous population of myeloid cells that orchestrate innate and adaptive immune responses and self-tolerance. Upon sensing exogenous and endogenous danger signals, mature DCs secrete proinflammatory factors, acquire migratory and antigen presenting capacities and thus contribute to neuroinflammation in trauma, autoimmunity, and neurodegenerative diseases. However, little is known about the involvement of DCs in the pathogenesis of AD. In this review, we summarize the current knowledge on DCs in peripheral immune responses and neuroinflammation in MDD and BD. In addition, we consider the impact of DCs on neuroinflammation and behavior in animal models of AD. Finally, we will discuss therapeutic perspectives targeting DCs and their effector molecules in mood disorders.
MRCKα Is Dispensable for Breast Cancer Development in the MMTV-PyMT Model
Authors: Kwa Mei Qi , Brandao Rafael , Phung Trong H. , Ge Jianfeng , Scieri Giuseppe , Brakebusch Cord
Published: April 2021

MRCKα is a ubiquitously expressed serine/threonine kinase involved in cell contraction and F-actin turnover, which is highly amplified in human breast cancer and part of a gene expression signature for bad prognosis. Nothing is known about the in vivo function of MRCKα. To explore MRCKα function in development and in breast cancer, we generated mice lacking a functional MRCKα gene. Mice were born close to the Mendelian ratio and showed no obvious phenotype including a normal mammary gland formation. Assessing breast cancer development using the transgenic MMTV-PyMT mouse model, loss of MRCKα did not affect tumor onset, tumor growth and metastasis formation. Deleting MRCKα and its related family member MRCKβ in two triple-negative breast cancer cell lines resulted in reduced invasion of MDA-MB-231 cells, but did not affect migration of 4T1 cells. Further genomic analysis of human breast cancers revealed that MRCKα is frequently co-amplified with the oncogenes ARID4B and AKT3 which might contribute to the prognostic value of MRCKα expression. Collectively, these data suggest that MRCKα might be a prognostic marker for breast cancer, but probably of limited functional importance.
Metal Nanoparticle and Quantum Dot Tags for Signal Amplification in Electrochemical Immunosensors for Biomarker Detection
Authors: Popov Anton , Brasiunas Benediktas , Kausaite-Minkstimiene Asta , Ramanaviciene Almira
Published: April 2021

With the increasing importance of healthcare and clinical diagnosis, as well as the growing demand for highly sensitive analytical instruments, immunosensors have received considerable attention. In this review, electrochemical immunosensor signal amplification strategies using metal nanoparticles (MNPs) and quantum dots (Qdots) as tags are overviewed, focusing on recent developments in the ultrasensitive detection of biomarkers. MNPs and Qdots can be used separately or in combination with other nanostructures, while performing the function of nanocarriers, electroactive labels, or catalysts. Thus, different functions of MNPs and Qdots as well as recent advances in electrochemical signal amplification are discussed. Additionally, the methods most often used for antibody immobilization on nanoparticles, immunoassay formats, and electrochemical methods for indirect biomarker detection are overviewed.
Enhancement of the Adhesion of Wire Arc Sprayed Coatings on Carbon Fiber-Reinforced Plastic by Surface Laser Structuring
Authors: Gustke Kevin , Gebauer Jana , Drehmann Rico , Lasagni Andrés Fabián , Lampke Thomas
Published: April 2021

Due to their outstanding stiffness-to-weight ratio, fiber-reinforced plastics are established materials for weight reduction in the aerospace and automotive industries. To improve certain properties, such as their low thermal and electrical conductivity, metallic coatings can be applied to the polymer surface. One of the methods used for this purpose is thermal spraying. Studies have shown that the adhesion strength of metallic coatings on polymer surfaces is low. To improve the adhesion strength, the surface of the fiber-reinforced plastics was pretreated with pulsed laser-based methods. This study describes in detail the process chain, the resulting surface conditions and their effect on the adhesion strength of wire arc sprayed copper coatings in pull-off and shear tensile testing. The results show up to ~200% increase in adhesion strength for the laser-structured samples compared to the grit-blasted reference samples in the pull-off test.
Fabrication and Characterization of Antimicrobial Magnetron Cosputtered TiO2/Ag/Cu Composite Coatings
Authors: Gospodonova Dilyana , Ivanova Iliana , Vladkova Todorka
Published: April 2021

The aim of this study was to prepare TiO2/Ag/Cu magnetron co-sputtered coatings with controlled characteristics and to correlate them with the antimicrobial activity of the coated glass samples. The elemental composition and distribution, surface morphology, wettability, surface energy and its component were estimated as the surface characteristics influencing the bioadhesion. Well expressed, specific, Ag/Cu concentration-dependent antimicrobial activity in vitro was demonstrated toward Gram-negative and Gram-positive standard test bacterial strains both by diffusion 21 assay and by Most Probable Number of surviving cells. Direct contact and eluted silver/coper nanoparticles killing were experimentally demonstrated as a mode of the antimicrobial action of the studied TiO2/Ag/Cu thin composite coatings. It is expected that they would ensure a broad spectrum bactericidal activity during the indwelling of the coated medical devices and for at least 12 h after that, with the supposition that the benefits will be over a longer time.
Corrosion Protection of 6061 Aluminum Alloys by Sol-Gel Coating Modified with ZnLaAl-LDHs
Authors: Wang Youbin , Huang Qiuyu , Zhou Bingtao , Yuan Zengyin , Wei Yuezhou , Fujita Toyohisa
Published: April 2021

In this work, ZnLaAl layered double hydroxides (LDHs) were prepared by the co-precipitation method, and the ZnLaAl-LDHs nanosheets were embedded in sol-gel coating for the corrosion protection of 6061 aluminum alloys. The structure, morphology, and long-term anti-corrosion performance of sol-gel coating modified with ZnLaAl-LDHs were investigated. The structure and morphology analysis showed that nanosheets of ZnLaAl-LDHs are finer than those of ZnAl-LDHs, with the results suggesting that the La can refine the size of LDHs’ nanosheets and improve their nucleation rate. The results of long-term corrosion tests showed that the sol-gel coating with ZnLaAl-LDHs exhibits higher corrosion resistance and better stability compared with the sol-gel coating with ZnAl-LDHs, which indicates that the addition of La enhances the anti-corrosion performance of the LDHs and improves the stability of sol-gel coating with LDHs. Finally, the formation mechanism of ZnLaAl-LDHs and the corrosion mechanism of sol-gel coating with ZnLaAl-LDHs on 6061 aluminum alloys are both discussed in detail.
Nucleation and Post-Nucleation Growth in Diffusion-Controlled and Hydrodynamic Theory of Solidification
Authors: Podmaniczky Frigyes , Gránásy László
Published: April 2021

Two-step nucleation and subsequent growth processes were investigated in the framework of the single mode phase-field crystal model combined with diffusive dynamics (corresponding to colloid suspensions) and hydrodynamical density relaxation (simple liquids). It is found that independently of dynamics, nucleation starts with the formation of solid precursor clusters that consist of domains with noncrystalline ordering (ringlike projections are seen from certain angles), and regions that have amorphous structure. Using the average bond order parameter q¯6, we distinguished amorphous, medium range crystallike order (MRCO), and crystalline local orders. We show that crystallization to the stable body-centered cubic phase is preceded by the formation of a mixture of amorphous and MRCO structures. We have determined the time dependence of the phase composition of the forming solid state. We also investigated the time/size dependence of the growth rate for solidification. The bond order analysis indicates similar structural transitions during solidification in the case of diffusive and hydrodynamic density relaxation.
Regression of Intracranial Meningiomas Following Treatment with Cabozantinib
Authors: Kotecha Rupesh , Tonse Raees , Appel Haley , Odia Yazmin , Kotecha Ritesh R. , Rabinowits Guilherme , Mehta Minesh P.
Published: April 2021

Recurrent meningiomas remain a substantial treatment challenge given the lack of effective therapeutic options aside from surgery and radiation therapy, which yield limited results in the retreatment situation. Systemic therapies have little effect, and responses are rare; the search for effective systemic therapeutics remains elusive. In this case report, we provide data regarding significant responses in two radiographically diagnosed intracranial meningiomas in a patient with concurrent thyroid carcinoma treated with cabozantinib, an oral multitarget tyrosine kinase inhibitor with potent activity against MET and VEGF receptor 2. Given the clinical experience supporting the role of VEGF agents as experimental therapeutics in meningioma and the current understanding of the biological pathways underlying meningioma growth, this may represent a new oral therapeutic alternative, warranting prospective evaluation.
Population Structures and Levels of Connectivity for Scyphozoan and Cubozoan Jellyfish
Authors: Kingsford Michael J. , Schlaefer Jodie A. , Morrissey Scott J.
Published: April 2021

Understanding the hierarchy of populations from the scale of metapopulations to mesopopulations and member local populations is fundamental to understanding the population dynamics of any species. Jellyfish by definition are planktonic and it would be assumed that connectivity would be high among local populations, and that populations would minimally vary in both ecological and genetic clade-level differences over broad spatial scales (i.e., hundreds to thousands of km). Although data exists on the connectivity of scyphozoan jellyfish, there are few data on cubozoans. Cubozoans are capable swimmers and have more complex and sophisticated visual abilities than scyphozoans. We predict, therefore, that cubozoans have the potential to have finer spatial scale differences in population structure than their relatives, the scyphozoans. Here we review the data available on the population structures of scyphozoans and what is known about cubozoans. The evidence from realized connectivity and estimates of potential connectivity for scyphozoans indicates the following. Some jellyfish taxa have a large metapopulation and very large stocks (>1000 s of km), while others have clade-level differences on the scale of tens of km. Data on distributions, genetics of medusa and polyps, statolith shape, elemental chemistry of statoliths and biophysical modelling of connectivity suggest that some of the ~50 species of cubozoans have populations of surprisingly small spatial scales and low levels of connectivity. Despite their classification as plankton, therefore, some scyphozoans and cubozoans have stocks of small spatial scales. Causal factors that influence the population structure in many taxa include the distribution of polyps, behavior of medusa, local geomorphology and hydrodynamics. Finally, the resolution of patterns of connectivity and population structures will be greatest when multiple methods are used.
Ecological, Historical, Economic, and Political Factors Shaping the Human–Gorilla Interface in the Mone-Oku Forest, Cameroon
Authors: Wade Alison H. , Malone Nicholas
Published: April 2021

Cross River gorillas are the least numerous of the African ape taxa. Since their rediscovery, several organisations have sought to conserve these critically endangered apes, resulting in a “crisis conservation narrative” focused on the threats posed by local human activities. However, landscapes are not just ecological, they are also social, shaped by political and economic processes. This study examines the interconnections between humans and gorillas by approaching the Mone-Oku forest as a combination of ecological, social, and political systems. Through a combined use of botanical surveys, analyses of nesting sites, participant observation, and semistructured interviews, we obtained nuanced ecological and ethnographic insights into the human–gorilla interface. The results illustrate a history of alterations within the Mone-Oku forest, some of which are human-induced. These alterations have had both positive and negative outcomes for the gorillas and continue to the present day, where political history has shaped limited livelihood alternatives, increasing the reliance on a forest that has remained a constant in the more recent history of “developmental” neglect and isolation. However, this situation is not static, with future alterations to the forest also subject to regional and international political and economic influences, such as the increased worldwide demand for cacao.
Association between Periodontitis and Genetic Polymorphisms in Interleukins among Patients with Diabetes Mellitus
Authors: Abdellatif Hoda M. , Binshabaib Munerah Saleh , Shawky Heba A. , ALHarthi Shatha Subhi
Published: April 2021

There is a perplexity in the association between interleukin (IL) polymorphisms and periodontitis among patients with and without diabetes mellitus (DM). The aim of the present study was to evaluate indexed data regarding the association between periodontitis and genetic polymorphisms in interleukins among patients with and without DM. The addressed question was “Is there an association between periodontitis and polymorphisms in interleukins among patients with and without DM?” Original studies were included. Indexed databases were searched, and the pattern of the present literature review was customized to summaries’ the pertinent information. Eight studies were included and processed for data extraction. Two studies showed that polymorphisms in IL-1B genes aggravate periodontitis in patients with type-2 DM, and two studies showed that IL-1B genes either do not or are less likely to contribute towards the progression of periodontitis in patients with type-2 DM. Two studies reported that IL genes do not show cross-susceptibility with periodontitis and type-2 DM. One study reported that the primary factor that governs the occurrence and progression of periodontitis in patients with and without type-2 DM is poor routine oral hygiene maintenance. Seven studies had a high risk of bias. The role of IL gene polymorphisms in the development and progression of periodontitis in patients with and without DM remains controversial.
Extended Lattice Boltzmann Model
Authors: Saadat Mohammad Hossein , Dorschner Benedikt , Karlin Ilya
Published: April 2021

Conventional lattice Boltzmann models for the simulation of fluid dynamics are restricted by an error in the stress tensor that is negligible only for small flow velocity and at a singular value of the temperature. To that end, we propose a unified formulation that restores Galilean invariance and the isotropy of the stress tensor by introducing an extended equilibrium. This modification extends lattice Boltzmann models to simulations with higher values of the flow velocity and can be used at temperatures that are higher than the lattice reference temperature, which enhances computational efficiency by decreasing the number of required time steps. Furthermore, the extended model also remains valid for stretched lattices, which are useful when flow gradients are predominant in one direction. The model is validated by simulations of two- and three-dimensional benchmark problems, including the double shear layer flow, the decay of homogeneous isotropic turbulence, the laminar boundary layer over a flat plate and the turbulent channel flow.
Hybrid Basketball Game Outcome Prediction Model by Integrating Data Mining Methods for the National Basketball Association
Authors: Chen Wei-Jen , Jhou Mao-Jhen , Lee Tian-Shyug , Lu Chi-Jie
Published: April 2021

The sports market has grown rapidly over the last several decades. Sports outcomes prediction is an attractive sports analytic challenge as it provides useful information for operations in the sports market. In this study, a hybrid basketball game outcomes prediction scheme is developed for predicting the final score of the National Basketball Association (NBA) games by integrating five data mining techniques, including extreme learning machine, multivariate adaptive regression splines, k-nearest neighbors, eXtreme gradient boosting (XGBoost), and stochastic gradient boosting. Designed features are generated by merging different game-lags information from fundamental basketball statistics and used in the proposed scheme. This study collected data from all the games of the NBA 2018–2019 seasons. There are 30 teams in the NBA and each team play 82 games per season. A total of 2460 NBA game data points were collected. Empirical results illustrated that the proposed hybrid basketball game prediction scheme achieves high prediction performance and identifies suitable game-lag information and relevant game features (statistics). Our findings suggested that a two-stage XGBoost model using four pieces of game-lags information achieves the best prediction performance among all competing models. The six designed features, including averaged defensive rebounds, averaged two-point field goal percentage, averaged free throw percentage, averaged offensive rebounds, averaged assists, and averaged three-point field goal attempts, from four game-lags have a greater effect on the prediction of final scores of NBA games than other game-lags. The findings of this study provide relevant insights and guidance for other team or individual sports outcomes prediction research.
Excitation Functions of Tsallis-Like Parameters in High-Energy Nucleus–Nucleus Collisions
Authors: Li Li-Li , Liu Fu-Hu , Olimov Khusniddin K.
Published: April 2021

The transverse momentum spectra of charged pions, kaons, and protons produced at mid-rapidity in central nucleus–nucleus (AA) collisions at high energies are analyzed by considering particles to be created from two participant partons, which are assumed to be contributors from the collision system. Each participant (contributor) parton is assumed to contribute to the transverse momentum by a Tsallis-like function. The contributions of the two participant partons are regarded as the two components of transverse momentum of the identified particle. The experimental data measured in high-energy AA collisions by international collaborations are studied. The excitation functions of kinetic freeze-out temperature and transverse flow velocity are extracted. The two parameters increase quickly from ≈3 to ≈10 GeV (exactly from 2.7 to 7.7 GeV) and then slowly at above 10 GeV with the increase of collision energy. In particular, there is a plateau from near 10 GeV to 200 GeV in the excitation function of kinetic freeze-out temperature.
Entanglement and Non-Locality in Quantum Protocols with Identical Particles
Authors: Benatti Fabio , Floreanini Roberto , Marzolino Ugo
Published: April 2021

We study the role of entanglement and non-locality in quantum protocols that make use of systems of identical particles. Unlike in the case of distinguishable particles, the notions of entanglement and non-locality for systems whose constituents cannot be distinguished and singly addressed are still debated. We clarify why the only approach that avoids incongruities and paradoxes is the one based on the second quantization formalism, whereby it is the entanglement of the modes that can be populated by the particles that really matters and not the particles themselves. Indeed, by means of a metrological and of a teleportation protocol, we show that inconsistencies arise in formulations that force entanglement and non-locality to be properties of the identical particles rather than of the modes they can occupy. The reason resides in the fact that orthogonal modes can always be addressed while identical particles cannot.
Novel Features for Binary Time Series Based on Branch Length Similarity Entropy
Authors: Lee Sang-Hee , Park Cheol-Min
Published: April 2021

Branch length similarity (BLS) entropy is defined in a network consisting of a single node and branches. In this study, we mapped the binary time-series signal to the circumference of the time circle so that the BLS entropy can be calculated for the binary time-series. We obtained the BLS entropy values for “1” signals on the time circle. The set of values are the BLS entropy profile. We selected the local maximum (minimum) point, slope, and inflection point of the entropy profile as the characteristic features of the binary time-series and investigated and explored their significance. The local maximum (minimum) point indicates the time at which the rate of change in the signal density becomes zero. The slope and inflection points correspond to the degree of change in the signal density and the time at which the signal density changes occur, respectively. Moreover, we show that the characteristic features can be widely used in binary time-series analysis by characterizing the movement trajectory of Caenorhabditis elegans. We also mention the problems that need to be explored mathematically in relation to the features and propose candidates for additional features based on the BLS entropy profile.
Information Theory in Molecular Evolution: From Models to Structures and Dynamics
Authors: Morcos Faruck
Published: April 2021

Historically, information theory has been closely interconnected with evolutionary theory [...]