bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive Profiling of Blood Coagulation and Fibrinolysis Marker Reveals Elevated Plasmin-Antiplasmin Complexes in Parkinson’s Disease
Authors: Sharma Amit , Müller Jens , Schuetze Karin , Rolfes Verena , Bissinger Rosi , Rosero Nathalia , Ahmad Ashar , Franklin Bernardo S , Zur Berndt , Fröhlich Holger , Lang Florian , Oldenburg Johannes , Pötzsch Bernd , Wüllner Ullrich
Published: July 2021

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease. Accumulating evidence demonstrates that alpha-synuclein (α-Syn), an apparently predominant neuronal protein, is a major contributor to PD pathology. As α-Syn is also highly abundant in blood, particularly in red blood cells (RBCs) and platelets, this in turn raises the question on the function of presumably dysfunctional α-Syn in “peripheral” cells and its putative effect on the other enclosed constituents. Herein, we detected the internal variance in erythrocytes of PD patients by Raman spectroscopy, but no measurable amount of erythrocytic behavioural change (eryptosis) or any haemoglobin variation was noticed. An elevated level of plasmin-antiplasmin complexes (PAP) was observed in the plasma of PD patients, indicating activation of the fibrinolytic system, but platelet activation after thrombin stimulation was not altered. Sex-specific patterns were noticed for blood coagulation factor XIII and factor XII activity in PD patients. Additionally, the alterations in homocysteine levels which have often been observed in PD patients were found to be independent from L-DOPA usage and PAP levels. Furthermore, a selective gene expression analysis identified subsets of genes related to different blood-associated compartments (RBCs, platelets, coagulation-fibrinolysis) also involved in PD-related pathways.
Sexual Dimorphism in Changes That Occur in Tissues, Organs and Plasma during the Early Stages of Obesity Development
Authors: Dhanraj Priyanka , van Heerden Marlene B. , Pepper Michael S. , Ambele Melvin A.
Published: July 2021

Despite obesity being a major health concern, information on the early clinical changes that occur in plasma and tissues during obesity development and the influence of sexual dimorphism is lacking. This study investigated changes in tissue and organ histology, macrophage infiltration, plasma hormones, lipid, and chemokine and cytokine levels in mice fed on a high fat diet for 11-weeks. An increase in adiposity, accompanied by adipocyte hypertrophy and macrophage infiltration, was observed to be significantly greater in males than females. Important changes in cell morphology and histology were noted in the lungs, liver, kidney, spleen, and heart, which may indicate early signs for developing obesity associated comorbidities. Leptin, but not adiponectin, was significantly altered during weight gain. Additionally, leptin, but not adiposity, correlated with insulin levels. Interestingly, GM-CSF, TNFα, and IL-12 (p70) were not produced in the early stages of obesity development. Meanwhile, the production of MCP-1, IP-10, RANTES, IL-10, IL-6, KC, and IL-9 were greatly influenced by sexual dimorphism. Importantly, IL-6/IL-10 axis of anti-inflammatory cytokine regulation was observed only in females and may account for their significantly lower weight gain compared to males. This study provides new knowledge on how sexual dimorphism may influence the development of obesity and associated comorbidities.
Phytochemicals in Cancer Immune Checkpoint Inhibitor Therapy
Authors: Lee Juwon , Han Youngjin , Wang Wenyu , Jo HyunA , Kim Heeyeon , Kim Soochi , Yang Kyung-Min , Kim Seong-Jin , Dhanasekaran Danny N. , Song Yong Sang
Published: July 2021

The interaction of immune checkpoint molecules in the tumor microenvironment reduces the anti-tumor immune response by suppressing the recognition of T cells to tumor cells. Immune checkpoint inhibitor (ICI) therapy is emerging as a promising therapeutic option for cancer treatment. However, modulating the immune system with ICIs still faces obstacles with severe immunogenic side effects and a lack of response against many cancer types. Plant-derived natural compounds offer regulation on various signaling cascades and have been applied for the treatment of multiple diseases, including cancer. Accumulated evidence provides the possibility of efficacy of phytochemicals in combinational with other therapeutic agents of ICIs, effectively modulating immune checkpoint-related signaling molecules. Recently, several phytochemicals have been reported to show the modulatory effects of immune checkpoints in various cancers in in vivo or in vitro models. This review summarizes druggable immune checkpoints and their regulatory factors. In addition, phytochemicals that are capable of suppressing PD-1/PD-L1 binding, the best-studied target of ICI therapy, were comprehensively summarized and classified according to chemical structure subgroups. It may help extend further research on phytochemicals as candidates of combinational adjuvants. Future clinical trials may validate the synergetic effects of preclinically investigated phytochemicals with ICI therapy.
Sirtuin 1, Visfatin and IL-27 Serum Levels of Type 1 Diabetic Females in Relation to Cardiovascular Parameters and Autoimmune Thyroid Disease
Authors: Łukawska-Tatarczuk Magdalena , Franek Edward , Czupryniak Leszek , Joniec-Maciejak Ilona , Pawlak Agnieszka , Wojnar Ewa , Zieliński Jakub , Mirowska-Guzel Dagmara , Mrozikiewicz-Rakowska Beata
Published: July 2021

The loss of cardioprotection observed in premenopausal, diabetic women may result from the interplay between epigenetic, metabolic, and immunological factors. The aim of this study was to evaluate the concentration of sirtuin 1, visfatin, and IL-27 in relation to cardiovascular parameters and Hashimoto’s disease (HD) in young, asymptomatic women with type 1 diabetes mellitus (T1DM). Thyroid ultrasound, carotid intima-media thickness (cIMT) measurement, electrocardiography, and echocardiography were performed in 50 euthyroid females with T1DM (28 with HD and 22 without concomitant diseases) and 30 controls. The concentrations of serum sirtuin 1, visfatin and IL-27 were assessed using ELISA. The T1DM and HD group had higher cIMT (p = 0.018) and lower left ventricular global longitudinal strain (p = 0.025) compared to females with T1DM exclusively. In women with a double diagnosis, the sirtuin 1 and IL-27 concentrations were non-significantly higher than in other groups and significantly positively correlated with each other (r = 0.445, p = 0.018) and thyroid volume (r = 0.511, p = 0.005; r = 0.482, p = 0.009, respectively) and negatively correlated with relative wall thickness (r = –0.451, p = 0.016; r = –0.387, p = 0.041, respectively). These relationships were not observed in the control group nor for the visfatin concentration. These results suggest that sirtuin 1 and IL-27 contribute to the pathogenesis of early cardiac dysfunction in women with T1DM and HD.
Full-Length Recombinant hSP-D Binds and Inhibits SARS-CoV-2
Authors: Arroyo Raquel , Grant Shawn N. , Colombo Miriam , Salvioni Lucia , Corsi Fabio , Truffi Marta , Ottolina Davide , Hurst Brett , Salzberg Marc , Prosperi Davide , Kingma Paul S.
Published: July 2021

SARS-CoV-2 infection of host cells is driven by binding of the SARS-CoV-2 spike-(S)-protein to lung type II pneumocytes, followed by virus replication. Surfactant protein SP-D, member of the front-line immune defense of the lungs, binds glycosylated structures on invading pathogens such as viruses to induce their clearance from the lungs. The objective of this study is to measure the pulmonary SP-D levels in COVID-19 patients and demonstrate the activity of SP-D against SARS-CoV-2, opening the possibility of using SP-D as potential therapy for COVID-19 patients. Pulmonary SP-D concentrations were measured in bronchoalveolar lavage samples from patients with corona virus disease 2019 (COVID-19) by anti-SP-D ELISA. Binding assays were performed by ELISAs. Protein bridge and aggregation assays were performed by gel electrophoresis followed by silver staining and band densitometry. Viral replication was evaluated in vitro using epithelial Caco-2 cells. Results indicate that COVID-19 patients (n = 12) show decreased pulmonary levels of SP-D (median = 68.9 ng/mL) when compared to levels reported for healthy controls in literature. Binding assays demonstrate that SP-D binds the SARS-CoV-2 glycosylated spike-(S)-protein of different emerging clinical variants. Binding induces the formation of protein bridges, the critical step of viral aggregation to facilitate its clearance. SP-D inhibits SARS-CoV-2 replication in Caco-2 cells (EC90 = 3.7 μg/mL). Therefore, SP-D recognizes and binds to the spike-(S)-protein of SARS-CoV-2 in vitro, initiates the aggregation, and inhibits viral replication in cells. Combined with the low levels of SP-D observed in COVID-19 patients, these results suggest that SP-D is important in the immune response to SARS-CoV-2 and that rhSP-D supplementation has the potential to be a novel class of anti-viral that will target SARS-CoV-2 infection.
Strong Associations between Plasma Osteopontin and Several Inflammatory Chemokines, Cytokines, and Growth Factors
Authors: Larsson Anders , Helmersson-Karlqvist Johanna , Lind Lars , Ärnlöv Johan , Feldreich Tobias Rudholm
Published: July 2021

Osteopontin is a member of the proinflammatory cytokine network, a complex system that involves many chemokines, cytokines, and growth factors. The aim of the present study was to study the associations between osteopontin and a large number of chemokines, cytokines, and growth factors. We analyzed plasma and urine osteopontin in 652 men from the Uppsala Longitudinal Study of Adult Men (ULSAM) study cohort and compared the levels with the levels of eighty-five chemokines, cytokines, and growth factors. We found significant associations between plasma osteopontin and 37 plasma biomarkers in a model adjusted for age, and 28 of those plasma biomarkers were significant in a model also adjusting for cardiovascular risk factors. There were no significant associations after Bonferroni adjustment between urine osteopontin and any of the studied plasma cytokine biomarkers. This study shows that circulating osteopontin participates in a protein–protein interaction network of chemokines, cytokines, and growth factors. The network contains responses, pathways, and receptor binding interactions relating to cytokines, regulation of the immune system, and also regulation of apoptosis and intracellular signal transduction.
Surgical Management of Adrenocortical Carcinoma: Current Highlights
Authors: Cavallaro Giuseppe , Tarallo Mariarita , Chiappini Ambra , Crocetti Daniele , Polistena Andrea , Petramala Luigi , Sibio Simone , De Toma Giorgio , Fiori Enrico , Letizia Claudio
Published: July 2021

Introduction: Adrenocortical carcinoma (ACC) is a rare tumor, often discovered at an advanced stage and associated with poor prognosis. Treatment is guided by staging according to the European Network for the Study of Adrenal Tumors (ENSAT) classification. Surgery is the treatment of choice for ACC. The aim of this review is to provide a complete overview on surgical approaches and management of adrenocortical carcinoma. Methods: This comprehensive review has been carried out according to the PRISMA statement. The literature sources were the databases PubMed, Scopus and Cochrane Library. The search thread was: ((surgery) OR (adrenalectomy)) AND (adrenocortical carcinoma). Results: Among all studies identified, 17 were selected for the review. All of them were retrospective. A total of 2498 patients were included in the studies, of whom 734 were treated by mini-invasive approaches and 1764 patients were treated by open surgery. Conclusions: Surgery is the treatment of choice for ACC. Open adrenalectomy (OA) is defined as the gold standard. In recent years laparoscopic adrenalectomy (LA) has gained more popularity. No significant differences were reported for overall recurrence rate, time to recurrence, and cancer-specific mortality between LA and OA, in particular for Stage I-II. Robotic adrenalectomy (RA) has several advantages compared to LA, but there is still a lack of specific documentation on RA use in ACC.
An Electrochemical Evaluation of Novel Ferrocene Derivatives for Glutamate and Liver Biomarker Biosensing
Authors: Soon Geok Hong , Deasy Mary , Dempsey Eithne
Published: July 2021

Here, we present an evaluation of two new monosubstituted ferrocene (Fc) derivatives, 3-(1H-pyrrol-1-yl)propanamidoferrocene and 1-hydroxy-2-[2-(thiophen-3-yl)-ethylamino]ethylferrocene, as glutamate oxidase mediators, together with their preparation and characterisation. Taking into consideration the influence of the electronic effects of substituents on the redox potentials of the Fc species, two candidates with pyrrole or thiophene moieties were proposed for investigation. Film studies involved potential sweeping in the presence of pyrrole or 3,4-ethylenedioxythiophene monomers resulting in stable electroactive films with % signal loss upon cycling ranging from 1 to 7.82% and surface coverage (Γ) 0.47–1.15 × 10−9 mol/cm2 for films formed under optimal conditions. Construction of a glutamate oxidase modified electrode resulted in second-generation biosensing with the aid of both cyclic voltammetry and hydrodynamic amperometry, resulting in glutamate sensitivity of 0.86–1.28 μA/mM and Km (app) values over the range 3.67–5.01 mM. A follow-up enzyme assay for liver biomarker γ-glutamyl transpeptidase realised unmediated and mediated measurement establishing reaction and incubation time investigations and a realising response over <100 U/L γ-glutamyl transpeptidase with a sensitivity of 5 nA/UL−1.
Does Etiology Matter? Comparative Analysis of a Singing-Enhanced Swallowing Protocol for Patients with Neurological Impairment versus Head and Neck Cancer
Authors: Yeo Myung Sun , Yoo Ga Eul , Cho Sung-Rae , Kim Soo Ji
Published: July 2021

Swallowing difficulties are a common complaint among patients with a variety of diseases. To address these concerns, a singing-enhanced swallowing protocol was constructed, and its differential benefits for two patient populations were investigated. Two patients with Parkinson’s disease (PD) and two patients with head and neck cancer (HNC) participated in this study. Each patient participated in 30-min individual sessions of a singing-enhanced swallowing protocol two times per week for 12 weeks. Following the intervention, laryngeal diadochokinesis and quality-of-life measurements were found to be higher in all four patients. However, the Videofluoroscopic Dysphagia Scale showed this improvement was associated with different swallowing tasks for each patient group. In addition, the maximum phonation time decreased for patients with HNC, while it increased for patients with PD. The findings support the use of a singing-enhanced swallowing protocol for patients whose swallowing difficulties are due to neurological or structural impairment. In addition, the study results suggest that different intervention components should be considered depending on the etiology of the patient’s swallowing difficulties.
Developing Innovative Integrated Business Solutions Using a Scrum Project Management Methodology
Authors: McLellan Jamie , Young William A. , Levin Elizabeth C. , Johnson Lester W.
Published: July 2021

Innovative manufacturers have used Integrated Business Solutions (IBSs) as a means to co-create products and services to solve diverse business problems and more effectively compete in their field of endeavour. However, the efficacy and benefits of IBSs have been diminished due to the rigid method in which project management has been applied. This paper provides a conceptual approach for manufacturers to create new revenue sources in collaboration with their customers by adopting an agile project methodology that accommodates the interactive and iterative nature of IBS development. The research findings highlight the lack of success in IBSs using traditional project management as the delivery method. It provides an alternative solution in the use of an agile project management approach with its customer-centred and iterative mindset. This paper provides a conceptual model of the agile method known as Scrum and describes how it better aligns with innovative IBS development. Though both IBSs and agile have been around for several decades, their development is still in a state of infancy. This research adds to the body of literature on the application of agile in IBSs and presents an argument for converting its conceptual model into a practice delivery.
Pre-Therapeutic VEGF Level in Plasma Is a Prognostic Bio-Marker in Head and Neck Squamous Cell Carcinoma (HNSCC)
Authors: Siemert Julia , Wald Theresa , Kolb Marlen , Pettinella Isolde , Böhm Ulrike , Pirlich Markus , Wiegand Susanne , Dietz Andreas , Wichmann Gunnar
Published: July 2021

Vascular endothelial growth factor (VEGF) is centrally involved in cancer angiogenesis. We hypothesized that pre-therapeutic VEGF levels in serum and plasma differ in their potential as biomarkers for outcomes in head and neck squamous cell carcinoma (HNSCC) patients. As prospectively defined in the study protocols of TRANSCAN-DietINT and NICEI-CIH, we measured VEGF in pretreatment serum and plasma of 75 HNSCC test cohort (TC) patients. We analyzed the prognostic value of VEGF concentrations in serum (VEGFSerum) and plasma (VEGFPlasma) for event-free survival (EFS) utilizing receiver-operating characteristics (ROC). Mean VEGF concentrations in plasma (34.6, 95% CI 26.0–43.3 ng/L) were significantly lower (p = 3.35 × 10−18) than in serum (214.8, 95% CI 179.6–250.0 ng/L) but, based on ROC (area under the curve, AUCPlasma = 0.707, 95% CI 0.573–0.840; p = 0.006 versus AUCSerum = 0.665, 95% CI 0.528–0.801; p = 0.030), superiorly correlated with event-free survival (EFS) of TC patients. Youden indices revealed optimum binary classification with VEGFPlasma 26 ng/L and VEGFSerum 264 ng/L. Kaplan–Meier plots demonstrated superiority of VEGFPlasma in discriminating patients regarding outcome. Patients with VEGFPlasma < 26 ng/L had superior nodal (NC), local (LC) and loco-regional control (LRC) leading to significant prolonged progression-free survival (PFS) and EFS. We successfully validated VEGFPlasma according the cut-off <26 ng/L as predictive for superior outcome in an independent validation cohort (iVC) of 104 HNSCC patients from the studies DeLOS-II and LIFE and found better outcomes including prolonged tumor-specific (TSS) and overall survival (OS). Outcomes in TC and iVC combined again was related to VEGFPlasma, and multivariate Cox regression revealed that VEGFPlasma was an independent outcome predictor. In HNSCC, pre-therapeutic VEGFPlasma is prognostic for outcomes.
Differential Effects of Combined ATR/WEE1 Inhibition in Cancer Cells
Authors: Rødland Gro Elise , Hauge Sissel , Hasvold Grete , Bay Lilli T. E. , Raabe Tine T. H. , Joel Mrinal , Syljuåsen Randi G.
Published: July 2021

Inhibitors of WEE1 and ATR kinases are considered promising for cancer treatment, either as monotherapy or in combination with chemo- or radiotherapy. Here, we addressed whether simultaneous inhibition of WEE1 and ATR might be advantageous. Effects of the WEE1 inhibitor MK1775 and ATR inhibitor VE822 were investigated in U2OS osteosarcoma cells and in four lung cancer cell lines, H460, A549, H1975, and SW900, with different sensitivities to the WEE1 inhibitor. Despite the differences in cytotoxic effects, the WEE1 inhibitor reduced the inhibitory phosphorylation of CDK, leading to increased CDK activity accompanied by ATR activation in all cell lines. However, combining ATR inhibition with WEE1 inhibition could not fully compensate for cell resistance to the WEE1 inhibitor and reduced cell viability to a variable extent. The decreased cell viability upon the combined treatment correlated with a synergistic induction of DNA damage in S-phase in U2OS cells but not in the lung cancer cells. Moreover, less synergy was found between ATR and WEE1 inhibitors upon co-treatment with radiation, suggesting that single inhibitors may be preferable together with radiotherapy. Altogether, our results support that combining WEE1 and ATR inhibitors may be beneficial for cancer treatment in some cases, but also highlight that the effects vary between cancer cell lines.
Fluorescence Image-Guided Surgery for Thyroid Cancer: Utility for Preventing Hypoparathyroidism
Authors: Demarchi Marco Stefano , Seeliger Barbara , Lifante Jean-Christophe , Alesina Pier Francesco , Triponez Frédéric
Published: July 2021

Background: Hypoparathyroidism is one of the most frequent complications of thyroid surgery, especially when associated with lymph node dissection in cases of thyroid cancer. Fluorescence-guided surgery is an emerging tool that appears to help reduce the rate of this complication. The present review aims to highlight the utility of fluorescence imaging in preserving parathyroid glands during thyroid cancer surgery. Methods: We performed a systematic review of the literature according to PRISMA guidelines to identify published studies on fluorescence-guided thyroid surgery with a particular focus on thyroid cancer. Articles were selected and analyzed per indication and type of surgery, autofluorescence or exogenous dye usage, and outcomes. The Methodological Index for Non-Randomized Studies (MINORS) was used to assess the methodological quality of the included articles. Results: Twenty-five studies met the inclusion criteria, with three studies exclusively assessing patients with thyroid cancer. The remaining studies assessed mixed cohorts with thyroid cancer and other thyroid or parathyroid diseases. The majority of the papers support the potential benefit of fluorescence imaging in preserving parathyroid glands in thyroid surgery. Conclusions: Fluorescence-guided surgery is useful in the prevention of post-thyroidectomy hypoparathyroidism via enhanced early identification, visualization, and preservation of the parathyroid glands. These aspects are notably beneficial in cases of associated lymphadenectomy for thyroid cancer.
Osteopontin as a Regulator of Colorectal Cancer Progression and Its Clinical Applications
Authors: Amilca-Seba Katyana , Sabbah Michèle , Larsen Annette K. , Denis Jérôme A.
Published: July 2021

A high expression of the phosphoprotein osteopontin (OPN) has been associated with cancer progression in several tumor types, including breast cancer, hepatocarcinoma, ovarian cancer, and colorectal cancer (CRC). Interestingly, OPN is overexpressed in CRC and is associated with a poor prognosis linked to invasion and metastasis. Here, we review the regulation and functions of OPN with an emphasis on CRC. We examine how epigenetic and genetic regulators interact with the key signaling pathways involved in this disease. Then, we describe the role of OPN in cancer progression, including proliferation, survival, migration, invasion, and angiogenesis. Furthermore, we outline the interest of using OPN as a clinical biomarker, and discuss if and how osteopontin can be implemented as a routine assay in clinical laboratories for monitoring CRC patients. Finally, we discuss the use of OPN an attractive, but challenging, therapeutic target.
Post-Vaccination Anti-SARS-CoV-2-Antibody Response in Patients with Multiple Myeloma Correlates with Low CD19+ B-Lymphocyte Count and Anti-CD38 Treatment
Authors: Ghandili Susanne , Schönlein Martin , Lütgehetmann Marc , Schulze zur Wiesch Julian , Becher Heiko , Bokemeyer Carsten , Sinn Marianne , Weisel Katja C. , Leypoldt Lisa B.
Published: July 2021

Few data are available regarding the efficacy of anti-SARS-CoV-2 vaccines in patients with hematological malignancies, and particular, plasma cell neoplasia. This ongoing single-center study aimed to describe the level of post-vaccination anti-SARS-CoV-2-antibodies depending on B lymphocyte count, current therapy, and remission status of patients with multiple myeloma and related plasma cell dyscrasia, after the first dose of anti-SARS-CoV-2 vaccination. The 82 patients included in this study received SARS-CoV-2 vaccines (including mRNA- and vector-based vaccines) as a routine measure. After the first vaccination, a positive SARS-CoV-2 spike protein antibody titer (SP-AbT) was detected in 23% of assessable patients. SARS-CoV-2 SP-AbT was significantly higher in patients with higher CD19+ B lymphocyte counts. A cut-off value of ≥30 CD19+ B cells/µL was significantly positive correlating with higher SARS-CoV-2 SP-AbT. In contrast, current treatment with anti-CD38-antibodies has led to significantly reduced SP-AbT titers. Furthermore, in multivariable linear regression, higher age and insufficiently controlled disease significantly correlated negatively with SARS-CoV-2 SP-AbT. Conversely, treatment with immunomodulatory drugs did not harm the development of antibody titers. Based on our results, the majority of myeloma patients respond poorly after receiving the first dose of any anti-SARS-CoV-2 vaccination and need booster vaccination.
Functional Analysis of Non-Genetic Resistance to Platinum in Epithelial Ovarian Cancer Reveals a Role for the MBD3-NuRD Complex in Resistance Development
Authors: Bauer Tabea L. , Collmar Katrin , Kaltofen Till , Loeffler Ann-Katrin , Decker Lorena , Mueller Jan , Pinter Sabine , Eisler Stephan A. , Mahner Sven , Fraungruber Patricia , Kommoss Stefan , Staebler Annette , Francis Lewis , Conlan R. Steven , Zuber Johannes , Jeschke Udo , Trillsch Fabian , Rathert Philipp
Published: July 2021

Epithelial ovarian cancer (EOC) is the most lethal disease of the female reproductive tract, and although most patients respond to the initial treatment with platinum (cPt)-based compounds, relapse is very common. We investigated the role of epigenetic changes in cPt-sensitive and -resistant EOC cell lines and found distinct differences in their enhancer landscape. Clinical data revealed that two genes (JAK1 and FGF10), which gained large enhancer clusters in resistant EOC cell lines, could provide novel biomarkers for early patient stratification with statistical independence for JAK1. To modulate the enhancer remodeling process and prevent the acquisition of cPt resistance in EOC cells, we performed a chromatin-focused RNAi screen in the presence of cPt. We identified subunits of the Nucleosome Remodeling and Deacetylase (NuRD) complex as critical factors sensitizing the EOC cell line A2780 to platinum treatment. Suppression of the Methyl-CpG Binding Domain Protein 3 (MBD3) sensitized cells and prevented the establishment of resistance under prolonged cPt exposure through alterations of H3K27ac at enhancer regions, which are differentially regulated in cPt-resistant cells, leading to a less aggressive phenotype. Our work establishes JAK1 as an independent prognostic marker and the NuRD complex as a potential target for combinational therapy.
Repurposing Ferumoxytol as a Breast Cancer-Associated Macrophage Tracer with Five-Dimensional Quantitative [Fe]MRI of SPION Dynamics
Authors: Sillerud Laurel O. , Neuwelt Alexander J. , Staquicini Fernanda I. , Arap Wadih , Pasqualini Renata
Published: July 2021

Tumor-associated macrophages (TAMs) in breast cancer regulate inflammation, immunosuppression, angiogenesis, and metastasis. However, TAM imaging remains a clinical challenge. Ferumoxytol has long been an FDA-approved superparamagnetic iron oxide nanoparticle (SPION) preparation used as an intravenous (IV) treatment for iron-deficiency anemia. Given its high transverse relaxivity, ferumoxytol produces a negative image contrast upon cellular uptake in T2-weighted magnetic resonance imaging (MRI) studies. Here we evaluated ferumoxytol as a contrast agent to image/quantify TAMs in an aggressive mouse model of breast cancer: We developed [Fe]MRI to measure the 5-dimensional function c(x,y,z,t), where c is the concentration of nanoparticle iron and {x,y,z,t} is the 4-dimensional set of tumor space-time coordinates. Ferumoxytol SPIONs are readily phagocytosed (~104/cell) by the F4/80+CD11b+ TAMs within breast tumors. Quantitative [Fe]MRIs served to determine both the spatial and the temporal distribution of the SPION iron, and hence to measure [Fe] = c(x,y,z,t), a surrogate for TAM density. In single-dose pharmacokinetic studies, after an IV dose of 5 mg/Kg iron, [Fe]MRI measurements showed that c(x,y,z,t) within breast tumors peaked around [Fe] = 70 μM at 42 h post-administration, and decayed below the [Fe]MRI detection limit (~2 μM) by day 7. There was no SPION uptake in control organs (muscle and adipose tissue). Optical microscopy of tissue sections confirmed that F4/80+CD11b+ TAMs infiltrated the tumors and accumulated SPION iron. Our methodology and findings have translational applications for breast cancer patients.
Characteristics and Treatment Challenges of Non-Clear Cell Renal Cell Carcinoma
Authors: Sepe Pierangela , Ottini Arianna , Pircher Chiara Carlotta , Franza Andrea , Claps Melanie , Guadalupi Valentina , Verzoni Elena , Procopio Giuseppe
Published: July 2021

Non-clear cell renal cell carcinomas (RCC) comprise several rare and poorly described diseases, often characterized by bad prognosis and with no standard treatments available. The gap in their clinical management is linked to the poor molecular characterization in handling the treatment of non clear-cell RCC with untailored therapies. Due to their rarity, non-clear RCC are in fact under-represented in prospective randomized trials. Thus, treatment choices are based on extrapolating results from clear cell RCC trials, retrospective data, or case reports. Over the last two decades, various options have been considered as the mainstay for the treatment of metastatic RCC (mRCC), including angiogenesis inhibitors, vascular endothelial growth factor receptor inhibitors, other tyrosine kinase inhibitors (TKIs), as well as MET inhibitors and mammalian targeting of rapamycin (mTOR) inhibitors. More recently, the therapeutic armamentarium has been enriched with immunotherapy, alone or in combination with targeted agents that have been shown to significantly improve outcomes of mRCC patients, if compared to TKI single-agent. It has been widely proven that non-clear cell RCC is a morphologically and clinically distinct entity from its clear cell counterpart but more knowledge about its biology is certainly needed. Histology-specific collaborative trials are in fact now emerging to investigate different treatments for non-clear cell RCC. This review summarizes pathogenetic mechanisms of non-clear cell RCC, the evolution of treatment paradigms over the last few decades, with a focus on immunotherapy-based trials, and future potential treatment options.
Enhanced Performance of Pt Nanoparticles on Ni-N Co-Doped Graphitized Carbon for Oxygen Reduction Reaction in Polymer Electrolyte Membrane Fuel Cells
Authors: Jung Won Suk
Published: July 2021

Since the reaction rate and cost for cathodic catalyst in polymer electrolyte membrane fuel cells are obstacles for commercialization, the high-performance catalyst for oxygen reduction reaction is necessary. The Ni encapsulated with N-doped graphitic carbon (Ni@NGC) prepared with ethylenediamine and carbon black is employed as an efficient support for the oxygen reduction reaction. Characterizations show that the Ni@NGC has a large surface area and mesoporous structure that is suitable to the support for the Pt catalyst. The catalyst structure is identified and the size of Pt nanoparticles distributed in the narrow range of 2–3 nm. Four different nitrogen species are doped properly into graphitic carbon structure. The Pt/Ni@NGC shows higher performance than the commercial Pt/C catalyst in an acidic electrolyte. The mass activity of the Pt/Ni@NGC in fuel cell tests exhibits over 1.5 times higher than that of commercial Pt/C catalyst. The Pt/Ni@NGC catalyst at low Pt loading exhibits 47% higher maximum power density than the Pt/C catalyst under H2-air atmosphere. These results indicate that the Ni@NGC as a support is significantly beneficial to improving activity.
Liquid Biopsy for Disease Monitoring in Non-Small Cell Lung Cancer: The Link between Biology and the Clinic
Authors: Fernandes Maria Gabriela O. , Sousa Catarina , Pereira Reis Joana , Cruz-Martins Natália , Souto  Moura Conceição , Guimarães Susana , Justino Ana , Pina Maria João , Magalhães Adriana , Queiroga Henrique , Marques José Agostinho , Machado José Carlos , Costa José Luís , Hespanhol Venceslau
Published: July 2021

Introduction: Cell-free DNA (cfDNA) analysis offers a non-invasive method to identify sensitising and resistance mutations in advanced Non-Small Cell Lung Cancer (NSCLC) patients. Next-generation sequencing (NGS) of circulating free DNA (cfDNA) is a valuable tool for mutations detection and disease′s clonal monitoring. Material and methods: An amplicon-based targeted gene NGS panel was used to analyse 101 plasma samples of advanced non-small cell lung cancer (NSCLC) patients with known oncogenic mutations, mostly EGFR mutations, serially collected at different clinically relevant time points of the disease. Results: The variant allelic frequency (VAF) monitoring in consecutive plasma samples demonstrated different molecular response and progression patterns. The decrease in or the clearance of the mutant alleles was associated with response and the increase in or the emergence of novel alterations with progression. At the best response, the median VAF was 0% (0.0% to 3.62%), lower than that at baseline, with a median of 0.53% (0.0% to 9.9%) (p = 0.004). At progression, the VAF was significantly higher (median 4.67; range: 0.0–36.9%) than that observed at the best response (p = 0.001) and baseline (p = 0.006). These variations anticipated radiographic changes in most cases, with a median time of 0.86 months. Overall, the VAF evolution of different oncogenic mutations predicts clinical outcomes. Conclusion: The targeted NGS of circulating tumour DNA (ctDNA) has clinical utility to monitor treatment response in patients with advanced lung adenocarcinoma.
Novel Human Podocyte Cell Model Carrying G2/G2 APOL1 High-Risk Genotype
Authors: Ekulu Pepe M. , Adebayo Oyindamola C. , Decuypere Jean-Paul , Bellucci Linda , Elmonem Mohamed A. , Nkoy Agathe B. , Mekahli Djalila , Bussolati Benedetta , van den Heuvel Lambertus P. , Arcolino Fanny O. , Levtchenko Elena N.
Published: July 2021

Apolipoprotein L1 (APOL1) high-risk genotypes (HRG), G1 and G2, increase the risk of various non-diabetic kidney diseases in the African population. To date, the precise mechanisms by which APOL1 risk variants induce injury on podocytes and other kidney cells remain unclear. Trying to unravel these mechanisms, most studies have used animal or cell models created by gene editing. We developed and characterised conditionally immortalised human podocyte cell lines derived from urine of a donor carrying APOL1 HRG G2/G2. Following induction of APOL1 expression by polyinosinic-polycytidylic acid (poly(I:C)), we assessed functional features of APOL1-induced podocyte dysfunction. As control, APOL1 wild type (G0/G0) podocyte cell line previously generated from a Caucasian donor was used. Upon exposure to poly(I:C), G2/G2 and G0/G0 podocytes upregulated APOL1 expression resulting in podocytes detachment, decreased cells viability and increased apoptosis rate in a genotype-independent manner. Nevertheless, G2/G2 podocyte cell lines exhibited altered features, including upregulation of CD2AP, alteration of cytoskeleton, reduction of autophagic flux and increased permeability in an in vitro model under continuous perfusion. The human APOL1 G2/G2 podocyte cell model is a useful tool for unravelling the mechanisms of APOL1-induced podocyte injury and the cellular functions of APOL1.
Memorial Issue Dedicated to Dr. Howard D. Flack: The Man behind the Flack Parameter
Authors: Housecroft Catherine E. , Fromm Katharina M.
Published: July 2021

This Special Issue of Chemistry is dedicated to Dr. Howard D. Flack (1943–2017), a renowned crystallographer who transformed the way in which, by using single crystal X-ray diffraction, we are able to determine the absolute structure of a crystalline material, and thereby determine the absolute configuration of molecular species within the material [...]
Effectiveness and Safety of Intravenous Sedation with Propofol in Non-Operating Room Anesthesia (NORA) for Dental Treatment in Uncooperative Paediatric Patients
Authors: Ferrazzano Gianmaria Fabrizio , Cantile Tiziana , Quaraniello Martina , Iannuzzi Michele , Palumbo Daniela , Servillo Giuseppe , Caruso Silvia , Fiasca Fabiana , Ingenito Aniello
Published: July 2021

Background: Uncooperative children require sedative approach for dental treatment. The aim was to assess the effectiveness of Propofol in “Non-Operating Room Anesthesia” (NORA) for paediatric dental treatment; intraoperative side effects; postoperative side effects; post-discharge effects. Methods: a prospective study, involving 109 uncooperative children undergoing sedation in NORA using Propofol for dental treatment, was performed. Working sessions, success/failure, intraoperative and postoperative side effects, number of treatment; type of procedure were assessed. Parents completed a post-discharge questionnaire on: pain; crying; fever; vomiting; headache; drowsiness; excitability; irritability; ability to eat; drugs and medical care needing. Results: Success: 96.7%. Intraoperative side effects: 33.3%. Postoperative side effects: 6.4%. Statistically significant association between: intraoperative side effects and age (p = 0.001), health status (p = 0.0007), weight (p = 0.038), respectively; intraoperative side effects and number/ type of dental treatment (p = 0.0055) and scaling (p = 0.0001), respectively. For post-discharge questionnaires, statistically significant association between: age and crying (p = 0.0001) and headache (p = 0.002), respectively; health status and crying (p = 0.015) and drugs needing (p = 0.04), respectively; weight and crying (p = 0.0004); extraction and pain (p = 0.0001) and crying (p= 0.0073), respectively; scaling and crying (p = 0.04), excitability and irritability (p = 0.03), respectively. Conclusion: Propofol in NORA was effective with minimal side effects.
Cluster Randomized Trial: Sun Protection Intervention ‘Clever in Sun and Shade for Preschools’—Effectiveness and Dissemination
Authors: Seidel Nadja , Fieber Vera , Breitbart Eckhard Wilhem , Bornhäuser Martin , Stölzel Friederike
Published: July 2021

Skin cancer is one of the most common types of cancer and UV radiation is one of the main risk factors. Therefore, sun protection, especially in childhood, is strongly recommended. We examined the effectiveness of the ‘Clever in Sun and Shade for Preschools’ program (CLEVER) in promoting sun protection behavior among preschool staff (trial registration: DRKS00023468) and describe its dissemination. Within a cluster randomized trial with 24 preschools (n = 273 staff members) stating a high need for sun protection measures, an educational workshop for preschool staff and a project kit with materials applicable in preschool groups was provided. Staff members of preschools taking part in CLEVER report significantly stronger sun protection behavior to avoid the sun (effect size [ES] 0.70, 95% confidence interval [CI] 0.04 0.71, p < 0.05) and less perceived impediments to avoid the sun (ES −0.56, CI −0.82 −0.17, p < 0.01) after 12 months as well as higher self-efficacy to avoid the sun (ES 1.09, CI 0.39 1.07, p < 0.001) and to use sunscreen (ES 0.71, CI 0.03 0.88, p < 0.05) after 1 month. Compared to the control group, there was no significant effect on sunscreen use and further psychosocial outcomes. The effectiveness of CLEVER may be underrated due to a high drop-out rate. Within three years, an enhanced free-of-charge program kit, including a media-based workshop and materials, had reached over 4000 preschools, i.e., 7.1% of all daycare centers in Germany. The results show that CLEVER can strengthen sun protection, offer high-quality information at low cost, and is easily disseminable.
Active Casein Coatings and Films for Perishable Foods: Structural Properties and Shelf-Life Extension
Authors: Khan Muhammad Rehan , Volpe Stefania , Valentino Marika , Miele Nicoletta Antonella , Cavella Silvana , Torrieri Elena
Published: July 2021

There is an urgent need to increase the food supplies to fulfil the demands of future generations as the population of the world is expected to grow beyond 10 billion by 2050. An essential component for ensuring global food security is to reduce food losses during the post-harvest stage. Active edible coatings and films are a promising sustainable preservation technology for shelf-life extension of food products by hindering decay kinetics of minimally processed fruits and vegetables (F&V), by restricting the mass transfer of moisture, aroma, or gases and carrying an active compound, such as an antioxidant or antimicrobial. Active protein-based coatings and films have the potential to extend the shelf-life of food products by decreasing their respiration rates, as they exhibit an excellent gas barrier and good mechanical properties as compared to other biopolymeric packaging. Among protein-based biopolymers, casein and its derivatives as packaging films have been extensively studied due to their low cost, complete biodegradability, and availability. Currently, there is no review study focusing on caseinate-based active coating and film, thus, this review aims to give insights on the composition, rheology, structure, and properties of caseinate-based formulations by critically discussing the results presented in the literature. A methodological approach was followed to obtain relevant literature to discuss the influence of additives on the shelf-life of F&V. Furthermore, changes in secondary structure of casein were observed after incorporation of bioactive compounds (i.e., phenolic acids). Likewise, there is a need to explore chemical interactions among bioactive compounds and biopolymer material by using in silico and laboratory trials as food additives have shown to influence the physicochemical properties of film and shelf-life of food products.
Localization of Native Mms13 to the Magnetosome Chain of Magnetospirillum magneticum AMB-1 Using Immunogold Electron Microscopy, Immunofluorescence Microscopy and Biochemical Analysis
Authors: Oestreicher Zachery , Valverde-Tercedor Carmen , Mumper Eric , Pérez-Guzmán Lumarie , Casillas-Ituarte Nadia N. , Jimenez-Lopez Concepcion , Bazylinski Dennis A. , Lower Steven K. , Lower Brian H.
Published: July 2021

Magnetotactic bacteria (MTB) biomineralize intracellular magnetite (Fe3O4) crystals surrounded by a magnetosome membrane (MM). The MM contains membrane-specific proteins that control Fe3O4 mineralization in MTB. Previous studies have demonstrated that Mms13 is a critical protein within the MM. Mms13 can be isolated from the MM fraction of Magnetospirillum magneticum AMB-1 and a Mms13 homolog, MamC, has been shown to control the size and shape of magnetite nanocrystals synthesized in-vitro. The objective of this study was to use several independent methods to definitively determine the localization of native Mms13 in M. magneticum AMB-1. Using Mms13-immunogold labeling and transmission electron microscopy (TEM), we found that Mms13 is localized to the magnetosome chain of M. magneticum AMB-1 cells. Mms13 was detected in direct contact with magnetite crystals or within the MM. Immunofluorescence detection of Mms13 in M. magneticum AMB-1 cells by confocal laser scanning microscopy (CLSM) showed Mms13 localization along the length of the magnetosome chain. Proteins contained within the MM were resolved by SDS-PAGE for Western blot analysis and LC-MS/MS (liquid chromatography with tandem mass spectrometry) protein sequencing. Using Anti-Mms13 antibody, a protein band with a molecular mass of ~14 kDa was detected in the MM fraction only. This polypeptide was digested with trypsin, sequenced by LC-MS/MS and identified as magnetosome protein Mms13. Peptides corresponding to the protein’s putative MM domain and catalytic domain were both identified by LC-MS/MS. Our results (Immunogold TEM, Immunofluorescence CLSM, Western blot, LC-MS/MS), combined with results from previous studies, demonstrate that Mms13 and homolog proteins MamC and Mam12, are localized to the magnetosome chain in MTB belonging to the class Alphaproteobacteria. Because of their shared localization in the MM and highly conserved amino acid sequences, it is likely that MamC, Mam12, and Mms13 share similar roles in the biomineralization of Fe3O4 nanocrystals.
Consumption Patterns of a Generalist Omnivore: Eastern Box Turtle Diets in the Long Island Pine Barrens
Authors: Figueras Miranda P. , Green Timothy M. , Burke Russell L.
Published: July 2021

Eastern Box Turtles (Terrapene carolina) are diet generalists and as such are predicted to have diverse diets in which familiar, low-quality foods are eaten consistently at low levels, and high-quality foods are rare but eaten whenever available. Previous work showed that they feed opportunistically on seasonally available plants (shoots, leaves, flowers, and fruit), invertebrates, mushrooms, and occasionally carrion. We used fecal samples to test optimal foraging predictions relevant to diet generalists and also whether the Eastern Box Turtle diets varied seasonally in a northeastern U.S. pine-oak habitat. We found that in-depth prey species consumption patterns of six different individuals were similar to those of the sampled population overall. Leaf and stem material was consumed by 100% of the turtles in all months despite being lower-quality than other prey available. Invertebrates were consumed by at least 80% of turtles in every study period; Coleopterans were found more commonly than other invertebrates. Snails were not eaten by more than 20% of the turtles in any study period, and mushroom consumption varied from 31–75% of samples in different study periods. Monthly diet overlap was measured using both Pianka’s Index of Overlap (PIO) and the Morisita–Horn Index (MH). The PIO method indicated that the prey consumption patterns were broadly similar from June–October, while the M–H method showed that only the July vs. August comparison was highly similar. The turtle diets changed only slightly between seasons, and they conform to predictions of diet generalist models usually applied to mammals.
Diversity and Diet Differences of Small Mammals in Commensal Habitats
Authors: Balčiauskas Linas , Balčiauskienė Laima , Garbaras Andrius , Stirkė Vitalijus
Published: July 2021

The stability of diversity of syntopic (inhabiting the same habitat in the same time) small mammals in commensal habitats, such as farmsteads and kitchen gardens, and, as a proxy of their diet, their isotopic niches, was investigated in Lithuania in 2019–2020. We tested whether the separation of species corresponds to the trophic guilds, whether their diets are related to possibilities of getting additional food from humans, and whether their diets are subject to seasonal trends. We analyzed diversity, dominance and distribution of hair δ13C and δ15N values. Diversity and dominance was not stable and differed according to human influence. The highest small mammal species richness occurred in commensal habitats that provided additional food. The degree of separation of species was higher in homestead habitats than in kitchen gardens, where a 1.27% to 35.97% overlap of isotopic niches was observed between pairs of species. Temporal changes in δ13C and δ15N values in the hair of the mammals were not equally expressed in different species. The isotopic overlap may depend on dietary plasticity, minimizing interspecific competition and allowing co-existence of syntopic species. Thus, small mammal trophic ecology is likely related to intensity of agricultural activities in the limited space of commensal habitats.