bluuebunny/crossref_metadata_2025 huggingface dataset:
Active Approaches to Vibration Absorption through Antiresonance Assignment: A Comparative Study
Authors: Richiedei Dario , Tamellin Iacopo
Published: January 2021

Vibration absorption is a core research topic in structural dynamics and the mechanics of machines, and antiresonance assignment is an effective solution to such a problem in the presence of harmonic excitation forces. Due to recent developments in the theory of feedback control systems, the use of active control approaches to antiresonance assignment has been recently gaining more attention in the literature. Therefore, several methods exploiting state feedback or output feedback have been proposed in recent years. These techniques that just rely on servo-controlled actuators are becoming an interesting alternative to active approaches that emulate the well-known Tuned Mass Damper in an active (or semi-active) framework. This paper reviews and compares the most important approaches, with a greater focus on the methods exploiting the concept of control theory without adding new degrees of freedom in the system. The theoretical results, with the underlying theory, are discussed to highlight the key features of each assignment techniques. Several numerical examples where different techniques are applied and compared, also providing some analysis usually neglected in the literature, enrich the paper and demonstrate the key concepts.
A Novel Method to Measure the Powder Consumption of Dental Air-Polishing Devices
Authors: Donnet Marcel , Fournier Maxime , Schmidlin Patrick R. , Lussi Adrian
Published: January 2021

Background: Oral preventive measures should be efficient, minimally invasive, and painless. Air-polishing has this potential. As the efficiency and abrasivity of powders are dependent on the amount of powder projected, a better understanding of this characteristic will help us to determine the most effective and least invasive device. Method: A new laboratory set-up was designed using light diffusion to measure powder consumption with high accuracy due to its high sampling rate, even at short time intervals (<1 s). We tested six different marketed air-polishers of two different working types: Table-top and Handy. Results: All of the devices presented some powder delivery fluctuations. These differences were manufacturer-dependent. The powder delivery stability varied by up to two times, and ranged among the Table-top devices in the following order: E1 < M2 < N2. The mean powder consumption also varied by up to 2.9 times, in the following order: E1 < N2 < M3. All of the Handy devices presented a short treatment time and poor flow regularity, and consumed significantly more powder than the Table-top devices (by approximately +25%). Conclusion: The powder consumption analysis showed distinct differences between the devices. Therefore, the clinical results among the devices cannot be compared, as their working mechanisms are very different.
The Effects of Display Type, Weather Type, and Pilot Experience on Pilot Interpretation of Weather Products
Authors: King Jayde M. , Blickensderfer Beth , Guinn Thomas , Kleber John L.
Published: January 2021

The majority of general aviation (GA) accidents involving adverse weather result in fatalities. Considering the high weather-related fatality rate among GA flight operations, it is imperative to ensure that GA pilots of all experience levels can incorporate available weather information into their flight planning. In the past decade, weather product development has incorporated increasing levels of automation, which has led to the generation of high-resolution, model-based aviation displays such as graphical turbulence guidance and current icing potential, which rival the resolution of radar and satellite imagery. This is in stark contrast to the traditional polygonal-based displays of aviation weather hazards (G-AIRMETs and SIGMETs). It is important to investigate the effects of these changes on the end user. Therefore, the purpose of this study was to compare the interpretability of weather products for two areas of interest: display type (traditional polygons vs. model-based imagery) and type of weather phenomena (ceiling/visibility, turbulence, and icing), across a range of pilot experience levels. Two hundred and four participants completed a series of weather product interpretation questions. The results indicated significant effects of product display type, as well as significant effects of weather phenomena and pilot experience on product interpretation. Further investigation is needed to assess possible extraneous variables.
Evolution of Aerosols in the Atmospheric Boundary Layer and Elevated Layers during a Severe, Persistent Haze Episode in a Central China Megacity
Authors: Zhang Yunfei , Zhang Yunpeng , Yu Changming , Yi Fan
Published: January 2021

Aerosol vertical profiling is crucial to understand the formation mechanism and evolution processes of haze, which have not yet been comprehensively clarified. In this study, we investigated a severe, persistent haze event in Wuhan (30.5° N, 114.4° E), China during 5–18 January 2013 by the use of a polarization lidar, a Cimel sun photometer, meteorological datasets, and the hybrid single-particle Lagrangian integrated trajectory (HYSPLIT) model, focusing on the time–height evolution of aerosols in both the atmospheric boundary layer (ABL) and elevated layers. During the haze period, the integrated particle depolarization ratio was 0.05 ± 0.02, and the fine mode fraction reached 0.91 ± 0.03, indicating haze particles were rather spherical and predominately submicron, that is, of anthropogenic nature. Compared with the clear period, columnar aerosol optical depth at 500 nm tripled to 1.32 ± 0.31, and the strongest enhancement in aerosol concentration occurred from near the ground to an altitude of 1.2 km during the haze period. The daytime evolution of aerosol vertical distribution in the ABL exhibited a distinct pattern under haze weather. Abundant particles accumulated below 0.5 km in the morning hours due to stable meteorological conditions, including a strong surface-based inversion (4.4–8.1 °C), late development (from 1000–1100 LT) of the convective boundary layer, and weak wind (<4 m∙s−1) in the lowermost troposphere. In the afternoon, improved ventilation delivered an overall reduction in boundary layer aerosols but was insufficient to eliminate haze. Particularly, the morning residual layer had an optical depth of 0.29–0.56. It influenced air quality indirectly by weakening convective activities in the morning and directly through the fumigation process around noon, suggesting it may be an important element in aerosol–ABL interactions during consecutive days with haze. Our lidar also captured the presence of the elevated aerosol layers (EALs) embodying regional/long-range transport. Most of the EALs were observed to subside to <1.2 km and exacerbate the pollution level. Backward trajectory analysis and lidar data revealed the EALs originated from the transport of anthropogenic pollutants from the Sichuan Basin, China, and of dust from the deserts in the northwest. They were estimated to contribute ~19% of columnar aerosol-loading, pointing to a non-negligible role of transport during the intense pollution episode. The results could benefit the complete understanding of aerosol–ABL interactions under haze weather and air quality forecasting and control in Wuhan.
Stark-Broadening of Ar K-Shell Lines: A Comparison between Molecular Dynamics Simulations and MERL Results
Authors: Gigosos Marco A. , Mancini Roberto C. , Martín-González Juan M. , Florido Ricardo
Published: January 2021

Analysis of Stark-broadened spectral line profiles is a powerful, non-intrusive diagnostic technique to extract the electron density of high-energy-density plasmas. The increasing number of applications and availability of spectroscopic measurements have stimulated new research on line broadening theory calculations and computer simulations, and their comparison. Here, we discuss a comparative study of Stark-broadened line shapes calculated with computer simulations using non-interacting and interacting particles, and with the multi-electron radiator line shape MERL code. In particular, we focus on Ar K-shell X-ray line transitions in He- and H-like ions, i.e., Heα, Heβ and Heγ in He-like Ar and Lyα, Lyβ and Lyγ in H-like Ar. These lines have been extensively used for X-ray spectroscopy of Ar-doped implosion cores in indirect- and direct-drive inertial confinement fusion (ICF) experiments. The calculations were done for electron densities ranging from 1023 to 3×1024 cm−3 and a representative electron temperature of 1 keV. Comparisons of electron broadening only and complete line profiles including electron and ion broadening effects, as well as Doppler, are presented. Overall, MERL line shapes are narrower than those from independent and interacting particles computer simulations performed at the same conditions. Differences come from the distinctive treatments of electron broadening and are more pronounced in α line transitions. We also discuss the recombination broadening mechanism that naturally emerges from molecular dynamics simulations and its influence on the line shapes. Furthermore, we assess the impact of employing either molecular dynamics or MERL line profiles on the diagnosis of core conditions in implosion experiments performed on the OMEGA laser facility.
Acknowledgment to Reviewers of Biology in 2020
Authors:   Biology Editorial Office
Published: January 2021

Peer review is the driving force of journal development and reviewers are gatekeepers who ensure that Biology maintains its standards for the high quality of its published papers [...]
Efficacy of Providing the PI3K p110α Inhibitor BYL719 (Alpelisib) to Middle-Aged Mice in Their Diet
Authors: Hedges Christopher P. , Boix Jordi , Jaiswal Jagdish K. , Shetty Bhoopika , Shepherd Peter R. , Merry Troy L.
Published: January 2021

BYL719 (alpelisib) is a small molecule inhibitor of PI3K p110α developed for cancer therapy. Targeted suppression of PI3K has led to lifespan extension in rodents and model organisms. If PI3K inhibitors are to be considered as an aging therapeutic, it is important to understand the potential consequences of long-term exposure, and the most practical way to achieve this is through diet administration. Here, we investigated the pharmacokinetics of BYL719 delivered in diet and the efficacy of BYL719 to suppress insulin signaling when administered in the diet of 8-month-old male and female mice. Compared to oral gavage, diet incorporation resulted in a lower peak plasma BYL719 (3.6 vs. 9.2 μM) concentration but similar half-life (~1.5 h). Consuming BYL719 resulted in decreased insulin signaling in liver and muscle within 72 h, and mice still showed impaired glucose tolerance and insulin sensitivity following 6 weeks of access to a diet containing 0.3 g/kg BYL719. However, consuming BYL719 did not affect food intake, body mass, muscle function (rotarod and hang time performance) or cognitive behaviors. This provides evidence that BYL719 has long-term efficacy without major toxicity or side effects, and suggests that administering BYL719 in diet is suitable for studying the effect of pharmacological suppression of PI3K p110α on aging and metabolic function.
Dissociation Constant of Integrin-RGD Binding in Live Cells from Automated Micropipette and Label-Free Optical Data
Authors: Gerecsei Tamás , Chrenkó Péter , Kanyo Nicolett , Péter Beatrix , Bonyár Attila , Székács Inna , Szabo Balint , Horvath Robert
Published: January 2021

The binding of integrin proteins to peptide sequences such as arginine-glycine-aspartic acid (RGD) is a crucial step in the adhesion process of mammalian cells. While these bonds can be examined between purified proteins and their ligands, live-cell assays are better suited to gain biologically relevant information. Here we apply a computer-controlled micropipette (CCMP) to measure the dissociation constant (Kd) of integrin-RGD-binding. Surface coatings with varying RGD densities were prepared, and the detachment of single cells from these surfaces was measured by applying a local flow inducing hydrodynamic lifting force on the targeted cells in discrete steps. The average behavior of the populations was then fit according to the chemical law of mass action. To verify the resulting value of Kd2d = (4503 ± 1673) 1/µm2, a resonant waveguide grating based biosensor was used, characterizing and fitting the adhesion kinetics of the cell populations. Both methods yielded a Kd within the same range. Furthermore, an analysis of subpopulations was presented, confirming the ability of CCMP to characterize cell adhesion both on single cell and whole population levels. The introduced methodologies offer convenient and automated routes to quantify the adhesivity of living cells before their further processing.
RETRACTED: Sex-Based Differences in Plasma Autoantibodies to Central Nervous System Proteins in Gulf War Veterans versus Healthy and Symptomatic Controls
Authors: Abou-Donia Mohamed , Krengel Maxine , Lapadula Elizabeth , Zundel Clara , LeClair Jessica , Massaro Joseph , Quinn Emily , Conboy Lisa , Kokkotou Efi , Nguyen Daniel , Abreu Maria , Klimas Nancy , Sullivan Kimberly
Published: January 2021

Veterans from the 1991 Gulf War (GW) have suffered from Gulf War illness (GWI) for nearly 30 years. This illness encompasses multiple body systems, including the central nervous system (CNS). Diagnosis and treatment of GWI is difficult because there has not been an objective diagnostic biomarker. Recently, we reported on a newly developed blood biomarker that discriminates GWI from GW healthy controls, and symptomatic controls with irritable bowel syndrome (IBS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The present study was designed to compare levels of these biomarkers between men and women with GWI, as well as sex-specific effects in comparison to healthy GW veterans and symptomatic controls (IBS, ME/CFS). The results showed that men and women with GWI differ in 2 of 10 plasma autoantibodies, with men showing significantly elevated levels. Men and women with GWI showed significantly different levels of autoantibodies in 8 of 10 biomarkers to neuronal and glial proteins in plasma relative to controls. In summary, the present study addressed the utility of the use of plasma autoantibodies for CNS proteins to distinguish among both men and women veterans with GWI and other healthy and symptomatic control groups.
Prevention in Autism Spectrum Disorder: A Lifelong Focused Approach
Authors: Francis Konstantinos , Karantanos Georgios , Al-Ozairi Abdullah , AlKhadhari Sulaiman
Published: January 2021

Autism Spectrum Disorder (ASD) is a complex highly heritable disorder, in which multiple environmental factors interact with the genes to increase its risk and lead to variable clinical presentations and outcomes. Furthermore, the inherent fundamental deficits of ASD in social attention and interaction critically diverge children from the typical pathways of learning, “creating” what we perceive as autism syndrome during the first three years of life. Later in life, training and education, the presence and management of comorbidities, as well as social and vocational support throughout the lifespan, will define the quality of life and the adaptation of an individual with ASD. Given the overall burden of ASD, prevention strategies seem like a cost-effective endeavour that we have to explore. In this paper, we take a life course approach to prevention. We will review the possibilities of the management of risk factors from preconception until the perinatal period, that of early intervention in the first three years of life and that of effective training and support from childhood until adulthood.
Preoperatively Treated Diffuse-Type Gastric Adenocarcinoma: Glucose vs. Other Energy Sources Substantially Influence Prognosis and Therapy Response
Authors: Abdelhakeem Ahmed A. , Wang Xuemei , Waters Rebecca E. , Patnana Madhavi , Estrella Jeannelyn S. , Blum Murphy Mariela , Trail Allison M. , Lu Yang , Devine Catherine E. , Ikoma Naruhiko , Das Prajnan , Badgwell Brian D. , Rogers Jane E. , Ajani Jaffer A.
Published: January 2021

Diffuse type of gastric adenocarcinoma (dGAC) generally confers a poor prognosis compared to intestinal type. Some dGACs are not avid on fluorine-18 fluoro-2-deoxy-D-glucose PET (FDG-PET) while others seem to consume glucose avidly. We analyzed the outcomes based on the avidity (high with standardized uptake value (SUV) > 3.5 or low with SUV ≤ 3.5) of the primary on baseline FDG-PET. We retrospectively selected 111 localized dGAC patients who had baseline FDG-PET (all were treated with preoperative chemotherapy and chemoradiation). FDG-PET avidity was compared with overall survival (OS) and response to therapy. The mean age was 59.4 years and with many females (47.7%). The high-SUV group (58 (52.3%) patients) and the low-SUV group (53 (47.7%) patients) were equally divided. While the median OS for all patients was 49.5 months (95% CI: 38.5–98.8 months), it was 98.0 months (95% CI: 49.5–NE months) for the low-SUV group and 36.0 months for the high-SUV (p = 0.003). While the median DFS for all patients was 38.2 months (95% CI: 27.7–97.6 months), it was 98.0 (95% CI: 36.9–NE months) months for the low-SUV group was and only 27.0 months (95% CI: 15.2–63.2 months) for the high-SUV group (p = 0.005). Clinical responses before surgery were more common in the low-SUV group but overall we observed only 4 pathologic complete responses in 111 patients. Our unique data suggest that if dGACs used glucose as an energy source then the prognosis was very poor while non-glucose sources improved prognosis. Multi-platform (including metabolomics) profiling of dGACs would yield useful biologic understanding.
Immunophenotype of Gastric Tumors Unveils a Pleiotropic Role of Regulatory T Cells in Tumor Development
Authors: Rocha Sara , Basto Afonso P , Ijsselsteijn Marieke E , Teles Sara P , Azevedo Maria M , Gonçalves Gilza , Gullo Irene , Almeida Gabriela M , Maqueda Joaquín J , Oliveira Marta I , Carneiro Fátima , Barata João T , Graça Luís , de Miranda Noel F C C , Carvalho Joana , Oliveira Carla
Published: January 2021

Gastric cancer (GC) patients display increased regulatory T cell (Tregs) numbers in peripheral blood and among tumor-infiltrating lymphocytes. Nevertheless, the role of Tregs in GC progression remains controversial. Here, we sought to explore the impact of Tregs in GCs with distinct histology, and whether Tregs can directly influence tumor cell behavior and GC development. We performed a comprehensive immunophenotyping of 82 human GC cases, through an integrated analysis of multispectral immunofluorescence detection of T cells markers and patient clinicopathological data. Moreover, we developed 3D in vitro co-cultures with Tregs and tumor cells that were followed by high-throughput and light-sheet imaging, and their biological features studied with conventional/imaging flow cytometry and Western blotting. We showed that Tregs located at the tumor nest were frequent in intestinal-type GCs but did not associate with increased levels of effector T cells. Our in vitro results suggested that Tregs preferentially infiltrated intestinal-type GC spheroids, induced the expression of IL2Rα and activation of MAPK signaling pathway in tumor cells, and promoted spheroid growth. Accumulation of Tregs in intestinal-type GCs was increased at early stages of the stomach wall invasion and in the absence of vascular and perineural invasion. In this study, we proposed a non-immunosuppressive mechanism through which Tregs might directly modulate GC cells and thereby promote tumor growth. Our findings hold insightful implications for therapeutic strategies targeting intestinal-type GCs and other tumors with similar immune context.
Emerging Roles of Urine-Derived Components for the Management of Bladder Cancer: One Man’s Trash Is Another Man’s Treasure
Authors: Minkler Sarah , Lucien Fabrice , Kimber Michael J. , Sahoo Dipak K. , Bourgois-Mochel Agnes , Musser Margaret , Johannes Chad , Frank Igor , Cheville John , Allenspach Karin , Mochel Jonathan P.
Published: January 2021

Urinary bladder cancer (UBC) is the most common malignancy of the urinary tract in humans, with an estimated global prevalence of 1.1 million cases over 5 years. Because of its high rates of recurrence and resistance to chemotherapy, UBC is one of the most expensive cancers to treat, resulting in significant health care costs. The development of innovative molecular and cellular tools is necessary to refine patient stratification and help predict response to treatment. Urine is an underused resource of biological components shed from bladder tumors, such as exfoliated cells and extracellular vesicles, that could serve as molecular fingerprints and provide valuable biological insights into tumor phenotype and mechanisms of resistance to chemotherapy. Additionally, characterization of urine-derived extracellular vesicles and cells could be used as reliable biomarkers for prediction of response to neoadjuvant therapy.
Cysteine and Folate Metabolism Are Targetable Vulnerabilities of Metastatic Colorectal Cancer
Authors: Tarragó-Celada Josep , Foguet Carles , Tarrado-Castellarnau Míriam , Marin Silvia , Hernández-Alias Xavier , Perarnau Jordi , Morrish Fionnuala , Hockenbery David , Gomis Roger R. , Ruppin Eytan , Yuneva Mariia , Atauri Pedro de , Cascante Marta
Published: January 2021

With most cancer-related deaths resulting from metastasis, the development of new therapeutic approaches against metastatic colorectal cancer (mCRC) is essential to increasing patient survival. The metabolic adaptations that support mCRC remain undefined and their elucidation is crucial to identify potential therapeutic targets. Here, we employed a strategy for the rational identification of targetable metabolic vulnerabilities. This strategy involved first a thorough metabolic characterisation of same-patient-derived cell lines from primary colon adenocarcinoma (SW480), its lymph node metastasis (SW620) and a liver metastatic derivative (SW620-LiM2), and second, using a novel multi-omics integration workflow, identification of metabolic vulnerabilities specific to the metastatic cell lines. We discovered that the metastatic cell lines are selectively vulnerable to the inhibition of cystine import and folate metabolism, two key pathways in redox homeostasis. Specifically, we identified the system xCT and MTHFD1 genes as potential therapeutic targets, both individually and combined, for combating mCRC.
Cancer Treatment-Induced Accelerated Aging in Cancer Survivors: Biology and Assessment
Authors: Wang Shuo , Prizment Anna , Thyagarajan Bharat , Blaes Anne
Published: January 2021

Rapid improvements in cancer survival led to the realization that many modalities used to treat or control cancer may cause accelerated aging in cancer survivors. Clinically, “accelerated aging” phenotypes in cancer survivors include secondary cancers, frailty, chronic organ dysfunction, and cognitive impairment, all of which can impact long-term health and quality of life in cancer survivors. The treatment-induced accelerated aging in cancer survivors could be explained by telomere attrition, cellular senescence, stem cell exhaustion, DNA damage, and epigenetic alterations. Several aging clocks and biomarkers of aging have been proposed to be potentially useful in estimating biological age, which can provide specific information about how old an individual is biologically independent of chronological age. Measuring biological age in cancer survivors may be important for two reasons. First, it can better predict the risk of cancer treatment-related comorbidities than chronological age. Second, biological age may provide additional value in evaluating the effects of treatments and personalizing cancer therapies to maximize efficacy of treatment. A deeper understanding of treatment-induced accelerated aging in individuals with cancer may lead to novel strategies that reduce the accelerated aging and improve the quality of life in cancer survivors.
Post-Neoadjuvant Surveillance and Surgery as Needed Compared with Post-Neoadjuvant Surgery on Principle in Multimodal Treatment for Esophageal Cancer: A Scoping Review
Authors: Hipp Julian , Nagavci Blin , Schmoor Claudia , Meerpohl Joerg , Hoeppner Jens , Schmucker Christine
Published: January 2021

Background: A substantial fraction of patients with esophageal cancer show post-neoadjuvant pathological complete response (pCR). Principal esophagectomy after neoadjuvant treatment is the standard of care for all patients, although surveillance and surgery as needed in case of local recurrence may be a treatment alternative for patients with complete response (CR). Methods: We performed a scoping review to describe key characteristics of relevant clinical studies including adults with non-metastatic esophageal cancer receiving multimodal treatment. Until September 2020, relevant studies were identified through systematic searches in the bibliographic databases Medline, Web of Science, Cochrane Library, Science Direct, ClinicalTrials, the German study register, and the WHO registry platform. Results: In total, three completed randomized controlled trials (RCTs, with 468 participants), three planned/ongoing RCTs (with a planned sample size of 752 participants), one non-randomized controlled study (NRS, with 53 participants), ten retrospective cohort studies (with 2228 participants), and one survey on patients’ preferences (with 100 participants) were identified. All studies applied neoadjuvant chemoradiation protocols. None of the studies examined neoadjuvant chemotherapeutic protocols. Studies investigated patient populations with esophageal squamous cell carcinoma, adenocarcinoma, and mixed cohorts. Important outcomes reported were overall, disease-free and local recurrence-free survival. Limitations of the currently available study pool include heterogeneous chemoradiation protocols, a lack of modern neoadjuvant treatment protocols in RCTs, short follow-up times, the use of heterogeneous diagnostic methods, and different definitions of clinical CR. Conclusion: Although post-neoadjuvant surveillance and surgery as needed compared with post-neoadjuvant surgery on principle has been investigated within different study designs, the currently available results are based on a wide variation of diagnostic tools to identify patients with pCR, short follow-up times, small sample sizes, and variations in therapeutic procedures. A thoroughly planned RCT considering the limitations in the currently available literature will be of great importance to provide patients with CR with the best and less harmful treatment.
Effective Prediction of Prostate Cancer Recurrence through the IQGAP1 Network
Authors: Gu Yan , Lin Xiaozeng , Kapoor Anil , Li Taosha , Major Pierre , Tang Damu
Published: January 2021

IQGAP1 expression was analyzed in: (1) primary prostate cancer, (2) xenografts produced from LNCaP, DU145, and PC3 cells, (3) tumor of PTEN−/− and TRAMP mice, and (4) castration resistant PC (CRPC) produced by LNCaP xenografts and PTEN−/− mice. IQGAP1 downregulations occurred in CRPC and advanced PCs. The downregulations were associated with rapid PC recurrence in the TCGA PanCancer (n = 492, p = 0.01) and MSKCC (n = 140, p = 4 × 10−6) cohorts. Differentially expressed genes (n = 598) relative to IQGAP1 downregulation were identified with enrichment in chemotaxis, cytokine signaling, and others along with reductions in immune responses. A novel 27-gene signature (Sig27gene) was constructed from these DEGs through random division of the TCGA cohort into a Training and Testing population. The panel was validated using an independent MSKCC cohort. Sig27gene robustly predicts PC recurrence at (hazard ratio) HR 2.72 and p < 2 × 10−16 in two independent PC cohorts. The prediction remains significant after adjusting for multiple clinical features. The novel and robust nature of Sig27gene underlie its great translational potential as a prognostic biomarker to predict PC relapse risk in patients with primary PC.
Targeted Metabolomics Identifies Plasma Biomarkers in Mice with Metabolically Heterogeneous Melanoma Xenografts
Authors: Weber Daniela D. , Thapa Maheshwor , Aminzadeh-Gohari Sepideh , Redtenbacher Anna-Sophia , Catalano Luca , Feichtinger René G. , Koelblinger Peter , Dallmann Guido , Emberger Michael , Kofler Barbara , Lang Roland
Published: January 2021

Melanomas are genetically and metabolically heterogeneous, which influences therapeutic efficacy and contributes to the development of treatment resistance in patients with metastatic disease. Metabolite phenotyping helps to better understand complex metabolic diseases, such as melanoma, and facilitates the development of novel therapies. Our aim was to characterize the tumor and plasma metabolomes of mice bearing genetically different melanoma xenografts. We engrafted the human melanoma cell lines A375 (BRAF mutant), WM47 (BRAF mutant), WM3000 (NRAS mutant), and WM3311 (BRAF, NRAS, NF1 triple-wildtype) and performed a broad-spectrum targeted metabolomics analysis of tumor and plasma samples obtained from melanoma-bearing mice as well as plasma samples from healthy control mice. Differences in ceramide and phosphatidylcholine species were observed between melanoma subtypes irrespective of the genetic driver mutation. Furthermore, beta-alanine metabolism differed between melanoma subtypes and was significantly enriched in plasma from melanoma-bearing mice compared to healthy mice. Moreover, we identified beta-alanine, p-cresol sulfate, sarcosine, tiglylcarnitine, two dihexosylceramides, and one phosphatidylcholine as potential melanoma biomarkers in plasma. The present data reflect the metabolic heterogeneity of melanomas but also suggest a diagnostic biomarker signature for melanoma screening.
MINDIN Exerts Protumorigenic Actions on Primary Prostate Tumors via Downregulation of the Scaffold Protein NHERF-1
Authors: Álvarez-Carrión Luis , Gutiérrez-Rojas Irene , Rodríguez-Ramos María Rosario , Ardura Juan A. , Alonso Verónica
Published: January 2021

Advanced prostate cancer preferential metastasis to bone is associated with osteomimicry. MINDIN is a secreted matrix protein upregulated in prostate tumors that overexpresses bone-related genes during prostate cancer progression. Na+/H+ exchanger regulatory factor (NHERF-1) is a scaffold protein that has been involved both in tumor regulation and osteogenesis. We hypothesize that NHERF-1 modulation is a mechanism used by MINDIN to promote prostate cancer progression. We analyzed the expression of NHERF-1 and MINDIN in human prostate samples and in a premetastatic prostate cancer mouse model, based on the implantation of prostate adenocarcinoma TRAMP-C1 (transgenic adenocarcinoma of the mouse prostate) cells in immunocompetent C57BL/6 mice. The relationship between NHERF-1 and MINDIN and their effects on cell proliferation, migration, survival and osteomimicry were evaluated. Upregulation of MINDIN and downregulation of NHERF-1 expression were observed both in human prostate cancer samples and in the TRAMP-C1 model. MINDIN silencing restored NHERF-1 expression to control levels in the mouse model. Stimulation with MINDIN reduced NHERF-1 expression and triggered its mobilization from the plasma membrane to the cytoplasm in TRAMP-C1 cells. MINDIN-dependent downregulation of NHERF-1 promoted tumor cell migration and proliferation without affecting osteomimicry and adhesion. We propose that MINDIN downregulates NHERF-1 expression leading to promotion of processes involved in prostate cancer progression.
Cerebrospinal Fluid Biomarkers in Childhood Leukemias
Authors: Ikonomidou Chrysanthy
Published: January 2021

Involvement of the central nervous system (CNS) in childhood leukemias remains a major cause of treatment failures. Analysis of the cerebrospinal fluid constitutes the most important diagnostic pillar in the detection of CNS leukemia and relies primarily on cytological and flow-cytometry studies. With increasing survival rates, it has become clear that treatments for pediatric leukemias pose a toll on the developing brain, as they may cause acute toxicities and persistent neurocognitive deficits. Preclinical research has demonstrated that established and newer therapies can injure and even destroy neuronal and glial cells in the brain. Both passive and active cell death forms can result from DNA damage, oxidative stress, cytokine release, and acceleration of cell aging. In addition, chemotherapy agents may impair neurogenesis as well as the function, formation, and plasticity of synapses. Clinical studies show that neurocognitive toxicity of chemotherapy is greatest in younger children. This raises concerns that, in addition to injury, chemotherapy may also disrupt crucial developmental events resulting in impairment of the formation and efficiency of neuronal networks. This review presents an overview of studies demonstrating that cerebrospinal fluid biomarkers can be utilized in tracing both CNS disease and neurotoxicity of administered treatments in childhood leukemias.
Preclinical Models of Pancreatic Ductal Adenocarcinoma and Their Utility in Immunotherapy Studies
Authors: Pham Thao N. D. , Shields Mario A. , Spaulding Christina , Principe Daniel R. , Li Bo , Underwood Patrick W. , Trevino Jose G. , Bentrem David J. , Munshi Hidayatullah G.
Published: January 2021

The advent of immunotherapy has transformed the treatment landscape for several human malignancies. Antibodies against immune checkpoints, such as anti-PD-1/PD-L1 and anti-CTLA-4, demonstrate durable clinical benefits in several cancer types. However, checkpoint blockade has failed to elicit effective anti-tumor responses in pancreatic ductal adenocarcinoma (PDAC), which remains one of the most lethal malignancies with a dismal prognosis. As a result, there are significant efforts to identify novel immune-based combination regimens for PDAC, which are typically first tested in preclinical models. Here, we discuss the utility and limitations of syngeneic and genetically-engineered mouse models that are currently available for testing immunotherapy regimens. We also discuss patient-derived xenograft mouse models, human PDAC organoids, and ex vivo slice cultures of human PDAC tumors that can complement murine models for a more comprehensive approach to predict response and resistance to immunotherapy regimens.
Whole-Body MRI for the Detection of Recurrence in Melanoma Patients at High Risk of Relapse
Authors: Jansen Yanina J. L. , Willekens Inneke , Seremet Teofila , Awada Gil , Schwarze Julia Katharina , De Mey Johan , Brussaard Carola , Neyns Bart
Published: January 2021

Introduction: No standard protocol for surveillance for melanoma patients is established. Whole-body magnetic resonance imaging (whole-body MRI) is a safe and sensitive technique that avoids exposure to X-rays and contrast agents. This prospective study explores the use of whole-body MRI for the early detection of recurrences. Material and Methods: Patients with American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7) stages IIIb/c or -IV melanoma who were disease-free following resection of macrometastases (cohort A), or obtained a durable complete response (CR) or partial response (PR) following systemic therapy (cohort B), were included. All patients underwent whole-body MRI, including T1, Short Tau Inversion Recovery, and diffusion-weighted imaging, every 4 months the first 3 years of follow-up and every 6 months in the following 2 years. A total body skin examination was performed every 6 months. Results: From November 2014 to November 2019, 111 patients were included (four screen failures, cohort A: 68 patients; cohort B: 39 patients). The median follow-up was 32 months. Twenty-six patients were diagnosed with suspected lesions. Of these, 15 patients were diagnosed with a recurrence on MRI. Eleven suspected lesions were considered to be of non-neoplastic origin. In addition, nine patients detected a solitary subcutaneous metastasis during self-examination, and two patients presented in between MRIs with recurrences. The overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were, respectively, 58%, 98%, 58%, 98%, and 98%. Sensitivity and specificity for the detection of distant metastases was respectively 88% and 98%. No patient experienced a clinically meaningful (>grade 1) adverse event. Conclusions: Whole-body MRI for the surveillance of melanoma patients is a safe and sensitive technique sparing patients′ cumulative exposure to X-rays and contrast media.
A Mathematical Model to Estimate Chemotherapy Concentration at the Tumor-Site and Predict Therapy Response in Colorectal Cancer Patients with Liver Metastases
Authors: Anaya Daniel A. , Dogra Prashant , Wang Zhihui , Haider Mintallah , Ehab Jasmina , Jeong Daniel K. , Ghayouri Masoumeh , Lauwers Gregory Y. , Thomas Kerry , Kim Richard , Butner Joseph D. , Nizzero Sara , Ramírez Javier Ruiz , Plodinec Marija , Sidman Richard L. , Cavenee Webster K. , Pasqualini Renata , Arap Wadih , Fleming Jason B. , Cristini Vittorio
Published: January 2021

Chemotherapy remains a primary treatment for metastatic cancer, with tumor response being the benchmark outcome marker. However, therapeutic response in cancer is unpredictable due to heterogeneity in drug delivery from systemic circulation to solid tumors. In this proof-of-concept study, we evaluated chemotherapy concentration at the tumor-site and its association with therapy response by applying a mathematical model. By using pre-treatment imaging, clinical and biologic variables, and chemotherapy regimen to inform the model, we estimated tumor-site chemotherapy concentration in patients with colorectal cancer liver metastases, who received treatment prior to surgical hepatic resection with curative-intent. The differential response to therapy in resected specimens, measured with the gold-standard Tumor Regression Grade (TRG; from 1, complete response to 5, no response) was examined, relative to the model predicted systemic and tumor-site chemotherapy concentrations. We found that the average calculated plasma concentration of the cytotoxic drug was essentially equivalent across patients exhibiting different TRGs, while the estimated tumor-site chemotherapeutic concentration (eTSCC) showed a quadratic decline from TRG = 1 to TRG = 5 (p < 0.001). The eTSCC was significantly lower than the observed plasma concentration and dropped by a factor of ~5 between patients with complete response (TRG = 1) and those with no response (TRG = 5), while the plasma concentration remained stable across TRG groups. TRG variations were driven and predicted by differences in tumor perfusion and eTSCC. If confirmed in carefully planned prospective studies, these findings will form the basis of a paradigm shift in the care of patients with potentially curable colorectal cancer and liver metastases.
Should Lymph Nodes Be Retrieved in Patients with Intrahepatic Cholangiocarcinoma? A Collaborative Korea–Japan Study
Authors: Kang Chang Moo , Suh Kyung-Suk , Yi Nam-Joon , Hong Tae Ho , Park Sang Jae , Ahn Keun Soo , Hayashi Hiroki , Choi Sae Byeol , Jeong Chi-Young , Takahara Takeshi , Shiozaki Shigehiro , Roh Young Hoon , Yu Hee Chul , Fukumoto Takumi , Matsuyama Ryusei , Naoki Uyama , Hashida Kazuki , Seo Hyung Il , Okabayashi Takehiro , Kitajima Tomoo , SATOI Sohei , Nagano Hiroaki , Kim Hongbeom , Taira Kaoru , Kubo Shoji , Choi Dong Wook
Published: January 2021

Background: This study was performed to investigate the oncologic role of lymph node (LN) management and to propose a surgical strategy for treating intrahepatic cholangiocarcinoma (IHCC). Methods: The medical records of patients with resected IHCC were retrospectively reviewed from multiple institutions in Korea and Japan. Short-term and long-term oncologic outcomes were analyzed according to lymph node metastasis (LNM). A nomogram to predict LNM in treating IHCC was established to propose a surgical strategy for managing IHCC. Results: A total of 1138 patients were enrolled. Of these, 413 patients underwent LN management and 725 did not. A total of 293 patients were found to have LNM. The No. 12 lymph node (36%) was the most frequent metastatic node, and the No. 8 lymph node (21%) was the second most common. LNM showed adverse long-term oncologic impact in patients with resected IHCC (14 months, 95% CI (11.4–16.6) vs. 74 months, 95% CI (57.2–90.8), p < 0.001), and the number of LNM (0, 1–3, 4≤) was also significantly related to negative oncologic impacts in patients with resected IHCC (74 months, 95% CI (57.2–90.8) vs. 19 months, 95% CI (14.4–23.6) vs. 11 months, 95% CI (8.1–13.8)), p < 0.001). Surgical retrieval of more than four (≥4) LNs could improve the survival outcome in resected IHCC with LNM (13 months, 95% CI (10.4–15.6)) vs. 30 months, 95% CI (13.1–46.9), p = 0.045). Based on preoperatively detectable parameters, a nomogram was established to predict LNM according to the tumor location. The AUC was 0.748 (95% CI: 0.706–0.788), and the Hosmer and Lemeshow goodness of fit test showed p = 0.4904. Conclusion: Case-specific surgical retrieval of more than four LNs is required in patients highly suspected to have LNM, based on a preoperative detectable parameter-based nomogram. Further prospective research is needed to validate the present surgical strategy in resected IHCC.
K3326X and Other C-Terminal BRCA2 Variants Implicated in Hereditary Cancer Syndromes: A Review
Authors: Baughan Scott , Tainsky Michael A.
Published: January 2021

Whole genome analysis and the search for mutations in germline and tumor DNAs is becoming a major tool in the evaluation of risk as well as the management of hereditary cancer syndromes. Because of the identification of cancer predisposition gene panels, thousands of such variants have been catalogued yet many remain unclassified, presenting a clinical challenge for the management of hereditary cancer syndromes. Although algorithms exist to estimate the likelihood of a variant being deleterious, these tools are rarely used for clinical decision-making. Here, we review the progress in classifying K3326X, a rare truncating variant on the C-terminus of BRCA2 and review recent literature on other novel single nucleotide polymorphisms, SNPs, on the C-terminus of the protein, defined in this review as the portion after the final BRC repeat (amino acids 2058–3418).
Early and Late Postoperative Seizures in Meningioma Patients and Prediction by a Recent Scoring System
Authors: Baumgarten Peter , Sarlak Mana , Monden Daniel , Spyrantis Andrea , Bernatz Simon , Gessler Florian , Dubinski Daniel , Hattingen Elke , Marquardt Gerhard , Strzelczyk Adam , Rosenow Felix , Harter Patrick N. , Seifert Volker , Freiman Thomas M.
Published: January 2021

Seizures are among the most common symptoms of meningioma. This retrospective study sought to identify risk factors for early and late seizures in meningioma patients and to evaluate a modified STAMPE2 score. In 556 patients who underwent meningioma surgery, we correlated different risk factors with the occurrence of postoperative seizures. A modified STAMPE2 score was applied. Risk factors for preoperative seizures were edema (p = 0.039) and temporal location (p = 0.038). For postoperative seizures preoperative tumor size (p < 0.001), sensomotory deficit (p = 0.004) and sphenoid wing location (p = 0.032) were independent risk factors. In terms of postoperative status epilepticus; sphenoid wing location (p = 0.022), tumor volume (p = 0.045) and preoperative seizures (p < 0.001) were independent risk factors. Postoperative seizures lead to a KPS deterioration and thus an impaired quality of life (p < 0.001). Late seizures occurred in 43% of patients with postoperative seizures. The small sub-cohort of patients (2.7%) with a STAMPE2 score of more than six points had a significantly increased risk for seizures (p < 0.001, total risk 70%). We concluded that besides distinct risk factors, high scores of the modified STAMPE2 score could estimate the risk of postoperative seizures. However, it seems not transferable to our cohort
Efficient Synthesis of Methyl Methacrylate by One Step Oxidative Esterification over Zn-Al-Mixed Oxides Supported Gold Nanocatalysts
Authors: Li Huayin , Tan Yuan , Chen Xingkun , Yang Wenshao , Huang Chuanqi , Li Jie , Ding Yunjie
Published: January 2021

Methyl methacrylate (MMA) is an important monomer in fine chemicals. The synthesis of MMA by one-step oxidative esterification from methacrolein with methanol over a heterogeneous catalyst with high activity, selectivity and stability is highly desirable. Herein, Zn-Al-hydrotalcites (HTs)-supported atomically precise Au25 nanoclusters with different molar ratios of Zn2+/Al3+ were prepared and used as the precursors for this reaction. They exhibited good performances in comparison with the gold catalysts prepared by the deposition precipitation method. The structural and electronic properties were evaluated by various characterization technologies, including X-ray diffraction (XRD), high-resolution transmission electron microscopy (HRTEM), in situ diffuse reflectance infrared Fourier-transform spectroscopy (DRIFTS) of CO adsorption, X-ray photoelectron spectroscopy (XPS), and CO2 temperature-programmed desorption (TPD). The combined characterization results suggested that the adsorption property of gold and the basicity of the catalyst contributes to their high activities. Substrates extended experiments and stability tests implied the potential application of Zn-Al-mixed oxides supported gold catalysts, which paves a new way for supported gold catalyst in the one-step oxidation esterification reaction.
Inflammatory Chemokines in Atherosclerosis
Authors: Gencer Selin , Evans Bryce R. , van der Vorst Emiel P.C. , Döring Yvonne , Weber Christian
Published: January 2021

Atherosclerosis is a long-term, chronic inflammatory disease of the vessel wall leading to the formation of occlusive or rupture-prone lesions in large arteries. Complications of atherosclerosis can become severe and lead to cardiovascular diseases (CVD) with lethal consequences. During the last three decades, chemokines and their receptors earned great attention in the research of atherosclerosis as they play a key role in development and progression of atherosclerotic lesions. They orchestrate activation, recruitment, and infiltration of immune cells and subsequent phenotypic changes, e.g., increased uptake of oxidized low-density lipoprotein (oxLDL) by macrophages, promoting the development of foam cells, a key feature developing plaques. In addition, chemokines and their receptors maintain homing of adaptive immune cells but also drive pro-atherosclerotic leukocyte responses. Recently, specific targeting, e.g., by applying cell specific knock out models have shed new light on their functions in chronic vascular inflammation. This article reviews recent findings on the role of immunomodulatory chemokines in the development of atherosclerosis and their potential for targeting.