bluuebunny/crossref_metadata_2025 huggingface dataset:
Ketamine Alters Functional Gamma and Theta Resting-State Connectivity in Healthy Humans: Implications for Schizophrenia Treatment Targeting the Glutamate System
Authors: Curic Stjepan , Andreou Christina , Nolte Guido , Steinmann Saskia , Thiebes Stephanie , Polomac Nenad , Haaf Moritz , Rauh Jonas , Leicht Gregor , Mulert Christoph
Published: June 2021

Disturbed functional connectivity is assumed to cause neurocognitive deficits in patients suffering from schizophrenia. A Glutamate N-methyl-D-aspartate receptor (NMDAR) dysfunction has been suggested as a possible mechanism underlying altered connectivity in schizophrenia, especially in the gamma- and theta-frequency range. The present study aimed to investigate the effects of the NMDAR-antagonist ketamine on resting-state power, functional connectivity, and schizophrenia-like psychopathological changes in healthy volunteers. In a placebo-controlled crossover design, 25 healthy subjects were recorded using resting-state 64-channel-electroencephalography (EEG) (eyes closed). The imaginary coherence-based Multivariate Interaction Measure (MIM) was used to measure gamma and theta connectivity across 80 cortical regions. The network-based statistic was applied to identify involved networks under ketamine. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). Ketamine caused an increase in all PANSS (p < 0.001) as well as 5D-ASC scores (p < 0.01). Significant increases in resting-state gamma and theta power were observed under ketamine compared to placebo (p < 0.05). The source-space analysis revealed two distinct networks with an increased mean functional gamma- or theta-band connectivity during the ketamine session. The gamma-network consisted of midline regions, the cuneus, the precuneus, and the bilateral posterior cingulate cortices, while the theta-band network involved the Heschl gyrus, midline regions, the insula, and the middle cingulate cortex. The current source density (CSD) within the gamma-band correlated negatively with the PANSS negative symptom score, and the activity within the gamma-band network correlated negatively with the subjective changed meaning of percepts subscale of the 5D-ASC. These results are in line with resting-state patterns seen in people who have schizophrenia and argue for a crucial role of the glutamate system in mediating dysfunctional gamma- and theta-band-connectivity in schizophrenia. Resting-state networks could serve as biomarkers for the response to glutamatergic drugs or drug development efforts within the glutamate system.
Psychological Distress, Loneliness, and Boredom Among the General Population of Tyrol, Austria During the COVID-19 Pandemic
Authors: Tutzer Franziska , Frajo-Apor Beatrice , Pardeller Silvia , Plattner Barbara , Chernova Anna , Haring Christian , Holzner Bernhard , Kemmler Georg , Marksteiner Josef , Miller Carl , Schmidt Martin , Sperner-Unterweger Barbara , Hofer Alex
Published: June 2021

Background: COVID-19-related mental health problems are considered a public health challenge. The aim of this study was to investigate psychological distress, loneliness, and boredom among the general population of the federal state of Tyrol, Austria.

Methods: Residents of Tyrol aged ≥ 18 years were recruited via dissemination of a link through social media and other advertisements and invited to complete an online survey from June 26th to August 20th, 2020. Next to the collection of sociodemographic and COVID-19 related variables the Brief Symptom Checklist (BSCL), the Three-Item Loneliness Scale (TILS), and the Multidimensional State Boredom Scale-Short Form (MSBS-SF) were used to assess psychological distress, loneliness, and boredom.

Results: 961 participants took part in the survey (68.3% woman). Of these, 14.4% were burdened from psychological distress (BSCL), 22.6% reached a TILS score ≥ 7 and were therefore classified as severely lonely, and boredom levels lay by a mean of 25.9 ± 11.0 points in the MSBS-SF (range: 7–56). Women, singles, low-income people as well as those who were unemployed were significantly more often affected by all of the selected outcomes compared to the remaining sample and they had significantly more frequently consumed alcohol or other substances since the outbreak of the pandemic in order to feel better. In addition, young and middle-aged adults were particularly burdened by loneliness and boredom.

Discussion: Our findings identify vulnerable groups and factors associated with higher psychological distress, loneliness, and boredom in the context of the pandemic. In order to prevent mental health problems it will be critical to identify options of maintaining social contacts and remaining active despite pandemic-related restrictions.
Perceptions of Study Conditions and Depressive Symptoms During the COVID-19 Pandemic Among University Students in Germany: Results of the International COVID-19 Student Well-Being Study
Authors: Matos Fialho Paula Mayara , Spatafora Franca , Kühne Lisa , Busse Heide , Helmer Stefanie M. , Zeeb Hajo , Stock Christiane , Wendt Claus , Pischke Claudia R.
Published: June 2021

Background: Results of previous studies examining the impact of the SARS-CoV-1 epidemic in 2003 on university students' mental well-being indicated severe mental health consequences. It is unclear how the current COVID-19 pandemic and the changes in study conditions due to federal regulations affected mental well-being in the German student population. We examined university students' perceptions of study conditions during the COVID-19 pandemic and investigated associations between study conditions and depressive symptoms.

Methods: A cross-sectional online survey was conducted in Germany in May 2020 at four universities (N = 5,021, 69% female, mean age: 24 years, SD: 5.1). Perceived study conditions, as well as sociodemographic information, were assessed with self-generated items and the CES-D 8 scale was used to determine depressive symptoms. Associations between perceived study conditions (academic stress and academic satisfaction), in general, and confidence to complete the semester, in particular, and depressive symptoms were analyzed using generalized linear regressions.

Results: Fifty-four percent of survey participants felt that the university workload had significantly increased since the COVID-19 pandemic; 48% were worried that they would not be able to successfully complete the academic year; 47% agreed that the change in teaching methods caused significant stress. Regarding depressive symptoms, the mean score of the CES-D 8 scale was 9.25. Further, a positive association between perceived study conditions and depressive symptoms was found (p < 0.001), indicating that better study conditions were associated with fewer depressive symptoms. Results of the generalized linear regression suggest that better student mental well-being was related to higher confidence in completing the semester.

Conclusions: This study provides first insights into perceived study conditions and associations with depressive symptoms among students during the COVID-19 pandemic in Germany. Findings underline the need for universities to provide intervention strategies targeting students' mental well-being during the course of the pandemic.
Information Extraction From FDA Drug Labeling to Enhance Product-Specific Guidance Assessment Using Natural Language Processing
Authors: Shi Yiwen , Ren Ping , Zhang Yi , Gong Xiajing , Hu Meng , Liang Hualou
Published: June 2021

Towards the objectives of the UnitedStates Food and Drug Administration (FDA) generic drug science and research program, it is of vital importance in developing product-specific guidances (PSGs) with recommendations that can facilitate and guide generic product development. To generate a PSG, the assessor needs to retrieve supportive information about the drug product of interest, including from the drug labeling, which contain comprehensive information about drug products and instructions to physicians on how to use the products for treatment. Currently, although there are many drug labeling data resources, none of them including those developed by the FDA (e.g., Drugs@FDA) can cover all the FDA-approved drug products. Furthermore, these resources, housed in various locations, are often in forms that are not compatible or interoperable with each other. Therefore, there is a great demand for retrieving useful information from a large number of textual documents from different data resources to support an effective PSG development. To meet the needs, we developed a Natural Language Processing (NLP) pipeline by integrating multiple disparate publicly available data resources to extract drug product information with minimal human intervention. We provided a case study for identifying food effect information to illustrate how a machine learning model is employed to achieve accurate paragraph labeling. We showed that the pre-trained Bidirectional Encoder Representations from Transformers (BERT) model is able to outperform the traditional machine learning techniques, setting a new state-of-the-art for labelling food effect paragraphs from drug labeling and approved drug products datasets.
Covid-19 Lockdown in Spring 2020 in France Provided Unexpected Opportunity to Assess Health Impacts of Falls in Air Pollution
Authors: Adélaïde Lucie , Medina Sylvia , Wagner Vérène , de Crouy-Chanel Perrine , Real Elsa , Colette Augustin , Couvidat Florian , Bessagnet Bertrand , Alter Maxime , Durou Amélie , Host Sabine , Hulin Marion , Corso Magali , Pascal Mathilde
Published: June 2021

Lockdown measures to limit the spread of Covid-19 in France in spring 2020 sharply reduced activities and lowered air-pollution concentrations. This study sought to determine the short- and long-term impacts on mortality in metropolitan France resulting from the temporary decrease in the population's exposure to air pollution. The reduction in exposure to air pollution was estimated by calculating the difference between modeled exposure of the population during the strict lockdown and the gradual lifting, and the simulated exposure that would have been observed in the absence of lockdown. A quantitative health impact assessment was used to estimate both the short-term impact of PM10 and NO2 reductions, and the long-term impact of PM2.5 and NO2 reductions on mortality. Reduced activities during the lockdown lowered NO2 and PM concentrations, resulting in about 2,300 deaths postponed for PM2.5 and nearly 1,200 for NO2, mainly due to avoided long-term effects. This study shows that, even in an unprecedented context that is certainly neither realistic nor desirable to improve air quality in the long run, public interventions appear to have a significant impact on health through reductions in air-pollution levels. In a long-term perspective, the study also reminds us that the total burden of air pollution on health remains a significant risk factor in France. Efforts to reduce ambient air pollution must thus be pursued sustainably for all sources of air pollution with suitably adapted but ambitious policies. Finally, the lockdown restrictions had other consequences, both positive and negative, on the population's health. These consequences highlight the need to conduct more integrated assessments of health impacts that include the multisectoral consequences of interventions, particularly in terms of population compliance with mitigating restrictions, behavior and mental health and, more broadly, climate change.
Left-Wing Xenophobia in Europe
Authors: Kopyciok Svenja , Silver Hilary
Published: June 2021

Given rising populist nationalism and multiplying meanings of “right” and “left,” this paper assesses whether Europeans who identify as extremely left-wing on the political spectrum hold anti-immigrant attitudes. In contrast to right-wing xenophobes, we further examine whether the political left, who conventionally emphasize class conflict, oppose immigrants less for cultural reasons and more for materialist reasons. We also consider whether socioeconomic status and values traditionally associated with the political left—favoring redistributive policies, egalitarianism, or social rights to benefits and services for immigrants—temper left- more than right-wing xenophobia. We find that a surprisingly large share of those who identify as far left do express extremely xenophobic attitudes, and we profile them in contrast to far right xenophobes. With logistic regression analysis of nine waves of the European Social Survey (2002–2018), we find that, all things equal, socioeconomic status influences far left xenophobia more than far right xenophobia, but inegalitarian values, less support for redistributive policies, and welfare chauvinism can only partially account for far left xenophobia and unexpectedly do not distinguish it from far right xenophobia. This implies that far left parties might adopt anti-immigrant policies to try to retain their loyal voters, even though such policies do not comport with broader left-wing values and may increase racial and ethnic inequality. Controlling for demographic and attitudinal differences reduces the probability of xenophobia among the far left by about sixty percent, but there remains some residual anti-immigrant attitudes among this group still to be explained.
Morphological and Fitness Attributes of Young Male Portuguese Basketball Players: Normative Values According to Chronological Age and Years From Peak Height Velocity
Authors: Ramos Sérgio Antunes , Massuça Luis Miguel , Volossovitch Anna , Ferreira António Paulo , Fragoso Isabel
Published: June 2021

The aims of the present study were: (i) to describe the structural and functional attributes of young male Portuguese basketball players aged 12–16 years and (ii) to generate normative data according to chronological age and years from peak height velocity. A total of 281 male Portuguese young basketball players between the ages of 12 and 16 years were assessed in this study. Chronological age, maturity parameters (maturity offset and predicted age at peak height velocity), morphological (body mass, height, and skinfolds and length), and fitness (sprint, change of direction ability, jump, and upper body strength) attributes were measured. Descriptive statistics were determined for the age and maturity status, and the 10th, 25th, 50th, 75th, and 90th percentiles were chosen as reference values. Descriptive and normative values of the players' morphological and fitness attributes, stratified by age and maturity status, are provided. The normative values of age at peak height velocity (category YAPHV = 0) showed that regional basketball players presented average values (50th percentile) of 169.8 cm for height, 173.3 cm for arm span, 55.6 kg for body mass, 3.34 s for the 20-m speed test, 10.31 s for the T-test, 4.75 m for the 2-kg medicine ball throw, 66.9 kg for the combined right and left handgrip strength, and 30.1 and 35.9 cm for jump height in the countermovement jump (CMJ) and CMJ with arm swing, respectively. In conclusion, these results may be helpful to quantify and control an athlete's performance over time and to adjust strength and conditioning programs to biological demands.
The Prevalence of Exercise Addiction Symptoms in a Sample of National Level Elite Athletes
Authors: Lichtenstein Mia Beck , Melin Anna Katarina , Szabo Attila , Holm Lars
Published: June 2021

Exaggerated exercise volumes, lack of control, withdrawal symptoms and conflicts with family and friends are core symptoms of exercise addiction. The condition can lead to health problems and social isolation because exercise is given the highest priority in any situation. The prevalence of the risk of exercise addiction has mostly been assessed in leisure time exercisers such as runners, fitness attendees and cyclists. The prevalence proportion ranges from 3 to 42% depending on the type of sport and the assessment tool. The proportion is greater among elite athletes, and increases with the level of competition. This study's primary aim was to assess the prevalence of exercise addiction among elite athletes competing at national level and its secondary aim was to evaluate the psychometric properties of the Exercise Addition Inventory (EAI) in elite sports. Participants (n= 417) from 15 sports disciplines and with 51% women completed an online survey. Results showed that 7.6% were at risk of exercise addiction. This group was younger, exhibited tendency to exercise despite pain and injury, felt guilty if not exercising enough, and reported substantial eating disorder symptoms. The reliability and validity of the EAI was good suggesting that the scale is appropriate for measuring the risk of exercise addiction in elite athletes.
Climate Change and Salinity Effects on Crops and Chemical Communication Between Plants and Plant Growth-Promoting Microorganisms Under Stress
Authors: Ullah Asad , Bano Asghari , Khan Naeem
Published: June 2021

During the last two decades the world has experienced an abrupt change in climate. Both natural and artificial factors are climate change drivers, although the effect of natural factors are lesser than the anthropogenic drivers. These factors have changed the pattern of precipitation resulting in a rise in sea levels, changes in evapotranspiration, occurrence of flood overwintering of pathogens, increased resistance of pests and parasites, and reduced productivity of plants. Although excess CO2promotes growth of C3plants, high temperatures reduce the yield of important agricultural crops due to high evapotranspiration. These two factors have an impact on soil salinization and agriculture production, leading to the issue of water and food security. Farmers have adopted different strategies to cope with agriculture production in saline and saline sodic soil. Recently the inoculation of halotolerant plant growth promoting rhizobacteria (PGPR) in saline fields is an environmentally friendly and sustainable approach to overcome salinity and promote crop growth and yield in saline and saline sodic soil. These halotolerant bacteria synthesize certain metabolites which help crops in adopting a saline condition and promote their growth without any negative effects. There is a complex interkingdom signaling between host and microbes for mutual interaction, which is also influenced by environmental factors. For mutual survival, nature induces a strong positive relationship between host and microbes in the rhizosphere. Commercialization of such PGPR in the form of biofertilizers, biostimulants, and biopower are needed to build climate resilience in agriculture. The production of phytohormones, particularly auxins, have been demonstrated by PGPR, even the pathogenic bacteria and fungi which also modulate the endogenous level of auxins in plants, subsequently enhancing plant resistance to various stresses. The present review focuses on plant-microbe communication and elaborates on their role in plant tolerance under changing climatic conditions.
Intramammary Immunisation Provides Short Term Protection Against Mannheimia haemolytica Mastitis in Sheep
Authors: Tassi Riccardo , Schiavo Martina , Filipe Joel , Todd Helen , Ewing David , Ballingall Keith T.
Published: June 2021

Mastitis affects both dairy and meat/wool sheep industries with losses due to reductions in milk quality and quantity, increased treatment costs and restricted lamb growth. Effective vaccines would be important tools for mastitis control. However, the development of vaccines against mastitis has proved challenging due to the failure to target protective immunity to the mammary gland. In order to target responses to the mammary gland, this study tested whether local administration directly into the gland through the teat canal or in the udder skin confers protection against an intramammary infection. In this study, we tested a vaccine that confers protection against respiratory disease caused byMannheimia haemolyticato determine if it also protects against intramammary infection by the same organism. No evidence of protection was observed in animals that received a subcutaneous immunisation in the udder skin, however, intramammary immunisation provided almost complete protection against an experimental challenge administered 7 days post immunisation but not if the challenge was delivered 14 days post immunisation. To investigate further the nature of this variation in response, the somatic cell count and concentration of cytokines Interleukin-1β, Interleukin-10 and Interleukin-17A was determined in milk over the course of each study. Intramammary immunisation induced an inflammatory response within the mammary gland, characterised by increases in SCC and in the production of cytokines IL-1β, IL-10, and IL-17A. This response was similar to that observed in un-vaccinated control animals post challenge. The SCC and cytokine levels had returned to levels comparable with un-vaccinated controls prior to challenge at both 7 and 14 days post immunisation. The transient nature of the protective effect is consistent with the priming of an innate antibacterial response within the mammary gland which provides protection against challenge at 7 days but is diminished by 14 days post-vaccination. Further studies are planned to determine the nature of the innate immune mechanisms associated with the protective effect described here to determine whether it may be exploited to improve ruminant udder health.
Evaluation of Three Commercial Interferon-γ Assays in a Bovine Tuberculosis Free Population
Authors: Ghielmetti Giovanni , Landolt Patricia , Friedel Ute , Morach Marina , Hartnack Sonja , Stephan Roger , Schmitt Sarah
Published: June 2021

The interferon-γ assay has been used worldwide as an ancillary test for the diagnosis of bovine tuberculosis (bTB). This study aimed to describe, based on the bTB-free status in Switzerland, the difference of applying a more stringent cutoff point of 0.05 compared with 0.1 for bTB surveillance. Moreover, the effect of time between blood collection and stimulation, culture results, optical density values, and the influence of testing different breeds were evaluated. Blood samples from a total of 118 healthy cows older than 6 months were tested with three commercial interferon-gamma assays. To confirm the bTB-free status of the tested animals and to investigate potential cross-reactions with nontuberculous mycobacteria, pulmonary and abdominal lymph nodes in addition to ileal mucosa from each cattle were used for the detection of viable Mycobacteria spp. by specific culture. Significant differences regarding the proportion of false-positive results between the two Bovigam tests and between Bovigam 2G and ID Screen were found. Samples analyzed with Bovigam 2G were 2.5 [95% confidence interval (CI) 1.6–3.9] times more likely to yield a false-positive test result than samples analyzed with Bovigam TB. Similarly, the odds ratio (OR) for testing samples false-positive with ID Screen compared with Bovigam TB was 1.9 (95% CI 1.21–2.9). The OR for testing false-positive with ID Screen compared with Bovigam 2G was less to equally likely with an OR of 0.75 (95% CI 0.5–1.1). When using a cutoff of 0.05 instead of 0.1, the OR for a false-positive test result was 2.2 (95% CI 1.6–3.1). Samples tested after 6 h compared with a delayed stimulation time of 22–24 h were more likely to yield a false-positive test result with an OR of 3.9 (95% CI 2.7–5.6). In conclusion, applying a more stringent cutoff of 0.05 with the Bovigam 2G kit generates a questionable high number of false-positive results of one of three tested animals. Furthermore, specific breeds might show an increased risk to result false-positive in the Bovigam 2G and the ID Screen assays.
Images and Landscape: The (Dis)ordering of Colonial Territory (Quito in the Eighteenth Century)
Authors: Fernández-Salvador Carmen
Published: June 2021

This article explores the role played by images of the Virgin Mary in the ordering of space during the colonial period, as well as in the disruption of such order as a gesture of resistance by subordinate groups. In the Real Audiencia de Quito of the sixteenth and seventeenth centuries, civil and religious authorities used miraculous images of the Virgin Mary as aids in the founding of reducciones, which assured the imposition of Christian civility upon the Native population. Legal records suggest that in the second half of the eighteenth century Indigenous communities deployed similar strategies as a means of asserting their own concerns. Native actors physically manipulated Marian images in times of conflict, moving them around or apprehending them either to legitimize their desertion of colonial settlements or to resist forced relocation. In both the early colonial period and in the eighteenth century, the key strategy of shaping sacred landscapes was implemented in both Andean and Christian traditions.
On the Relationship between Circulation Patterns, the Southern Annular Mode, and Rainfall Variability in Western Cape
Authors: Ibebuchi Chibuike Chiedozie
Published: June 2021

This study investigates circulation types (CTs) in Africa, south of the equator, that are related to wet and dry conditions in the Western Cape, the statistical relationship between the selected CTs and the Southern Annular Mode (SAM), and changes in the frequency of occurrence of the CTs related to the SAM under the ssp585 scenario. Obliquely rotated principal component analysis applied to sea level pressure (SLP) was used to classify CTs in Africa, south of the equator. Three CTs were found to have a high probability of being associated with wet days in the Western Cape, and four CTs were equally found to have a high probability of being associated with dry days in the Western Cape. Generally, the dry/wet CTs feature the southward/northward track of the mid-latitude cyclone, adjacent to South Africa; anti-cyclonic/cyclonic relative vorticity, and poleward/equatorward track of westerlies, south of South Africa. One of the selected wet CTs was significantly related to variations of the SAM. Years with an above-average SAM index correlated with the below-average frequency of occurrences of the wet CT. The results suggest that through the dynamics of the CT, the SAM might control the rainfall variability of the Western Cape. Under the ssp585 scenario, the analyzed climate models indicated a possible decrease in the frequency of occurrence of the aforementioned wet CT associated with cyclonic activity in the mid-latitudes, and an increase in the frequency of the occurrence of CT associated with enhanced SLP at mid-latitudes.
Predicting Major Storm Surge Levels
Authors: Mendelsohn Robert
Published: June 2021

The National Atmospheric and Oceanic Administration (NOAA) calculates the surge probability distribution along the coast from their long-term tidal stations. This process is sufficient for predicting the surge from common storms but tends to underestimate large surges. Across 23 long-term tidal stations along the East Coast of the United States, 100-year surges were observed 49 times, although they should have occurred only 23 times. We hypothesize that these 100-year surges are not the tail outcome from common storms but are actually caused by major hurricanes. Matching these 100-year surges with major hurricanes revealed that major hurricanes caused 43 of the 49 surges. We consequently suggest a revised approach to estimating the surge probability distribution. We used tidal data to estimate the probability of common surges but analyzed major hurricane surges separately, using the return rate of major hurricanes and the observed surge from each major hurricane to predict hurricane surges. The revision reveals that expected coastal flooding damage is higher than we thought, especially in the southeast United States.
About Cogredient and Contragredient Linear Differential Equations
Authors: Gorelov Vasily
Published: June 2021

The notions of cogredience and contragredience, which have great importance to the question of algebraic independence of linear differential equation solutions, are discussed in the paper. Conditions of equivalence of two definitions of cogredience and contragredience are found.
Impact of Depression and Anxiety on Dimensions of Health-Related Quality of Life in Subjects with Parkinson’s Disease Enrolled in an Association of Patients
Authors: Chuquilín-Arista Fany , Álvarez-Avellón Tania , Menéndez-González Manuel
Published: June 2021

Parkinson’s disease (PD) is a complex disorder characterized by a wide spectrum of symptoms. Depression and anxiety are common manifestations in PD and may be determinants of health-related quality of life (HRQoL). The objective of this study is to determine the association of depression and anxiety with the dimensions of HRQoL in subjects with PD enrolled in an association of patients. Ninety-five community-based patients with PD diagnosis at different disease stages were studied. HRQoL was assessed using the Parkinson’s Disease Questionnaire (PDQ-39); depression and anxiety were assessed using the Beck Depression Inventory (BDI-II) and the State-Trait Anxiety Inventory (STAI), respectively. Our results showed that depression and anxiety were negatively associated with HRQoL measured by PDSI. Higher motor dysfunction measured by Hoehn and Yahr (H&Y) staging was also associated with worse HRQoL. Depression was the most influential variable in the model. All PDQ-39 dimensions except social support and bodily discomfort were associated with depression. Anxiety was associated with the emotional well-being and bodily discomfort dimensions. These results suggest that physicians should pay attention to the presence of psychiatric symptoms and treat them appropriately.
Tumor-Associated Neutrophils in Hepatocellular Carcinoma Pathogenesis, Prognosis, and Therapy
Authors: Arvanitakis Konstantinos , Mitroulis Ioannis , Germanidis Georgios
Published: June 2021

Hepatocellular carcinoma represents the most prevalent primary liver cancer worldwide, and it is either caused by intrinsic genetic mutations or by a multitude of extrinsic risk factors. Even though the interplay between chronic inflammatory changes and hepatocarcinogenesis has been at the forefront of clinical investigation for the past few decades, the role of tumor-associated neutrophils (TANs) in HCC development still remains ambiguous. On the one hand, N1 TANs exhibit an anti-tumorigenic activity, mediated by direct or indirect tumor cell lysis, whereas on the other hand, N2 TANs have been correlated with increased HCC growth, invasiveness, and metastasis. The association of an elevated Neutrophil-to-Lymphocyte Ratio (NLR) with poor prognosis in patients with HCC, has been recently brought into spotlight, consolidating its widespread use as a reliable biomarker. Due to the decisive involvement of TANs in HCC pathogenesis and development, the utilization of various neutrophil-centered anticancer treatment modalities has been under clinical experimentation, selectively targeting and modulating the processes of neutrophil recruitment, activation, and migration. This review summarizes current evidence on the role of TANs in HCC pathogenesis and progression, as well as in their potential involvement in tumor therapy, shedding light on emerging anticancer treatment methods targeting neutrophils.
Successful Patient-Derived Organoid Culture of Gynecologic Cancers for Disease Modeling and Drug Sensitivity Testing
Authors: Bi Jianling , Newtson Andreea M. , Zhang Yuping , Devor Eric J. , Samuelson Megan I. , Thiel Kristina W. , Leslie Kimberly K.
Published: June 2021

Developing reliable experimental models that can predict clinical response before treating the patient is a high priority in gynecologic cancer research, especially in advanced or recurrent endometrial and ovarian cancers. Patient-derived organoids (PDOs) represent such an opportunity. Herein, we describe our successful creation of 43 tumor organoid cultures and nine adjacent normal tissue organoid cultures derived from patients with endometrial or ovarian cancer. From an initial set of 45 tumor tissues and seven ascites fluid samples harvested at surgery, 83% grew as organoids. Drug sensitivity testing and organoid cell viability assays were performed in 19 PDOs, a process that was accomplished within seven days of obtaining the initial surgical tumor sample. Sufficient numbers of cells were obtained to facilitate testing of the most commonly used agents for ovarian and endometrial cancer. The models reflected a range of sensitivity to platinum-containing chemotherapy as well as other relevant agents. One PDO from a patient treated prior to surgery with neoadjuvant trastuzumab successfully predicted the patient’s postoperative chemotherapy and trastuzumab resistance. In addition, the PDO drug sensitivity assay identified alternative treatment options that are currently used in the second-line setting. Our findings suggest that PDOs could be used as a preclinical platform for personalized cancer therapy for gynecologic cancer patients.
Identifying High-Risk Tumors within AJCC Stage IB–III Melanomas Using a Seven-Marker Immunohistochemical Signature
Authors: Reschke Robin , Gussek Philipp , Ziemer Mirjana
Published: June 2021

Background: We aim to validate a seven-marker immunohistochemical signature, consisting of Bax, Bcl-X, PTEN, COX-2, (loss of) ß-Catenin, (loss of) MTAP and (presence of) CD20, in an independent patient cohort and test clinical feasibility. Methods: We performed staining of the mentioned antibodies in tissue of 88 primary melanomas and calculated a risk score for each patient. Data were correlated with clinical parameters and outcome (recurrence-free, distant metastasis-free and melanoma-specific survival). Results: The seven-marker signature was able to identify high-risk patients within stages IB-III melanoma patients that have a significantly higher risk of disease recurrence, metastasis, and death. In particular, the high sensitivity of relapse prediction (>94%) in sentinel negative patients (stages IB–IIC) was striking (negative predictive value of 100% for melanoma-specific survival and distant metastasis-free survival, and 97.5% for relapse-free survival). For stage III patients (positive nodal status), the negative predictive value was 100% with the seven-marker signature. Conclusions: The seven-marker signature can help to further select high-risk patients in stages IIB-C but also in earlier stages IB–IIA and be a useful tool for therapy decisions in the adjuvant and future neo-adjuvant settings. Stage III patients with measurable lymph node disease classified as high-risk with the seven-marker signature are potential candidates for neoadjuvant immunotherapy.
Integrative Transcriptomic Analysis Reveals Distinctive Molecular Traits and Novel Subtypes of Collecting Duct Carcinoma
Authors: Gargiuli Chiara , Sepe Pierangela , Tessari Anna , Sheetz Tyler , Colecchia Maurizio , de Braud Filippo Guglielmo Maria , Procopio Giuseppe , Sensi Marialuisa , Verzoni Elena , Dugo Matteo
Published: June 2021

Collecting duct carcinoma (CDC) is a rare and highly aggressive kidney cancer subtype with poor prognosis and no standard treatments. To date, only a few studies have examined the transcriptomic portrait of CDC. Through integration of multiple datasets, we compared CDC to normal tissue, upper-tract urothelial carcinomas, and other renal cancers, including clear cell, papillary, and chromophobe histologies. Association between CDC gene expression signatures and in vitro drug sensitivity data was evaluated using the Cancer Therapeutic Response Portal, Genomics of Drug Sensitivity in Cancer datasets, and connectivity map. We identified a CDC-specific gene signature that predicted in vitro sensitivity to different targeted agents and was associated to worse outcome in clear cell renal cell carcinoma. We showed that CDC are transcriptionally related to the principal cells of the collecting ducts providing evidence that this tumor originates from this normal kidney cell type. Finally, we proved that CDC is a molecularly heterogeneous disease composed of at least two subtypes distinguished by cell signaling, metabolic and immune-related alterations. Our findings elucidate the molecular features of CDC providing novel biological and clinical insights. The identification of distinct CDC subtypes and their transcriptomic traits provides the rationale for patient stratification and alternative therapeutic approaches.
Plasticity in Neuroblastoma Cell Identity Defines a Noradrenergic-to-Mesenchymal Transition (NMT)
Authors: Gautier Margot , Thirant Cécile , Delattre Olivier , Janoueix-Lerosey Isabelle
Published: June 2021

Neuroblastoma, a pediatric cancer of the peripheral sympathetic nervous system, is characterized by an important clinical heterogeneity, and high-risk tumors are associated with a poor overall survival. Neuroblastoma cells may present with diverse morphological and biochemical properties in vitro, and seminal observations suggested that interconversion between two phenotypes called N-type and S-type may occur. In 2017, two main studies provided novel insights into these subtypes through the characterization of the transcriptomic and epigenetic landscapes of a panel of neuroblastoma cell lines. In this review, we focus on the available data that define neuroblastoma cell identity and propose to use the term noradrenergic (NOR) and mesenchymal (MES) to refer to these identities. We also address the question of transdifferentiation between both states and suggest that the plasticity between the NOR identity and the MES identity defines a noradrenergic-to-mesenchymal transition, reminiscent of but different from the well-established epithelial-to-mesenchymal transition.
High miR-30 Expression Associates with Improved Breast Cancer Patient Survival and Treatment Outcome
Authors: Jamshidi Maral , Fagerholm Rainer , Muranen Taru A. , Kaur Sippy , Potdar Swapnil , Khan Sofia , Netti Eliisa , Mpindi John-Patrick , Yadav Bhagwan , Kiiski Johanna I. , Aittomäki Kristiina , Heikkilä Päivi , Saarela Jani , Bützow Ralf , Blomqvist Carl , Nevanlinna Heli
Published: June 2021

Deregulated miRNA expression has been suggested in several stages of breast cancer pathogenesis. We have studied the miR-30 family, in particular miR-30d, in relation to breast cancer patient survival and treatment outcomes. With tumor specimens from 1238 breast cancer patients, we analyzed the association of miR-30d expression with tumor characteristics with the 5-year occurrence of breast cancer-specific death or distant metastasis (BDDM), and with 10-year breast cancer survival (BCS). We conducted a two-stage drug-screen to investigate the impact of miR-30 family members (miR-30a-30e) on sensitivity to doxorubicin and lapatinib in six breast cancer cell lines HCC1937, HCC1954, MDA-MB-361, MCF7, MDA-MB-436 and CAL-120, using drug sensitivity scores (DSS) to compare the miR-30 family mimics to their specific inhibitors. The study was complemented with Ingenuity Pathway Analysis (IPA) with the METABRIC data. We found that while high miR-30d expression is typical for aggressive tumors, it predicts better metastasis-free (pBDDM = 0.035, HR = 0.63, 95% CI = 0.4–0.9) and breast cancer-specific survival (pBCS = 0.018, HR = 0.61, 95% CI = 0.4–0.9), especially in HER2-positive (pBDDM = 0.0009), ER-negative (pBDDM = 0.003), p53-positive (pBDDM = 0.011), and highly proliferating (pBDDM = 0.0004) subgroups, and after adjuvant chemotherapy (pBDDM = 0.035). MiR-30d predicted survival independently of standard prognostic markers (pBDDM = 0.0004). In the drug-screening test, the miR-30 family sensitized the HER2-positive HCC1954 cell line to lapatinib (p < 10−2) and HCC1937, MDA-MB-361, MDA-MB-436 and CAL120 to doxorubicin (p < 10−4) with an opposite impact on MCF7. According to the pathway analysis, the miR-30 family has a suppressive effect on cell motility and metastasis in breast cancer. Our results suggest prognostic and predictive potential for the miR-30 family, which warrants further investigation.
Predicting Colorectal Cancer Occurrence in IBD
Authors: Yalchin Mehmet , Baker Ann-Marie , Graham Trevor A. , Hart Ailsa
Published: June 2021

Patients with colonic inflammatory bowel disease (IBD) are at an increased risk of developing colorectal cancer (CRC), and are therefore enrolled into a surveillance programme aimed at detecting dysplasia or early cancer. Current surveillance programmes are guided by clinical, endoscopic or histological predictors of colitis-associated CRC (CA-CRC). We have seen great progress in our understanding of these predictors of disease progression, and advances in endoscopic technique and management, along with improved medical care, has been mirrored by the falling incidence of CA-CRC over the last 50 years. However, more could be done to improve our molecular understanding of CA-CRC progression and enable better risk stratification for patients with IBD. This review summarises the known risk factors associated with CA-CRC and explores the molecular landscape that has the potential to complement and optimise the existing IBD surveillance programme.
Development of a Virus-Like Particle-Based Anti-HER2 Breast Cancer Vaccine
Authors: Hu He , Steinmetz Nicole F.
Published: June 2021

To develop a human epidermal growth factor receptor-2 (HER2)-specific cancer vaccine, using a plant virus-like particle (VLP) platform. Copper-free click chemistry and infusion encapsulation protocols were developed to prepare VLPs displaying the HER2-derived CH401 peptide epitope, with and without Toll-like receptor 9 (TLR9) agonists loaded into the interior cavity of the VLPs; Physalis mottle virus (PhMV)-based VLPs were used. After prime-boost immunization of BALB/c mice through subcutaneous administration of the vaccine candidates, sera were collected and analyzed by enzyme-linked immunosorbent assay (ELISA) for the CH401-specific antibodies; Th1 vs. Th2 bias was determined by antibody subtyping and splenocyte assay. Efficacy was assessed by tumor challenge using DDHER2 tumor cells. We successful developed two VLP-based anti-HER2 vaccine candidates—PhMV-CH401 vs. CpG-PhMV-CH401; however, the addition of the CpG adjuvant did not confer additional immune priming. Both VLP-based vaccine candidates elicited a strong immune response, including high titers of HER2-specific immunoglobulins and increased toxicity of antisera to DDHER2 tumor cells. DDHER2 tumor growth was delayed, leading to prolonged survival of the vaccinated vs. naïve BALB/C mice. The PhMV-based anti-HER2 vaccine PhMV-CH401, demonstrated efficacy as an anti-HER2 cancer vaccine. Our studies highlight that VLPs derived from PhMV are a promising platform to develop cancer vaccines.
Neural Network Methodology for the Identification and Classification of Lipopeptides Based on SMILES Annotation
Authors: Yadav Manisha , Jujjavarapu Satya Eswari
Published: June 2021

Artificial Neural Networks can be applied for the identification and classification of prospective drug candidates such as complex compounds, including lipopeptide, based on their SMILES string representation. The training of neural networks is done with SMILES strings, which are predictive of structural identification; the ANNs are efficient of correctly classifying all compounds, substructures and their analogues distinguishing the drugs based upon atomic organization to obtain lead optimization in drug discovery. The proficiency of the trained ANN models in recognizing and classifying the analogous compounds was tested for analysis of similar compounds, which were not taken previously for training and achieved results with correct classification in the validation set. The best result was achieved with 10 numbers of hidden layers. The R2 value for training is 0.90586; the R2 value for testing is 0.99508; the R2 value after validation is 0.94151; the final value of R2 for total sets is 0.89456. The graphs are plotted between 21 epochs and mean square error (MSE) to report the performance of the model. The value of 798.1735 for the gradient of the curve after 21 iterations and 6 validation checks was obtained. A successful model was developed for the identification and classification of lipopeptides from their SMILES annotation that efficiently classifies similar compounds and supports in decision making for analogue-based drug discovery. This will help in appropriate lead optimization studies for the prediction of potential anticancer and antimicrobial lipopeptide-based therapeutics.
The Investigation on Mid-Far Infrared Nonlinear Crystal AgGaGe5Se12 (AGGSe)
Authors: Ni Youbao , Hu Qianqian , Wu Haixin , Han Weimin , Yu Xuezhou , Mao Mingsheng
Published: June 2021

3–5, 8–14 μm mid-far infrared (MF-IR) coherent lights generated by nonlinear optical (NLO) crystals are crucial for many industrial and military applications. AgGaGe5Se12 (AGGSe) is a promising NLO candidate because of its good optical performance. In this paper, the large AGGSe single crystal of 35 mm diameter and 80 mm length was obtained by the seed-aided Bridgman method. The crystalline quality was characterized with X-ray diffraction, rocking curve, transmission spectrum. The FWHM of the (210) peak was about 0.05° and the IR transmission was about 60% (1–10 μm, 6 mm thick). Additionally, it performed well in 8 μm frequency doubling, with a maximum output power of about 41 mW, corresponding to an optical-to-optical conversion efficiency of 3.2%. The laser induced damage threshold (LIDT) value was about 200 MW/cm2 (1.06 μm, 20 ns, 1 Hz).
Multi-Particle Interference in an Electronic Mach–Zehnder Interferometer
Authors: Kotilahti Janne , Burset Pablo , Moskalets Michael , Flindt Christian
Published: June 2021

The development of dynamic single-electron sources has made it possible to observe and manipulate the quantum properties of individual charge carriers in mesoscopic circuits. Here, we investigate multi-particle effects in an electronic Mach–Zehnder interferometer driven by a series of voltage pulses. To this end, we employ a Floquet scattering formalism to evaluate the interference current and the visibility in the outputs of the interferometer. An injected multi-particle state can be described by its first-order correlation function, which we decompose into a sum of elementary correlation functions that each represent a single particle. Each particle in the pulse contributes independently to the interference current, while the visibility (given by the maximal interference current) exhibits a Fraunhofer-like diffraction pattern caused by the multi-particle interference between different particles in the pulse. For a sequence of multi-particle pulses, the visibility resembles the diffraction pattern from a grid, with the role of the grid and the spacing between the slits being played by the pulses and the time delay between them. Our findings may be observed in future experiments by injecting multi-particle pulses into a Mach–Zehnder interferometer.