bluuebunny/crossref_metadata_2025 huggingface dataset:
Bayesian Optimization Based Efficient Layer Sharing for Incremental Learning
Authors: Kim Bomi , Kim Taehyeon , Choe Yoonsik
Published: March 2021

Incremental learning is a methodology that continuously uses the sequential input data to extend the existing network’s knowledge. The layer sharing algorithm is one of the representative methods which leverages general knowledge by sharing some initial layers of the existing network. To determine the performance of the incremental network, it is critical to estimate how much the initial convolutional layers in the existing network can be shared as the fixed feature extractors. However, the existing algorithm selects the sharing configuration through improper optimization strategy but a brute force manner such as searching for all possible sharing layers case. This is a non-convex and non-differential problem. Accordingly, this can not be solved using powerful optimization techniques such as the gradient descent algorithm or other convex optimization problem, and it leads to high computational complexity. To solve this problem, we firstly define this as a discrete combinatorial optimization problem, and propose a novel efficient incremental learning algorithm-based Bayesian optimization, which guarantees the global convergence in a non-convex and non-differential optimization. Additionally, our proposed algorithm can adaptively find the optimal number of sharing layers via adjusting the threshold accuracy parameter in the proposed loss function. With the proposed method, the global optimal sharing layer can be found in only six or eight iterations without searching for all possible layer cases. Hence, the proposed method can find the global optimal sharing layers by utilizing Bayesian optimization, which achieves both high combined accuracy and low computational complexity.
In a Time Loop: Politics and the Ideological Significance of Monuments to Those Who Perished on Saint Anne Mountain (1934–1955, Germany/Poland)
Authors: Tomaszewicz Agnieszka , Majczyk Joanna
Published: March 2021

Polish Góra św. Anny (Saint Anne Mountain), previously German Annaberg, is one of the few places in the world where art was utilized to promote two regimes—fascist and communist. With the use of art, the refuge of pagan gods and then, Christian Saint John’s Mountain with Saint Ann’s church and a calvary site were transformed into a mausoleum of the victims of uprisings and wars—those placed by politics on opposite sides of the barricade. The “sacred” character of the mountain was appropriated in the 1930s by the fascist Thingstätte under the form of an open-air theatre with a mausoleum, erected to commemorate fallen German soldiers in the Third Silesian Uprising. After the Second World War, the same place was “sacralized” by the Monument of the Insurgents’ Deed, which replaced the German object. The aim of both of them was to commemorate those who had perished in the same armed conflicts—uprisings from the years 1919–1921, when the Poles opposed German administration of Upper Silesia. According to the assumptions of both national socialism as well as communism, the commemorative significance of both monuments was subjected to ideological messages. Both monuments were supposed to constitute not only the most important element of the place where patriotic manifestations were intended to be held, but also a kind of counterbalance for the local pilgrims’ center dedicated to the cult of Saint Anne. The aim of the paper is to present the process of transforming a Nazi monument into its communist counterpart, at the same time explaining the significance of both monuments in the context of changing political reality. This paper has not been based on one exclusive research method—historical and field studies have been conducted, together with iconographical and iconological analyses of the monuments viewed from their comparative perspective. The text relies on archive materials—documents, press releases, and projects, including architectural drawings of the monument staffage—discovered by the authors and never published before. They would connect the structure not only to the surrounding landscape but, paradoxically, to the fascist Thingstätte.
Feature Learning for Stock Price Prediction Shows a Significant Role of Analyst Rating
Authors: Singh Jaideep , Khushi Matloob
Published: March 2021

Efficient Market Hypothesis states that stock prices are a reflection of all the information present in the world and generating excess returns is not possible by merely analysing trade data which is already available to all public. Yet to further the research rejecting this idea, a rigorous literature review was conducted and a set of five technical indicators and 23 fundamental indicators was identified to establish the possibility of generating excess returns on the stock market. Leveraging these data points and various classification machine learning models, trading data of the 505 equities on the US S&P500 over the past 20 years was analysed to develop a classifier effective for our cause. From any given day, we were able to predict the direction of change in price by 1% up to 10 days in the future. The predictions had an overall accuracy of 83.62% with a precision of 85% for buy signals and a recall of 100% for sell signals. Moreover, we grouped equities by their sector and repeated the experiment to see if grouping similar assets together positively effected the results but concluded that it showed no significant improvements in the performance—rejecting the idea of sector-based analysis. Also, using feature ranking we could identify an even smaller set of 6 indicators while maintaining similar accuracies as that from the original 28 features and also uncovered the importance of buy, hold and sell analyst ratings as they came out to be the top contributors in the model. Finally, to evaluate the effectiveness of the classifier in real-life situations, it was backtested on FAANG (Facebook, Amazon, Apple, Netflix & Google) equities using a modest trading strategy where it generated high returns of above 60% over the term of the testing dataset. In conclusion, our proposed methodology with the combination of purposefully picked features shows an improvement over the previous studies, and our model predicts the direction of 1% price changes on the 10th day with high confidence and with enough buffer to even build a robotic trading system.
Air Quality and Industrial Emissions in the Cities of Kazakhstan
Authors: Assanov Daulet , Zapasnyi Valeryi , Kerimray Aiymgul
Published: March 2021

Industrial emissions are of major concern, especially in developing countries. Hence, there is a need for studies that investigate the trends in industrial emissions in these countries. The purpose of this study is to discuss trends in industrial emissions in Kazakhstan and the air pollution level in its industrial cities. Data on emission limit values from the permitting documents of twenty-one power plants and nine metallurgical enterprises of Kazakhstan were analyzed. Eight cities (out of fourteen) had a “high” level of atmospheric air pollution according to the Air Pollution Index in 2019. Most of the considered enterprises increased their emission limit values compared to the previous permitting period. In some cities there is a lack of monitoring stations, indicating the need for improving the spatial coverage of the air quality monitoring network in the industrial cities of Kazakhstan. The location of industrial plants far outside the cities could reduce the exposure of the urban population to air pollution. Kazakhstan urgently needs to adopt stringent emissions standards for coal-fired power plants and heavy industrial plants. The national air quality standards and definitions of air pollutants need to be updated based on the latest scientific knowledge.
Development and Assessment of Spatially Continuous Predictive Algorithms for Fine Particulate Matter in New York State
Authors: Lightstone Sam , Gross Barry , Moshary Fred , Castillo Paulo
Published: March 2021

Health risks connected with fine particulate matter (PM2.5) pollutants are well documented; increased risks of asthma, heart attack and heart failure are a few of the effects associated with PM2.5. Accurately forecasting PM2.5 is crucial for state agencies directed to devise State Implementation Plans (SIPS) to deal with National Ambient Air Quality Standards (NAAQS) exceedances. In previous work, we explored the application of multi-temporal data-driven neural networks (NNs) to forecasting PM2.5. Our work showed that under different input conditions, the NN approach achieves higher forecasting scores for local (12 km) resolution when compared to the other Chemical Transport Model forecast models, such as the Community Multi-Scale Air Quality system (CMAQ). Critical to our approach was the inclusion of prior PM2.5 concentrations, retrieved from ground monitoring stations, as part of the input dataset for the NN. The NN approach can provide high-level forecasting accuracy; however, because of the dependency on ground monitoring stations, the forecast coverage is sparse. Here, we extend our previous station-specific efforts by forecasting hourly PM2.5 values that are spatially continuous through the use of a deep neural network (DNN). The DNN approach combines spatial Kriging with additional local source variables to interpolate the measured PM2.5 concentrations across non-station locations. These interpolated PM2.5 values are used as inputs in the original forecasting NN. Cross-validation testing, using all New York State AirNow PM2.5 stations, showed that this forecast approach achieves accurate results, with a regression coefficient (R2) of 0.59, and a root mean square error (RMSE) of 2.22μgm3. Additionally, herein we demonstrate the usefulness of this approach on specific temporal events where significant dynamics of PM2.5 were observed; particularly, we show that even bias-corrected CMAQ forecasts do not track these transients and our NN method.
Radiative Effect and Mixing Processes of a Long-Lasting Dust Event over Athens, Greece, during the COVID-19 Period
Authors: Kokkalis Panagiotis , Soupiona Ourania , Papanikolaou Christina-Anna , Foskinis Romanos , Mylonaki Maria , Solomos Stavros , Vratolis Stergios , Vasilatou Vasiliki , Kralli Eleni , Anagnou Dimitra , Papayannis Alexandros
Published: March 2021

We report on a long-lasting (10 days) Saharan dust event affecting large sections of South-Eastern Europe by using a synergy of lidar, satellite, in-situ observations and model simulations over Athens, Greece. The dust measurements (11–20 May 2020), performed during the confinement period due to the COVID-19 pandemic, revealed interesting features of the aerosol dust properties in the absence of important air pollution sources over the European continent. During the event, moderate aerosol optical depth (AOD) values (0.3–0.4) were observed inside the dust layer by the ground-based lidar measurements (at 532 nm). Vertical profiles of the lidar ratio and the particle linear depolarization ratio (at 355 nm) showed mean layer values of the order of 47 ± 9 sr and 28 ± 5%, respectively, revealing the coarse non-spherical mode of the probed plume. The values reported here are very close to pure dust measurements performed during dedicated campaigns in the African continent. By utilizing Libradtran simulations for two scenarios (one for typical midlatitude atmospheric conditions and one having reduced atmospheric pollutants due to COVID-19 restrictions, both affected by a free tropospheric dust layer), we revealed negligible differences in terms of radiative effect, of the order of +2.6% (SWBOA, cooling behavior) and +1.9% (LWBOA, heating behavior). Moreover, the net heating rate (HR) at the bottom of the atmosphere (BOA) was equal to +0.156 K/d and equal to +2.543 K/d within 1–6 km due to the presence of the dust layer at that height. On the contrary, the reduction in atmospheric pollutants could lead to a negative HR (−0.036 K/d) at the bottom of the atmosphere (BOA) if dust aerosols were absent, while typical atmospheric conditions are estimated to have an almost zero net HR value (+0.006 K/d). The NMMB-BSC forecast model provided the dust mass concentration over Athens, while the air mass advection from the African to the European continent was simulated by the Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) model.
Self-Organization through the Inner Heliosphere: Insights from Parker Solar Probe
Authors: Stumpo Mirko , Quattrociocchi Virgilio , Benella Simone , Alberti Tommaso , Consolini Giuseppe
Published: March 2021

The interplanetary medium variability has been extensively studied by means of different approaches showing the existence of a wide variety of dynamical features, such as self-similarity, self-organization, turbulence and intermittency, and so on. Recently, by means of Parker solar probe measurements, it has been found that solar wind magnetic field fluctuations in the inertial range show a clear transition near 0.4 AU, both in terms of spectral features and multifractal properties. This breakdown of the scaling features has been interpreted as the evidence of a dynamical phase transition. Here, by using the Klimontovich S-theorem, we investigate how the process of self-organization is under way through the inner heliosphere, going deeper into the characterization of this dynamical phase transition by measuring the evolution of entropic-based measures through the inner heliosphere.
Use of an Extra-Tympanic Membrane Electrode to Record Cochlear Microphonics with Click, Tone Burst and Chirp Stimuli
Authors: Coraci Laura M. , Beynon Andy J.
Published: March 2021

This study determined electrocochleography (ECochG) parameter settings to obtain cochlear microphonics (CM) with less invasive flexible extra-tympanic membrane electrodes. In 24 adult normal-hearing subjects, CMs were elicited by presenting click stimuli at 100 dBnHL, tone bursts (2 kHz) and broadband (BB) CE-chirps® LS (Interacoustics, Middelfart, Denmark), both at 80 dBnHL. Different high-pass filters (HPFs) (3.3 Hz and 100 Hz, respectively) were used to investigate response quality of the CM. CMs were successfully obtained in 92–100% with click-, 75–83% with 2 kHz tone burst- and 58–63% with CE-chirp®-LS stimuli. Click stimuli elicited significantly larger CM amplitudes compared to 2 kHz tone bursts and BB CE-chirp® LS (Interacoustics, Middelfart, Denmark). No significant differences were found between the two different high-pass filter (HPF) settings. The present study shows that it is possible to obtain clear CMs with the flexible extra-tympanic membrane electrodes using click stimuli. In contrast to 2 kHz tone bursts and CE-chirp® (Interacoustics, Middelfart, Denmark) LS, clicks show a significantly higher success rate and are the preferred stimuli to confirm the presence or absence of CMs.
Nourin-Dependent miR-137 and miR-106b: Novel Early Inflammatory Diagnostic Biomarkers for Unstable Angina Patients
Authors: Elgebaly Salwa A. , Christenson Robert H. , Kandil Hossam , El-Khazragy Nashwa , Rashed Laila , Yacoub Beshoy , Eldeeb Heba , Ali Mahmoud , Sharafieh Roshanak , Klueh Ulrike , Kreutzer Donald L.
Published: March 2021

Background: Currently, no blood biomarkers exist that can diagnose unstable angina (UA) patients. Nourin is an early inflammatory mediator rapidly released within 5 min by reversible ischemic myocardium, and if ischemia persists, it is also released by necrosis. Nourin is elevated in acute coronary syndrome (ACS) patients but not in symptomatic noncardiac and healthy subjects. Recently, circulating microRNAs (miRNAs) have been established as markers of disease, including cardiac injury and inflammation. Objectives: To profile and validate the potential diagnostic value of Nourin-dependent miR-137 (marker of cell damage) and miR-106b-5p (marker of inflammation) as early biomarkers in suspected UA patients and to investigate the association of their target and regulating genes. Methods: Using Nourin amino acid sequence, an integrated bioinformatics analysis was conducted. Analysis indicated that Nourin is a direct target for miR-137 and miR-106b-5p in myocardial ischemic injury. Two linked molecular networks of lncRNA/miRNAs/mRNAs were also retrieved, including CTB89H12.4/miR-137/FTHL-17 and CTB89H12.4/miR-106b-5p/ANAPC11. Gene expression profiling was assessed in serum samples collected at presentation to an emergency department (ED) from: (1) UA patients (n = 30) (confirmed by invasive coronary angiography with stenosis greater than 50% and troponin level below the clinical decision limit); (2) patients with acute ST elevation myocardial infarction (STEMI) (n = 16) (confirmed by persistent ST-segment changes and elevated troponin level); and (3) healthy subjects (n = 16). Results: Gene expression profiles showed that miR-137 and miR-106b-5p were significantly upregulated by 1382-fold and 192-fold in UA compared to healthy, and by 2.5-fold and 4.6-fold in STEMI compared to UA, respectively. Healthy subjects showed minimal expression profile. Receiver operator characteristics (ROC) analysis revealed that the two miRNAs were sensitive and specific biomarkers for assessment of UA and STEMI patients. Additionally, Spearman’s correlation analysis revealed a significant association of miRNAs with the associated mRNA targets and the regulating lncRNA. Conclusions: Nourin-dependent gene expression of miR-137 and miR-106b-5p are novel blood-based biomarkers that can diagnose UA and STEMI patients at presentation and stratify severity of myocardial ischemia, with higher expression in STEMI compared to UA. Early diagnosis of suspected UA patients using the novel Nourin biomarkers is key for initiating guideline-based therapy that improves patients’ health outcomes.
Impacts of Maternal Diet and Alcohol Consumption during Pregnancy on Maternal and Infant Gut Microbiota
Authors: Wang Ying , Xie Tianqu , Wu Yinyin , Liu Yanqun , Zou Zhijie , Bai Jinbing
Published: March 2021

(1) Background: Maternal diet and alcohol consumption can influence both maternal and infant’s gut microbiota. These relationships are still not examined in the Chinese population. The purpose of this study was to explore the effect of alcohol consumption and maternal diet during pregnancy on maternal and infant’s gut microbiota. (2) Methods: Twenty-nine mother-child dyads were enrolled in central China. Fecal samples of mothers during late pregnancy and of newborns within 48 h were collected. The V3–V4 regions of 16S rRNA sequences were analyzed. A self-administrated questionnaire about simple diet frequency in the past week was completed by mothers before childbirth. The demographic information was finished by mothers at 24 h after childbirth. (3) Results: Among these 29 mothers, 10 mothers reported alcohol consumption during pregnancy. The PCoA (β-diversity) showed significant difference in maternal gut microbiota between the alcohol consumption group vs. the non-alcohol consumption group (abund-Jaccard, r = 0.2, p = 0.006). The same phenomenon was observed in newborns (unweighted-UniFrac full tree, r = 0.174, p = 0.031). Maternal alcohol consumption frequency showed positive associations with maternal Phascolarctobacterium (p = 0.032) and Blautia (p = 0.019); maternal Faecalibacterium (p = 0.013) was negatively correlated with frequency of alcohol consumption. As for newborns, a positive relationship showed between Megamonas (p = 0.035) and newborns with maternal alcohol consumption. The diet was not associated with both maternal and infant’s gut microbiota. (4) Conclusions: Maternal alcohol consumption during pregnancy influenced the gut microbiota on both mothers and the newborns. Future research is needed to explore these relationships in a lager birth cohort. Understanding the long-term effect of alcohol consumption on maternal and newborns’ gut microbiota is needed.
Obituary for Prof. Dr. Ulrich Siebenlist
Authors: Murphy Philip M. , Lenardo Michael J.
Published: March 2021

Ulrich Siebenlist, Ph [...]
Extended fMRI-Guided Anodal and Cathodal Transcranial Direct Current Stimulation Targeting Perilesional Areas in Post-Stroke Aphasia: A Pilot Randomized Clinical Trial
Authors: Cherney Leora R. , Babbitt Edna M. , Wang Xue , Pitts Laura L.
Published: March 2021

Transcranial direct current stimulation (tDCS) may enhance speech and language treatment (SLT) for stroke survivors with aphasia; however, to date, there is no standard protocol for the application of tDCS in post-stroke aphasia. We explored the safety and efficacy of fMRI-guided tDCS on functional language and cortical activity when delivered to the lesioned left hemisphere concurrently with SLT across an extended, six-week treatment period. Twelve persons with chronic, nonfluent aphasia following a single left-hemisphere stroke participated in the three-arm (anodal vs. cathodal vs. sham) single-blind, parallel, pilot trial. No serious adverse events occurred during 30 treatment sessions or in the following six weeks. All groups demonstrated functional language gains following intensive treatment; however, active tDCS resulted in greater gains in standardized, probe, and caregiver-reported measures of functional language than sham. Evidence declaring one polarity as superior for inducing language recovery was mixed. However, cathodal stimulation to the lesioned left hemisphere, expected to have a down-regulating effect, resulted in increased areas of cortical activation across both hemispheres, and specifically perilesionally. Generalization of these preliminary findings is limited; however, results are nevertheless compelling that tDCS combined with SLT can be safely applied across extended durations, with the potential to enhance functional language and cortical activation for persons with aphasia.
Higher Cognitive Reserve Is Associated with Better Working Memory Performance and Working-Memory-Related P300 Modulation
Authors: Gutiérrez-Zamora Velasco Gabriela , Fernández Thalía , Silva-Pereyra Juan , Reynoso-Alcántara Vicenta , Castro-Chavira Susana
Published: March 2021

This study aims to examine how two levels of cognitive reserve, as evidenced by reading syntactic skill, modify performance and neural activity in a two-load-level (high vs. low) working memory (WM) task. Two groups of participants with different reading skills, high and low, were obtained from clustering analysis. We collected the P300 event-related potential component during the performance of the WM Sternberg task. The high reading performance (HRP) group showed a higher percentage of correct answers than the low reading performance (LRP) group in the negative probes of the WM task, which were probe stimuli not included in the memory set presented immediately before. Both groups showed P300 amplitude modulations, that is, larger WM-related P300 amplitudes for low than for high WM loads. Following the behavioral results, the HRP group displayed smaller WM-related amplitude modulations than the LRP group in the negative probes. The findings together suggest that higher levels of reading skill are associated with improved neural efficiency, which reflects in a better working memory performance.
The Synergism between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia
Authors: Gaidano Valentina , Houshmand Mohammad , Vitale Nicoletta , Carrà Giovanna , Morotti Alessandro , Tenace Valerio , Rapelli Stefania , Sainas Stefano , Pippione Agnese Chiara , Giorgis Marta , Boschi Donatella , Lolli Marco Lucio , Cilloni Daniela , Cignetti Alessandro , Saglio Giuseppe , Circosta Paola
Published: March 2021

Dihydroorotate Dehydrogenase (DHODH) is a key enzyme of the de novo pyrimidine biosynthesis, whose inhibition can induce differentiation and apoptosis in acute myeloid leukemia (AML). DHODH inhibitors had shown promising in vitro and in vivo activity on solid tumors, but their effectiveness was not confirmed in clinical trials, probably because cancer cells exploited the pyrimidine salvage pathway to survive. Here, we investigated the antileukemic activity of MEDS433, the DHODH inhibitor developed by our group, against AML. Learning from previous failures, we mimicked human conditions (performing experiments in the presence of physiological uridine plasma levels) and looked for synergic combinations to boost apoptosis, including classical antileukemic drugs and dipyridamole, a blocker of the pyrimidine salvage pathway. MEDS433 induced apoptosis in multiple AML cell lines, not only as a consequence of differentiation, but also directly. Its combination with antileukemic agents further increased the apoptotic rate, but when experiments were performed in the presence of physiological uridine concentrations, results were less impressive. Conversely, the combination of MEDS433 with dipyridamole induced metabolic lethality and differentiation in all AML cell lines; this extraordinary synergism was confirmed on AML primary cells with different genetic backgrounds and was unaffected by physiological uridine concentrations, predicting in human activity.
Obesity-Activated Lung Stromal Cells Promote Myeloid Lineage Cell Accumulation and Breast Cancer Metastasis
Authors: Hillers-Ziemer Lauren E. , Williams Abbey E. , Janquart Amanda , Grogan Caitlin , Thompson Victoria , Sanchez Adriana , Arendt Lisa M.
Published: March 2021

Obesity is correlated with increased incidence of breast cancer metastasis; however, the mechanisms underlying how obesity promotes metastasis are unclear. In a diet-induced obese mouse model, obesity enhanced lung metastasis in both the presence and absence of primary mammary tumors and increased recruitment of myeloid lineage cells into the lungs. In the absence of tumors, obese mice demonstrated increased numbers of myeloid lineage cells and elevated collagen fibers within the lung stroma, reminiscent of premetastatic niches formed by primary tumors. Lung stromal cells isolated from obese tumor-naïve mice showed increased proliferation, contractility, and expression of extracellular matrix, inflammatory markers and transforming growth factor beta-1 (TGFβ1). Conditioned media from lung stromal cells from obese mice promoted myeloid lineage cell migration in vitro in response to colony-stimulating factor 2 (CSF2) expression and enhanced invasion of tumor cells. Together, these results suggest that prior to tumor formation, obesity alters the lung microenvironment, creating niches conducive to metastatic growth.
Osteopontin Blockade Immunotherapy Increases Cytotoxic T Lymphocyte Lytic Activity and Suppresses Colon Tumor Progression
Authors: Klement John D. , Poschel Dakota B. , Lu Chunwan , Merting Alyssa D. , Yang Dafeng , Redd Priscilla S. , Liu Kebin
Published: March 2021

Human colorectal cancers are mostly microsatellite-stable with no response to anti-PD-1 blockade immunotherapy, necessitating the development of a new immunotherapy. Osteopontin (OPN) is elevated in human colorectal cancer and may function as an immune checkpoint. We aimed at elucidating the mechanism of action of OPN and determining the efficacy of OPN blockade immunotherapy in suppression of colon cancer. We report here that OPN is primarily expressed in tumor cells, myeloid cells, and innate lymphoid cells in human colorectal carcinoma. Spp1 knock out mice exhibit a high incidence and fast growth rate of carcinogen-induced tumors. Knocking out Spp1 in colon tumor cells increased tumor-specific CTL cytotoxicity in vitro and resulted in decreased tumor growth in vivo. The OPN protein level is elevated in the peripheral blood of tumor-bearing mice. We developed four OPN neutralization monoclonal antibodies based on their efficacy in blocking OPN inhibition of T cell activation. OPN clones 100D3 and 103D6 increased the efficacy of tumor-specific CTLs in killing colon tumor cells in vitro and suppressed colon tumor growth in tumor-bearing mice in vivo. Our data indicate that OPN blockade immunotherapy with 100D3 and 103D6 has great potential to be further developed for colorectal cancer immunotherapy and for rendering a colorectal cancer response to anti-PD-1 immunotherapy.
Fertility-Sparing Surgery in Gynecologic Cancer: A Systematic Review
Authors: Schuurman Teska , Zilver Sanne , Samuels Sanne , Schats Winnie , Amant Frédéric , van Trommel Nienke , Lok Christianne
Published: March 2021

Fertility-sparing surgery (FSS) is increasingly being offered to women with a gynecological malignancy who wish to preserve fertility. In this systematic review, we evaluate the best evidence currently available on oncological and reproductive outcome after FSS for early stage cervical cancer, epithelial ovarian cancer, and endometrial cancer. An extensive literature search was conducted using the electronic databases Medline (OVID), Embase, and Cochrane Library to identify eligible studies published up to December 2020. In total, 153 studies were included with 7544, 3944, and 1229 patients who underwent FSS for cervical, ovarian, and endometrial cancer, respectively. We assessed the different FSS techniques that are available to preserve fertility, i.e., omitting removal of the uterine body and preserving at least one ovary. Overall, recurrence rates after FSS are reassuring and therefore, these conservative procedures seem oncologically safe in the current selection of patients with low-stage and low-grade disease. However, generalized conclusions should be made with caution due to the methodology of available studies, i.e., mostly retrospective cohort studies with a heterogeneous patient population, inducing selection bias. Moreover, about half of patients do not pursue pregnancy despite FSS and the reasons for these decisions have not yet been well studied. International collaboration will facilitate the collection of solid evidence on FSS and the related decision-making process to optimize patient selection and counseling.
Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo
Authors: De Oliveira Tiago , Goldhardt Tina , Edelmann Marcus , Rogge Torben , Rauch Karsten , Kyuchukov Nikola Dobrinov , Menck Kerstin , Bleckmann Annalen , Kalucka Joanna , Khan Shawez , Gaedcke Jochen , Haubrock Martin , Beissbarth Tim , Bohnenberger Hanibal , Planque Mélanie , Fendt Sarah-Maria , Ackermann Lutz , Ghadimi Michael , Conradi Lena-Christin
Published: March 2021

Background: Despite substantial progress made in the last decades in colorectal cancer (CRC) research, new treatment approaches are still needed to improve patients’ long-term survival. To date, the promising strategy to target tumor angiogenesis metabolically together with a sensitization of CRC to chemo- and/or radiotherapy by PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) inhibition has never been tested. Therefore, initial evaluation and validation of newly developed compounds such as KAN0438757 and their effects on CRC cells are crucial steps preceding to in vivo preclinical studies, which in turn may consolidate new therapeutic targets. Materials and Methods: The efficiency of KAN0438757 to block PFKFB3 expression and translation in human CRC cells was evaluated by immunoblotting and real-time PCR. Functional in vitro assays assessed the effects of KAN0438757 on cell viability, proliferation, survival, adhesion, migration and invasion. Additionally, we evaluated the effects of KAN0438757 on matched patient-derived normal and tumor organoids and its systemic toxicity in vivo in C57BL6/N mice. Results: High PFKFB3 expression is correlated with a worse survival in CRC patients. KAN0438757 reduces PFKFB3 protein expression without affecting its transcriptional regulation. Additionally, a concentration-dependent anti-proliferative effect was observed. The migration and invasion capacity of cancer cells were significantly reduced, independent of the anti-proliferative effect. When treating colonic patient-derived organoids with KAN0438757 an impressive effect on tumor organoids growth was apparent, surprisingly sparing normal colonic organoids. No high-grade toxicity was observed in vivo. Conclusion: The PFKFB3 inhibitor KAN0438757 significantly reduced CRC cell migration, invasion and survival. Moreover, on patient-derived cancer organoids KAN0438757 showed significant effects on growth, without being overly toxic in normal colon organoids and healthy mice. Our findings strongly encourage further translational studies to evaluate KAN0438757 in CRC therapy.
FLASH Proton Pencil Beam Scanning Irradiation Minimizes Radiation-Induced Leg Contracture and Skin Toxicity in Mice
Authors: Cunningham Shannon , McCauley Shelby , Vairamani Kanimozhi , Speth Joseph , Girdhani Swati , Abel Eric , Sharma Ricky A. , Perentesis John P. , Wells Susanne I. , Mascia Anthony , Sertorio Mathieu
Published: March 2021

Ultra-high dose rate radiation has been reported to produce a more favorable toxicity and tumor control profile compared to conventional dose rates that are used for patient treatment. So far, the so-called FLASH effect has been validated for electron, photon and scattered proton beam, but not yet for proton pencil beam scanning (PBS). Because PBS is the state-of-the-art delivery modality for proton therapy and constitutes a wide and growing installation base, we determined the benefit of FLASH PBS on skin and soft tissue toxicity. Using a pencil beam scanning nozzle and the plateau region of a 250 MeV proton beam, a uniform physical dose of 35 Gy (toxicity study) or 15 Gy (tumor control study) was delivered to the right hind leg of mice at various dose rates: Sham, Conventional (Conv, 1 Gy/s), Flash60 (57 Gy/s) and Flash115 (115 Gy/s). Acute radiation effects were quantified by measurements of plasma and skin levels of TGF-β1 and skin toxicity scoring. Delayed irradiation response was defined by hind leg contracture as a surrogate of irradiation-induced skin and soft tissue toxicity and by plasma levels of 13 different cytokines (CXCL1, CXCL10, Eotaxin, IL1-beta, IL-6, MCP-1, Mip1alpha, TNF-alpha, TNF-beta, VEGF, G-CSF, GM-CSF and TGF- β1). Plasma and skin levels of TGF-β1, skin toxicity and leg contracture were all significantly decreased in FLASH compared to Conv groups of mice. FLASH and Conv PBS had similar efficacy with regards to growth control of MOC1 and MOC2 head and neck cancer cells transplanted into syngeneic, immunocompetent mice. These results demonstrate consistent delivery of FLASH PBS radiation from 1 to 115 Gy/s in a clinical gantry. Radiation response following delivery of 35 Gy indicates potential benefits of FLASH versus conventional PBS that are related to skin and soft tissue toxicity.
Identification of Novel Transcriptome Signature as a Potential Prognostic Biomarker for Anti-Angiogenic Therapy in Glioblastoma Multiforme
Authors: Zheng Shuhua , Tao Wensi
Published: March 2021

Glioblastoma multiforme (GBM) is the most common and devastating type of primary brain tumor, with a median survival time of only 15 months. Having a clinically applicable genetic biomarker would lead to a paradigm shift in precise diagnosis, personalized therapeutic decisions, and prognostic prediction for GBM. Radiogenomic profiling connecting radiological imaging features with molecular alterations will offer a noninvasive method for genomic studies of GBM. To this end, we analyzed over 3800 glioma and GBM cases across four independent datasets. The Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases were employed for RNA-Seq analysis, whereas the Ivy Glioblastoma Atlas Project (Ivy-GAP) and The Cancer Imaging Archive (TCIA) provided clinicopathological data. The Clinical Proteomic Tumor Analysis Consortium Glioblastoma Multiforme (CPTAC-GBM) was used for proteomic analysis. We identified a simple three-gene transcriptome signature—SOCS3, VEGFA, and TEK—that can connect GBM’s overall prognosis with genes’ expression and simultaneously correlate radiographical features of perfusion imaging with SOCS3 expression levels. More importantly, the rampant development of neovascularization in GBM offers a promising target for therapeutic intervention. However, treatment with bevacizumab failed to improve overall survival. We identified SOCS3 expression levels as a potential selection marker for patients who may benefit from early initiation of angiogenesis inhibitors.
The Multifaceted Roles of EGFL7 in Cancer and Drug Resistance
Authors: Heissig Beate , Salama Yousef , Takahashi Satoshi , Okumura Ko , Hattori Koichi
Published: March 2021

Invasion of cancer cells into surrounding tissue and the vasculature is an important step for tumor progression and the establishment of distant metastasis. The extracellular matrix (ECM) is home to many biomolecules that support new vessel formation and cancer growth. Endothelial cells release growth factors such as epidermal growth factor-like protein-7 (EGFL7), which contributes to the formation of the tumor vasculature. The signaling axis formed by EGFL7 and one of its receptors, beta 3 integrin, has emerged as a key mediator in the regulation of tumor metastasis and drug resistance. Here we summarize recent studies on the role of the ECM-linked angiocrine factor EGFL7 in primary tumor growth, neoangiogenesis, tumor metastasis by enhancing epithelial-mesenchymal transition, alterations in ECM rigidity, and drug resistance. We discuss its role in cellular adhesion and migration, vascular leakiness, and the anti-cancer response and provide background on its transcriptional regulation. Finally, we discuss its potential as a drug target as an anti-cancer strategy.
Immune Checkpoints Pathways in Head and Neck Squamous Cell Carcinoma
Authors: Veigas Florencia , Mahmoud Yamil D. , Merlo Joaquin , Rinflerch Adriana , Rabinovich Gabriel Adrian , Girotti María Romina
Published: March 2021

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors usually diagnosed at an advanced stage and characterized by a poor prognosis. The main risk factors associated with its development include tobacco and alcohol consumption and Human Papillomavirus (HPV) infections. The immune system has a significant role in the oncogenesis and evolution of this cancer type. Notably, the immunosuppressive tumor microenvironment triggers immune escape through several mechanisms. The improved understanding of the antitumor immune response in solid tumors and the role of the immune checkpoint molecules and other immune regulators have led to the development of novel therapeutic strategies that revolutionized the clinical management of HNSCC. However, the limited overall response rate to immunotherapy urges identifying predictive biomarkers of response and resistance to treatment. Here, we review the role of the immune system and immune checkpoint pathways in HNSCC, the most relevant clinical findings linked to immunotherapeutic strategies and predictive biomarkers of response and future treatment perspectives.
Statin Use Decreases the Risk of Metachronous Gastric Cancer in Patients without Helicobacter pylori Infection
Authors: Kwon Tae Jin , Kim Tae Jun , Lee Hyuk , Min Yang Won , Min Byung-Hoon , Lee Jun Haeng , Kim Jae J.
Published: March 2021

Previous studies have shown that statins reduce the risk of gastric cancer; however, their role has not been adequately studied in patients without Helicobacterpylori infection. We aimed to investigate whether statins reduced the risk of metachronous gastric cancer (GC) in H. pylori-negative patients who underwent endoscopic resection for early gastric cancer (EGC). Retrospective data of 2153 patients recruited between January 2007 and December 2016, with no H. pylori infection at baseline, who underwent resection for EGC, were analyzed. Metachronous GC was defined as a newly developed GC at least 1 year after endoscopic resection. Patients who used statins for at least 28 days during the follow-up period were considered as statin users. During a median follow-up of 5 years (interquartile range, 3.5–6.2), metachronous GC developed in 165 (7.6%) patients. In the multivariate Cox regression analysis, statin use was an independent factor associated with GC recurrence (adjusted hazard ratio (HR), 0.46; 95% confidence interval (CI), 0.26–0.82). Moreover, the risk of GC reduced with increasing duration (<3 years: HR 0.40, 95% CI 0.14–1.13; ≥3 years: HR 0.21, 95% CI 0.05–0.90; p trend = 0.011) and the dose of statin (cumulative defined daily dose (cDDD) < 500: HR 0.45, 95% CI 0.16–1.28; cDDD ≥ 500: HR 0.19, 95% CI 0.04–0.80; p trend = 0.008) in the propensity score-matched cohort. Statin use was associated with a lower risk of GC recurrence in H. pylori-negative patients with resected EGC in a dose-response relationship.
TRAF4/6 Is Needed for CD44 Cleavage and Migration via RAC1 Activation
Authors: Kolliopoulos Constantinos , Chatzopoulos Athanasios , Skandalis Spyros S. , Heldin Carl-Henrik , Heldin Paraskevi
Published: March 2021

The hyaluronan receptor CD44 can undergo proteolytic cleavage in two steps, leading to the release of its intracellular domain; this domain is translocated to the nucleus, where it affects the transcription of target genes. We report that CD44 cleavage in A549 lung cancer cells and other cells is promoted by transforming growth factor-beta (TGFβ) in a manner that is dependent on ubiquitin ligase tumor necrosis factor receptor-associated factor 4 or 6 (TRAF4 or TRAF6, respectively). Stem-like A549 cells grown in spheres displayed increased TRAF4-dependent expression of CD44 variant isoforms, CD44 cleavage, and hyaluronan synthesis. Mechanistically, TRAF4 activated the small GTPase RAC1. CD44-dependent migration of A549 cells was inhibited by siRNA-mediated knockdown of TRAF4, which was rescued by the transfection of a constitutively active RAC1 mutant. Our findings support the notion that TRAF4/6 mediates pro-tumorigenic effects of CD44, and suggests that inhibitors of CD44 signaling via TRAF4/6 and RAC1 may be beneficial in the treatment of tumor patients.
Current Trends and Characteristics of Hepatocellular Carcinoma in Patients with Autoimmune Liver Diseases
Authors: Rigopoulou Eirini I. , Dalekos George N.
Published: March 2021

Hepatocellular carcinoma (HCC), the commonest among liver cancers, is one of the leading causes of mortality among malignancies worldwide. Several reports demonstrate autoimmune liver diseases (AILDs), including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) to confer increased risk of hepatobiliary malignancies, albeit at lower frequencies compared to other liver diseases. Several parameters have been recognized as risk factors for HCC development in AIH and PBC, including demographics such as older age and male sex, clinical features, the most decisive being cirrhosis and other co-existing factors, such as alcohol consumption. Moreover, biochemical activity and treatment response have been increasingly recognized as prognostic factors for HCC development in AIH and PBC. As available treatment modalities are effective only when HCC diagnosis is established early, surveillance has been proven essential for HCC prognosis. Considering that the risk for HCC is not uniform between and within disease groups, refinement of screening strategies according to prevailing demographic, clinical, and molecular risk factors is mandated in AILDs patients, as personalized HCC risk prediction will offer significant advantage in patients at high and/or medium risk. Furthermore, future investigations should draw attention to whether modification of immunosuppression could benefit AIH patients after HCC diagnosis.
Genomic Signature of Oral Squamous Cell Carcinomas from Non-Smoking Non-Drinking Patients
Authors: Koo Kendrick , Mouradov Dmitri , Angel Christopher M. , Iseli Tim A. , Wiesenfeld David , McCullough Michael J. , Burgess Antony W. , Sieber Oliver M.
Published: March 2021

Molecular alterations in 176 patients with oral squamous cell carcinomas (OSCC) were evaluated to delineate differences in non-smoking non-drinking (NSND) patients. Somatic mutations and DNA copy number variations (CNVs) in a 68-gene panel and human papilloma virus (HPV) status were interrogated using targeted next-generation sequencing. In the entire cohort, TP53 (60%) and CDKN2A (24%) were most frequently mutated, and the most common CNVs were EGFR amplifications (9%) and deletions of BRCA2 (5%) and CDKN2A (4%). Significant associations were found for TP53 mutation and nodal disease, lymphovascular invasion and extracapsular spread, CDKN2A mutation or deletion with advanced tumour stage, and EGFR amplification with perineural invasion and extracapsular spread. PIK3CA mutation, CDKN2A deletion, and EGFR amplification were associated with worse survival in univariate analyses (p < 0.05 for all comparisons). There were 59 NSND patients who tended to be female and older than patients who smoke and/or drink, and showed enrichment of CDKN2A mutations, EGFR amplifications, and BRCA2 deletions (p < 0.05 for all comparisons), with a younger subset showing higher mutation burden. HPV was detected in three OSCC patients and not associated with smoking and drinking habits. NSND OSCC exhibits distinct genomic profiles and further exploration to elucidate the molecular aetiology in these patients is warranted.
Angiogenesis in the Normal Adrenal Fetal Cortex and Adrenocortical Tumors
Authors: Pereira Sofia S. , Oliveira Sofia , Monteiro Mariana P. , Pignatelli Duarte
Published: March 2021

Angiogenesis plays an important role in several physiological and pathological processes. Pharmacological angiogenesis modulation has been robustly demonstrated to achieve clinical benefits in several cancers. Adrenocortical carcinomas (ACC) are rare tumors that often have a poor prognosis. In addition, therapeutic options for ACC are limited. Understanding the mechanisms that regulate adrenocortical angiogenesis along the embryonic development and in ACC could provide important clues on how these processes could be pharmacologically modulated for ACC treatment. In this report, we performed an integrative review on adrenal cortex angiogenesis regulation in physiological conditions and ACC. During embryonic development, adrenal angiogenesis is regulated by both VEGF and Ang-Tie signaling pathways. In ACC, early research efforts were focused on VEGF signaling and this pathway was identified as a good prognostic factor and thus a promising therapeutic target. However, every clinical trial so far conducted in ACC using VEGF pathway- targeting drugs, alone or in combination, yielded disappointing results. In contrast, although the Ang-Tie pathway has been pointed out as an important regulator of fetal adrenocortical angiogenesis, its role is yet to be explored in ACC. In the future, further research on the role and efficacy of modulating both Ang-Tie and VEGF pathways in ACC is needed.
Engineering and Performance of Ruthenium Complexes Immobilized on Mesoporous Siliceous Materials as Racemization Catalysts
Authors: Heba Monika , Stradomska Dominika , Szymańska Katarzyna , Jarzębski Andrzej , Ambroziak Krzysztof , Masternak Monika , Kolanowska Anna , Pudło Wojciech , Kuźnik Nikodem
Published: March 2021

Dynamic kinetic resolution (DKR) is one of the most attractive routes to enantioselective synthesis, and ruthenium complexes are often applied as racemization catalysts. Two substituted cyclopentadienyl ruthenium complexes were immobilized covalently and non-covalently on mesoporous silica of mesocellular foam (MCF) and Santa Barbara Amorphous (SBA)-15 type functionalized with a 3 carbon spacer and 4-(chloromethyl)-N-amidobenzoate moiety. The catalysts were studied in a model reaction of secondary alcohol racemization. The immobilization decreased catalyst activity, considerably more for SBA-15 than for MCFs, and complete racemization of 1-phenylethanol was achieved within 24 h with the MCF-supported catalyst. The catalyst could be recovered and reused, thus paving the way for further development of the DKR process. The synthesized materials were fully characterized by Fourier-transform infrared spectroscopy analysis, thermogravimetry analysis, inductively cou-pled plasma optical emission spectrometry, and nitrogen adsorption at 77 K.