bluuebunny/crossref_metadata_2025 huggingface dataset:
Mesenchymal stem cell transplantation after acute myocardial infarction: a meta-analysis of clinical trials
Authors: Attar Armin , Bahmanzadegan Jahromi Fateme , Kavousi Shahin , Monabati Ahmad , Kazemi Asma
Published: December 2021

Background

Trials investigating the role of mesenchymal stem cells (MSCs) in increasing ejection fraction (LVEF) after acute myocardial infarction (AMI) have raised some controversies. This study was conducted to find whether transplantation of MSCs after AMI can help improve myocardial performance indices or clinical outcomes.

Methods

Randomized trials which evaluated transplantation of MSCs after AMI were enrolled. The primary outcome was LVEF change. We also assessed the role of cell origin, cell number, transplantation time interval after AMI, and route of cell delivery on the primary outcome.

Results

Thirteen trials including 956 patients (468 and 488 in the intervention and control arms) were enrolled. After excluding the biased data, LVEF was significantly increased compared to the baseline among those who received MSC (WMD = 3.78%, 95% CI: 2.14 to 5.42, p < 0.001, I2 = 90.2%) with more pronounced effect if the transplantation occurred within the first week after AMI (MD = 5.74%, 95%CI: 4.297 to 7.183; I2 = 79.2% p < 0.001). The efficacy of trans-endocardial injection was similar to that of intracoronary infusion (4% [95%CI: 2.741 to 5.259, p < 0.001] vs. 3.565% [95%CI: 1.912 to 5.218, p < 0.001], respectively). MSC doses of lower and higher than 107 cells did not improve LVEF differently (5.24% [95%CI: 2.06 to 8.82, p = 0.001] vs. 3.19% [95%CI: 0.17 to 6.12, p = 0.04], respectively).

Conclusion

Transplantation of MSCs after AMI significantly increases LVEF, showing a higher efficacy if done in the first week. Further clinical studies should be conducted to investigate long-term clinical outcomes such as heart failure and cardiovascular mortality.
Co-administration of human MSC overexpressing HIF-1α increases human CD34+ cell engraftment in vivo
Authors: Preciado Silvia , Sirerol-Piquer Mª Salomé , Muntión Sandra , Osugui Lika , Martí-Chillón Gerardo J. , Navarro-Bailón Almudena , Sepúlveda Pilar , Sánchez-Guijo Fermín
Published: December 2021

Background

Poor graft function or graft failure after allogeneic stem cell transplantation is an unmet medical need, in which mesenchymal stromal cells (MSC) constitute an attractive potential therapeutic approach. Hypoxia-inducible factor-1α (HIF-1α) overexpression in MSC (HIF-MSC) potentiates the angiogenic and immunomodulatory properties of these cells, so we hypothesized that co-transplantation of MSC-HIF with CD34+ human cord blood cells would also enhance hematopoietic stem cell engraftment and function both in vitro and in vivo.

Methods

Human MSC were obtained from dental pulp. Lentiviral overexpression of HIF-1α was performed transducing cells with pWPI-green fluorescent protein (GFP) (MSC WT) or pWPI-HIF-1α-GFP (HIF-MSC) expression vectors. Human cord blood CD34+ cells were co-cultured with MSC WT or HIF-MSC (4:1) for 72 h. Then, viability (Annexin V and 7-AAD), cell cycle, ROS expression and immunophenotyping of key molecules involved in engraftment (CXCR4, CD34, ITGA4, c-KIT) were evaluated by flow cytometry in CD34+ cells. In addition, CD34+ cells clonal expansion was analyzed by clonogenic assays. Finally, in vivo engraftment was measured by flow cytometry 4-weeks after CD34+ cell transplantation with or without intrabone MSC WT or HIF-MSC in NOD/SCID mice.

Results

We did not observe significant differences in viability, cell cycle and ROS expression between CD34+ cells co-cultured with MSC WT or HIF-MSC. Nevertheless, a significant increase in CD34, CXCR4 and ITGA4 expression (p = 0.009; p = 0.001; p = 0.013, respectively) was observed in CD34+ cells co-cultured with HIF-MSC compared to MSC WT. In addition, CD34+ cells cultured with HIF-MSC displayed a higher CFU-GM clonogenic potential than those cultured with MSC WT (p = 0.048). We also observed a significant increase in CD34+ cells engraftment ability when they were co-transplanted with HIF-MSC compared to CD34+ co-transplanted with MSC WT (p = 0.016) or alone (p = 0.015) in both the injected and contralateral femurs (p = 0.024, p = 0.008 respectively).

Conclusions

Co-transplantation of human CD34+ cells with HIF-MSC enhances cell engraftment in vivo. This is probably due to the ability of HIF-MSC to increase clonogenic capacity of hematopoietic cells and to induce the expression of adhesion molecules involved in graft survival in the hematopoietic niche.
Splitting chemical structure data sets for federated privacy-preserving machine learning
Authors: Simm Jaak , Humbeck Lina , Zalewski Adam , Sturm Noe , Heyndrickx Wouter , Moreau Yves , Beck Bernd , Schuffenhauer Ansgar
Published: December 2021

With the increase in applications of machine learning methods in drug design and related fields, the challenge of designing sound test sets becomes more and more prominent. The goal of this challenge is to have a realistic split of chemical structures (compounds) between training, validation and test set such that the performance on the test set is meaningful to infer the performance in a prospective application. This challenge is by its own very interesting and relevant, but is even more complex in a federated machine learning approach where multiple partners jointly train a model under privacy-preserving conditions where chemical structures must not be shared between the different participating parties. In this work we discuss three methods which provide a splitting of a data set and are applicable in a federated privacy-preserving setting, namely: a. locality-sensitive hashing (LSH), b. sphere exclusion clustering, c. scaffold-based binning (scaffold network). For evaluation of these splitting methods we consider the following quality criteria (compared to random splitting): bias in prediction performance, classification label and data imbalance, similarity distance between the test and training set compounds. The main findings of the paper are a. both sphere exclusion clustering and scaffold-based binning result in high quality splitting of the data sets, b. in terms of compute costs sphere exclusion clustering is very expensive in the case of federated privacy-preserving setting.
Co-dimension two bifurcations analysis of a delayed tumor model with Allee effect
Authors: Dai Qinrui
Published: December 2021

The mathematical model has become an important means to study tumor treatment and has developed with the discovery of medical phenomena. In this paper, we establish a delayed tumor model, in which the Allee effect is considered. Different from the previous similar tumor models, this model is mainly studied from the point of view of stability and co-dimension two bifurcations, and some nontrivial phenomena and conclusions are obtained. By calculation, there are at most two positive equilibria in the system, and their stability is investigated. Based on these, we find that the system undergoes Bautin bifurcation, zero-Hopf bifurcation, and Hopf–Hopf bifurcation with time delay and tumor growth rate as bifurcation parameters. The interesting thing is that there is a Zero-Hopf bifurcation, which is not common in tumor models, making abundant dynamic phenomena appear in the system. By using the bifurcation theory of functional differential equations, we calculate the normal form of these Co-dimension two bifurcations. Finally, with the aid of MATLAB package DDE-BIFTOOL, some numerical simulations have been performed to support our theoretical results. In particular, we obtain the bifurcation diagram of the system in the two parameter plane and divide its regions according to the bifurcation curves. Meanwhile, the phenomena of multistability and periodic coexistence of some regions can be also demonstrated. Combined with the simulation results, we can know that when the tumor growth rate and the delay of immune cell apoptosis are small, the tumor may tend to be stable, and vice versa.
GR-mediated transcriptional regulation of m6A metabolic genes contributes to diet-induced fatty liver in hens
Authors: Feng Yue , Li Yanlin , Jiang Wenduo , Hu Yun , Jia Yimin , Zhao Ruqian
Published: December 2021

Background

Glucocorticoid receptor (GR) mediated corticosterone-induced fatty liver syndrome (FLS) in the chicken by transactivation of Fat mass and obesity associated gene (FTO), leading to demethylation of N6-methyladenosine (m6A) and post-transcriptional activation of lipogenic genes. Nutrition is considered the main cause of FLS in the modern poultry industry. Therefore, this study was aimed to investigate whether GR and m6A modification are involved in high-energy and low protein (HELP) diet-induced FLS in laying hens, and if true, what specific m6A sites of lipogenic genes are modified and how GR mediates m6A-dependent lipogenic gene activation in HELP diet-induced FLS in the chicken.

Results

Laying hens fed HELP diet exhibit excess (P < 0.05) lipid accumulation and lipogenic genes activation in the liver, which is associated with significantly increased (P < 0.05) GR expression that coincided with global m6A demethylation. Concurrently, the m6A demethylase FTO is upregulated (P < 0.05), whereas the m6A reader YTHDF2 is downregulated (P < 0.05) in the liver of FLS chickens. Further analysis identifies site-specific demethylation (P < 0.05) of m6A in the mRNA of lipogenic genes, including FASN, SREBP1 and SCD. Moreover, GR binding to the promoter of FTO gene is highly enriched (P < 0.05), while GR binding to the promoter of YTHDF2 gene is diminished (P < 0.05).

Conclusions

These results implicate a possible role of GR-mediated transcriptional regulation of m6A metabolic genes on m6A-depenent post-transcriptional activation of lipogenic genes and shed new light in the molecular mechanism of FLS etiology in the chicken.
Performance-efficient distributed transfer and transformation of big spatial histopathology datasets in the cloud
Authors: Yildirim Esma
Published: December 2021

Whole Slide Image (WSI) datasets are giga-pixel resolution, unstructured histopathology datasets that consist of extremely big files (each can be as large as multiple GBs in compressed format). These datasets have utility in a wide range of diagnostic and investigative pathology applications. However, the datasets present unique challenges: The size of the files, propriety data formats, and lack of efficient parallel data access libraries limit the scalability of these applications. Commercial clouds provide dynamic, cost-effective, scalable infrastructure to process these datasets, however, we lack the tools and algorithms that will transfer/transform them onto the cloud seamlessly, providing faster speeds and scalable formats. In this study, we present novel algorithms that transfer these datasets onto the cloud while at the same time transforming them into symmetric scalable formats. Our algorithms use intelligent file size distribution, and pipelining transfer and transformation tasks without introducing extra overhead to the underlying system. The algorithms, tested in the Amazon Web Services (AWS) cloud, outperform the widely used transfer tools and algorithms, and also outperform our previous work. The data access to the transformed datasets provides better performance compared to the related work. The transformed symmetric datasets are fed into three different analytics applications: a distributed implementation of a content-based image retrieval (CBIR) application for prostate carcinoma datasets, a deep convolutional neural network application for classification of breast cancer datasets, and to show that the algorithms can work with any spatial dataset, a Canny Edge Detection application on satellite image datasets. Although different in nature, all of the applications can easily work with our new symmetric data format and performance results show near-linear speed-ups as the number of processors increases.
Dynamic order Markov model for categorical sequence clustering
Authors: Chen Rongbo , Sun Haojun , Chen Lifei , Zhang Jianfei , Wang Shengrui
Published: December 2021

Markov models are extensively used for categorical sequence clustering and classification due to their inherent ability to capture complex chronological dependencies hidden in sequential data. Existing Markov models are based on an implicit assumption that the probability of the next state depends on the preceding context/pattern which is consist of consecutive states. This restriction hampers the models since some patterns, disrupted by noise, may be not frequent enough in a consecutive form, but frequent in a sparse form, which can not make use of the information hidden in the sequential data. A sparse pattern corresponds to a pattern in which one or some of the state(s) between the first and last one in the pattern is/are replaced by wildcard(s) that can be matched by a subset of values in the state set. In this paper, we propose a new model that generalizes the conventional Markov approach making it capable of dealing with the sparse pattern and handling the length of the sparse patterns adaptively, i.e. allowing variable length pattern with variable wildcards. The model, named Dynamic order Markov model (DOMM), allows deriving a new similarity measure between a sequence and a set of sequences/cluster. DOMM builds a sparse pattern from sub-frequent patterns that contain significant statistical information veiled by the noise. To implement DOMM, we propose a sparse pattern detector (SPD) based on the probability suffix tree (PST) capable of discovering both sparse and consecutive patterns, and then we develop a divisive clustering algorithm, named DMSC, for Dynamic order Markov model for categorical sequence clustering. Experimental results on real-world datasets demonstrate the promising performance of the proposed model.
Letter the editor: serious methodological concerns about a recently published meta-analysis on oxygen therapy
Authors: Klitgaard Thomas Lass , Schjørring Olav Lilleholt , Nielsen Frederik Mølgaard , Meyhoff Christian Sylvest , Barbateskovic Marija , Wetterslev Jørn , Perner Anders , Rasmussen Bodil Steen
Published: December 2021

In a recent paper, Chen et al. report the findings of a systematic review with meta-analysis concerning conservative versus conventional oxygen therapy for critically ill patients. We wish to commend the authors for their interest in the matter. However, the authors appear to misquote findings, fail to report results for all specified analyses, do not identify all relevant trials, have post hoc changed the eligibility criteria, and have seemingly switched directions of effects in analyses of secondary outcomes. These issues have led to incorrect conclusions concerning the effects of targeted oxygen therapy in critically ill patients.
Automated alert and activation of medical emergency team using early warning score
Authors: Na Soo Jin , Ko Ryoung-Eun , Ko Myeong Gyun , Jeon Kyeongman
Published: December 2021

Background

Timely recognition of warning signs from deteriorating patients and proper treatment are important in improving patient safety. In comparison to the traditional medical emergency team (MET) activation triggered by phone calls, automated activation of MET may minimize activation delays. However, limited data are available on the effects of automated activation systems on the time from derangement to MET activation and on clinical outcomes. The objective of this study was to determine the impact of an automated alert and activation system for MET on clinical outcomes in unselected hospitalized patients.

Methods

This is an observational study using prospectively collected data from consecutive patients managed by the MET at a university-affiliated, tertiary hospital from March 2013 to December 2019. The automated alert system automatically calculates the Modified Early Warning Score (MEWS) and subsequently activates MET when the MEWS score is 7 or higher, which was implemented since August 2016. The outcome measures of interest including hospital mortality in patients with MEWS of 7 or higher were compared between pre-implementation and post-implementation groups of the automated alert and activation system in the primary analysis. The association between the implementation of the system and hospital mortality was evaluated with logistic regression analysis.

Results

Of the 7678 patients who were managed by MET during the study period, 639 patients during the pre-implementation period and 957 patients during the post-implementation period were included in the primary analysis. MET calls due to abnormal physiological variables were more common during the pre-implementation period, while MET calls due to medical staff’s worries or concern about the patient’s condition were more common during the post-implementation period. The median time from deterioration to MET activation was significantly shortened in the post-implementation period compared to the pre-implementation period (34 min vs. 60 min, P < 0.001). In addition, unplanned ICU admission rates (41.2% vs. 71.8%, P < 0.001) was reduced during the post-implementation period. Hospital mortality was decreased after implementation of the automated alert system (27.2% vs. 38.5%, P < 0.001). The implementation of the automated alert and activation system was associated with decreased risk of death in the multivariable analysis (adjusted OR 0.73, 95% CI 0.56–0.90).

Conclusions

After implementing an automated alert and activation system, the time from deterioration to MET activation was shortened and clinical outcomes were improved in hospitalized patients.
Sporadic E morphology based on COSMIC radio occultation data and its relationship with wind shear theory
Authors: Luo Jia , Liu Haifeng , Xu Xiaohua
Published: December 2021

The S4max data retrieved from the Constellation Observing System for the Meteorology, Ionosphere, and Climate (COSMIC) radio occultation (RO) measurements during 2007 to 2015 is adopted to investigate the global distribution and seasonal variation of the sporadic E (Es) layers in the present work. The long-term and short-term global Es occurrence maps are presented and the spatial and temporal distributions of Es occurrence rates (ORs) are further confirmed and studied. The International Geomagnetic Reference Field model (IGRF12) is used to calculate the horizontal intensity and inclination of the Earth’s magnetic field. The analysis shows that the Earth’s magnetic field is one of the fundamental reasons for the global distribution of the Es layers. In addition, the Horizontal Wind Field model HWM14 and the IGRF12 model were employed to calculate the vertical ion convergence (VIC) to examine the role of neutral wind shear in the global distribution of the Es ORs. The results reveal that the middle latitude distribution of simulated vertical concentration of Fe+ is similar to that of Es ORs, which indicates that the VIC induced by the neutral wind shear is an important factor in determining the geographical distribution, summer maximum (or winter minimum) and diurnal characteristics of Es ORs in middle latitudes. The new findings mainly include the following two aspects: (1) in summer over mid-latitudes, VIC peaks in the morning and afternoon to evening, which explains the semidiurnal behavior of Es ORs; (2) VIC reaches its minimum value in low-altitude (100 km) areas, which is the reason for the significant decrease in Es ORs in low-altitude areas. The disagreements between the VIC and Es ORs indicate that other processes, such as the meteor influx rate, the ionospheric electric fields and atmospheric tides, should also be considered as they may have an important impact on the variation of Es layers.

Graphical Abstract
Small-scale analysis to rank municipalities requiring slow-moving landslide risk mitigation measures: the case study of the Calabria region (southern Italy)
Authors: Gullà Giovanni , Nicodemo Gianfranco , Ferlisi Settimio , Borrelli Luigi , Peduto Dario
Published: December 2021

This paper proposes a three-phase method that combines multi-source (i.e. topographic, thematic, monitoring) input data in a GIS environment to rank—at small (1:250,000) scale—administrative units (e.g. municipalities) based on their exposure to slow-moving landslide risk within a selected area (e.g. a region) and, accordingly, detect those primarily requiring mitigation measures. The method is applied in the Calabria region (southern Italy) where several municipalities are widely affected by slow-moving landslides that systematically cause damage to buildings and infrastructure networks resulting in significant economic losses. The results obtained are validated based on the information gathered from previous studies carried out at large (municipal) scale. The work undertaken represents a first, fundamental step of a wider circular approach that can profitably facilitate the decision makers in addressing the issue of the slow-moving landslide risk mitigation in a sustainable way.
Results on patient-reported outcomes are underreported in summaries of product characteristics for new drugs
Authors: Haag Susanne , Junge Lisa , Lotz Fabian , McGauran Natalie , Paulides Marios , Potthast Regine , Kaiser Thomas
Published: December 2021

Background

Summaries of product characteristics (SmPCs) are regulatory documents published upon drug approval. They should report all relevant study data and advise how to use drugs safely and effectively. Patient-reported outcomes (PROs) are increasingly used in clinical trials to incorporate the patient perspective—SmPCs should thus adequately report PROs. In Germany, new drugs undergo mandatory early benefit assessment. Pharmaceutical companies submit dossiers containing all evidence; the subsequent dossier assessments focus on patient-relevant outcomes and comprehensively report PROs.

Objective

The primary aim was to investigate to what extent PROs recorded as outcomes in clinical trials of new drugs are reported in SmPCs.

Methods

We analysed dossier assessments with randomized controlled trials (RCTs) of new drugs entering the market between 01/2014 and 07/2018 and the corresponding SmPCs, and compared PRO reporting in both document types. For this purpose, we evaluated dossier assessment characteristics (e.g. drug name, indication, disease category) and study characteristics (e.g. evaluable PROs available?). PROs were divided into symptoms and health-related quality of life (HRQoL). SmPCs were screened to identify RCTs. We conducted 3 main evaluation steps: (1) Did the RCT included in the dossier assessment contain evaluable PROs? (2) If yes, was the RCT included in the SmPC? (3) If yes, were the PROs reported in the SmPC? Results are presented descriptively.

Results

88 dossier assessments including 143 RCTs on 72 drugs were considered: 109 (76.2%) RCTs included evaluable PROs, of which 89 were included in SmPCs. 38 RCTs (42.7%) investigated oncologics, 18 (20.2%) anti-infectives, and 33 (37.1%) other drugs. The RCTs considered symptoms more often than HRQoL (82 vs. 66 RCTs). In SmPCs, PROs were reported for 41 RCTs (46.1%), with a slightly higher reporting rate for RCTs considering HRQoL (43.9%) than for RCTs considering symptoms (41.5%). In oncologic indications, PROs were reported for 36.7% of RCTs considering HRQoL and 33.3% of RCTs considering symptoms. In infectious diseases, the rates were 21.4% (symptoms) and 0% (HRQoL), and for other diseases about 60% (symptoms) to 70% (HRQoL).

Conclusion

Even though a large amount of PRO data on new drugs is available from clinical trials included in SmPCs, the corresponding results are underreported.
Small Cell Undifferentiated Histology Does Not Adversely Affect Outcome in Hepatoblastoma: A Report From the Children's Oncology Group (COG) AHEP0731 Study Committee
Authors: Trobaugh-Lotrario Angela , Katzenstein Howard M. , Ranganathan Sarangarajan , Lopez-Terrada Dolores , Krailo Mark D. , Piao Jin , Chung Nadia , Randazzo Jessica , Malogolowkin Marcio H. , Furman Wayne L. , McCarville Elizabeth B. , Towbin Alexander J. , Tiao Greg M. , Dunn Stephen P. , Langham Max R. , McGahren Eugene D. , Feusner James , Rodriguez-Galindo Carlos , Meyers Rebecka L. , O'Neill Allison F. , Finegold Milton J.
Published: December 2021

PURPOSE

Small cell undifferentiated (SCU) histology in hepatoblastoma (HB) tumors has historically been associated with a poor prognosis. Tumors from patients enrolled on Children's Oncology Group (COG) study AHEP0731 underwent institutional and central pathologic review for identification of SCU histology.

PATIENTS AND METHODS

Patients with SCU histology identified at the local treating institution who had otherwise low-risk tumors were upstaged to the intermediate-risk treatment stratum, whereas those only identified by retrospective central review were treated per the local institution as low-risk. Patients with otherwise intermediate- or high-risk tumors remained in that treatment stratum, respectively. Central review was to be performed for all tissue samples obtained at any time point. Treatment was per local review, whereas analysis of outcome was based on central review.

RESULTS

Thirty-five patients had some elements (1%-25%) of SCU identified on central review of diagnostic specimens. All but two patient tissue sample retained nuclear INI1 expression. The presence of SCU histology did not correlate with age, alpha-fetoprotein level at diagnosis, or sex. The presence of SCU did not affect event-free survival (EFS). EFS at 5 years for patients with low-risk, intermediate-risk, and high-risk with SCU HB was 86% (95% CI, 33 to 98), 81% (95% CI, 57 to 92), and 29% (95% CI, 4 to 61), respectively, compared with EFS at 5 years for patients without SCU enrolled with low-risk, intermediate-risk, and high-risk of 87% (95% CI, 72 to 95), 88% (95% CI, 79 to 94), and 55% (95% CI, 32 to 74; P = .17), respectively.

CONCLUSION

The presence of SCU histology in HB does not appear to adversely affect outcome. Future studies should be able to treat patients with SCU HB according to risk stratification without regard to the presence of SCU histology.
Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03)
Authors: Gnant Michael , Dueck Amylou C. , Frantal Sophie , Martin Miguel , Burstein Hal J. , Greil Richard , Fox Peter , Wolff Antonio C. , Chan Arlene , Winer Eric P. , Pfeiler Georg , Miller Kathy D. , Colleoni Marco , Suga Jennifer M. , Rubovsky Gabor , Bliss Judith M. , Mayer Ingrid A. , Singer Christian F. , Nowecki Zbigniew , Hahn Olwen , Thomson Jacqui , Wolmark Norman , Amillano Kepa , Rugo Hope S. , Steger Guenther G. , Hernando Fernández de Aránguiz Blanca , Haddad Tufia C. , Perelló Antonia , Bellet Meritxell , Fohler Hannes , Metzger Filho Otto , Jallitsch-Halper Anita , Solomon Kadine , Schurmans Céline , Theall Kathy P. , Lu Dongrui R. , Tenner Kathleen , Fesl Christian , DeMichele Angela , Mayer Erica L. ,   on behalf of the PALLAS groups and investigators
Published: December 2021

PURPOSE

Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor–positive breast cancer has not been confirmed.

PATIENTS AND METHODS

In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer–free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival.

RESULTS

Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial.

CONCLUSION

At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor–positive breast cancer.
A novel electrochemical synthesis of graphene oxide: Converting waste product to utility
Authors: Neog Ashamoni , Biswas Rajib , Bharali Nishant
Published: December 2021

We comprehensively report here a green route for synthesizing graphene oxide (GO) from waste Zn-C dry cell batteries. Here LiCl was used as electrolyte for the electrochemical synthesis of GO from graphite rods extracted from waste batteries. The satisfactory yield of 0.0305 g/h, formulated wholly through basic medium (at pH 9.36), was validated through confirmatory characterizations such as X-ray diffraction (XRD) analysis, Fourier-transform infrared spectroscopy (FTIR), UV-Vis and Raman spectroscopy, etc. A prominent diffraction peak around 26.70° in the XRD spectra and two prominent excitonic peaks around

and

in the Raman spectra were observed for the obtained samples. The overall scheme turned out to be engaging less reactants as well as facile; thus, converting a waste material to a useful product.
Ribociclib Cytotoxicity Alone or Combined With Progesterone and/or Mitotane in in Vitro Adrenocortical Carcinoma Cells
Authors: Abate Andrea , Rossini Elisa , Tamburello Mariangela , Laganà Marta , Cosentini Deborah , Grisanti Salvatore , Fiorentini Chiara , Tiberio Guido A M , Scatolini Maria , Grosso Enrico , Hantel Constanze , Memo Maurizio , Berruti Alfredo , Sigala Sandra
Published: December 2021

Mitotane is the only approved drug for treating adrenocortical carcinoma (ACC). The regimen added to mitotane is chemotherapy with etoposide, doxorubicin, and cisplatin. This pharmacological approach, however, has a limited efficacy and significant toxicity. Target-therapy agents represent a new promising approach to cancer therapy. Among these, a preeminent role is played by agents that interfere with cell-cycle progression, such as CDK4/6-inhibitors. Here, we investigate whether ribociclib could induce a cytotoxic effect both in ACC cell line and patient-derived primary cell cultures, alone or in combined settings. Cell viability was determined by 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide assay, whereas cell proliferation was evaluated by direct count. Binary combination experiments were performed using Chou and Talalay method. Gene expression was analyzed by quantitative RT-PCR, whereas protein expression was evaluated by immunofluorescence. A double staining assay revealed that ribociclib induced a prevalent apoptotic cell death. Cell-cycle analysis was performed to evaluate the effect of ribociclib treatment on cell-cycle progression in ACC cell models. Our results indicate that ribociclib was cytotoxic and reduced the cell proliferation rate. The effect on cell viability was enhanced when ribociclib was combined with progesterone and/or mitotane. The effect of ribociclib on cell-cycle progression revealed a drug-induced cell accumulation in G2 phase. The positive relationship underlined by our results between ribociclib, progesterone, and mitotane strengthen the clinical potential of this combination.
Oxygen-sensing mechanisms in development and tissue repair
Authors: Jiang Yida , Duan Li-Juan , Fong Guo-Hua
Published: December 2021

Under normoxia, hypoxia inducible factor (HIF) α subunits are hydroxylated by PHDs (prolyl hydroxylase domain proteins) and subsequently undergo polyubiquitylation and degradation. Normal embryogenesis occurs under hypoxia, which suppresses PHD activities and allows HIFα to stabilize and regulate development. In this Primer, we explain molecular mechanisms of the oxygen-sensing pathway, summarize HIF-regulated downstream events, discuss loss-of-function phenotypes primarily in mouse development, and highlight clinical relevance to angiogenesis and tissue repair.
Nonstandard RNA/RNA interactions likely enhance folding and stability of segmented ribosomes
Authors: Rivas Mario , Fox George E.
Published: December 2021

The ribosome is the molecular factory that catalyzes all coded protein synthesis in extant organisms. Eukaryotic ribosomes are typically assembled out of four rRNAs; namely, 5S, 5.8S, 18S, and 28S. However, the 28S rRNA of some trypanosomatid organisms has been found to be segmented into six independent rRNAs of different sizes. The two largest segments have multiple sites where they jointly form stems comprised of standard base pairs that can hold them together. However, such regions of interaction are not observed among the four smaller RNAs. Early reports suggested that trypanosomatid segmented ribosome assembly was essentially achieved thanks to their association with rProteins. However, examination of cryo-EM ribosomal structures from Trypanosoma brucei, Leishmania donovani, and Trypanosoma cruzi reveals several long-range nonstandard RNA/RNA interactions. Most of these interactions are clusters of individual hydrogen bonds and so are not readily predictable. However, taken as a whole, they represent significant stabilizing energy that likely facilitates rRNA assembly and the overall stability of the segmented ribosomes. In the context of origin of life studies, the current results provide a better understanding of the true nature of RNA sequence space and what might be possible without an RNA replicase.
Ethics for "intelligent" beings created by man: scenarios of the future
Authors: Mijartovic Zorica , Jašić Orhan
Published: December 2021

Artificial intelligence is a challenge for many scientists and researchers today. On the one hand, the development of artificial intelligence can be beneficial for people as it can significantly facilitate their daily lives and jobs. On the other hand, there is the fear that we will not succeed in developing "friendly artificial intelligence" and that these created intelligent beings becoming  autonomous persons will bring many problems. Worries go so far as to assume that artificial intelligence will displace humans and take their place in all spheres of life. In this article, we have tried to present future scenarios concerning the development of artificial intelligence and indicate how necessary it is to have ethics in this discourse.Keywords: Artificial Intelligence, Algorithms, Bioethics, Ethics, Software, Science Fiction, Technology.
Μισό μάθημα τοξοβολίας; Ερωτικό αντάρτικο πόλης; Ο χυμός των λέξεων;
Authors: Κατωγιάννης Θέμης
Published: December 2021

Ποιήματα
Στα εκατόχρονα της Λευτεριάς; Πρέβεζα
Authors: Κολιός Βαγγέλης Ν.
Published: December 2021

Ποίηση
Study on human subjects – influence of stress and alcohol in simulated traffic situations
Authors: Ahmed Mobyen Uddin , Islam Mir Riyanul , Barua Shaibal , Hök Bertil , Jonforsen Emma , Begum Shahina
Published: December 2021

This report presents a research study plan on human subjects – the influence of stress and alcohol in simulated traffic situations under an H2020 project named SIMUSAFE. This research study focuses on road-users’, i.e., car drivers, motorcyclists, bicyclists and pedestrians, behaviour in relation to retrospective studies, where interaction between the users are considered. Here, the study includes sample size, inclusion/exclusion criteria, detailed study plan, protocols, potential test scenarios and all related ethical issues. The study plan has been included in a national ethics application and received approval for implementation.
On Special Issue «The Politization of social problems in mass media»
Authors: Bykov Ilya
Published: December 2021

The thematic issue of the magazine is devoted to the problems of politicization of socially significant topics in the media space and ultimately touched on a very wide and diverse range of issues, which, nevertheless, revolve around the role of the media and social media in modern politics. In this context, politicization is interpreted as the process of involving non-political issues in political communication. That is why the choice of political problems discussed in the media can reveal the essence of the political regime in a particular country, reveal the adequacy of political institutions to the needs of society and assess the effectiveness of political governance. Most of the articles are in the nature of empirical research, which investigate important problems of modern political communications in Russia and abroad. The range of research methods is also very extensive and includes polls, questionnaires, focus groups, content analysis, discourse analysis, case studies, etc. Following the problem of "politicization", among the most important concepts are the ideas of "media literacy", “network leadership”, “political mobilization”, “personification of politics”, “corporate citizenship”, etc. Research shows that social media has become an important factor in the politicization of socially significant topics. This thematic issue is aimed at specialists in the field of applied political science and political communication.
Social Media Users Behavior before the Mass Street Protests in Russia in January and April 2021
Authors: Garbuznyak A.
Published: December 2021

The purpose of this work is to identify the specifics of the online audience behavior before major street actions in Russia: how users react to current events, what is the focus of their attention, which authors, publics and publications are gaining popularity. The research was held on 7 social media platforms and based on content analysis including both a quantitative and a qualitative methodology. A certain similarity was revealed in the behavior of users of different platforms within the same period: they were interested in the same news and the positions of the same personalities. In addition, Twitter and social media users showed an increased interest in each other's reactions to the events that concerned them. The «climate of opinions» investigation held by social media users was especially obvious before the rally, announced suddenly. The research also revealed similarities in media consumption, interest in the same opinion leaders and a similar level of politicization before rallies among users of 5 platforms. These social media form a unified segment of the public sphere. The research data suggest that the platforms where «the climate of opinions» leans in favor of the protest agenda are more likely to influence protest activity. At the same time, direct calls to take to the streets seem to have an insignificant impact on protest behavior.
Macedonian Language as an Object of an International Dispute (According to Media Materials)
Authors: Sorokin D.
Published: December 2021

The purpose of this article is to study the issue of politicization of the language dispute between the Republic of North Macedonia and the Republic of Bulgaria. This academic dispute became a political argument not only in relations between two countries, but also in resolving issues in the world. The main method was content analysis the English-language news portal’s materials - Balkan Insight. This analysis provides the opportunity to research the components of this dispute. As a result, it can be stated that in the scientific community there is no consensus about how much and to what extent the Macedonian language is "similar" to other languages of the Balkan Peninsula. Bulgarian scientists do not acknowledge the existence of the Macedonian language, claiming that the language of North Macedonia is a dialect of Bulgarian. The Macedonian scientific community takes a different point of view, arguing that the language developed historically, through the BI media platform, is trying to form European public opinion. The collective West officially support the integration of Macedonia into European structures, but does not reject the positions of individual EU states, such as Bulgaria, which play a significant role.
Iwan Kriwoziercew jako świadek niektórych okoliczności zbrodni katyńskiej
Authors: Bosiacki Adam
Published: December 2021

Artykuł systematyzuje częściowo nieznane dotychczas aspekty biografii rosyjskiego chłopa Iwana Kriwoziercewa, będącego po 1945 r. do ujawnienia zbrodni w latach dziewięćdziesiątych XX w. najważniejszym świadkiem zbrodni katyńskiej. Tekst przedstawia szczegóły represji i śmierci ojca świadka, dostępne obecnie informacje na temat jego rodziny, ucieczki z miejsca zamieszkania, kompletu zeznań składanych polskim władzom i pisarzom oraz śledztwa podjętego po niewyjaśnionej do dziś śmierci Kriwoziercewa. Przedmiotem artykułu jest także prawnicza analiza i weryfikacja zeznań złożonych przez Kriwoziercewa, ocena pobudek postępowania świadka i rekonstrukcja charakteru postaci, także w związku z filmem fabularnym.
Pierwsza francusko-polska koncesja kolejowa z 1924 roku. Przyczynek do relacji finansowo-gospodarczych Polski i Francji po I wojnie światowej
Authors: Łazor Jerzy
Published: December 2021

Francja była głównym sojusznikiem Drugiej Rzeczypospolitej, a zarazem kluczowym dla niej źródłem kapitału. Różnica sił między obydwoma krajami i francuskie inwestycje w polski sektor surowcowy i infrastrukturę powodowały imperialistyczne interpretacje wzajemnych stosunków gospodarczych w obydwu historiografiach. W tekście analizuję historię koncesji kolejowej, udzielonej w 1924 r. polsko-francuskiemu konsorcjum przez władze w Warszawie. Pokazuję, że nawet w ramach asymetrycznych relacji między krajami słabsza strona miała manewr negocjacyjny, a powodzenie przedsięwzięć francuskich firm niekiedy zależało od decyzji Warszawy.
Wybrane prawnoadministracyjne aspekty realizacji zasady jawności w sferze funkcjonowania administracji publicznej
Authors: Romaniuk Paweł
Published: December 2021

Przedmiotowa zasada jawności w sferze aktywności administracji publicznej, a także jawność informacji na temat funkcjonowania państwa i reprezentujących je funkcjonariuszy publicznych są jednymi z fundamentalnych kryteriów rozwoju każdego demokratycznego państwa prawa. Jawność, jako dobro wspólne, musi być identyfikowana jako konsekwencja wiernej służby wszelkich organów i instytucji publicznych oraz reprezentujących je funkcjonariuszy publicznych. Wszyscy powinni być zainteresowani tym, aby państwo prawa funkcjonowało praworządnie, szanując przyjęte wolności i prawa wszystkich, którzy znajdują się pod jego władzą, korzystając jednocześnie z prawa dostępu do informacji publicznej.
European Integration in the teachings of John Paul II: Selected aspects
Authors: Witkowska-Chrzczonowicz Katarzyna
Published: December 2021

Nowadays, European integration is going through a crisis that has been observed for several years. The financial crisis, Brexit, the COVID-19 pandemic, and anti-democratic tendencies in many countries (unfortunately also including the EU member states) are leading to a new rise of the ideology of nation states. Moreover, many politicians are also promoting anti-EU slogans, highlighting the concept of national sovereignty and the need to protect it. Following this type of rhetoric and political narrative, the United Kingdom left the European Union in 2020. This situation encourages reflection on how this process was perceived by John Paul II, who is still regarded by many Poles as an unquestionable authority figure, and his teachings remain an important signpost for the future for many Poles. This paper is an attempt to explore the issue of European integration in the teachings of the Polish Pope. John Paul II’s statements on European integration were always deeply balanced and dealt primarily with the spiritual and cultural aspects. However, he did not omit economic or even political issues whenever he deemed them rightful and meaningful. In fact, up until the end of his life and his pontificate, John Paul II was an avid supporter of the idea of European integration, and this attitude shines through in his texts and speeches analysed for this study. Of course, in his perceptive mind, the Pope did notice the flaws and imperfections of European integration projects and warned clearly against reducing the European cooperation only to economic aspects, disregarding the spiritual, cultural or moral dimension. Above all, however, he noticed and appreciated the achievements of European cooperation mechanisms, which ensured peace and robust economic development in the second half of the 20th century for the countries which were actively involved in it.
Glosa do wyroku Naczelnego Sądu Administracyjnego z dnia 14 marca 2019 r., sygn. I OSK 1429/17
Authors: Chrabkowski Marek
Published: December 2021

Glosa krytyczna do wyroku Naczelnego Sądu Administracyjnego, który odwołując się do przepisów charakteryzujących się niskim poziomem określoności, nakazał udostępnienie danych chronionych tajemnicą telekomunikacyjną na potrzeby sprawy o wykroczenie. Autor glosy podnosi istotną z punktu widzenia bezpieczeństwa informacji kwestię, że przepisy ogólne nie mogą stanowić podstawy ingerencji w tajemnicę komunikowania, która podlega konstytucyjnej ochronie.
Fragment „zaginionej kroniki dominikańskiej” w zbiorach Rosyjskiej Biblioteki Narodowej w Petersburgu
Authors: Gałuszka Tomasz
Published: December 2021

Przedmiotem artykułu jest prezentacja odnalezionego w zbiorach Rosyjskiej Biblioteki Narodowej w Petersburgu nowego źródła do najstarszych dziejów polskich dominikanów. Powstało ono zapewne w pierwszej połowie XIII w. Zawiera wiele nowych informacji, m.in. ostatecznie przecina spekulacje na temat czasu przybycia św. Jacka do Krakowa, który niewątpliwie został posłany do Polski w 1222 r. Odnaleziony tekst jest najprawdopodobniej fragmentem tzw. zaginionej kroniki dominikańskiej.
Brand Capital and Stock Price Crash Risk
Authors: Hasan Mostafa Monzur , Taylor Grantley , Richardson Grant
Published: December 2021

We examine the relationship between brand capital and stock price crash risk. Crash risk, defined as the negative skewness in the distribution of returns for individual stocks, captures asymmetry in risk, and has important implications for investment choices and risk management. Using a sample of 39,685 publicly listed U.S. firm-year observations covering 1975 to 2018, we show that brand capital is significantly and negatively related to crash risk. We also use an advanced machine learning approach and confirm that brand capital is a strong predictor of future stock price crashes. Our cross-sectional analyses show that this negative relationship is more evident for subsamples with transitory poor earnings performance or persistent good earnings performance, greater corporate tax avoidance, and weak corporate governance structures. The results survive numerous robustness tests, including the use of alternative measures of brand capital, crash risk, and several endogeneity tests. In sum, our findings are consistent with agency theory, suggesting that high levels of brand capital expose firms to investor and customer scrutiny, which reduces managerial opportunistic behavior that may include the accumulation and concealment of negative information.

This paper was accepted by Karl Diether, finance.