bluuebunny/crossref_metadata_2025 huggingface dataset:
Adenoviral CD40 Ligand Immunotherapy in 32 Canine Malignant Melanomas–Long-Term Follow Up
Authors: Saellstrom Sara , Sadeghi Arian , Eriksson Emma , Segall Thomas , Dimopoulou Maria , Korsgren Olle , Loskog Angelica SI. , Tötterman Thomas H. , Hemminki Akseli , Ronnberg Henrik
Published: July 2021

Malignant melanoma is a serious disease in both humans and dogs, and the high metastatic potential results in poor prognosis for many patients. Its similarities with human melanoma make spontaneous canine melanoma an excellent model for comparative studies of novel therapies and tumor biology. Gene therapy using adenoviruses encoding the immunostimulatory gene CD40L (AdCD40L) has shown promise in initial clinical trials enrolling human patients with various malignancies including melanoma. We report a study of local AdCD40L treatment in 32 cases of canine melanoma (23 oral, 5 cutaneous, 3 ungual and 1 conjunctival). Eight patients were World Health Organization (WHO) stage I, 9 were stage II, 12 stage III, and 3 stage IV. One to six intratumoral injections of AdCD40L were given every seven days, combined with cytoreductive surgery in 20 cases and only immunotherapy in 12 cases. Tumor tissue was infiltrated with T and B lymphocytes after treatment, suggesting immune stimulation. The best overall response based on result of immunotherapy included 7 complete responses, 5 partial responses, 5 stable and 2 progressive disease statuses according to the World Health Organization response criteria. Median survival was 285 days (range 20–3435 d). Our results suggest that local AdCD40L therapy is safe and could have beneficial effects in dogs, supporting further treatment development. Clinical translation to human patients is ongoing.
Providing Humans With Practical, Best Practice Handling Guidelines During Human-Cat Interactions Increases Cats' Affiliative Behaviour and Reduces Aggression and Signs of Conflict
Authors: Haywood Camilla , Ripari Lucia , Puzzo Jo , Foreman-Worsley Rachel , Finka Lauren R.
Published: July 2021

The importance of animals' experiences and associated comfort during Human-Animal Interactions (HAI), and particularly Animal Assisted Interventions (AAI), are increasingly recognised. However, there remains a paucity of published research, particularly concerning less formal but frequent HAIs to which companion animals are typically exposed, such as stroking or petting. Additionally, few practical evidence-based guides to facilitate humans' optimal animal handling and interaction in these contexts exist. A simple set of Human-Cat Interaction (HCI) guidelines were therefore created, with the aim to enhance domestic cats' comfort during generic HCI contexts. Based around a “CAT” acronym, guidelines focused on providing the cat with choice and control (“C”), paying attention (“A”) to the cats' behaviour and body language and limiting touch (“T”), primarily to their temporal regions. Guidelines were presented to human participants during a brief training intervention, and guideline efficacy was subsequently assessed. Domestic cats available for rehoming at Battersea Dogs and Cats Home, UK (n= 100) were filmed during interactions with novel members of the public (n= 120). Cats were exposed to a maximum of six, 5-min interaction sessions, balanced across “control” (interactions with humans pre-training) and “intervention” conditions (interactions with humans post-training). For each observation, cat behaviour and posture were coded and humans' cat-directed behaviour rated on the degree to which it reflected best practice principles. Data were extracted from a total of 535 observations and average human interaction ratings and cat behaviour values compared between control and intervention conditions via paired Wilcoxon tests. Compared to the control, humans' interaction styles were rated as significantly more closely aligned with best practice principles in the intervention condition. Cats also displayed significantly greater frequencies and/or durations of affiliative and positively-valenced behaviours in the intervention. In contrast, cats in the control displayed significantly greater frequencies of human-directed aggression, in addition to greater frequencies and/or durations of behaviours associated with conflict and negative valence. Results demonstrate the positive impact of practical interaction guidelines on cats' social behaviour and comfort during HCI, with the potential to improve cats' general experiences during interactions, reduce human-directed aggression and ultimately improve cat-human relationships.
The Human Aspect of Horse Care: How the COVID-19 Pandemic Impacted the Wellbeing of Equestrian Industry Stakeholders
Authors: Ward Ashley , Stephen Kate , Argo Caroline , Watson Christine , Harris Patricia , Neacsu Madalina , Russell Wendy , Grove-White Dai , Morrison Philippa
Published: July 2021

During the lockdown phase of the COVID-19 pandemic, equestrian stakeholders faced a dilemma whereby they were required to balance caring for the welfare of horses with adapting to the restrictions imposed to protect public health. The present study investigated the impact of the pandemic on the wellbeing of a sample of industry stakeholders, including horse owners, equine veterinarians, farriers and welfare centre managers (n = 26) using a qualitative methodology. Findings from the interviews indicated that the mental health and wellbeing of veterinarians and horse owners was negatively affected by pandemic-related obstacles to communication and limitations to horse–owner interactions. However, this study also identified several positive outcomes for wellbeing during lockdown resulting from pro-social activities that were engaged with by horse owners to overcome social isolation, the separation of the community and loneliness. These findings provide accounts of ways in which those caring for horses might be challenged during national emergency scenarios, pointing to areas that would benefit from future mental health and wellbeing interventions.
Effects of Weaning Age at 21 and 28 Days on Growth Performance, Intestinal Morphology and Redox Status in Piglets
Authors: Ming Dongxu , Wang Wenhui , Huang Caiyun , Wang Zijie , Shi Chenyu , Ding Jian , Liu Hu , Wang Fenglai
Published: July 2021

The study objective was to assess effects of different weaning ages on growth performance, intestinal morphology and redox status in Duroc × Landrace × Large White piglets (n = 96) fed diets without antibiotic growth promoters. Piglets were selected from 24 litters based on similar body weight at 14 d of age. All piglets were allocated to two groups in a completely random design with six replicates and eight pigs per replicate (four barrows and four gilts), which were weaned at 21 (n = 48; BW = 6.87 ± 0.33 kg) and 28 (n = 48; BW = 8.49 ± 0.41 kg) days of age. After weaning, pigs were fed a corn–soybean meal-based diet. Average daily gain (ADG), average daily feed intake (ADFI), feed conversion (F:G), diarrhea incidence, gastrointestinal pH, intestinal morphology and redox status were determined. Pigs weaned at 28 d displayed increased ADG from d 8 to 14 (p < 0.01) compared with pigs weaned at 21 d. Pigs weaned at 28 d had a higher ADFI from d 0 to 7 (p < 0.01), d 8 to 14 (p < 0.01), d 15 to 28 (p < 0.05) and during the entire experimental period (p < 0.01) compared with pigs weaned at 21 d. Pigs weaned at 21 d had an improved F:G from d 15 to 28 (p < 0.05) compared with pigs weaned at 28 d. Pigs weaned at 28 d had decreased diarrhea incidence from d 8 to 14 (p < 0.01) and the entire experimental period (p < 0.01) compared with pigs weaned at 21 d. On d 28, the pH of the stomach contents in pigs weaned at 21 d was significantly higher compared with pigs weaned at 28 d (p < 0.01). On d 14, the morphology of the duodenum, jejunum and ileum in pigs weaned at 28 d was improved compared with pigs weaned at 21 d. During the experiment period, the antioxidant abilities of pigs weaned at 28 d of the heart, liver, kidney, intestinal and serum were better than pigs weaned at 21 d. In conclusion, intestinal morphology, pH of the stomach and antioxidant status of pigs weaned at 28 d were better than pigs weaned at 21 d. These factors supported better growth performance and decreased diarrhea incidence.
Potential Distribution of Amphibians with Different Habitat Characteristics in Response to Climate Change in South Korea
Authors: Kim Hyun Woo , Adhikari Pradeep , Chang Min Ho , Seo Changwan
Published: July 2021

Amphibian species are highly vulnerable to climate change with significant species decline and extinction predicted worldwide. However, there are very limited studies on amphibians in South Korea. Here, we assessed the potential impacts of climate change on different habitat groups (wetland amphibians, Group 1; migrating amphibians, Group 2; and forest-dwelling amphibians, Group 3) under future climate change and land cover change in South Korea using a maximum entropy modelling approach. Our study revealed that all amphibians would suffer substantial loss of suitable habitats in the future, except Lithobates catesbeianus, Kaloula borealis, and Karsenia koreana. Similarly, species richness for Groups 2 and 3 will decline by 2030, 2050, and 2080. Currently, amphibian species are widely distributed across the country; however, in future, suitable habitats for amphibians would be concentrated along the Baekdudaegan Mountain Range and the southeastern region. Among the three groups, Group 3 amphibians are predicted to be the most vulnerable to climate change; therefore, immediate conservation action is needed to protect them. We expect this study could provide crucial baseline information required for the government to design climate change mitigation strategies for indigenous amphibians.
Two-Dimensional Full-Waveform Joint Inversion of Surface Waves Using Phases and Z/H Ratios
Authors: Zhang Chao , Lei Ting , Wang Yi
Published: July 2021

Surface-wave dispersion and the Z/H ratio are important parameters used to resolve the Earth’s structure, especially for S-wave velocity. Several previous studies have explored using joint inversion of these two datasets. However, all of these studies used a 1-D depth-sensitivity kernel, which lacks precision when the structure is laterally heterogeneous. Adjoint tomography (i.e., full-waveform inversion) is a state-of-the-art imaging method with a high resolution. It can obtain better-resolved lithospheric structures beyond the resolving ability of traditional ray-based travel-time tomography. In this study, we present a systematic investigation of the 2D sensitivities of the surface wave phase and Z/H ratio using the adjoint-state method. The forward-modeling experiments indicated that the 2D phase and Z/H ratio had different sensitivities to the S-wave velocity. Thus, a full-waveform joint-inversion scheme of surface waves with phases and a Z/H ratio was proposed to take advantage of their complementary sensitivities to the Earth’s structure. Both applications to synthetic data sets in large- and small-scale inversions demonstrated the advantage of the joint inversion over the individual inversions, allowing for the creation of a more unified S-wave velocity model. The proposed joint-inversion scheme offers a computationally efficient and inexpensive alternative to imaging fine-scale shallow structures beneath a 2D seismic array.
Assessment of a Weak Mode of Bacterial Adhesion by Applying an Electric Field
Authors: Araujo George , Zheng Zhaoyi , Oh Jae Jong , Tang Jay X.
Published: July 2021

Microbial attachment to surfaces is ubiquitous in nature. Most species of bacteria attach and adhere to surfaces via special appendages such as pili and fimbriae, the roles of which have been extensively studied. Here, we report an experiment on pilus-less mutants of Caulobacter crescentus weakly attached to polyethylene surface. We find that some individual cells transiently but repeatedly adhere to the surface in a stick-slip fashion in the presence of an electric field parallel to the surface. These bacteria move significantly slower than the unattached ones in the same field of view undergoing electrophoretic motion. We refer this behavior of repeated and transient attachment as “quasi-attachment”. The speed of the quasi-attached bacteria exhibits large variation, frequently dropping close to zero for short intervals of time. We propose a polymeric tethering model to account for the experimental findings. This study sheds light on bacteria–surface interaction, which is significant in broader contexts such as infection and environmental control.
Assessment of Climate Variability among Seasonal Trends Using In Situ Measurements: A Case Study of Punjab, Pakistan
Authors: Syed Alishbah , Liu Xingpeng , Moniruzzaman Md , Rousta Iman , Syed Warda , Zhang Jiquan , Olafsson Haraldur
Published: July 2021

This research assessed the changes in spatial patterns and the seasonal trends in temperature, precipitation, and relative humidity over 36 years (1979–2014) using Climate Forecast System Reanalysis (CFSR) datasets. The evaluation of climate deviations was the prime objective of this research. The augmented Dickey–Fuller Test (ADF) was used to scrutinize whether the data was either stationary or non-stationary. The results of the ADF test showed that all the datasets were found to be stationary at lag order 3. To observe undulations in the time series data, trend analyses were done using Sen’s slope (SS), Mann–Kendall (MK), and Cox and Stuart (CS) tests. For all the statistical analyses, we considered the 5% significance level (α = 0.05) and p < 0.05 to be statistically significant. We observed significant (p < 0.05) trends in spring (MAM) and autumn (SON) for minimum temperature (Tmin) in Punjab. We also noted a significant (p < 0.05) trend in precipitation during autumn (SON). Annually, all the variables showed a non-significant (p > 0.05) trend for Punjab, Pakistan, during the period 1979–2014. Climate variability, such as a decrease in precipitation, higher temperature, and relative humidity fluctuations, were the reasons for the imbalance in the sustainability of Punjab, Pakistan.
Mediterranean-Scale Drought: Regional Datasets for Exceptional Meteorological Drought Events during 1975–2019
Authors: Mathbout Shifa , Lopez-Bustins Joan Albert , Royé Dominic , Martin-Vide Javier
Published: July 2021

Drought is one of the most complex climate-related phenomena and is expected to progressively affect our lives by causing very serious environmental and socioeconomic damage by the end of the 21st century. In this study, we have extracted a dataset of exceptional meteorological drought events between 1975 and 2019 at the country and subregional scales. Each drought event was described by its start and end date, intensity, severity, duration, areal extent, peak month and peak area. To define such drought events and their characteristics, separate analyses based on three drought indices were performed at 12-month timescale: the Standardized Precipitation Index (SPI), the Standardized Precipitation Evapotranspiration Index (SPEI), and the Reconnaissance Drought Index (RDI). A multivariate combined drought index (DXI) was developed by merging the previous three indices for more understanding of droughts’ features at the country and subregional levels. Principal component analysis (PCA) was used to identify five different drought subregions based on DXI-12 values for 312 Mediterranean stations and a new special score was defined to classify the multi-subregional exceptional drought events across the Mediterranean Basin (MED). The results indicated that extensive drought events occurred more frequently since the late 1990s, showing several drought hotspots in the last decades in the southeastern Mediterranean and northwest Africa. In addition, the results showed that the most severe events were more detected when more than single drought index was used. The highest percentage area under drought was also observed through combining the variations of three drought indices. Furthermore, the drought area in both dry and humid areas in the MED has also experienced a remarkable increase since the late 1990s. Based on a comparison of the drought events during the two periods—1975–1996 and 1997–2019—we find that the current dry conditions in the MED are more severe, intense, and frequent than the earlier period; moreover, the strongest dry conditions occurred in last two decades. The SPEI-12 and RDI-12 have a higher capacity in providing a more comprehensive description of the dry conditions because of the inclusion of temperature or atmospheric evaporative demand in their scheme. A complex range of atmospheric circulation patterns, particularly the Western Mediterranean Oscillation (WeMO) and East Atlantic/West Russia (EATL/WRUS), appear to play an important role in severe, intense and region-wide droughts, including the two most severe droughts, 1999–2001 and 2007–2012, with lesser influence of the NAO, ULMO and SCAND.
Atmospheric Impacts of COVID-19 on NOx and VOC Levels over China Based on TROPOMI and IASI Satellite Data and Modeling
Authors: Stavrakou Trissevgeni , Müller Jean-François , Bauwens Maite , Doumbia Thierno , Elguindi Nellie , Darras Sabine , Granier Claire , Smedt Isabelle De , Lerot Christophe , Van Roozendael Michel , Franco Bruno , Clarisse Lieven , Clerbaux Cathy , Coheur Pierre-François , Liu Yiming , Wang Tao , Shi Xiaoqin , Gaubert Benjamin , Tilmes Simone , Brasseur Guy
Published: July 2021

China was the first country to undergo large-scale lockdowns in response to the pandemic in early 2020 and a progressive return to normalization after April 2020. Spaceborne observations of atmospheric nitrogen dioxide (NO2) and oxygenated volatile organic compounds (OVOCs), including formaldehyde (HCHO), glyoxal (CHOCHO), and peroxyacetyl nitrate (PAN), reveal important changes over China in 2020, relative to 2019, in response to the pandemic-induced shutdown and the subsequent drop in pollutant emissions. In February, at the peak of the shutdown, the observed declines in OVOC levels were generally weaker (less than 20%) compared to the observed NO2 reductions (−40%). In May 2020, the observations reveal moderate decreases in NO2 (−15%) and PAN (−21%), small changes in CHOCHO (−3%) and HCHO (6%). Model simulations using the regional model MAGRITTEv1.1 with anthropogenic emissions accounting for the reductions due to the pandemic explain to a large extent the observed changes in lockdown-affected regions. The model results suggest that meteorological variability accounts for a minor but non-negligible part (~−5%) of the observed changes for NO2, whereas it is negligible for CHOCHO but plays a more substantial role for HCHO and PAN, especially in May. The interannual variability of biogenic and biomass burning emissions also contribute to the observed variations, explaining e.g., the important column increases of NO2 and OVOCs in February 2020, relative to 2019. These changes are well captured by the model simulations.
A Weather-Type Classification and Its Application to Near-Surface Wind Climate Change Projections over the Adriatic Region
Authors: Belušić Vozila Andreina , Telišman Prtenjak Maja , Güttler Ivan
Published: July 2021

The main goal of this study is to present a recently developed classification method for weather types based on the vorticity and the location of the synoptic centers relative to the Adriatic region. The basis of the present objective classification, applied to the Adriatic region, is the subjective classification developed by Poje. Our algorithm considered daily mean sea-level pressure and 500 hPa geopotential height to define one out of 17 possible weather types. We applied the algorithm to identify which weather type was relevant in the generation of the two typical near-surface winds over the Adriatic region, namely Bora and Sirocco. Two high-resolution (0.11°) EURO-CORDEX regional climate models were used, SMHI-RCA4 and DHMZ-RegCM4, forced by several CMIP5 global climate models and analyzed for two 30-year periods: near-present day and mid-21st century climate conditions under the high-end Representative Concentration Pathway (RCP8.5) scenario. Bora and Sirocco days were extracted for each weather type and a distribution over the 30-year period was presented. Our results suggest that in the winter season, climate model projections indicate a reduction in the main cyclonic types relevant in the formation of Bora over the entire Adriatic region and an increase in the number of anticyclonic types relevant in Sirocco events. In contrast, for the summer season, an increase in the main anticyclonic Bora-related weather types is found in the ensemble over the northern Adriatic region.
Essential Oil of Foeniculum vulgare Mill. as a Green Fungicide and Defense-Inducing Agent against Fusarium Root Rot Disease in Vicia faba L.
Authors: Khaleil Mona M. , Alnoman Maryam M. , Elrazik Elsayed S. Abd , Zagloul Hayat , Khalil Ahmed Mohamed Aly
Published: July 2021

Fusarium solani, the causative agent of root rot disease is one of the major constraints of faba bean (Vicia faba L.) yield worldwide. Essential oils have become excellent plant growth stimulators besides their antifungal properties. Foeniculum vulgare Mill. (fennel) is a familiar medicinal plant that has inhibitory effects against phytopathogenic fungi. Herein, different concentrations of fennel seed essential oil (FSEO) (12.5, 25, 50, 100, 200 and 400 μL/mL) were examined against F. solani KHA10 (accession number MW444555) isolated from rotted roots of faba bean in vitro and in vivo. The chemical composition of FSEO, through gas chromatography/mass spectroscopy, revealed 10 major compounds. In vitro, FSEO inhibited F. solani with a minimum inhibitory concentration (MIC) of 25 µL/mL. In vivo, FSEO suppressed Fusarium root rot disease in Vicia faba L. by decreasing the disease severity (61.2%) and disease incidence (50%), and acted as protective agent (32.5%) of Vicia faba L. Improvements in morphological and biochemical parameters were recorded in FSEO-treated faba seeds. Moreover, the expression level of the defense-related genes defensin and chitinase was noticeably enhanced in treated plants. This study suggested using FSEO as a promising antifungal agent against F. solani not only to control root rot disease but also to enhance plant growth and activate plant defense.
Bovine Serum Albumin-Immobilized Black Phosphorus-Based γ-Fe2O3 Nanocomposites: A Promising Biocompatible Nanoplatform
Authors: Naskar Atanu , Lee Sohee , Ko Dongjoon , Kim Semi , Kim Kwang-sun
Published: July 2021

The interactions between proteins and nanoparticles need to be fully characterized as the immobilization of proteins onto various nanoplatforms in the physiological system often results in the change of surface of the protein molecules to avoid any detrimental issues related to their biomedical applications. Hence, in this article, the successful low-temperature synthesis of a BP-based γ-Fe2O3 (IB) nanocomposite and its interactive behavior with bovine serum albumin (BSA)—a molecule with chemical similarity and high sequence identity to human serum albumin—are described. To confirm the formation of γ-Fe2O3 and the IB nanocomposite, X-ray diffraction, transmission electron microscopy, and X-ray photoelectron spectroscopy analyses of the materials were performed. Additionally, the physical interaction between BSA and the IB nanocomposite was confirmed via UV–Vis and photoluminescence spectral analyses. Finally, the biocompatibility of the BSA-immobilized IB nanocomposite was verified using an in vitro cytotoxicity assay with HCT-15 colon cancer cells. Our findings demonstrate that this newly developed nanocomposite has potential utility as a biocompatible nanoplatform for various biomedical applications.
The 3-Year Effect of the Mediterranean Diet Intervention on Inflammatory Biomarkers Related to Cardiovascular Disease
Authors: Urpi-Sarda Mireia , Casas Rosa , Sacanella Emilio , Corella Dolores , Andrés-Lacueva Cristina , Llorach Rafael , Garrabou Gloria , Cardellach Francesc , Sala-Vila Aleix , Ros Emilio , Ruiz-Canela Miguel , Fitó Montserrat , Salas-Salvadó Jordi , Estruch Ramon
Published: July 2021

The intervention with the Mediterranean diet (MD) pattern has evidenced short-term anti-inflammatory effects, but little is known about its long-term anti-inflammatory properties at molecular level. This study aims to investigate the 3-year effect of MD interventions compared to low-fat diet (LFD) on changes on inflammatory biomarkers related to atherosclerosis in a free-living population with a high-risk of cardiovascular disease (CD). Participants (n = 285) in the PREDIMED trial were randomly assigned into three intervention groups: MD with extra-virgin olive oil (EVOO) or MD-Nuts, and a LFD. Fourteen plasma inflammatory biomarkers were determined by Luminex assays. An additional pilot study of gene expression (GE) was determined by RT-PCR in 35 participants. After 3 years, both MDs showed a significant reduction in the plasma levels of IL-1β, IL-6, IL-8, TNF-α, IFN-γ, hs-CRP, MCP-1, MIP-1β, RANTES, and ENA78 (p < 0.05; all). The decreased levels of IL-1β, IL-6, IL-8, and TNF-α after MD significantly differed from those in the LFD (p < 0.05). No significant changes were observed at the gene level after MD interventions, however, the GE of CXCR2 and CXCR3 tended to increase in the control LFD group (p = 0.09). This study supports the implementation of MD as a healthy long-term dietary pattern in the prevention of CD in populations at high cardiovascular risk.
CD40 Agonist Monoclonal Antibody-Mediated Hepatitis in TNF-Receptor 1 Gene Knockout Mice
Authors: Raabe Oksana , Birchler Thomas , Rehrauer Hubert , Eppler Elisabeth
Published: July 2021

Tumor necrosis factor-alpha (TNF-α) plays an important role in liver inflammation. CD40-CD40 ligand (CD40-CD40L) is a key receptor–ligand signaling pair involved in the adaptive immune response and pathogenesis of autoimmune diseases. In mice, CD40 activation leads to sickness behavior syndrome (SBS) comprising weight loss, sleep disruption and depression, which can be blocked by administration of the TNF-inhibitor etanercept. In the present study, we assessed the extent of hepatic inflammation in mice devoid of the TNF-receptor 1 (TNFR1)-mediated signaling pathway. The TNFR1-depleted (TNFR1−/−) adult mice and their wild type littermates were given a single intra-peritoneal injection of CD40 agonist monoclonal antibody (mAb) or rat IgG2a isotope control. As described previously, TNFR1−/− mice were protected from SBS upon CD40 mAb treatment. Cd40, tnf and tnfr1 mRNA and Tnf-α peptide were increased in the liver of CD40 mAb-stimulated wild type mice. Serum alanine aminotransferase was elevated in both CD40-activated wild type and TNFR1−/− mice. TNFR1−/− mice showed much less intra-parenchymal infiltrates, hepatocellular necrosis, and perivascular clusters upon CD40 mAb activation than their wild type littermates. A gene expression microarray detected increased activity of metabolic and detoxification pathways and decreased activity of inflammatory pathways. We conclude that immune activation and development of liver inflammation in CD40L interactions depend on TNFR1-mediated signaling pathways and are counteracted by alterations in metabolic pathways.
Synergistic AHR Binding Pathway with EMT Effects on Serous Ovarian Tumors Recognized by Multidisciplinary Integrated Analysis
Authors: Su Kuo-Min , Gao Hong-Wei , Chang Chia-Ming , Lu Kai-Hsi , Yu Mu-Hsien , Lin Yi-Hsin , Liu Li-Chun , Chang Chia-Ching , Li Yao-Feng , Chang Cheng-Chang
Published: July 2021

Epithelial ovarian cancers (EOCs) are fatal and obstinate among gynecological malignancies in advanced stage or relapsed status, with serous carcinomas accounting for the vast majority. Unlike EOCs, borderline ovarian tumors (BOTs), including serous BOTs, maintain a semimalignant appearance. Using gene ontology (GO)-based integrative analysis, we analyzed gene set databases of serous BOTs and serous ovarian carcinomas for dysregulated GO terms and pathways and identified multiple differentially expressed genes (DEGs) in various aspects. The SRC (SRC proto-oncogene, non-receptor tyrosine kinase) gene and dysfunctional aryl hydrocarbon receptor (AHR) binding pathway consistently influenced progression-free survival and overall survival, and immunohistochemical staining revealed elevated expression of related biomarkers (SRC, ARNT, and TBP) in serous BOT and ovarian carcinoma samples. Epithelial–mesenchymal transition (EMT) is important during tumorigenesis, and we confirmed the SNAI2 (Snail family transcriptional repressor 2, SLUG) gene showing significantly high performance by immunohistochemistry. During serous ovarian tumor formation, activated AHR in the cytoplasm could cooperate with SRC, enter cell nuclei, bind to AHR nuclear translocator (ARNT) together with TATA-Box Binding Protein (TBP), and act on DNA to initiate AHR-responsive genes to cause tumor or cancer initiation. Additionally, SNAI2 in the tumor microenvironment can facilitate EMT accompanied by tumorigenesis. Although it has not been possible to classify serous BOTs and serous ovarian carcinomas as the same EOC subtype, the key determinants of relevant DEGs (SRC, ARNT, TBP, and SNAI2) found here had a crucial role in the pathogenetic mechanism of both tumor types, implying gradual evolutionary tendencies from serous BOTs to ovarian carcinomas. In the future, targeted therapy could focus on these revealed targets together with precise detection to improve therapeutic effects and patient survival rates.
Post-Operative Adhesions: A Comprehensive Review of Mechanisms
Authors: Fatehi Hassanabad Ali , Zarzycki Anna N. , Jeon Kristina , Deniset Justin F. , Fedak Paul W. M.
Published: July 2021

Post-surgical adhesions are common in almost all surgical areas and are associated with significant rates of morbidity, mortality, and increased healthcare costs, especially when a patient requires repeat operative interventions. Many groups have studied the mechanisms driving post-surgical adhesion formation. Despite continued advancements, we are yet to identify a prevailing mechanism. It is highly likely that post-operative adhesions have a multifactorial etiology. This complex pathophysiology, coupled with our incomplete understanding of the underlying pathways, has resulted in therapeutic options that have failed to demonstrate safety and efficacy on a consistent basis. The translation of findings from basic and preclinical research into robust clinical trials has also remained elusive. Herein, we present and contextualize the latest findings surrounding mechanisms that have been implicated in post-surgical adhesion formation.
Involvement of Gut Microbiota in Schizophrenia and Treatment Resistance to Antipsychotics
Authors: Manchia Mirko , Fontana Andrea , Panebianco Concetta , Paribello Pasquale , Arzedi Carlo , Cossu Eleonora , Garzilli Mario , Montis Maria Antonietta , Mura Andrea , Pisanu Claudia , Congiu Donatella , Copetti Massimiliano , Pinna Federica , Pazienza Valerio , Squassina Alessio , Carpiniello Bernardo
Published: July 2021

The gut microbiota is constituted by more than 40,000 bacterial species involved in key processes including high order brain functions. Altered composition of gut microbiota has been implicated in psychiatric disorders and in modulating the efficacy and safety of psychotropic medications. In this work we characterized the composition of the gut microbiota in 38 patients with schizophrenia (SCZ) and 20 healthy controls (HC), and tested if SCZ patients with different response to antipsychotics (18 patients with treatment resistant schizophrenia (TRS), and 20 responders (R)) had specific patterns of gut microbiota composition associated with different response to antipsychotics. Moreover, we also tested if patients treated with typical antipsychotics (n = 20) presented significant differences when compared to patients treated with atypical antipsychotics (n = 31). Our findings showed the presence of distinct composition of gut microbiota in SCZ versus HC, with several bacteria at the different taxonomic levels only present in either one group or the other. Similar findings were observed also depending on treatment response and exposure to diverse classes of antipsychotics. Our results suggest that composition of gut microbiota could constitute a biosignatures of SCZ and TRS.
Primitive Reflex Activity in Relation to Motor Skills in Healthy Preschool Children
Authors: Pecuch Anna , Gieysztor Ewa , Wolańska Ewelina , Telenga Marlena , Paprocka-Borowicz Małgorzata
Published: July 2021

Psychomotor development in the first year of life is possible due to activity and then integration of primitive (neonatal) reflexes. The presence of active primitive reflexes (APRs) in preschool and school-aged children indicates neuromotor immaturity. Studies show dependencies between the preserved activity of primary reflexes and developmental problems such as learning difficulties (problems with reading, writing, reduced mathematics skills, and dyslexia), difficulties with coordination, and attention deficit. The primary purpose of this study is to present the activity of three tonic reflexes in a sample of 112 Polish children aged 4–6 in relation to their motor skills. The children were examined for the presence of the asymmetric tonic neck reflex (ATNR), symmetric tonic neck reflex (STNR), and tonic labyrinthine reflex (TLR). Motor performance was examined with the MOT 4–6. Statistical analysis shows an inverse correlation between the score in the test of reflexes and motor efficiency (MOT 4–6) at p < 0.05 (−0.33). Children with increased reflex activity presented a lower level of motor efficiency. The multiple regression model showed that with the older age of the child and the decrease in the level of reflex activity, the motor skills of children improve. Thus, there is a need for early screening of primitive reflexes in children. Properly selected exercises and therapeutic activities aimed at integrating APRs in children with developmental difficulties can improve their motor skills, perceptual abilities, and emotional behavior.
Tackling Tumour Cell Heterogeneity at the Super-Resolution Level in Human Colorectal Cancer Tissue
Authors: Lang Fabian , Contreras-Gerenas María F. , Gelléri Márton , Neumann Jan , Kröger Ole , Sadlo Filip , Berniak Krzysztof , Marx Alexander , Cremer Christoph , Wagenknecht Hans-Achim , Allgayer Heike
Published: July 2021

Tumour cell heterogeneity, and its early individual diagnosis, is one of the most fundamental problems in cancer diagnosis and therapy. Single molecule localisation microscopy (SMLM) resolves subcellular features but has been limited to cultured cell lines only. Since nuclear chromatin architecture and microRNAs are critical in metastasis, we introduce a first-in-field approach for quantitative SMLM-analysis of chromatin nanostructure in individual cells in resected, routine-pathology colorectal carcinoma (CRC) patient tissue sections. Chromatin density profiles proved to differ for cells in normal and carcinoma colorectal tissues. In tumour sections, nuclear size and chromatin compaction percentages were significantly different in carcinoma versus normal epithelial and other cells of colorectal tissue. SMLM analysis in nuclei from normal colorectal tissue revealed abrupt changes in chromatin density profiles at the nanoscale, features not detected by conventional widefield microscopy. SMLM for microRNAs relevant for metastasis was achieved in colorectal cancer tissue at the nuclear level. Super-resolution microscopy with quantitative image evaluation algorithms provide powerful tools to analyse chromatin nanostructure and microRNAs of individual cells from normal and tumour tissue at the nanoscale. Our new perspectives improve the differential diagnosis of normal and (metastatically relevant) tumour cells at the single-cell level within the heterogeneity of primary tumours of patients.
Triple Negative Breast Cancer: A Mountain Yet to Be Scaled Despite the Triumphs
Authors: Wu Qitong , Siddharth Sumit , Sharma Dipali
Published: July 2021

Metastatic progression and tumor recurrence pertaining to TNBC are certainly the leading cause of breast cancer-related mortality; however, the mechanisms underlying TNBC chemoresistance, metastasis, and tumor relapse remain somewhat ambiguous. TNBCs show 77% of the overall 4-year survival rate compared to other breast cancer subtypes (82.7 to 92.5%). TNBC is the most aggressive subtype of breast cancer, with chemotherapy being the major approved treatment strategy. Activation of ABC transporters and DNA damage response genes alongside an enrichment of cancer stem cells and metabolic reprogramming upon chemotherapy contribute to the selection of chemoresistant cells, majorly responsible for the failure of anti-chemotherapeutic regime. These selected chemoresistant cells further lead to distant metastasis and tumor relapse. The present review discusses the approved standard of care and targetable molecular mechanisms in chemoresistance and provides a comprehensive update regarding the recent advances in TNBC management.
Development of a Selective Tumor-Targeted Drug Delivery System: Hydroxypropyl-Acrylamide Polymer-Conjugated Pirarubicin (P-THP) for Pediatric Solid Tumors
Authors: Makimoto Atsushi , Fang Jun , Maeda Hiroshi
Published: July 2021

Most pediatric cancers are highly chemo-sensitive, and cytotoxic chemotherapy has always been the mainstay of treatment. Anthracyclines are highly effective against most types of childhood cancer, such as neuroblastoma, hepatoblastoma, nephroblastoma, rhabdomyosarcoma, Ewing sarcoma, and so forth. However, acute and chronic cardiotoxicity, one of the major disadvantages of anthracycline use, limits their utility and effectiveness. Hydroxypropyl acrylamide polymer-conjugated pirarubicin (P-THP), which targets tumor tissue highly selectively via the enhanced permeability and retention (EPR) effect, and secondarily releases active pirarubicin molecules quickly into the acidic environment surrounding the tumor. Although, the latter rarely occurs in the non-acidic environment surrounding normal tissue. This mechanism has the potential to minimize acute and chronic toxicities, including cardiotoxicity, as well as maximize the efficacy of chemotherapy through synergy with tumor-targeting accumulation of the active molecules and possible dose-escalation. Simply replacing doxorubicin with P-THP in a given regimen can improve outcomes in anthracycline-sensitive pediatric cancers with little risk of adverse effects, such as cardiotoxicity. As cancer is a dynamic disease showing intra-tumoral heterogeneity during its course, continued parallel development of cytotoxic agents and molecular targeting agents is necessary to find potentially more effective treatments.
Cancer Organoids in Basic Science and Translational Medicine
Authors: Memeo Lorenzo , Canzonieri Vincenzo , Rizzolio Flavio
Published: July 2021

Organoids are revolutionizing approaches to cancer therapy and even diagnosis [...]
Machine Learning Models to Predict Survival Outcomes According to the Surgical Approach of Primary Radical Hysterectomy in Patients with Early Cervical Cancer
Authors: Kim Se Ik , Lee Sungyoung , Choi Chel Hun , Lee Maria , Suh Dong Hoon , Kim Hee Seung , Kim Kidong , Chung Hyun Hoon , No Jae Hong , Kim Jae-Weon , Park Noh Hyun , Song Yong-Sang , Kim Yong Beom
Published: July 2021

We purposed to develop machine learning models predicting survival outcomes according to the surgical approach for radical hysterectomy (RH) in early cervical cancer. In total, 1056 patients with 2009 FIGO stage IB cervical cancer who underwent primary type C RH by either open or laparoscopic surgery were included in this multicenter retrospective study. The whole dataset consisting of patients’ clinicopathologic data was split into training and test sets with a 4:1 ratio. Using the training set, we developed models predicting the probability of 5-year progression-free survival (PFS) and overall survival (OS) with tenfold cross validation. The developed models were validated in the test set. In terms of predictive performance, we measured the area under the receiver operating characteristic curve (AUC) values. The logistic regression models comprised of preoperative variables yielded AUCs of 0.679 and 0.715 for predicting 5-year PFS and OS rates, respectively. Combining both logistic regression and multiple machine learning models, we constructed hybrid ensemble models, and these models showed much improved predictive performance, with 0.741 and 0.759 AUCs for predicting 5-year PFS and OS rates, respectively. We successfully developed models predicting disease recurrence and mortality after primary RH in patients with early cervical cancer. As the predicted value is calculated based on the preoperative factors, such as the surgical approach, these ensemble models would be useful for making decisions when choosing between open or laparoscopic RH.
Racial Differences in Hepatocellular Carcinoma Incidence and Risk Factors among a Low Socioeconomic Population
Authors: Muhimpundu Sylvie , Conway Rebecca Baqiyyah N. , Warren Andersen Shaneda , Lipworth Loren , Steinwandel Mark D. , Blot William J. , Shu Xiao-Ou , Sudenga Staci L.
Published: July 2021

The purpose of this study was to examine differences in risk factors associated with hepatocellular carcinoma (HCC) among White and African Americans from low socioeconomic backgrounds in the Southern Community Cohort Study (SCCS). The SCCS is a prospective cohort study with participants from the southeastern US. HCC incidence rates were calculated. Multivariable Cox regression was used to calculate HCC-adjusted hazard ratios (aHR) associated with known baseline HCC risk factors for White and African Americans, separately. There were 294 incident HCC. The incidence rate ratio for HCC was higher (IRR = 1.4, 95%CI: 1.1–1.9) in African Americans compared to White Americans. White Americans saw a stronger association between self-reported hepatitis C virus (aHR = 19.24, 95%CI: 10.58–35.00) and diabetes (aHR = 3.55, 95%CI: 1.96–6.43) for the development of HCC compared to African Americans (aHR = 7.73, 95%CI: 5.71–10.47 and aHR = 1.48, 95%CI: 1.06–2.06, respectively) even though the prevalence of these risk factors was similar between races. Smoking (aHR = 2.91, 95%CI: 1.87–4.52) and heavy alcohol consumption (aHR = 1.59, 95%CI: 1.19–2.11) were significantly associated with HCC risk among African Americans only. In this large prospective cohort, we observed racial differences in HCC incidence and risk factors associated with HCC among White and African Americans.
Differences in Extracellular Vesicle Protein Cargo Are Dependent on Head and Neck Squamous Cell Carcinoma Cell of Origin and Human Papillomavirus Status
Authors: Goudsmit Christine , da Veiga Leprevost Felipe , Basrur Venkatesha , Peters Lila , Nesvizhskii Alexey , Walline Heather
Published: July 2021

To identify potential extracellular vesicle (EV) biomarkers in head and neck squamous cell carcinoma (HNSCC), we evaluated EV protein cargo and whole cell lysates (WCL) from HPV-positive and -negative HNSCC cell lines, as well as normal oral keratinocytes and HPV16-transformed cells. EVs were isolated from serum-depleted, conditioned cell culture media by polyethylene glycol (PEG) precipitation/ultracentrifugation. EV and WCL preparations were analyzed by LC-MS/MS. Candidate proteins detected at significantly higher levels in EV compared with WCL, or compared with EV from normal oral keratinocytes, were identified and confirmed by Wes Simple Western protein analysis. Our findings suggest that these proteins may be potential HNSCC EV markers as proteins that may be (1) selectively included in EV cargo for export from the cell as a strategy for metastasis, tumor cell survival, or modification of tumor microenvironment, or (2) representative of originating cell composition, which may be developed for diagnostic or prognostic use in clinical liquid biopsy applications. This work demonstrates that our method can be used to reliably detect EV proteins from HNSCC, normal keratinocyte, and transformed cell lines. Furthermore, this work has identified HNSCC EV protein candidates for continued evaluation, specifically tenascin-C, HLA-A, E-cadherin, EGFR, EPHA2, and cytokeratin 19.
The Glyoxalase System in Age-Related Diseases: Nutritional Intervention as Anti-Ageing Strategy
Authors: Aragonès Gemma , Rowan Sheldon , Francisco Sarah G. , Whitcomb Elizabeth A. , Yang Wenxin , Perini-Villanueva Giuliana , Schalkwijk Casper G. , Taylor Allen , Bejarano Eloy
Published: July 2021

The glyoxalase system is critical for the detoxification of advanced glycation end-products (AGEs). AGEs are toxic compounds resulting from the non-enzymatic modification of biomolecules by sugars or their metabolites through a process called glycation. AGEs have adverse effects on many tissues, playing a pathogenic role in the progression of molecular and cellular aging. Due to the age-related decline in different anti-AGE mechanisms, including detoxifying mechanisms and proteolytic capacities, glycated biomolecules are accumulated during normal aging in our body in a tissue-dependent manner. Viewed in this way, anti-AGE detoxifying systems are proposed as therapeutic targets to fight pathological dysfunction associated with AGE accumulation and cytotoxicity. Here, we summarize the current state of knowledge related to the protective mechanisms against glycative stress, with a special emphasis on the glyoxalase system as the primary mechanism for detoxifying the reactive intermediates of glycation. This review focuses on glyoxalase 1 (GLO1), the first enzyme of the glyoxalase system, and the rate-limiting enzyme of this catalytic process. Although GLO1 is ubiquitously expressed, protein levels and activities are regulated in a tissue-dependent manner. We provide a comparative analysis of GLO1 protein in different tissues. Our findings indicate a role for the glyoxalase system in homeostasis in the eye retina, a highly oxygenated tissue with rapid protein turnover. We also describe modulation of the glyoxalase system as a therapeutic target to delay the development of age-related diseases and summarize the literature that describes the current knowledge about nutritional compounds with properties to modulate the glyoxalase system.
Understanding Cervical Cancer through Proteomics
Authors: Martínez-Rodríguez Fátima , Limones-González Jared E. , Mendoza-Almanza Brenda , Esparza-Ibarra Edgar L. , Gallegos-Flores Perla I. , Ayala-Luján Jorge L. , Godina-González Susana , Salinas Eva , Mendoza-Almanza Gretel
Published: July 2021

Cancer is one of the leading public health issues worldwide, and the number of cancer patients increases every day. Particularly, cervical cancer (CC) is still the second leading cause of cancer death in women from developing countries. Thus, it is essential to deepen our knowledge about the molecular pathogenesis of CC and propose new therapeutic targets and new methods to diagnose this disease in its early stages. Differential expression analysis using high-throughput techniques applied to biological samples allows determining the physiological state of normal cells and the changes produced by cancer development. The cluster of differential molecular profiles in the genome, the transcriptome, or the proteome is analyzed in the disease, and it is called the molecular signature of cancer. Proteomic analysis of biological samples of patients with different grades of cervical intraepithelial neoplasia (CIN) and CC has served to elucidate the pathways involved in the development and progression of cancer and identify cervical proteins associated with CC. However, several cervical carcinogenesis mechanisms are still unclear. Detecting pathologies in their earliest stages can significantly improve a patient’s survival rate, prognosis, and recurrence. The present review is an update on the proteomic study of CC.