bluuebunny/crossref_metadata_2025 huggingface dataset:
RoSummary: Control Tokens for Romanian News Summarization
Authors: Niculescu Mihai Alexandru , Ruseti Stefan , Dascalu Mihai
Published: December 2022

Significant progress has been achieved in text generation due to recent developments in neural architectures; nevertheless, this task remains challenging, especially for low-resource languages. This study is centered on developing a model for abstractive summarization in Romanian. A corresponding dataset for summarization is introduced, followed by multiple models based on the Romanian GPT-2, on top of which control tokens were considered to specify characteristics for the generated text, namely: counts of sentences and words, token ratio, and n-gram overlap. These are special tokens defined in the prompt received by the model to indicate traits for the text to be generated. The initial model without any control tokens was assessed using BERTScore (F1 = 73.43%) and ROUGE (ROUGE-L accuracy = 34.67%). Control tokens improved the overall BERTScore to 75.42% using , while the model was influenced more by the second token specified in the prompt when performing various combinations of tokens. Six raters performed human evaluations of 45 generated summaries with different models and decoding methods. The generated texts were all grammatically correct and consistent in most cases, while the evaluations were promising in terms of main idea coverage, details, and cohesion. Paraphrasing still requires improvements as the models mostly repeat information from the reference text. In addition, we showcase an exploratory analysis of the generated summaries using one or two specific control tokens.
Early Exposure to Environmental Pollutants: Imidacloprid Potentiates Cadmium Toxicity on Zebrafish Retinal Cells Death
Authors: Di Paola Davide , Gugliandolo Enrico , Capparucci Fabiano , Cordaro Marika , Iaria Carmelo , Siracusa Rosalba , D’Amico Ramona , Fusco Roberta , Impellizzeri Daniela , Cuzzocrea Salvatore , Di Paola Rosanna , Crupi Rosalia , Peritore Alessio Filippo
Published: December 2022

In the present study, we analyzed the combination of non-toxic concentrations per se, of Cd and a pesticide the imidacloprid (IMI) (10 and 50 μM for Cd and 195 μM for IMI), to highlight early developmental toxicity and possible damage to retinal cells. Co-exposure to Cd and IMI showed a toxic effect in zebrafish larval development, with lowered degrees of survival and hatching, and in some cases the induction of structural alterations and edema. In addition, co-exposure to 50 and 195 μM, respectively, for Cd and IMI, also showed increased apoptosis in eye cells, accompanied by up regulation of genes associated with antioxidant markers (cat, sod1, nrf2 and ho-1). Thus, the present study aims to highlight how the presence of multiple contaminants, even at low concentrations, can be a risk factor in a model of zebrafish (Danio rerio). The presence of other contaminants, such as IMI, can cause an enhancement of the toxic action of Cd on morphological changes in the early life stage of zebrafish, but more importantly disrupt the normal development of the retina, eventually triggering apoptosis.
Long-Term Changes in the Distribution and Abundance of Nine Deep-Water Skates (Arhynchobatidae: Rajiformes: Chondrichthyes) in the Northwestern Pacific
Authors: Orlov Alexei M. , Volvenko Igor V.
Published: December 2022

Based on the analysis of long-term data from bottom trawl surveys (1977–2021), changes in the spatial distribution, position of the boundaries of the ranges and the catch rates of the nine most common deep-sea skates of the genus Bathyraja in the Russian waters of the Northwestern Pacific (B. violacea, B. aleutica, B. matsubarai, B. maculata, B. bergi, B. taranetzi, B. minispinosa, B. interrupta, and B. isotrachys) are considered. During the surveyed period, significant changes in the spatial distribution were observed, which are probably due to both subjective reasons (changes in the number of trawling stations, surveyed depths, etc.) and climatic changes. No monotonous displacement of the northern or southern boundaries of the range or its center in one direction was observed in any area of any species during the entire observation period. At the same time, shifts in the boundaries of the ranges of different species in different areas occurred for different decades, i.e., the boundaries of the ranges slowly fluctuated or “pulsed” near some average annual position. In general, from the 1970s to the 1980s, the number of skates grew; from the 1980s to the 1990s, it decreased; from the 1990s to the 2000s, it fluctuated at the achieved level; from the 2000s to the 2010s, it grew again; and from the 2010s to the 2020s, it decreased again. These trends coincide with previously identified ecosystem rearrangements under the influence of climatic and oceanological changes. The identification of links between changes in spatial distribution, range boundaries and catch rates with climatic and oceanological factors require separate additional studies.
Nutritional Values of Industrial Hemp Byproducts for Dairy Cattle
Authors: Wang Yiqiang , Gao Jianxu , Cheng Chuanteng , Lv Jingyi , Lambo Modinat Tolani , Zhang Guangning , Li Yang , Zhang Yonggen
Published: December 2022

The objective of this experiment was to explore the nutritional components of industrial hemp byproducts (industrial hemp ethanol extraction byproduct, IHEEB; industrial hemp stalk, IHS; industrial hemp seed meal, IHSM; industrial hemp oil filter residue, IHOFR) and provide theoretical support for the application of industrial hemp byproducts in dairy cattle production. This experiment used a combination of a wet chemical method with Cornell Net Carbohydrate and Protein System, in situ nylon bag technique, and three-step in vitro method to compare the chemical composition, carbohydrate and protein composition, in situ ruminal degradability and intestinal digestibility of industrial hemp byproducts and conventional feeds (alfalfa hay, AH; soybean meal, SBM). Available energy values were estimated based on the National Academies of Sciences, Engineering, and Medicine. The results showed that the nutritional composition of different feeds varied greatly. The two types of IHEEB were enriched with ash, crude protein (CP), neutral detergent fiber (NDF), and calcium, while the contents of neutral detergent insoluble crude protein, acid detergent insoluble crude protein, and acid detergent lignin were higher. As a result, the non-degradable carbohydrate and protein components were higher, and the effective degradation rate of rumen dry matter and protein was lower. IHS contains higher non-protein nitrogen and NDF, which enables it to provide more CP rumen effective degradation rate and carbohydrates, but the high acid detergent fiber also limits its application. IHSM possesses 296 g/kg CP and high rumen undegradable protein and intestinal digested protein, which can provide rumen bypass protein in dairy cows, making it a potentially good protein source. IHOFR had higher ether extract, rumen available protein degradation rate, and total tract digested protein, which can provide more energy and easily degradable protein for lactating cows. The available energy value of IHEEB and IHS was lower than AH, while SBM is between IHFOR and IHSM. In addition, the tetrahydrocannabinol of three industrial hemp byproducts that have not been assessed by the European Food Safety Authority (EFSA) was tested to evaluate their safety, and all of them were less than the limit set by ESFA. In conclusion, industrial hemp byproducts can be considered for inclusion in dietary formulations as unconventional feed sources for dairy cattle, but the purpose of use needs to be properly considered.
Effects of a Dietary Multi-Strain Probiotic and Vaccination with a Live Anticoccidial Vaccine on Growth Performance and Haematological, Biochemical and Redox Status Indicators of Broiler Chickens
Authors: Arczewska-Włosek Anna , Świątkiewicz Sylwester , Ognik Katarzyna , Józefiak Damian
Published: December 2022

A total of 256 male Ross 308 chickens were assigned to four treatments in a 2 × 2 factorial design with two levels of the anticoccidial vaccine (ACV) Livacox T (none or 1 × dose) with or without dietary supplementation with the probiotic Protexin® (P). The growth performance parameters for the test periods (1–21, 22–42, and 1–42 d) and oocyst per gram (OPG) at weekly intervals were analysed. Blood samples were collected at 16 post-vaccination (pv) days to measure selected haematological, biochemical, redox, and immunological parameters. ACV administration worsened the performance parameters of the chickens for 1–21 d pv, while supplementation with P reduced this negative effect with a significant improvement in 1–21 d body weight gain and feed conversion ratio. ACV administration increased % phagocytic cells (%PC), phagocytic index (PI), respiratory burst activity, proportion of monocytes, and activities of aspartate aminotransferase (AST) and lactate dehydrogenase, while it decreased the catalase activity and concentration of malondialdehyde and peroxides. The dietary administration of P significantly increased counts of red blood cells and white blood cells and increased %PC and PI, while it decreased the heterophil proportion, heterophil/lymphocyte ratio (p = 0.059), and alanine aminotransferase and AST activities. The oocyst counts were comparable in all sampling periods, except on 14 d pv, as supplementation with P significantly decreased 14 d OPG, thus indicating a positive influence of P on immunity development. In conclusion, dietary supplementation with P led to improved performance, better immunity, and benefits in health status in broilers vaccinated with the ACV, without interfering with the circulating vaccine strains.
Brazilian Horses from Bahia State Are Highly Infected with Sarcocystis bertrami
Authors: Marques Caroline , da Silva Bruno , Nogueira Yuri , Bezerra Taynar , Tavares Aline , Borges-Silva Waléria , Gondim Luís
Published: December 2022

The protozoan Sarcocystis bertrami (syn. Sarcocystis fayeri) infects horses and has dogs as definitive hosts. Herein we aimed to detect S. bertrami in Brazilian horses destined for human consumption and to determine the frequency of infection in the examined animals. Muscle fragments from 51 horses were collected in a slaughterhouse in Bahia State during three different seasons of the year. Samples from six tissues from each animal were prepared for macroscopic and microscopic evaluation, using tissue grinding, squash and histology. Sarcocystis sp. was observed in 100% of the examined horses. Selected samples were processed for transmission electron microscopy (TEM). Species identification was confirmed using a PCR targeted to the mitochondrial cytochrome c oxidase subunit 1 gene (cox1). Histological examination revealed sarcocysts with variable sizes and shapes, and dispersed within the muscle fibers. When observed by TEM, the sarcocyst wall was wavy and covered by an electrodense layer. The villar protrusions were digitiform and bent. To our knowledge, this study is the first morphological and molecular confirmation of S. bertrami in horses in Brazil and South America.
Correction to a Simple Biosphere Model 2 (SiB2) Simulation of Energy and Carbon Dioxide Fluxes over a Wheat Cropland in East China Using the Random Forest Model
Authors: Zhang Shiqi , Duan Zexia , Zhou Shaohui , Gao Zhiqiu
Published: December 2022

Modeling the heat and carbon dioxide (CO2) exchanges in agroecosystems is critical for better understanding water and carbon cycling, improving crop production, and even mitigating climate change, in agricultural regions. While previous studies mainly focused on simulations of the energy and CO2 fluxes in agroecosystems on the North China Plain, their corrections, simulations and driving forces in East China are less understood. In this study, the dynamic variations of heat and CO2 fluxes were simulated by a standalone version of the Simple Biosphere 2 (SiB2) model and subsequently corrected using a Random Forest (RF) machine learning model, based on measurements from 1 January to 31 May 2015–2017 in eastern China. Through validation with direct measurements, it was found that the SiB2 model overestimated the sensible heat flux (H) and latent heat flux (LE), but underestimated soil heat flux (G0) and CO2 flux (Fc). Thus, the RF model was used to correct the results modeled by SiB2. The RF model showed that disturbances in temperature, net radiation, the G0 output of SiB2, and the Fc output of SiB2 were the key driving factors modulating the H, LE, G0, and Fc. The RF model performed well and significantly reduced the biases for H, LE, G0, and Fc simulated by SiB2, with higher R2 values of 0.99, 0.87, 0.75, and 0.71, respectively. The SiB2 and RF models combine physical mechanisms and mathematical correction to enable simulations with both physical meaning and accuracy.
Characteristics of Rainstorm Intensity and Its Future Risk Estimation in the Upstream of Yellow River Basin
Authors: Li Wanzhi , Chen Ruishan , Sun Shao , Yu Di , Wang Min , Liu Caihong , Qi Menziyi
Published: December 2022

Under the background of climate warming, the occurrence of extreme events upstream of the Yellow River Basin has increased significantly. Extreme precipitation tends to be even more intense, and occurs more frequently. The impacts of various extreme weather and climate events in the basin have become increasingly complex, which is increasingly difficult to cope with and affects the basin’s long-term stability and ecological security. Based on the daily precipitation data of 33 meteorological stations in the upper reaches of the Yellow River Basin from 1961 to 2021, this paper analyzes the characteristics of rainstorm intensity. Moreover, combined with the simulation results of 10 global climate models of the Coupled Model Intercomparison Project (CMIP6) and the social and economic prediction data from SSPs, it analyzes the possible changes of rainstorm disaster risk in the upper reaches of the Yellow River Basin in the 21st century, under the three emission scenarios of SSP126, SSP245, and SSP370. The results show that the precipitation in the upstream area of the Yellow River Basin is increasing at a rate of 8.1 mm per 10 years, and the number of rainstorm processes and their indicators is increasing, which indicates an increase in the extremeness of precipitation; the rainstorm process intensity index shows an increasing trend, especially in the northeast region with a concentrated population and economy, where the rainstorm process intensity index is high; it is estimated that the number of rainstorm days in low-, medium-, and high-risk scenarios will increase, which leads to an increase in the social risk by at least 60% by around 2050 (2036–2065); with the increasing disaster risk, the population exposure to rainstorm disasters is also on the rise. If no measures are taken, the population exposure will increase to 7.316 million people per day by around 2050, increasing by more than double, especially in the northeast. This study shows that, with the increasing rainstorm disaster risk and population exposure in the upper reaches of the Yellow River Basin, relevant measures need to be taken to ensure the safety of people’s lives and property.
Seasonal Variations of Ecosystem Water Use Efficiency and Their Responses to Climate Factors in Inner Mongolia of China
Authors: Wang Wenjun , Wu Yingjie , Wang Sinan , Yin Hang , Li Wei , Zhao Shuixia
Published: December 2022

Ecosystem water use efficiency (eWUE) is a useful metric to examine the interactions between water and carbon cycles in ecosystems. To reveal the response and adaptation characteristics of different vegetation types within the context of global warming on a regional scale, the spatiotemporal characteristics and influencing factors of the seasonal eWUE of various vegetation types in Inner Mongolia from 2001 to 2020 were explored. Based on MODIS gross primary productivity (GPP), evapotranspiration (ET) data and meteorological data, in this study, we estimated eWUE in different seasons in Inner Mongolia and used trend analysis and correlation analysis methods to analyze the relationship between eWUE in spring, summer and autumn and the temperature–precipitation. From 2001 to 2020, in this region, the GPP and ET in spring, summer and autumn showed increasing trends. In addition, the growth rates of GPP and ET in spring and summer were higher than those in autumn. Under the combined effect of GPP and ET, eWUE in different seasons showed a significant decreasing trend (p < 0.05)—this is ascribed to the extent of ET increasing more than GPP, especially in summer, with the most obvious decreasing rate. In terms of spatial trend, in spring and summer, there is a decreasing trend from northeast to southwest. The effects of precipitation and temperature on the eWUE in Inner Mongolia were mainly negatively correlated in the northeastern part of Inner Mongolia with higher altitudes during the spring and autumn seasons. In total, 95.096% of the total area had positive correlations between eWUE and temperature in spring. In summer, the region in which the WUE of the vegetation had an inverse relationship with both the temperature and the amount of precipitation was the largest compared to these regions in spring and autumn.
Black Carbon in Atmosphere: Instrumentation, Chemical-Physical Behavior, Human Health Implications
Authors: Avino Pasquale
Published: December 2022

Carbonaceous aerosol is the most significant contributor to the particulate matter in the atmosphere. It is composed of a complex mixture of compounds containing carbon atoms and is usually classified into two main fractions: black carbon (BC) and organic carbon (OC). BC is essentially a primary pollutant emitted in particulate form, and its chemical stability excludes chemical transformations during its lifetime in the atmosphere. Therefore, it should be considered a tracer for the long-range transport of anthropogenic air pollution. OC has both primary and secondary origins: primary OC particulate is formed during combustion and emitted mainly as submicron particles, whereas secondary OC particulate originates from gas-to-particle conversion processes. This SI aims to deepen the state of the art on this important topic ranging from theory to the development of new instrumentation useful for this determination, to the chemical–physical problems in the atmosphere, to the health and toxicological implications related to exposure to these pollutants as well as papers showing historical data series both in urban, rural, and remote areas are also appreciated.
The Association of CD8+ Cytotoxic T Cells and Granzyme B+ Lymphocytes with Immunosuppressive Factors, Tumor Stage and Prognosis in Cutaneous Melanoma
Authors: Salmi Satu , Hälinen Kaisla , Lin Anton , Suikkanen Sanna , Jokelainen Otto , Rahunen Eija , Siiskonen Hanna , Pasonen-Seppänen Sanna
Published: December 2022

The immunosuppressive tumor microenvironment (TME) consists of suppressive cells producing a variety of immunomodulatory proteins, such as programmed death ligand 1 (PD-L1) and indoleamine-2,3-dioxygenase (IDO). Although granzyme B (GrB) is known to convey the cytolytic activities of CD8+ cytotoxic lymphocytes, it is also expressed by other cells, such as regulatory T and B cells, for immunosuppressive purposes. The role of GrB+ lymphocytes in melanoma has not been examined extensively. In this study, benign, premalignant, and malignant melanocytic tumors were stained immunohistochemically for CD8 and GrB. PD-L1 was also stained from malignant samples that had accompanying clinicopathological data. The association of CD8+ and GrB+ lymphocytes with PD-L1 expression, tumor stage, prognosis, and previously analyzed immunosuppressive factors were evaluated. Our aim was to obtain a more comprehensive perception of the immunosuppressive TME in melanoma. The results show that both CD8+ and GrB+ lymphocytes were more abundant in pT4 compared to pT1 melanomas, and in lymph node metastases compared to primary melanomas. Surprisingly, a low GrB/CD8 ratio was associated with better recurrence-free survival in primary melanomas, which indicates that GrB+ lymphocytes might represent activated immunosuppressive lymphocytes rather than cytotoxic T cells. In the present study, CD8+ lymphocytes associated positively with both tumor and stromal immune cell PD-L1 and IDO expression. In addition, PD-L1+ tumor and stromal immune cells associated positively with IDO+ stromal immune and melanoma cells. The data suggest that IDO and PD-L1 seem to be key immunosuppressive factors in CD8+ lymphocyte-predominant tumors in CM.
Potential Therapeutic Effects of NAMPT-Mediated NAD Biosynthesis in Depression In Vivo
Authors: Wang Jue , Sun Runxuan , Xia Linhan , Zhu Xinying , Zhang Qi , Ye Yilu
Published: December 2022

This study aimed to investigate the potential therapeutic effects of nicotinamide phosphoribosyltransferase (NAMPT)-mediated adenine dinucleotide (NAD) biosynthesis in depression models in vivo. Namptflox/flox mice were used to evaluate the role of NAMPT in depression. NAMPT and NAD levels in the prefrontal cortex (PFC) were measured, and depression-associated behavior, cognitive function, and social interaction were evaluated. The expression levels of BDNF, pCREB, CREB, monoamine neurotransmitters, and corticosterone (CORT) were also detected in the PFC. The contents of NAMPT and NAD decreased in the PFC in Namptflox/flox mice. Namptflox/flox mice showed depression-like behaviors, cognitive function deterioration, decreased social ability, and decreased dominance. Meanwhile, there were decreased expression levels of the pCREB/CREB ratio, but not BDNF, in the PFC. Levels of DA, 5-HT, and NE were decreased, and CORT was activated in the PFC of Namptflox/flox mice. Additionally, the role of NAMPT-NAD was examined in rats treated with nicotinamide riboside (NR) after being exposed to chronic unexpected mild stress (CUMS). NR reversed the decreased NAMPT expression in the PFC and HIP, and the NAD content in the PFC, but not HIP in rats with CUMS-induced depression. NR also improved depressive- and anxiolytic-like behaviors, locomotor activity, and cognitive function. BDNF expression and the pCREB/CREB ratio were significantly increased in both the PFC and HIP after NR treatment. The activation of CORT and decreased content of DA were reversed after NR treatment in the PFC. There was no difference in the 5-HT content among groups in both the PFC and HIP. Taken together, NAD synthesis induced by NAMPT could be associated with depression-like behaviors in mice, and the elevated NAD level by NR improved depression in rats.
Enhanced Strength, Durability, and Microstructural Attributes of Graphene Oxide-Modified Ultrafine Slag Cement Mortar
Authors: Tatineni Yeswanth Sai , Putta Jagadeesh
Published: December 2022

The work described in this paper assays in detail the improvements in the prominent features of cement mortar cube (CMC) specimens by blending them with 53 grade ordinary Portland cement (OPC), ultrafine slag (UFS), river sand, and graphene oxide (GO). These combinations were evaluated to determine which mixture best provided impressive strength attributes to the mortar. GO, in four different quantities, was explored as a blend (0.01%, 0.02%, 0.03%, and 0.04%). The combination with 10% UFS and 0.03% GO-infused CMCs exhibited improved compressive strength compared to all samples after being cured for three, seven, and twenty-eight days. The higher performance of the 10% UFS and 0.03% GO mortar cubes was further endorsed by durability and microstructural tests, such as water absorption, sorptivity, ultrasonic pulse velocity, rapid chloride permeability, electric resistivity, carbonation, FE-SEM/EDX, and XRD. From all the results, it was evident that the mortar containing 10% UFS and 0.03% GO has the best properties for shielding it from deterioration and may be employed as an augmenting structural material in the construction sector.
Associations of Physical Activity and Handgrip Strength with Health-Related Quality of Life in Older Korean Cancer Survivors
Authors: Kim Jeonghyeon , Kang Seamon , Kim Donghyun , Kang Hyunsik
Published: December 2022

Background: Uncertainty exists regarding the associations between physical activity (PA), relative handgrip strength (RHGS), and health-related quality of life (HRQoL) among elderly Korean cancer survivors. This study investigated the moderating effect of RHGS on the relationship between PA and HRQoL in 308 cancer survivors aged ≥65 years using the data from the Korean National Health and Nutrition Examination Survey in 2014–2019. Methods: HRQoL was evaluated with the EuroQol-5-dimension instrument. PA and handgrip strength were assessed with the Global Physical Activity Questionnaire and a hand dynamometer, respectively. Age, sex, body mass index, income, marital status, educational background, heavy alcohol consumption, smoking status, multimorbidity, and hemoglobin were included as covariates. Results: Bivariate logistic regression showed that insufficient PA and no PA were associated with higher odds of a low HRQoL (odds ratio, OR = 2.6, 95% confidence interval, CI = 1.3~5.1, p = 0.005; OR = 2.4, 95% CI = 1.1~5.0, p = 0.024, respectively), compared with sufficient PA (OR = 1). Weak RHGS was associated with high odds of a low HRQoL (OR = 2.6, 95%= 1.530~4.6, p < 0.001) compared with normal RHGS (OR = 1). Particularly, RHGS (β = −0.0573, 95% CI = −0.1033~−0.0112) had a significant moderating effect on the relationship between PA and HRQoL even after adjustments for all the covariates. The negative influence of physical inactivity on HRQoL was observed in cancer survivors with weak RHGS but not in cancer survivors with normal RHGS. Conclusions: The current findings suggest that maintaining or promoting muscular strength through regular exercise is critical for the HRQoL of elderly Korean cancer survivors.
Extensive Phenotypic Characterization of T Cells Infiltrating Liver Metastasis from Colorectal Cancer: A Potential Role in Precision Medicine
Authors: Sampaio-Ribeiro Gabriela , Ruivo Ana , Silva Ana , Santos Ana Lúcia , Oliveira Rui Caetano , Laranjeira Paula , Gama João , Cipriano Maria Augusta , Tralhão José Guilherme , Paiva Artur
Published: December 2022

Colorectal cancer (CRC) is one of the most common cancers worldwide, with liver metastasis being its main cause of death. This study harvested fresh biological material from non-tumor and tumor tissue from 47 patients with CRC liver metastasis after surgery, followed by mechanical cellular extraction and stain-lyse-wash direct immunofluorescence technique. Here, 60 different T-cell populations were characterized by flow cytometry. Tumor samples were also subdivided according to their growth pattern into desmoplastic and non-desmoplastic. When we compared tumor versus non-tumor samples, we observed a significantly lower percentage of T-lymphocyte infiltration in the tumor in which the CD4+ T-cell density increased compared to the CD8+ T cells. T regulatory cells also increased within the tumor, even with an activated phenotype (HLA-DR+). A higher percentage of IL-17-producing cells was present in tumor samples and correlated with the metastasis size. In contrast, we also observed a significant increase in CD8+ follicular-like T cells (CD185+), suggesting a cytotoxic response to cancer cells. Additionally, most infiltrated T cells exhibit an intermediate activation phenotype (CD25+). In conclusion, our results revealed potential new targets and prognostic biomarkers that could take part in an algorithm for personalized medicine approaches improving CRC patients’ outcomes.
Androgen Receptor Signaling Inhibition in Advanced Castration Resistance Prostate Cancer: What Is Expected for the Near Future?
Authors: Pozas Javier , Álvarez Rodríguez Sara , Fernández Víctor Albarrán , Burgos Javier , Santoni Matteo , Manneh Kopp Ray , Molina-Cerrillo Javier , Alonso-Gordoa Teresa
Published: December 2022

The androgen signaling pathway is the cornerstone in the treatment of high risk or advanced prostate cancer patients. However, in recent years, different mechanisms of resistance have been defined in this field, limiting the efficacy of the currently approved antiandrogen drugs. Different therapeutic approaches are under research to assess the role of combination therapies against escape signaling pathways or the development of novel antiandrogen drugs to try to solve the primary or acquired resistance against androgen dependent or independent pathways. The present review aims to summarize the current state of androgen inhibition in the therapeutic algorithm of patients with advanced prostate cancer and the mechanisms of resistance to those available drugs. In addition, this review conducted a comprehensive overview of the main present and future research approaches in the field of androgen receptor inhibition to overcome these resistances and the potential new drugs under research coming into this setting.
Cytology Smears: An Enhanced Alternative Method for Colorectal Cancer pN Stage—A Multicentre Study
Authors: Diaz-Mercedes Sherley , Archilla Ivan , Lahoz Sara , Rodrigo-Calvo Maria Teresa , Lopez-Prades Sandra , Tarragona Jordi , Landolfi Stefania , Concha Angel , Machado Isidro , Maurel Joan , Chic Nuria , Castells Antoni , Balaguer Francesc , Camps Jordi , Cuatrecasas Miriam
Published: December 2022

Stage II colorectal cancer (CRC) recurrence remains a clinical problem. Some of these patients are true stage III CRC with a pN0 pathology stage. This large prospective multicentre cohort study aimed at evaluating the diagnostic ability of lymph node (LN) cytology smears to perform the pN stage and compare it with the conventional haematoxylin and eosin (H&E) pathology pN stage. Additionally, we used the One-Step Nucleic Acid Amplification (OSNA), a high-sensitive molecular method of LN staging. A total of 3936 fresh LNs from 217 CRC surgical specimens were examined by three methods, H&E, LN cytology smears, and OSNA. H&E detected 29% of patients with positive LNs, cytology smears 35%, and OSNA 33.2% (p < 0.0001). H&E and cytology concordantly classified 92.2% of tumours, and 88.5% between OSNA and H&E. Cytology had 96.8% sensitivity and 90.3% specificity to discriminate positive/negative patients compared to H&E (p = 0.004), and 87.3% sensitivity and 89% specificity when compared to OSNA (p = 0.56). Patients with positive LNs detected by any of the three methods had significantly worse disease-free and overall survival. We conclude that pN stage accuracy for detecting positive LNs is superior with LN cytological smears than with conventional H&E, which would enable a better pN stage and management of early-stage CRC patients.
Selection Criteria and Treatment Outcome for Advanced Non-Small Cell Lung Cancer (NSCLC) Patients Unfit for Platinum-Based First-Line Therapy: Results of the MOON-OSS Observational Trial
Authors: Camerini Andrea , Del Conte Alessandro , Pezzuto Aldo , Scotti Vieri , Facchinetti Francesco , Ciccone Lucia Pia , Perna Marco , Sartori Giulia , Puccetti Cheti , Ricci Alberto , Santo Antonio , Tiseo Marcello , Amoroso Domenico
Published: December 2022

Limited evidence is available concerning the selection criteria and the outcomes of platinum unfit newly diagnosed advanced NSCLC patients receiving single-agent chemotherapy. We retrospectively collected data on consecutive, stage IIIB-IV, EGFR/ALK negative and PD-L1 < 50% NSCLC patients treated with first-line single agent chemotherapy. Baseline characteristics, outcome measures and toxicities were recorded, as well as criteria according to which treatment selection was made and what percentage of patients did not receive a first-line platinum-based chemotherapy. Two-hundred and twenty-one patients were included. Median age was 79 (range 56–92) years, M/F 165(74.6%)/56(25.4%), ECOG performance status (PS) 0/1/ ≥ 2 23(10.9%)/94(42.5%)/103(46.6%), with a median of two serious comorbidities. A median of 25% (range 10%-30%) of newly diagnosed NSCLC did not receive a first-line platinum combination. Clinical criteria according to which decision was made were older age (76.5%), comorbidities (72%), poor PS (55.2%) and familiar or social issues (10%). Single-agent treatment consisted of oral metronomic vinorelbine (MetV 78.6%), gemcitabine (Gem 10%), oral standard vinorelbine (Vin 8.2%) and other (O 3.2%). Median progression-free survival (PFS) and overall survival (OS) of single agent treatments ranged from 4.5 to 5 months and from 9 to 10.5 months, respectively. All grade toxicities did not differ among single agents, while grade 3–4 toxicities were less frequent with MetV. Up to 30% of newly diagnosed advanced EGFR/ALK negative and PD-L1 < 50% NSCLC patients do not receive a first-line platinum doublet. Main clinical selection criteria were older age (>70 years), comorbidities and poor PS. An oral treatment was frequently proposed with MetV being the most frequent choice according to its safety profile.
Increased MARCKS Activity in BRAF Inhibitor-Resistant Melanoma Cells Is Essential for Their Enhanced Metastatic Behavior Independent of Elevated WNT5A and IL-6 Signaling
Authors: Yadav Vikas , Jobe Njainday , Satapathy Shakti Ranjan , Mohapatra Purusottam , Andersson Tommy
Published: December 2022

Treatment of melanoma with a BRAF inhibitor (BRAFi) frequently initiates development of BRAFi resistance, leading to increased tumor progression and metastasis. Previously, we showed that combined inhibition of elevated WNT5A and IL-6 signaling reduced the invasion and migration of BRAFi-resistant (BRAFi-R) melanoma cells. However, the use of a combined approach per se and the need for high inhibitor concentrations to achieve this effect indicate a need for an alternative and single target. One such target could be myristoylated alanine-rich C-kinase substrate (MARCKS), a downstream target of WNT5A in BRAFi-sensitive melanoma cells. Our results revealed that MARCKS protein expression and activity are significantly elevated in PLX4032 and PLX4720 BRAFi-R A375 and HTB63 melanoma cells. Surprisingly, neither WNT5A nor IL-6 contributed to the increases in MARCKS expression and activity in BRAFi-R melanoma cells, unlike in BRAFi-sensitive melanoma cells. However, despite the above findings, our functional validation experiments revealed that MARCKS is essential for the increased metastatic behavior of BRAFi-R melanoma cells. Knockdown of MARCKS in BRAFi-R melanoma cells caused reductions in the F-actin content and the number of filopodia-like protrusions, explaining the impaired migration, invasion and metastasis of these cells observed in vitro and in an in vivo zebrafish model. In our search for an alternative explanation for the increased activity of MARCKS in BRAFi-R melanoma cells, we found elevated basal activities of PKCα, PKCε, PKCι, and RhoA. Interestingly, combined inhibition of basal PKC and RhoA effectively impaired MARCKS activity in BRAFi-R melanoma cells. Our results reveal that MARCKS is an attractive single antimetastatic target in BRAFi-R melanoma cells.
Current Insights and Progress in the Clinical Management of Head and Neck Cancer
Authors: Amaral Mariana Neves , Faísca Pedro , Ferreira Hugo Alexandre , Gaspar Maria Manuela , Reis Catarina Pinto
Published: December 2022

Head and neck cancer (HNC), also known as the cancer that can affect the structures between the dura mater and the pleura, is the 6th most common type of cancer. This heterogeneous group of malignancies is usually treated with a combination of surgery and radio- and chemotherapy, depending on if the disease is localized or at an advanced stage. However, most HNC patients are diagnosed at an advanced stage, resulting in the death of half of these patients. Thus, the prognosis of advanced or recurrent/metastatic HNC, especially HNC squamous cell carcinoma (HNSCC), is notably poorer than the prognosis of patients diagnosed with localized HNC. This review explores the epidemiology and etiologic factors of HNC, the histopathology of this heterogeneous cancer, and the diagnosis methods and treatment approaches currently available. Moreover, special interest is given to the novel therapies used to treat HNC subtypes with worse prognosis, exploring immunotherapies and targeted/multi-targeted drugs undergoing clinical trials, as well as light-based therapies (i.e., photodynamic and photothermal therapies).
Cellular and Molecular Effects of Eribulin in Preclinical Models of Hematologic Neoplasms
Authors: Vicari Hugo Passos , Lima Keli , Costa-Lotufo Leticia Veras , Machado-Neto João Agostinho
Published: December 2022

Despite the advances in understanding the biology of hematologic neoplasms which has resulted in the approval of new drugs, the therapeutic options are still scarce for relapsed/refractory patients. Eribulin is a unique microtubule inhibitor that is currently being used in the therapy for metastatic breast cancer and soft tissue tumors. Here, we uncover eribulin’s cellular and molecular effects in a molecularly heterogeneous panel of hematologic neoplasms. Eribulin reduced cell viability and clonogenicity and promoted apoptosis and cell cycle arrest. The minimal effects of eribulin observed in the normal leukocytes suggested selectivity for malignant blood cells. In the molecular scenario, eribulin induces DNA damage and apoptosis markers. The ABCB1, ABCC1, p-AKT, p-NFκB, and NFκB levels were associated with responsiveness to eribulin in blood cancer cells, and a resistance eribulin-related target score was constructed. Combining eribulin with elacridar (a P-glycoprotein inhibitor), but not with PDTC (an NFkB inhibitor), increases eribulin-induced apoptosis in leukemia cells. In conclusion, our data indicate that eribulin leads to mitotic catastrophe and cell death in blood cancer cells. The expression and activation of MDR1, PI3K/AKT, and the NFκB-related targets may be biomarkers of the eribulin response, and the combined treatment of eribulin and elacridar may overcome drug resistance in these diseases.
Dual NGS Comparative Analysis of Liquid Biopsy (LB) and Formalin-Fixed Paraffin-Embedded (FFPE) Samples of Non-Small Cell Lung Carcinoma (NSCLC)
Authors: Buburuzan Laura , Zamfir (Irofei) Maria-Anca , Ardeleanu Carmen Maria , Muresan Alin Horatiu , Vasilescu Florina , Hudita Ariana , Costache Marieta , Galateanu Bianca , Puscasu Alexandra , Filippi Alexandru , Motas Natalia
Published: December 2022

Lung cancer ranks second worldwide after breast cancer and third in Europe after breast and colorectal cancers when both sexes and all ages are considered. In this context, the aim of this study was to emphasize the power of dual analysis of the molecular profile both in tumor tissue and plasma by NGS assay as a liquid biopsy approach with impact on prognosis and therapy modulation in NSCLC patients. NGS analysis was performed both from tissue biopsies and from cfNAs isolated from peripheral blood samples. Out of all 29 different mutations detectable by both NGS panels (plasma and tumor tissue), seven different variants (24.13%; EGFR L858R in two patients, KRAS G13D and Q61H and TP53 G244D, V197M, R213P, and R273H) were detected only in plasma and not in the tumor itself. These mutations were detected in seven different patients, two of them having known distant organ metastasis. Our data show that NGS analysis of cfDNA could identify actionable mutations in advanced NSCLC and, therefore, this analysis could be used to monitor the disease progression and the treatment response and even to modulate the therapy in real time.
A Meta-Analysis on the Impact of the COVID-19 Pandemic on Cutaneous Melanoma Diagnosis in Europe
Authors: Seretis Konstantinos , Bounas Nikolaos , Gaitanis Georgios , Bassukas Ioannis
Published: December 2022

The COVID-19 pandemic has been the epicenter of healthcare attention globally for the past two years, and large-scale adaptations in healthcare provision have been required. This study aimed to investigate the impact of the pandemic and the resulting lockdowns on cutaneous melanoma diagnosis and tumor burdens in Europe. A relevant literature search in electronic databases was conducted from inception to September 2022. The inclusion criteria were: controlled studies published in a peer-reviewed journal evaluating cutaneous melanoma in Europe and reporting data on melanoma characteristics from diagnoses. The quality of studies was evaluated using the Cochrane ROBINS-I tool for assessing bias in non-randomized studies. Meta-analysis was conducted utilizing a random effects model to synthesize the data. A total of 25 studies involving 32,231 patients were included in the data analysis models. Statistically significant increases in mean Breslow thickness (0.29 mm (0.03–0.55 mm)), ulceration rates (OR = 1.66 (1.29–2.13)), and resultant tumor staging were observed in the PostCovid group, with subgroup analysis revealing that lockdown-derived data were responsible for this trend. This meta-analysis reported on the impact of COVID-19 restrictions on melanoma diagnosis in Europe, emphasizing the higher tumor burden and disease progression state provoked by healthcare adaptations in the pandemic period.
Neurological Complications of Conventional and Novel Anticancer Treatments
Authors: Alberti Paola , Salvalaggio Alessandro , Argyriou Andreas A. , Bruna Jordi , Visentin Andrea , Cavaletti Guido , Briani Chiara
Published: December 2022

Various neurological complications, affecting both the central and peripheral nervous system, can frequently be experienced by cancer survivors after exposure to conventional chemotherapy, but also to modern immunotherapy. In this review, we provide an overview of the most well-known adverse events related to chemotherapy, with a focus on chemotherapy induced peripheral neurotoxicity, but we also address some emerging novel clinical entities related to cancer treatment, including chemotherapy-related cognitive impairment and immune-mediated adverse events. Unfortunately, efficacious curative or preventive treatment for all these neurological complications is still lacking. We provide a description of the possible mechanisms involved to drive future drug discovery in this field, both for symptomatic treatment and neuroprotection.
Changes in ALBI Score and PIVKA-II within Three Months after Commencing Atezolizumab Plus Bevacizumab Treatment Affect Overall Survival in Patients with Unresectable Hepatocellular Carcinoma
Authors: Unome Shinji , Imai Kenji , Takai Koji , Miwa Takao , Hanai Tatsunori , Nishigaki Yoichi , Hayashi Hideki , Kochi Takahiro , Shimizu Shogo , Nagano Junji , Iritani Soichi , Suetsugu Atsushi , Shimizu Masahito
Published: December 2022

In this study, we aimed to evaluate the efficacy and safety of atezolizumab plus bevacizumab (Atez/Bev) treatment for unresectable hepatocellular carcinoma (HCC) and to analyze the factors affecting overall survival (OS). A total of 69 patients who received Atez/Bev at our institutions for unresectable HCC were enrolled in this study. OS and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Changes in clinical indicators within 3 months were defined as delta (∆) values, and the Cox proportional hazards model was used to identify which ∆ values affected OS. The median OS, PFS, objective response rate, and disease control rate were 12.5 months, 5.4 months, 23.8%, and 71.4%, respectively. During the observational period, 62 patients (92.5%) experienced AEs (hypertension (33.3%) and general fatigue), and 27 patients (47.4%) experienced grade ≥ 3 AEs (hypertension (10.1%) and anemia (7.2%)). There was a significant deterioration in the albumin-bilirubin (ALBI) score (−2.22 to −1.97; p < 0.001), and a reduction in PIVKA-II levels (32,458 to 11,584 mAU/mL; p = 0.040) within 3 months after commencing Atez/Bev. Both the worsening ∆ ALBI score (p = 0.005) and increasing ∆ PIVKA-II (p = 0.049) were significantly associated with the OS of patients.
Prognostic Indicators of EIF1AX-Mutated Thyroid Tumor Malignancy and Cancer Aggressiveness
Authors: Bandargal Saruchi , Chen Tanya , Pusztaszeri Marc Philippe , Forest Véronique-Isabelle , da Silva Sabrina Daniela , Payne Richard J.
Published: December 2022

The risk of malignancy (ROM) of EIF1AX-mutated thyroid nodules has been theorized to be contingent on the position of the mutation within the gene and the presence of co-existing mutations. However, due to EIF1AX’s low mutation frequency, sample sizes currently reported in the literature are too diminutive to appraise the clinical utility of molecular diagnostic testing. The objective of this study was to elucidate prognostic indicators of EIF1AX-mutated thyroid tumors and cancer aggressiveness by examining a large cohort of cytologically indeterminate thyroid nodules (CITNs) that underwent molecular testing and subsequent surgical resection. This is a multicenter study involving 764 subtotal and total thyroidectomy patients that underwent preoperative molecular testing at two quaternary care hospitals. A five-year retrospective review was performed on the 42 charts of patients that opted for surgery following a positive EIF1AX mutation on ThyroseqV3 results from January 2018 to May 2022. Patient demographics, cytopathology results, molecular testing results, and postoperative histopathology were reviewed. Of the 42 surgically resected nodules that harbored an EIF1AX mutation, 16 (38.1%) were benign, six (14.3%) were non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs) or well-differentiated thyroid neoplasms of uncertain malignant potential (WDT-UMPs), and 20 (47.6%) were malignant. An isolated EIF1AX mutation conferred a ROM of 47.6%, whereas the ROM for nodules with at least one additional molecular alteration was 72.7%. The ROM increased to 100% for nodules with at least one additional molecular alteration and the A113_splice site mutation. Six malignant nodules were aggressive, with five having variegated components of poorly differentiated thyroid carcinoma (PDTC). EIF1AX-mutated thyroid nodules are more susceptible to malignancy in the presence of the A113_splice site mutation and when co-mutated with RAS and/or TP53. This deleterious amalgam is associated with aggressive disease and renders these nodules PDTC. A preoperative molecular test finding of an EIF1AX mutation can be a useful tool for thyroid specialists to optimize clinical management.
Prospective Investigation of 18FDG-PET/MRI with Intravoxel Incoherent Motion Diffusion-Weighted Imaging to Assess Survival in Patients with Oropharyngeal or Hypopharyngeal Carcinoma
Authors: Chan Sheng-Chieh , Yeh Chih-Hua , Ng Shu-Hang , Lin Chien-Yu , Wang Jen-Hung , Chang Joseph Tung-Chieh , Cheng Nai-Ming , Chang Kai-Ping , Hsieh Jason Chia-Hsun
Published: December 2022

To prospectively investigate the prognostic value of 18F-FDG PET/MRI in patients with oropharyngeal or hypopharyngeal squamous cell carcinomas (OHSCC) treated by chemoradiotherapy. The study cohort consisted of patients with OHSCC who had undergone integrated PET/MRI prior to chemoradiotherapy or radiotherapy. Imaging parameters derived from intravoxel incoherent motion (IVIM), dynamic contrast-enhanced MRI (DCE-MRI), and 18F-FDG PET were analyzed in relation to overall survival (OS) and recurrence-free survival (RFS). In multivariable analysis, T classification (p < 0.001), metabolic tumor volume (p = 0.013), and pseudo-diffusion coefficient (p = 0.008) were identified as independent risk factors for OS. The volume transfer rate constant (p = 0.015), initial area under the curve (p = 0.043), T classification (p = 0.018), and N classification (p = 0.018) were significant predictors for RFS. The Harrell’s c-indices of OS and RFS obtained from prognostic models incorporating clinical and PET/MRI predictors were significantly higher than those derived from the traditional TNM staging system (p = 0.001). The combination of clinical risk factors with functional parameters derived from IVIM and DCE-MRI plus metabolic PET parameters derived from 18F-FDG PET in integrated PET/MRI outperformed the information provided by traditional TNM staging in predicting the survival of patients with OHSCC.