bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival Evidence of Local Control for Colorectal Cancer Liver Metastases by Hepatectomy and/or Radiofrequency Ablation
Authors: Canseco Lariza Marie , Liu Yueh-Wei , Lu Chien-Chang , Lee Ko-Chao , Chen Hong-Hwa , Hu Wan-Hsiang , Tsai Kai-Lung , Yang Yao-Hsu , Wang Chih-Chi , Hung Chao-Hung
Published: September 2023

Hepatectomy and/or local ablation therapy have been recommended for colorectal cancer liver metastases (CRLM). However, they still lack strong evidence for their survival benefits, in addition to systemic therapy. This study aims to evaluate the survival evidence of hepatectomy and/or radiofrequency ablation (RFA) therapy in CRLM patients from a large multi-institutional database. A total of 20,251 patients with colorectal cancer, 4521 of whom were with CRLM, were screened for eligibility. Finally, 2612 patients (637 hepatectomy, 93 RFA, 92 combined hepatectomy and RFA, and 1790 non-aggressive treatment) were enrolled. Frequency matching analysis was used to adjust for baseline differences. The 5-year overall survival (OS) was as follows: hepatectomy alone was 47.8%, combined hepatectomy plus RFA was 35.9%, RFA alone was 29.2%, and the non-aggressive treatment group was 7.4%. Kaplan–Meier curves showed that hepatectomy, RFA, and combination were significantly associated with a better OS compared to those without aggressive local therapy (p < 0.001). Multivariate Cox regression analysis showed that male gender (hazard ratio (HR) 0.89; 95% confidence interval (CI), 0.81–0.97; p = 0.011), old age (≥60 years) (HR 1.20; 95% CI, 1.09–1.32; p < 0.001), high CEA level (>5 ng/mL) (HR 2.14; 95% CI, 1.89–2.42; p < 0.001), primary right-sided cancer (HR 1.35; 95% CI, 1.22–1.51; p < 0.001), extrahepatic metastasis (HR 1.46; 95% CI, 1.33–1.60; p < 0.001), systemic therapy (HR 0.7; 95% CI, 0.62–0.79; p < 0.001), and aggressive local therapy (hepatectomy vs. non-local therapy HR 0.22; 95% CI, 0.20–0.26; p < 0.001; RFA vs. non-local therapy HR 0.29; 95% CI, 0.29–0.41; p < 0.001) were independent factors associated with OS. In the frequency matching analysis, patients receiving hepatectomy and/or RFA resulted in a better OS than those without (p < 0.001). In conclusion, aggressive local treatment provides survival advantages over systemic therapy alone among CRLM patients.
COMBI-r: A Prospective, Non-Interventional Study of Dabrafenib Plus Trametinib in Unselected Patients with Unresectable or Metastatic BRAF V600-Mutant Melanoma
Authors: Berking Carola , Livingstone Elisabeth , Debus Dirk , Loquai Carmen , Weichenthal Michael , Leiter Ulrike , Kiecker Felix , Mohr Peter , Eigentler Thomas K. , Remy Janina , Schober Katharina , Heppt Markus V. , von Wasielewski Imke , Schadendorf Dirk , Gutzmer Ralf
Published: September 2023

Combined BRAF/MEK-inhibition constitutes a relevant treatment option for BRAF-mutated advanced melanoma. The prospective, non-interventional COMBI-r study assessed the effectiveness and tolerability of the BRAF-inhibitor dabrafenib combined with the MEK-inhibitor trametinib in patients with advanced melanoma under routine clinical conditions. Progression-free survival (PFS) was the primary objective, and secondary objectives included overall survival (OS), disease control rate, duration of therapy, and the frequency and severity of adverse events. This study enrolled 472 patients at 55 German sites. The median PFS was 8.3 months (95%CI 7.1–9.3) and the median OS was 18.3 months (14.9–21.3), both tending to be longer in pre-treated patients. In the 147 patients with CNS metastases, PFS was similar in those requiring corticosteroids (probably representing symptomatic patients, 5.6 months (3.9–7.2)) compared with those not requiring corticosteroids (5.9 months (4.8–6.9)); however, OS was shorter in patients with brain metastases who received corticosteroids (7.8 (6.3–11.6)) compared to those who did not (11.9 months (9.6–19.5)). The integrated subjective assessment of tumor growth dynamics proved helpful to predict outcome: investigators’ upfront categorization correlated well with time-to-event outcomes. Taken together, COMBI-r mirrored PFS outcomes from other prospective, observational studies and confirmed efficacy and safety findings from the pivotal phase III COMBI-d/-v and COMBI-mb trials.
D-Dimer Assessment to Predict Pulmonary Embolism in ICU Patients with COVID-19 Pneumonia
Authors: Louwsma Jelger , Langeveld Bas , Luyendijk Jacqueline M. , van den Oever Huub L. A.
Published: September 2023

The value of D-dimer assessments in ICU patients with COVID-19 for the prediction of pulmonary embolism (PE) is unclear. The present study had two purposes: 1. To assess the specificity of elevated absolute D-dimer values for PE on admission to the ICU. 2. To assess the specificity of a D-dimer increment for the development of PE during an ICU stay. D-dimer values were paired with the results of a CT pulmonary angiogram (CTPA) and compared in patients with and without PE on admission. In patients without PE on initial imaging and available repeat CTPA during an ICU stay, D-dimer increments between initial and repeat imaging of patients developing PE during an ICU stay were compared with those with persistently no PE. On admission, D-dimers in patients with PE were higher than those in patients without PE (median 850 vs. 6060 μg/L; p < 0.0001). Using a cut-off of 9000 μg/L, the specificity for predicting PE was 100% (CI 95.3–100%). Delta D-dimer during an ICU stay was greater in patients with PE (median 7983 vs. 3815 μg/L; p < 0.005). Using a cut-off of 8000 μg/L, specificity was 100% (CI 79.4–100%). Strongly elevated D-dimer values on admission and marked increases in D-dimer during ICU stays have a high specificity for predicting pulmonary embolism in critically ill COVID-19 patients.
Diagnostic Performance of Preoperative Imaging in Endometrial Cancer
Authors: Hashimoto Chiaki , Shigeta Shogo , Shimada Muneaki , Shibuya Yusuke , Ishibashi Masumi , Kageyama Sakiko , Sato Tomomi , Tokunaga Hideki , Takase Kei , Yaegashi Nobuo
Published: September 2023

Background: Endometrial cancer is one of the most common gynecological malignancies. Because the findings mentioned in radiogram interpretation reports issued by diagnostic radiologists influence treatment strategies, we aimed to evaluate the diagnostic accuracy of preoperative computed tomography (CT) and magnetic resonance imaging (MRI) interpretation results in clinically relevant settings. Methods: The clinical records of patients diagnosed with endometrial cancer treated at Tohoku University Hospital from January 2012 to December 2021 were reviewed. The preoperative and pathologically estimated cancer stages were compared based on the results mentioned in the radiogram interpretation report. Results: The preoperative and postoperative cancer stages were concordant in 70.0% of the patients. By contrast, the cancer stage was underdiagnosed and overdiagnosed in 21.7% and 8.2% of the patients, respectively. The sensitivities of MRI for deep myometrial invasion, cervical stromal invasion, vaginal invasion, and adnexal metastasis were 65.1%, 58.2%, 33.3%, and 18.4%, respectively. The sensitivity and specificity for pelvic lymph node metastasis using a combination of CT and MRI were 40.9% and 98.4%, respectively. Those for para-aortic lymph node metastases using CT were 37.0% and 99.5%, respectively. Conclusions: The low sensitivity observed in this study clarified the limitations of preoperative diagnostic performance in current clinical practice.
The Confusion Assessment Method Could Be More Accurate than the Memorial Delirium Assessment Scale for Diagnosing Delirium in Older Cancer Patients: An Exploratory Study
Authors: Llisterri-Sánchez Paula , Benlloch María , Pérez-Ros Pilar
Published: September 2023

Background: Older people with cancer carry a high risk of delirium, an underdiagnosed syndrome due to its diagnostic complexity and often subtle presentation. Tools based on the Diagnostic and Statistical Manual of Mental Disorders (DSM) are available to different health professionals. Our aim is to assess the prevalence of delirium in older people with cancer in an inpatient unit and the accuracy of the Confusion Assessment Method (CAM) and Memorial Delirium Assessment Scale (MDAS). Methods: This exploratory, cross-sectional study included people aged 65 years or older with a diagnosis of cancer and admitted to the medical oncology unit from June 2021 to December 2022. The diagnostic accuracy of CAM and MDAS was analyzed against the gold standard medical diagnosis based on DSM-5 criteria by two medical oncologists. The cutoff point for the MDAS was determined using a receiver-operating characteristics (ROC) curve. Results. Among the 75 included patients (mean age 71.6 years, standard deviation 4.1; 52% males), the prevalence of delirium was 62.7%. The most prevalent types of cancer in patients with delirium were hematological and lung cancer. The scale with the highest diagnostic accuracy was the CAM, with a sensitivity of 100% and specificity of 86%, followed by the MDAS, with a sensitivity of 88% and specificity of 30%. The presence of cognitive impairment hindered the detection of delirium. Conclusions. The CAM scale was more accurate than the MDAS pre-existing cognitive impairment in our sample. Further studies are needed to analyze the diagnostic accuracy of delirium tools in older populations with cancer and in the presence of cognitive impairment.
“Out-of-Hospital and with Qualified Exercise Professionals”: Keys to the CORTEX-SP Physical Exercise Program According to the Experience of the Participants
Authors: Tous-Espelosin Mikel , Fernandez-Lasa Uxue , Romaratezabala Estibaliz
Published: September 2023

Physical exercise programs are useful and necessary for the treatment of schizophrenia. The aim of this study was to assess the experiences of participants with schizophrenia in an out-of-hospital exercise program designed and supervised by qualified exercise professionals. Thirty-five individuals with schizophrenia from the intervention group of the CORTEX-SP study were interviewed. The interviews were transcribed verbatim and content analysis was performed using inductive coding. Two main categories emerged: the importance of the program being conducted out-of-hospital, and the individuals responsible for the program being qualified exercise professionals. The participants highlighted the importance of conducting the program outside the psychiatric center since it gave them greater satisfaction. They perceived greater seriousness and a greater number of resources and felt encouraged to repeat the program or prolong it. The success of the program, in addition to the space, was due to the personnel in charge of the program, i.e., the qualified exercise professionals, and the fact that the activities were designed and supervised. Participants emphasized the qualifications of the exercise professionals, key for this type of program, their social skills and the level of involvement with participants and their follow-up.
Energy Analysis of a Novel Turbo-Compound System for Mild Hybridization of a Gasoline Engine
Authors: Lombardi Simone , Ricci Federico , Martinelli Roberto , Tribioli Laura , Grimaldi Carlo Nazareno , Bella Gino
Published: September 2023

Efficient and low-polluting mobility is a major demand in all countries. Hybrid electric vehicles have already shown to be suitable to respond to this need, being a reliable alternative to conventional cars, at least in urban environments. Nevertheless, such vehicles present a yet unexplored potential. In this paper, we will investigate how the powertrain efficiency may possibly benefit, in an integrated drivetrain for a hybrid electric vehicle, based on a turbocharged gasoline engine, of an innovative supercharging system. The compressor and turbine will be mechanically decoupled so as to independently optimize their operation, avoiding turbo lag and maximizing energy recovery by completely eliminating the waste-gate valve. This, in turns, requires changing the turbine so as to have a flattest possible efficiency/load curve. Therefore, an ad-hoc designed turbine will be implemented in the decoupled configuration, to be used to drive an electrical generator and produce electrical energy for charging the battery. This study presents a preliminary assessment of the potential of a turbo-compounded system for a 1L turbocharged gasoline engine for a small city car. To this aim, a one-dimensional dynamic model of the engine has been built in GT-Suite and has been calibrated and validated by means of experimental data obtained on a dynamometer, both in steady state and dynamic conditions. In particular, the model has been calibrated by means of experimental data obtained in stationary conditions and its robustness has then been verified through experimental data obtained under transient conditions. The model also includes data retrieved from the characterization of the existing turbine and compressor, while a new performance map for the turbine has been designed to better exploit the potential of the components’ decoupling. Results include the estimation of energy recovery potential of such a solution. Under the implementation of a straightforward control strategy, which runs both compressor and turbine at the same speed, the system is able to achieve a 60.57% increase in energy recovered from the exhaust gasses in the turbine. Afterwards, an attempt was made to limit the minimum turbine speed to 45000 rpm and simultaneously decrease the instantaneous speed by 3000 rpm compared to the compressor, attaining a further increase of 1.7% in the energy recovered by the turbine.
Research on the Effect of Fire Thermal Energy on the Microstructure and Properties Mechanical of Fiber-Reinforced Cement Mortars
Authors: Ogrodnik Paweł , Rutkowska Gabriela , Powęzka Aleksandra , Żółtowski Mariusz , Szulej Jacek , Wiśniewski Krzysztof , Howorus Patryk
Published: September 2023

Cement mortar is made of a combination of cement, sand, and water, mixed in the right proportions. It is ideal for erecting walls and masonry structures, including those that must bear heavy loads. In addition, it is used in places that are exposed to higher humidity and in facilities located below ground level. The potential uses of a mortar are determined by material modification. The aim of the experimental studies was to evaluate the effect of high temperature on the microstructure and mechanical properties of cement mortars modified with polypropylene fiber. The novelty of this study is an attempt to compare the use of different types of polypropylene fibers in mortars heated at different temperatures. Cement mortars based on Portland cement CEM I 42.5 R with a constant content of three types of fibers in the amount of 0.9 kg/m3 were designed. The samples were cured and then heated in an oven at 300, 500 and 700 °C. The functional properties of cement mortars, i.e., density, flexural and compressive strength after 28 and 56 days of maturation, as well as flexural and compressive strength at elevated temperature, were determined using samples of 40 × 40 × 160 mm. By modifying cement mortars with fibers, it is possible to obtain a cement composite with good strength parameters which is, at the same time, resistant to high temperature.
Modeling and Predicting the Mechanical Behavior of Standard Insulating Kraft Paper Used in Power Transformers under Thermal Aging
Authors: Sayadi Ahmed , Mahi Djillali , Fofana Issouf , Bessissa Lakhdar , Bessedik Sid Ahmed , Arroyo-Fernandez Oscar Henry , Jalbert Jocelyn
Published: September 2023

The aim of this research is to predict the mechanical properties along with the behaviors of standard insulating paper used in power transformers under thermal aging. This is conducted by applying an artificial neural network (ANN) trained with a multiple regression model and a particle swarm optimization (MR-PSO) model. The aging of the paper insulation is monitored directly by the tensile strength and the degree of polymerization of the solid insulation and indirectly by chemical markers using 2-furfuraldehyde compound content in oil (2-FAL). A mathematical model is then developed to simulate the mechanical properties (degree of polymerization (DPV) and tensile index (Tidx)) of the aged insulation paper. First, the datasets obtained from experimental results are used to create the MR model, and then the optimizer method PSO is used to optimize its coefficients in order to improve the MR model. Then, an ANN method is trained using the MR-PSO to create a nonlinear correlation between the DPV and the time, temperature, and 2-FAL values. The acquired results are assessed and compared with the experimental data. The model presents almost the same behavior. In particular, it has the capability to accurately simulate the nonlinear property behavior of insulation under thermal aging with an acceptable margin of error. Since the life expectancy of power transformers is directly related to that of the insulating paper, the proposed model can be useful to maintenance planners.
Post-Fire Restoration and Deadwood Management: Microsite Dynamics and Their Impact on Natural Regeneration
Authors: Lingua Emanuele , Marques Gonçalo , Marchi Niccolò , Garbarino Matteo , Marangon Davide , Taccaliti Flavio , Marzano Raffaella
Published: September 2023

After large and severe wildfires, the establishment of tree regeneration, particularly for species without specific fire-adaptive traits, can be challenging. Within harsh environments, the presence of favorable microsites, as those provided by deadwood, enhancing microclimatic conditions, is crucial to the re-establishment of forest cover and thus to foster recovery dynamics. Active restoration strategies can have an impact on these dynamics, altering or hindering them. The main hypothesis of this study is that manipulating deadwood in terms of quantity and spatial arrangement can result in differences in natural regeneration density and composition. Post-disturbance regeneration dynamics and the role played by deadwood over time in the creation of safe sites for seedling establishment were investigated in an area affected by a high-severity wildfire that underwent different post-fire restoration treatments along a gradient of increasing deadwood manipulation, spanning from salvage logging to non-intervention. Two inventories were performed 5 and 11 years after the fire. Ground cover proportion was significantly different among treatments, with lower values of lying deadwood in salvaged sites. A higher probability of regeneration establishment close to deadwood was found in both surveys, confirming the facilitating role of deadwood on post-fire forest regeneration. Microsite dynamics resulting from deadwood facilitation were highlighted, with establishment probability and anisotropic relationships between deadwood elements and seedlings changing over time, as recovery processes slowly improved environmental conditions. In dry mountain areas affected by stand-replacing wildfires, by removing deadwood, salvage logging reduces the number of safe sites for regeneration, further impairing the ecosystem recovery. Passive management should be the ecologically preferred management strategy in these conditions, although intermediate interventions (e.g., felling without delimbing, leaving deadwood on the ground) could be effective alternatives, accelerating snag fall dynamics and immediately increasing favorable microsite availability.
Biomass Harvesting from Salvage Clearcuts on Young Eucalypt Stands and Post-Wildfire Pine Thinnings with Fixteri FX15a Feller-Bundler in Spain
Authors: Tolosana Eduardo , Laina Rubén , González-Prieto Óscar
Published: September 2023

We studied two Eucalyptus globulus salvage clearcuts—after a wildfire and a Gonipterus attack—and a strong thinning on a dense Pinus pinaster stand which was regenerated 20 years after a wildfire and also affected by a Matsococcus pest. Biomass harvesting was performed using the feller-bundler Fixteri FX-15a, which was time-studied during several weeks using GNSS combined with an automatic weight/time registration system (WNexus-2®). Detailed in situ time studies were applied during shorter periods as well. The productivity equations found as main explanative factors for the salvage clearcuts the unit weight per tree and the felling reason (wildfire vs. pest); for the thinning, besides the unit weight, the percentage of extracted basal area explained the productivity. Biomass collection did not allow an economic positive balance: in the Gonipterus-affected plantation the cost was reduced to 125 €·ha−1, reaching a zero balance for unit weights greater than 33 kg (dry matter) per tree; the restoration cost in the pine stand was 265 €·ha−1, much lower than the cost without biomass harvesting. In the burned eucalypt, the zero cost would be achieved for a dry unit weight much greater than the observed values. Although Fixteri performance and utilization were remarkable, recommendations about possible improvements of its design and operation were concluded from the detailed time studies.
Genetic Uniqueness and Genetic Structure of Populations of Picea obovata Ledeb. and Larix sibirica Ledeb. in the Northern and Middle Urals
Authors: Zhulanov Andrei , Chertov Nikita , Nechaeva Yulia , Pechenkina Viktoriia , Zhulanova Larisa , Boronnikova Svetlana , Kalendar Ruslan
Published: September 2023

Establishing sustainable plantations with genetic diversity equivalent to that of natural populations is vital for successful reforestation efforts. In this study, we present an innovative approach for selecting populations suitable for reforestation, taking into account their genetic uniqueness using Inter Simple Sequence Repeats (ISSR) markers. Our investigation focused on six populations of Picea obovata Ledeb and six populations of Larix sibirica Ledeb, collected from the Northern and Middle Urals. We found that the indicators of genetic diversity were significantly higher in L. sibirica compared to P. obovata, while the number of rare alleles was greater in Siberian spruce (R = 19). Among the P. obovata populations, the Cherdyn’s forestry exhibited notably high genetic diversity, and for L. sibirica, the Gainy’s forestry stood out in this regard. Moreover, the genetic subdivision of the six P. obovata populations (GST = 0.331) was higher than that of the six L. sibirica populations (GST = 0.177). To ensure optimal seed selection considering the genetic originality coefficient (GOC) and population differentiation, we recommend utilizing the P. obovata population from Gainy’s forestry with a GOC of 0.554 and the L. sibirica population from Cherdyn’s forestry with a GOC of 0.372. These populations harbor typical alleles characteristic of the research region, making them ideal candidates for seed selection. Furthermore, the specific alleles identified can serve as valuable markers for determining the geographic origin of P. obovata and L. sibirica wood, aiding in efforts to trace the sources of these species in forestry and trade practices.
Experimental and Numerical Studies on the Explosion Characteristics of Ethanol–Air Mixtures under Aviation Conditions
Authors: Ning Xiaoyao , Zhang Zhihui , Zheng Kangxue , Wang Xuehui , Wang Jian
Published: September 2023

As a representative renewable biofuel, ethanol can reduce mankind’s dependence on petroleum resources and the emission of greenhouse gases and other pollutants. In recent years, the application of ethanol in the aviation field has begun to be a concern of scholars. As ethanol is a flammable liquid, it is significant to study its explosion characteristics in aviation conditions from a safety perspective. In this work, at 20 kPa, the explosion characteristics of ethanol–air mixtures (concentration 6~12%) were experimentally and numerically studied under an initial temperature range of 303 K~363 K. The effects of the initial temperature and concentration on the maximum explosion pressure, maximum rate of pressure rise, explosion time, and fast burning time were analyzed. In addition, the heat loss fraction and sensitivity analysis were examined and discussed. The main conclusions are as follows: A linear relationship exists between the maximum explosion pressure and the reciprocal of the initial temperature. The maximum rate of a pressure rise appears to decrease or at least approach a constant value as the initial temperature increases. The explosion time is significantly dependent on the concentration. At a constant concentration, the proportions of heat loss are approximately constant except for 12%. In our sensitivity analysis, R1 (H + O2 <=> O + OH) was the dominant elementary reaction.
Comment on Wang et al. Consumption of JUUL vs. Other E-Cigarette Brands among U.S. E-Cigarette Users: Evidence from Wave 5 of the PATH Study. Int. J. Environ. Res. Public Health 2022, 19, 10837
Authors: Foxon Floe , Shiffman Saul
Published: September 2023

This comment is to express concern about an article by Wang et al. [...]
Reply to Foxon, F.; Shiffman, S. Comment on “Wang et al. Consumption of JUUL vs. Other E-Cigarette Brands among U.S. E-Cigarette Users: Evidence from Wave 5 of the PATH Study. Int. J. Environ. Res. Public Health 2022, 19, 10837”
Authors: Wang Yu , Duan Zongshuan , Weaver Scott R. , Popova Lucy , Spears Claire A. , Ashley David L. , Pechacek Terry F. , Eriksen Michael P. , Huang Jidong
Published: September 2023

In this reply, we respond to the comments by Foxon and Shiffman [...]
Family Resilience and Dyadic Coping during the Outbreak of the COVID-19 Pandemic in Italy: Their Protective Role in Hedonic and Eudaimonic Well-Being
Authors: Paleari Francesca Giorgia , Ertan Irem , Cavagnis Lucrezia , Donato Silvia
Published: September 2023

The COVID-19 pandemic outbreak has dramatically worsened people’s psychological well-being. Our aim was to examine for the first time the concurrent and longitudinal relations of family resilience with hedonic and eudaimonic well-being, and the moderating role of socio-demographics. For people having a romantic partner, we also explored whether family resilience and dyadic coping were uniquely related to well-being. One cross-sectional study (N = 325) and one 10-week follow-up study (N = 112) were carried out during the outbreak of the COVID-19 pandemic (April–May 2020) in Northern Italy. Adult participants completed an online questionnaire in both studies. Correlation, multivariate regression, and moderation analyses were carried out with IBM SPSS version 28 and its PROCESS macro. Significance of differences in correlation and regression coefficients was tested through Steiger’s procedure, Wald test, and SUEST method. Family resilience was found to relate more strongly to eudaimonic (versus hedonic) well-being concurrently and to hedonic (versus eudaimonic) well-being longitudinally. The concurrent or longitudinal relations with hedonic well-being were generally stronger for females, part-time workers, and people undergoing multiple stressors. For people having a romantic partner, family resilience was concurrently associated with well-being independently of dyadic coping, whereas dyadic coping was longitudinally related to well-being independently of family resilience. Family resilience was found to protect, in the short term, the psychological well-being of people facing the pandemic outbreak. Its protective role mainly concerned hedonic well-being and was more pronounced for more vulnerable people. For persons having a romantic partner, however, dyadic coping seemed to have equal, if not greater, positive short-term effects.
Euphorbiasteroid Induces Apoptosis as Well as Autophagy through Modulating SHP-1/STAT3 Pathway in Hepatocellular Carcinoma Cells
Authors: Kim Na Young , Sethi Gautam , Um Jae-Young , Ahn Kwang Seok
Published: September 2023

Euphorbiasteroid (EPBS) has gained attention for its activity against human lung cancer and sarcoma; however, its impact on hepatocellular carcinoma has not yet been elucidated. Here, we investigated the cytotoxic effect of EPBS on human hepatocellular carcinoma (HCC) cells. We found that EPBS induced both apoptosis and autophagy in HCC cells. Additionally, we observed that EPBS treatment suppressed the constitutive as well as the inducible activation of a signal transducer and activator of transcription 3 (STAT3) protein expression. Moreover, EPBS promoted the expression of SHP-1 protein and the production of reactive oxidative stress (ROS). Furthermore, the knockdown of SHP-1 by siRNA transfection reversed the effects of EPBS, which have inductive effects related to apoptosis and autophagy. Therefore, EPBS can potentially function as an anti-cancer agent by inducing apoptosis and autophagy when targeting the SHP-1/STAT3 pathway.
Effects of In Utero EtOH Exposure on 18S Ribosomal RNA Processing: Contribution to Fetal Alcohol Spectrum Disorder
Authors: Darbinian Nune , Gallia Gary L. , Darbinyan Armine , Vadachkoria Ekaterina , Merabova Nana , Moore Amos , Goetzl Laura , Amini Shohreh , Selzer Michael E.
Published: September 2023

Fetal alcohol spectrum disorders (FASD) are leading causes of neurodevelopmental disability. The mechanisms by which alcohol (EtOH) disrupts fetal brain development are incompletely understood, as are the genetic factors that modify individual vulnerability. Because the phenotype abnormalities of FASD are so varied and widespread, we investigated whether fetal exposure to EtOH disrupts ribosome biogenesis and the processing of pre-ribosomal RNAs and ribosome assembly, by determining the effect of exposure to EtOH on the developmental expression of 18S rRNA and its cleaved forms, members of a novel class of short non-coding RNAs (srRNAs). In vitro neuronal cultures and fetal brains (11–22 weeks) were collected according to an IRB-approved protocol. Twenty EtOH-exposed brains from the first and second trimester were compared with ten unexposed controls matched for gestational age and fetal gender. Twenty fetal-brain-derived exosomes (FB-Es) were isolated from matching maternal blood. RNA was isolated using Qiagen RNA isolation kits. Fetal brain srRNA expression was quantified by ddPCR. srRNAs were expressed in the human brain and FB-Es during fetal development. EtOH exposure slightly decreased srRNA expression (1.1-fold; p = 0.03). Addition of srRNAs to in vitro neuronal cultures inhibited EtOH-induced caspase-3 activation (1.6-fold, p = 0.002) and increased cell survival (4.7%, p = 0.034). The addition of exogenous srRNAs reversed the EtOH-mediated downregulation of srRNAs (2-fold, p = 0.002). EtOH exposure suppressed expression of srRNAs in the developing brain, increased activity of caspase-3, and inhibited neuronal survival. Exogenous srRNAs reversed this effect, possibly by stabilizing endogenous srRNAs, or by increasing the association of cellular proteins with srRNAs, modifying gene transcription. Finally, the reduction in 18S rRNA levels correlated closely with the reduction in fetal eye diameter, an anatomical hallmark of FASD. The findings suggest a potential mechanism for EtOH-mediated neurotoxicity via alterations in 18S rRNA processing and the use of FB-Es for early diagnosis of FASD. Ribosome biogenesis may be a novel target to ameliorate FASD in utero or after birth. These findings are consistent with observations that gene–environment interactions contribute to FASD vulnerability.
Analysis of the Structural Dynamics of Proteins in the Ligand-Unbound and -Bound States by Diffracted X-ray Tracking
Authors: Oda Masayuki
Published: September 2023

Although many protein structures have been determined at atomic resolution, the majority of them are static and represent only the most stable or averaged structures in solution. When a protein binds to its ligand, it usually undergoes fluctuation and changes its conformation. One attractive method for obtaining an accurate view of proteins in solution, which is required for applications such as the rational design of proteins and structure-based drug design, is diffracted X-ray tracking (DXT). DXT can detect the protein structural dynamics on a timeline via gold nanocrystals attached to the protein. Here, the structure dynamics of single-chain Fv antibodies, helix bundle-forming de novo designed proteins, and DNA-binding proteins in both ligand-unbound and ligand-bound states were analyzed using the DXT method. The resultant mean square angular displacements (MSD) curves in both the tilting and twisting directions clearly demonstrated that structural fluctuations were suppressed upon ligand binding, and the binding energies determined using the angular diffusion coefficients from the MSD agreed well with the binding thermodynamics determined using isothermal titration calorimetry. In addition, the size of gold nanocrystals is discussed, which is one of the technical concerns of DXT.
Transcriptome Signature of Immature and In Vitro-Matured Equine Cumulus–Oocytes Complex
Authors: de la Fuente Alejandro , Scoggin Charles , Bradecamp Etta , Martin-Pelaez Soledad , van Heule Machteld , Troedsson Mats , Daels Peter , Meyers Stuart , Dini Pouya
Published: September 2023

Maturation is a critical step in the development of an oocyte, and it is during this time that the oocyte advances to metaphase II (MII) of the meiotic cycle and acquires developmental competence to be fertilized and become an embryo. However, in vitro maturation (IVM) remains one of the limiting steps in the in vitro production of embryos (IVP), with a variable percentage of oocytes reaching the MII stage and unpredictable levels of developmental competence. Understanding the dynamics of oocyte maturation is essential for the optimization of IVM culture conditions and subsequent IVP outcomes. Thus, the aim of this study was to elucidate the transcriptome dynamics of oocyte maturation by comparing transcriptomic changes during in vitro maturation in both oocytes and their surrounding cumulus cells. Cumulus–oocyte complexes were obtained from antral follicles and divided into two groups: immature and in vitro-matured (MII). RNA was extracted separately from oocytes (OC) and cumulus cells (CC), followed by library preparation and RNA sequencing. A total of 13,918 gene transcripts were identified in OC, with 538 differentially expressed genes (DEG) between immature OC and in vitro-matured OC. In CC, 13,104 genes were expressed with 871 DEG. Gene ontology (GO) analysis showed an association between the DEGs and pathways relating to nuclear maturation in OC and GTPase activity, extracellular matrix organization, and collagen trimers in CC. Additionally, the follicle-stimulating hormone receptor gene (FSHR) and luteinizing hormone/choriogonadotropin receptor gene (LHCGR) showed differential expressions between CC-MII and immature CC samples. Overall, these results serve as a foundation to further investigate the biological pathways relevant to oocyte maturation in horses and pave the road to improve the IVP outcomes and the overall clinical management of equine assisted reproductive technologies (ART).
The Role of Selected Epigenetic Pathways in Cardiovascular Diseases as a Potential Therapeutic Target
Authors: Wołowiec Anna , Wołowiec Łukasz , Grześk Grzegorz , Jaśniak Albert , Osiak Joanna , Husejko Jakub , Kozakiewicz Mariusz
Published: September 2023

Epigenetics is a rapidly developing science that has gained a lot of interest in recent years due to the correlation between characteristic epigenetic marks and cardiovascular diseases (CVDs). Epigenetic modifications contribute to a change in gene expression while maintaining the DNA sequence. The analysis of these modifications provides a thorough insight into the cardiovascular system from its development to its further functioning. Epigenetics is strongly influenced by environmental factors, including known cardiovascular risk factors such as smoking, obesity, and low physical activity. Similarly, conditions affecting the local microenvironment of cells, such as chronic inflammation, worsen the prognosis in cardiovascular diseases and additionally induce further epigenetic modifications leading to the consolidation of unfavorable cardiovascular changes. A deeper understanding of epigenetics may provide an answer to the continuing strong clinical impact of cardiovascular diseases by improving diagnostic capabilities, personalized medical approaches and the development of targeted therapeutic interventions. The aim of the study was to present selected epigenetic pathways, their significance in cardiovascular diseases, and their potential as a therapeutic target in specific medical conditions.
Sardinian Infants of Diabetic Mothers: A Metabolomics Observational Study
Authors: Dessì Angelica , Bosco Alice , Cesare Marincola Flaminia , Pintus Roberta , Paci Giulia , Atzori Luigi , Fanos Vassilios , Piras Cristina
Published: September 2023

Gestational diabetes mellitus (GDM) is a condition characterized by glucose intolerance, with hyperglycemia of varying severity with onset during pregnancy. An uncontrolled GDM can lead to an increased risk of morbidity in the fetus and newborn, and an increased risk of obesity or developing type 2 diabetes, hypertension or neurocognitive developmental impairment in adulthood. In this study, we used nuclear magnetic resonance (NMR) spectroscopy and gas chromatography–mass spectrometry (GS-MS) to analyze the urinary metabolomic profile of newborns of diabetic mothers (NDMs) with the aim of identifying biomarkers useful for the monitoring of NDMs and for early diagnosis of predisposition to develop related chronic diseases. A total of 26 newborns were recruited: 21 children of diabetic mothers, comprising 13 in diet therapy (NDM-diet) and 8 in insulin therapy (NDM-insulin), and 5 control children of non-diabetic mothers (CTR). Urine samples were collected at five time points: at birth (T1), on the third day of life (T2), one week (T3), one month (T4) and six months postpartum (T5). At T1, variations were observed in the levels of seven potential biomarkers (acetate, lactate, glycylproline/proline, isocitrate, N,N-dimethylglycine, N-acetylglucosamine and N-carbamoyl-aspartate) in NMD-insulin infants compared to NDM-diet and CTR infants. In particular, the altered metabolites were found to be involved in several metabolic pathways such as citrate metabolism, glycine, serine and threonine metabolism, arginine and proline metabolism, amino sugar and nucleotide sugar metabolism, and pyruvate metabolism. In contrast, these changes were not visible at subsequent sampling times. The impact of early nutrition (maternal and formula milk) on the metabolomic profile was considered as a potential contributing factor to this finding.
Establishment of a Seven-Gene Signature Associated with CD8+ T Cells through the Utilization of Both Single-Cell and Bulk RNA-Sequencing Techniques in Clear Cell Renal Cell Carcinoma
Authors: Chen Yubin , Zhou Xinyu , Xie Yanwei , Wu Jianan , Li Tingting , Yu Tian , Pang Yipeng , Du Wenlong
Published: September 2023

Tumor immune microenvironment constituents, such as CD8+ T cells, have emerged as crucial focal points for cancer immunotherapy. Given the absence of reliable biomarkers for clear cell renal cell carcinoma (ccRCC), we aimed to ascertain a molecular signature that could potentially be linked to CD8+ T cells. The differentially expressed genes (DEGs) linked to CD8+ T cells were identified through an analysis of single-cell RNA sequencing (scRNA-seq) data obtained from the Gene Expression Omnibus (GEO) database. Subsequently, immune-associated genes were obtained from the InnateDB and ImmPort datasets and were cross-referenced with CD8+ T-cell-associated DEGs to generate a series of DEGs linked to immune response and CD8+ T cells. Patients with ccRCC from the Cancer Genome Atlas (TCGA) were randomly allocated into testing and training groups. A gene signature was established by conducting LASSO-Cox analysis and subsequently confirmed using both the testing and complete groups. The efficacy of this signature in evaluating immunotherapy response was assessed on the IMvigor210 cohort. Finally, we employed various techniques, including CIBERSORT, ESTIMATE, ssGSEA, and qRT-PCR, to examine the immunological characteristics, drug responses, and expression of the signature genes in ccRCC. Our findings revealed 206 DEGs linked to immune response and CD8+ T cells, among which 65 genes were correlated with overall survival (OS) in ccRCC. A risk assessment was created utilizing a set of seven genes: RARRES2, SOCS3, TNFSF14, XCL1, GRN, CLDN4, and RBP7. The group with a lower risk showed increased expression of CD274 (PD-L1), suggesting a more favorable response to anti-PD-L1 treatment. The seven-gene signature demonstrated accurate prognostic prediction for ccRCC and holds potential as a clinical reference for treatment decisions.
Proteomic Analysis Reveals Salt-Tolerant Mechanism in Soybean Applied with Plant-Derived Smoke Solution
Authors: Komatsu Setsuko , Kimura Taiki , Rehman Shafiq Ur , Yamaguchi Hisateru , Hitachi Keisuke , Tsuchida Kunihiro
Published: September 2023

Salt stress of soybean is a serious problem because it reduces plant growth and seed yield. To investigate the salt-tolerant mechanism of soybean, a plant-derived smoke (PDS) solution was used. Three-day-old soybeans were subjected to PDS solution under 100 mM NaCl for 2 days, resulting in PDS solution improving soybean root growth, even under salt stress. Under the same condition, proteins were analyzed using the proteomic technique. Differential abundance proteins were associated with transport/formaldehyde catabolic process/sucrose metabolism/glutathione metabolism/cell wall organization in the biological process and membrane/Golgi in the cellular component with or without PDS solution under salt stress. Immuno-blot analysis confirmed that osmotin, alcohol dehydrogenase, and sucrose synthase increased with salt stress and decreased with additional PDS solution; however, H+ATPase showed opposite effects. Cellulose synthase and xyloglucan endotransglucosylase/hydrolase increased with salt and decreased with additional PDS solution. Furthermore, glycoproteins decreased with salt stress and recovered with additional treatment. As mitochondrion-related events, the contents of ATP and gamma-aminobutyric acid increased with salt stress and recovered with additional treatment. These results suggest that PDS solution improves the soybean growth by alleviating salt stress. Additionally, the regulation of energy metabolism, protein glycosylation, and cell wall construction might be an important factor for the acquisition of salt tolerance in soybean.
LINC01605 Is a Novel Target of Mutant p53 in Breast and Ovarian Cancer Cell Lines
Authors: Coan Michela , Toso Martina , Cesaratto Laura , Rigo Ilenia , Borgna Silvia , Dalla Pietà Anna , Zandonà Luigi , Iuri Lorenzo , Zucchetto Antonella , Piazza Carla , Baldassarre Gustavo , Spizzo Riccardo , Nicoloso Milena Sabrina
Published: September 2023

TP53 is the most frequently mutated gene in human cancers. Most TP53 genomic alterations are missense mutations, which cause a loss of its tumour suppressor functions while providing mutant p53 (mut_p53) with oncogenic features (gain-of-function). Loss of p53 tumour suppressor functions alters the transcription of both protein-coding and non-protein-coding genes. Gain-of-function of mut_p53 triggers modification in gene expression as well; however, the impact of mut_p53 on the transcription of the non-protein-coding genes and whether these non-protein-coding genes affect oncogenic properties of cancer cell lines are not fully explored. In this study, we suggested that LINC01605 (also known as lincDUSP) is a long non-coding RNA regulated by mut_p53 and proved that mut_p53 directly regulates LINC01605 by binding to an enhancer region downstream of the LINC01605 locus. We also showed that the loss or downregulation of LINC01605 impairs cell migration in a breast cancer cell line. Eventually, by performing a combined analysis of RNA-seq data generated in mut_TP53-silenced and LINC01605 knockout cells, we showed that LINC01605 and mut_p53 share common gene pathways. Overall, our findings underline the importance of ncRNAs in the mut_p53 network in breast and ovarian cancer cell lines and in particular the importance of LINC01605 in mut_p53 pro-migratory pathways.
Single-Nucleus RNA-Seq: Open the Era of Great Navigation for FFPE Tissue
Authors: Guo Yunxia , Wang Wenjia , Ye Kaiqiang , He Liyong , Ge Qinyu , Huang Yan , Zhao Xiangwei
Published: September 2023

Single-cell sequencing (scRNA-seq) has revolutionized our ability to explore heterogeneity and genetic variations at the single-cell level, opening up new avenues for understanding disease mechanisms and cell–cell interactions. Single-nucleus RNA-sequencing (snRNA-seq) is emerging as a promising solution to scRNA-seq due to its reduced ionized transcription bias and compatibility with richer samples. This approach will provide an exciting opportunity for in-depth exploration of billions of formalin-fixed paraffin-embedded (FFPE) tissues. Recent advancements in single-cell/nucleus gene expression workflows tailored for FFPE tissues have demonstrated their feasibility and provided crucial guidance for future studies utilizing FFPE specimens. In this review, we provide a broad overview of the nuclear preparation strategies, the latest technologies of snRNA-seq applicable to FFPE samples. Finally, the limitations and potential technical developments of snRNA-seq in FFPE samples are summarized. The development of snRNA-seq technologies for FFPE samples will lay a foundation for transcriptomic studies of valuable samples in clinical medicine and human sample banks.
Antiproliferative and Antimetastatic Properties of 16-Azidomethyl Substituted 3-O-Benzyl Estrone Analogs
Authors: Senobar Tahaei Seyyed Ashkan , Kulmány Ágnes , Minorics Renáta , Kiss Anita , Szabó Zoltán , Germán Péter , Szebeni Gábor J. , Gémes Nikolett , Mernyák Erzsébet , Zupkó István
Published: September 2023

Four diastereomers of 16-azidomethyl substituted 3-O-benzyl estradiol (1–4) and their two estrone analogs (16AABE and 16BABE) were tested for their antiproliferative properties against human gynecological cancer cell lines. The estrones were selected for additional experiments based on their outstanding cell growth-inhibiting activities. Both compounds increased hypodiploid populations of breast cancer cells, and 16AABE elicited cell cycle disturbance as evidenced by flow cytometry. The two analogs substantially increased the rate of tubulin polymerization in vitro. 16AABE and 16BABE inhibited breast cancer cells’ migration and invasive ability, as evidenced by wound healing and Boyden chamber assays. Since both estrone analogs exerted remarkable estrogenic activities, as documented by a luciferase reporter gene assay, they can be considered as promising drug candidates for hormone-independent malignancies.