bluuebunny/crossref_metadata_2025 huggingface dataset:
Wearable Electrocardiography for Physical Activity Monitoring: Definition of Validation Protocol and Automatic Classification
Authors: Cosoli Gloria , Antognoli Luca , Scalise Lorenzo
Published: January 2023

Wearable devices are rapidly spreading thanks to multiple advantages. Their use is expanding in several fields, from medicine to personal assessment and sport applications. At present, more and more wearable devices acquire an electrocardiographic (ECG) signal (in correspondence to the wrist), providing potentially useful information from a diagnostic point of view, particularly in sport medicine and in rehabilitation fields. They are remarkably relevant, being perceived as a common watch and, hence, considered neither intrusive nor a cause of the so-called “white coat effect”. Their validation and metrological characterization are fundamental; hence, this work aims at defining a validation protocol tested on a commercial smartwatch (Samsung Galaxy Watch3, Samsung Electronics Italia S.p.A., Milan, Italy) with respect to a gold standard device (Zephyr BioHarness 3.0, Zephyr Technology Corporation, Annapolis, MD, USA, accuracy of ±1 bpm), reporting results on 30 subjects. The metrological performance is provided, supporting final users to properly interpret the results. Moreover, machine learning and deep learning models are used to discriminate between resting and activity-related ECG signals. The results confirm the possibility of using heart rate data from wearable sensors for activity identification (best results obtained by Random Forest, with accuracy of 0.81, recall of 0.80, and precision of 0.81, even using ECG signals of limited duration, i.e., 30 s). Moreover, the effectiveness of the proposed validation protocol to evaluate measurement accuracy and precision in a wide measurement range is verified. A bias of −1 bpm and an experimental standard deviation of 11 bpm (corresponding to an experimental standard deviation of the mean of ≈0 bpm) were found for the Samsung Galaxy Watch3, indicating a good performance from a metrological point of view.
Effect of Various Intermittent Fasting Protocols on Hyperglycemia-Induced Cognitive Dysfunction in Rats
Authors: Alfheeaid Hani , Alhowail Ahmad , Ahmed Faiyaz , Zaki Abdel , Alkhaldy Areej
Published: January 2023

Diabetes mellitus is a highly prevalent metabolic disorder that causes cognitive decline. Here, we investigated the impact of various intermittent fasting protocols on type 2 diabetes mellitus (T2DM)-induced cognitive dysfunction in a rodent model. Male Sprague–Dawley rats (aged 3 months) were randomly assigned to five groups (n = 6 per group) and T2DM was induced by streptozotocin (60 mg/kg, IM). The control group was untreated. Cognitive function was tested (Y-maze, novel object recognition, and elevated plus maze tests) and glucose was assessed. The T2DM rats exhibited significantly higher blood glucose, which is associated with cognitive dysfunction. Compared to the validated animal model of T2DM in rats, various intermittent fasting protocols decreased blood glucose and improved cognitive function. These results indicate that various intermittent fasting protocols may be a potential strategy for managing the hyperglycemia-associated cognitive dysfunction.
Acknowledgment to the Reviewers of Brain Sciences in 2022
Authors:   Brain Sciences Editorial Office
Published: January 2023

High-quality academic publishing is built on rigorous peer review [...]
Maternal Psychopathological Profile during Childbirth and Neonatal Development during the COVID-19 Pandemic: A Pre-Posttest Study
Authors: Martinez-Vazquez Sergio , Riquelme-Gallego Blanca , Lugo-Toro Leydi Jhoansy , Lucena-Prieto Lidia , Garrido-Torres Nathalia , Lopez-Soto Teresa , Caparros-Gonzalez Rafael A. , De la Torre-Luque Alejandro
Published: January 2023

The coronavirus SARS-CoV-2 generated an alert that became a state of emergency in health issues worldwide, a situation that affected the entire population, including pregnant women. The present study aims to understand the effect of the psychopathological profile of a sample of pregnant women at the time of the COVID-19 pandemic on themselves during childbirth (Phase 1) and after childbirth and the anthropometric measures of the neonate at birth (Phase 2). The total sample comprises 81 pregnant women aged 32.07 years (SD = 5.45) and their neonates. Sociodemographic and obstetric data of the sample were collected. During pregnancy, psychopathology was measured by means of the SCL-90, as well as other psychological measures on stress and social support. Cluster k-means techniques were used to uncover the heterogeneous profiles of psychopathology in Phase 1. Two main psychopathological profiles were found (Cluster 1: High psychopathological symptoms; Cluster 2: Low psychopathological symptoms). The clusters generated show significant differences in all the SCL-90-R subscales used and in the general index at Phase 1. After childbirth, high psychopathology profile membership was associated with a greater probability of having a non-eutocic delivery. On the other hand, the low psychopathological symptoms cluster shows higher levels of depressive symptoms, hostility, paranoid ideation, and psychotic symptoms in Phase 2. In conclusion, there seemed to exist two heterogeneous profiles of psychopathology in pregnant women during the pandemic; the stress related to the pandemic seemed uninfluential on the development of a profile of high psychopathological symptoms and the psychopathology profile may influence delivery and postpartum outcomes.
Phenomenological 2D and 3D Models of Ductile Fracture for Girth Weld of X80 Pipeline
Authors: Li Naixian , Jia Bin , Chen Junhong , Sheng Ying , Deng Songwen
Published: January 2023

Welding is the main method for oil/gas steel pipeline connection, and a large number of girth welds are a weak part of the pipeline. Under extremely complex loads, a steel pipeline undergoes significant plastic deformations and eventually leads to pipeline fracture. A damage mechanics model is a promising approach, capable of describing material fracture problems according to the stress states of the materials. In this study, an uncoupled fracture 2D model with a function of fracture strain and stress triaxiality, two uncoupled 3D fracture models, a consider the effect of Lode parameter stress-modified critical strain (LSMCS) model, and an extended Rice–Tracey (ERT) criterion were applied to X80 pipeline girth welds. Comprehensive experimental research was conducted on different notched specimens, covering a wide range of stress states, and the corresponding finite element models were established. A phenomenon-based hybrid numerical–experimental calibration method was also applied to determine the fracture parameter for these three models, and the stress triaxiality of the influence law of the tensile strength was analyzed. The results showed that the proposed fracture criterion could better characterize the ductile fracture behaviors of the girth welds of the X80 pipeline; however, the prediction accuracy of the 3D fracture model was higher than that of the 2D fracture model. The functional relationship between the tensile strength and stress triaxiality of the X80 pipeline girth welds satisfied the distribution form of the quadratic function and increased monotonically. The research results can be used to predict the fracture of X80 pipeline girth welds under various complex loads.
Seismic Retrofitting of Dual Structural Systems—A Case Study of an Educational Building in Croatia
Authors: Uroš Mario , Demšić Marija , Baniček Maja , Pilipović Ante
Published: January 2023

On 29 December 2020, a devastating Mw6.4 earthquake struck near the town of Petrinja, Croatia. The main earthquake was preceded by a Mw4.9 foreshock the day before. The earthquakes caused extensive damage to buildings, especially historic buildings made of unreinforced masonry but also to buildings of other typologies and to critical infrastructure. Today, recovery efforts in Croatia focus primarily on reconstruction and seismic retrofitting. Family homes and public, cultural, educational, and other facilities are top priorities. In this paper, a comprehensive study of existing building in the educational sector is presented as a case study. The seismic performance of the building is evaluated using numerical methods, first for the as-built condition and then for the retrofitted building. For each condition, the collapse mechanisms of the building were determined and critical structural elements were identified. The presented retrofit strategy of the dual structural system consisting of RC frame system and masonry walls aims to reduce the displacements of the RC frame system to a level sufficient to prevent the early brittle failure of the concrete. Additionally, the discrepancies when using different modelling approaches are discussed.
Mechanical Properties and Numerical Analysis of Underground Continuous Wall in Underground Grain Silo Foundation Pit
Authors: Zhao Chen , Feng Yong , Wang Weijian , Niu Zijuan
Published: January 2023

Foundation pit monitoring can only provide feedback regarding the deformation of the formation and envelope structure after construction, and it is difficult to predict the deformation law of a continuous underground wall in the later stage of underground grain silo support. Taking the deep foundation pit of a continuous underground wall of an underground grain silo as an example, this paper uses Abaqus software to simulate the force of the project, explores the calculation results of the planar elastic foundation beam considering the arch effect and the numerical simulation technology of the foundation pit’s support, and analyzes and compares the rationality of the model. The analysis of the deformation form of the continuous underground wall by both calculation methods is a parabolic combination. The maximum horizontal displacement of the continuous underground wall, according to the Abaqus software, is 6.23 mm, and the other calculation result is 4.7 mm; the maximum settlement on the surface is 11.34 mm, according to the Abaqus software, and the other maximum settlement is 8 mm. The simulation results show that the simulated value is basically consistent with the measured value, and the simulated value is slightly larger than the measured value because the interference conditions are idealized during simulation. The accuracy and rationality of the numerical simulation are verified, and the parameters, such as the thickness and burial depth of the continuous underground wall, can be changed to provide a reference for the support method of a deep foundation pit similar to a continuous underground wall.
Spatial Heterogeneity and Influence Factors of Traditional Villages in the Wuling Mountain Area, Hunan Province, China Based on Multiscale Geographically Weighted Regression
Authors: Li Ting , Li Chaokui , Zhang Rui , Cong Zheng , Mao Yan
Published: January 2023

Traditional villages are the spatial carriers of the excellent traditional culture of the Chinese nation, the concentrated expression of thousands of years of farming civilization, and a nonrenewable precious cultural heritage. However, in recent decades, with the rapid development of urbanization and modernization, traditional villages have rapidly declined or even disappeared. Therefore, exploring the spatial distribution characteristics and influencing factors of traditional villages and clarifying their formation and development laws, can provide a new perspective for the continuity protection of traditional villages on a cross-regional scale. This study takes six batches of 462 traditional villages in the Wuling Mountains, Hunan, China as the research object. On the basis of the analysis of the spatial distribution characteristics of overall and different ethnic minority traditional villages, this research proposes the idea of simulating the spatial distribution mechanism of traditional villages by using the multiscale geographical weighted regression (MGWR) model. Results indicate that (1) the spatial distribution of the traditional villages of the overall and different ethnic minorities shows significant agglomeration characteristics (among them, traditional Miao and Tujia villages have formed the main and sub cores of the space gathering of traditional villages in the Wuling Mountains in Hunan); and (2) compared with the least squares (OLS) method and the classic geographical (GWR) weighted regression model, the MGWR model can reflect the impact scales of different factors, and the simulation effect is better. From the perspective of influence factors, natural factors are the basis of affecting the distribution of traditional villages in the Wuling Mountain area and are generally positively correlated. Socioeconomic factors have a dual influence on the spatial distribution of traditional villages and generally have a negative correlation. Cultural factors are the key to the spatial distribution of traditional villages and are generally positively correlated. Spatial factors have no significant impact on the spatial distribution of traditional villages. On the basis of these conclusions, this study discusses the relevant strategies for the protection and development of traditional villages.
Determination of Solar-Surface-Area-to-Volume Ratio: Early Design Stage Solar Performance Assessment of Buildings
Authors: Hajtmanek Roman , Morgenstein Peter , Hubinský Tomáš , Legény Ján , Špaček Robert
Published: January 2023

One of the main targets of globally aimed strategies such as the UN-supported Race to Zero campaign or the European Green Deal is the decarbonisation of the building sector. The implementation of renewable energy sources in new urban structures, as well as the complex reconstruction of existing buildings, represents a key area of sustainable urban development. Supporting this approach, this paper introduces the solar-surface-area-to-volume ratio (Rsol) and the solar performance indicator (Psol), applicable for evaluation of the energy performance of basic building shapes at early design stages. The indicators are based on the preprocessors calculated using two different mathematical models—Robinson and Stone’s cumulative sky algorithm and Kittler and Mikler’s model—which are then compared and evaluated. Contrary to the commonly used surface-area-to-volume ratio, the proposed indicators estimate the potential for energy generation by active solar appliances integrated in the building envelope and allow optimisation of building shape in relation to potential energy losses and potential solar gains simultaneously. On the basis of the mathematical models, an online application optimising building shape to maximise sun-exposed surfaces has been developed. In connection with the solar-surface-area-to-volume ratio, it facilitates the quantitative evaluation of energy efficiency of various shapes by the wider professional public. The proposed indicators, verified in a case study presented, shall result in the increased sustainability of building sector by improving the utilisation of solar energy and overall energy performance of buildings.
The Effect of Climate Factors on 400 Years of Traditional Chinese Residential Building Roof Design: A Study from Southwest China
Authors: Xu Qinghua , Ding Zhifan , Wang Hui , Wang Yuncai , Mao Lingfeng
Published: January 2023

Indigenous people have used architecture over millennia to adapt to climatic factors and achieve stable and comfortable living. These adaptations can still inform the design of contemporary regional architecture. In order to explore the relationship between traditional dwellings and climatic factors, we examine buildings in four provinces and cities in southwest China. A database was created using detailed data obtained from the literature on indicators of climatic factors (e.g., temperature, precipitation, temperature difference, wind speed, solar radiation) and architectural elements (e.g., roof slope and eave length). Thorough statistical analysis shows that (1) MPWM has the most significant correlation with the slope angle of traditional building roofs but is not recommended as a predictor in multivariate equations. (2) Temperature and wind speed were significant correlates of roof slope, and a multiple regression model dominated by AMT and AWS serves as a good predictor of roof slope. (3) Solar radiation was not correlated with roof slope but was the largest correlate of eaves length in traditional buildings. AMSR and AWS also dominantly affect eaves length in a regression relationship. These results serve not only as a reference to catalog the use of traditional passive technologies but can guide the design of green buildings. However, more research is needed to refine the use of passive technologies to adapt to climate change
Thin-Slice Prostate MRI Enabled by Deep Learning Image Reconstruction
Authors: Gassenmaier Sebastian , Warm Verena , Nickel Dominik , Weiland Elisabeth , Herrmann Judith , Almansour Haidara , Wessling Daniel , Afat Saif
Published: January 2023

Objectives: Thin-slice prostate MRI might be beneficial for prostate cancer diagnostics. However, prolongation of acquisition time is a major drawback of thin-slice imaging. Therefore, the purpose of this study was to investigate the impact of a thin-slice deep learning accelerated T2-weighted (w) TSE imaging sequence (T2DLR) of the prostate as compared to conventional T2w TSE imaging (T2S). Materials and Methods: Thirty patients were included in this prospective study at one university center after obtaining written informed consent. T2S (3 mm slice thickness) was acquired first in three orthogonal planes followed by thin-slice T2DLR (2 mm slice thickness) in axial plane. Acquisition time of axial conventional T2S was 4:12 min compared to 4:37 min for T2DLR. Imaging datasets were evaluated by two radiologists using a Likert-scale ranging from 1–4, with 4 being the best regarding the following parameters: sharpness, lesion detectability, artifacts, overall image quality, and diagnostic confidence. Furthermore, preference of T2S versus T2DLR was evaluated. Results: The mean patient age was 68 ± 8 years. Sharpness of images and lesion detectability were rated better in T2DLR with a median of 4 versus a median of 3 in T2S (p < 0.001 for both readers). Image noise was evaluated to be significantly worse in T2DLR as compared to T2S (p < 0.001 and p = 0.021, respectively). Overall image quality was also evaluated to be superior in T2DLR versus T2S with a median of 4 versus 3 (p < 0.001 for both readers). Both readers chose T2DLR in 29 cases as their preference. Conclusions: Thin-slice T2DLR of the prostate provides a significant improvement of image quality without significant prolongation of acquisition time.
Identification of a Novel Model for Predicting the Prognosis and Immune Response Based on Genes Related to Cuproptosis and Ferroptosis in Ovarian Cancer
Authors: Li Ying , Fang Tian , Shan Wanying , Gao Qinglei
Published: January 2023

(1) Background: Ovarian cancer (OV) presents a high degree of malignancy and a poor prognosis. Cell death is necessary to maintain tissue function and morphology. Cuproptosis and ferroptosis are two novel forms of death, and we look forward to finding their relationship with OV and providing guidance for treatment. (2) Methods: We derived information about OV from public databases. Based on cuproptosis-related and ferroptosis-related genes, a risk model was successfully constructed, and exceptional subtypes were identified. Next, various methods are applied to assess prognostic value and treatment sensitivity. Besides, the comprehensive analysis of the tumor environment, together with immune cell infiltration, immune function status, immune checkpoint, and human HLA genes, is expected to grant assistance for the prognosis and treatment of OV. (3) Results: Specific molecular subtypes and models possessed excellent potential to predict prognosis. Immune infiltration abundance varied between groups. The susceptibility of individuals to different chemotherapy drugs and immunotherapies could be predicted based on specific groups. (4) Conclusions: Our molecular subtypes and risk model, with strong immune prediction and prognostic prediction capabilities, are committed to guiding ovarian cancer treatment.
Performance of Node-RADS Scoring System for a Standardized Assessment of Regional Lymph Nodes in Bladder Cancer Patients
Authors: Leonardo Costantino , Flammia Rocco Simone , Lucciola Sara , Proietti Flavia , Pecoraro Martina , Bucca Bruno , Licari Leslie Claire , Borrelli Antonella , Bologna Eugenio , Landini Nicholas , Del Monte Maurizio , Chung Benjamin I. , Catalano Carlo , Magliocca Fabio Massimo , De Berardinis Ettore , Del Giudice Francesco , Panebianco Valeria
Published: January 2023

Background: Current cross-sectional imaging modalities exhibit heterogenous diagnostic performances for the detection of a lymph node invasion (LNI) in bladder cancer (BCa) patients. Recently, the Node-RADS score was introduced to provide a standardized comprehensive evaluation of LNI, based on a five-item Likert scale accounting for both size and configuration criteria. In the current study, we hypothesized that the Node-RADS score accurately predicts the LNI and tested its diagnostic performance. Methods: We retrospectively reviewed BCa patients treated with radical cystectomy (RC) and bilateral extended pelvic lymph node dissection, from January 2019 to June 2022. Patients receiving preoperative systemic chemotherapy were excluded. A logistic regression analysis tested the correlation between the Node-RADS score and LNI both at patient and lymph-node level. The ROC curves and the AUC depicted the overall diagnostic performance. In addition, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for different cut-off values (>1, >2, >3, >4). Results: Overall, data from 49 patients were collected. Node-RADS assigned on CT scans images, was found to independently predict the LNI after an adjusted multivariable regression analysis, both at the patient (OR 3.36, 95%CI 1.68–9.40, p = 0.004) and lymph node (OR 5.18, 95%CI 3.39–8.64, p < 0.001) levels. Node-RADS exhibited an AUC of 0.87 and 0.91 at the patient and lymph node levels, respectively. With increasing Node-RADS cut-off values, the specificity and PPV increased from 57.1 to 97.1% and from 48.3 to 83.3%, respectively. Conversely, the sensitivity and NPV decreased from 100 to 35.7% and from 100 to 79.1%, respectively. Similar trends were recorded at the lymph node level. Potentially, Node-RADS > 2 could be considered as the best cut-off value due to balanced values at both the patient (77.1 and 78.6%, respectively) and lymph node levels (82.4 and 93.4%, respectively). Conclusions: The current study lays the foundation for the introduction of Node-RADS for the regional lymph-node evaluation in BCa patients. Interestingly, the Node-RADS score exhibited a moderate-to-high overall accuracy for the identification of LNI, with the possibility of setting different cut-off values according to specific clinical scenarios. However, these results need to be validated on larger cohorts before drawing definitive conclusions.
The Current Status of Photodynamic Therapy in Cancer Treatment
Authors: Jiang Wenqi , Liang Mingkang , Lei Qifang , Li Guangzhi , Wu Song
Published: January 2023

Although we have made great strides in treating deadly diseases over the years, cancer therapy still remains a daunting challenge. Among numerous anticancer methods, photodynamic therapy (PDT), a non-invasive therapeutic approach, has attracted much attention. PDT exhibits outstanding performance in cancer therapy, but some unavoidable disadvantages, including limited light penetration depth, poor tumor selectivity, as well as oxygen dependence, largely limit its therapeutic efficiency for solid tumors treatment. Thus, numerous strategies have gone into overcoming these obstacles, such as exploring new photosensitizers with higher photodynamic conversion efficiency, alleviating tumor hypoxia to fuel the generation of reactive oxygen species (ROS), designing tumor-targeted PS, and applying PDT-based combination strategies. In this review, we briefly summarized the PDT related tumor therapeutic approaches, which are mainly characterized by advanced PSs, these PSs have excellent conversion efficiency and additional refreshing features. We also briefly summarize PDT-based combination therapies with excellent therapeutic effects.
Correction: Zheng et al. Glycolysis-Related SLC2A1 Is a Potential Pan-Cancer Biomarker for Prognosis and Immunotherapy. Cancers 2022, 14, 5344
Authors: Zheng Haosheng , Long Guojie , Zheng Yuzhen , Yang Xingping , Cai Weijie , He Shiyun , Qin Xianyu , Liao Hongying
Published: January 2023

The authors wish to make the following corrections to this paper [...]
GBM Cells Exhibit Susceptibility to Metformin Treatment According to TLR4 Pathway Activation and Metabolic and Antioxidant Status
Authors: Moretti Isabele Fattori , Lerario Antonio Marcondes , Sola Paula Rodrigues , Macedo-da-Silva Janaína , Baptista Mauricio da Silva , Palmisano Giuseppe , Oba-Shinjo Sueli Mieko , Marie Suely Kazue Nagahashi
Published: January 2023

Glioblastoma (GBM) is an aggressive brain cancer associated with poor overall survival. The metabolic status and tumor microenvironment of GBM cells have been targeted to improve therapeutic strategies. TLR4 is an important innate immune receptor capable of recognizing pathogens and danger-associated molecules. We have previously demonstrated the presence of TLR4 in GBM tumors and the decreased viability of the GBM tumor cell line after lipopolysaccharide (LPS) (TLR4 agonist) stimulation. In the present study, metformin (MET) treatment, used in combination with temozolomide (TMZ) in two GBM cell lines (U87MG and A172) and stimulated with LPS was analyzed. MET is a drug widely used for the treatment of diabetes and has been repurposed for cancer treatment owing to its anti-proliferative and anti-inflammatory actions. The aim of the study was to investigate MET and LPS treatment in two GBM cell lines with different metabolic statuses. MET treatment led to mitochondrial respiration blunting and oxidative stress with superoxide production in both cell lines, more markedly in U87MG cells. Decreased cell viability after MET + TMZ and MET + LPS + TMZ treatment was observed in both cell lines. U87MG cells exhibited apoptosis after MET + LPS + TMZ treatment, promoting increased ER stress, unfolded protein response, and BLC2 downregulation. LPS stimulation of U87MG cells led to upregulation of SOD2 and genes related to the TLR4 signaling pathway, including IL1B and CXCL8. A172 cells attained upregulated antioxidant gene expression, particularly SOD1, TXN and PRDX1-5, while MET treatment led to cell-cycle arrest. In silico analysis of the TCGA-GBM-RNASeq dataset indicated that the glycolytic plurimetabolic (GPM)-GBM subtype had a transcriptomic profile which overlapped with U87MG cells, suggesting GBM cases exhibiting this metabolic background with an activated inflammatory TLR4 pathway may respond to MET treatment. For cases with upregulated CXCL8, coding for IL8 (a pro-angiogenic factor), combination treatment with an IL8 inhibitor may improve tumor growth control. The A172 cell line corresponded to the mitochondrial (MTC)-GBM subtype, where MET plus an antioxidant inhibitor, such as anti-SOD1, may be indicated as a combinatory therapy.
Update on Prevalence of Pain in Patients with Cancer 2022: A Systematic Literature Review and Meta-Analysis
Authors: Snijders Rolf , Brom Linda , Theunissen Maurice , van den Beuken-van Everdingen Marieke
Published: January 2023

Experiencing pain and insufficient relief can be devastating and negatively affect a patient’s quality of life. Developments in oncology such as new treatments and adjusted pain management guidelines may have influenced the prevalence of cancer pain and severity in patients. This review aims to provide an overview of the prevalence and severity of pain in cancer patients in the 2014–2021 literature period. A systematic literature search was performed using the databases PubMed, Embase, CINAHL, and Cochrane. Titles and abstracts were screened, and full texts were evaluated and assessed on methodological quality. A meta-analysis was performed on the pooled prevalence and severity rates. A meta-regression analysis was used to explore differences between treatment groups. We identified 10,637 studies, of which 444 studies were included. The overall prevalence of pain was 44.5%. Moderate to severe pain was experienced by 30.6% of the patients, a lower proportion compared to previous research. Pain experienced by cancer survivors was significantly lower compared to most treatment groups. Our results imply that both the prevalence of pain and pain severity declined in the past decade. Increased attention to the assessment and management of pain might have fostered the decline in the prevalence and severity of pain.
A High-Throughput Sequencing Data-Based Classifier Reveals the Metabolic Heterogeneity of Hepatocellular Carcinoma
Authors: Ye Maolin , Li Xuewei , Chen Lirong , Mo Shaocong , Liu Jie , Huang Tiansheng , Luo Feifei , Zhang Jun
Published: January 2023

Metabolic heterogeneity plays a key role in poor outcomes in malignant tumors, but its role in hepatocellular carcinoma (HCC) remains largely unknown. In the present study, we aim to disentangle the metabolic heterogeneity features of HCC by developing a classification system based on metabolism pathway activities in high-throughput sequencing datasets. As a result, HCC samples were classified into two distinct clusters: cluster 1 showed high levels of glycolysis and pentose phosphate pathway activity, while cluster 2 exhibited high fatty acid oxidation and glutaminolysis status. This metabolic reprogramming-based classifier was found to be highly correlated with several clinical variables, including overall survival, prognosis, TNM stage, and 𝛼-fetoprotein (AFP) expression. Of note, activated oncogenic pathways, a higher TP53 mutation rate, and increased stemness were also observed in cluster 1, indicating a causal relationship between metabolic reprogramming and carcinogenesis. Subsequently, distinct metabolism-targeted therapeutic strategies were proven in human HCC cell lines, which exhibit the same metabolic properties as corresponding patient samples based on this classification system. Furthermore, the metabolic patterns and effects of different types of cells in the tumor immune microenvironment were explored by referring to both bulk and single-cell data. It was found that malignant cells had the highest overall metabolic activities, which may impair the anti-tumor capacity of CD8+ T cells through metabolic competition, and this provided a potential explanation for why immunosuppressive cells had higher overall metabolic activities than those with anti-tumor functions. Collectively, this study established an HCC classification system based on the gene expression of energy metabolism pathways. Its prognostic and therapeutic value may provide novel insights into personalized clinical practice in patients with metabolic heterogeneity.
Changes in Serum Growth Factors during Resistance to Atezolizumab Plus Bevacizumab Treatment in Patients with Unresectable Hepatocellular Carcinoma
Authors: Yang Zijian , Suda Goki , Maehara Osamu , Ohara Masatsugu , Yoda Tomoka , Sasaki Takashi , Kohya Risako , Yoshida Sonoe , Hosoda Shunichi , Tokuchi Yoshimasa , Kitagataya Takashi , Suzuki Kazuharu , Kawagishi Naoki , Nakai Masato , Sho Takuya , Natsuizaka Mitsuteru , Ogawa Koji , Ohnishi Shunsuke , Sakamoto Naoya
Published: January 2023

The possible mechanisms of resistance to atezolizumab/bevacizumab for unresectable HCC, and the subsequent response to these therapies, remain underexplored. The sequential changes in serum growth factors, including VEGF-A, VEGF-C, VEGF-D, ANG-2, FGF-19, HGF, and EGF during atezolizumab/bevacizumab for unresectable HCC were evaluated in 46 patients. Patients who experienced PD after CR, PR, or SD to atezolizumab/bevacizumab were evaluated. A total of 4, 9, 19, and 14 patients showed CR, PR, SD, and PD, respectively. Of 32 patients with disease control, 28 experienced PD after CR, PR, or SD with atezolizumab/bevacizumab. Baseline growth factor levels were similar between patients with or without disease control and those with or without an objective response. Growth factor changes between the baseline and the best overall response points (BOR) for patients with disease control showed that FGF-19 significantly increased and ANG2 significantly decreased at the BOR. Growth factor changes between the BOR and the PD point in 28 patients who experienced PD after disease control showed that VEGF-D and ANG2 significantly increased at the PD point compared with that at the BOR. Summarily, increased serum VEGF-D and ANG-2 levels might contribute to developing resistance to atezolizumab/bevacizumab for unresectable HCC and might be target molecules in subsequent salvage therapies.
Breast Cancer Survivors and Healthy Women: Could Gut Microbiota Make a Difference?—“BiotaCancerSurvivors”: A Case-Control Study
Authors: Caleça Telma , Ribeiro Pedro , Vitorino Marina , Menezes Maria , Sampaio-Alves Mafalda , Mendes Ana Duarte , Vicente Rodrigo , Negreiros Ida , Faria Ana , Costa Diogo Alpuim
Published: January 2023

In this first analysis, samples from 23 BC survivors (group 1) and 291 healthy female controls (group 2) were characterised through the V3 and V4 regions that encode the “16S rRNA” gene of each bacteria. The samples were sequenced by next-generation sequencing (NGS), and the taxonomy was identified by resorting to Kraken2 and improved with Bracken, using a curated database called ‘GutHealth_DB’. The α and β-diversity analyses were used to determine the richness and evenness of the gut microbiota. A non-parametric Mann-Whitney U test was applied to assess differential abundance between both groups. The Firmicutes/Bacteroidetes (F/B) ratio was calculated using a Kruskal-Wallis chi-squared test. The α-diversity was significantly higher in group 1 (p = 0.28 × 10−12 for the Chao index and p = 1.64 × 10−12 for the ACE index). The Shannon index, a marker of richness and evenness, was not statistically different between the two groups (p = 0.72). The microbiota composition was different between the two groups: a null hypothesis was rejected for PERMANOVA (p = 9.99 × 10−5) and Anosim (p = 0.04) and was not rejected for β-dispersion (p = 0.158), using Unifrac weighted distance. The relative abundance of 14 phyla, 29 classes, 25 orders, 64 families, 116 genera, and 74 species differed significantly between both groups. The F/B ratio was significantly lower in group 1 than in group 2, p < 0.001. Our study allowed us to observe significant taxonomic disparities in the two groups by testing the differences between BC survivors and healthy controls. Additional studies are needed to clarify the involved mechanisms and explore the relationship between microbiota and BC survivorship.
Helicobacter Species and Hepato-Biliary Tract Malignancies: A Systematic Review and Meta-Analysis
Authors: Gros Beatriz , Gómez Pérez Alberto , Pleguezuelo María , Serrano Ruiz Francisco Javier , de la Mata Manuel , Rodríguez-Perálvarez Manuel
Published: January 2023

Helicobacter species may cause chronic inflammation of the biliary tract, but its relationship with cancer is controversial. We performed a systematic review and meta-analysis to evaluate the association between Helicobacter species and hepatobiliary tract malignancies. Twenty-six studies (4083 patients) were included in qualitative synthesis, and 18 studies (n = 1895 qualified for meta-analysis. All studies were at high-intermediate risk of bias. Most studies combined several direct microbiological methods, mostly PCR (23 studies), culture (8 studies), and/or CLOtest (5 studies). Different specimens alone or in combination were investigated, most frequently bile (16 studies), serum (7 studies), liver/biliary tissue (8 studies), and gastric tissue (3 studies). Patients with Helicobacter species infection had an increased risk of hepatobiliary tract malignancies (OR = 3.61 [95% CI 2.18–6.00]; p < 0.0001), with high heterogeneity in the analysis (I2 = 61%; p = 0.0003). This effect was consistent when Helicobacter was assessed in bile (OR = 3.57 [95% CI 1.73–7.39]; p = 0.0006), gastric tissue (OR = 42.63 [95% CI 5.25–346.24]; p = 0.0004), liver/biliary tissue (OR = 4.92 [95% CI 1.90–12.76]; p = 0.001) and serum (OR = 1.38 [95% CI 1.00–1.90]; p = 0.05). Heterogeneity was reduced in these sub-analyses (I2 = 0–27%; p = ns), except for liver/biliary tissue (I2 = 57%; p = 0.02). In conclusion, based on low-certainty data, Helicobacter species chronic infection is associated with a tripled risk of hepatobiliary tract malignancy. Prospective studies are required to delineate public health interventions.
Prognostic Implications of the Residual Tumor Microenvironment after Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer Patients without Pathological Complete Response
Authors: Lejeune Marylène , Reverté Laia , Sauras Esther , Gallardo Noèlia , Bosch Ramon , Roso Albert , Petit Anna , Peg Vicente , Riu Francisco , García-Fontgivell Joan , Ibáñez José , Relea Fernanda , Vieites Begoña , Bor Catherine , de la Cruz-Merino Luis , Arenas Meritxell , Rodriguez Valerie , Galera Juana , Korzynska Anna , Belhomme Philippe , Plancoulaine Benoît , Álvaro Tomás , López Carlos
Published: January 2023

With a high risk of relapse and death, and a poor or absent response to therapeutics, the triple-negative breast cancer (TNBC) subtype is particularly challenging, especially in patients who cannot achieve a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Although the tumor microenvironment (TME) is known to influence disease progression and the effectiveness of therapeutics, its predictive and prognostic potential remains uncertain. This work aimed to define the residual TME profile after NAC of a retrospective cohort with 96 TNBC patients by immunohistochemical staining (cell markers) and chromogenic in situ hybridization (genetic markers). Kaplan–Meier curves were used to estimate the influence of the selected TME markers on five-year overall survival (OS) and relapse-free survival (RFS) probabilities. The risks of each variable being associated with relapse and death were determined through univariate and multivariate Cox analyses. We describe a unique tumor-infiltrating immune profile with high levels of lymphocytes (CD4, FOXP3) and dendritic cells (CD21, CD1a and CD83) that are valuable prognostic factors in post-NAC TNBC patients. Our study also demonstrates the value of considering not only cellular but also genetic TME markers such as MUC-1 and CXCL13 in routine clinical diagnosis to refine prognosis modelling.
Qualitative Investigation of Experience and Quality of Life in Patients Treated with Calcium Electroporation for Cutaneous Metastases
Authors: Vestergaard Kitt , Vissing Mille , Gehl Julie , Lindhardt Christina Louise
Published: January 2023

(1) Background: Calcium electroporation is a novel cancer treatment. It includes injecting calcium-solution and applying electric pulses to tumour tissue. Data on quality of life for patients with cutaneous metastases treated with calcium electroporation is limited. We evaluated quality of life in patients with skin metastases treated with calcium electroporation using qualitative interviews. (2) Methods: This investigation featured a subgroup from a non-randomised phase II study (CaEP-R) at Zealand University Hospital, Denmark, studying response to calcium electroporation in cutaneous metastasis (ClinicalTrials no. NCT04225767). Participants were interviewed at baseline before calcium electroporation treatment and after two months. Data was analysed phenomenologically; (3) Results: Interviews were conducted February 2020–November 2021. Nine patients were included, of which seven participated in both interviews. All seven patients expected treated tumours to disappear, symptom relief and minimal side effects. Most patients requested peer accounts. All patients found the treatment uncomfortable but acceptable; all thought their fears of electric pulses exceeded their experience. All would repeat the treatment if effective. Successful treatment had a positive effect on pain, symptomatic wounds, sleep, vigour and social inclination; (4) Conclusions: Calcium electroporation enhanced health-related quality of life by reducing symptoms and increasing social inclination. Peer accounts provide patients with a shortcut to confidence in treatment on top of doctors’ recommendations.
Neoadjuvant Immune Checkpoint Inhibitors for Resectable Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis
Authors: Zhao Mei , Chen Shanwen , Li Conggui , Du Yingying , Li Ping
Published: January 2023

Resectable hepatocellular carcinoma (HCC) has poor prognosis because of its high recurrence rate. Immunotherapy has been tried for neoadjuvant therapy as it has shown excellent performance in the treatment of advanced HCC. This systematic review and meta-analysis aimed to assess the reported efficacy and safety of neoadjuvant immune checkpoint inhibitors (ICIs) for resectable HCC. Electronic databases, including PubMed (MEDLINE), Embase, the Cochrane Library, and ClinicalTrials.gov were systematically searched to identify published and ongoing studies evaluating the efficacy and safety of neoadjuvant ICIs for resectable HCC up to October 2022. The odds ratio (OR) and 95% confidence interval (CI) were calculated. Heterogeneity and subgroup analyses were performed, and data quality was assessed. The study was registered with PROSPERO (registration number: CRD42022371495). A total of 193 patients from 9 studies were included in this meta-analysis. The overall pathological complete response (pCR) rate was 12.9% (95%CI, 6.7–19.1%), and major pathological response (MPR) rate was 27.3% (95%CI, 15.1–39.4%), indicating a favorable association with neoadjuvant ICIs (pCR: OR = 0.17, p < 0.00001; MPR: OR = 0.38, p = 0.001). The pooled OR values for the incidence of grade 3 to 4 treatment-related adverse events and surgical delay rate were 0.26 and 0.05, respectively, which were significantly in favor of neoadjuvant ICIs (p < 0.0001; p < 0.00001, respectively). The subgroup analyses did not demonstrate superiority of one ICI over another ICI or combination therapy. The present study found that neoadjuvant ICIs were well tolerated by patients with resectable HCC and conferred therapeutic benefits in view of histopathological response results.
Tumor Growth Suppression of Pancreatic Cancer Orthotopic Xenograft Model by CEA-Targeting CAR-T Cells
Authors: Sato Osamu , Tsuchikawa Takahiro , Kato Takuma , Amaishi Yasunori , Okamoto Sachiko , Mineno Junichi , Takeuchi Yuta , Sasaki Katsunori , Nakamura Toru , Umemoto Kazufumi , Suzuki Tomohiro , Wang Linan , Wang Yizheng , Hatanaka Kanako C. , Mitsuhashi Tomoko , Hatanaka Yutaka , Shiku Hiroshi , Hirano Satoshi
Published: January 2023

Chimeric antigen receptor engineered T cell (CAR-T) therapy has high therapeutic efficacy against blood cancers, but it has not shown satisfactory results in solid tumors. Therefore, we examined the therapeutic effect of CAR-T therapy targeting carcinoembryonic antigen (CEA) in pancreatic adenocarcinoma (PDAC). CEA expression levels on the cell membranes of various PDAC cell lines were evaluated using flow cytometry and the cells were divided into high, medium, and low expression groups. The relationship between CEA expression level and the antitumor effect of anti-CEA-CAR-T was evaluated using a functional assay for various PDAC cell lines; a significant correlation was observed between CEA expression level and the antitumor effect. We created orthotopic PDAC xenograft mouse models and injected with anti-CEA-CAR-T; only the cell line with high CEA expression exhibited a significant therapeutic effect. Thus, the therapeutic effect of CAR-T therapy was related to the target antigen expression level, and the further retrospective analysis of pathological findings from PDAC patients showed a correlation between the intensity of CEA immunostaining and tumor heterogeneity. Therefore, CEA expression levels in biopsies or surgical specimens can be clinically used as biomarkers to select PDAC patients for anti-CAR-T therapy.
LncRNA NR120519 Blocks KRT17 to Promote Cell Proliferation and Migration in Hypopharyngeal Squamous Carcinoma
Authors: Zhou Zheng , Zhang Gehou , Li Tieqi , Ai Jingang , Li Wei , Zeng Shiyu , Ye Maoyu , Liu Qian , Xiao Jian , Li Yunqiu , Tan Guolin , Zhang Xiaowei
Published: January 2023

Background: Hypopharyngeal carcinoma is the worst type of head and neck squamous cell carcinoma. It is necessary to identify the key molecular targets related to the carcinogenesis and development of hypopharyngeal carcinoma. Methods: Differentially expressed lncRNAs in hypopharyngeal carcinoma were selected by microarray, and lncRNA-associated proteins were found by RIP assay. Colony formation, CCK-8, wound healing and Transwell assays were performed to detect the effects of lncRNA and its associated protein on cell proliferation and migration in vitro. Downstream pathways of lncRNA and its associated protein were detected by WB. Through a subcutaneous tumor model, the effects of lncRNA and its associated protein on cell proliferation were detected. The expressions of lncRNA and its associated protein in hypopharyngeal cancer tissues were detected by qRT-PCR and immunohistochemistry assays, respectively, and survival analyses were performed by Kaplan-Meier curve. Results: A total of 542 and 265 lncRNAs were upregulated and downregulated in microarrays, respectively. LncRNA NR120519 was upregulated and promoted cell proliferation and migration of hypopharyngeal carcinoma in vitro and cell proliferation in vivo. RIP and WB assays showed that KRT17 was associated with and blocked by NR120519.The silencing of KRT17 promoted cell proliferation and the migration of hypopharyngeal carcinoma in vitro and cell proliferation in vivo by activating the AKT/mTOR pathway and epithelial-mesenchymal transformation (EMT). Finally, the NR120519 high expression and KRT17 low expression groups showed shorter overall survival. Conclusion: NR120519 activated the AKT/mTOR pathway and EMT by blocking KRT17 to promote cell proliferation and the migration of hypopharyngeal carcinoma.
MET Amplification as a Resistance Driver to TKI Therapies in Lung Cancer: Clinical Challenges and Opportunities
Authors: Qin Kang , Hong Lingzhi , Zhang Jianjun , Le Xiuning
Published: January 2023

Targeted therapy has emerged as an important pillar for the standard of care in oncogene-driven non-small cell lung cancer (NSCLC), which significantly improved outcomes of patients whose tumors harbor oncogenic driver mutations. However, tumors eventually develop resistance to targeted drugs, and mechanisms of resistance can be diverse. MET amplification has been proven to be a driver of resistance to tyrosine kinase inhibitor (TKI)-treated advanced NSCLC with its activation of EGFR, ALK, RET, and ROS-1 alterations. The combined therapy of MET-TKIs and EGFR-TKIs has shown outstanding clinical efficacy in EGFR-mutated NSCLC with secondary MET amplification-mediated resistance in a series of clinical trials. In this review, we aimed to clarify the underlying mechanisms of MET amplification-mediated resistance to tyrosine kinase inhibitors, discuss the ways and challenges in the detection and diagnosis of MET amplifications in patients with metastatic NSCLC, and summarize the recently published clinical data as well as ongoing trials of new combination strategies to overcome MET amplification-mediated TKI resistance.