bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep-Learning Algorithms for Prescribing Insoles to Patients with Foot Pain
Authors: Kim Jeoung Kun , Choo Yoo Jin , Park In Sik , Choi Jin-Woo , Park Donghwi , Chang Min Cheol
Published: February 2023

Foot pain is a common musculoskeletal disorder. Orthotic insoles are widely used in patients with foot pain. Inexperienced clinicians have difficulty prescribing orthotic insoles appropriately by considering various factors associated with the alteration of foot alignment. We attempted to develop deep-learning algorithms that can automatically prescribe orthotic insoles to patients with foot pain and assess their accuracy. In total, 838 patients were included in this study; 70% (n = 586) and 30% (n = 252) were used as the training and validation sets, respectively. The resting calcaneal stance position and data related to pelvic elevation, pelvic tilt, and pelvic rotation were used as input data for developing the deep-learning algorithms for insole prescription. The target data were the foot posture index for the modified root technique and the necessity of heel lift, entire lift, and lateral wedge, medial wedge, and calcaneocuboid arch supports. In the results, regarding the foot posture index for the modified root technique, for the left foot, the mean absolute error (MAE) and root mean square error (RMSE) of the validation dataset for the developed model were 1.408 and 3.365, respectively. For the right foot, the MAE and RMSE of the validation dataset for the developed model were 1.601 and 3.549, respectively. The accuracies for heel lift, entire lift, and lateral wedge, medial wedge, and calcaneocuboid arch supports were 89.7%, 94.8%, 72.2%, 98.4%, and 79.8%, respectively. The micro-average area under the receiver operating characteristic curves for heel lift, entire lift, and lateral wedge, medial wedge, and calcaneocuboid arch supports were 0.949, 0.941, 0.826, 0.792, and 0.827, respectively. In conclusion, our deep-learning models automatically prescribed orthotic insoles in patients with foot pain and showed outstanding to acceptable accuracy.
Biomedical Imaging Technologies for Cardiovascular Disease
Authors: Garcia Julio
Published: February 2023

Non-invasive biomedical imaging technologies for investigating the heart’s physiology, performance, function, and structure have increased in number and diversity over the past several years [...]
Airglow Observation and Statistical Analysis of Plasma Bubbles over China
Authors: Ma Xin , Wu Mengjie , Guo Peng , Xu Jing
Published: February 2023

Airglow observation is a very effective method to investigate plasma bubbles, and can obtain their horizontal structure. In this study, the image processing method was used to process airglow data, including image enhancement, azimuth correction, and image projection, and the clear image products of equatorial plasma bubbles (EPBs) were obtained. Based on the optical data of the airglow imager in Hainan, we investigated the main optical features of EPBs, and statistically analyzed the occurrence of EPBs from September 2014 to August 2015. The observation results show that EPB exhibits plume-shaped structures, usually tilting westward, and EPB extends to a long distance along the geomagnetic field lines. It is found that the west wall of EPB is relatively stable, while there are some bifurcations on the east wall of EPB, and the bifurcation of EPB becomes more pronounced with time. Moreover, the spatial scale of EPB gradually increases with time, which is about several hundred kilometers, and the drift velocity of EPB is in the range of 40–130 m/s (+/−20 m/s). The statistical results show that EPBs mainly occur in the months of September to November and February to April, with a higher occurrence rate. In terms of seasonal occurrence, EPBs tend to appear more frequently in spring and autumn, and the occurrence rate of EPBs is relatively low in winter and summer.
Urban Heat Risk: Protocols for Mapping and Implications for Colombo, Sri Lanka
Authors: Emmanuel Rohinton , Jalal Mushfik , Ogunfuyi Samson , Maharoof Nusrath , Zala Megi , Perera Narein , Ratnayake Rangajeewa
Published: February 2023

Global and urban-induced local warming lead to increasing heat risk in cities. The rapid increase in urban population, weak infrastructure, poverty, as well as an ageing population, make the risk more acute in developing cities. However, heat risk is not uniformly distributed and a detailed exploration of the link between urban characteristics and local variations in heat risk is needed to aid targeted mitigation. In this paper, we demonstrate a fine-grained heat risk map using existing data combined with expert opinion in a humid tropical city (Colombo, Sri Lanka) with the objective of highlighting the relative heat risk as a function of physical and socioeconomic conditions across the city. We then simulate the effects of shading and greening on the ‘high’ heat risk areas, and greening on the ‘low’ heat risk areas, to show that a combined approach will be needed to reduce risk at ‘high’ risk areas. In ‘low’ risk areas, maintaining the green cover is crucial to heat risk reduction. The paper, thus, establishes a protocol for detailed heat risk mapping with existing data and points to the differing importance of shading and greening in different parts of the city, thus, showing where, and to what extent, mitigation actions could be beneficial.
Fine Particulate Matter Concentration and Early Deaths Related to Thermal Power Plants and National Industrial Complexes in South Korea
Authors: Ha Jongsik , Moon Nankyoung , Seo Jihyun
Published: February 2023

Thermal power plants (TPPs) and national industrial complexes (NICs) are widely known as being among the major causes of changes in the concentrations of fine particulate matter (PM2.5). However, little is known about the changes in PM2.5 concentration caused by the operation of these facilities in South Korea and the health burden attributable to them, including early death. There were two purposes to this study. The first was to quantitatively evaluate the changes in PM2.5 concentration caused by TPPs and NICs in Korea. The second was to estimate the number of early deaths as a health burden attributable to such changes in PM2.5 concentration. The changes in PM2.5 concentration caused by the operation of TPPs and NICs were investigated within TPPs in 2013 and within NICs in 2015. The number of early deaths in 2015 caused by changes in PM2.5 concentration was estimated using the Environmental Benefits Mapping and Analysis Program (BenMAP). Nationwide, the annual average concentration of PM2.5 caused by the operation of TPPs and NICs was estimated to increase by 0.611 μg/m3 and 1.245 μg/m3, respectively, suggesting that NICs contributed about twice as much to this concentration as TPPs. The same trend was also observed regarding the number of early deaths, with TPPs and NICs accounting for 1017 and 2091 early deaths per year, respectively, indicating that the operation of NICs causes a health burden about twice as high as that caused by TPPs. However, the changes in PM2.5 concentration were found to be high near TPPs and NICs, while the health burden caused by exposure to PM2.5 varied according to the level of population distribution and mortality in each air (quality) control zone (ACZ) to which one is exposed. The findings of this study are expected to be utilized as reference data when setting goals to strengthen air quality management (AQM) in each ACZ in Korea.
Resource Partitioning among “Ancillary” Pelagic Fishes (Scomber spp., Trachurus spp.) in the Adriatic Sea
Authors: Da Ros Zaira , Fanelli Emanuela , Cassatella Sacha , Biagiotti Ilaria , Canduci Giovanni , Menicucci Samuele , De Felice Andrea , Malavolti Sara , Leonori Iole
Published: February 2023

The Mediterranean is one of the most overfished seas of the world where mesopredators are severely threatened. The trophic strategies of four pelagic species that inhabit the Adriatic Sea (Scomber spp. and Trachurus spp.) were investigated through an integrated approach of stomach contents and stable isotopes analyses. Our study demonstrated that Scomber colias feeds mainly on strictly pelagic prey, with fish larvae as a secondary prey in the Southern Adriatic Sea, while S. scombrus feeds on prey belonging to higher trophic levels. Smaller specimens of Trachurus mediterraneus have a diet mainly based on pelagic prey, while larger fishes rely on prey such as benthic decapods, showing an ontogenetic shift in the diet of the species. Trachurus trachurus shows a preference for offshore and deeper areas and a diet such as that of its congeneric, but no clear ontogenetic shift was observed. This spatial segregation allows the co-existence of these two species of Trachurus. Scomber colias mainly inhabits southern areas and S. scombrus shows a preference for the northern sectors. This latitudinal gradient avoids the overlap of their trophic niches. Bayesian mixing models confirmed that the trophic niches of these species only partially overlap in the middle of the trophic web.
New Psychoactive Substances Intoxications and Fatalities during the COVID-19 Epidemic
Authors: Lo Faro Alfredo , Berardinelli Diletta , Cassano Tommaso , Dendramis Gregory , Montanari Eva , Montana Angelo , Berretta Paolo , Zaami Simona , Busardò Francesco , Huestis Marilyn
Published: February 2023

In January 2020, the World Health Organization (WHO) issued a Public Health Emergency of International Concern, declaring the COVID-19 outbreak a pandemic in March 2020. Stringent measures decreased consumption of some drugs, moving the illicit market to alternative substances, such as New Psychoactive Substances (NPS). A systematic literature search was performed, using scientific databases such as PubMed, Scopus, Web of Science and institutional and government websites, to identify reported intoxications and fatalities from NPS during the COVID-19 pandemic. The search terms were: COVID-19, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, coronavirus disease 2019, intox*, fatal*, new psychoactive substance, novel psychoactive substance, smart drugs, new psychoactive substance, novel synthetic opioid, synthetic opioid, synthetic cathinone, bath salts, legal highs, nitazene, bath salt, legal high, synthetic cannabinoid, phenethylamine, phencyclidine, piperazine, novel benzodiazepine, benzodiazepine analogue, designer benzodiazepines, tryptamine and psychostimulant. From January 2020 to March 2022, 215 NPS exposures were reported in Europe, UK, Japan and USA. Single NPS class intoxications accounted for 25, while mixed NPS class intoxications represented only 3 cases. A total of 130 NPS single class fatalities and 56 fatalities involving mixed NPS classes were published during the pandemic. Synthetic opioids were the NPS class most abused, followed by synthetic cathinones and synthetic cannabinoids. Notably, designer benzodiazepines were frequently found in combination with fentalogues. Considering the stress to communities and healthcare systems generated by the pandemic, NPS-related information may be underestimated. However, we could not define the exact impacts of COVID-19 on processing of toxicological data, autopsy and death investigations.
Reversibility and Low Commitment to Forward Catalysis in the Conjugation of Lipid Alkenals by Glutathione Transferase A4-4
Authors: Scian Michele , Paço Lorela , Murphree Taylor A. , Shireman Laura M. , Atkins William M.
Published: February 2023

High concentrations of electrophilic lipid alkenals formed during oxidative stress are implicated in cytotoxicity and disease. However, low concentrations of alkenals are required to induce antioxidative stress responses. An established clearance pathway for lipid alkenals includes conjugation to glutathione (GSH) via Michael addition, which is catalyzed mainly by glutathione transferase isoform A4 (GSTA4-4). Based on the ability of GSTs to catalyze hydrolysis or retro-Michael addition of GSH conjugates, and the antioxidant function of low concentrations of lipid alkenals, we hypothesize that GSTA4-4 contributes a homeostatic role in lipid metabolism. Enzymatic kinetic parameters for retro-Michael addition with trans-2-Nonenal (NE) reveal the chemical competence of GSTA4-4 in this putative role. The forward GSTA4-4-catalyzed Michael addition occurs with the rapid exchange of the C2 proton of NE in D2O as observed by NMR. The isotope exchange was completely dependent on the presence of GSH. The overall commitment to catalysis, or the ratio of first order kcat,f for ‘forward’ Michael addition to the first order kcat,ex for H/D exchange is remarkably low, approximately 3:1. This behavior is consistent with the possibility that GSTA4-4 is a regulatory enzyme that contributes to steady-state levels of lipid alkenals, rather than a strict ‘one way’ detoxication enzyme.
Quantum Dot-Sensitised Estrogen Receptor-α-Based Biosensor for 17β-Estradiol
Authors: Jijana Abongile N. , Feleni Usisipho , Ndangili Peter M. , Bilibana Mawethu , Ajayi Rachel F. , Iwuoha Emmanuel I.
Published: February 2023

17β-estradiol (E2) is an important natural female hormone that is also classified as an estrogenic endocrine-disrupting compound (e-EDC). It is, however, known to cause more damaging health effects compared to other e-EDCs. Environmental water systems are commonly contaminated with E2 that originates from domestic effluents. The determination of the level of E2 is thus very crucial in both wastewater treatment and in the aspect of environmental pollution management. In this work, an inherent and strong affinity of the estrogen receptor-α (ER-α) for E2 was used as a basis for the development of a biosensor that was highly selective towards E2 determination. A gold disk electrode (AuE) was functionalised with a 3-mercaptopropionic acid-capped tin selenide (SnSe-3MPA) quantum dot to produce a SnSe-3MPA/AuE electroactive sensor platform. The ER-α-based biosensor (ER-α/SnSe-3MPA/AuE) for E2 was produced by the amide chemistry of carboxyl functional groups of SnSe-3MPA quantum dots and the primary amines of ER-α. The ER-α/SnSe-3MPA/AuE receptor-based biosensor exhibited a formal potential (E0′) value of 217 ± 12 mV, assigned as the redox potential for monitoring the E2 response using square-wave voltammetry (SWV). The response parameters of the receptor-based biosensor for E2 include a dynamic linear range (DLR) value of 1.0–8.0 nM (R2 = 0.99), a limit of detection (LOD) value of 1.69 nM (S/N = 3), and a sensitivity of 0.04 µA/nM. The biosensor exhibited high selectivity for E2 and good recoveries for E2 determination in milk samples.
Optic Fiber Microsensor Reveals Specific Spatiotemporal Oxygen Uptake Profiles at the Mammalian Ocular Surface
Authors: Sun Qin , Ma Li , Ferreira Fernando , Brown Chelsea , Reid Brian , Zhao Min
Published: February 2023

Oxygen (O2) uptake by cells and tissues is a critical indicator of metabolic demand, changes in microenvironment, and pathophysiology. O2 uptake from the atmosphere accounts for virtually all the O2 consumption in the avascular cornea; however, a detailed spatiotemporal profile of corneal O2 uptake (COU) remains undetermined. Here, we used a non-invasive self-referencing optical fiber O2 sensor—the scanning micro-optrode technique (SMOT)—to report the O2 partial pressure and flux variations at the ocular surface of rodents and non-human primates. In vivo spatial mapping in mice revealed a distinct COU, characterized by a centripetal gradient with a significantly higher O2 influx at the limbus and conjunctiva regions than at the center of the cornea. This regional COU profile was reproduced ex vivo in freshly enucleated eyes. The centripetal gradient was conserved across the following species analyzed: mice, rats, and rhesus monkeys. In vivo temporal mapping in mice showed a significant increase in the O2 flux in the limbus in the evening compared to other times. Altogether, the data unveiled a conserved centripetal COU profile, which may be associated with the limbal epithelial stem cells residing at the intersection of the limbus and conjunctiva. These physiological observations will serve as a useful baseline for comparative studies with contact lens wear, ocular disease, diabetes, etc. Moreover, the sensor may be applied to understand the responses of the cornea and other tissues to various insults, drugs, or changes in the environment.
Objective and Subjective Sleep Measures Are Related to Suicidal Ideation and Are Transdiagnostic Features of Major Depressive Disorder and Social Anxiety Disorder
Authors: Klumpp Heide , Chang Fini , Bauer Brian W. , Burgess Helen J.
Published: February 2023

Suicide is a major public health problem and previous studies in major depression and anxiety show problematic sleep is a risk factor for suicidal ideation (SI). However, less is known about sleep and SI in social anxiety disorder (SAD), despite the pervasiveness of SAD. Therefore, the current study comprised participants with major depressive disorder (MDD) (without comorbid SAD) (n = 26) and participants with SAD (without comorbid MDD) (n = 41). Wrist actigraphy was used to estimate sleep duration, wake after sleep onset, and sleep efficiency; sleep quality was evaluated with self-report. Self-report was also used to examine SI. These measures were submitted to independent t-tests and multiple regression analysis. t-test results revealed sleep and SI did not differ between MDD and SAD groups. Multiple regression results showed shorter sleep duration and worse sleep quality related to greater SI when taking symptom severity and age into account. Post-hoc partial correlational analysis showed these sleep–SI relationships remained significant after controlling for symptom severity and age. Preliminary findings indicate sleep and SI may be transdiagnostic features of MDD and SAD. Evidence of distinct sleep–SI relationships are consistent with previous reports showing that sleep difficulties contribute to SI. Altogether, improving sleep duration and sleep quality may reduce the risk of SI.
The Role of Tryptophan Metabolism in Alzheimer’s Disease
Authors: Savonije Karl , Weaver Donald F.
Published: February 2023

The need to identify new potentially druggable biochemical mechanisms for Alzheimer’s disease (AD) is an ongoing priority. The therapeutic limitations of amyloid-based approaches are further motivating this search. Amino acid metabolism, particularly tryptophan metabolism, has the potential to emerge as a leading candidate and an alternative exploitable biomolecular target. Multiple avenues support this contention. Tryptophan (trp) and its associated metabolites are able to inhibit various enzymes participating in the biosynthesis of β-amyloid, and one metabolite, 3-hydroxyanthranilate, is able to directly inhibit neurotoxic β-amyloid oligomerization; however, whilst certain trp metabolites are neuroprotectant, other metabolites, such as quinolinic acid, are directly toxic to neurons and may themselves contribute to AD progression. Trp metabolites also have the ability to influence microglia and associated cytokines in order to modulate the neuroinflammatory and neuroimmune factors which trigger pro-inflammatory cytotoxicity in AD. Finally, trp and various metabolites, including melatonin, are regulators of sleep, with disorders of sleep being an important risk factor for the development of AD. Thus, the involvement of trp biochemistry in AD is multifactorial and offers a plethora of druggable targets in the continuing quest for AD therapeutics.
Leader Boundary-Spanning Behavior and Employee Voice Behavior: The Job Demands–Resources Perspective
Authors: Lee Jihye , Choi Dongwon , Cheong Minyoung
Published: February 2023

Drawing on the job demands–resources model, we suggest and test a motivational mechanism that underlies the relationship between leader boundary-spanning behavior and employee voice behavior. Based on the field survey data of 383 leader-employee pairs collected from various organizations in South Korea, the results of our mediation model showed that leader boundary-spanning behavior, as a potential job resource, enhances employee voice behavior by increasing employee self-efficacy. The results of our moderated mediation model also showed that the focal leader’s abusive supervision, as a potential job demand, could attenuate the beneficial effect of leader boundary-spanning behavior on employee voice behavior by diminishing employee self-efficacy. These findings highlight the importance of leader boundary-spanning behavior in enhancing employee voice behavior, the roles of employee self-efficacy as a key mediating mechanism, and the focal leader’s abusive supervision as a preventable boundary condition within these relationships. Theoretical and practical implications are discussed.
Sensitivity Analysis of Factors Influencing Rural Housing Energy Consumption in Different Household Patterns in the Zhejiang Province
Authors: Chen Chen , Wang MeiYan , Shen Chengzhu , Huang Yingying , Zhu Minhua , Wang Huifang , He Liping , Julien Dewancker Bart
Published: February 2023

Unlike urban dwellings, it is very common for elderly people to stay at home alone in Chinese rural families, and some families have three generations in the same house who are in different situations, and their different family patterns lead to different highly sensitive parameters of building energy consumption. This paper first selects the three most common family patterns based on a questionnaire survey. The measured energy consumption behavior and electrical parameters, energy consumption time, and basic building parameters were input into DesignBuilder to build three building simulation models, and these were verified by comparing the predicted and measured values of the residential month-by-month electricity consumption. The global sensitivity analysis was then conducted using DesignBuilder software to determine the interactions between the variables by using the second-order Sobol index for cooling load, heating load, and comfort of the models to obtain standardized regression coefficients (SRC) for each factor to determine the most sensitive parameters. The results show that the different household patterns had little influence on the ranking of highly sensitive factors for heating and cooling, but annual electricity consumption and discomfort in different household patterns had a significant influence on the ranking of highly sensitive factors. For example, model 1 showed the most sensitivity to general lighting power density when optimizing the total amount of electricity was the goal, while the one that had the greatest degree of influence on the total amount of electricity in model 2 and model 3 was equipment power density.
Disintegration Characteristics Investigation of Carbonaceous Shale in High-Latitude Cold Regions
Authors: Wang Rui , Zheng Mingjie , Ao Bin , Liu Hongqing , Cheng Peifeng
Published: February 2023

To investigate the disintegration and microstructure characteristics of carbonaceous shale in high-latitude cold regions, indoor, outdoor, initial particle size, and freeze–thaw disintegration experiments were conducted concerning dry–wet cycles. Two tests were performed: sieving and microscopic scanning electron analysis. The carbonaceous shale disintegration, particle size variation rule, disintegration resistance, and fractal characteristics were studied. The microstructure variations of carbonaceous rock before and after water immersion were compared, and the microscopic mechanism of calving in water was discussed. The results show that: (1) the disintegration of carbonaceous shale is basically achieved after eight dry–wet cycles, and the particle size is concentrated at 2 mm~10 mm; (2) the temperature and freeze–thaw cycle conditions accelerated the disintegration rate and shortened the disintegration stability time of carbonaceous shale; (3) there is a negative correlation between the disintegration resistance index and the disintegrating fractal dimension of carbonaceous shale, and the disintegration resistance of disintegrating carbonaceous shale can be indirectly characterized by the fractional dimension; (4) carbonaceous shale contains two hydrophilic clay particles, kaolinite and montmorillonite, and the difference between the lattice expansion of clay particles, the expansion of adsorbed water film, and mineral dissolution are the main factors leading to the disintegration of carbonaceous rock.
Research on the Preferred Illuminance in Office Environments Based on EEG
Authors: Tong Li , Liu Nian , Hu Songtao , Lu Mingli , Zheng Yuxi , Ma Xiaohui
Published: February 2023

The quality of the indoor light environment in buildings directly influences the emotional state, health condition, and work efficiency of people. The application of EEG to indoor light environments is beneficial to further reveal the neural mechanisms of light comfort. In this study, the absolute power of spontaneous EEG was calculated as an objective physiological index, and its trend with the illuminance level of the task area was analyzed. Then, the absolute power of the band, which has the strongest correlation with subjective evaluation and task performance, was selected as the characteristic value. The subjective and objective parameters were validated to explore the preferred illuminance choices for subjects’ comfort and efficiency during the rest stage and the task stage, respectively. The results showed that the power of the δ band and β band at partial channels in the parietal region had statistically significant differences under five illuminance levels in the resting state. The total logarithmic power of EEG and the logarithmic power of the δ band at the Cz channel were negatively correlated with the subjective evaluation. The total logarithmic power of EEG was relatively low when the subjective evaluation was comfortable. There was no statistical difference in the total EEG logarithmic power among the five illuminance levels in the task state, but the subjects had the highest performance indicator and the best cognitive task performance at 500 lux and 750 lux conditions. This research may provide a design reference for the selection of task area illuminance levels for staff during high-intensity mental work and rest.
Effect of Cancer-Related Cachexia and Associated Changes in Nutritional Status, Inflammatory Status, and Muscle Mass on Immunotherapy Efficacy and Survival in Patients with Advanced Non-Small Cell Lung Cancer
Authors: Madeddu Clelia , Busquets Silvia , Donisi Clelia , Lai Eleonora , Pretta Andrea , López-Soriano Francisco Javier , Argilés Josep Maria , Scartozzi Mario , Macciò Antonio
Published: February 2023

Immune checkpoint inhibitor (ICI)-based immunotherapy has significantly improved the survival of patients with advanced non-small cell lung cancer (NSCLC); however, a significant percentage of patients do not benefit from this approach, and predictive biomarkers are needed. Increasing evidence demonstrates that cachexia, a complex syndrome driven by cancer-related chronic inflammation often encountered in patients with NSCLC, may impair the immune response and ICI efficacy. Herein, we carried out a prospective study aimed at evaluating the prognostic and predictive role of cachexia with the related changes in nutritional, metabolic, and inflammatory parameters (assessed by the multidimensional miniCASCO tool) on the survival and clinical response (i.e., disease control rate) to ICI-based immunotherapy in patients with advanced NSCLC. We included 74 consecutive patients. Upon multivariate regression analysis, we found a negative association between IL-6 levels (odds ratio (OR) = 0.9036; 95%CI = 0.8408–0.9711; p = 0.0025) and the miniCASCO score (OR = 0.9768; 95%CI = 0.9102–0.9999; p = 0.0310) with the clinical response. As for survival outcomes, multivariate COX regression analysis found that IL-6 levels and miniCASCO-based cachexia severity significantly affected PFS (hazard ratio (HR) = 1.0388; 95%CI = 1.0230–1.0548; p < 0.001 and HR = 1.2587; 95%CI = 1.0850–1.4602; p = 0.0024, respectively) and OS (HR = 1.0404; 95%CI = 1.0221–1.0589; p < 0.0001 and HR = 2.3834; 95%CI = 1.1504–4.9378; p = 0.0194, respectively). A comparison of the survival curves by Kaplan–Meier analysis showed a significantly lower OS in patients with cachexia versus those without cachexia (p = 0.0323), as well as higher miniCASCO-based cachexia severity (p = 0.0428), an mGPS of 2 versus those with a lower mGPS (p = 0.0074), and higher IL-6 levels (>6 ng/mL) versus those with lower IL-6 levels (≤6 ng/mL) (p = 0.0120). In conclusion, our study supports the evidence that cachexia, with its related changes in inflammatory, body composition, and nutritional parameters, is a key prognostic and predictive factor for ICIs. Further larger studies are needed to confirm these findings and to explore the potential benefit of counteracting cachexia to improve immunotherapy efficacy.
RBM15 Promates the Proliferation, Migration and Invasion of Pancreatic Cancer Cell Lines
Authors: Dong Hui , Zhang Haidong , Mao Xinyu , Liu Shiwei , Xu Wenjing , Zhang Yewei
Published: February 2023

(1) Background: Pancreatic cancer is increasingly becoming the leading cause of cancer deaths worldwide. In eukaryotic cells, m6A is the most abundant mRNA methylation modification. (2) Methods: We performed a bioinformatic multidimensional analysis using files containing the clinical data of patients and m6A-related gene expression differences downloaded from web-based databases, and performed a statistical analysis and image mapping mainly using R-package. Next, we studied the RBM15 expression in cancer and paracancerous tissues. We then validated these findings in two cell lines by western blot, PCR, Transwell, CCK-8, and EDU animal models. (3) Results: We discovered that RBM15 was highly expressed in pancreatic cancer patients and that it is a significant cause of poor prognosis. Its association with lymphatic T cell family aggregation was established through immune infiltration analysis. A retrospective analysis of data from clinical patient specimens revealed that high expression of RBM15 in patients was closely and positively correlated with preoperative glucose values, gender, and lymphocyte counts. Results from cellular experiments and animal experiments indicated that when the RBM15 gene was silenced, cell proliferation, migration, and metastasis were inhibited. (4) Conclusions: We propose that RBM15 plays a key role in the progression of pancreatic cancer by promoting tumor proliferation, migration and metastasis.
Management of Patients Diagnosed with Endometrial Cancer: Comparison of Guidelines
Authors: Restaino Stefano , Paglietti Chiara , Arcieri Martina , Biasioli Anna , Della Martina Monica , Mariuzzi Laura , Andreetta Claudia , Titone Francesca , Bogani Giorgio , Raimondo Diego , Perelli Federica , Buda Alessandro , Petrillo Marco , Greco Pantaleo , Ercoli Alfredo , Fanfani Francesco , Scambia Giovanni , Driul Lorenza , Vizzielli Giuseppe ,   The Udine Hospital Gynecological-Oncological Tumor Board Group
Published: February 2023

Endometrial cancer is the most common gynecological malignancy in Europe and its management involves a variety of health professionals. In recent years, big discoveries were made concerning the management of patients diagnosed with endometrial cancer, particularly in the field of molecular biology and minimally invasive surgery. This requires the continuous updating of guidelines and protocols over the years. In this paper, we aim to summarize and compare common points and disparities among protocols for management of patients diagnosed with endometrial cancer by leading international gynecological oncological societies. We therefore systematically report the parallel among the guidelines based on the various steps patients with endometrial cancer usually undergo. The comparison between American and European protocols revealed some relevant disparities, in particular regarding surgical staging, molecular biology application as a prognostic tool and follow up regimens. This could possibly cause differences in interpreting and applying protocols in clinical practice in small centers, leading to a lack of adherence to guidelines or even prompting a confusing mix of them.
Radiotherapy, PARP Inhibition, and Immune-Checkpoint Blockade: A Triad to Overcome the Double-Edged Effects of Each Single Player
Authors: Rosado Maria Manuela , Pioli Claudio
Published: February 2023

Radiotherapy and, more recently, PARP inhibitors (PARPis) and immune-checkpoint inhibitors represent effective tools in cancer therapy. Radiotherapy exerts its effects not only by damaging DNA and inducing tumor cell death, but also stimulating anti-tumor immune responses. PARPis are known to exert their therapeutic effects by inhibiting DNA repair, and they may be used in combination with radiotherapy. Both radiotherapy and PARPis modulate inflammatory signals and stimulate type I IFN (IFN-I)-dependent immune activation. However, they can also support the development of an immunosuppressive tumor environment and upregulate PD-L1 expression on tumor cells. When provided as monotherapy, immune-checkpoint inhibitors (mainly antibodies to CTLA-4 and the PD-1/PD-L1 axis) result particularly effective only in immunogenic tumors. Combinations of immunotherapy with therapies that favor priming of the immune response to tumor-associated antigens are, therefore, suitable strategies. The widely explored association of radiotherapy and immunotherapy has confirmed this benefit for several cancers. Association with PARPis has also been investigated in clinical trials. Immunotherapy counteracts the immunosuppressive effects of radiotherapy and/or PARPis and synergies with their immunological effects, promoting and unleashing immune responses toward primary and metastatic lesions (abscopal effect). Here, we discuss the beneficial and counterproductive effects of each therapy and how they can synergize to overcome single-therapy limitations.
Lithium in Cancer Therapy: Friend or Foe?
Authors: Yang Chunhao , Zhu Bo , Zhan Mingjie , Hua Zi-Chun
Published: February 2023

Lithium, a trace element important for fetal health and development, is considered a metal drug with a well-established clinical regime, economical production process, and a mature storage system. Several studies have shown that lithium affects tumor development by regulating inositol monophosphate (IMPase) and glycogen synthase kinase-3 (GSK-3). Lithium can also promote proliferation and programmed cell death (PCD) in tumor cells through a number of new targets, such as the nuclear receptor NR4A1 and Hedgehog-Gli. Lithium may increase cancer treatment efficacy while reducing side effects, suggesting that it can be used as an adjunctive therapy. In this review, we summarize the effects of lithium on tumor progression and discuss the underlying mechanisms. Additionally, we discuss lithium’s limitations in antitumor clinical applications, including its narrow therapeutic window and potential pro-cancer effects on the tumor immune system.
Oral Human Papillomavirus Benign Lesions and HPV-Related Cancer in Healthy Children: A Systematic Review
Authors: Di Spirito Federica , Pantaleo Giuseppe , Di Palo Maria Pia , Amato Alessandra , Raimondo Annunziata , Amato Massimo
Published: February 2023

The present systematic review aimed to assess the prevalence of oral HPV-related lesions, categorized as benign (verruca vulgaris “VV”, squamous cell papilloma “SP”, condyloma acuminata “CA”, and focal epithelial hyperplasia “FEH”) and malignant (oral squamous cell carcinoma “OSCC”), in descending order of occurrence in pediatric subjects (≤18 years of age). The secondary objectives were to evaluate the frequency and types of oral lesions described in relation to HPV genotypes and the HPV vaccine type (if any). The study protocol, compliant with the PRISMA statement, was registered at PROSPERO (CRD42022352268). Data from 60 studies, of which quality was assessed using the ROBINS-I tool, were independently extracted and synthesized. Along with seven poorly described benign HPV-related oral lesions that could not be categorized, a total of 146 HPV-related oral lesions, namely 47.26% (n = 69) VV, SP, and CA, 51.37% (n = 75) FEH, and 1.37% (n = 2) OSSC, were diagnosed in 153 pediatric subjects (M:F ratio = 1:1.4) with a mean age of lesion onset of 8.46 years. The viral genotypes detected were HPV-13 (30.61%), -6 (20.41%), -11 (16.33%), HPV-2 (12.24%), -32 (10.20%), -57 (6.12%), and -16 (4.08%). No HPV vaccination was reported in any case. Further studies should be conducted to evaluate the prevalence of HPV-related benign and malignant lesions and the potential role of HPV and associated vaccination in oral carcinogenesis in pediatric subjects.
The KRAS-Mutant Consensus Molecular Subtype 3 Reveals an Immunosuppressive Tumor Microenvironment in Colorectal Cancer
Authors: Tanjak Pariyada , Chaiboonchoe Amphun , Suwatthanarak Tharathorn , Acharayothin Onchira , Thanormjit Kullanist , Chanthercrob Jantappapa , Suwatthanarak Thanawat , Wannasuphaphol Bundit , Chumchuen Kemmapon , Suktitipat Bhoom , Sampattavanich Somponnat , Korphaisarn Krittiya , Pongpaibul Ananya , Poungvarin Naravat , Grove Harald , Riansuwan Woramin , Trakarnsanga Atthaphorn , Methasate Asada , Pithukpakorn Manop , Chinswangwatanakul Vitoon
Published: February 2023

Colorectal cancers (CRC) with KRAS mutations (KRASmut) are frequently included in consensus molecular subtype 3 (CMS3) with profound metabolic deregulation. We explored the transcriptomic impact of KRASmut, focusing on the tumor microenvironment (TME) and pathways beyond metabolic deregulation. The status of KRASmut in patients with CRC was investigated and overall survival (OS) was compared with wild-type KRAS (KRASwt). Next, we identified CMS, and further investigated differentially expressed genes (DEG) of KRASmut and distinctive pathways. Lastly, we used spatially resolved gene expression profiling to define the effect of KRASmut in the TME regions of CMS3-classified CRC tissues. CRC patients with KRASmut were mainly enriched in CMS3. Their specific enrichments of immune gene signatures in immunosuppressive TME were associated with worse OS. Activation of TGFβ signaling by KRASmut was related to reduced pro-inflammatory and cytokine gene signatures, leading to suppression of immune infiltration. Digital spatial profiling in TME regions of KRASmut CMS3-classified tissues suggested up-regulated genes, CD40, CTLA4, ARG1, STAT3, IDO, and CD274, that could be characteristic of immune suppression in TME. This study may help to depict the complex transcriptomic profile of KRASmut in immunosuppressive TME. Future studies and clinical trials in CRC patients with KRASmut should consider these transcriptional landscapes.
The Impact of Psychological Distress on Cervical Cancer
Authors: Wu Chen-Ta , Chiu Lu-Ting
Published: February 2023

Objective: Psychological distress is considered a factor for cancer development. However, the impact of mood disorders (depression and bipolar) on the development of cervical cancer remains uncertain. We conducted a nationwide population-based retrospective cohort study to investigate the association between mood disorders and the subsequent risk of developing cervical cancer. Methods: A total of 138,130 participants’ profiles between 2000 and 2012 were extracted from the National Health Insurance Research Database and subdivided into a mood-disorder cohort (27,626 participants) and a non-mood-disorder cohort (110,504 participants). Cohorts were propensity-matched for a 1:4 ratio according to age and index year. The Cox proportional hazards regression model was utilized for assessing cervical cancer risk between cohorts. Results: Kaplan–Meier analysis revealed that the mood-disorder cohort had a higher cumulative incidence of cervical cancer. The mood-disorder cohort was also associated with an increased risk of cervical cancer after adjustments for potential confounders. Subgroup analysis revealed a negative impact of mood disorders on cervical cancer, especially in the 30–50 years and white-collar groups. Conclusions: Our findings demonstrated that mood disorders were associated with an increased risk of cervical cancer development, which provide helpful information for clinical strategies to reduce the incidence of cervical cancer in this vulnerable population.
Prognosis of Pancreatic Cancer Based on Resectability: A Single Center Experience
Authors: Einama Takahiro , Takihata Yasuhiro , Aosasa Suefumi , Konno Fukumi , Kobayashi Kazuki , Yonamine Naoto , Fujinuma Ibuki , Tsunenari Takazumi , Nakazawa Akiko , Shinto Eiji , Ueno Hideki , Kishi Yoji
Published: February 2023

Although conversion surgery has increasingly been performed for initially unresectable advanced pancreatic ductal adenocarcinoma (PDAC), the rate of conversion, including that for patients who do not undergo resection, remains unclear. Patients with PDAC who were treated between January 2013 and December 2018 were classified into three groups: resectable (R), borderline resectable (BR), and unresectable (UR). We analyzed patient outcomes, including the rate of surgical resection and survival, in each of these groups. In total, 211 patients (R, 118; BR, 22; UR, 81) were selected. Among them, 117 (99%), 18 (82%), and 15 (19%) patients in the R, BR, and UR groups, respectively, underwent surgical resection. R0 resection rates were 88, 78, and 67%, whereas median overall survival (OS) from treatment initiation were 31, 18, and 11 months (p < 0.0001) in the R, BR, and UR groups, respectively. In patients who underwent surgical resection, relapse-free survival (RFS) and OS were similar among the three groups (R vs. BR vs. UR; median RFS (months), 17 vs. 13 vs. 11, p = 0.249; median OS (months), 31 vs. 26 vs. 32, p = 0.742). Lymph node metastases and incomplete adjuvant chemotherapy were identified as independent prognostic factors for OS. Although the surgical resection rate was low, particularly in the BR and UR groups, the prognosis of patients who underwent surgical resection was similar irrespective of the initial resectability status.
Potential Role of Non-Steroidal Anti-Inflammatory Drugs in Colorectal Cancer Chemoprevention for Inflammatory Bowel Disease: An Umbrella Review
Authors: Newman Peri , Muscat Joshua
Published: February 2023

Inflammatory Bowel Disease (IBD) is a category of autoimmune diseases that targets the destruction of the gastrointestinal system and includes both Crohn’s Disease and Ulcerative Colitis (UC). Patients with IBD are at a higher risk of developing colorectal cancer (CRC) throughout their lives due to chronically increased inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are potential chemopreventative agents that can inhibit the development of CRC in persons without IBD. However, the use of NSAIDs for CRC chemoprevention in IBD patients is further complicated by NSAIDs’ induction of damage to the bowel mucosal layer and ulcer formation. There has been a push in new research on chemopreventative properties of certain NSAIDs for IBD. The purpose of this umbrella review is to investigate the potential of low-dose NSAID compounds as chemopreventative agents for patients with IBD. This paper will also suggest future areas of research in the prevention of CRC for patients with IBD.
Upfront Advanced Radiotherapy and New Drugs for NSCLC Patients with Synchronous Brain Metastases: Is the Juice Worth the Squeeze? A Real-World Analysis from Lombardy, Italy
Authors: Corrao Giulia , Franchi Matteo , Zaffaroni Mattia , Vincini Maria Giulia , de Marinis Filippo , Spaggiari Lorenzo , Orecchia Roberto , Marvaso Giulia , Jereczek-Fossa Barbara Alicja
Published: February 2023

Aim: Healthcare administrative databases represent a valuable source for real-life data analysis. The primary aim of this study is to compare effectiveness and cost profile in non-small-cell lung cancer (NSCLC) patients harboring synchronous brain metastases (BMs) who received non-chemo first-line systemic therapy with or without advanced radiotherapy (aRT). Methods: Diagnostic ICD-9-CM codes were used for identifying all patients with a new diagnosis of lung cancer between 2012 and 2019. Among these, patients who had started a first-line systemic treatment with either TKIs or pembrolizumab, alone or in combination with intensity-modulated or stereotactic RT, were selected. Clinical outcomes investigated included overall survival (OS), progression-free survival (PFS), and time-to-treatment failure (TTF). The cost outcome was defined as the average per capita cumulative healthcare direct costs of the treatment, including all inpatient and outpatient costs. Results: The final cohort included 177 patients, of whom 58 were treated with systemic treatment plus aRT (STRT) and 119 with systemic treatment alone. The addition of aRT to systemic treatment was associated with a significantly better OS (p = 0.020) and PFS (p = 0.041) than systemic therapy alone. The ICER (incremental cost-effectiveness ratio) value indicated an average cost of €3792 for each month of survival after STRT treatment and confirmed clinical effectiveness but higher healthcare costs. Conclusions: This real-world study suggests that upfront aRT for NCLSC patients with synchronous BMs represents a valid treatment strategy, boosting the efficacy of novel and emerging drug classes with sustainable costs for the health service. Translational relevance: The present real-world study reports that the use of upfront advanced radiotherapyaRT and new-generation systemic agents, such as TKIs and pembrolizumab, may have higher oncological control and an improved cost-effectiveness profile than the use of new-generation systemic agents alone in NCLSC patients with synchronous brain metastases. Acquired evidence can also be used to inform policymakers that adding advanced radiotherapy results is a sustainable cost for the health service. Since approximately 50% of patients do not meet RCT inclusion criteria, a significant proportion of them is receiving treatment that is not evidence-informed; therefore, these results warrant further studies to identify the best radiotherapy timing and possible dose escalation approaches to improving treatment efficacy in patient subgroups not typically represented in randomized controlled trials.
Pathophysiological Mechanisms of Cardiac Dysfunction in Transgenic Mice with Viral Myocarditis
Authors: Rohrbeck Matthias , Hoerr Verena , Piccini Ilaria , Greber Boris , Schulte Jan Sebastian , Hübner Sara-Sophie , Jeworutzki Elena , Theiss Carsten , Matschke Veronika , Stypmann Jörg , Unger Andreas , Ho Huyen Tran , Disse Paul , Strutz-Seebohm Nathalie , Faber Cornelius , Müller Frank Ulrich , Ludwig Stephan , Rescher Ursula , Linke Wolfgang A. , Klingel Karin , Busch Karin , Peischard Stefan , Seebohm Guiscard
Published: February 2023

Viral myocarditis is pathologically associated with RNA viruses such as coxsackievirus B3 (CVB3), or more recently, with SARS-CoV-2, but despite intensive research, clinically proven treatment is limited. Here, by use of a transgenic mouse strain (TG) containing a CVB3ΔVP0 genome we unravel virus-mediated cardiac pathophysiological processes in vivo and in vitro. Cardiac function, pathologic ECG alterations, calcium homeostasis, intracellular organization and gene expression were significantly altered in transgenic mice. A marked alteration of mitochondrial structure and gene expression indicates mitochondrial impairment potentially contributing to cardiac contractile dysfunction. An extended picture on viral myocarditis emerges that may help to develop new treatment strategies and to counter cardiac failure.