bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the Saline–Alkaline Tolerance of Rice (Oryza sativa L.) Mutants Induced by Heavy-Ion Beam Mutagenesis
Authors: Zhang Xin , Yang Fu , Ma Hongyuan , Li Jingpeng
Published: January 2022

Soil salinity is a widespread and important abiotic factor impeding rice production by adversely affecting seed germination, seedling growth, and plant productivity. In this study, the rice cultivar TH899 was treated with 200 Gy of heavy-ion beam irradiation, and 89 mutant lines with stable phenotypes were selected using the pedigree method based on continuous assessment over six years. The seed germination performance of these mutants was tested under different saline–alkaline concentrations. Five highly tolerant lines were further evaluated in a series of experiments at the seedling stage and in the field. During the seedling stage, the reduction of seedling length, root length, fresh weight, and dry weight were dramatically lower in these five mutants than those in TH899 under saline–alkali stress. The K+/Na+ ratio was higher in these five mutants than in TH899. In the field experiment, the grain yield of mutant lines was higher than that of TH899. In addition, the grain yield of mutant line M89 was higher than that of the local cultivar in actual production. These mutant lines are expected to increase grain yield in soda saline–alkaline regions in northeast China.
Effect of Displacement Degree of Distal Chevron Osteotomy on Metatarsal Stress: A Finite Element Method
Authors: Zhang Qiaolin , Zhang Yan , Huang Jialu , Teo Ee Chon , Gu Yaodong
Published: January 2022

Background: The stress of foot bone can effectively evaluate the functional damage caused by foot deformity and the results of operation. In this study, the finite element method was used to investigate the degree of displacement of distal chevron osteotomy on metatarsal stress and metatarsophalangeal joint load; Methods: Four finite element models of displacement were established by using the CT images of a patient with moderate hallux valgus (hallux valgus angle and intermetatarsal angle were 26.74° and 14.09°, respectively), and the validity of the model was verified. Each finite element model consisted of bones and various cartilage structures, ligaments, and plantar fascia, as well as encapsulated soft tissue. Except for soft tissue, the material properties of other parts were isotropic linear elastic material, and the encapsulated soft tissue was set as nonlinear hyperelastic material. The mesh was tetrahedral mesh. Link elements were used in ligament and plantar fascia. A ground reaction force with a half-body weight was applied at the bottom of the floor to simulate the ground reaction when standing. The upper surfaces of the encapsulated soft tissue, distal tibia, and distal fibula were fixed. The stress distribution of metatarsals and the stress of cartilage of the first metatarsophalangeal joint were compared and analyzed; Results: Compared with the hallux valgus without osteotomy, the stress of the first metatarsals and second metatarsals of 2–4 mm decreased, and the stress of the interarticular cartilage of the first metatarsophalangeal joint with 4 mm was reduced. In the case of 6 mm, the stress value between the first metatarsal and the first metatarsophalangeal joint increased, and 4 mm was the most suitable distance; Conclusions: Compared with the hallux valgus without osteotomy, the stress of the first metatarsals and second metatarsals of 2–4 mm decreased, and the stress of the interarticular cartilage of the first metatarsophalangeal joint with 4 mm was reduced. In the case of 6 mm, the stress value between the first metatarsal and the first metatarsophalangeal joint increased, and 4 mm was the most suitable distance. For the degree of displacement of the distal chevron osteotomy, the postoperative stability and the stress distribution of metatarsal bone should be considered. Factors such as hallux valgus angle, intermetatarsal angle, patient’s age, body weight, and metatarsal width should be considered comprehensively. The factors affecting osteotomy need to be further explored. The degree of displacement of osteotomy can be evaluated by FE method before the operation, and the most suitable distance can be obtained.
The Role of Epstein-Barr Virus in Modulating Key Tumor Suppressor Genes in Associated Malignancies: Epigenetics, Transcriptional, and Post-Translational Modifications
Authors: Fierti Adelaide Ohui , Yakass Michael Bright , Okertchiri Ernest Adjei , Adadey Samuel Mawuli , Quaye Osbourne
Published: January 2022

Epstein-Barr virus (EBV) is ubiquitous and carried by approximately 90% of the world’s adult population. Several mechanisms and pathways have been proposed as to how EBV facilitates the pathogenesis and progression of malignancies, such as Hodgkin’s lymphoma, Burkitt’s lymphoma, nasopharyngeal carcinoma, and gastric cancers, the majority of which have been linked to viral proteins that are expressed upon infection including latent membrane proteins (LMPs) and Epstein-Barr virus nuclear antigens (EBNAs). EBV expresses microRNAs that facilitate the progression of some cancers. Mostly, EBV induces epigenetic silencing of tumor suppressor genes, degradation of tumor suppressor mRNA transcripts, post-translational modification, and inactivation of tumor suppressor proteins. This review summarizes the mechanisms by which EBV modulates different tumor suppressors at the molecular and cellular levels in associated cancers. Briefly, EBV gene products upregulate DNA methylases to induce epigenetic silencing of tumor suppressor genes via hypermethylation. MicroRNAs expressed by EBV are also involved in the direct targeting of tumor suppressor genes for degradation, and other EBV gene products directly bind to tumor suppressor proteins to inactivate them. All these processes result in downregulation and impaired function of tumor suppressors, ultimately promoting malignances.
The GooD Pregnancy Network: An Alternative Approach for Gestational Diabetes
Authors: Ikomi Amaju , Mannan Shaheen
Published: January 2022

Basildon and Thurrock University Hospital in the East of England region of the United Kingdom (UK) witnessed rapidly increasing numbers of pregnant women with diabetes, causing overburdened specialist clinics, poorer patient experience and worsening clinical outcomes. This prompted the multidisciplinary team’s remodelling of care pathways, launching the General ownership of Diabetes (GooD) Pregnancy Network in 2014. Contrary to the conventional limitation of care to specialist diabetes antenatal clinics, this novel initiative highlights the contemporary necessity to equip and empower all maternity stakeholders to deliver the basic care of gestational diabetes (GDM). It strategically connects a Midwife Tele-Clinic “hub” to Educating Gestational Diabetics Group Sessions (EGGS) and standard antenatal clinics. Patients were key partners, regularly participating in feedback surveys and promoting public awareness by co-producing local newspaper articles that served up their stories as case studies. Furthermore, the EGGS “faculty” includes a former GDM patient whose video testimony has inspired almost 2000 patients and their families, aiming to foster long term healthy lifestyle changes. The final summative evaluation in November 2019 showed the new culture of wider consciousness has shortened the “diagnosis to first consultation” intervals and eliminated overbooked specialist clinics (none since January 2016), without further worsening of clinical outcomes. It also boosted research recruitment and avoided additional running costs to the tune of GBP 66,384 a year.
Prognostic Role of Androgen Receptor Expression in HER2+ Breast Carcinoma Subtypes
Authors: Orrù Sandra , Pascariello Emanuele , Sotgiu Giovanni , Piras Daniela , Saderi Laura , Muroni Maria Rosaria , Carru Ciriaco , Arru Caterina , Mocci Cristina , Pinna Giampietro , Barbara Raffaele , Cossu-Rocca Paolo , De Miglio Maria Rosaria
Published: January 2022

HER2+ breast cancer (BC) is an aggressive subtype representing a genetically and biologically heterogeneous group of tumors resulting in variable prognosis and treatment response to HER2-targeted therapies according to estrogen (ER) and progesterone receptor (PR) expression. The relationship with androgen receptors (AR), a member of the steroid hormone’s family, is unwell known in BC. The present study aims to evaluate the prognostic impact of AR expression in HER2+ BC subtypes. A total of 695 BCs were selected and reviewed, AR, ER, PR and HER2 expression in tumor cells were examined by immunohistochemical method, and the SISH method was used in case of HER2 with equivocal immunohistochemical score (2+). A high prevalence of AR expression (91.5%) in BC HER+ was observed, with minimal differences between luminal and non-luminal tumor. According to steroid receptor expression, tumors were classified in four subgroups, including BC luminal and non-luminal HER2+ expressing or not AR. The luminal BC HER2 + AR+ was associated with lower histological grade, lower tumor size, higher PR expression and lower HER2 intensity of expression (2+). Also, the non-luminal tumors AR+ showed lower tumor size and lower prognostic stage but frequently higher grade and higher HER2 intensity of expression (3+). These findings should suggest a different progression of luminal and non-luminal tumors, both expressing AR, and allow us to speculate that the molecular mechanisms of AR, involved in the biology of BC HER2 + AR+, differ in relation to ER and PR expression. Moreover, AR expression may be a useful predictor of prognosis for overall survival (OS) in HER2+ BC subtypes. Our findings suggest that AR expression evaluation in clinical practice could be utilized in clinical oncology to establish different aggressiveness in BC HER2+ subtypes.
Cellular Prion Protein Is Essential for Myocardial Regeneration but Not the Recovery of Left Ventricular Function from Apical Ballooning
Authors: Sheu Jiunn-Jye , Chai Han-Tan , Chiang John Y. , Sung Pei-Hsun , Chen Yi-Ling , Yip Hon-Kan
Published: January 2022

This study tested the hypothesis that cellular prion protein (PrPC) played an essential role in myocardial regeneration and recovery of left ventricular ejection fraction (LVEF) from apical takotsubo cardiomyopathy (TCM) induced by transaortic constriction (TAC). In vitro study was categorized into G1 (H9C2), G2 (H9C2-overexpression-PrPC), G3 (H9C2-overexpression-PrPC + Stelazine/1 uM), and G4 (H9C2 + siRNA-PrPC), respectively. The results showed that the protein expressions of PrPC, cell-stress signaling (p-PI3K/p-Akt/p-m-TOR) and signal transduction pathway for cell proliferation/division (RAS/c-RAF/p-MEK/p-ERK1/2) were lowest in G1, highest in G2, significantly higher in G3 than in G4 (all p < 0.001). Adult-male B6 mice (n = 30) were equally categorized in group 1 (sham-control), group 2 (TAC) for 14 days, then relieved the knot and administered BrdU (50 ug/kg/intravenously/q.6.h for two times from day-14 after TAC) and group 3 (TAC + Stelazine/20 mg/kg/day since day 7 after TAC up to day 21 + BrdU administered as group 2), and animals were euthanized at day 28. The results showed that by day 28, the LVEF was significantly higher in group 1 than in groups 2/3 and significantly higher in group 3 than in group 2, whereas the LV chamber size exhibited an opposite pattern of LVEF (all p < 0.0001). The protein expressions of PrPC/p-PI3K/p-Akt/p-m-TOR/cyclin D/cyclin E and cellular-proliferation biomarkers (Ki67/PCNA/BrdU) exhibited an opposite pattern of LVEF (all p < 0.0001) among the three groups, whereas the protein expressions of RAS/c-RAF/p-MEK/p-ERK1/2 were significantly and progressively increased from groups 1 to 3 (all p < 0.0001). In conclusion, PrPC participated in regulating the intrinsic response of cell-stress signaling and myocardial regeneration but did not offer significant benefit on recovery of the heart function in the setting of TCM.
The Effect of Coenzyme Q10 on Liver Injury Induced by Valproic Acid and Its Antiepileptic Activity in Rats
Authors: Alqarni Fahad , Eweis Hala S. , Ali Ahmed , Alrafiah Aziza , Alsieni Mohammed , Karim Shahid , Alkathyri Mosleh Ayed
Published: January 2022

Valproic acid (VPA) has toxic metabolites that can elevate oxidative stress markers, and the hepatotoxicity of VPA has been reported. Coenzyme Q10 (CoQ10) is one of the most widely used antioxidants. The effect of CoQ10 on epileptogenesis and VPA hepatotoxicity were examined. Rats were randomly divided into five groups: the control group received 0.5% methylcellulose by oral gavages daily and saline by intraperitoneal injection three times weekly. The PTZ group received 1% methylcellulose by gavages daily and 30 mg/kg PTZ by intraperitoneal injection three times weekly. The valproic acid group received 500 mg/kg valproic acid by gavage and 30 mg/kg PTZ, as above. The CoQ10 group received 200 mg/kg CoQ10 by gavages daily and 30 mg/kg PTZ, as above. The Valproic acid + CoQ10 group received valproic acid and CoQ10, as above. Results: CoQ10 exhibited anticonvulsant activity and potentiated the anticonvulsant effect of VPA. CoQ10 combined with VPA induced a more significant reduction in oxidative stress and improved the histopathological changes in the brain and liver compared to VPA treatment. In addition, CoQ10 reduced the level of toxic VPA metabolites. These findings suggest that the co-administration of CoQ10 with VPA in epilepsy might have therapeutic potential by increasing antiepileptic activity and reducing the hepatotoxicity of VPA.
Diagnostic Blood Biomarkers in Alzheimer’s Disease
Authors: Park Jung Eun , Gunasekaran Tamil Iniyan , Cho Yeong Hee , Choi Seong-Min , Song Min-Kyung , Cho Soo Hyun , Kim Jahae , Song Ho-Chun , Choi Kyu Yeong , Lee Jang Jae , Park Zee-Yong , Song Woo Keun , Jeong Han-Seong , Lee Kun Ho , Lee Jung Sup , Kim Byeong C.
Published: January 2022

Potential biomarkers for Alzheimer’s disease (AD) include amyloid β1–42 (Aβ1–42), t-Tau, p-Tau181, neurofilament light chain (NFL), and neuroimaging biomarkers. Their combined use is useful for diagnosing and monitoring the progress of AD. Therefore, further development of a combination of these biomarkers is essential. We investigated whether plasma NFL/Aβ1–42 can serve as a plasma-based primary screening biomarker reflecting brain neurodegeneration and amyloid pathology in AD for monitoring disease progression and early diagnosis. We measured the NFL and Aβ1–42 concentrations in the CSF and plasma samples and performed correlation analysis to evaluate the utility of these biomarkers in the early diagnosis and monitoring of AD spectrum disease progression. Pearson’s correlation analysis was used to analyse the associations between the fluid biomarkers and neuroimaging data. The study included 136 participants, classified into five groups: 28 cognitively normal individuals, 23 patients with preclinical AD, 22 amyloid-negative patients with amnestic mild cognitive impairment, 32 patients with prodromal AD, and 31 patients with AD dementia. With disease progression, the NFL concentrations increased and Aβ1–42 concentrations decreased. The plasma and CSF NFL/Aβ1–42 were strongly correlated (r = 0.558). Plasma NFL/Aβ1–42 was strongly correlated with hippocampal volume/intracranial volume (r = 0.409). In early AD, plasma NFL/Aβ1–42 was associated with higher diagnostic accuracy than the individual biomarkers. Moreover, in preclinical AD, plasma NFL/Aβ1–42 changed more rapidly than the CSF t-Tau or p-Tau181 concentrations. Our findings highlight the utility of plasma NFL/Aβ1–42 as a non-invasive plasma-based biomarker for early diagnosis and monitoring of AD spectrum disease progression.
Is It Time to Test the Antiseizure Potential of Palmitoylethanolamide in Human Studies? A Systematic Review of Preclinical Evidence
Authors: Bortoletto Riccardo , Balestrieri Matteo , Bhattacharyya Sagnik , Colizzi Marco
Published: January 2022

Antiseizure medications are the cornerstone pharmacotherapy for epilepsy. They are not devoid of side effects. In search for better-tolerated antiseizure agents, cannabinoid compounds and other N-acylethanolamines not directly binding cannabinoid receptors have drawn significant attention. Among these, palmitoylethanolamide (PEA) has shown neuroprotective, anti-inflammatory, and analgesic properties. All studies examining PEA’s role in epilepsy and acute seizures were systematically reviewed. Preclinical studies indicated a systematically reduced PEA tone accompanied by alterations of endocannabinoid levels. PEA supplementation reduced seizure frequency and severity in animal models of epilepsy and acute seizures, in some cases, similarly to available antiseizure medications but with a better safety profile. The peripheral-brain immune system seemed to be more effectively modulated by subchronic pretreatment with PEA, with positive consequences in terms of better responding to subsequent epileptogenic insults. PEA treatment restored the endocannabinoid level changes that occur in a seizure episode, with potential preventive implications in terms of neural damage. Neurobiological mechanisms for PEA antiseizure effect seemed to include the activation of the endocannabinoid system and the modulation of neuroinflammation and excitotoxicity. Although no human study was identified, there is ground for testing the antiseizure potential of PEA and its safety profile in human studies of epilepsy.
Mindfulness Practice with a Brain-Sensing Device Improved Cognitive Functioning of Elementary School Children: An Exploratory Pilot Study
Authors: Vekety Boglarka , Logemann Alexander , Takacs Zsofia K.
Published: January 2022

This is the first pilot study with children that has assessed the effects of a brain–computer interface-assisted mindfulness program on neural mechanisms and associated cognitive performance. The participants were 31 children aged 9–10 years who were randomly assigned to either an eight-session mindfulness training with EEG-feedback or a passive control group. Mindfulness-related brain activity was measured during the training, while cognitive tests and resting-state brain activity were measured pre- and post-test. The within-group measurement of calm/focused brain states and mind-wandering revealed a significant linear change. Significant positive changes were detected in children’s inhibition, information processing, and resting-state brain activity (alpha, theta) compared to the control group. Elevated baseline alpha activity was associated with less reactivity in reaction time on a cognitive test. Our exploratory findings show some preliminary support for a potential executive function-enhancing effect of mindfulness supplemented with EEG-feedback, which may have some important implications for children’s self-regulated learning and academic achievement.
Understanding Estimations of Magnitudes: An fMRI Investigation
Authors: Ashkenazi Sarit , Gliksman Yarden , Henik Avishai
Published: January 2022

The current study examined whether discrete numerical estimation is based on the same cognitive process as estimation of continuous magnitudes such as weight and time. While the verbal estimation of numerical quantities has a contingent unit of measurement (e.g., how many cookies fit in a cookie jar? _X_ cookies), estimation of time and weight does not (e.g., how much time does it take to fill a bath with water? _X_ minutes/hours/seconds). Therefore, estimation of the latter categories has another level of difficulty, requiring extensive involvement of cognitive control. During a functional magnetic resonance imaging (fMRI) scan, 18 students performed estimations with three estimation categories: number, time, and weight. Estimations elicited activity in multiple brain regions, mainly: (1) visual regions including bilateral lingual gyrus), (2) parietal regions including the left angular gyrus and right supramarginal gyrus, and (3) the frontal regions (cingulate gyrus and the inferior frontal cortex). Continuous magnitude estimations (mostly time) produced different frontal activity than discrete numerical estimations did, demonstrating different profiles of brain activations between discrete numerical estimations and estimations of continuous magnitudes. The activity level in the right middle and inferior frontal gyrus correlated with the tendency to give extreme responses, signifying the importance of the right prefrontal lobe in estimations.
The Impacts of Emotional Intelligence on Students’ Study Habits in Blended Learning Environments: The Mediating Role of Cognitive Engagement during COVID-19
Authors: Iqbal Javed , Asghar Muhammad Zaheer , Ashraf Muhammad Azeem , Yi Xie
Published: January 2022

Emotional intelligence is a main area in educational psychology and a key factor in the academic life of students. It deals with deviant behavior through self-awareness and self-motivation, regulates emotional and social skills, and converts emotional energy into positive energy. This study examined direct and indirect relationships between emotional intelligence and study habits in blended learning environments. Blended learning is conceptualized as a hybrid learning approach that combines online learning opportunities and the traditional classroom approach. Furthermore, the study explored the mediating role of cognitive engagement in the relationship between emotional intelligence and study habits. We used 26 items in a paper-based questionnaire in a quantitative study to collect data on emotional intelligence, cognitive engagement and study habits from health sciences students (N = 338) enrolled in blended learning courses in universities in the Hunan province of China. Emotional intelligence included self-awareness, self-motivation, and the regulation of emotion; social skills were also examined. A partial least squares structural-equation modeling approach was applied through SmartPLS software to explore the relationships. The results indicate that self-awareness and self-motivation have direct, significant, and positive connections with study habits. Similarly, the results indicate that all four dimensions of emotional intelligence (self-awareness, self-motivation, emotion regulation and social skills) had indirect, significant, and positive relationships with study habits using cognitive engagement as a mediator variable. It was concluded that students face higher-than-usual challenges in building study habits in blended learning environments during the COVID-19 pandemic, and that emotional intelligence helps them to develop their study habits to greater effect. Similarly, it was concluded that cognitive engagement strengthens the connection between emotional intelligence and study habits. Therefore, it is recommended that universities take specific measures to enhance students’ emotional intelligence and cognitive engagement, which will ultimately improve their study habits. Moreover, valuable and practical implications for teachers, practitioners, and university management were also discussed in the study.
Insulin-like Growth Factor-1 Influences Prostate Cancer Cell Growth and Invasion through an Integrin α3, α5, αV, and β1 Dependent Mechanism
Authors: Siech Carolin , Rutz Jochen , Maxeiner Sebastian , Grein Timothy , Sonnenburg Marlon , Tsaur Igor , Chun Felix K.-H. , Blaheta Roman A.
Published: January 2022

Insulin-like growth factor-1 (IGF-1)-related signaling is associated with prostate cancer progression. Links were explored between IGF-1 and expression of integrin adhesion receptors to evaluate relevance for growth and migration. Androgen-resistant PC3 and DU145 and androgen-sensitive LNCaP and VCaP prostate cancer cells were stimulated with IGF-1 and tumor growth (all cell lines), adhesion and chemotaxis (PC3, DU145) were determined. Evaluation of Akt/mTOR-related proteins, focal adhesion kinase (FAK) and integrin α and β subtype expression followed. Akt knock-down was used to investigate its influence on integrin expression, while FAK blockade served to evaluate its influence on mTOR signaling. Integrin knock-down served to investigate its influence on tumor growth and chemotaxis. Stimulation with IGF-1 activated growth in PC3, DU145, and VCaP cells, and altered adhesion and chemotactic properties of DU145 and PC3 cells. This was associated with time-dependent alterations of the integrins α3, α5, αV, and β1, FAK phosphorylation and Akt/mTOR signaling. Integrin blockade or integrin knock-down in DU145 and PC3 cells altered tumor growth, adhesion, and chemotaxis. Akt knock-down (DU145 cells) cancelled the effect of IGF-1 on α3, α5, and αV integrins, whereas FAK blockade cancelled the effect of IGF-1 on mTOR signaling (DU145 cells). Prostate cancer growth and invasion are thus controlled by a fine-tuned network between IGF-1 driven integrin-FAK signaling and the Akt-mTOR pathway. Concerted targeting of integrin subtypes along with Akt-mTOR signaling could, therefore, open options to prevent progressive dissemination of prostate cancer.
Magnetic Compression of Tumor Spheroids Increases Cell Proliferation In Vitro and Cancer Progression In Vivo
Authors: Mary Gaëtan , Malgras Brice , Perez Jose Efrain , Nagle Irène , Luciani Nathalie , Pimpie Cynthia , Asnacios Atef , Pocard Marc , Reffay Myriam , Wilhelm Claire
Published: January 2022

A growing tumor is submitted to ever-evolving mechanical stress. Endoscopic procedures add additional constraints. However, the impact of mechanical forces on cancer progression is still debated. Herein, a set of magnetic methods is proposed to form tumor spheroids and to subject them to remote deformation, mimicking stent-imposed compression. Upon application of a permanent magnet, the magnetic tumor spheroids (formed from colon cancer cells or from glioblastoma cells) are compressed by 50% of their initial diameters. Such significant deformation triggers an increase in the spheroid proliferation for both cell lines, correlated with an increase in the number of proliferating cells toward its center and associated with an overexpression of the matrix metalloproteinase−9 (MMP−9). In vivo peritoneal injection of the spheroids made from colon cancer cells confirmed the increased aggressiveness of the compressed spheroids, with almost a doubling of the peritoneal cancer index (PCI), as compared with non-stimulated spheroids. Moreover, liver metastasis of labeled cells was observed only in animals grafted with stimulated spheroids. Altogether, these results demonstrate that a large compression of tumor spheroids enhances cancer proliferation and metastatic process and could have implications in clinical procedures where tumor compression plays a role.
Breast Tumour Classification Using Ultrasound Elastography with Machine Learning: A Systematic Scoping Review
Authors: Mao Ye-Jiao , Lim Hyo-Jung , Ni Ming , Yan Wai-Hin , Wong Duo Wai-Chi , Cheung James Chung-Wai
Published: January 2022

Ultrasound elastography can quantify stiffness distribution of tissue lesions and complements conventional B-mode ultrasound for breast cancer screening. Recently, the development of computer-aided diagnosis has improved the reliability of the system, whilst the inception of machine learning, such as deep learning, has further extended its power by facilitating automated segmentation and tumour classification. The objective of this review was to summarize application of the machine learning model to ultrasound elastography systems for breast tumour classification. Review databases included PubMed, Web of Science, CINAHL, and EMBASE. Thirteen (n = 13) articles were eligible for review. Shear-wave elastography was investigated in six articles, whereas seven studies focused on strain elastography (5 freehand and 2 Acoustic Radiation Force). Traditional computer vision workflow was common in strain elastography with separated image segmentation, feature extraction, and classifier functions using different algorithm-based methods, neural networks or support vector machines (SVM). Shear-wave elastography often adopts the deep learning model, convolutional neural network (CNN), that integrates functional tasks. All of the reviewed articles achieved sensitivity ³ 80%, while only half of them attained acceptable specificity ³ 95%. Deep learning models did not necessarily perform better than traditional computer vision workflow. Nevertheless, there were inconsistencies and insufficiencies in reporting and calculation, such as the testing dataset, cross-validation, and methods to avoid overfitting. Most of the studies did not report loss or hyperparameters. Future studies may consider using the deep network with an attention layer to locate the targeted object automatically and online training to facilitate efficient re-training for sequential data.
Temozolomide-Acquired Resistance Is Associated with Modulation of the Integrin Repertoire in Glioblastoma, Impact of α5β1 Integrin
Authors: Sani Saidu , Pallaoro Nikita , Messe Mélissa , Bernhard Chloé , Etienne-Selloum Nelly , Kessler Horst , Marinelli Luciana , Entz-Werle Natacha , Foppolo Sophie , Martin Sophie , Reita Damien , Dontenwill Monique
Published: January 2022

Despite extensive treatment, glioblastoma inevitably recurs, leading to an overall survival of around 16 months. Understanding why and how tumours resist to radio/chemotherapies is crucial to overcome this unmet oncological challenge. Primary and acquired resistance to Temozolomide (TMZ), the standard-of-care chemotherapeutic drug, have been the subjects of several studies. This work aimed to evaluate molecular and phenotypic changes occurring during and after TMZ treatment in a glioblastoma cell model, the U87MG. These initially TMZ-sensitive cells acquire long-lasting resistance even after removal of the drug. Transcriptomic analysis revealed that profound changes occurred between parental and resistant cells, particularly at the level of the integrin repertoire. Focusing on α5β1 integrin, which we proposed earlier as a glioblastoma therapeutic target, we demonstrated that its expression was decreased in the presence of TMZ but restored after removal of the drug. In this glioblastoma model of recurrence, α5β1 integrin plays an important role in the proliferation and migration of tumoral cells. We also demonstrated that reactivating p53 by MDM2 inhibitors concomitantly with the inhibition of this integrin in recurrent cells may overcome the TMZ resistance. Our results may explain some integrin-based targeted therapy failure as integrin expressions are highly switchable during the time of treatment. We also propose an alternative way to alter the viability of recurrent glioblastoma cells expressing a high level of α5β1 integrin.
Correction: Lai et al. MicroRNA-21 Plays Multiple Oncometabolic Roles in the Process of NAFLD-Related Hepatocellular Carcinoma via PI3K/AKT, TGF-β, and STAT3 Signaling. Cancers 2021, 13, 940
Authors: Lai Chi-Yu , Yeh Kun-Yun , Lin Chiu-Ya , Hsieh Yang-Wen , Lai Hsin-Hung , Chen Jim-Ray , Hsu Chia-Chun , Her Guor Mour
Published: January 2022

The authors wish to make the following corrections to this paper [...]
Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial
Authors: Bailey Simon , André Nicolas , Gandola Lorenza , Massimino Maura , Wheatley Keith , Gates Simon , Homer Victoria , Rutkowski Stefan , Clifford Steven
Published: January 2022

Medulloblastoma patients receive adapted therapies stratified according to their risk-profile. Favourable, standard, and high disease-risk groups are each defined by the status of clinical and pathological risk factors, alongside an evolving repertoire of diagnostic and prognostic biomarkers. Medulloblastoma clinical trials in Europe are coordinated by the International Society for Paediatric Oncology (SIOP-Europe) brain tumour group. Favourable and standard-risk patients are eligible for the SIOP-PNET5-MB clinical trial protocol. In contrast, therapies for high-risk disease worldwide have, to date, encompassed a range of different treatment philosophies, with no clear consensus on approach. Higher radiotherapy doses are typically deployed, delivered either conventionally or in hyper-fractionated/accelerated regimens. Similarly, both standard and high-dose chemotherapies were assessed. However, trials to date in high-risk medulloblastoma have commonly been institutional or national, based on modest cohort sizes, and have not evaluated the relative performance of different strategies in a randomised fashion. We describe the concepts and design of the SIOP-E high-risk medulloblastoma clinical trial (SIOP-HR-MB), the first international biomarker-driven, randomised, clinical trial for high-risk medulloblastoma. SIOP-HR-MB is programmed to recruit >800 patients in 16 countries across Europe; its primary objectives are to assess the relative efficacies of the alternative established regimens. The HR-MB patient population is molecularly and clinically defined, and upfront assessments incorporate a standardised central review of molecular pathology, radiology, and radiotherapy quality assurance. Secondary objectives include the assessment of (i) novel therapies within an upfront ‘window’ and (ii) therapy-associated neuropsychology, toxicity, and late effects, alongside (iii) the collection of materials for comprehensive integrated studies of biological determinants within the SIOP-HR-MB cohort.
Fully Automatic Deep Learning Framework for Pancreatic Ductal Adenocarcinoma Detection on Computed Tomography
Authors: Alves Natália , Schuurmans Megan , Litjens Geke , Bosma Joeran S. , Hermans John , Huisman Henkjan
Published: January 2022

Early detection improves prognosis in pancreatic ductal adenocarcinoma (PDAC), but is challenging as lesions are often small and poorly defined on contrast-enhanced computed tomography scans (CE-CT). Deep learning can facilitate PDAC diagnosis; however, current models still fail to identify small (<2 cm) lesions. In this study, state-of-the-art deep learning models were used to develop an automatic framework for PDAC detection, focusing on small lesions. Additionally, the impact of integrating the surrounding anatomy was investigated. CE-CT scans from a cohort of 119 pathology-proven PDAC patients and a cohort of 123 patients without PDAC were used to train a nnUnet for automatic lesion detection and segmentation (nnUnet_T). Two additional nnUnets were trained to investigate the impact of anatomy integration: (1) segmenting the pancreas and tumor (nnUnet_TP), and (2) segmenting the pancreas, tumor, and multiple surrounding anatomical structures (nnUnet_MS). An external, publicly available test set was used to compare the performance of the three networks. The nnUnet_MS achieved the best performance, with an area under the receiver operating characteristic curve of 0.91 for the whole test set and 0.88 for tumors <2 cm, showing that state-of-the-art deep learning can detect small PDAC and benefits from anatomy information.
Genomic Landscape of Vinflunine Response in Metastatic Urothelial Cancer
Authors: Bernardini Alejandra , Dueñas Marta , Martín-Soberon María Cruz , Rubio Carolina , Suarez-Cabrera Cristian , Ruiz-Palomares Raquel , Munera-Maravilla Ester , Lázaro Sara , Lodewijk Iris , Rueda Daniel , Gómez-Sánchez David , Alonso-Gordoa Teresa , Puente Javier , Pinto Álvaro , González-Peramato Pilar , Aguado Carlos , Herrera Mercedes , López Flora , Martinez Victor M. G. , Morales Lucía , Castellano Daniel , Paramio Jesús M. , de Velasco Guillermo
Published: January 2022

Background and Aims: Metastatic urothelial carcinoma (mUC) remains an incurable disease with limited treatment options after platinum-based chemotherapy and immune checkpoint blockade (ICB). Vinflunine has shown a modest increase in overall survival and remains a therapeutic option for chemo- and immunotherapy refractory tumours. However, biomarkers that could identify responding patients to vinflunine and possible alternative therapies after failure to treatment are still missing. In this study, we aimed to identify potential genomic biomarkers of vinflunine response in mUC patient samples and potential management alternatives. Methods: Formalin-fixed paraffin-embedded samples of mUC patients (n = 23) from three university hospitals in Spain were used for genomic targeted-sequencing and transcriptome (using the Immune Profile panel by NanoString) analyses. Patients who received vinflunine after platinum-based chemotherapy failure were classified in non-responders (NR: progressive disease ≤ 3 months; n= 11) or responders (R: response ≥ 6 months; n = 12). Results: Genomic characterization revealed that the most common alteration, TP53 mutations, had comparable frequency in R (6/12; 50%) and NR (4/11; 36%). Non-synonymous mutations in KTM2C (4/12; 33.3%), PIK3CA (3/12; 25%) and ARID2 (3/12; 25%) were predominantly associated with response. No significant difference was observed in tumour mutational burden (TMB) between R and NR patients. The NR tumours showed increased expression of diverse immune-related genes and pathways, including various interferon gamma-related genes. We also identified increased MAGEA4 expression as a potential biomarker of non-responding tumours to vinflunine treatment. Conclusions: Our data may help to identify potential genomic biomarkers of response to vinflunine. Moreover, tumours refractory to vinflunine showed immune signatures potentially associated with response to ICB. Extensive validation studies, including longitudinal series, are needed to corroborate these findings.
Spade-Shaped Anastomosis after Laparoscopic Proximal Gastrectomy Using Double Suture Anchoring between the Posterior Wall of the Esophagus and the Anterior Wall of the Stomach (SPADE Operation): A Case Series
Authors: Park Sin Hye , Khalayleh Harbi , Kim Sung Gon , Eom Sang Soo , Merei Fahed , Ryu Junsun , Kim Young-Woo
Published: January 2022

We introduced SPADE operation, a novel anastomotic method after laparoscopic proximal gastrectomy (PG). Technical modifications were performed and settled. This report aimed to demonstrate the short-term clinical outcomes after settlement. Data from 34 consecutive patients who underwent laparoscopic PG with SPADE between June 2017 and March 2020 were retrospectively reviewed. Reflux was evaluated based on the patients’ symptoms and follow-up endoscopy using Los Angeles (LA) classification and RGB Classification (Residue, Gastritis, Bile). Other complications were classified using the Clavien–Dindo method. The incidence of reflux esophagitis was 2.9% (1/34). Bile reflux was observed in six patients (17.6%), and residual food was observed in 16 patients (47.1%) in the endoscopy. Twenty-eight patients had no reflux symptoms (82.4%), while five patients (14.7%) and one patient (2.9%) had mild and moderate reflux symptoms, respectively. The rates of anastomotic stricture and ileus were 14.7% (5/34) and 11.8% (4/34), respectively. No anastomotic leakage was observed. The incidence of major complications (Clavien-Dindo grade III or higher) was 14.7%. The SPADE operation following laparoscopic PG is effective in reducing gastroesophageal reflux. Its clinical usefulness should be validated using prospective clinical trials.
Whole-Body MRI Surveillance—Baseline Findings in the Swedish Multicentre Hereditary TP53-Related Cancer Syndrome Study (SWEP53)
Authors: Omran Meis , Tham Emma , Brandberg Yvonne , Ahlström Håkan , Lundgren Claudia , Paulsson-Karlsson Ylva , Kuchinskaya Ekaterina , Silander Gustav , Rosén Anna , Persson Fredrik , Leonhardt Henrik , Stenmark-Askmalm Marie , Berg Johanna , van Westen Danielle , Bajalica-Lagercrantz Svetlana , Blomqvist Lennart ,   on behalf of the Swedish Clinical TP53 Study Group (SweClinTP53)
Published: January 2022

A surveillance strategy of the heritable TP53-related cancer syndrome (hTP53rc), commonly referred to as the Li–Fraumeni syndrome (LFS), is studied in a prospective observational nationwide multi-centre study in Sweden (SWEP53). The aim of this sub-study is to evaluate whole-body MRI (WB-MRI) regarding the rate of malignant, indeterminate, and benign imaging findings and the associated further workup generated by the baseline examination. Individuals with hTP53rc were enrolled in a surveillance program including annual whole-body MRI (WB-MRI), brain-MRI, and in female carriers, dedicated breast MRI. A total of 68 adults ≥18 years old have been enrolled to date. Of these, 61 fulfilled the inclusion criteria for the baseline MRI scan. In total, 42 showed a normal scan, while 19 (31%) needed further workup, of whom three individuals (3/19 = 16%) were diagnosed with asymptomatic malignant tumours (thyroid cancer, disseminated upper GI cancer, and liver metastasis from a previous breast cancer). Forty-three participants were women, of whom 21 had performed risk-reducing mastectomy prior to inclusion. The remaining were monitored with breast MRI, and no breast tumours were detected on baseline MRI. WB-MRI has the potential to identify asymptomatic tumours in individuals with hTP53rc syndrome. The challenge is to adequately and efficiently investigate all indeterminate findings. Thus, a multidisciplinary team should be considered in surveillance programs for individuals with hTP53rc syndrome.
Autophagy Regulation on Cancer Stem Cell Maintenance, Metastasis, and Therapy Resistance
Authors: Wang Xin , Lee Jihye , Xie Changqing
Published: January 2022

Cancer stem cells (CSCs) are a subset of the tumor population that play critical roles in tumorigenicity, metastasis, and relapse. A key feature of CSCs is their resistance to numerous therapeutic strategies which include chemotherapy, radiation, and immune checkpoint inhibitors. In recent years, there is a growing body of literature that suggests a link between CSC maintenance and autophagy, a mechanism to recycle intracellular components during moments of environmental stress, especially since CSCs thrive in a tumor microenvironment that is plagued with hypoxia, acidosis, and lack of nutrients. Autophagy activation has been shown to aid in the upkeep of a stemness state along with bolstering resistance to cancer treatment. However, recent studies have also suggested that autophagy is a double-edged sword with anti-tumorigenic properties under certain circumstances. This review summarizes and integrates what has been published in the literature in terms of what role autophagy plays in stemness maintenance of CSCs and suggests that there is a more complex interplay between autophagy and apoptosis which involves multiple pathways of regulation. Future cancer therapy strategies are needed to eradicate this resistant subset of the cell population through autophagy regulation.
Distal Gastrectomy for Symptomatic Stage IV Gastric Cancer Contributes to Prognosis with Acceptable Safety Compared to Gastrojejunostomy
Authors: Fujikuni Nobuaki , Tanabe Kazuaki , Hattori Minoru , Yamamoto Yuji , Tazawa Hirofumi , Toyota Kazuhiro , Tokumoto Noriaki , Hotta Ryuichi , Yanagawa Senichiro , Saeki Yoshihiro , Sugiyama Yoichi , Ikeda Masahiro , Shishida Masayuki , Fukuda Toshikatsu , Okano Keisuke , Nishihara Masahiro , Ohdan Hideki ,   on behalf of Hiroshima Surgical study group of Clinical Oncology (HiSCO)
Published: January 2022

Background: The prognostic prolongation effect of reduction surgery for asymptomatic stage IV gastric cancer (GC) is unfavorable; however, its prognostic effect for symptomatic stage IV GC remains unclear. We aimed to compare the prognosis of gastrectomy and gastrojejunostomy for symptomatic stage IV GC. Methods: This multicenter retrospective study analyzed record-based data of patients undergoing palliative surgery for symptomatic stage IV GC in the middle or lower-third regions between January 2015 and December 2019. Patients were divided into distal gastrectomy and gastrojejunostomy groups. We compared clinicopathological features and outcomes after propensity score matching (PSM). Results: Among the 126 patients studied, 46 and 80 underwent distal gastrectomy and gastrojejunostomy, respectively. There was no difference in postoperative complications between the groups. Regarding prognostic factors, surgical procedures and postoperative chemotherapy were significantly different in multivariate analysis. Each group was further subdivided into groups with and without postoperative chemotherapy. After PSM, the data of 21 well-matched patients with postoperative chemotherapy and 8 without postoperative chemotherapy were evaluated. Overall survival was significantly longer in the distal gastrectomy group (p = 0.007 [group with postoperative chemotherapy], p = 0.02 [group without postoperative chemotherapy]). Conclusions: Distal gastrectomy for symptomatic stage IV GC contributes to prognosis with acceptable safety compared to gastrojejunostomy.
A Breakthrough Brought about by Targeting KRASG12C: Nonconformity Is Punished
Authors: Ning Wenjuan , Yang Zhang , Kocher Gregor J. , Dorn Patrick , Peng Ren-Wang
Published: January 2022

KRAS is the most frequently mutated oncogene in lung carcinomas, accounting for 25% of total incidence, with half of them being KRASG12C mutations. In past decades, KRAS enjoyed the notorious reputation of being untargetable—that is, until the advent of G12C inhibitors, which put an end to this legend by covalently targeting the G12C (glycine to cysteine) substitution in the switch-II pocket of the protein, inhibiting the affinity of the mutant KRAS with GTP and subsequently the downstream signaling pathways, such as Raf/MEK/ERK. KRASG12C-selective inhibitors, e.g., the FDA-approved AMG510 and MRTX849, have demonstrated potent clinical efficacy and selectivity in patients with KRASG12C-driven cancers only, which spares other driver KRAS mutations (e.g., G12D/V/S, G13D, and Q61H) and has ushered in an unprecedented breakthrough in the field in recent decades. However, accumulating evidence from preclinical and clinical studies has shown that G12C-targeted therapeutics as single agents are inevitably thwarted by drug resistance, a persistent problem associated with targeted therapies. A promising strategy to optimize G12C inhibitor therapy is combination treatments with other therapeutic agents, the identification of which is empowered by the insightful appreciation of compensatory signaling pathways or evasive mechanisms, such as those that attenuate immune responses. Here, we review recent advances in targeting KRASG12C and discuss the challenges of KRASG12C inhibitor therapy, as well as future directions.
Longitudinal CT Imaging to Explore the Predictive Power of 3D Radiomic Tumour Heterogeneity in Precise Imaging of Mantle Cell Lymphoma (MCL)
Authors: Lisson Catharina Silvia , Lisson Christoph Gerhard , Achilles Sherin , Mezger Marc Fabian , Wolf Daniel , Schmidt Stefan Andreas , Thaiss Wolfgang M. , Bloehdorn Johannes , Beer Ambros J. , Stilgenbauer Stephan , Beer Meinrad , Götz Michael
Published: January 2022

The study’s primary aim is to evaluate the predictive performance of CT-derived 3D radiomics for MCL risk stratification. The secondary objective is to search for radiomic features associated with sustained remission. Included were 70 patients: 31 MCL patients and 39 control subjects with normal axillary lymph nodes followed over five years. Radiomic analysis of all targets (n = 745) was performed and features selected using the Mann Whitney U test; the discriminative power of identifying “high-risk MCL” was evaluated by receiver operating characteristics (ROC). The four radiomic features, “Uniformity”, “Entropy”, “Skewness” and “Difference Entropy” showed predictive significance for relapse (p < 0.05)—in contrast to the routine size measurements, which showed no relevant difference. The best prognostication for relapse achieved the feature “Uniformity” (AUC-ROC-curve 0.87; optimal cut-off ≤0.0159 to predict relapse with 87% sensitivity, 65% specificity, 69% accuracy). Several radiomic features, including the parameter “Short Axis,” were associated with sustained remission. CT-derived 3D radiomics improves the predictive estimation of MCL patients; in combination with the ability to identify potential radiomic features that are characteristic for sustained remission, it may assist physicians in the clinical management of MCL.