bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis of Copper Nanocluster and Its Application in Pollutant Analysis
Authors: Xue Yan , Cheng Zehua , Luo Mai , Hu Hao , Xia Chenglai
Published: October 2021

Copper nanoclusters (Cu NCs) with their inherent optical and chemical advantages have gained increasing attention as a kind of novel material that possesses great potential, primarily in the use of contaminants sensing and bio-imaging. With a focus on environmental safety, this article comprehensively reviews the recent advances of Cu NCs in the application of various contaminants, including pesticide residues, heavy metal ions, sulfide ions and nitroaromatics. The common preparation methods and sensing mechanisms are summarized. The typical high-quality sensing probes based on Cu NCs towards various target contaminants are presented; additionally, the challenges and future perspectives in the development and application of Cu NCs in monitoring and analyzing environmental pollutants are discussed.
Effects of Physical Exercise on Cognition and Telomere Length in Healthy Older Women
Authors: Sánchez-González Juan Luis , Sánchez-Rodríguez Juan Luis , Martín-Vallejo Javier , Martel-Martel Abel , González-Sarmiento Rogelio
Published: October 2021

Background: Physical exercise is an effective measure for preventing the onset of cognitive decline and has a direct influence on the aging process. The purpose of this study was to assess the effect of a 6-month physical exercise program on cognition and telomere length in adults over 65 years of age. Method: Seventy-four healthy women were separated into two groups: 41 were included in the intervention group (IG) (72.70 ± 4.127 years and 8.18 ± 1.551 years of education) and 33 in the control group (CG) (71.21 ± 4.127 years and 8.42 ± 2.562). The participants included within the IG carried out three sessions of physical exercise per week for six months. Cognitive function was assessed using the Mini-Mental State Examination (MMSE), the Stroop test and the Trail Making Test (TMT). Saliva samples were taken and analyzed and relative telomere length was calculated. Those conducting the analysis were blind to the group to which the participants had been assigned. Results: An improvement was observed in global cognitive function, in both attentional and executive functions, in the group of adults doing physical exercise as compared to the control group. Six months after the physical exercise program had finished, relative telomere length was found to have increased in the participants in the intervention group. Conclusion: Physical exercise programs can lead to an improvement in both cognitive functions and telomere length.
Parenting Stress and Social Style in Mothers and Fathers of Children with Autism Spectrum Disorder: A Cross-Cultural Investigation in Italy and Japan
Authors: Giannotti Michele , Bonatti Sophia Marlene , Tanaka Sanae , Kojima Haruyuki , de Falco Simona
Published: October 2021

Parents of children with autism spectrum disorder (ASD) face unique challenges, which may affect parenting functioning. However, little is known about gender and cultural variations in parenting stress and styles in these families. The aims of this study were to investigate: (1a) the differences in parenting stress and (1b) social style between Italian and Japanese mothers and fathers of children with ASD; (2) the predictive role of culture, sociodemographic, and child’s characteristics on parenting stress; (3) the predictors of the social parenting style, including parenting stress dimensions. The study involved 92 Italians and 89 Japanese parents of school-age children (5–12 years) with ASD who completed the Parenting Stress Index and the Parenting Style Questionnaire. Results revealed that Japanese parents showed higher parenting stress and less engagement in social style than Italians. Across cultures, mothers used more social style than fathers. Being Japanese and having a child with greater ASD severity predicted higher levels of parenting stress. We also found that country, parent’s gender, and stress related to the dysfunctional interaction were significant predictors of parenting social style. Our findings highlight the importance of a cross-cultural approach to better understand the experiences and needs of mothers and fathers of children with ASD.
Assessment of Motor Planning and Inhibition Performance in Non-Clinical Sample—Reliability and Factor Structure of the Tower of London and Go/No Go Computerized Tasks
Authors: Tyburski Ernest , Kerestey Magdalena , Kerestey Pavlo , Radoń Stanisław , Mueller Shane T.
Published: October 2021

In two studies, we examine the test-retest reliability and factor structure of the computerized Tower of London (TOL) and Go/No Go (GNG). Before analyses, raw results of variables that were not normally distributed were transformed. Study 1 examined the reliability of a broad spectrum of indicators (Initial Time Thinking, ITT; Execution Time, ET; Full Time, FT; Extra Moves, EM; No Go Errors, NGE; Reaction Time for Go Responses, RTGR) across an eight-week delay in a sample of 20 young adults. After correction for multiple comparisons and correlations, our results demonstrate that the tasks have ambiguous test-retest reliability coefficients (non-significant r for all indicators, and interclass correlation (ICC) for TOL; significant ICC for GNG; show lack of reliable change over time for all indicators in both tasks); moreover, ITT exhibits strong practice effects. Study 2 investigated both tasks’ factor structure and conducted a more detailed analysis of indicators for each trial (ITT, ET, EM) in the TOL task in the group of 95 young adults. Results reveal a satisfactory 2-factor solution, with the first factor (planning inhibition) defined by ITT, NGE, and RTGR, and the second factor (move efficiency) defined by EM and ET. The detailed analysis identified a 6-factor solution with the first factor defined by ITT for more difficult trials and the remaining five factors defined by EM and ET for each trial, reflecting move efficiency for each trial separately.
Reaction Time and Visual Memory in Connection to Hazardous Drinking Polygenic Scores in Schizophrenia, Schizoaffective Disorder and Bipolar Disorder
Authors: Mazumder Atiqul Haq , Barnett Jennifer , Isometsä Erkki Tapio , Lindberg Nina , Torniainen-Holm Minna , Lähteenvuo Markku , Lahdensuo Kaisla , Kerkelä Martta , Ahola-Olli Ari , Hietala Jarmo , Kampman Olli , Kieseppä Tuula , Jukuri Tuomas , Häkkinen Katja , Cederlöf Erik , Haaki Willehard , Kajanne Risto , Wegelius Asko , Männynsalo Teemu , Niemi-Pynttäri Jussi , Suokas Kimmo , Lönnqvist Jouko , Tiihonen Jari , Paunio Tiina , Vainio Seppo Juhani , Palotie Aarno , Niemelä Solja , Suvisaari Jaana , Veijola Juha
Published: October 2021

The purpose of this study was to explore the association of cognition with hazardous drinking Polygenic Scores (PGS) in 2649 schizophrenia, 558 schizoaffective disorder, and 1125 bipolar disorder patients in Finland. Hazardous drinking PGS was computed using the LDPred program. Participants performed two computerized tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB) on a tablet computer: the 5-choice serial reaction time task, or Reaction Time (RT) test, and the Paired Associative Learning (PAL) test. The association between hazardous drinking PGS and cognition was measured using four cognition variables. Log-linear regression was used in Reaction Time (RT) assessment, and logistic regression was used in PAL assessment. All analyses were conducted separately for males and females. After adjustment of age, age of onset, education, household pattern, and depressive symptoms, hazardous drinking PGS was not associated with reaction time or visual memory in male or female patients with schizophrenia, schizoaffective, and bipolar disorder.
Tart Cherry Extract and Omega Fatty Acids Reduce Behavioral Deficits and Gliosis in the 5xFAD Mouse Model of Alzheimer’s Disease
Authors: Bowers Zackary , Maiti Panchanan , Bourcier Ali , Morse Jarod , Jenrow Kenneth , Rossignol Julien , Dunbar Gary
Published: October 2021

Combined treatments using polyphenols and omega fatty acids provide several therapeutic benefits for a variety of age-related disorders, including Alzheimer’s disease (AD). Previously, we found a commercial product, Total Body Rhythm (TBR), consisting of tart cherry extract, a potent polyphenol, and omega fatty acids, significantly reduced memory, and neuropathological deficits in the 192 IgG-saporin mouse model of AD. The present study assessed the efficacy of TBR for treating behavioral and neuropathological deficits in the 5xFAD model of AD. Both 6- and 12-month-old 5xFAD mice and age-matched wild-type controls received TBR (60 mg/kg) or the equivalent dose of vehicle (0.5% methylcellulose) via oral administration, every other day for two months. All mice were tested in the open field (OF), novel object recognition (NOR), and the Morris water maze (MWM) tasks. In addition, neuronal morphology, neurodegeneration, Aβ plaque load, and glial activation were assessed. TBR treatment reduced memory deficits in the MWM and NOR tests and lessened anxiety levels in the OF task, mostly in the 6-month-old male mice. TBR also protected and reduced activation of astrocytes and microglia, primarily in 6-month-old mice. These results suggest that the combination of tart cherry extract and omega fatty acids in TBR can reduce AD-like deficits in 5xFAD mice.
Sleep Instability Correlates with Attentional Impairment in Boys with Attention Deficit Hyperactivity Disorder
Authors: Gagnon Katia , Labrosse Mélanie , Gingras Marc-André , Godbout Roger
Published: October 2021

Theoretical models of sleep and attention deficit hyperactivity disorder (ADHD) suggest that symptoms of ADHD are associated with daytime sleepiness, but it has received little support. The present study aimed at testing an alternative model involving the association of attentional instability with sleep instability, i.e., sleep stage transitions and arousals. Twelve ADHD and 15 healthy control (HC) boys aged between 8 and 12 years old underwent polysomnography recording and attentional testing. The microarousal index, the number of awakenings, and the number of stage shifts between stages 1, 2, 3, 4 and REM sleep throughout the night were computed as sleep stability parameters. Attentional functioning was assessed using the Continuous Performance Test-II. We found significantly higher sleep instability in ADHD compared to HC. Sleep arousals and stage transitions (micro arousal index, stage 4/3 and 2/4 transitions) in ADHD significantly correlated with lower attentional scores. No association whatsoever was found between sleep instability and attentional functioning in HC. The results show that sleep instability is associated with lower attentional performance in boys with ADHD, but not in HC. This could be compatible with a model according to which attention and sleep stability share a common neural substrate in ADHD.
Verification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human Skull
Authors: Park Chan Yuk , Seo Hyeon , Lee Eun-Hee , Han Mun , Choi Hyojin , Park Ki-Su , Yoon Sang-Youl , Chang Sung Hyun , Park Juyoung
Published: October 2021

Methods to improve drug delivery efficiency through blood-brain barrier disruption (BBBD) based on microbubbles and focused ultrasound (FUS) are continuously being studied. However, most studies are being conducted in preclinical trial environments using small animals. The use of the human skull shows differences between the clinical and preclinical trials. BBBD results from preclinical trials are difficult to represent in clinical trials because various distortions of ultrasound by the human skull are excluded in the former. Therefore, in our study, a clinical validation platform based on a preclinical trial environment, using a human skull fragment and a rat model, was developed to induce BBBD under conditions similar to clinical trials. For this, a human skull fragment was inserted between the rat head and a 250 kHz FUS transducer, and optimal ultrasound parameters for the free field (without human skull fragment) and human skull (with human skull fragment) were derived by 300 mVpp and 700 mVpp, respectively. BBBD was analyzed according to each case using magnetic resonance images, Evans blue dye, cavitation, and histology. Although it was confirmed using magnetic resonance images and Evans blue dye that a BBB opening was induced in each case, multiple BBB openings were observed in the brain tissues. This phenomenon was analyzed by numerical simulation, and it was confirmed to be due to standing waves owing to the small skull size of the rat model. The stable cavitation doses (SCDh and SCDu) in the human skull decreased by 13.6- and 5.3-fold, respectively, compared to those in the free field. Additionally, the inertial cavitation dose in the human skull decreased by 1.05-fold compared to that of the free field. For the histological analysis, although some extravasated red blood cells were observed in each case, it was evaluated as recoverable based on our previous study results. Therefore, our proposed platform can help deduct optimal ultrasound parameters and BBBD results for clinical trials in the preclinical trials with small animals because it considers variables relevant to the human skull.
Impact of Alternate Gait Training Using Knee–Ankle–Foot Orthoses with Oil Damper Ankle Hinge in Patients with Subacute Severe Hemiplegia
Authors: Abe Hiroaki , Nishiyama Kazutaka , Yamamoto Yuichi , Okanuka Toru , Yonezawa Yasuhito , Matsumoto Koji
Published: October 2021

Patients with severe hemiplegia along with knee instability require knee–ankle–foot orthoses (KAFOs) for gait training. However, in these patients, it is unclear which type of walking training is more effective to improve gait function. Providing alternate gait training (AGT) improves walking function in patients with spinal cord injury, but it is still unclear whether this is effective in hemiplegic stroke patients. In this study, we defined “unified AGT” as AGT performed with the same therapeutic concept by physiotherapists. We then investigated whether AGT improved gait function quicker than our traditional gait training in hemiplegic stroke patients. We enrolled 15 subjects with severe hemiplegia and knee instability who had undergone unified AGT using KAFOs with hinged oil dampers at the ankles, and 30 historical control (HC) subjects who had undergone traditional gait training. We used multiple comparison and survival analyses to analyze the differences in the functional independence measure (FIM) gait score changes between the two groups. The multiple comparison revealed a significant increase (p < 0.05) in the FIM gait score compared with its initial score in the subjects with unified AGT. However, this improvement was not seen in the HC subjects. Additionally, the survival analysis of time taken to recover revealed a significant difference between the subjects with unified AGT and HC subjects (p < 0.05). These findings suggest that unified AGT using a KAFO facilitates gait improvement in patients with severe hemiplegia and knee instability.
Influence of Topiramate on the Synaptic Endings of the Temporal Lobe Neocortex in an Experimental Model of Hyperthermia-Induced Seizures: An Ultrastructural Study
Authors: Sobaniec Piotr , Lotowska Joanna Maria , Sobaniec-Lotowska Maria Elzbieta , Zochowska-Sobaniec Milena
Published: October 2021

The objective of this pioneering study was to assess potentially neuroprotective properties of topiramate (TPM), a broad spectrum and newer-generation antiepileptic used against damage to synaptic endings of the temporal lobe neocortex in experimental hyperthermia-induced seizures (HS). TPM (80 mg/kg b.m.) was administered in young male Wistar rats with an intragastric tube before and immediately after HS. Specimens (1 mm3) collected from the neocortex, fixed via transcardial perfusion with paraformaldehyde and glutaraldehyde solution, were routinely processed for transmission-electron microscopic study, i.e., for descriptive and morphometric analysis. The ultrastructure of neocortical neuropil components affected by hyperthermic stress showed distinct swelling of pre and post-synaptic axodendritic and axospinal endings, including total disintegration. Mitochondria were markedly damaged in synaptic structures. Axoplasm of presynaptic boutons contained a decreased number of synaptic vesicles. Synaptic junctions showed active zone-shortening. Preventive administration of TPM before HS induction demonstrated neuroprotective effects against synaptic damage in approximately 1/4 of these structures. Interestingly, beneficial effects on synapsis morphology were more common in perivascular zones close to well-preserved capillaries. They were demonstrated by smaller swelling of both presynaptic and postsynaptic parts, well-preserved mitochondria, an increased number and regular distribution of synaptic vesicles within axoplasm, and a significantly increased synaptic active zones. However, topiramate used directly after HS was ineffective in the prevention of hyperthermia-evoked synaptic injury. Our findings support the hypothesis that topiramate applied before HS can protect some neocortical synapses via the vascular factor by enhancing blood–brain barrier components and improving the blood supply of gray matter in the temporal lobe, which may be significant in febrile seizure-prevention in children.
Non-Immersive Virtual Reality to Improve Balance and Reduce Risk of Falls in People Diagnosed with Parkinson’s Disease: A Systematic Review
Authors: García-López Héctor , Obrero-Gaitán Esteban , Castro-Sánchez Adelaida María , Lara-Palomo Inmaculada Carmen , Nieto-Escamez Francisco Antonio , Cortés-Pérez Irene
Published: October 2021

(1) Objective: To evaluate the effectiveness of non-immersive virtual reality in reducing falls and improving balance in patients diagnosed with Parkinson’s disease. (2) Methods: The following databases were searched: PUBMED, PEDro, Scielo, CINAHL, Web of Science, Dialnet, Scopus and MEDLINE. These databases were searched for randomized controlled trials published using relevant keywords in various combinations. The methodological quality of the articles was evaluated using the PEDro scale. (3) Results: A total of 10 studies with a total of 537 subjects, 58.7% of which (n = 315) were men, have been included in the review. The age of the participants in these studies ranged between 55 and 80 years. Each session lasted between 30 and 75 min, and the interventions lasted between 5 and 12 weeks. These studies showed that non-immersive virtual reality is effective in reducing the number of falls and improving both static and dynamic balance in patients diagnosed with Parkinson’s disease. Results after non-immersive virtual reality intervention showed an improvement in balance and a decrease in the number and the risk of falls. However, no significant differences were found between the intervention groups and the control groups for all the included studies regarding balance. (4) Conclusions: There is evidence that non-immersive virtual reality can improve balance and reduce the risk and number of falls, being therefore beneficial for people diagnosed with Parkinson’s disease.
The Relevant Role of Navigated Tractography in Speech Eloquent Area Glioma Surgery: Single Center Experience
Authors: Salvati Luca Francesco , De Marco Raffaele , Palmieri Giuseppe , Minardi Massimiliano , Massara Armando , Pesaresi Alessandro , Cagetti Bernarda , Melcarne Antonio , Garbossa Diego
Published: October 2021

Background: Gliomas are among the most challenging pathologies for neurosurgeons due to their infiltrative and recurrent nature in functionally relevant regions. Current knowledge confirms that gross total resection highly influence survival in patient with glioma. However, surgery performed in eloquent brain area, could seriously compromise the quality of life in patient with reduced life expectancy even more if it concerns the language function. Methods: 18 right-handed patients with perisylvian gliomas on the left hemisphere were prospectively analyzed over a period of 12 months. Standardized preoperative Diffusion-Tensor-Imaging based tractography of the five main language Tracts (Arcuate Fasciculus, Frontal Aslant Tract, Inferior Fronto-Occipital Fasciculus, Inferior Longitudinal Fasciculus, Uncinate Fasciculus) was navigated during the surgical procedure. Using a validated method, correlations were made between the pre-operative fascicles and their possible infiltration and surgical damage. The language status was assessed using the Aachen Aphasia Test. Results: In all nine patients who developed a permanent disorder there was pre-operative involvement of at least one fascicle and resection of at least one of these. In this way, areas of high risk of permanent language damage have emerged as a result of surgical injury: the temporoparietal junction, the middle portion of the FAT and the temporal stem. Conclusions: Navigated tractography has proven to be a user-friendly tool that can assess perioperative risk, guide surgical resection, and help the neurosurgeon to find that balance between tumor resection and function preservation.
Proteomics Profiling with SWATH-MS Quantitative Analysis of Changes in the Human Brain with HIV Infection Reveals a Differential Impact on the Frontal and Temporal Lobes
Authors: Doke Mayur , Ramasamy Tamizhselvi , Sundar Vaishnavi , McLaughlin Jay P. , Samikkannu Thangavel
Published: October 2021

The chronic irreversible regression of cognitive ability and memory function in human immunodeficiency virus (HIV)-associated dementia (HAND) is linked with late-stage HIV infection in the brain. The molecular-level signatures of neuroinflammation and neurodegeneration are linked with dysfunction in HAND patients. Protein expression changes and posttranslational modification are epigenetic cues for dementia and neurodegenerative disease. In this study quantitative proteome analysis was performed to comprehensively elucidate changes in protein profiles in HIV-positive (HIV+) human brains. Frontal and temporal lobes of normal and HIV+ brains were subjected to label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis using the data-independent acquisition method. Comprehensive proteomic identification and quantification analysis revealed that 3294 total proteins and 251 proteins were differentially expressed in HIV+ brains; specifically, HIV+ frontal and temporal lobes had 132 and 119 differentially expressed proteins, respectively. Proteomic and bioinformatic analyses revealed protein alterations predominantly in the HIV+ frontal lobe region. The expression of GOLPH3, IMPDH2, DYNLL1, RPL11, and GPNMB proteins was significantly altered in HIV+ frontal lobes compared to that in normal brains. These proteins are associated with metabolic pathways, neurodegenerative disorders, and dementia. These proteomic-level changes may be potential biological markers and therapeutic targets to relieve the dementia-associated symptoms in individuals with HAND.
Deep Vision for Breast Cancer Classification and Segmentation
Authors: Fulton Lawrence , McLeod Alex , Dolezel Diane , Bastian Nathaniel , Fulton Christopher P.
Published: October 2021

(1) Background: Female breast cancer diagnoses odds have increased from 11:1 in 1975 to 8:1 today. Mammography false positive rates (FPR) are associated with overdiagnoses and overtreatment, while false negative rates (FNR) increase morbidity and mortality. (2) Methods: Deep vision supervised learning classifies 299 × 299 pixel de-noised mammography images as negative or non-negative using models built on 55,890 pre-processed training images and applied to 15,364 unseen test images. A small image representation from the fitted training model is returned to evaluate the portion of the loss function gradient with respect to the image that maximizes the classification probability. This gradient is then re-mapped back to the original images, highlighting the areas of the original image that are most influential for classification (perhaps masses or boundary areas). (3) Results: initial classification results were 97% accurate, 99% specific, and 83% sensitive. Gradient techniques for unsupervised region of interest mapping identified areas most associated with the classification results clearly on positive mammograms and might be used to support clinician analysis. (4) Conclusions: deep vision techniques hold promise for addressing the overdiagnoses and treatment, underdiagnoses, and automated region of interest identification on mammography.
An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML
Authors: van der Lee Dyantha , Koutsoumpli Georgia , Reijmers Rogier , Honders M. , de Jong Rob , Remst Dennis , Wachsmann Tassilo , Hagedoorn Renate , Franken Kees , Kester Michel , Harber Karl , Roelofsen Lisanne , Schouten Annemiek , Mulder Arend , Drijfhout Jan , Veelken Hendrik , van Veelen Peter , Heemskerk Mirjam , Falkenburg J.H. , Griffioen Marieke
Published: October 2021

Acute myeloid leukemia (AML) is a hematological malignancy caused by clonal expansion of myeloid progenitor cells. Most patients with AML respond to chemotherapy, but relapses often occur and infer a very poor prognosis. Thirty to thirty-five percent of AMLs carry a four base pair insertion in the nucleophosmin 1 gene (NPM1) with a C-terminal alternative reading frame of 11 amino acids. We previously identified various neopeptides from the alternative reading frame of mutant NPM1 (dNPM1) on primary AML and isolated an HLA-A*02:01-restricted T-cell receptor (TCR) that enables human T-cells to kill AML cells upon retroviral gene transfer. Here, we isolated T-cells recognizing the dNPM1 peptide AVEEVSLRK presented in HLA-A*11:01. The TCR cloned from a T-cell clone recognizing HLA-A*11:01+ primary AML cells conferred in vitro recognition and lysis of AML upon transfer to CD8 cells, but failed to induce an anti-tumor effect in immunodeficient NSG mice engrafted with dNPM1 OCI-AML3 cells. In conclusion, our data show that AVEEVSLRK is a dNPM1 neoantigen on HLA-A*11:01+ primary AMLs. CD8 cells transduced with an HLA-A*11:01-restricted TCR for dNPM1 were reactive against AML in vitro. The absence of reactivity in a preclinical mouse model requires further preclinical testing to predict the potential efficacy of this TCR in clinical development.
Biological Mechanisms and Therapeutic Opportunities in Mammographic Density and Breast Cancer Risk
Authors: Archer Maddison , Dasari Pallave , Evdokiou Andreas , Ingman Wendy V.
Published: October 2021

Mammographic density is an important risk factor for breast cancer; women with extremely dense breasts have a four to six fold increased risk of breast cancer compared to women with mostly fatty breasts, when matched with age and body mass index. High mammographic density is characterised by high proportions of stroma, containing fibroblasts, collagen and immune cells that suggest a pro-tumour inflammatory microenvironment. However, the biological mechanisms that drive increased mammographic density and the associated increased risk of breast cancer are not yet understood. Inflammatory factors such as monocyte chemotactic protein 1, peroxidase enzymes, transforming growth factor beta, and tumour necrosis factor alpha have been implicated in breast development as well as breast cancer risk, and also influence functions of stromal fibroblasts. Here, the current knowledge and understanding of the underlying biological mechanisms that lead to high mammographic density and the associated increased risk of breast cancer are reviewed, with particular consideration to potential immune factors that may contribute to this process.
TP53 in Myelodysplastic Syndromes
Authors: Jiang Yan , Gao Su-Jun , Soubise Benoit , Douet-Guilbert Nathalie , Liu Zi-Ling , Troadec Marie-Bérengère
Published: October 2021

Myelodysplastic syndromes (MDSs) are heterogeneous for their morphology, clinical characteristics, survival of patients, and evolution to acute myeloid leukemia. Different prognostic scoring systems including the International Prognostic Scoring System (IPSS), the Revised IPSS, the WHO Typed Prognostic Scoring System, and the Lower-Risk Prognostic Scoring System have been introduced for categorizing the highly variable clinical outcomes. However, not considered by current MDS prognosis classification systems, gene variants have been identified for their contribution to the clinical heterogeneity of the disease and their impact on the prognosis. Notably, TP53 mutation is independently associated with a higher risk category, resistance to conventional therapies, rapid transformation to leukemia, and a poor outcome. Herein, we discuss the features of monoallelic and biallelic TP53 mutations within MDS, their corresponding carcinogenic mechanisms, their predictive value in current standard treatments including hypomethylating agents, allogeneic hematopoietic stem cell transplantation, and lenalidomide, together with the latest progress in TP53-targeted therapy strategies, especially MDS clinical trial data.
APC and TP53 Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes
Authors: Thota Ramya , Yang Mingli , Pflieger Lance , Schell Michael J. , Rajan Malini , Davis Thomas B. , Wang Heiman , Presson Angela , Pledger Warren Jack , Yeatman Timothy J.
Published: October 2021

Recently, it was suggested that consensus molecular subtyping (CMS) may aide in predicting response to EGFR inhibitor (cetuximab) therapies. We recently identified that APC and TP53 as two tumor suppressor genes, when mutated, may enhance cetuximab sensitivity and may represent easily measured biomarkers in tumors or blood. Our study aimed to use APC and TP53 mutations (AP) to refine the CMS classification to better predict responses to cetuximab. In total, 433 CRC tumors were classified into CMS1-4 subtypes. The cetuximab sensitivity (CTX-S) signature scores of AP vs. non-AP tumors were determined across each of the CMS classes. Tumors harboring combined AP mutations were predominantly enriched in the CMS2 class, and to a lesser degree, in the CMS4 class. On the other hand, AP mutated CRCs had significantly higher CTX-S scores compared to non-AP CRCs across all CMS classes. Similar results were also obtained in independent TCGA tumor collections (n = 531) and in PDMR PDX/PDO/PDC models (n = 477). In addition, the in vitro cetuximab growth inhibition was preferentially associated with the CMS2 cell lines harboring A/P genotypes. In conclusion, the AP mutation signature represents a convenient biomarker that refines the CMS classification to identify CRC subpopulations predicted to be sensitive to EGFR targeted therapies.
Lymphoma-Associated Biomarkers Are Increased in Current Smokers in Twin Pairs Discordant for Smoking
Authors: Wang Jun , Conti David V. , Epeldegui Marta , Ollikainen Miina , Tyndale Rachel F. , Hwang Amie Eunah , Magpantay Larry , Mack Thomas McCulloch , Martinez-Maza Otoniel , Kaprio Jaakko , Cozen Wendy
Published: October 2021

Smoking is associated with a moderate increased risk of Hodgkin and follicular lymphoma. To understand why, we examined lymphoma-related biomarker levels among 134 smoking and non-smoking twins (67 pairs) ascertained from the Finnish Twin Cohort. Previously collected frozen serum samples were tested for cotinine to validate self-reported smoking history. In total, 27 immune biomarkers were assayed using the Luminex Multiplex platform (R & D Systems). Current and non-current smokers were defined by a serum cotinine concentration of >3.08 ng/mL and ≤3.08 ng/mL, respectively. Associations between biomarkers and smoking were assessed using linear mixed models to estimate beta coefficients and standard errors, adjusting for age, sex and twin pair as a random effect. There were 55 never smokers, 43 current smokers and 36 former smokers. CCL17/TARC, sgp130, haptoglobin, B-cell activating factor (BAFF) and monocyte chemoattractant protein-1 (MCP1) were significantly (p < 0.05) associated with current smoking and correlated with increasing cotinine concentrations (Ptrend < 0.05). The strongest association was observed for CCL17/TARC (Ptrend = 0.0001). Immune biomarker levels were similar in former and never smokers. Current smoking is associated with increased levels of lymphoma-associated biomarkers, suggesting a possible mechanism for the link between smoking and risk of these two B-cell lymphomas.
Outcome and Safety after 103 Radioembolizations with Yttrium-90 Resin Microspheres in 73 Patients with Unresectable Intrahepatic Cholangiocarcinoma—An Evaluation of Predictors
Authors: Paprottka Karolin J. , Galiè Franziska , Ingrisch Michael , Geith Tobias , Ilhan Harun , Todica Andrei , Michl Marlies , Nadjiri Jonathan , Paprottka Philipp M.
Published: October 2021

Trans-arterial radioembolization (TARE) is increasingly evaluated for unresectable intrahepatic cholangiocarcinoma (ICC). Not all ICC patients benefit equally well from TARE. Therefore, we sought to evaluate variables predicting progression-free survival (PFS) and overall survival (OS). Patients with non-resectable ICC underwent TARE and were treated with 90Y resin microspheres. Baseline characteristics, biochemical/clinical toxicities, and response were examined for impact on PFS and OS. A total of 103 treatments were administered to 73 patients without major complications or toxicity. Mean OS was 18.9 months (95% confidence intervals (CI); 13.9–23.9 months). Mean and median PFS were 10.1 months (95% CI; 7.9–12.2) and 6.4 months (95% CI; 5.20–7.61), respectively. Median OS and PFS were significantly prolonged in patients with baseline cholinesterase (CHE) ≥ 4.62 kU/L (OS: 14.0 vs. 5.5 months; PFS: 6.9 vs. 3.2 months; p < 0.001). Patients with a tumor burden ≤ 25% had a significantly longer OS (15.2 vs. 6.6 months; p = 0.036). Median PFS was significantly longer for patients with multiple TARE cycles (24.4 vs. 5.8 months; p = 0.04). TARE is a considerable and safe option for unresectable ICC. CA-19-9, CHE, and tumor burden have predictive value for survival in patients treated with TARE. Multiple TARE treatments might further improve survival; this has to be confirmed by further studies.
Correction: Pan et al. Impact of FAK Expression on the Cytotoxic Effects of CIK Therapy in Triple-Negative Breast Cancer. Cancers 2020, 12, 94
Authors: Pan Mei-Ren , Wu Cheng-Che , Kan Jung-Yu , Li Qiao-Lin , Chang Shu-Jyuan , Wu Chun-Chieh , Li Chung-Liang , Ou-Yang Fu , Hou Ming-Feng , Yip Hon-Kan , Luo Chi-Wen
Published: October 2021

In the original article [...]
Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death
Authors: Hoshiko Toshimi , Kubota Yasushi , Onodera Risako , Higashi Taishi , Yokoo Masako , Motoyama Keiichi , Kimura Shinya
Published: October 2021

2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is widely used as an enabling excipient in pharmaceutical formulations. We previously demonstrated that HP-β-CyD disrupted cholesterol homeostasis, and inhibited the proliferation of leukemia cells by inducing apoptosis and cell-cycle arrest. Recently developed drug delivery systems using folic acid (FA) and folic acid receptors (FR) are currently being used in cancer treatment. To confer tumor cell-selectivity to HP-β-CyD, we synthesized folate-appended HP-β-CyD (FA-HP-β-CyD) and evaluated the potential of FA-HP-β-CyD as an anticancer agent using chronic myeloid leukemia (CML) cells in vitro and in vivo. FA-HP-β-CyD inhibited the growth of FR-expressing cells but not that of FR-negative cells. FA-HP-β-CyD had stronger anti-leukemia and cell-binding activities than HP-β-CyD in CML cells. Unlike HP-β-CyD, FA-HP-β-CyD entered CML cells through endocytosis and induced both apoptosis and autophagy via mitophagy. FA-HP-β-CyD increased the inhibitory effects of the ABL tyrosine kinase inhibitors imatinib mesylate and ponatinib, which are commonly used in CML. In vivo experiments in a BCR-ABL leukemia mouse model showed that FA-HP-β-CyD was more effective than HP-β-CyD at a ten-fold lower dose. These results indicate that FA-HP-β-CyD may be a novel tumor-targeting agent for the treatment of leukemia.
Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment
Authors: Muñoz Raquel , Girotti Alessandra , Hileeto Denise , Arias Francisco Javier
Published: October 2021

The concept of cancer as a systemic disease, and the therapeutic implications of this, has gained special relevance. This concept encompasses the interactions between tumor and stromal cells and their microenvironment in the complex setting of primary tumors and metastases. These factors determine cellular co-evolution in time and space, contribute to tumor progression, and could counteract therapeutic effects. Additionally, cancer therapies can induce cellular and molecular responses in the tumor and host that allow them to escape therapy and promote tumor progression. In this study, we describe the vascular network, tumor-infiltrated immune cells, and cancer-associated fibroblasts as sources of heterogeneity and plasticity in the tumor microenvironment, and their influence on cancer progression. We also discuss tumor and host responses to the chemotherapy regimen, at the maximum tolerated dose, mainly targeting cancer cells, and a multimodal metronomic chemotherapy approach targeting both cancer cells and their microenvironment. In a combination therapy context, metronomic chemotherapy exhibits antimetastatic efficacy with low toxicity but is not exempt from resistance mechanisms. As such, a better understanding of the interactions between the components of the tumor microenvironment could improve the selection of drug combinations and schedules, as well as the use of nano-therapeutic agents against certain malignancies.
Disparities in Female Pediatric, Adolescent and Young Adult Oncofertility: A Needs Assessment
Authors: Coker Appiah Leslie , Fei Yueyang Frances , Olsen Mallery , Lindheim Steven R. , Puccetti Diane M.
Published: October 2021

Advancements in cancer screening and implementation of targeted treatments have significantly improved survival rates to 85% for pediatric and AYA survivors. Greater than 75% of survivors will live to experience the long-term adverse outcomes of cancer therapies, termed late effects (LE), that disrupt quality of life (QoL). Infertility and poor reproductive outcomes are significant disruptors of QoL in survivorship, affecting 12–88% of survivors who receive at-risk therapies. To mitigate risk, fertility preservation (FP) counseling is recommended as standard of care prior to gonadotoxic therapy. However, disparities in FP counseling, implementation of FP interventions, and screening for gynecologic late effects in survivorship persist. Barriers to care include a lack of provider and patient knowledge of the safety and breadth of current FP options, misconceptions about the duration of time required to implement FP therapies, cost, and health care team bias. Developing strategies to address barriers and implement established guidelines are necessary to ensure equity and improve quality of care across populations.
The Biochemical and Molecular Analysis of Changes in Melanogenesis Induced by UVA-Activated Fluoroquinolones—In Vitro Study on Human Normal Melanocytes
Authors: Kowalska Justyna , Banach Klaudia , Beberok Artur , Rok Jakub , Rzepka Zuzanna , Wrześniok Dorota
Published: October 2021

Fluoroquinolones cause phototoxic reactions, manifested as different types of skin lesions, including hyperpigmentation. The disturbances of melanogenesis indicate that fluoroquinolones may affect cellular processes in melanocytes. It has been reported that these antibiotics may bind with melanin and accumulate in pigmented cells. The study aimed to examine the changes in melanogenesis in human normal melanocytes exposed to UVA radiation and treated with lomefloxacin and moxifloxacin, the most and the least fluoroquinolone, respectively. The obtained results demonstrated that both tested fluoroquinolones inhibited melanogenesis through a decrease in tyrosinase activity and down-regulation of tyrosinase and microphthalmia-associated transcription factor production. Only lomefloxacin potentiated UVA-induced melanogenesis. Under UVA irradiation lomefloxacin significantly enhanced melanin content and tyrosinase activity in melanocytes, although the drug did not cause an increased expression of tyrosinase or microphthalmia-associated transcription factor. The current studies revealed that phototoxic activity of fluoroquinolones is associated with alterations in the melanogenesis process. The difference in phototoxic potential of fluoroquinolones derivatives may be connected with various effects on UVA-induced events at a cellular level.
Inhibition of Vasculogenic Mimicry and Angiogenesis by an Anti-EGFR IgG1-Human Endostatin-P125A Fusion Protein Reduces Triple Negative Breast Cancer Metastases
Authors: Shin Seung-Uon , Cho Hyun-Mi , Das Rathin , Gil-Henn Hava , Ramakrishnan Sundaram , Al Bayati Ahmed , Carroll Stephen F. , Zhang Yu , Sankar Ankita P. , Elledge Christian , Pimentel Augustin , Blonska Marzenna , Rosenblatt Joseph D.
Published: October 2021

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited therapeutic options. Metastasis is the major cause of TNBC mortality. Angiogenesis facilitates TNBC metastases. Many TNBCs also form vascular channels lined by tumor cells rather than endothelial cells, known as ‘vasculogenic mimicry’ (VM). VM has been linked to metastatic TNBC behavior and resistance to anti-angiogenic agents. Epidermal growth factor receptor (EGFR) is frequently expressed on TNBC, but anti-EGFR antibodies have limited efficacy. We synthesized an anti-EGFR antibody–endostatin fusion protein, αEGFR IgG1-huEndo-P125A (αEGFR-E-P125A), designed to deliver a mutant endostatin, huEndo-P125A (E-P125A), to EGFR expressing tumors, and tested its effects on angiogenesis, TNBC VM, and motility in vitro, and on the growth and metastasis of two independent human TNBC xenograft models in vivo. αEGFR-E-P125A completely inhibited the ability of human umbilical vein endothelial cells to form capillary-like structures (CLS) and of TNBC cells to engage in VM and form tubes in vitro. αEGFR-E-P125A treatment reduced endothelial and TNBC motility in vitro more effectively than E-P125A or cetuximab, delivered alone or in combination. Treatment of TNBC with αEGFR-E-P125A was associated with a reduction in cytoplasmic and nuclear β-catenin and reduced phosphorylation of vimentin. αEGFR-E-P125A treatment of TNBC xenografts in vivo inhibited angiogenesis and VM, reduced primary tumor growth and lung metastasis of orthotopically implanted MDA-MB-468 TNBC cells, and markedly decreased lung metastases following intravenous injection of MDA-MB-231-4175 lung-tropic TNBC cells. Combined inhibition of angiogenesis, VM, and TNBC motility mediated by αEGFR-E-P125A is a promising strategy for the prevention of TNBC metastases.
Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors
Authors: Alvarez Reinier , Mandal Debjani , Chittiboina Prashant
Published: October 2021

PFKFB3 is a bifunctional enzyme that modulates and maintains the intracellular concentrations of fructose-2,6-bisphosphate (F2,6-P2), essentially controlling the rate of glycolysis. PFKFB3 is a known activator of glycolytic rewiring in neoplastic cells, including central nervous system (CNS) neoplastic cells. The pathologic regulation of PFKFB3 is invoked via various microenvironmental stimuli and oncogenic signals. Hypoxia is a primary inducer of PFKFB3 transcription via HIF-1alpha. In addition, translational modifications of PFKFB3 are driven by various intracellular signaling pathways that allow PFKFB3 to respond to varying stimuli. PFKFB3 synthesizes F2,6P2 through the phosphorylation of F6P with a donated PO4 group from ATP and has the highest kinase activity of all PFKFB isoenzymes. The intracellular concentration of F2,6P2 in cancers is maintained primarily by PFKFB3 allowing cancer cells to evade glycolytic suppression. PFKFB3 is a primary enzyme responsible for glycolytic tumor metabolic reprogramming. PFKFB3 protein levels are significantly higher in high-grade glioma than in non-pathologic brain tissue or lower grade gliomas, but without relative upregulation of transcript levels. High PFKFB3 expression is linked to poor survival in brain tumors. Solitary or concomitant PFKFB3 inhibition has additionally shown great potential in restoring chemosensitivity and radiosensitivity in treatment-resistant brain tumors. An improved understanding of canonical and non-canonical functions of PFKFB3 could allow for the development of effective combinatorial targeted therapies for brain tumors.
Transcriptional and Metabolic Investigation in 5′-Nucleotidase Deficient Cancer Cell Lines
Authors: Cadassou Octavia , Forey Prescillia , Machon Christelle , Petrotto Edoardo , Chettab Kamel , Tozzi Maria Grazia , Guitton Jérôme , Dumontet Charles , Cros-Perrial Emeline , Jordheim Lars Petter
Published: October 2021

Enzymes of nucleoside and nucleotide metabolism regulate important cellular processes with potential impacts on nucleotide-unrelated parameters. We have used a set of CRISPR/Cas9-modified cell models expressing both, one, or none of the 5′-nucleotidases cN-II and CD73, together with RNA sequencing and targeted metabolomics, to decipher new regulatory roles of these proteins. We observed important transcriptional modifications between models as well as upon exposure to adenosine. Metabolite content varied differently between cell models in response to adenosine exposure but was rather similar in control conditions. Our original cell models allowed us to identify a new unobvious link between proteins in the nucleotide metabolism and other cellular pathways. Further analyses of our models, including additional experiments, could help us to better understand some of the roles played by these enzymes.
Corosolic Acid Attenuates the Invasiveness of Glioblastoma Cells by Promoting CHIP-Mediated AXL Degradation and Inhibiting GAS6/AXL/JAK Axis
Authors: Sun Li-Wei , Kao Shao-Hsuan , Yang Shun-Fa , Jhang Shang-Wun , Lin Yi-Chen , Chen Chien-Min , Hsieh Yi-Hsien
Published: October 2021

Corosolic acid (CA), a bioactive compound obtained from Actinidia chinensis, has potential anti-cancer activities. Glioblastoma (GBM) is a malignant brain tumor and whether CA exerts anti-cancer activity on GBM remains unclear. This study was aimed to explore the anticancer activity and its underlying mechanism of CA in GBM cells. Our findings showed that CA ≤ 20 μM did not affect cell viability and cell proliferative rate of normal astrocyte and four GBM cells. Notably, 10 or 20 μM CA significantly inhibited cell migration and invasion of three GBM cells, decreased the protein level of F-actin and disrupted F-actin polymerization in these GBM cells. Further investigation revealed that CA decreased AXL level by promoting ubiquitin-mediated proteasome degradation and upregulating the carboxyl terminus of Hsc70-interacting protein (CHIP), an inducer of AXL polyubiquitination. CHIP knock-down restored the CA-reduced AXL and invasiveness of GBM cells. Additionally, we observed that CA-reduced Growth arrest-specific protein 6 (GAS6) and inhibited JAK2/MEK/ERK activation, and GAS6 pre-treatment restored attenuated JAK2/MEK/ERK activation and invasiveness of GBM cells. Furthermore, molecular docking analysis revealed that CA might bind to GAS6 and AXL. These findings collectively indicate that CA attenuates the invasiveness of GBM cells, attributing to CHIP upregulation and binding to GAS6 and AXL and subsequently promoting AXL degradation and downregulating GAS6-mediated JAK2/MEK/ERK cascade. Conclusively, this suggests that CA has potential anti-metastatic activity on GBM cells by targeting the CHIP/GAS6/AXL axis.