bluuebunny/crossref_metadata_2025 huggingface dataset:
Enterococcus faecalis Bacteriophage vB_EfaS_efap05-1 Targets the Surface Polysaccharide and ComEA Protein as the Receptors
Authors: Huang Lingqiong , Guo Wenqiong , Lu Jiahui , Pan Wuliang , Song Fuqiang , Wang Peng
Published: March 2022

Enterococcus faecalis is a Gram-positive opportunistic pathogen that causes nosocomial infections in humans. Due to the growing threat of antibiotic resistance of E. faecalis, bacteriophage therapy is a promising option for treating of E. faecalis infection. Here, we characterized a lytic E. faecalis bacteriophage vB_EfaS_efap05-1 with a dsDNA genome of 56,563 bp. Phage vB_EfaS_efap05-1 had a prolate head and a tail, and belongs to Saphexavirus which is a member of Siphoviridae. Efap05-1 uses either surface polysaccharide or membrane protein ComEA as the receptor because the mutation of both genes (ComEA and UDP-glucose 4-epimerase galE) prevents phage adsorption and leads to phage resistance, and complementation of ComEA or galE could recover its phage sensitivity. Our results provided a comprehensive analysis of a new E. faecalis phage and suggest efap05-1 as a potential antimicrobial agent.
Auditory Cognitive Training Improves Brain Plasticity in Healthy Older Adults: Evidence From a Randomized Controlled Trial
Authors: Kawata Natasha Y. S. , Nouchi Rui , Oba Kentaro , Matsuzaki Yutaka , Kawashima Ryuta
Published: March 2022

The number of older adults is increasing globally. Aging is associated with cognitive and sensory decline. Additionally, declined auditory performance and cognitive function affect the quality of life of older adults. Therefore, it is important to develop an intervention method to improve both auditory and cognitive performances. The current study aimed to investigate the beneficial effects of auditory and cognitive training on auditory ability and cognitive functions in healthy older adults. Fifty healthy older adults were randomly divided into four training groups—an auditory-cognitive training group (AC training; n = 13), an auditory training group (A training; n = 13), a cognitive training group (C training; n = 14), and an active control group (n = 12). During the training period, we reduced the sound intensity level in AC and A training groups and increase training task difficulty in AC, A, and C training groups based on participants’ performance. Cognitive function measures [digit-cancelation test (D-CAT); logical memory (LM); digit span (DS)], auditory measures [pure-tone audiometry (PTA)], and magnetic resonance imaging (MRI) scans were performed before and after the training periods. We found three key findings. First, the AC training group showed difference between other training groups (A, C, and active control training groups) in regional gray matter volume (rGMV) in the right dorsolateral prefrontal cortex, the left inferior temporal gyrus (L. ITG), the left superior frontal gyrus, the left orbitofrontal cortex, the right cerebellum (lobule 7 Crus 1). Second, the auditory training factor groups (ATFGs, the AC and A training groups) improved auditory measures and increased the rGMV and functional connectivity (FC) in the left temporal pole compared to the non-ATFGs (the C training group and active control group). Third, the cognitive training factor groups (CTFGs; the AC and C training groups) showed statistically significant improvement in cognitive performances in LM and D-CAT compared to the non-CTFGs (the A training group and active control group). Therefore, the auditory training factor and cognitive training factor would be useful in enhancing the quality of life of older adults. The current AC training study, the plasticity of the brain structure was observed after 4 weeks of training.
Simultaneous Alteration of the Circadian Variation of Memory, Hippocampal Synaptic Plasticity, and Metabolism in a Triple Transgenic Mouse Model of Alzheimer’s Disease
Authors: Carvalho da Silva António M. , Lemos Cristina , Silva Henrique B. , Ferreira Ildete L. , Tomé Angelo R. , Rego A. Cristina , Cunha Rodrigo A.
Published: March 2022

Alzheimer’s disease (AD) is characterized by progressive memory deficits accompanied by synaptic and metabolic deficits, namely of mitochondrial function. AD patients also display a disrupted circadian pattern. Thus, we now compared memory performance, synaptic plasticity, and mitochondria function in 24-week-old non-transgenic (non-Tg) and triple transgenic male mice modeling AD (3xTg-AD) at Zeitgeber 04 (ZT-4, inactive phase) and ZT-16 (active phase). Using the Morris water maze test to minimize the influence of circadian-associated locomotor activity, we observed a circadian variation in hippocampus-dependent learning performance in non-Tg mice, which was impaired in 3xTg-AD mice. 3xTg-AD mice also displayed a lack of circadian variation of their performance in the reversal spatial learning task. Additionally, the amplitude of hippocampal long-term potentiation also exhibited a circadian profile in non-Tg mice, which was not observed in 3xTg-AD mice. Moreover, cerebral cortical synaptosomes of non-Tg mice also displayed a circadian variation of FCCP-stimulated oxygen consumption as well as in mitochondrial calcium retention that were blunted in 3xTg-AD mice. In sum, this multidimensional study shows that the ability to maintain a circadian oscillation in brain behavior, synaptic plasticity, and synaptic mitochondria function are simultaneously impaired in 3xTg-AD mice, highlighting the effects of circadian misalignment in AD.
Study on the Association of Dietary Fatty Acid Intake and Serum Lipid Profiles With Cognition in Aged Subjects With Type 2 Diabetes Mellitus
Authors: Li Pengfei , Gao Yanyan , Ma Xiaojun , Zhou Shaobo , Guo Yujie , Xu Jingjing , Wang Xixiang , Van Halm-Lutterodt Nicholas , Yuan Linhong
Published: March 2022

Background

The correlation between dietary fatty acid (FA) intake and serum lipid profile levels with cognition in the aged population has been reported by previous studies. However, the association of dietary FA intake and serum lipid profile levels with cognition in subjects with type 2 diabetes mellitus (T2DM) is seldom reported.

Objective

A cross-sectional study was conducted to explore the correlation between dietary FA intake and serum lipid profiles with cognition in the aged Chinese population with T2DM.

Methods

A total of 1,526 aged Chinese subjects were recruited from communities. Fasting blood samples were collected for parameter measurement. The food frequency questionnaire (FFQ) method was applied for a dietary survey. Cognition was assessed using the Montreal Cognitive Assessment (MoCA) test. Dietary FA intake and serum lipid levels were compared between subjects with T2DM and control subjects. A logistic regression analysis was carried out for analyzing the association of FA intake and serum lipid levels with the risk of mild cognitive impairment (MCI) in subjects with T2DM and control subjects.

Results

There was a significant difference in the serum lipid level between the T2DM group and the control group. Results of the logistic regression analysis demonstrated the potential associations of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and dietary n-3 polyunsaturated fatty acids (PUFAs) intake with the risk of MCI in subjects with T2DM, but the associations were not observed in control subjects.

Conclusion

The T2DM phenotype might affect the relationship between dietary FA intake, circulating lipids, and cognitive performance. Large prospective cohort studies are needed to uncover the underlying mechanism of how dietary FA intake and serum lipid levels affect cognition in aged subjects with T2DM.
Effects of Exergames on Brain and Cognition in Older Adults: A Review Based on a New Categorization of Combined Training Intervention
Authors: Torre Marta Maria , Temprado Jean-Jacques
Published: March 2022

The literature on exergames has reported inconsistent benefits on brain and cognitive functions. Moreover, it is still unknown whether they yield to equal or superior benefits as compared to other forms of physical exercise. However, until now, a review of exergaming literature was lacking, that would reverse the “product first” approach to replacing it with a “training first” approach that is, an analysis of the different studies based on a detailed description of the type of combined training interventions that was supported by the utilized exergames. In the present review, thanks to a structured framework build around seven interacting constructs (stimuli, settings, targets, markers, outcomes, moderators, and mechanisms), which collectively afford a global picture of the determining factors of exergames training, we aimed to determine whether and under which conditions exergames could be more effective than conventional training. Twenty three studies were finally selected for review and analyzed. We concluded that, in spite of their potential to improve brain and cognition, beneficial factors contributing to exergaming efficacy as well as its underlying mechanisms need to be investigated more systematically thanks to common experimental designs based on gold standards. We proposed some directions in this respect.
The Infraslow Frequency Oscillatory Transcranial Direct Current Stimulation Over the Left Dorsolateral Prefrontal Cortex Enhances Sustained Attention
Authors: Qiao Jingwen , Li Xinyu , Wang Youhao , Wang Yifeng , Li Gen , Lu Ping , Wang Shouyan
Published: March 2022

Background

The vigilance fluctuation and decrement of sustained attention have large detrimental consequences to most tasks in daily life, especially among the elderly. Non-invasive brain stimulations (e.g., transcranial direct current stimulation, tDCS) have been widely applied to improve sustained attention, however, with mixed results.

Objective

An infraslow frequency oscillatory tDCS approach was designed to improve sustained attention.

Methods

The infraslow frequency oscillatory tDCS (O-tDCS) over the left dorsolateral prefrontal cortex at 0.05 Hz was designed and compared with conventional tDCS (C-tDCS) to test whether this new protocol improves sustained attention more effectively. The sustained attention was evaluated by reaction time and accuracy.

Results

Compared with the C-tDCS and sham, the O-tDCS significantly enhanced sustained attention by increasing response accuracy, reducing response time, and its variability. These effects were predicted by the evoked oscillation of response time at the stimulation frequency.

Conclusion

Similar to previous studies, the modulation effect of C-tDCS on sustained attention is weak and unstable. In contrast, the O-tDCS effectively and systematically enhances sustained attention by optimizing vigilance fluctuation. The modulation effect of O-tDCS is probably driven by neural oscillations at the infraslow frequency range.
L-F001, a Multifunctional Fasudil-Lipoic Acid Dimer Prevents RSL3-Induced Ferroptosis via Maintaining Iron Homeostasis and Inhibiting JNK in HT22 Cells
Authors: Peng Weijia , Ouyang Ying , Wang Shuyi , Hou Jiawei , Zhu Zeyu , Yang Yang , Zhou Ruiyu , Pi Rongbiao
Published: March 2022

Ferroptosis, an iron-dependent form of non-apoptotic cell death, plays important roles in cerebral ischemia. Previously we have found that L-F001, a novel fasudil-lipoic acid dimer with good pharmacokinetic characters has good neuroprotection against toxin-induced cell death in vitro and in vivo. Here, we investigated the protective effects of L-F001 against a Glutathione peroxidase 4 (GPX4) inhibitor Ras-selective lethality 3 (RSL3) -induced ferroptosis in HT22 cells. We performed MTT, Transmission Electron Microscope (TEM), Western blot, and immunofluorescence analyses to determine the protective effects of L-F001 treatment. RSL3 treatment significantly reduced HT22 cell viability and L-F001 significantly protected RSL3-induced cell death in a concentration-dependent manner and significantly attenuated Mitochondrial shrinkage observed by TEM. Meanwhile, L-F001 significantly decreased RSL3-induced ROS and lipid peroxidation levels in HT22 cells. Moreover L-F001could restore GPX4 and glutamate-cysteine ligase modifier subunit (GCLM) levels, and significantly deceased Cyclooxygenase (COX-2) levels to rescue the lipid peroxidation imbalance. In addition, FerroOrange fluorescent probe and Western blot analysis revealed that L-F001 treatment decreased the total number of intracellular Fe2+ and restore Ferritin heavy chain 1 (FTH1) level in RSL3-induced HT22 cells. Finally, L-F001 could reduce RSL3-induced c-Jun N-terminal kinase (JNK) activation, which might be a potential drug target for LF-001. Considering that L-F001 has a good anti-ferroptosis effect, our results showed that L-F001 might be a multi-target agent for the therapy of ferroptosis-related diseases, such as cerebral ischemia.
The Severity of Sensorimotor Tracts Degeneration May Predict Motor Performance in Chronic Stroke Patients, While Brain Structural Network Dysfunction May Not
Authors: Astrakas Loukas G. , Li Shasha , Elbach Sabrina , Tzika A. Aria
Published: March 2022

Although the relationship between corticospinal tract (CST) fiber degeneration and motor outcome after stroke has been established, the relationship of sensorimotor cortical areas with CST fibers has not been clarified. Also limited research has been conducted on how abnormalities in brain structural networks are related to motor recovery. To address these gaps in knowledge, we conducted a diffusion tensor imaging (DTI) study with 12 chronic stroke patients (CSPs) and 12 age-matched healthy controls (HCs). We compared fractional anisotropy (FA) and mean diffusivity (MD) in 60 CST segments using the probabilistic sensorimotor area tract template (SMATT). Least Absolute Shrinkage and Selection Operator (LASSO) regressions were used to select independent predictors of Fugl-Meyer upper extremity (FM-UE) scores among FA and MD values of SMATT regions. The Graph Theoretical Network Analysis Toolbox was used to assess the structural network of each subject's brain. Global and nodal metrics were calculated, compared between the groups, and correlated with FM-UE scores. Mann–Whitney U-tests revealed reduced FA values in CSPs, compared to HCs, in many ipsilesional SMATT regions and in two contralesional regions. Mean FA value of the left (L.) primary motor cortex (M1)/supplementary motor area (SMA) region was predictive of FM-UE score (P = 0.004). Mean MD values for the L. M1/ventral premotor cortex (PMv) region (P = 0.001) and L. PMv/SMA region (P = 0.001) were found to be significant predictors of FM-UE scores. Network efficiency was the only global metric found to be reduced in CSPs (P = 0.006 vs. HCs). Nodal efficiency of the L. hippocampus, L. parahippocampal gyrus, L. fusiform gyrus (P = 0.001), and nodal local efficiency of the L. supramarginal gyrus (P < 0.001) were reduced in CSPs relative to HCs. No graph metric was associated with FM-UE scores. In conclusion, the integrity of CSTs connected to M1, SMA, and PMv were shown to be independent predictors of motor performance in CSPs, while stroke-induced topological changes in the brain's structural connectome may not be. A sensorimotor cortex-specific tract template can refine CST degeneration data and the relationship of CST degeneration with motor performance.
Dopamine-Related Reduction of Semantic Spreading Activation in Patients With Parkinson’s Disease
Authors: Tiedt Hannes Ole , Ehlen Felicitas , Klostermann Fabian
Published: March 2022

Impaired performance in verbal fluency (VF) tasks is a frequent observation in Parkinson’s disease (PD). As to the nature of the underlying cognitive deficit, it is commonly attributed to a frontal-type dysexecutive syndrome due to nigrostriatal dopamine depletion. Whereas dopaminergic medication typically improves VF performance in PD, e.g., by ameliorating impaired lexical switching, its effect on semantic network activation is unclear. Data from priming studies suggest that dopamine causes a faster decay of semantic activation spread. The aim of the current study was to examine the impact of dopaminergic medication on the dynamic change of word frequency during VF performance as a measure of semantic spreading activation. To this end, we performed a median split analysis of word frequency during phonemic and semantic VF task performance in a PD group tested while receiving dopaminergic medication (ON) as well as after drug withdrawal (i.e., OFF), and in a sample of age-matched healthy volunteers (both groups n = 26). Dopaminergic medication in the PD group significantly affected phonemic VF with improved word production as well as increased error-rates. The expected decrease of word frequency during VF task performance was significantly smaller in the PD group ON medication than in healthy volunteers across semantic and phonemic VF. No significant group-difference emerged between controls and the PD group in the OFF condition. The comparison between both treatment conditions within the PD group did not reach statistical significance. The observed pattern of results indicates a faster decay of semantic network activation during lexical access in PD patients on dopaminergic medication. In view of improved word generation, this finding is consistent with a concept of more focused neural activity by an increased signal-to-noise ratio due to dopaminergic neuromodulation. However, the effect of dopaminergic stimulation on VF output suggests a trade-off between these beneficial effects and increased error-rates.
Peripheral Blood Circular RNAs as a Biomarker for Major Depressive Disorder and Prediction of Possible Pathways
Authors: Zhang Dandan , Ji Yao , Chen Xiongjin , Chen RunSen , Wei Yaxue , Peng Qian , Lin Juda , Yin Jingwen , Li Hezhan , Cui Lili , Lin Zhixiong , Cai Yujie
Published: March 2022

Circular RNAs (circRNAs) are highly expressed in the central nervous system and have been reported to be associated with neuropsychiatric diseases, but their potential role in major depressive disorder (MDD) remains unclear. Here, we demonstrated that there was a disorder of circRNAs in the blood of MDD patients. It has been preliminarily proved that hsa_circ_0002473, hsa_circ_0079651, hsa_circ_0137187, hsa_circ_0006010, and hsa_circ_0113010 were highly expressed in MDD patients and can be used as diagnostic markers for MDD. Bioinformatics analysis revealed that hsa_circ_0079651, hsa_circ_0137187, hsa_circ_0006010, and hsa_circ_0113010 may affect the neuroplasticity of MDD through the ceRNA mechanism.
A Pilot Study of Radiomic Based on Routine CT Reflecting Difference of Cerebral Hemispheric Perfusion
Authors: Ren Qingguo , An Panpan , Jin Ke , Xia Xiaona , Huang Zhaodi , Xu Jingxu , Huang Chencui , Jiang Qingjun , Meng Xiangshui
Published: March 2022

Background

To explore the effectiveness of radiomics features based on routine CT to reflect the difference of cerebral hemispheric perfusion.

Methods

We retrospectively recruited 52 patients with severe stenosis or occlusion in the unilateral middle cerebral artery (MCA), and brain CT perfusion showed an MCA area with deficit perfusion. Radiomics features were extracted from the stenosis side and contralateral of the MCA area based on precontrast CT. Two different region of interest drawing methods were applied. Then the patients were randomly grouped into training and testing sets by the ratio of 8:2. In the training set, ANOVA and the Elastic Net Regression with fivefold cross-validation were conducted to filter and choose the optimized features. Moreover, different machine learning models were built. In the testing set, the area under the receiver operating characteristic (AUC) curve, calibration, and clinical utility were applied to evaluate the predictive performance of the models.

Results

The logistic regression (LR) for the triangle-contour method and artificial neural network (ANN) for the semiautomatic-contour method were chosen as radiomics models for their good prediction efficacy in the training phase (AUC = 0.869, 0.873) and the validation phase (AUC = 0.793, 0.799). The radiomics algorithms of the triangle-contour and semiautomatic-contour method were implemented in the whole training set (AUC = 0.870, 0.867) and were evaluated in the testing set (AUC = 0.760, 0.802). According to the optimal cutoff value, these two methods can classify the vascular stenosis side class and normal side class.

Conclusion

Radiomic predictive feature based on precontrast CT image could reflect the difference of cerebral hemispheric perfusion to some extent.
Understanding Is a Process
Authors: Blaha Leslie M. , Abrams Mitchell , Bibyk Sarah A. , Bonial Claire , Hartzler Beth M. , Hsu Christopher D. , Khemlani Sangeet , King Jayde , St. Amant Robert , Trafton J. Gregory , Wong Rachel
Published: March 2022

How do we gauge understanding? Tests of understanding, such as Turing's imitation game, are numerous; yet, attempts to achieve a state of understanding are not satisfactory assessments. Intelligent agents designed to pass one test of understanding often fall short of others. Rather than approaching understanding as a system state, in this paper, we argue that understanding is a process that changes over time and experience. The only window into the process is through the lens of natural language. Usefully, failures of understanding reveal breakdowns in the process. We propose a set of natural language-based probes that can be used to map the degree of understanding a human or intelligent system has achieved through combinations of successes and failures.
Anthocyanin-Rich Supplementation: Emerging Evidence of Strong Potential for Sport and Exercise Nutrition
Authors: Willems Mark E. T. , Blacker Sam D.
Published: March 2022

Dark-colored fruits, especially berries, have abundant presence of the polyphenol anthocyanin which have been show to provide health benefits. Studies with the berry blackcurrant have provided notable observations with application for athletes and physically active individuals. Alterations in exercise-induced substrate oxidation, exercise performance of repeated high-intensity running and cycling time-trial and cardiovascular function at rest and during exercise were observed with intake of New Zealand blackcurrant. The dynamic plasma bioavailability of the blackcurrant anthocyanins and the anthocyanin-derived metabolites must have changed cell function to provide meaningful in-vivo physiological effects. This perspective will reflect on the research studies for obtaining the applied in-vivo effects by intake of anthocyanin-rich supplementation, the issue of individual responses, and the emerging strong potential of anthocyanins for sport and exercise nutrition. Future work with repeated intake of known amount and type of anthocyanins, gut microbiota handling of anthocyanins, and coinciding measurements of plasma anthocyanin and anthocyanin-derived metabolites and in-vivo cell function will be required to inform our understanding for the unique potential of anthocyanins as a nutritional ergogenic aid for delivering meaningful effects for a wide range of athletes and physically active individuals.
Potential Resistance to Antineoplastic Aminated Fullerenes Mediated by M2-Like Monocyte-Derived Exosomes
Authors: Huo Jiawei , Zhou Wei , Liu Yang , Yang Sifen , Li Jie , Wang Chunru
Published: March 2022

Exosomes are small extracellular vesicles critical for intercellular signaling via their delivery of cargoes, including proteins, DNA, RNA, lipids, and metabolites. Exosomes play essential roles in remodeling the tumor microenvironment (TME) for tumor growth, metastasis, and drug resistance. Aminated fullerenes (e.g., C70-ethylenediamine [EDA]) exhibit antineoplastic effects by targeting multiple functional proteins. Nanosized C70-EDA with positive surface charges tends to be taken up by monocytes in the bloodstream and monocyte-derived macrophages in the TME. Herein, the alterations of monocytes and monocyte-derived exosomes by C70-EDA have been investigated. C70-EDA reprogramed THP-1 monocyte to an M2-like state and substantially increased the protein content in exosomes secreted by M2-like monocytes. Notably, C70-EDA-induced M2-like monocytes released exosomes that triggered the proliferation of recipient tumor cells, which may alleviate the antineoplastic efficacy of C70-EDA. As revealed by proteomic profiling of exosomes, this outcome is probably a result of Rho GTPase/p21-activated kinase (PAK) pathway activation in recipient tumor cells induced by upregulated exosomal proteins. This work indicates a promising strategy in which aminated fullerenes can be combined with PAK inhibitors for cancer therapy.
Chemotherapeutic Risk lncRNA-PVT1 SNP Sensitizes Metastatic Colorectal Cancer to FOLFOX Regimen
Authors: Wu Shenshen , Yang Xi , Tang Weiyan , Familiari Giuseppe , Relucenti Michela , Aschner Michael , Li Xiaobo , Chen Rui
Published: March 2022

Recent studies have identified that long noncoding RNA (lncRNA) might affect the responses to anticancer drug treatment, including colorectal cancer (CRC). However, the association between single-nucleotide polymorphisms (SNPs) in PVT1 and the chemotherapy response in metastatic colorectal cancer has yet to be clarified. In this study, the PVT1 rs2278176 CT/TT genotypes were found to be associated with an increased overall survival (OS) and progression-free survival (PFS) compared with the CC genotype. Furthermore, patients harboring the rs2278176 CT/TT genotypes had a greater chance of achieving clinical benefit from 5-Fluorouracil/leucovorin combined with oxaliplatin (FOLFOX). In vivo nude mice experiments demonstrated that the CRISPR/Cas9 mediated rs2278176 C to T mutation significantly inhibited the tumorigenesis of colorectal cancer cells treated with 5-Fu, but not control DMSO treated cells. Furthermore, the apoptotic rate was significantly enhanced by treatment with 5-Fu in the CRC cells carrying with the CT/TT genotypes. Functional studies demonstrated that the PVT1 rs2278176 C to T mutation altered the binding site for hsa-miR-297, and that hsa-miR-297 downregulated Glutathione S-Transferase Alpha 2(GSTA2), a member of phase II detoxification enzyme, in an Argonaute 2(Ago2)-dependent manner. Moreover, GSTA2 levels were downregulated in the cancer tissues of patients carrying rs2278176 CT/TT genotypes. High GSTA2 expression predicted poor clinical outcome in metastatic colorectal cancer treated with FOLFOX. In conclusion, this study provided that PVT1 with rs2278176 T allele altered the binding affinity with hsa-miR-297, leading to decreased GSTA2 expression and sensitized CRC cells to FOLFOX chemotherapy, suggesting rs2278176 CT/TT genotypes might serve as a predictive biomarker to improve prognosis in patients with metastatic CRC treated with FOLFOX.
Multi-Parameter MR Radiomics Based Model to Predict 5-Year Progression-Free Survival in Endometrial Cancer
Authors: Liu Defeng , Yang Linsha , Du Dan , Zheng Tao , Liu Lanxiang , Wang Zhanqiu , Du Juan , Dong Yanchao , Yi Huiling , Cui Yujie
Published: March 2022

Background

Relapse is the major cause of mortality in patients with resected endometrial cancer (EC). There is an urgent need for a feasible method to identify patients with high risk of relapse.

Purpose

To develop a multi-parameter magnetic resonance imaging (MRI) radiomics-based nomogram model to predict 5-year progression-free survival (PFS) in EC.

Methods

For this retrospective study, 202 patients with EC followed up for at least 5 years after hysterectomy. A radiomics signature was extracted from T2-weighted imaging (T2WI), apparent diffusion coefficient (ADC) and a dynamic contrast-enhanced three-dimensional volumetric interpolated breath-hold examination (3D-VIBE). The radiomics score (RS) was calculated based on the least absolute shrinkage and selection operator (LASSO) regression. We have developed a radiomics based nomogram model (ModelN) incorporating the RS and clinical and conventional MR (cMR) risk factors. The performance was evaluated by the receiver operating characteristic curve (ROC), calibration curve and decision curve analysis (DCA).

Results

The ModelN demonstrated a good calibration and satisfactory discrimination, with a mean area under the curve (AUC) of 0.840 and 0.958 in the training and test cohorts, respectively. In comparison with clinical prediction model (ModelC), the discrimination ability of ModelN showed an improvement with P < 0.001 for the training cohort and P=0.032 for the test cohort. Compared to the radiomics prediction model (ModelR), ModelN discrimination ability showed an improvement for the training cohort with P = 0.021, with no statistically significant difference in the test cohort (P = 0.106). Calibration curves suggested a good fit for probability (Hosmer–Lemeshow test, P = 0.610 and P = 0.956 for the training and test cohorts, respectively).

Conclusion

This multi-parameter nomogram model incorporating clinical and cMR findings is a valid method to predict 5-year PFS in patients with EC.
Analysis of L Antigen Family Member 3 as a Potential Biomarker and Therapeutic Target Associated With the Progression of Hepatocellular Carcinoma
Authors: Chen Qianhui , Lu Xinyu , Xie Jiayi , Ma Na , Xu Weikang , Zhang Zhiming , Huang Xuan , Liu Hongyan , Hou Jinlin , Zhang Xiaoyong , Zhu Wei
Published: March 2022

Background

Hepatocellular carcinoma (HCC) is the third cause of cancer-related deaths worldwide. L antigen family member 3 (LAGE3) is a prognostic biomarker and associated with progression in a variety of tumors. However, little has been reported about the role and potential mechanism of LAGE3 in HCC.

Methods

The clinical value and function of LAGE3 in HCC were obtained from multiple online databases. The potential functions and pathways of LAGE3 in HCC were analysed by R package of “clusterProfiler”. LAGE3 knockdown cells were constructed in HepG2, HuH7 and MHCC97H cell lines, respectively. The biological roles of LAGE3 were examined by in vitro and in vivo experiments.

Results

LAGE3 was upregulated in HCC tissues compared with normal tissues, and high expression of LAGE3 was significantly associated with several clinical characteristics and indicated a worse prognosis of HCC. The co-expressed genes of LAGE3 could be enriched in the mTOR signaling pathway in HCC. LAGE3 was upregulated in HCC cell lines. Functionally, knocking down LAGE3 expression not only increased apoptosis and inhibited growth rate, cell death mediated by T cells, colony formation, migration and invasion ability of HCC cell lines in vitro, but also reduced the progression of HCC in the subcutaneous xenotransplanted tumor model.

Conclusion

Our results suggested that LAGE3 served as an oncogenic factor of HCC and could be a potential biomarker and therapeutic target for HCC.
Rapidly Evolving Landscape and Future Horizons in Hepatocellular Carcinoma in the Era of Immuno-Oncology
Authors: Kang Sandra Mirie , Khalil Lana , El-Rayes Bassel F. , Akce Mehmet
Published: March 2022

Hepatocellular carcinoma (HCC) is a serious global health problem as one of the leading causes of cancer-related death worldwide. Systemic therapy for advanced HCC has progressed with the development of molecular targeted agents, however survival benefits remain modest. More recently, immune checkpoint inhibitors (ICI) have emerged and exhibited promising therapeutic benefits in a subset of patients. Physiologically, the intrinsic microenvironment in the liver is immunosuppressive, which represents a major obstacle for effective immune therapies in primary and secondary liver malignancies. For this reason, combination therapies that can overcome immune inhibitory mechanisms and enhance the immune response are a rationale approach for drug development in HCC. A recent example is the combination of the anti-PD-L1 antibody (atezolizumab) and anti-VEGF-A antibody (bevacizumab), which has shown significant improvement in survival as compared to standard of care in the first-line treatment for HCC. Other immunotherapy approaches including cancer vaccines and adoptive cell therapy are also under investigation. This review summarizes the key trials leading to our current HCC treatment options and provides an overview of future immune-based strategies in development.
Pembrolizumab Combined With Neoadjuvant Chemotherapy Versus Neoadjuvant Chemoradiotherapy Followed by Surgery for Locally Advanced Oesophageal Squamous Cell Carcinoma: Protocol for a Multicentre, Prospective, Randomized-Controlled, Phase III Clinical Study (Keystone-002)
Authors: Shang Xiaobin , Zhang Wencheng , Zhao Gang , Liang Fei , Zhang Chen , Yue Jie , Duan Xiaofeng , Ma Zhao , Chen Chuangui , Pang Qingsong , Zhang Weihong , Liu Liang , Ren Xiubao , Meng Bin , Zhang Peng , Ma Yegang , Zhang Lin , Li Hecheng , Kang Xiaozheng , Li Yin , Jiang Hongjing
Published: March 2022

Background

To compare the efficacy and safety of pembrolizumab combined with neoadjuvant chemotherapy (neoCT) versus neoadjuvant chemoradiotherapy (neoCRT) followed by surgery for locally advanced resectable oesophageal squamous cell carcinoma (ESCC).

Methods

This study is a multicentre, prospective, randomized-controlled, phase III clinical study. Eligible ESCC (staging: cT1N2M0 or cT2-3N0-2M0 (stage II/III, high-risk lesions in T2N0M0)) patients will be randomly assigned to either the experimental group (pembrolizumab with neoCT, n = 228) or the control group (neoCRT, n = 114) at a ratio of 2:1. Within 4–6 weeks after preoperative therapy, the McKeown procedure will be performed. Patients in the experimental group will also receive pembrolizumab alone as adjuvant therapy after surgery until 1 year or until the radiographically confirmed PD or other condition indicated for premature termination is observed. The primary endpoint is event-free survival (EFS). The secondary endpoints are 1-, 3-, and 5-year overall survival (OS) and disease-free survival (DFS), short-term outcomes, and quality of life.

Discussion

This is the first prospectively randomized controlled trial designed to compare pembrolizumab plus chemotherapy and chemoradiotherapy as neoadjuvant therapy for resectable ESCC. According to our hypothesis, preoperative pembrolizumab combined with chemotherapy will result in a better tumour response and prolong the survival of patients, with acceptable toxicity. This study started in December 2021, and the enrolment time is estimated to be 2 years.

Trial Registration

This prospective study has been registered at ClinicalTrials.gov (NCT04807673), March 2021.
Case Report: Delayed Onset Multi-Organ Toxicities in a Melanoma Patient Achieving Complete Response to BRAF/MEK Inhibition
Authors: Knochelmann Hannah M. , Ware Michael Brandon , Rali Aditya , Linderman Susanne , Shantha Jessica G. , Lawson David H. , Yushak Melinda , Swerlick Robert , Paulos Chrystal M. , Yeh Steven , Kudchadkar Ragini
Published: March 2022

Autoimmune toxicities, while common following treatment with cancer immunotherapies, are not well-characterized in patients treated with BRAF/MEK inhibitors. Emerging data suggest that autoimmune effects may be linked with superior responses to both treatment modalities; however, there is little evidence describing mechanisms of immune-related toxicity for patients on BRAF/MEK inhibitors. Here we describe the experience of a 59-year-old HLA-A2, A29, B27-positive male with recurrent/metastatic melanoma. After progression on checkpoint inhibitor therapy, he was treated with dabrafenib/trametinib followed by encorafenib/binimetinib, which were well-tolerated and resulted in a complete response. Eighteen months into BRAF/MEK inhibitor therapy, and three months after initially finding a complete response, he developed a series of sudden-onset, severe toxicities: namely, bilateral panuveitis, cytopenias, joint pain, skin rash, hypercalcemia, and interstitial nephritis, which led to BRAF/MEKi cessation. Immunological analyses revealed induction of a peripheral type-17 cytokine signature characterized by high IL-23, IL-6, IL-10, IL-17A/F, IL-1β, and IL-21 among other cytokines in plasma corresponding with the height of symptoms. These findings highlight a novel instance of delayed autoimmune-like reaction to BRAF/MEK inhibition and identify a possible role for Th/Tc17 activation in their pathogenesis thus warranting future clinical and immunological characterization.
Tumor Glucose and Fatty Acid Metabolism in the Context of Anthracycline and Taxane-Based (Neo)Adjuvant Chemotherapy in Breast Carcinomas
Authors: Tőkés Anna Mária , Vári-Kakas Stefan , Kulka Janina , Törőcsik Beáta
Published: March 2022

Breast cancer is characterized by considerable metabolic diversity. A relatively high percentage of patients diagnosed with breast carcinoma do not respond to standard-of-care treatment, and alteration in metabolic pathways nowadays is considered one of the major mechanisms responsible for therapeutic resistance. Consequently, there is an emerging need to understand how metabolism shapes therapy response, therapy resistance and not ultimately to analyze the metabolic changes occurring after different treatment regimens. The most commonly applied neoadjuvant chemotherapy regimens in breast cancer contain an anthracycline (doxorubicin or epirubicin) in combination or sequentially administered with taxanes (paclitaxel or docetaxel). Despite several efforts, drug resistance is still frequent in many types of breast cancer, decreasing patients’ survival. Understanding how tumor cells rapidly rewire their signaling pathways to persist after neoadjuvant cancer treatment have to be analyzed in detail and in a more complex system to enable scientists to design novel treatment strategies that target different aspects of tumor cells and tumor resistance. Tumor heterogeneity, the rapidly changing environmental context, differences in nutrient use among different cell types, the cooperative or competitive relationships between cells pose additional challenges in profound analyzes of metabolic changes in different breast carcinoma subtypes and treatment protocols. Delineating the contribution of metabolic pathways to tumor differentiation, progression, and resistance to different drugs is also the focus of research. The present review discusses the changes in glucose and fatty acid pathways associated with the most frequently applied chemotherapeutic drugs in breast cancer, as well the underlying molecular mechanisms and corresponding novel therapeutic strategies.
Circulating MicroRNAs as Quantitative Biomarkers for Diagnosis and Prognosis of Uveal Melanoma
Authors: Zhou Wen-Da , Shao Lei , Dong Li , Zhang Rui-Heng , Li Yi-Fan , Li He-Yan , Wu Hao-Tian , Shi Xu-Han , Wei Wen-Bin
Published: March 2022

For uveal melanoma (UM) patients, it is significant to establish diagnosis and prognosis evaluation systems through imaging techniques. However, imaging examinations are short of quantitative biomarkers and it is difficult to finish early diagnosis of UM. In order to discover new molecular biomarkers for the diagnosis and prognostic evaluation of UM, six circulating miRNAs (mir-132-3p, mir-21-5p, mir-34a-5p, mir-126-3p, mir-199a-3p, mir-214-3p) were chosen as candidates for independent validation. Validation of these miRNAs was performed in a cohort of 20 patients, including 10 spindle-shaped melanoma and 10 epithelioid cell melanoma, and 10 healthy donors. Then 5 patients with metastatic UM were included to validate the performance of miRNAs in advanced UM. Serum levels of miRNAs were determined using quantitative real-time PCR. We confirmed significantly higher levels of three miRNAs in serum of UM patients in comparison to healthy controls, and miR-199a-3p had the best performance (p < 0.0001; AUC = 0.985). MiR-214-3p and miR-21-5p were significantly upregulated in serum of epithelioid cell melanoma patients compared to spindle-shaped melanoma patients and miR-132-3p and, conversely, were significantly downregulated in serum of epithelioid cell melanoma patients. MiR-21-5p shows their best performance (p < 0.0001; AUC = 0.980). Both miR-199a-3p and miR-21-5p showed great performance in advanced UM. Significantly higher levels of miR-21-5p (p < 0.001) were found in serum of metastatic UM patients compared to patients with localized spindle-shaped melanoma, and significantly higher levels of miR-199a-3p (p < 0.001) were detected in serum of metastatic UM patients compared to healthy controls. Our preliminary data indicate promising diagnostic utility of circulating miR-199a-3p and promising prognostic utility of circulating miR-21-5p in both early and advanced UM patients.
The Incidence of Cancer Is Increased in Hospitalized Adult Patients With Obstructive Sleep Apnea in China: A Retrospective Cohort Study
Authors: Xiong Hailin , Lao Miaochan , Wang Longlong , Xu Yanxia , Pei Guo , Lu Bin , Shi Qianping , Chen Jialian , Zhang Shuyi , Ou Qiong
Published: March 2022

Background

The association between obstructive sleep apnea (OSA) and the incidence and mortality of cancer remain unclear, especially in Asian populations. Thus, this study was conducted to explore the relationship between OSA and the incidence and mortality of cancer in hospitalized patients.

Methods

This retrospective cohort study evaluated inpatients from Guangdong Provincial People’s Hospital for suspected OSA between January 2005 and December 2015. Cancer incidence, all-cause mortality, and cancer mortality and were determined using data from the hospital information system and Centers for Disease Control. Between-group comparisons were carried out by performing a chi-square test and analysis of variance. Kaplan–Meier analysis and the Cox proportional risk model were applied to investigate the association between OSA and cancer incidence and mortality.

Results

Of the 4,623 hospitalized patients included, 3,786 (81.9%) patients were diagnosed with OSA. After a median follow-up of 9.1 years (interquartile range, 9.79–11.44), the incidence of cancer was 6.6% (251/3,786), with lung cancer having the highest incidence at 1.6% (60/3,786). The mortality rate of OSA patients was higher than that of non-OSA patients (16.83% vs.12.78%, p=0.008), but the relationship between apnea-hypopnea index (AHI), oxygen saturation less than 90% (TSat90), and cancer mortality was not statistically significant (p>0.05).The mortality rate for all types of cancer was 2.8% (105/3,786), with lung cancer having the highest mortality rate at 0.8% (32/3,786). The cumulative incidence of cancer in the severe OSA group was 8.2%, which was higher than that in the normal, mild, and moderate OSA groups (P=0.010). Further, the Cox proportional risk regression model showed a progressive enhancement in the risk of cancer incidence as the AHI increased (adjusted hazard ratio [HR]: 1.009 [95% confidence interval (CI): 1.003–1.016], P=0.005). Based on subgroup analysis, the risk of cancer increased as the AHI increased in patients aged <65 years (adjusted HR: 1.019 [95% CI: 1.007–1.031], P=0.002). In addition, the cancer incidence was significantly higher in the severe OSA group than in the normal, mild, and moderate OSA groups (adjusted HR: 2.825 [95% CI: 1.358–5.878], P=0.019).

Conclusion

The incidence of cancer is higher in patients with OSA than in non-OSA patients and is significantly positively associated with the severity of OSA. Particularly, for OSA patients aged <65 years, lung cancer is the main cause of death in those with new-onset cancer. Mortality was higher in OSA patients than in non-OSA patients.
miR-139-5p Was Identified as Biomarker of Different Molecular Subtypes of Breast Carcinoma
Authors: Sun Haohang , Dai Ji , Chen Mengze , Chen Qi , Xie Qiong , Zhang Weijun , Li Guoqing , Yan Meidi
Published: March 2022

Located on chromosome 11q13.4, miR-139-5p has been confirmed by several studies as a possible attractive biomarker for cancer, including breast cancer, but its mechanism of correlation in different molecular subtypes of breast cancer has not been reported. In this study, comprehensive bioinformatics analysis was used to evaluate the expression of miR-139-5p in different molecular subtypes of breast cancer (luminal A, luminal B, HER2-enriched, and basal-like). The target genes of miR-139-5p were predicted by using an online database TargetScan and miRDB, and three key genes, FBN2, MEX3A, and TPD52, were screened in combination with differentially expressed genes in different molecular subtypes of breast cancer. The expression of the three genes was verified separately, and the genes were analyzed for pathway and functional enrichment. Bone marrow mesenchymal stem cells (BMSC) are another kind of highly plastic cell population existing in bone marrow besides hematopoietic stem cells. BMSC can affect the proliferation and migration of cancer cells, promote the metastasis and development of cancer, and regulate the tumor microenvironment by secreting exosome mirnas, thus affecting the malignant biological behavior of tumor cells. Finally, human bone marrow mesenchymal stem cells exosomes were obtained by ultracentrifugation, and the morphology of exosomes was observed by transmission electron microscopy. The expression of miR-139-5p in normal breast cells MCF-10A, human breast cancer cell line MDA-MB-231 cells, and BMSCs-derived exosomes were compared; the exosomes and MDA-MB-231 cells were co-cultured to observe their effects on the proliferation of the MDA-MB-231 cells. Human bone marrow mesenchymal stem cell-derived exosomes inhibited the growth of breast cancer cells and promoted the expression of FBN2, MEX3A, and TPD52 by transporting miR-139-5p.
Case Report: Personalized Therapeutical Approaches with Lenalidomide in Del(5q): A Case Series
Authors: Stein Anna , Kubasch Anne Sophie , Haferlach Claudia , Platzbecker Uwe
Published: March 2022

Myelodysplastic Syndrome (MDS) with del(5q) represents a unique WHO entity, which is often treated with lenalidomide according to standard clinical practice. Guidelines concerning treatment duration have thus far not been implemented, but rather comprise an indefinite therapy until loss of response. This review presents three red blood cell (RBC) transfusion-dependent MDS with del(5q) cases, starting with one rare case with an unbalanced translocation t(2;5), involving the breakpoint of del(5q) and loss of the 5q15-5q31 region. To the best of our knowledge, no comparable case has been described before with a response to lenalidomide. Strikingly, treatment-induced and maintained cytogenetic complete remission (cCR) in this patient. Furthermore, we report two cases of classical del(5q), in which lenalidomide was interrupted after a short period of lenalidomide therapy at the time cCR was achieved. Despite drug holiday cCR was maintained for seven and nine years, respectively. Then del(5q) re-emerged in the absence of novel molecular aberrations and re-treatment with lenalidomide could again achieve cCR in both cases. Together, this series presents three cases of personalized therapy of MDS with del(5q).