bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive Analysis of G-Quadruplexes in African Swine Fever Virus Genome Reveals Potential Antiviral Targets by G-Quadruplex Stabilizers
Authors: Muturi Elishiba , Meng Fei , Liu Huan , Jiang Mengwei , Wei Hongping , Yang Hang
Published: December 2021

African Swine Fever Virus (ASFV), a lethal hemorrhagic fever of the swine, poses a major threat to the world’s swine population and has so far resulted in devastating socio-economic consequences. The situation is further compounded by the lack of an approved vaccine or antiviral drug. Herein, we investigated a novel anti-ASFV approach by targeting G-Quadruplexes (G4s) in the viral genome. Bioinformatics analysis of putative G-quadruplex-forming sequences (PQSs) in the genome of ASFV BA71V strain revealed 317 PQSs on the forward strand and 322 PQSs on the reverse strand of the viral genome, translating to a density of 3.82 PQSs/kb covering 9.52% of the entire genome, which means that 85% of genes in the ASFV genome have at least 1 PQS on either strand. Biochemical characterization showed that 8 out of 13 conserved PQSs could form stable G4s in the presence of K+, and 4 of them could be stabilized by G4 ligands, N-Methyl Mesoporphyrin (NMM), and pyridostatin (PDS)in vitro. An enhanced green fluorescent protein (EGFP)-based reporter system revealed that the expression of two G4-containing genes, i.e., P1192R and D117L, could be significantly suppressed by NMM and PDS in 293T cells. In addition, a virus infection model showed that NMM could inhibit the replication of ASFV in Porcine Alveolar Macrophages (PAM) cells with an EC50value of 1.16 μM. Altogether, the present study showed that functional PQSs existent in the promoters, CDS, 3′ and 5′ UTRs of the ASFV genome could be stabilized by G4 ligands, such as NMM and PDS, and could serve as potential targets for antivirals.
Liraglutide Reduces Vascular Damage, Neuronal Loss, and Cognitive Impairment in a Mixed Murine Model of Alzheimer’s Disease and Type 2 Diabetes
Authors: Carranza-Naval Maria Jose , del Marco Angel , Hierro-Bujalance Carmen , Alves-Martinez Pilar , Infante-Garcia Carmen , Vargas-Soria Maria , Herrera Marta , Barba-Cordoba Belen , Atienza-Navarro Isabel , Lubian-Lopez Simon , Garcia-Alloza Monica
Published: December 2021

Alzheimer’s disease is the most common form of dementia, and epidemiological studies support that type 2 diabetes (T2D) is a major contributor. The relationship between both diseases and the fact that Alzheimer’s disease (AD) does not have a successful treatment support the study on antidiabetic drugs limiting or slowing down brain complications in AD. Among these, liraglutide (LRGT), a glucagon-like peptide-1 agonist, is currently being tested in patients with AD in the Evaluating Liraglutide in Alzheimer’s Disease (ELAD) clinical trial. However, the effects of LRGT on brain pathology when AD and T2D coexist have not been assessed. We have administered LRGT (500 μg/kg/day) to a mixed murine model of AD and T2D (APP/PS1xdb/db mice) for 20 weeks. We have evaluated metabolic parameters as well as the effects of LRGT on learning and memory. Postmortem analysis included assessment of brain amyloid-β and tau pathologies, microglia activation, spontaneous bleeding and neuronal loss, as well as insulin and insulin-like growth factor 1 receptors. LRGT treatment reduced glucose levels in diabetic mice (db/db and APP/PS1xdb/db) after 4 weeks of treatment. LRGT also helped to maintain insulin levels after 8 weeks of treatment. While we did not detect any effects on cortical insulin or insulin-like growth factor 1 receptor m-RNA levels, LRGT significantly reduced brain atrophy in the db/db and APP/PS1xdb/db mice. LRGT treatment also rescued neuron density in the APP/PS1xdb/db mice in the proximity (p = 0.008) far from amyloid plaques (p < 0.001). LRGT reduced amyloid plaque burden in the APP/PS1 animals (p < 0.001), as well as Aβ aggregates levels (p = 0.046), and tau hyperphosphorylation (p = 0.009) in the APP/PS1xdb/db mice. Spontaneous bleeding was also ameliorated in the APP/PS1xdb/db animals (p = 0.012), and microglia burden was reduced in the proximity of amyloid plaques in the APP/PS1 and APP/PS1xdb/db mice (p < 0.001), while microglia was reduced in areas far from amyloid plaques in the db/db and APP/PS1xdb/db mice (p < 0.001). This overall improvement helped to rescue cognitive impairment in AD-T2D mice in the new object discrimination test (p < 0.001) and Morris water maze (p < 0.001). Altogether, our data support the role of LRGT in reduction of associated brain complications when T2D and AD occur simultaneously, as regularly observed in the clinical arena.
Diagnostic and Therapeutic Potential of Exosomes in Neurodegenerative Diseases
Authors: Gao Panyue , Li Xinrong , Du Xinzhe , Liu Sha , Xu Yong
Published: December 2021

Neurodegenerative diseases are closely related to brain function and the progression of the diseases are irreversible. Due to brain tissue being not easy to acquire, the study of the pathophysiology of neurodegenerative disorders has many limitations—lack of reliable early biomarkers and personalized treatment. At the same time, the blood-brain barrier (BBB) limits most of the drug molecules into the damaged areas of the brain, which makes a big drop in the effect of drug treatment. Exosomes, a kind of endogenous nanoscale vesicles, play a key role in cell signaling through the transmission of genetic information and proteins between cells. Because of the ability to cross the BBB, exosomes are expected to link peripheral changes to central nervous system (CNS) events as potential biomarkers, and can even be used as a therapeutic carrier to deliver molecules specifically to CNS. Here we summarize the role of exosomes in pathophysiology, diagnosis, prognosis, and treatment of some neurodegenerative diseases (Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis).
Morphological and Ultrastructural Characterization of Antennal Sensilla and the Detection of Floral Scent Volatiles in Eupeodes corollae (Diptera: Syrphidae)
Authors: Dong Wan-Ying , Wang Bing , Wang Gui-Rong
Published: December 2021

The olfactory sensing system of the syrphid fly Eupeodes corollae is essential in pollination and prey localization, but little is known about the ultrastructural organization of their olfactory organs. In this study, the morphology, distribution, and ultrastructural organization of antennal sensilla of E. corollae in both sexes were observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Neuronal responses of a subtype of sensilla basiconica to floral scent compounds were recorded by single sensillum recording (SSR). Ten morphological types, including Böhm bristles, sensilla chaetica, microtrichiae, sensilla trichodea, sensilla basiconica, sensilla clavate, sensilla coeloconica, sensilla styloconica, sensilla placodea, and sensory pit, were identified. Except for Böhm bristles and sensilla chaetica, which were distributed on the scape and pedicel of E. corollae antennae, innervated sensilla were densely distributed on the flagellum, a vital sensory organ. Further, observing ultrastructural organization showed that the sensilla trichodea, basiconica, and clavate are single-walled with multiple nanoscale pores perforating the cuticle. Sensilla coeloconica are double-walled and have no wall pores, but instead, have longitudinal grooves along with the pegs. Sensilla chaetica, Böhm bristles, and microtrichiae did not have wall pores on the cuticle or sensory cells at the base. The SSR results indicated that neuron B housed in the subtype of sensilla basiconica I (SBI) mainly responded to methyl eugenol and other aromatic compounds. Overall, our results provide valuable information to understand the morphology and ultrastructure of antennal sensilla from E. corollae. These findings are beneficial for the studies of the neuronal function map of olfactory sensilla and for determining evolutionary relationships in Diptera.
Self-Administration of Entactogen Psychostimulants Dysregulates Gamma-Aminobutyric Acid (GABA) and Kappa Opioid Receptor Signaling in the Central Nucleus of the Amygdala of Female Wistar Rats
Authors: Khom Sophia , Nguyen Jacques D. , Vandewater Sophia A. , Grant Yanabel , Roberto Marisa , Taffe Michael A.
Published: December 2021

Male rats escalate intravenous self-administration of entactogen psychostimulants, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxymethamphetamine (MDMA) under extended access conditions, as with typical psychostimulants. Here, we investigated whether female rats escalate self-administration of methylone, 3,4-methylenedioxypentedrone (pentylone), and MDMA and then studied consequences of MDMA and pentylone self-administration on GABAA receptor and kappa opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA), a brain area critically dysregulated by extended access self-administration of alcohol or cocaine. Adult female Wistar rats were trained to self-administer methylone, pentylone, MDMA (0.5 mg/kg/infusion), or saline-vehicle using a fixed-ratio 1 response contingency in 6-h sessions (long-access: LgA) followed by progressive ratio (PR) dose-response testing. The effects of pentylone-LgA, MDMA-LgA and saline on basal GABAergic transmission (miniature post-synaptic inhibitory currents, mIPSCs) and the modulatory role of KOR at CeA GABAergic synapses were determined in acute brain slices using whole-cell patch-clamp. Methylone-LgA and pentylone-LgA rats similarly escalated their drug intake (both obtained more infusions compared to MDMA-LgA rats), however, pentylone-LgA rats reached higher breakpoints in PR tests. At the cellular level, baseline CeA GABA transmission was markedly elevated in pentylone-LgA and MDMA-LgA rats compared to saline-vehicle. Specifically, pentylone-LgA was associated with increased CeA mIPSC frequency (GABA release) and amplitude (post-synaptic GABAA receptor function), while mIPSC amplitudes (but not frequency) was larger in MDMA-LgA rats compared to saline rats. In addition, pentylone-LgA and MDMA-LgA profoundly disrupted CeA KOR signaling such as both KOR agonism (1 mM U50488) and KOR antagonism (200 nM nor-binaltorphimine) decreased mIPSC frequency suggesting recruitment of non-canonical KOR signaling pathways. This study confirms escalated self-administration of entactogen psychostimulants under LgA conditions in female rats which is accompanied by increased CeA GABAergic inhibition and altered KOR signaling. Collectively, our study suggests that CeA GABA and KOR mechanisms play a critical role in entactogen self-administration like those observed with escalation of alcohol or cocaine self-administration.
Adaptation Strategies for Personalized Gait Neuroprosthetics
Authors: Koelewijn Anne D. , Audu Musa , del-Ama Antonio J. , Colucci Annalisa , Font-Llagunes Josep M. , Gogeascoechea Antonio , Hnat Sandra K. , Makowski Nathan , Moreno Juan C. , Nandor Mark , Quinn Roger , Reichenbach Marc , Reyes Ryan-David , Sartori Massimo , Soekadar Surjo , Triolo Ronald J. , Vermehren Mareike , Wenger Christian , Yavuz Utku S. , Fey Dietmar , Beckerle Philipp
Published: December 2021

Personalization of gait neuroprosthetics is paramount to ensure their efficacy for users, who experience severe limitations in mobility without an assistive device. Our goal is to develop assistive devices that collaborate with and are tailored to their users, while allowing them to use as much of their existing capabilities as possible. Currently, personalization of devices is challenging, and technological advances are required to achieve this goal. Therefore, this paper presents an overview of challenges and research directions regarding an interface with the peripheral nervous system, an interface with the central nervous system, and the requirements of interface computing architectures. The interface should be modular and adaptable, such that it can provide assistance where it is needed. Novel data processing technology should be developed to allow for real-time processing while accounting for signal variations in the human. Personalized biomechanical models and simulation techniques should be developed to predict assisted walking motions and interactions between the user and the device. Furthermore, the advantages of interfacing with both the brain and the spinal cord or the periphery should be further explored. Technological advances of interface computing architecture should focus on learning on the chip to achieve further personalization. Furthermore, energy consumption should be low to allow for longer use of the neuroprosthesis. In-memory processing combined with resistive random access memory is a promising technology for both. This paper discusses the aforementioned aspects to highlight new directions for future research in gait neuroprosthetics.
Role of RAGE and Its Ligands on Inflammatory Responses to Brain Tumors
Authors: Otazu Griffith Kyle , Dayyani Mojtaba , Badie Behnam
Published: December 2021

Gliomas, the most common form of brain cancer, can range from relatively slow-growing low-grade to highly aggressive glioblastoma that has a median overall survival of only 15 months despite multimodal standard therapy. Although immunotherapy with checkpoint inhibitors has significantly improved patient survival for some cancers, to date, these agents have not shown consistent efficacy against malignant gliomas. Therefore, there is a pressing need to better understand the impact of host inflammatory responses on the efficacy of emerging immunotherapy approaches for these resistant tumors. RAGE is a multi-ligand pattern recognition receptor that is activated in various inflammatory states such as diabetes, Alzheimer’s disease, cystic fibrosis, and cancer. Low levels of RAGE can be found under normal physiological conditions in neurons, immune cells, activated endothelial, and vascular smooth muscle cells, but it is over-expressed under chronic inflammation due to the accumulation of its ligands. RAGE binds to a range of damage-associated molecular pattern molecules (DAMPs) including AGEs, HMGB1, S100s, and DNA which mediate downstream cellular responses that promote tumor growth, angiogenesis, and invasion. Both in vitro and in vivo studies have shown that inhibition of RAGE signaling can disrupt inflammation and cancer progression and metastasis. Here, we will review our current understanding of the role of RAGE pathway on glioma progression and how it could be exploited to improve the efficacy of immunotherapy approaches.
Safety and Efficacy of Endovascular Treatment for Progressive Stroke in Patients With Acute Basilar Artery Occlusion
Authors: Wang Yinxu , Ke Yingbing , Wang Lingling , Wu Qing , Zhou Jing , Tan Xiaolin , Liu Jiazuo , Geng Wanjie , Cheng Daoyou , Liu Zongtao , Yu Yinquan , Song Jiaxing , Qiu Zhongming , Li Fengli , Luo Weidong , Yang Jie , Zi Wenjie , Wang Xiaoming , Yuan Zhengzhou
Published: December 2021

Background and Purpose: It is unknown the benefit of endovascular therapy (EVT) for progressive stroke in patients with basilar artery occlusion (BAO). The aim of this study was to compare the efficacy and safety of EVT with standard medical therapy (SMT) in a population of BAO patients with progressive stroke.

Methods: The EVT for Acute Basilar Artery Occlusion Study (BASILAR) is a national prospective registry of consecutive patients with acute BAO within 24 h of symptom onset. According to the applied therapy, all patients were divided into SMT and EVT groups. Subsequently, the EVT group was divided into early (≤6 h) and late groups (>6 h) according to the time window. The efficacy outcome was favorable functional outcomes (modified Rankin Scale score ≤ 3) at 90 days. The safety outcomes included mortality within 90 days and symptomatic intracerebral hemorrhage (sICH) after EVT.

Results: The EVT cohort presented more frequently with a favorable functional outcome (adjusted odds ratio, 5.49; 95% confidence interval, 2.06–14.61, p = 0.01) and with a decreased mortality (adjusted odds ratio, 0.3; 95% confidence interval, 0.17–0.54, p < 0.001). What's more, EVT still safe (P = 0.584, P = 0.492, respectively) and effective (P = 0.05) in patients with progressive stroke when the treatment time window exceeds 6 h.

Conclusions: EVT was more effective and safer than SMT for progressive stroke in patients with BAO. Besides, EVT remains safe and effective in patients with progressive stroke when the treatment time window exceeds 6 h. Predictors of desirable outcome in progressive stroke patients undergoing EVT included lower baseline NIHSS score, higher baseline pc-ASPECTs, successful recanalization and shorter puncture to recanalization time.
Sleep in Children With Pallister Killian Syndrome: A Prospective Clinical and Videopolysomnographic Study
Authors: Fetta Anna , Di Pisa Veronica , Ruscelli Martina , Soliani Luca , Sperti Giacomo , Ubertiello Sara , Ricci Emilia , Mainieri Greta , Rocca Alessandro , Mancardi Maria Margherita , Giordano Lucio , Pruna Dario , Vignoli Aglaia , Provini Federica , Cordelli Duccio Maria
Published: December 2021

Objectives: Pallister-Killian syndrome (PKS) is a rare genetic disorder with multi-organ involvement caused by mosaic tetrasomy of chromosome 12p. Although many caregivers report the presence of impaired sleep in their children, there are no clear data in the literature on this issue and no systematic study has ever been performed. With this study, we aimed to characterize the features of sleep in Pallister-Killian syndrome and identify the possible influence of clinical and demographic features. Moreover, our aim was to verify the effectiveness of conventional screening questionnaires in this particular group of patients.

Methods: We prospectively enrolled 14 patients aged 1–17 years in collaboration with PKS Kids Italia ONLUS. The Sleep Disturbance Scale for Children (SDSC) questionnaire was administered to caregivers. Then, video polysomnography (VPSG) of at least 24 h was performed and results were compared with a same-aged control group.

Results: A total of 92% of patients had abnormal SDSC scores, extremely high in the “disorder of initiating and maintaining sleep” (DIMS) and “sleep breathing disorders” (SBD) subscales. VPSG showed a significantly impaired macrostructure in PKS patients, with a higher Arousal Index (p < 0.00001) and percentage of time spent in N3 (p < 0.00001), and reduced Sleep Efficiency (p = 0.0006). After dividing both PKS and controls into two groups based on median age, some peculiarities emerged: the younger group had higher Awakenings Index (p = 0.0207) and percentage of time spent in N1 (p = 0.015) while the older group showed higher time in bed (TIB) (p = 0.0485), compared with controls. Due to poor compliance, the Apnea-Hypopnea Index (AHI) was evaluated only for 10 PKS children, being significantly increased (p = 0.0427) compared with controls. SBD subscale scores in SDSC were significantly related to AHI values in VPSG (p = 0.0099).

Conclusions: This study constitutes the first attempt to describe the sleep pattern in PKS. Despite small numbers due to the rarity of the syndrome, our VPSG results confirm the high prevalence of sleep disorders (SDs) in these patients. It is therefore essential to investigate and treat them. The SDSC scale is a good screening tool for early detection also in these patients, with particular sensitivity in detecting breathing disorders.
Changes in the Shape and Volume of Subcortical Structures in Patients With End-Stage Renal Disease
Authors: Gu Wen , He Ronghua , Su Hang , Ren Zhuanqin , Zhang Lei , Yuan Huijie , Zhang Ming , Ma Shaohui
Published: December 2021

Introduction: End-stage renal disease (ESRD) typically causes changes in brain structure, and patients with ESRD often experience cognitive and sleep disorders. We aimed to assess the changes in the subcortical structure of patients with ESRD and how they are associated with cognitive and sleep disorders.

Methods: We involved 36 adult patients for maintenance hemodialysis and 35 age- and gender-matched control individuals. All participants underwent neuropsychological examination and 3T magnetic resonance imaging (MRI) to acquire T1 anatomical images. The laboratory blood tests were performed in all patients with ESRD close to the time of the MR examination. We used volumetric and vertex-wise shape analysis approaches to investigate the volumes of 14 subcortical structural (e.g., bilateral accumbens, amygdala, hippocampus, caudate, globus pallidus, putamen, and thalamus) abnormalities in the two groups. Analyses of partial correlations and shape correlations were performed in order to identify the associations between subcortical structure, cognition, and sleep quality in patients with ESRD.

Results: The volumetric analysis showed that compared with the healthy control group, patients with ESRD had less bilateral thalamus (left: p < 0.001; right: p < 0.001), bilateral accumbens (left: p < 0.001; right: p = 0.001), and right amygdala (p = 0.002) volumes. In the vertex-wise shape analysis, patients with ESRD had abnormal regional surface atrophy in the bilateral thalamus, right accumbens, left putamen, and bilateral caudate. Moreover, the Montreal Cognitive Assessment (MoCA) score was associated with volume reduction in the bilateral thalamus (left: Spearman ρ = 0.427, p = 0.009; right: ρ = 0.319, p = 0.018), and the Pittsburgh Sleep Quality Index (PSQI) score was associated with volume reduction in the bilateral accumbens (left: ρ = −0.546, p = 0.001; right: ρ = −0.544, p = 0.001). In vertex-wise shape correlation analysis, there was a positive significant correlation between regional shape deformations on the bilateral thalamus and MoCA score in patients with ESRD.

Conclusion: Our study suggested that patients with ESRD have subcortical structural atrophy, which is related to impaired cognitive performance and sleep disturbances. These findings may help to further understand the underlying neural mechanisms of brain changes in patients with ESRD.
Self-Administration of Right Vagus Nerve Stimulation Activates Midbrain Dopaminergic Nuclei
Authors: Brougher Jackson , Aziz Umaymah , Adari Nikitha , Chaturvedi Muskaan , Jules Aryela , Shah Iqra , Syed Saba , Thorn Catherine A.
Published: December 2021

Background: Left cervical vagus nerve stimulation (l-VNS) is an FDA-approved treatment for neurological disorders including epilepsy, major depressive disorder, and stroke, and l-VNS is increasingly under investigation for a range of other neurological indications. Traditional l-VNS is thought to induce therapeutic neuroplasticity in part through the coordinated activation of multiple broadly projecting neuromodulatory systems in the brain. Recently, it has been reported that striking lateralization exists in the anatomical and functional connectivity between the vagus nerves and the dopaminergic midbrain. These emerging findings suggest that VNS-driven activation of this important plasticity-promoting neuromodulatory system may be preferentially driven by targeting the right, rather than the left, cervical nerve.

Objective: To compare the effects of right cervical VNS (r-VNS) vs. traditional l-VNS on self-administration behavior and midbrain dopaminergic activation in rats.

Methods: Rats were implanted with a stimulating cuff electrode targeting either the right or left cervical vagus nerve. After surgical recovery, rats underwent a VNS self-administration assay in which lever pressing was paired with r-VNS or l-VNS delivery. Self-administration was followed by extinction, cue-only reinstatement, and stimulation reinstatement sessions. Rats were sacrificed 90 min after completion of behavioral training, and brains were removed for immunohistochemical analysis of c-Fos expression in the dopaminergic ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), as well as in the noradrenergic locus coeruleus (LC).

Results: Rats in the r-VNS cohort performed significantly more lever presses throughout self-administration and reinstatement sessions than did rats in the l-VNS cohort. Moreover, this appetitive behavioral responding was associated with significantly greater c-Fos expression among neuronal populations within the VTA, SNc, and LC. Differential c-Fos expression following r-VNS vs. l-VNS was particularly prominent within dopaminergic midbrain neurons.

Conclusion: Our results support the existence of strong lateralization within vagal-mesencephalic signaling pathways, and suggest that VNS targeted to the right, rather than left, cervical nerve preferentially activates the midbrain dopaminergic system. These findings raise the possibility that r-VNS could provide a promising strategy for enhancing dopamine-dependent neuroplasticity, opening broad avenues for future research into the efficacy and safety of r-VNS in the treatment of neurological disease.
ELK3: A New Molecular Marker for the Diagnosis and Prognosis of Glioma
Authors: Liu Zhendong , Ren Zhishuai , Zhang Cheng , Qian Rongjun , Wang Hongbo , Wang Jialin , Zhang Wang , Liu Binfeng , Lian Xiaoyu , Wang Yanbiao , Guo Yuqi , Gao Yanzheng
Published: December 2021

ETS transcription factor ELK3 (ELK3), a novel oncogene, affects pathological processes and progression of many cancers in human tissues. However, it remains unclear whether ELK3, as a key gene, affects the pathological process of gliomas and the prognosis of patients with gliomas. This study aimed to comprehensively and systematically reveal the correlation between ELK3 and the malignant progression of gliomas by analyzing clinical sample information stored in multiple databases. We revealed the putative mechanism of ELK3 involvement in malignant gliomas progression and identified a new and efficient biomarker for glioma diagnosis and targeted therapy. Based on the sample data from multiple databases and real-time quantitative polymerase chain reaction (RT-qPCR), the abnormally high expression of ELK3 in gliomas was confirmed. Kaplan-Meier and Cox regression analyses demonstrated that a high ELK3 expression was markedly associated with low patient survival and served as an independent biomarker of gliomas. Wilcox and Kruskal-Wallis tests revealed that expression of ELK3 was positively correlated with several clinical characteristics of patients with gliomas, such as age, WHO classification, and recurrence. Moreover, Cell Counting Kit‐8 (CCK-8), immunofluorescence, and wound healing assays confirmed that ELK3 overexpression markedly promoted the proliferation and migration of glioma cells. Finally, gene set enrichment analysis (GSEA) and western blotting confirmed that overexpression of ELK3 regulated the JAK–STAT signaling pathway and upregulate the expression of signal transducer and activator of transcription 3 (STAT3) and phosphorylated STAT3 (P-STAT3) to promote the malignant transition of gliomas. Therefore, ELK3 may serve as an efficient biomarker for the diagnosis and prognosis of gliomas and it can also be used as a therapeutic target to improve the poor prognosis of patients with gliomas.
Case Report: Significant Efficacy of Pyrotinib in the Treatment of Extensive Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Cutaneous Metastases: A Report of Five Cases
Authors: Wang Nan , Li Lin , Xiong Youyi , Chi Jiangrui , Liu Xinwei , Zhong Chaochao , Wang Fang , Gu Yuanting
Published: December 2021

Background

Breast cancer (BC) is the most common tumor to develop cutaneous metastases. Most BCs with cutaneous metastasis are human epidermal growth factor receptor 2 (HER2)-positive subtypes. Although the molecular mechanisms of breast cancer metastasis to different sites and the corresponding treatment methods are areas of in-depth research, there are few studies on cutaneous metastasis.

Case Presentation

Five HER2-positive BC patients with extensive cutaneous metastases were treated with a regimen containing pyrotinib, a novel small-molecule tyrosine kinase inhibitor that irreversibly blocks epidermal growth factor receptor (EGFR), HER2, and human epidermal growth factor receptor 4 (HER4), then their cutaneous metastases quickly resolved at an astonishing speed and their condition was well controlled during the follow-up period.

Conclusions

This case series reports the significant therapeutic effect of pyrotinib on cutaneous metastases of HER2-positive BC for the first time. Based on this, we recommend that pyrotinib can be used as a supplement to trastuzumab for HER2-positive BC patients with cutaneous metastases. In addition, we should consider that the pan-inhibitory effect of pyrotinib on EGFR, HER2, and HER4 may provide a dual therapeutic effect against HER2 and mucin 1.
Inferring Homologous Recombination Deficiency of Ovarian Cancer From the Landscape of Copy Number Variation at Subchromosomal and Genetic Resolutions
Authors: Zhang Meng , Ma Si-Cong , Tan Jia-Le , Wang Jian , Bai Xue , Dong Zhong-Yi , Zhang Qing-Xue
Published: December 2021

Background

Homologous recombination deficiency (HRD) is characterized by overall genomic instability and has emerged as an indispensable therapeutic target across various tumor types, particularly in ovarian cancer (OV). Unfortunately, current detection assays are far from perfect for identifying every HRD patient. The purpose of this study was to infer HRD from the landscape of copy number variation (CNV).

Methods

Genome-wide CNV landscape was measured in OV patients from the Australian Ovarian Cancer Study (AOCS) clinical cohort and >10,000 patients across 33 tumor types from The Cancer Genome Atlas (TCGA). HRD-predictive CNVs at subchromosomal resolution were identified through exploratory analysis depicting the CNV landscape of HRD versus non-HRD OV patients and independently validated using TCGA and AOCS cohorts. Gene-level CNVs were further analyzed to explore their potential predictive significance for HRD across tumor types at genetic resolution.

Results

At subchromosomal resolution, 8q24.2 amplification and 5q13.2 deletion were predominantly witnessed in HRD patients (both p < 0.0001), whereas 19q12 amplification occurred mainly in non-HRD patients (p < 0.0001), compared with their corresponding counterparts within TCGA-OV. The predictive significance of 8q24.2 amplification (p < 0.0001), 5q13.2 deletion (p = 0.0056), and 19q12 amplification (p = 0.0034) was externally validated within AOCS. Remarkably, pan-cancer analysis confirmed a cross-tumor predictive role of 8q24.2 amplification for HRD (p < 0.0001). Further analysis of CNV in 8q24.2 at genetic resolution revealed that amplifications of the oncogenes, MYC (p = 0.0001) and NDRG1 (p = 0.0004), located on this fragment were also associated with HRD in a pan-cancer manner.

Conclusions

The CNV landscape serves as a generalized predictor of HRD in cancer patients not limited to OV. The detection of CNV at subchromosomal or genetic resolution could aid in the personalized treatment of HRD patients.
Differentially Expressed Genes in Clear Cell Renal Cell Carcinoma as a Potential Marker for Prognostic and Immune Signatures
Authors: Tong Ying , Yu Yiwen , Zheng Hui , Wang Yanchun , Xie Suhong , Chen Cuncun , Lu Renquan , Guo Lin
Published: December 2021

Clear cell renal cell carcinoma (ccRCC) is characterized by the inactivation of the von Hippel–Lindau (VHL) gene. Of note, no other gene is mutated as frequently as VHL in ccRCC, turning out that patients with inactivated VHL constitute the majority of ccRCC-related character. Thus, differentially expressed genes (DEGs) and their molecular networks caused by VHL mutation were considered as important factors for influencing the prognosis of ccRCC. Here, we first screened out six DEGs (GSTA1, GSTA2, NAT8, FABP7, SLC17A3, and SLC17A4) which downregulated in ccRCC patients with VHL non-mutation than with the mutation. Generally, most DEGs with high expression were associated with a favorable prognosis and low-risk score. Meanwhile, we spotted transcription factors and their kinases as hubs of DEGs. Finally, we clustered ccRCC patients into three subgroups according to the expression of hub proteins, and analyzed these subgroups with clinical profile, outcome, immune infiltration, and potential Immune checkpoint blockade (ICB) response. Herein, DEGs might be a promising biomarker panel for immunotherapy and prognosis in ccRCC. Moreover, the ccRCC subtype associated with high expression of hubs fit better for ICB therapy.
Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin
Authors: Havaei Seyed Mehdi , Aucoin Marc G. , Jahanian-Najafabadi Ali
Published: December 2021

Cancer is one of the prominent causes of death worldwide. Despite the existence of various modalities for cancer treatment, many types of cancer remain uncured or develop resistance to therapeutic strategies. Furthermore, almost all chemotherapeutics cause a range of side effects because they affect normal cells in addition to malignant cells. Therefore, the development of novel therapeutic agents that are targeted specifically toward cancer cells is indispensable. Immunotoxins (ITs) are a class of tumor cell-targeted fusion proteins consisting of both a targeting moiety and a toxic moiety. The targeting moiety is usually an antibody/antibody fragment or a ligand of the immune system that can bind an antigen or receptor that is only expressed or overexpressed by cancer cells but not normal cells. The toxic moiety is usually a protein toxin (or derivative) of animal, plant, insect, or bacterial origin. To date, three ITs have gained Food and Drug Administration (FDA) approval for human use, including denileukin diftitox (FDA approval: 1999), tagraxofusp (FDA approval: 2018), and moxetumomab pasudotox (FDA approval: 2018). All of these ITs take advantage of bacterial protein toxins. The toxic moiety of the first two ITs is a truncated form of diphtheria toxin, and the third is a derivative of Pseudomonas exotoxin (PE). There is a growing list of ITs using PE, or its derivatives, being evaluated preclinically or clinically. Here, we will review these ITs to highlight the advances in PE-based anticancer strategies, as well as review the targeting moieties that are used to reduce the non-specific destruction of non-cancerous cells. Although we tried to be as comprehensive as possible, we have limited our review to those ITs that have proceeded to clinical trials and are still under active clinical evaluation.
Protective Effect of Mannitol on Cisplatin-Induced Nephrotoxicity: A Systematic Review and Meta-Analysis
Authors: Li Songtao , He Xiuyun , Ruan Linjie , Ye Ting , Wen Yulong , Song Zhihua , Hu Siying , Chen Yu , Peng Bo , Li Shijie
Published: December 2021

Introduction

Cisplatin, a chemotherapeutic drug, is widely used for the treatment of various malignant tumors with good effects. However, cisplatin-induced nephrotoxicity is a major dose-limiting factor and a significant adverse event. Mannitol is used to reduce cisplatin-induced nephrotoxicity, which is controversial. This study aimed to evaluate the efficacy and safety of a hydration regimen containing mannitol against cisplatin-induced nephrotoxicity through a meta-analysis.

Methods

Potential records from PubMed, EMBASE, Cochrane Library, and ClinicalTrials that met the inclusion criteria were included from inception to May 2021. Cochrane Collaboration tools were used to assess the risk of bias in the included studies. Jadad’s and NOS scores were applied to assess the quality of randomized controlled trials (RCTs) and case-control studies. A random-effects model or fixed-effects model was used depending on the heterogeneity. Subgroup analyses were performed to evaluate the potential study characteristics. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were evaluated.

Results

Four RCTs and seven case-control studies involving 4168 patients were included. Pooled results showed that mannitol use could reduce the incidence of cisplatin-induced nephrotoxicity (OR = 0.66, 95% CI [0.45–0.97], p = 0.03), especially reducing grade 3 nephrotoxicity events according to CTCAE 4.0 (OR = 0.37,95% CI [0.16–0.84]). Moreover, mannitol use was not significantly associated with creatinine clearance, serum creatine, and electrolyte disturbance (p > 0.05). Gastrointestinal cancer (OR = 0.36, 95% CI [0.15–0.83], p = 0.02) and urinary tract cancer (OR = 0.32,95% CI [0.14–0.73], p = 0.007) may be more sensitive to mannitol, although the test for overall effect was significantly different (OR = 0.66, 95% CI [0.49–0.89], p = 0.007). For patients with diabetes and hypertension, mannitol may worsen renal function (OR = 1.80, 95% CI [1.18–2.72], p = 0.006; OR = 2.19, 95% CI [1.50, 3.19], p < 0.0001, respectively). Mannitol may have a better protective effect when doses of mannitol were ≥ 25 g (OR = 0.58, 95% CI [0.39–0.88], p = 0.01) and doses of cisplatin < 75 mg/m2 (OR = 0.59, 95% CI [0.36–0.94], p = 0.03). It revealed that mannitol use was likely to cause nausea or vomiting (OR = 1.86, 95% CI [1.20–2.89], p = 0.006).

Conclusion

Current evidence revealed that mannitol was an effective and safe drug to reduce cisplatin-induced nephrotoxicity events, especially Grade 3 events. However, it may cause more nausea/vomiting events and deteriorate renal function in patients with diabetes or hypertension. We also found that mannitol had the best effect when mannitol was ≥ 25 g in total or cisplatin was < 75 mg/m2. Meanwhile, mannitol may have a better effect on gastrointestinal and urinary tract cancers.

Systematic Review Registration

crd. york. ac. uk/PROSPERO, CRD 42021253990
Lifestyle Clusters and Cardiometabolic Risks in Adolescents: A Chinese School-Based Study Using a Latent Class Analysis Approach
Authors: Zhao Weiying , Su Danyan , Mo Luxia , Chen Cheng , Ye Bingbing , Qin Suyuan , Liu Jie , Pang Yusheng
Published: December 2021

Background: Unhealthy dietary and lifestyle behaviors are associated with a higher prevalence of non-communicable chronic diseases and higher mortality in adults. However, there remains some uncertainty about the magnitude of the associations between lifestyle behaviors and cardiovascular factors in adolescents.

Methods: We conducted a school-based cross-sectional study of 895 Chinese adolescents aged 15–19 years. They participated in a questionnaire survey, physical examination, and blood sample collection. Latent class analysis (LCA) was used to identify heterogeneous subgroups of lifestyle behaviors. A set of 12 latent class indicators, which reflected lifestyle behaviors including dietary habits, physical activity, sleep duration, screen time, and pressure perception, were included in the analysis. Logistic regression analysis was performed to determine whether the derived classes were related to a cardiometabolic risk.

Results: In total, 13.7 and 5.6% of the participants were overweight and obese, respectively, and 8.4 and 14.1% reported having pre-hypertension and hypertension, respectively. A two-class model provided the best fit with a healthy lifestyle pattern (65.8%) and a sub-healthy lifestyle pattern (34.2%). There were more female participants with a healthy lifestyle (56.2 vs. 43.8%), whereas there were more males with a sub-healthy lifestyle (45.4 vs. 54.6%), (all P = 0.002). Increased risk of cardiometabolic abnormality (BMI categories, blood pressure and lipids) was not significant across lifestyle patterns, except for waist circumference (70.5 vs 69.1 cm, P = 0.044). There was no significant difference in physical activity and intake of fruit and vegetable between the two patterns.

Conclusion: Primary prevention based on lifestyle modification should target patterns of behaviors at high risk in adolescents. Due to the complex effect of lifestyle clusters on cardiometabolic risks, well-designed and prospective studies in adolescents are needed in the future.
Cost–Utility Analysis of Wide-Field Imaging as an Auxiliary Technology for Retinopathy of Prematurity Care in Brazil
Authors: Neves Luiza M , Haefeli Lorena M , Zin Andrea A , Steffen Ricardo E , Vasconcelos Zilton F. M , Pinto Márcia
Published: December 2021

Purpose: To evaluate the cost–utility of wide-field imaging (WFI) as a complementary technology for retinopathy of prematurity (ROP) screening from the Brazilian Unified Health System's perspective.

Introduction: ROP is one of the leading causes of avoidable childhood blindness worldwide, especially in middle-income countries. The current ROP screening involves indirect binocular ophthalmoscopy (IBO) by ROP expert ophthalmologists. However, there is still insufficient ROP screening coverage. An alternative screening strategy is the combination of WFI with IBO.

Methods: A cost–utility analysis was performed using a deterministic decision-tree simulation model to estimate incremental cost–utility for ROP care. Two screening strategies were compared: (1) IBO and (2) combination of WFI of all eligible preterm infants and IBO for type 2 ROP or worse and for non-readable images. Eligible population included preterm infants <32 weeks of gestational age or birth weight equal to or <1,500 g. The temporal horizon was lifetime. Visual outcome data was converted to utility, and the health benefits were estimated on quality-adjusted life-years (QALY). Incremental cost per QALY gained was calculated from the health system perspective. Costs were estimated considering equipment, maintenance, consumables, and staff. A micro-costing approach was used for WFI. Two technician nurses were trained for imaging execution and had their time evaluated. Two ROP expert ophthalmologists had their time evaluated for imaging reading. One-way sensitivity analysis and probabilistic sensitivity analysis were performed.

Results: Combined screening strategy resulted in a cost-effective program considering 90% ROP screening coverage. Costs per examination: (1) screening with IBO: US dollar (US $) 34.36; (2) screening with combination: US $58.20; (3) laser treatment: US $642.09; (4) long-term follow-up: ranged from US $69.33 to 286.91, based on the infant's visual function. Incremental cost per QALY gained was US $1,746.99/QALY per infant screened with the combination strategy. One-way sensitivity analysis resulted in cost-effectiveness for all parameters. Probabilistic sensitivity analyses yielded a 100% probability of combination being cost-effective in a willingness-to-pay threshold of US $1,800/QALY.

Conclusion: The combined strategy for ROP screening was cost-effective. It enhances access for appropriate ROP care in middle-income countries and dminishes opportunity costs for ophthalmologists.
2-Dodecyl-6-Methoxycyclohexa-2,5-Diene-1,4-Dione Ameliorates Diabetic Cognitive Impairment Through Inhibiting Hif3α and Apoptosis
Authors: Wang Lihui , Cao Jinjin , Xu Qianqian , Lu Xiaomei , Yang Xin , Song Qiong , Chen Shuai , Du Kechen , Huang Renbin , Zou Chunlin
Published: December 2021

Diabetes mellitus (DM) is an independent risk factor for cognitive impairment. Although the etiology of diabetic cognitive impairment is complex and multifactorial, the hippocampus neuronal apoptosis is recognized as a main cause of diabetes-induced cognitive impairment. 2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) was purified from the roots of Averrhoa carambola L. Previous research demonstrated that DMDD was safe and effective in delaying some diabetic complications. However, the efficacy of DMDD to ameliorate diabetic cognitive impairment in type 2 diabetes mice has not been reported. In the present study, the behavioral evaluation was performed by Y maze and novel object recognition in db/db mice. Gene expression profiles were detected using mouse lncRNA microarray analysis in the hippocampi of db/db mice. Changes in the neurodegeneration-associated proteins and the apoptosis-related proteins were determined in both db/db mice and high glucose-treated HT22 cells by Western blotting. We observed that DMDD treatment significantly ameliorated the spatial working memory and object recognition memory impairment in db/db mice. Further study showed that neurodegeneration-associated protein tau was decreased after DMDD treatment in the hippocampi of db/db mice. Eleven lncRNAs and four mRNAs including pro-apoptotic gene Hif3a were significantly differently expressed after DMDD treatment in the hippocampi of db/db mice. The expression of Hif3a, cleaved parp, and caspase 3 proteins was significantly increased in the hippocampi of diabetic db/db mice compared with db/m control mice and then decreased after DMDD treatment. Similar beneficial effects of DMDD were observed in HG-treated HT22 cells. These data indicate that DMDD can alleviate cognitive impairment by inhibiting neuronal apoptosis through decreasing the expression of pro-apoptotic protein Hif3a. In conclusion, our study suggests that DMDD has great potential to be a new preventive and therapeutic compound for diabetic cognitive impairment.
Antimicrobial and Anti-inflammatory Effects of a Novel Peptide From the Skin of Frog Microhyla pulchra
Authors: Tian Maolin , Liu Junfang , Chai Jinwei , Wu Jiena , Xu Xueqing
Published: December 2021

Brevinins are an important antimicrobial peptide (AMP) family identified in the skin of Ranidae frogs and generally contain a characteristic ranabox structure at their C-terminal sequence. Herein a novel AMP named brevinin-2MP has been identified from the skin of the frog Microhyla pulchra by molecular cloning. Brevinin-2MP (GVITDTLKGVAKTVAAELLRKAHCKLTNSC) with a high amphipathic α-helix in sodium dodecyl sulfate solutions can destroy bacterial cell membrane and kill microbes. Furthermore, brevinin-2MP has been found to inhibit the lipopolysaccharide (LPS)-induced expression of pro-inflammatory NO, MCP-1, IL-6, and TNF-α via binding unidentified targets on the cell membrane and consequently suppressing the activation of MAPK/NF-κB signaling cascades induced by LPS in RAW 264.7 cells. Consistently, brevinin-2MP significantly alleviates the acute inflammatory response in carrageenan-induced mice paw. In conclusion, brevinin-2MP with anti-inflammatory and antimicrobial properties will be an ideal candidate drug molecule for bacterial inflammation treatment.
Triple-Regimen of Vemurafenib, Irinotecan, and Cetuximab for the Treatment of BRAFV600E-Mutant CRC: A Case Report and Review
Authors: Cho Su Min , Esmail Abdullah , Abdelrahim Maen
Published: December 2021

Mutation of the BRAF proto-oncogene is found in approximately 10% of colorectal cancers (CRC), with much of the mutation conferred by a V600E mutation. Unlike other CRC subtypes, BRAF-mutant CRC have had relatively limited response to conventional therapies and overall poor survival. We present the case of a 75-year-old man with severe nonischemic cardiomyopathy on a LifeVest who was found to have a transverse colonic mass with widespread hepatic metastatic disease and was subsequently found to have BRAFV600E-mutant CRC (MSI High/dMMR). After a failed therapy with FOLFOX and pembrolizumab, the patient was started on a regimen of vemurafenib, irinotecan, and cetuximab (VIC) based on the SWOG 1406 trial which had shown improved progression-free survival and response rate for the treatment of BRAFV600E-mutant metastatic CRC. After 40 cycles of VIC, the patient attained complete response and is in remission off chemotherapy with significant improvement. This case highlights the effectiveness of the triple-regimen of vemurafenib, irinotecan, and cetuximab as a treatment option for BRAFV600E-mutant CRC, which is a treatment regimen based on the SWOG 1406 trial, and also demonstrates the synergistic role of BRAFV600E inhibitors and EGFR inhibitors in the treatment of BRAFV600E-mutant CRC.