bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations of Serum Liver Function Markers With Brain Structure, Function, and Perfusion in Healthy Young Adults
Authors: Chen Jingyao , Liu Siyu , Wang Chunli , Zhang Cun , Cai Huanhuan , Zhang Min , Si Li , Zhang Shujun , Xu Yuanhong , Zhu Jiajia , Yu Yongqiang
Published: February 2021

Background: Previous neuroimaging studies have demonstrated brain abnormalities in patients with hepatic diseases. However, the identified liver–brain associations are largely limited to disease-affected populations, and the nature and extent of such relations in healthy subjects remain unclear. We hypothesized that serum liver function markers within a normal level would affect brain properties.

Method: One hundred fifty-seven healthy young adults underwent structural, resting-state functional, and arterial spin labeling MRI scans. Gray matter volume (GMV), regional homogeneity (ReHo), and cerebral blood flow (CBF) analyses were performed to assess brain structure, function, and perfusion, respectively. Peripheral venous blood samples were collected to measure serum liver function markers. Correlation analyses were conducted to test potential associations between liver function markers and brain imaging parameters.

Results: First, serum proteins showed relations to brain structure characterized by higher albumin associated with increased GMV in the parahippocampal gyrus and amygdala and lower globulin and a higher albumin/globulin ratio with increased GMV in the olfactory cortex and parahippocampal gyrus. Second, serum bilirubin was linked to brain function characterized by higher bilirubin associated with increased ReHo in the precuneus, middle cingulate gyrus, inferior parietal lobule, and supramarginal gyrus and decreased ReHo in the caudate nucleus. Third, serum alanine transaminase (ALT) was related to brain perfusion characterized by higher ALT associated with increased CBF in the superior frontal gyrus and decreased CBF in the middle occipital gyrus, angular gyrus, precuneus, and middle temporal gyrus. More importantly, we found that CBF in the superior frontal gyrus was a significant mediator of the association between serum ALT level and working memory performance.

Conclusion: These findings may not only expand existing knowledge about the relationship between the liver and the brain but also have clinical implications for studying brain impairments secondary to liver diseases as well as providing potential neural targets for their diagnosis and treatment.
Low-Cost, Accurate, Effective Treatment of Hypertensive Cerebral Hemorrhage With Three-Dimensional Printing Technology
Authors: Li Ke , Ding Xiangqian , Wang Qingbo , Fan Gangxian , Guo Wei , Li Chenglong , Li Meng , Li Zefu
Published: February 2021

Background: Hypertensive intracerebral hemorrhage (HICH) is an acute, severe neurosurgical disease. Puncture drainage of the hematoma has gradually been accepted as a surgical treatment for HICH because of its minimally invasive nature. The precision of the puncture is extremely high because of particular physiological functions. This study was performed to explore the effect of a navigation mold created by three-dimensional printing (3DP) technology in the surgical treatment of HICH.

Material and methods: We conducted a retrospective analysis of all consecutive patients with ICH treated with minimally invasive surgery using 3DP navigation or craniotomy to remove the hematoma through a small bone window at the Binzhou Medical University Hospital from June 2017 to March 2019. In total, 61 patients were treated with minimally invasive surgery using 3DP navigation (3DP group), and 67 patients were treated with craniotomy to remove the hematoma through a small bone window (craniotomy group). A comparative study of the two groups was conducted to assess the preoperative and postoperative conditions.

Results: The duration of the surgery was significantly longer in the craniotomy group than in the 3DP group (3.27 ± 1.14 h vs. 1.52 ± 0.23 h). Postoperative complication rates were significantly lower in the 3DP group than in the craniotomy group (18.0 vs. 34.3%). Moreover, the rate of patients with a Glasgow Outcome Scale score ≥4 points was not statistically significantly different in the two groups.

Conclusion: Minimally invasive surgery assisted by 3DP navigation to treat patients with HICH appears to be safe and effective. The 3DP technique may improve the individualization and accuracy of the surgery.
Event-Related Potential Correlates of Valence, Arousal, and Subjective Significance in Processing of an Emotional Stroop Task
Authors: Imbir Kamil K. , Duda-Goławska Joanna , Pastwa Maciej , Jankowska Marta , Żygierewicz Jarosław
Published: February 2021

The present study is the first to measure event-related potentials associated with the processing of the emotional Stroop task (EST) with the use of an orthogonal factorial manipulation for emotional valence, arousal, and subjective significance (the importance of the current experience for goals and plans for the future). The current study aimed to investigate concurrently the role of the three dimensions describing the emotion-laden words for interference control measured in the classical version of the EST paradigm. The results showed that reaction times were affected by the emotional valence of presented words and the interactive effect of valence and arousal. The expected emotional arousal effect was only found in behavioral results for neutrally valenced words. Electrophysiological results showed valence and subjective significance correlated with the amplitude differences in the P2 component. Moreover, the amplitude of the N450 component varied with the level of subjective significance. This study also demonstrated that exploratory event-related potential analysis provides additional information beyond the classical component-based analysis. The obtained results show that cognitive control effects in the EST may be altered by manipulation in the subjective significance dimension.
Infantile Iron Deficiency Affects Brain Development in Monkeys Even After Treatment of Anemia
Authors: Vlasova Roza M. , Wang Qian , Willette Auriel , Styner Martin A. , Lubach Gabriele R. , Kling Pamela J. , Georgieff Michael K. , Rao Raghavendra B. , Coe Christopher L.
Published: February 2021

A high percent of oxidative energy metabolism is needed to support brain growth during infancy. Unhealthy diets and limited nutrition, as well as other environmental insults, can compromise these essential developmental processes. In particular, iron deficiency anemia (IDA) has been found to undermine both normal brain growth and neurobehavioral development. Even moderate ID may affect neural maturation because when iron is limited, it is prioritized first to red blood cells over the brain. A primate model was used to investigate the neural effects of a transient ID and if deficits would persist after iron treatment. The large size and postnatal growth of the monkey brain makes the findings relevant to the metabolic and iron needs of human infants, and initiating treatment upon diagnosis of anemia reflects clinical practice. Specifically, this analysis determined whether brain maturation would still be compromised at 1 year of age if an anemic infant was treated promptly once diagnosed. The hematology and iron status of 41 infant rhesus monkeys was screened at 2-month intervals. Fifteen became ID; 12 met clinical criteria for anemia and were administered iron dextran and B vitamins for 1–2 months. MRI scans were acquired at 1 year. The volumetric and diffusion tensor imaging (DTI) measures from the ID infants were compared with monkeys who remained continuously iron sufficient (IS). A prior history of ID was associated with smaller total brain volumes, driven primarily by significantly less total gray matter (GM) and smaller GM volumes in several cortical regions. At the macrostructual level, the effect on white matter volumes (WM) was not as overt. However, DTI analyses of WM microstructure indicated two later-maturating anterior tracts were negatively affected. The findings reaffirm the importance of iron for normal brain development. Given that brain differences were still evident even after iron treatment and following recovery of iron-dependent hematological indices, the results highlight the importance of early detection and preemptive supplementation to limit the neural consequences of ID.
Parkinson’s Disease: Can Targeting Inflammation Be an Effective Neuroprotective Strategy?
Authors: Gundersen Vidar
Published: February 2021

The reason why dopamine neurons die in Parkinson’s disease remains largely unknown. Emerging evidence points to a role for brain inflammation in neurodegeneration. Essential questions are whether brain inflammation happens sufficiently early so that interfering with this process can be expected to slow down neuronal death and whether the contribution from inflammation is large enough so that anti-inflammatory agents can be expected to work. Here I discuss data from human PD studies indicating that brain inflammation is an early event in PD. I also discuss the role of T-lymphocytes and peripheral inflammation for neurodegeneration. I critically discuss the failure of clinical trials targeting inflammation in PD.
Optimized Inner-Volume 3D TSE for High-Resolution Vessel Wall Imaging of Intracranial Perforating Arteries at 7T
Authors: Kong Qingle , Wu Yue , Weng Dehe , An Jing , Zhuo Yan , Zhang Zihao
Published: February 2021

The impairment of microvessels can lead to neurologic diseases such as stroke and vascular dementia. The imaging of lumen and vessel wall of perforating arteries requires an extremely high resolution due to their small caliber size. Current imaging techniques have the difficulty in observing the wall of perforating arteries. In this study, we developed a 3D inner-volume (IV) TSE (SPACE) sequence with optimized 2D spatially selective excitation (SSE) RF pulses. The optimized SSE RF pulses were designed through a series of optimization including iterative RF pulse design, trajectory optimization, and phase convention of Carr-Purcell-Meiboom-Gill (CPMG) condition to meet the perforating arteries imaging demands. High resolution of isotropic 0.30 mm within 10 min was achieved for the black- blood images of lenticulostriate artery (LSA). The LSA lumen and vessel wall were imaged by the IV-SPACE sequence simultaneously. Images obtained by the optimized RF pulse has fewer aliasing artifacts from outside of ROI than the traditional pulse. The IV-SPACE images showed clearer delineation of vessel wall and lumen of LSA than conventional SPACE images. IV-SPACE might be a promising method for detecting microvasculopathies of cerebral vascular diseases.
Local Differences in Cortical Excitability – A Systematic Mapping Study of the TMS-Evoked N100 Component
Authors: Roos Daniela , Biermann Lea , Jarczok Tomasz A. , Bender Stephan
Published: February 2021

Transcranial magnetic stimulation (TMS) with simultaneous electroencephalography applied to the primary motor cortex provides two parameters for cortical excitability: motor evoked potentials (MEPs) and TMS-evoked potentials (TEPs). This study aimed to evaluate the effects of systematic coil shifts on both the TEP N100 component and MEPs in addition to the relationship between both parameters. In 12 healthy adults, the center of a standardized grid was fixed above the hot spot of the target muscle of the left primary motor cortex. Twelve additional positions were arranged in a quadratic grid with positions between 5 and 10 mm from the hot spot. At each of the 13 positions, TMS single pulses were applied. The topographical maximum of the resulting N100 was located ipsilateral and slightly posterior to the stimulation site. A source analysis revealed an equivalent dipole localized more deeply than standard motor cortex coordinates that could not be explained by a single seeded primary motor cortex dipole. The N100 topography might not only reflect primary motor cortex activation, but also sum activation of the surrounding cortex. N100 amplitude and latency decreased significantly during stimulation anterior-medial to the hot spot although MEP amplitudes were smaller at all other stimulation sites. Therefore, N100 amplitudes might be suitable for detecting differences in local cortical excitability. The N100 topography, with its maximum located posterior to the stimulation site, possibly depends on both anatomical characteristics of the stimulated cortex and differences in local excitability of surrounding cortical areas. The less excitable anterior cortex might contribute to a more posterior maximum. There was no correlation between N100 and MEP amplitudes, but a single-trial analysis revealed a trend toward larger N100 amplitudes in trials with larger MEPs. Thus, functionally efficient cortical excitation might increase the probability of higher N100 amplitudes, but TEPs are also generated in the absence of MEPs.
The Neurobiology of Selenium: Looking Back and to the Future
Authors: Schweizer Ulrich , Bohleber Simon , Zhao Wenchao , Fradejas-Villar Noelia
Published: February 2021

Eighteen years ago, unexpected epileptic seizures in Selenop-knockout mice pointed to a potentially novel, possibly underestimated, and previously difficult to study role of selenium (Se) in the mammalian brain. This mouse model was the key to open the field of molecular mechanisms, i.e., to delineate the roles of selenium and individual selenoproteins in the brain, and answer specific questions like: how does Se enter the brain; which processes and which cell types are dependent on selenoproteins; and, what are the individual roles of selenoproteins in the brain? Many of these questions have been answered and much progress is being made to fill remaining gaps. Mouse and human genetics have together boosted the field tremendously, in addition to traditional biochemistry and cell biology. As always, new questions have become apparent or more pressing with solving older questions. We will briefly summarize what we know about selenoproteins in the human brain, glance over to the mouse as a useful model, and then discuss new questions and directions the field might take in the next 18 years.
The Mechanical Basis of Memory – the MeshCODE Theory
Authors: Goult Benjamin T.
Published: February 2021

One of the major unsolved mysteries of biological science concerns the question of where and in what form information is stored in the brain. I propose that memory is stored in the brain in a mechanically encoded binary format written into the conformations of proteins found in the cell-extracellular matrix (ECM) adhesions that organise each and every synapse. The MeshCODE framework outlined here represents a unifying theory of data storage in animals, providing read-write storage of both dynamic and persistent information in a binary format. Mechanosensitive proteins that contain force-dependent switches can store information persistently, which can be written or updated using small changes in mechanical force. These mechanosensitive proteins, such as talin, scaffold each synapse, creating a meshwork of switches that together form a code, the so-called MeshCODE. Large signalling complexes assemble on these scaffolds as a function of the switch patterns and these complexes would both stabilise the patterns and coordinate synaptic regulators to dynamically tune synaptic activity. Synaptic transmission and action potential spike trains would operate the cytoskeletal machinery to write and update the synaptic MeshCODEs, thereby propagating this coding throughout the organism. Based on established biophysical principles, such a mechanical basis for memory would provide a physical location for data storage in the brain, with the binary patterns, encoded in the information-storing mechanosensitive molecules in the synaptic scaffolds, and the complexes that form on them, representing the physical location of engrams. Furthermore, the conversion and storage of sensory and temporal inputs into a binary format would constitute an addressable read-write memory system, supporting the view of the mind as an organic supercomputer.
Immune Checkpoint Inhibitors in Triple Negative Breast Cancer Treatment: Promising Future Prospects
Authors: Thomas Remy , Al-Khadairi Ghaneya , Decock Julie
Published: February 2021

Immunotherapy has emerged as the fifth pillar of cancer treatment alongside surgery, radiotherapy, chemotherapy, and targeted therapy. Immune checkpoint inhibitors are the current superheroes of immunotherapy, unleashing a patient’s own immune cells to kill tumors and revolutionizing cancer treatment in a variety of cancers. Although breast cancer was historically believed to be immunologically silent, treatment with immune checkpoint inhibitors has been shown to induce modest responses in metastatic breast cancer. Given the inherent heterogeneity of breast tumors, this raised the question whether certain breast tumors might benefit more from immune-based interventions and which cancer cell-intrinsic and/or microenvironmental factors define the likelihood of inducing a potent and durable anti-tumor immune response. In this review, we will focus on triple negative breast cancer as immunogenic breast cancer subtype, and specifically discuss the relevance of tumor mutational burden, the plethora and diversity of tumor infiltrating immune cells in addition to the immunoscore, the presence of immune checkpoint expression, and the microbiome in defining immune checkpoint blockade response. We will highlight the current immune checkpoint inhibitor treatment options, either as monotherapy or in combination with standard-of-care treatment modalities such as chemotherapy and targeted therapy. In addition, we will look into the potential of immunotherapy-based combination strategies using immune checkpoint inhibitors to enhance both innate and adaptive immune responses, or to establish a more immune favorable environment for cancer vaccines. Finally, the review will address the need for unambiguous predictive biomarkers as one of the main challenges of immune checkpoint blockade. To conclude, the potential of immune checkpoint blockade for triple negative breast cancer treatment could be enhanced by exploration of aforementioned factors and treatment strategies thereby providing promising future prospects.
Clinical Implication of Systemic Immune-Inflammation Index and Prognostic Nutritional Index in Skull Base Chordoma Patients
Authors: Li Mingxuan , Bai Jiwei , Wang Shuai , Zhai Yixuan , Zhang Shuheng , Li Chuzhong , Du Jiang , Zhang Yazhuo
Published: February 2021

Inflammation associated markers and nutritional indexes are associated with survival, and act as novel prognostic grading systems in patients with cancer, though the role of these markers in chordoma remains unclear. The current study aimed to characterize systemic immune-inflammation index (SII) and prognostic nutritional index (PNI), and their relationship with clinicopathological data and survival in skull base chordoma. Our retrospective study enrolled 183 patients with primary skull base chordoma who received surgical treatment. Clinicopathological data and preoperative blood tests including neutrophil, lymphocyte, platelet counts and albumin level were collected from medical records. Neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), SII, PNI were calculated and the optimal cut-off values of these markers were used for further survival analysis via Kaplan–Meier survival analysis and Cox proportional hazards regression analysis. The value of NLR, PLR, SII, and PNI in skull base chordoma ranged from 0.44–6.48, 45.36–273.94, 113.37–1761.45, and 43.40–70.65, respectively. PNI was significantly correlated with patients' sex (p = 0.005) and age (p = 0.037). SII was positively correlated with NLR and PLR, but negatively correlated with PNI. The median overall survival (OS) time was 74.0 months and Kaplan–Meier survival analysis indicated that all four indexes were associated with OS. Multivariable Cox proportional hazards regression analysis identified that high SII was an independent prognostic factor for poor OS. More importantly, patients with high SII and PNI had the worst outcomes and combined use of SII and PNI increased the predictive ability for patients' survival in skull base chordoma. Our results suggest SII and PNI may be effective prognostic indicators of OS for patients with primary skull base chordoma after surgical resection.
High Nuclear Expression of Yes-Associated Protein 1 Correlates With Metastasis in Patients With Breast Cancer
Authors: Cha Yoon Jin , Bae Soong June , Kim Dooreh , Ahn Sung Gwe , Jeong Joon , Koo Ja Seung , Yoo Tae-Kyung , Park Woo-Chan , Lee Ahwon , Yoon Chang Ik
Published: February 2021

Background

Yes-associated protein 1 (YAP1) is a transcription factor regulated by the Hippo pathway and functions as an oncogene in various solid tumors under dysregulated Hippo pathway. However, the role of YAP1 in breast cancer remains controversial. Here, we investigated the impact of different levels of nuclear YAP1 expression on the clinical characteristics and survival outcome in patients with breast cancer.

Patients and Methods

Retrospectively obtained 455 breast tumor samples at Gangnam Severance Hospital were examined for YAP1 expression by immunohistochemistry, and the clinical data were analyzed. External validation was performed using a retrospective cohort and tissues in 482 patients from Severance Hospital.

Results

High nuclear YAP1 expression was associated with hormone receptor negativity and aggressive tumor behavior, including lymph node metastasis, high Ki67 labeling index and inferior distant metastasis-free survival (DMFS, hazard ratio [HR] 2.271, 95% confidence intervals [CIs] 1.109–4.650, P = 0.0249), and also confirmed inferior disease free survival (HR 3.208, 95% CIs 1.313–7.833, P = 0.0105) in external validation cohort. In patients with triple-negative breast cancer (TNBC), high nuclear YAP1 expression was an independent significant determinant of poor DMFS (HR 2.384, 95% CIs 1.055–5.386, P = 0.0367).

Conclusion

Our findings suggest that nuclear YAP1 expression is a biomarker of adverse prognosis and a potential therapeutic target in patients with breast cancer, especially in TNBC.
Precision Medicine Approaches to Overcome Resistance to Therapy in Head and Neck Cancers
Authors: Ortiz-Cuaran Sandra , Bouaoud Jebrane , Karabajakian Andy , Fayette Jérôme , Saintigny Pierre
Published: February 2021

Head and neck squamous cell carcinoma (HNSCC) is the sixth most incident cancer worldwide. More than half of HNSCC patients experience locoregional or distant relapse to treatment despite aggressive multimodal therapeutic approaches that include surgical resection, radiation therapy, and adjuvant chemotherapy. Before the arrival of immunotherapy, systemic chemotherapy was previously employed as the standard first-line protocol with an association of cisplatin or carboplatin plus 5-fluorouracil plus cetuximab (anti-EFGR antibody). Unfortunately, acquisition of therapy resistance is common in patients with HNSCC and often results in local and distant failure. Despite our better understanding of HNSCC biology, no other molecular-targeted agent has been approved for HNSCC. In this review, we outline the mechanisms of resistance to the therapeutic strategies currently used in HNSCC, discuss combination treatment strategies to overcome them, and summarize the therapeutic regimens that are presently being evaluated in early- and late-phase clinical trials.
Decreased DUSP26 Expression Promotes Malignant Behavior in Glioblastoma Cells via Deregulation of MAPK and Akt Signaling Pathway
Authors: Chen Jiajia , Zeng Yuecan , Wu Rong , Xuan Ying , Jiang Min , Teng Hao
Published: February 2021

Purpose

Dual-specificity protein phosphatases 26 (DUSP26) is a recently identified phosphatase enzyme that regulates MAPK and Akt signaling pathways. The role of DUSP26 in the development and prognosis of high-grade gliomas (HGGs) and primary glioblastoma (GBM) has remained unclear and was the focus of this study.

Materials and Methods

The prognostic value of DUSP26 was assessed using retrospective analyses using online data sets and tissue microarray of HGGs. U251 and U87 cells modified to overexpress DUSP26 were utilized to study the role of DUSP26 in cell growth, migration, and cell apoptosis analyzed by CCK-8 assay, clonogenic, transwell migration, and TUNEL, respectively. The phosphorylation of proteins in MAPK and Akt signaling pathways was assayed by Western blot and immunofluorescence assays.

Results

Analyses using available online data sets and tissue microarray showed that DUSP26 is down-regulated in high-grade gliomas and GBM as compared to normal brain. Stratification of glioma patients based on DUSP26 expression level showed an inverse correlation between DUSP26 expression and patient survival. At the cellular level, DUSP26 overexpression led to decreased cell proliferation, migration, and senescence in U251 and U87 cells, whereas apoptosis was increased as compared to corresponding controls. Interestingly, the biologic effects of DUSP26 overexpression were associated with the dephosphorylation of proteins in the MAPK and Akt signaling pathways.

Conclusions

These findings suggest that the loss of DUSP26 expression, seen in a subset of high-grade gliomas and GBM patients, facilitates malignant behavior; and with inverse correlation between its expression levels with patient survival. DUSP26 can serve as an independent prognostic factor.
Immunotherapy-Associated Pancreatic Adverse Events: Current Understanding of Their Mechanism, Diagnosis, and Management
Authors: Liu Ya , Zhang Hao , Zhou Li , Li Weichun , Yang Le , Li Wen , Li Kezhou , Liu Xubao
Published: February 2021

Immune checkpoint inhibitors (ICIs) such as anti-programmed death-1 (PD-1) and its ligand PD-L1 and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibodies, are involved in T cell-mediated immune response augmentation and promote anti-tumor immunity. Cancer patients treated with combination of immunotherapy, chemotherapy, radiotherapy, and targeted therapy exhibit superior clinical outcomes and tolerance compared with patients treated with monotherapies. However, immutherapy is associated with several concomitant immune-related adverse events (irAEs). For instance, IrAEs interferes with function of gastrointestinal tract, endocrine, dermatological, nervous system and musculoskeletal systems. ICIs-associated pancreatic injury might causes decrease in endocrine and exocrine pancreatic function, resulting in metabolic and nutritional disorders. Clinicians who administer immune checkpoint inhibitors to cancer patients are diagnosed with hyperglycemia, abdominal pain and steatorrhea. Currently, the precise mechanism of ICIs-associated pancreatic injury has not been fully explored. This paper summarizes incidence, diagnosis, clinical characteristics, potential mechanisms, and treatment management patterns of ICIs-associated pancreatic AEs based on previous studies. In addition, possible management approaches of these adverse effects are presented in this paper. in the findings summarized in this paper lay a basis for management of ICIs-associated pancreatic AEs and expanding future immunotherapy applications.
Adjuvant Radiation in Older Patients With Glioblastoma: A Retrospective Single Institution Analysis
Authors: Lee Jessica W. , Kirkpatrick John P. , McSherry Frances , Herndon James E. , Lipp Eric S. , Desjardins Annick , Randazzo Dina M. , Friedman Henry S. , Ashley David M. , Peters Katherine B. , Johnson Margaret O.
Published: February 2021

Objectives

Standard 6-week and hypofractionated 3-week courses of adjuvant radiation therapy (RT) are both options for older patients with glioblastoma (GBM), but deciding the optimal regimen can be challenging. This analysis explores clinical factors associated with selection of RT course, completion of RT, and outcomes following RT.

Materials and Methods

This IRB-approved retrospective analysis identified patients ≥70 years old with GBM who initiated adjuvant RT at our institution between 2004 and 2016. We identified factors associated with standard or hypofractionated RT using the Cochran-Armitage trend test, estimated time-to-event endpoints using the Kaplan-Meier method, and found predictors of overall survival (OS) using Cox proportional hazards models.

Results

Sixty-two patients with a median age of 74 (range 70–90) initiated adjuvant RT, with 43 (69%) receiving standard RT and 19 (31%) receiving hypofractionated RT. Selection of short-course RT was associated with older age (p = 0.04) and poor KPS (p = 0.03). Eight (13%) patients did not complete RT, primarily for hospice care due to worsening symptoms. After a median follow-up of 37 months, median OS was 12.3 months (95% CI 9.0–15.1). Increased age (p < 0.05), poor KPS (p < 0.0001), lack of MGMT methylation (p < 0.05), and lack of RT completion (p < 0.0001) were associated with worse OS on multivariate analysis. In this small cohort, GTV size and receipt of standard or hypofractionated RT were not associated with OS.

Conclusions

In this cohort of older patients with GBM, age and KPS was associated with selection of short-course or standard RT. These regimens had similar OS, though a subset of patients experienced worsening symptoms during RT and discontinued treatment. Further investigation into predictors of RT completion and survival may help guide adjuvant therapies and supportive care for older patients.
Neonates and Young Infants With COVID-19 Presented With Sepsis-Like Syndrome: A Retrospective Case Controlled Study
Authors: Hassan Manasik , Khalil Ahmed , Magboul Samar , Alomari Ohood , Abdalla Tasneim , Alsliman Hafez , Alhothi Abdulla , Al Maslamani Eman , AlAmri Mohammed , Soliman Ashraf
Published: February 2021

Objective: We aimed to describe the presentations and biochemical characteristics of sepsis-like syndrome (SLS) in infants aged <2 months who tested positive for SARS-CoV-2-in comparison to those in the same age group who were SARS-CoV-2-negative.

Background: COVID-19 presents with a spectrum of manifestations, and children seem to have a favorable clinical course compared to other age groups. Limited data are available for symptomatic infants.

Design: This was a case-controlled single-institution retrospective study on infants aged <2 months admitted with SLS between 1 April 2020 and 1 July 2020. These infants were divided into 2 groups: Group 1 (n = 41), infants with positive nasal/oropharyngeal swab polymerase chain reaction (PCR) results for SARS-CoV-2; and Group 2 (n = 40), infants with negative PCR results for SARS-CoV-2 (control group). Details between both groups were reviewed and analyzed.

Outcome: The clinical and laboratory data for SARS-CoV-2 -positive infants who presented with SLS may differ from those for infants with SLS who tested negative for SARS-CoV-2.

Results: Overall, 105 infants were admitted with clinical sepsis: 41 were SARS-CoV-2-positive, and 64 were negative. Fever was present in 90% of SARS-CoV-2-positive infants vs. 80% of the negative group. SARS-CoV-2-positive infants had a higher incidence of nasal congestion and cough (39 and 29%, respectively) compared to the SARS-CoV-2-negative group (20 and 3%, respectively) (P < 0.05). Poor feeding and hypoactivity occurred more frequently in the SARS-CoV-2-negative group (58 and 45%, respectively) than in the SARS-CoV-2-positive group (22 and 12%, respectively, P < 0.004). Sepsis workup, including lumbar puncture, was performed in 67% and partial septic workup was performed in 23% of the SARS-CoV-2-positive infants. Full sepsis workup was performed in 92% of the SARS-CoV-2-negative group. Cerebrospinal fluid (CSF) cultures were negative in 26/27SARS-CoV-2-positive infants (an infant had Klebsiella meningitis). All the SARS-CoV-2-negative infants had negative CSF cultures. Blood culture was negative in both groups. Urine culture showed bacterial growth in 9 infants with SARS-CoV-2-negative sepsis.

Conclusions: Our study showed that respiratory symptoms (cough and nasal congestion) were more prominent in the SARS-CoV-2-positive group, while poor feeding and hypoactivity were reported more frequently in the negative group. However, the clinical differentiation between COVID-19 disease and sepsis in such age groups is difficult. Therefore, screening young infants with SLS for SARS-CoV-2- is necessary during this pandemic.
Case Report: Low Dose of Valsartan/Sacubitril Leads to Successful Reversal of Acute Heart Failure in Chemotherapy-Induced Cardiomyopathy
Authors: Lo Shih-Hsing , Liu Yi-Ching , Dai Zen-Kong , Chen I-Chen , Wu Yen-Hsien , Hsu Jong-Hau
Published: February 2021

Valsartan/sacubitril is a new agent approved for the treatment of chronic heart failure in adults, with a combination of angiotensin receptor inhibitor and neprilysin inhibitor. However, the benefit of valsartan/sacubitril in pediatric patients is unknown. We herein report its clinical benefit in a case of acute decompensated heart failure in chemotherapy-induced cardiomyopathy. This case suggests that in children with acute heart failure refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
The Serum Immunoglobulin E Level: Is There a Relationship With the Clinical Course of the Gianotti-Crosti Syndrome?
Authors: Bassi Andrea , Pedaci Fausto , Oranges Teresa , Azzari Chiara , Galli Luisa , Ricci Silvia , Filippeschi Cesare , Venturini Elisabetta
Published: February 2021

Background: Gianotti Crosti syndrome (GCS) is a self-healing condition with a spontaneous resolution in 2–6 weeks but, even if rarely, recurrent episodes have been reported.

Objective: The aim of this observational study is to investigate serum Immunoglobulin E (IgE) level in children with GCS, evaluating if there is a relationship between IgE level and clinical course of the disease.

Methods: Children with GCS diagnosed at a tertiary care children's university hospital between June 2018 and November 2019 were prospectively enrolled. Demographic, clinical and hematochemical data of children investigated were collected. In particular, IgE level were investigated at symptoms onset and, if available, at the following blood tests. Patients were divided in 2 groups on the bases of the clinical course: children with a chronic relapsing course and children who did not present any relapse.

Results: Among 29 patients enrolled in this study, 14 (48.3%) children had a chronic relapsing course and 15 (51.7%) did not present any relapse. A statistically significant difference was present considering the length of the disease: 210 days (IQR: 161.25–255) for patients with a chronic relapsing course compared to 40 days (IQR: 30–75) for the other group (p < 0.0001). About the median IgE level in the 2 groups, a value about 10 time higher was found in children with chronic course compared to the other group (1,144 vs. 116 U/mL) with a statistically significant difference (p < 0.0001).

Conclusion: Despite the study limitations, a significant correlation between higher IgE levels and chronic-relapsing course of the GCS can be assumed.
Prospective: Evolution of Chinese Medicine to Treat COVID-19 Patients in China
Authors: Wu Jieya , Sun Baoguo , Hou Li , Guan Fulan , Wang Liyuan , Cheng Peikwen , Scobell Sophia , Cheng Yung-Chi , Lam Wing
Published: February 2021

During the outbreak of the novel coronavirus disease (COVID-19), the Chinese government took a series of public health measures to tackle the outbreak and recommended six traditional Chinese medicine (TCM) evolved formulas, collectively referred to as “3-drugs-3-formulas”, for the treatment. In this prospective article, we will discuss how these six formulas evolved from TCM and what their underlying mechanisms of actions may be by evaluating the historical usage of the component formulas, the potential targeted pathways for the individual herbs used by STAR (signal transduction activity response) database from our laboratory, and the pathogenesis of COVID-19. Five of the six recommended formulas are administered orally, while the sixth is taken as an injection. Five classic categories of herbs in the six formulas including “Qing-Re”, “Qu-Shi”, “Huo-Xue”, “Bu-Yi” and “Xing-Qi” herbs are used based on different stages of disease. All five oral formulas build upon the core formula Maxingshigan Decoction (MD) which has anti-inflammatory and perhaps antiviral actions. While MD can have some desired effects, it may not be sufficient to treat COVID-19 on its own; consequently, complementary classic formulas and/or herbs have been added to potentiate each recommended formula’s anti-inflammatory, and perhaps anti-renin-angiotensin system (RAS)-mediated bradykinin storm (RBS) and antiviral effects to address the unique medical needs for different stages of COVID-19. The key actions of these formulas are likely to control systemic inflammation and/or RBS. The usage of Chinese medicine in the six formulas is consistent with the pathogenesis of COVID-19. Thus, an integrative systems biology approach—combining botanical treatments of conventional antiviral, anti-inflammatory or anti-RBS drugs to treat COVID-19 and its complications – should be explored.
Common Endothelial Nitric Oxide Synthase Single Nucleotide Polymorphisms are not Related With the Risk for Restless Legs Syndrome
Authors: Jiménez-Jiménez Félix Javier , Agúndez Blanca G. , Gómez-Tabales Javier , Alonso-Navarro Hortensia , Turpín-Fenoll Laura , Millán-Pascual Jorge , Díez-Fairén Mónica , Álvarez Ignacio , Pastor Pau , Calleja Marisol , García-Ruiz Rafael , Navarro-Muñoz Santiago , Recio-Bermejo Marta , Plaza-Nieto José Francisco , García-Albea Esteban , García-Martín Elena , Agúndez José A. G.
Published: February 2021

Because nitric oxide and endothelial dysfunction could play a role in the pathogenesis of idiopathic restless legs syndrome (RLS), as was suggested by some preliminary data, we investigated the possible association between the rs2070744 variants in the endothelial nitric oxide synthase (eNOS or NOS3) gene (chromosome 7q36.1) and the risk for RLS in a Caucasian Spanish population. We assessed the frequencies of NOS3 single nucleotide polymorphisms (SNPs) rs2070744, rs1799983, and rs79467411 genotypes and allelic variants in 273 patients with idiopathic RLS and 325 healthy controls using a TaqMan-based qPCR assay. We also analyzed the possible influence of genotype frequency on age at onset of RLS symptoms, gender, family history of RLS, and response to drugs commonly used in the treatment of RLS such as dopaminergic drugs, clonazepam, and GABAergic drugs. The frequencies of genotypes and allelic variants were not associated with the risk for RLS and were not influenced by gender, age, and positive family history of RLS. We identified weak statistical associations of the SNP rs1799983 with the response to dopamine agonists (Pc = 0.018 for the rs1799983 G/T genotype) and of the SNP rs79467411 with the response to clonazepam (Pc = 0.018 for the rs79467411 G allele), although these findings should be cautiously interpreted and require further confirmation. These associations aside, our findings suggest that common NOS3 SNPs are not associated with the risk for idiopathic RLS in Caucasian Spanish people.
Gastroprotective Effect of Sinapic Acid on Ethanol-Induced Gastric Ulcers in Rats: Involvement of Nrf2/HO-1 and NF-κB Signaling and Antiapoptotic Role
Authors: Raish Mohammad , Shahid Mudassar , Bin Jardan Yousef A. , Ansari Mushtaq Ahmad , Alkharfy Khalid M. , Ahad Abdul , Abdelrahman Ibrahim Abdelsalam , Ahmad Ajaz , Al-Jenoobi Fahad I.
Published: February 2021

Background: In the current study, we evaluated the therapeutic potential of sinapic acid (SA) in terms of the mechanism underlying its gastroprotective action against ethanol-induced gastric ulcers in rats.

Methods: These effects were examined through gross macroscopic evaluation of the stomach cavity [gastric ulcer index (GUI)], alteration in pH, gastric juice volume, free acidity, total acidity, total gastric wall mucus, and changes in PGE2. In addition, we evaluated lipid peroxidation (malondialdehyde), antioxidant systems (catalase and glutathione), inflammatory markers [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and myeloperoxidase (MPO)], apoptotic markers (caspase-3, Bax, and Bcl-2), nuclear factor-κB [NF-κB (p65)], NO levels, and histopathological staining (H and E and PAS).

Results: In rats with ethanol-induced ulcers, pre-treatment with SA (40 mg/kg p. o.) decreased the sternness of ethanol-induced gastric mucosal injuries by decreasing the GUI, gastric juice volume, free acidity, and total acidity. In addition, the pH and total gastric mucosa were increased, together with histopathological alteration, neutrophil incursion, and increases in PGE2 and NO2. These effects were similar to those observed for omeprazole, a standard anti-ulcer drug. SA was shown to suppress gastric inflammation through decreasing TNF-α, IL-6, and MPO, as well as curbing gastric oxidative stress through the inhibition of lipid peroxidation (MDA) and restoration of depleted glutathione and catalase activity. SA inhibited Bcl-2-associated X (Bax) and caspase-3 activity, and restored the antiapoptotic protein Bcl-2; these findings indicate the antiapoptotic potential of SA, leading to enhanced cell survival. SA also repressed NF-κB signaling and increased IκBα. Moreover, SA upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), thereby restoring depleted antioxidant defense enzymes and implicating the NRF2/HO-1 signaling pathways.

Conclusion: These results suggest that the prophylactic administration of SA (40 mg/kg) can ameliorate ethanol-induced gastric ulcers in rats primarily via the modulation of Nrf2/HO-1 and NF-κB signaling and subsequent enhancement of cell viability.
Sodium Transporters in Human Health and Disease
Authors: Gagnon Kenneth B. , Delpire Eric
Published: February 2021

Sodium (Na+) electrochemical gradients established by Na+/K+ATPase activity drives the transport of ions, minerals, and sugars in both excitable and non-excitable cells. Na+-dependent transporters can move these solutes in the same direction (cotransport) or in opposite directions (exchanger) across both the apical and basolateral plasma membranes of polarized epithelia. In addition to maintaining physiological homeostasis of these solutes, increases and decreases in sodium may also initiate, directly or indirectly, signaling cascades that regulate a variety of intracellular post-translational events. In this review, we will describe how the Na+/K+ATPase maintains a Na+gradient utilized by multiple sodium-dependent transport mechanisms to regulate glucose uptake, excitatory neurotransmitters, calcium signaling, acid-base balance, salt-wasting disorders, fluid volume, and magnesium transport. We will discuss how several Na+-dependent cotransporters and Na+-dependent exchangers have significant roles in human health and disease. Finally, we will discuss how each of these Na+-dependent transport mechanisms have either been shown or have the potential to use Na+in a secondary role as a signaling molecule.
Traditional Versus Velocity-Based Resistance Training in Competitive Female Cyclists: A Randomized Controlled Trial
Authors: Montalvo-Pérez Almudena , Alejo Lidia B. , Valenzuela Pedro L. , Gil-Cabrera Jaime , Talavera Eduardo , Lucia Alejandro , Barranco-Gil David
Published: February 2021

We assessed the effects of a short-term velocity-based resistance training (VBRT, where exercise intensity is individualized based on the loads and repetitions that maximize power output) program compared with traditional resistance training (TRT, where the same number of repetitions and relative load are used for every individual) on body composition, muscle strength/power, and endurance performance in competitive female cyclists. Seventeen participants were randomly assigned to 6 weeks (two sessions/week) of TRT (n = 8) or VBRT (n = 9), during which they maintained their usual endurance program. Both interventions included squat, hip thrust, and split squat exercises. Training loads were continuously registered, and outcomes were measures of muscle strength/power, body composition, and endurance performance (incremental test and 8-min time trial). No differences between TRT and VBRT groups were found for overall internal training loads during resistance training or cycling sessions (p > 0.05). Both interventions led to significant improvements in all strength/power-related outcomes, but VBRT induced greater improvements than TRT in maximum muscle strength and power as assessed with the hip thrust exercise (p < 0.05 for the group by time interaction effect). However, no significant group by time interaction effect was found for body composition or endurance performance-related outcomes. In conclusion, the addition of a short-term intervention of VBRT or TRT to the usual training regimen of competitive female cyclists improves muscle strength/power, albeit VBRT might induce superior gains on maximum strength/power for the hip thrust exercise.
RF9 Rescues Cortisol-Induced Repression of Testosterone Levels in Adult Male Macaques
Authors: Ullah Rahim , Naz Rabia , Batool Aalia , Wazir Madiha , Rahman Tanzil Ur , Nabi Ghulam , Wahab Fazal , Fu Junfen , Shahab Muhammad
Published: February 2021

Cortisol inhibits hypothalamic-pituitary-gonadal (HPG) axis whereas RF9, a potent agonist of kisspeptin receptor (GPR54) activates HPG-axis during fasting-induced stress and under normal physiological conditions. However, the effect of RF9 on the cortisol-induced repressed HPG-axis is not studied yet. This study investigated whether exogenous cortisol-induced repression of the HPG-axis can be rescued by RF9. Six intact adult male rhesus monkeys (Macaca mulatta) habituated to chair-restraint were administered hydrocortisone sodium succinate at a rate of 20 mg/kg of body weight (BW) per day for 12 days. Single blood sample was taken by venipuncture from each animal on alternate days for hormones analyses. On experimental day 12, hydrocortisone treated monkeys received a single intravenous bolus of RF9 (n = 3) and vehicle (n = 3). The animals were bled for a period of 4 h at 60 min intervals from an indwelling cannula in the saphenous vein. RF9 was administered intravenously at the dose of 0.1 mg/kg BW immediately after taking 0 min sample. Plasma cortisol and testosterone concentrations were measured by using specific enzyme immunoassays. Hydrocortisone treatment increased plasma cortisol levels (P ≤ 0.0001) and decreased plasma testosterone (P ≤ 0.0127) levels. Interestingly, compared to vehicle, RF9 treatment significantly increased plasma testosterone levels at 120 min (P ≤ 0.0037), 180 min (P ≤ 0.0016), and 240 min (P ≤ 0.0001) intervals in the hydrocortisone treated monkeys. From these results, we concluded that RF9 administration relieves the suppressed HPG-axis in term of plasma testosterone levels in the cortisol treated monkeys.