bluuebunny/crossref_metadata_2025 huggingface dataset:
Using a Robot to Treat Non-specific Low Back Pain: Results From a Two-Arm, Single-Blinded, Randomized Controlled Trial
Authors: Marín-Méndez Honorio , Marín-Novoa Patricia , Jiménez-Marín Silvia , Isidoro-Garijo Itziar , Ramos-Martínez Mercedes , Bobadilla Miriam , Mirpuri Eduardo , Martínez Alfredo
Published: September 2021

Non-specific low back pain (NSLBP) affects many people and represents a high cost for health care. Manual pressure release of myofascial trigger points is used to treat NSLBP and is very effective but difficult to standardize since it is provided by different therapists, which also suffer musculoskeletal complications from this highly repetitive activity. A robot designed for this purpose may help in reducing these problems. Here, we present data from a two-arm, single-blinded, randomized controlled clinical trial evaluating the efficiency of a therapeutic massage robot (ADAMO) in reducing NSLBP (clinicaltrials.gov, registration number: NCT04882748). Forty-four patients were randomly distributed into the two arms of the study (robot vs. control). A physician filled the Oswestry disability index (ODI) before starting the treatment and at the end of it, in a blind fashion. In addition, patients filled a visual analogue scale (VAS) after each of the 10 treatment sessions. The ODI and the VAS were analyzed as the primary and secondary outcome measures. Both treatments (robot and control) resulted in a significantly lower ODI (p < 0.05). On the other hand, robot-treated patients significantly reduced their VAS levels (p = 0.0001) whereas control treatment did not reach statistical significance. Patients of both sexes obtained similar benefits from either treatment. Overweight patients (body mass index ≥ 25kg/m2) in the robot arm benefited more from the treatment (p = 0.008) than patients with normal weight. In conclusion, the ADAMO robot is, at least, as efficient as regular treatment in reducing low back pain, and may be more beneficial for specific patients, such as those with excessive weight.
Trajectory of Long-Term Outcome in Severe Pediatric Diffuse Axonal Injury: An Exploratory Study
Authors: Lang Shih-Shan , Kilbaugh Todd , Friess Stuart , Sotardi Susan , Kim Chong Tae , Mazandi Vanessa , Zhang Bingqing , Storm Phillip B. , Heuer Gregory G. , Tucker Alexander , Ampah Steve B. , Griffis Heather , Raghupathi Ramesh , Huh Jimmy W.
Published: September 2021

Introduction: Pediatric severe traumatic brain injury (TBI) is one of the leading causes of disability and death. One of the classic pathoanatomic brain injury lesions following severe pediatric TBI is diffuse (multifocal) axonal injury (DAI). In this single institution study, our overarching goal was to describe the clinical characteristics and long-term outcome trajectory of severe pediatric TBI patients with DAI.

Methods: Pediatric patients (<18 years of age) with severe TBI who had DAI were retrospectively reviewed. We evaluated the effect of age, sex, Glasgow Coma Scale (GCS) score, early fever ≥ 38.5°C during the first day post-injury, the extent of ICP-directed therapy needed with the Pediatric Intensity Level of Therapy (PILOT) score, and MRI within the first week following trauma and analyzed their association with outcome using the Glasgow Outcome Score—Extended (GOS-E) scale at discharge, 6 months, 1, 5, and 10 years following injury.

Results: Fifty-six pediatric patients with severe traumatic DAI were analyzed. The majority of the patients were >5 years of age and male. There were 2 mortalities. At discharge, 56% (30/54) of the surviving patients had unfavorable outcome. Sixty five percent (35/54) of surviving children were followed up to 10 years post-injury, and 71% (25/35) of them made a favorable recovery. Early fever and extensive DAI on MRI were associated with worse long-term outcomes.

Conclusion: We describe the long-term trajectory outcome of severe pediatric TBI patients with pure DAI. While this was a single institution study with a small sample size, the majority of the children survived. Over one-third of our surviving children were lost to follow-up. Of the surviving children who had follow-up for 10 years after injury, the majority of these children made a favorable recovery.
Postoperative Evaluation of the Quality of Life, Depression, and Anxiety of Temporal Lobe Epilepsy Cohort: A Single Institute Experience in Indonesia
Authors: Bakhtiar Yuriz , Pratama Brilliantika Surya , Bunyamin Jacob , Arifin Muhammad Thohar , Hardian Hardian , Bintoro Aris Catur , Muttaqin Zainal
Published: September 2021

Background: Besides seizure control, quality of life (QoL) should be considered as an equally important outcome for epilepsy surgery service providers. The paucity of QoL reports from developing countries has enlarged the representation gap between wealthy countries and countries with fewer resources. In this study, we evaluated postoperative QoL in the Indonesian drug-resistant epilepsy cohort where the epilepsy surgery service faces limited resource availability.

Methods: We evaluated the QoL in patients with temporal lobe epilepsy who underwent surgery in our epilepsy surgery center in Semarang, Indonesia, from 2001 until 2015. The follow–up period started in 2018 through 2019. Postoperative QoL, depression, and anxiety were evaluated with self-reporting questionnaires including the Quality of Life in Epilepsy Inventory-31, Beck Depression Inventory-II, and Zung Self-Rating Anxiety Scales.

Results: Forty returned questionnaires were included in the analysis (male 25, 62.5%; mean age 27.6 ± 9.05 years). The seizure-free cohort (n = 22, 55.0%) reported higher scores in most QoL dimensions particularly adjustment, overall QoL, and seizure worry compared to those with persistent seizures. The overall QoL level was correlated with seizure freedom and surgery type. QoL dimensions were negatively correlated with anxiety and depression levels.

Conclusions: Postoperative seizure freedom was a major factor of postoperative QoL level. Besides seizure freedom, anxiety and depression levels were also negatively correlated with QoL levels in the Indonesian population.
Distinct and Dissociable EEG Networks Are Associated With Recovery of Cognitive Function Following Anesthesia-Induced Unconsciousness
Authors: Rokos Alexander , Mišić Bratislav , Berkun Kathleen , Duclos Catherine , Tarnal Vijay , Janke Ellen , Picton Paul , Golmirzaie Goodarz , Basner Mathias , Avidan Michael S. , Kelz Max B. , Mashour George A. , Blain-Moraes Stefanie
Published: September 2021

The temporal trajectories and neural mechanisms of recovery of cognitive function after a major perturbation of consciousness is of both clinical and neuroscientific interest. The purpose of the present study was to investigate network-level changes in functional brain connectivity associated with the recovery and return of six cognitive functions after general anesthesia. High-density electroencephalograms (EEG) were recorded from healthy volunteers undergoing a clinically relevant anesthesia protocol (propofol induction and isoflurane maintenance), and age-matched healthy controls. A battery of cognitive tests (motor praxis, visual object learning test, fractal-2-back, abstract matching, psychomotor vigilance test, digital symbol substitution test) was administered at baseline, upon recovery of consciousness (ROC), and at half-hour intervals up to 3 h following ROC. EEG networks were derived using the strength of functional connectivity measured through the weighted phase lag index (wPLI). A partial least squares (PLS) analysis was conducted to assess changes in these networks: (1) between anesthesia and control groups; (2) during the 3-h recovery from anesthesia; and (3) for each cognitive test during recovery from anesthesia. Networks were maximally perturbed upon ROC but returned to baseline 30–60 min following ROC, despite deficits in cognitive performance that persisted up to 3 h following ROC. Additionally, during recovery from anesthesia, cognitive tests conducted at the same time-point activated distinct and dissociable functional connectivity networks across all frequency bands. The results highlight that the return of cognitive function after anesthetic-induced unconsciousness is task-specific, with unique behavioral and brain network trajectories of recovery.
Neurocognitive Disorder and Emotional Symptoms in HIV+ Brazilian Elderly: Influence of Gender, Income, Diet, and Sleep
Authors: Barroso Sabrina Martins , Sousa Kelly Cristina Ramira
Published: September 2021

The purpose of this study was to identify factors associated with HIV-associated neurocognitive disorder (HAND) and symptoms of anxiety and depression in HIV+ Brazilian elderly on antiretroviral treatments. The study included 112 HIV+ elderly who completed a questionnaire, tests for cognitive screening, attention, problem solving, processing speed, visual perception, memory, and anxiety and depression scales. The results showed presence of HAND (89.3%), pathological anxiety (48.2%) and depression (58%) in the sample. Higher income was a protective factor for HAND (OR = 0.33). Waking up well-rested (OR = 0.63) and better diet quality (OR = 0.62) reduced the chance of pathological anxiety. Higher education (OR = 0.74) and waking up well-rested (OR = 0.61) reduced the chance of depression. Being female (OR = 7.73) increased the chance of depression. It can be concluded that it is important to evaluate cognitive and emotional aspects of HIV+ elders and to consider social and educational status, diet, and sleep in interventions, paying special attention to elderly women.
Reactive, Adult Neurogenesis From Increased Neural Progenitor Cell Proliferation Following Alcohol Dependence in Female Rats
Authors: Nawarawong Natalie N. , Thompson K. Ryan , Guerin Steven P. , Anasooya Shaji Chinchusha , Peng Hui , Nixon Kimberly
Published: September 2021

Hippocampal neurodegeneration is a consequence of excessive alcohol drinking in alcohol use disorders (AUDs), however, recent studies suggest that females may be more susceptible to alcohol-induced brain damage. Adult hippocampal neurogenesis is now well accepted to contribute to hippocampal integrity and is known to be affected by alcohol in humans as well as in animal models of AUDs. In male rats, a reactive increase in adult hippocampal neurogenesis has been observed during abstinence from alcohol dependence, a phenomenon that may underlie recovery of hippocampal structure and function. It is unknown whether reactive neurogenesis occurs in females. Therefore, adult female rats were exposed to a 4-day binge model of alcohol dependence followed by 7 or 14 days of abstinence. Immunohistochemistry (IHC) was used to assess neural progenitor cell (NPC) proliferation (BrdU and Ki67), the percentage of increased NPC activation (Sox2+/Ki67+), the number of immature neurons (NeuroD1), and ectopic dentate gyrus granule cells (Prox1). On day seven of abstinence, ethanol-treated females showed a significant increase in BrdU+ and Ki67+ cells in the subgranular zone of the dentate gyrus (SGZ), as well as greater activation of NPCs (Sox2+/Ki67+) into active cycling. At day 14 of abstinence, there was a significant increase in the number of immature neurons (NeuroD1+) though no evidence of ectopic neurogenesis according to either NeuroD1 or Prox1 immunoreactivity. Altogether, these data suggest that alcohol dependence produces similar reactive increases in NPC proliferation and adult neurogenesis. Thus, reactive, adult neurogenesis may be a means of recovery for the hippocampus after alcohol dependence in females.
Outer Retinal Layer Thickness Changes in White Matter Hyperintensity and Parkinson's Disease
Authors: Zhao Yitian , Zhao Jinyu , Gu Yuanyuan , Chen Bang , Guo Jiaqi , Xie Jianyang , Yan Qifeng , Ma Yuhui , Wu Yufei , Zhang Jiong , Lu Qinkang , Liu Jiang
Published: September 2021

Purpose: To investigate the thickness changes of outer retinal layers in subjects with white matter hyperintensities (WMH) and Parkinson's Disease (PD).

Methods: 56 eyes from 31 patients with WMH, 11 eyes from 6 PD patients, and 58 eyes from 32 healthy controls (HC) were enrolled in this study. A macular-centered scan was conducted on each participant using a spectral-domain optical coherence tomography (SD-OCT) device. After speckle noise reduction, a state-of-the-art deep learning method (i.e., a context encoder network) was employed to segment the outer retinal layers from OCT B-scans. Thickness quantification of the outer retinal layers was conducted on the basis of the segmentation results.

Results: WMH patients had significantly thinner Henle fiber layers, outer nuclear layers (HFL+ONL) and photoreceptor outer segments (OS) than HC (p = 0.031, and p = 0.005), while PD patients showed a significant increase of mean thickness in the interdigitation zone and the retinal pigment epithelium/Bruch complex (IZ+RPE) (19.619 ± 4.626) compared to HC (17.434 ± 1.664). There were no significant differences in the thickness of the outer plexiform layer (OPL), the myoid and ellipsoid zone (MEZ), and the IZ+RPE layer between WMH and HC subjects. Similarly, there were also no obvious differences in the thickness of the OPL, HFL+ONL, MEZ and the OS layer between PD and HC subjects.

Conclusion: Thickness changes in HFL+ONL, OS, and IZ+RPE layers may correlate with brain-related diseases such as WMH and PD. Further longitudinal study is needed to confirm HFL+ONL/OS/IZ+RPE layer thickness as potential biomarkers for detecting certain brain-related diseases.
NMDARs Drive the Expression of Neuropsychiatric Disorder Risk Genes Within GABAergic Interneuron Subtypes in the Juvenile Brain
Authors: Mahadevan Vivek , Mitra Apratim , Zhang Yajun , Yuan Xiaoqing , Peltekian Areg , Chittajallu Ramesh , Esnault Caroline , Maric Dragan , Rhodes Christopher , Pelkey Kenneth A. , Dale Ryan , Petros Timothy J. , McBain Chris J.
Published: September 2021

Medial ganglionic eminence (MGE)-derived parvalbumin (PV)+, somatostatin (SST)+and Neurogliaform (NGFC)-type cortical and hippocampal interneurons, have distinct molecular, anatomical, and physiological properties. However, the molecular mechanisms regulating their maturation remain poorly understood. Here, via single-cell transcriptomics, we show that the obligate NMDA-type glutamate receptor (NMDAR) subunit gene Grin1 mediates transcriptional regulation of gene expression in specific subtypes of MGE-derived interneurons, leading to altered subtype abundances. Notably, MGE-specific early developmental Grin1 loss results in a broad downregulation of diverse transcriptional, synaptogenic and membrane excitability regulatory programs in the juvenile brain. These widespread gene expression abnormalities mirror aberrations that are typically associated with neurodevelopmental disorders. Our study hence provides a road map for the systematic examination of NMDAR signaling in interneuron subtypes, revealing potential MGE-specific genetic targets that could instruct future therapies of psychiatric disorders.
Effects of Oral Vitamin C Supplementation on Liver Health and Associated Parameters in Patients With Non-Alcoholic Fatty Liver Disease: A Randomized Clinical Trial
Authors: He Zhangya , Li Xiaomin , Yang Hexiang , Wu Pei , Wang Shanshan , Cao Dan , Guo Xiaoxiao , Xu Zhangrui , Gao Jiayi , Zhang Wanyu , Luo Xiaoqin
Published: September 2021

Non-alcoholic fatty liver disease (NAFLD) is now recognized as the most prevalent hepatic disorder worldwide, and an unhealthy lifestyle is the leading risk factor for its occurrence. Vitamin C (VC) has been suggested to protect NAFLD, whereas evidence from randomized controlled trials (RCTs) is sparse. In this study, we aimed to investigate the potential benefits of VC supplementation daily on liver health and associated parameters in patients with NAFLD. In this double-blind, RCT, 84 patients with NAFLD, aged 18–60 years old, were assigned to 12 weeks of oral treatment with either low (250 mg/day, n = 26), medium (1,000 mg/day, n = 30), or high (2,000 mg/day, n = 28) doses of VC supplements. After the intervention, the Medium group had a more significant decrease in aspartate aminotransferase [Medium, −5.00 (−10.25, −1.75) vs. High, −2.50 (−7.75, 0.00), P = 0.02] and alanine aminotransferase [Medium, −8.00 (−18.00, −1.75) vs. High, −3.50 (−13.75, 4.25), P = 0.05; Medium vs. Low, −3.00 (−9.00, 5.50), P = 0.031]. The levels of other indicators of liver health, such as gamma-glutamyl transferase, alkaline phosphatase, total bilirubin, and direct bilirubin were decreased after the intervention but comparable among the three groups and so did the parameters of glucose metabolism, such as fasting insulin, fasting glucose, and homeostasis model assessment for insulin resistance. The plasma level of VC in patients and total adiponectin and high molecular weight (HMW) adiponectin levels were also elevated but not in a dose-dependent manner. Meanwhile, analysis of fecal microbiota composition showed an increase in the alpha diversity (Abundance-based Coverage Estimator (ACE), Shannon, chao1, and Simpson) both in the Low and the Medium groups. A total of 12 weeks of VC supplementation, especially 1,000 mg/day, improved liver health and glucose metabolism in patients with NAFLD. The elevated plasma levels of VC, total and HMW adiponectin, and the improvement of intestinal microbiota may have made some contributions.
Preoperative Metastatic Brain Tumor-Associated Intracerebral Hemorrhage Is Associated With Dismal Prognosis
Authors: Hamed Motaz , Schäfer Niklas , Bode Christian , Borger Valeri , Potthoff Anna-Laura , Eichhorn Lars , Giordano Frank A. , Güresir Erdem , Heimann Muriel , Ko Yon-Dschun , Landsberg Jennifer , Lehmann Felix , Radbruch Alexander , Scharnböck Elisa , Schaub Christina , Schwab Katjana S. , Weller Johannes , Herrlinger Ulrich , Vatter Hartmut , Schuss Patrick , Schneider Matthias
Published: September 2021

Object

Intra-tumoral hemorrhage is considered an imaging characteristic of advanced cancer disease. However, data on the influence of intra-tumoral hemorrhage in patients with brain metastases (BM) remains scarce. We aimed at investigating patients with BM who underwent neurosurgical resection of the metastatic lesion for a potential impact of preoperative hemorrhagic transformation on overall survival (OS).

Methods

Between 2013 and 2018, 357 patients with BM were surgically treated at the authors’ neuro-oncological center. Preoperative magnetic resonance imaging (MRI) examinations were assessed for the occurrence of malignant hemorrhagic transformation.

Results

122 of 375 patients (34%) with BM revealed preoperative intra-tumoral hemorrhage. Patients with hemorrhagic transformed BM exhibited a median OS of 5 months compared to 12 months for patients without intra-tumoral hemorrhage. Multivariate analysis revealed preoperative hemorrhagic transformation as an independent and significant predictor for worsened OS.

Conclusions

The present study identifies preoperative intra-tumoral hemorrhage as an indicator variable for poor prognosis in patients with BM undergoing neurosurgical treatment.
Ovarian Function Suppression With Luteinizing Hormone-Releasing Hormone Agonists for the Treatment of Hormone Receptor-Positive Early Breast Cancer in Premenopausal Women
Authors: Lu Yen-Shen , Wong Andrea , Kim Hee-Jeong
Published: September 2021

Chemotherapy and endocrine therapies are mainstays of treatment for early and advanced hormone receptor-positive (HR+) breast cancer. In premenopausal women with HR+ tumors, the benefits of adding ovarian function suppression (OFS) to endocrine therapy have been debated. Consequently, for many years, tamoxifen monotherapy has been the standard of care for endocrine treatment in the adjuvant setting. Recent studies have, however, provided new evidence that, in some premenopausal patients, OFS in combination with tamoxifen or aromatase inhibitors (AIs) can significantly increase survival versus tamoxifen alone. Luteinizing hormone-releasing hormone agonists (LHRHa), including goserelin, triptorelin, and leuprorelin, achieve OFS through sustained suppression of the release of follicle-stimulating hormone and luteinizing hormone from the pituitary. In turn, this suppresses production and secretion of estradiol, an ovarian hormone that supports cancer cell growth, survival, and proliferation. In this review, we discuss the clinical evidence supporting the addition of LHRHa to adjuvant endocrine therapies, including tamoxifen and AIs, for premenopausal women with breast cancer. We also discuss the role of LHRHa use in combination with adjuvant chemotherapy to preserve ovarian function and fertility in young patients with breast cancer. Finally, we discuss important practical aspects of the use of LHRHa in breast cancer treatment, including side-effects, patient adherence to treatment, and the use of slow-release, long-acting drug formulations.
AGTRAP Is a Prognostic Biomarker Correlated With Immune Infiltration in Hepatocellular Carcinoma
Authors: Liu Shanshan , Zhao Wei , Li Xuemei , Zhang La , Gao Yu , Peng Qiling , Du Chengyou , Jiang Ning
Published: September 2021

Background

Recently, it has been reported that angiotensin II receptor-associated protein (AGTRAP) plays a substantial role in tumor progression. Nevertheless, the possible role of AGTRAP in hepatocellular carcinoma (HCC) remains unrecognized.

Methods

The metabolic gene rapid visualizer, Cancer Cell Line Encyclopedia, Human Protein Atlas, and Hepatocellular Carcinoma Database were used to analyze the expression of AGTRAP in HCC tissues and normal liver tissues or adjacent tissues. Kaplan-Meier plotter and UALCAN analysis were used to assess the prognostic and diagnostic value of AGTRAP. LinkedOmics and cBioPortal were used to explore the genes co-expressed with AGTRAP in HCC. To further understand the potential mechanism of AGTRAP in HCC, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment pathway analyses were performed using R software, the protein-protein interaction (PPI) network was established using the STRING database, and the immune infiltration and T-cell exhaustion related to AGTRAP were explored via Timer and GEPIA. In addition, immunohistochemistry was used to detect the expression of AGTRAP protein in HCC tissues and paired adjacent tissues from clinical specimens.

Results

This study found that the mRNA and protein levels of AGTRAP in HCC tissues were higher than those in normal liver tissues and adjacent tissues, and higher mRNA levels of AGTRAP were associated with higher histological grade and a poor overall survival in HCC patients. The area under the receiver operating characteristic curve (AUC) of AGTRAP was 0.856, suggesting that it could be a diagnostic marker for HCC. Moreover, the alteration rate of AGTRAP in HCC was 8%, and AGTRAP was involved in HCC probably through the NF-κB and MAPK signaling pathways. Furthermore, AGTRAP was positively correlated with the infiltration of CD8+ T cells, CD4+ T cells, B cells, macrophages, dendritic cells, and neutrophils, and the levels of AGTRAP were significantly correlated with T-cell exhaustion biomarkers. The immunohistochemistry results confirmed that the protein levels of AGTRAP were consistently higher in HCC tissues than in paired adjacent tissues.

Conclusion

The clinical value of AGTRAP and its correlation with immune infiltration in HCC was effectively identified in clinical data from multiple recognized databases. These findings indicate that AGTRAP could serve as a potential biomarker in the treatment of HCC, thereby informing its prognosis, diagnosis, and even immunotherapy.
Incidence, Clinical Characteristics, and Survival of Collecting Duct Carcinoma of the Kidney: A Population-Based Study
Authors: Tang Chaopeng , Zhou Yulin , Ge Silun , Yi Xiaoming , Lv Huichen , Zhou Wenquan
Published: September 2021

Objective

To investigate the exact age‐adjusted incidence (AAI), clinical characteristics, and survival data of collecting duct carcinoma of the kidney (CDCK) recorded in the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute.

Methods

Patients with CDCK confirmed by microscopic examination from 2004 to 2018 were selected from the SEER database. AAI rates were calculated using SEER*Stat software (version 8.3.9). The Kaplan‐Meier method was used to evaluate cancer-specific survival (CSS) rates according to tumor size, tumor stage, and treatment methods, and differences among these variables were assessed by the log‐rank test. Cox regression analysis was employed to identify variables independently related to CSS.

Results

A total of 286 patients with CDCK were identified from the database. The majority of the patients were white (69.2%), male (67.5%), and married (60.5%), and the median age was 59 years. Most patients with CDCK (74.4%) presented with stages III or IV disease. The diameter of most (59.4%) tumors was less than 7 cm, and the tumors were more commonly found on the left than on the right (55.2% vs. 44.8%). The incidence of CDCK decreased over time. The median CSS time was 17 months. In terms of the treatment modalities used, 83.9% of the patients underwent surgery; 32.9% underwent chemotherapy, and 13.6% underwent radiotherapy. The CSS rates at 1, 2, and 5 years were 57.3%, 43.2%, and 30.7%, respectively. In patients with stage IV CDCK treated with surgery alone, chemotherapy alone, and surgery plus chemotherapy, the median survival time was 5 months, 9 months, and 14 months, respectively (P =0.024). Multivariate Cox regression analysis showed surgery, chemotherapy, stage, regional lymph node metastasis, and distant metastasis were independent prognostic factors for patients with CDCK.

Conclusions

CDCK is an uncommon malignant renal carcinoma, and its incidence is decreasing based on the analysis of current data. CDCK is a high stage, regional lymph-nodes positive, and metastatic disease. Compared with surgery alone or chemotherapy alone, patients with stage IV could gain survival benefit from surgery combined with chemotherapy.
Fluorescence Lifetime Imaging and Spectroscopic Co-Validation for Protoporphyrin IX-Guided Tumor Visualization in Neurosurgery
Authors: Reichert David , Erkkilae Mikael T. , Gesperger Johanna , Wadiura Lisa I. , Lang Alexandra , Roetzer Thomas , Woehrer Adelheid , Andreana Marco , Unterhuber Angelika , Wilzbach Marco , Hauger Christoph , Drexler Wolfgang , Kiesel Barbara , Widhalm Georg , Leitgeb Rainer A.
Published: September 2021

Maximal safe resection is a key strategy for improving patient prognosis in the management of brain tumors. Intraoperative fluorescence guidance has emerged as a standard in the surgery of high-grade gliomas. The administration of 5-aminolevulinic acid prior to surgery induces tumor-specific accumulation of protoporphyrin IX, which emits red fluorescence under blue-light illumination. The technology, however, is substantially limited for low-grade gliomas and weakly tumor-infiltrated brain, where low protoporphyrin IX concentrations are outweighed by tissue autofluorescence. In this context, fluorescence lifetime imaging has shown promise to distinguish spectrally overlapping fluorophores. We integrated frequency-domain fluorescence lifetime imaging in a surgical microscope and combined it with spatially registered fluorescence spectroscopy, which can be considered a research benchmark for sensitive protoporphyrin IX detection. Fluorescence lifetime maps and spectra were acquired for a representative set of fresh ex-vivo brain tumor specimens (low-grade gliomas n = 15, high-grade gliomas n = 80, meningiomas n = 41, and metastases n = 35). Combining the fluorescence lifetime with fluorescence spectra unveiled how weak protoporphyrin IX accumulations increased the lifetime respective to tissue autofluorescence. Infiltration zones (4.1ns ± 1.8ns, p = 0.017) and core tumor areas (4.8ns ± 1.3ns, p = 0.040) of low-grade gliomas were significantly distinguishable from non-pathologic tissue (1.6ns ± 0.5ns). Similarly, fluorescence lifetimes for infiltrated and reactive tissue as well as necrotic and core tumor areas were increased for high-grade gliomas and metastasis. Meningioma tumor specimens showed strongly increased lifetimes (12.2ns ± 2.5ns, p = 0.005). Our results emphasize the potential of fluorescence lifetime imaging to optimize maximal safe resection in brain tumors in future and highlight its potential toward clinical translation.
Interaction Between Modern Radiotherapy and Immunotherapy for Metastatic Prostate Cancer
Authors: Ollivier Luc , Labbé Maureen , Fradin Delphine , Potiron Vincent , Supiot Stéphane
Published: September 2021

Prostate cancer is the most frequently diagnosed cancer in men and a leading cause of cancer-related death. In recent decades, the development of immunotherapies has resulted in great promise to cure metastatic disease. However, prostate cancer has failed to show any significant response, presumably due to its immunosuppressive microenvironment. There is therefore growing interest in combining immunotherapy with other therapies able to relieve the immunosuppressive microenvironment. Radiation therapy remains the mainstay treatment for prostate cancer patients, is known to exhibit immunomodulatory effects, depending on the dose, and is a potent inducer of immunogenic tumor cell death. Optimal doses of radiotherapy are thus expected to unleash the full potential of immunotherapy, improving primary target destruction with further hope of inducing immune-cell-mediated elimination of metastases at distance from the irradiated site. In this review, we summarize the current knowledge on both the tumor immune microenvironment in prostate cancer and the effects of radiotherapy on it, as well as on the use of immunotherapy. In addition, we discuss the utility to combine immunotherapy and radiotherapy to treat oligometastatic metastatic prostate cancer.
Ginsenoside Rb1 Lessens Gastric Precancerous Lesions by Interfering With β-Catenin/TCF4 Interaction
Authors: Zeng Jinhao , Ma Xiao , Zhao Ziyi , Chen Yu , Wang Jundong , Hao Yanwei , Yu Junrong , Zeng Zhongzhen , Chen Nianzhi , Zhao Maoyuan , Tang Jianyuan , Gong Daoyin
Published: September 2021

Background: Seeking novel and effective therapies for gastric precancerous lesions (GPL) is crucial to reducing the incidence of gastric cancer. Ginsenoside Rb1 (GRb1) is a major ginsenoside in ginseng and has been proved to possess multiple bioactivities. However, whether GRb1 could protect against GPL and the underlying mechanisms have not been explored.

Methods: We evaluated the effects of GRb1 on gastric precancerous lesions in rats on macroscopic, microscopic and ultramicroscopic levels. Then, an antibody array was employed to screen differential expression proteins (DEPs). Validation for the targeting DEP and investigation for the possible mechanism was conducted using immunohistochemistry, qRT-PCR, TUNEL apoptosis assay, immunoprecipitation and immunoblotting.

Results: GRb1 was found to reverse intestinal metaplasia and a portion of dysplasia in the MNNG-induced GPL rats. The antibody array assay revealed seven DEPs in GPL rats as compared to control rats (5 DEPs were up-regulated, while two DEPs were down-regulated). Among the DEPs, β-catenin, beta-NGF and FSTL1 were significantly down-regulated after GRb1 administration. Our validation results revealed that enhanced protein expression and nuclear translocation of β-catenin were present in animal GPL samples. In addition, analysis of human gastric specimens demonstrated that β-catenin up-regulation and nuclear translocation were significantly associated with advanced GPL pathology. GRb1 intervention not only decreased protein expression and nuclear translocation of β-catenin, but interfered with β-catenin/TCF4 interaction. Along with this, declined transcriptional and protein expression levels of downstream target genes including c-myc, cyclin D1 and Birc5 were observed in GRb1-treated GPL rats.

Conclusion: GRb1 is capable of preventing the occurrence and progression of GPL, which might be contributed by diminishing protein expression and nuclear translocation of β-catenin and interfering with β-catenin/TCF4 interaction.
Arbutin Ameliorates Murine Colitis by Inhibiting JAK2 Signaling Pathway
Authors: Wang Liang , Feng Yuntao , Wang Jianwen , Luo Tenglong , Wang Xinyue , Wu Mengze , Wang Runxia , Chen Dapeng , Li Jiyan , Wang Jingyu
Published: September 2021

Background and objective: Abnormal activation of Janus kinase 2 (JAK2) promotes the pathogenesis and progress of inflammatory bowel disease (IBD) by stimulating the cytokine traffic. Based on docking studies, arbutin, a natural product extracted from a traditional medicinal plant bearberry, was found to bind to JAK2. The study aimed to investigate the effects and mechanisms of regulating JAK2 by arbutin on colitis in mice.

Methods: A mice colitis model was established to mimic human IBD. The mice freely drank water containing dextran sulfate sodium. Inflammation in epithelial (IEC6) and immune (RAW264.7) cells was analyzed following treatment with lipopolysaccharides (LPS).

Results: Colitis symptoms, including body weight loss, increased disease activity index, and increased colon weight/length ratio, were significantly alleviated by arbutin. Mediators of colonic pro-inflammatory cytokines as well as apoptosis markers in colitis were suppressed by the glycoside. High expression of phosphorylated JAK2 in colitis was significantly reversed by arbutin. The effects of arbutin treatment on colitis were considerably inhibited by the JAK2 inhibitor AG490. LPS-induced inflammatory responses were also suppressed by arbutin, which was notably inhibited by the JAK2 inhibitor AG490.

Conclusion: The findings obtained herein suggest the protective role of arbutin and provide novel insights into alternative colitis treatments, which involve inhibition of the JAK2 signaling pathway.
Organic Anion Transporting Polypeptide 2B1 (OATP2B1) Genetic Variants: In Vitro Functional Characterization and Association With Circulating Concentrations of Endogenous Substrates
Authors: Medwid Samantha , Price Hayley R. , Taylor Daniel P. , Mailloux Jaymie , Schwarz Ute I. , Kim Richard B. , Tirona Rommel G.
Published: September 2021

Organic anion transporting polypeptide 2B1 (OATP2B1, gene SLCO2B1) is an uptake transporter that is thought to determine drug disposition and in particular, the oral absorption of medications. At present, the clinical relevance of SLCO2B1 genetic variation on pharmacokinetics is poorly understood. We sought to determine the functional activity of 5 of the most common missense OATP2B1 variants (c.76_84del, c.601G>A, c.917G>A, c.935G>A, and c.1457C>T) and a predicted dysfunctional variant (c.332G>A) in vitro. Furthermore, we measured the basal plasma concentrations of endogenous OATP2B1 substrates, namely estrone sulfate, dehydroepiandrosterone sulfate (DHEAS), pregnenolone sulfate, coproporphyrin I (CPI), and CPIII, and assessed their relationships with SLCO2B1 genotypes in 93 healthy participants. Compared to reference OATP2B1, the transport activities of the c.332G>A, c.601G>A and c.1457C>T variants were reduced among the substrates examined (estrone sulfate, DHEAS, CPI, CPIII and rosuvastatin), although there were substrate-dependent effects. Lower transport function of OATP2B1 variants could be explained by diminished cell surface expression. Other OATP2B1 variants (c.76-84del, c.917G>A and c.935G>A) had similar activity to the reference transporter. In the clinical cohort, the SLCO2B1 c.935G>A allele was associated with both higher plasma CPI (42%) and CPIII (31%) concentrations, while SLCO2B1 c.917G>A was linked to lower plasma CPIII by 28% after accounting for the effects of age, sex, and SLCO1B1 genotypes. No association was observed between SLCO2B1 variant alleles and estrone sulfate or DHEAS plasma concentrations, however 45% higher plasma pregnenolone sulfate level was associated with SLCO2B1 c.1457C>T. Taken together, we found that the impacts of OATP2B1 variants on transport activities in vitro were not fully aligned with their associations to plasma concentrations of endogenous substrates in vivo. Additional studies are required to determine whether circulating endogenous substrates reflect OATP2B1 activity.
Opioids and Gabapentinoids Utilisation and Their Related-Mortality Trends in the United Kingdom Primary Care Setting, 2010–2019: A Cross-National, Population-Based Comparison Study
Authors: Kurdi Amanj
Published: September 2021

Background: There is growing concern over the increasing utilisation trends of opioids and gabapentinoids across but there is lack of data assessing and comparing the utilisation trends across the four United Kingdom countries. We assessed/compared opioids and gabapentinoids utilisation trends across the four United Kingdom countries then evaluated the correlation between their utilisation with related mortality.

Methods: This repeated cross-national study used Prescription Cost Analysis (PCA) datasets (2010–2019). Opioids and gabapentinoids utilisation were measured using number of items dispensed/1,000 inhabitants and defined daily doses (DDDs)/1,000 inhabitant/day. Number of Opioids and gabapentinoids-related mortality were extracted from the United Kingdom Office for National Statistics (2010–2018). Data were analysed using descriptive statistics including linear trend analysis; correlation between the Opioids and gabapentinoids utilisation and their related mortality using Pearson correlation coefficient.

Results: The results illustrated an overall significant increasing trend in the utilisation of opioids (12.5–14%) and gabapentinoids (205–207%) with substantial variations among the four United Kingdom countries. For opioids, Scotland had the highest level of number of items dispensed/1,000 inhabitant (156.6% higher compared to the lowest level in England), whereas in terms of DDD/1,000 inhabitant/day, NI had the highest level. Utilisation trends increased significantly across the four countries ranging from 7.7% in Scotland to 20.5% in NI (p < 0.001). Similarly, for gabapentinoids, there were significant increasing trends ranging from 126.5 to 114.9% in NI to 285.8–299.6% in Wales (p < 0.001) for number of items/1,000 inhabitants and DDD/1,000 inhabitant/day, respectively. Although the utilisation trends levelled off after 2016, this was not translated into comparable reduction in opioids and gabapentinoids-related mortality as the latter continued to increase with the highest level in Scotland (3.5 times more deaths in 2018 compared to England- 280.1 vs. 79.3 deaths/million inhabitants). There were significant moderate-strong positive correlations between opioids and gabapentinoids utilisation trends and their related mortality.

Conclusion: The utilisation trends of opioids and gabapentinoids have increased significantly with substantial variations among the four United Kingdom countries. This coincided with significant increase in their related mortality. Our findings support the call for immediate actions including radical changes in official United Kingdom policies on drug use and effective strategies to promote best clinical practice in opioids and gabapentinoids prescribing.
Necroptosis in Pulmonary Diseases: A New Therapeutic Target
Authors: Wang Lingling , Zhou Ling , Zhou Yuhao , Liu Lu , Jiang Weiling , Zhang Huojun , Liu Huiguo
Published: September 2021

In the past decades, apoptosis has been the most well-studied regulated cell death (RCD) that has essential functions in tissue homeostasis throughout life. However, a novel form of RCD called necroptosis, which requires receptor-interacting protein kinase-3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL), has recently been receiving increasing scientific attention. The phosphorylation of RIPK3 enables the recruitment and phosphorylation of MLKL, which oligomerizes and translocates to the plasma membranes, ultimately leading to plasma membrane rupture and cell death. Although apoptosis elicits no inflammatory responses, necroptosis triggers inflammation or causes an innate immune response to protect the body through the release of damage-associated molecular patterns (DAMPs). Increasing evidence now suggests that necroptosis is implicated in the pathogenesis of several human diseases such as systemic inflammation, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, neurological diseases, and cancer. This review summarizes the emerging insights of necroptosis and its contribution toward the pathogenesis of lung diseases.
Pharmacological Characterization of Toludesvenlafaxine as a Triple Reuptake Inhibitor
Authors: Zhu Haibo , Wang Wenyan , Sha Chunjie , Guo Wei , Li Chunmei , Zhao Fengjuan , Wang Hongbo , Jiang Wanglin , Tian Jingwei
Published: September 2021

Toludesvenlafaxine hydrochloride dihydrate is a novel chemical entity and a potential triple monoamine reuptake inhibitor. This study characterized the in vitro triple reuptake inhibition activity, antidepressant-like activity in animals, and pharmacokinetic profiles in rats of toludesvenlafaxine. Binding affinity was determined using human serotonin transporter (SERT) protein, norepinephrine transporter (NET) protein and dopamine transporter (DAT) protein, and the reuptake inhibition was determined using Chinese hamster ovary cells expressing human SERT, NET and DAT. The antidepressant-like activity was examined in rat chronic unpredictable mild stress model and olfactory bulbectomized model. In rats, the tissue distribution and pharmacokinetic parameters were determined. Toludesvenlafaxine had high binding affinity on SERT, NET and DAT, and significantly inhibited the reuptake of serotonin (IC50 = 31.4 ± 0.4 nM), norepinephrine (IC50 = 586.7 ± 83.6 nM) and dopamine (IC50 = 733.2 ± 10.3 nM) in vitro. Toludesvenlafaxine demonstrated significant antidepressant-like effects in rat models at 8–16 mg/kg. In addition, toludesvenlafaxine significantly reduced serum corticosterone and significantly increased testosterone levels in rats. Toludesvenlafaxine was quickly absorbed and converted to O-desvenlafaxine (ODV) after oral administration, both of which were selectively distributed into the hypothalamus with high concentration. Plasma ODV exposure was proportionally related to the doses after oral dosing. These results suggest that toludesvenlafaxine is a triple reuptake inhibitor with relatively fast-acting antidepressant-like activity and good therapeutic profile including improvement of anhedonia and sexual function.
Polar Quasinormal Modes of Neutron Stars in Massive Scalar-Tensor Theories
Authors: Blázquez-Salcedo Jose Luis , Khoo Fech Scen , Kunz Jutta , Preut Vincent
Published: September 2021

We study polar quasinormal modes of relativistic stars in scalar-tensor theories, where we include a massive gravitational scalar field and employ the standard Brans-Dicke coupling function. For the potential of the scalar field we consider a simple mass term as well as a potential associated withR2gravity. The presence of the scalar field makes the spectrum of quasinormal modes much richer than the spectrum in General Relativity. We here investigate radial modes (l= 0) and quadrupole modes (l= 2). The general relativisticl= 0 normal modes turn into quasinormal modes in scalar-tensor theories, that are able to propagate outside of the stars. In addition to the pressure-led modes new scalar-ledϕ-modes arise. We analyze the dependence of the quasinormal mode frequencies and decay times on the scalar field mass.
SBP Is Superior to MAP to Reflect Tissue Perfusion and Hemodynamic Abnormality Perioperatively
Authors: Sun Jie , Yuan Jing , Li Bin
Published: September 2021

Many articles have reported that intraoperative low mean artery pressure (MAP) or low systolic blood pressure (SBP) impacts on organs’ function and patients’ outcomes perioperatively. On the contrary, what type of blood pressure should be obtained still needs to be clarified. In our paper, we compared the influencing factors of MAP and SBP, and mathematical formula, arterial pulse contour calculation, and cardiovascular physiological knowledge were adopted to discuss how blood pressure can effectively reflect tissue perfusion and hemodynamic abnormality perioperatively. We concluded that MAP can reflect cardiac output change sensitively and SBP can reflect stroke volume change sensitively. Moreover, SBP can reflect the early hemodynamic changes, organs’ perfusion, and heart systolic function. Compared with MAP, perioperative monitoring of SBP and timely detection and treatment of abnormal SBP are very important for the early detection of hemodynamic abnormalities.
Biological Roles of Lipocalins in Chemical Communication, Reproduction, and Regulation of Microbiota
Authors: Stopková Romana , Otčenášková Tereza , Matějková Tereza , Kuntová Barbora , Stopka Pavel
Published: September 2021

Major evolutionary transitions were always accompanied by genetic remodelling of phenotypic traits. For example, the vertebrate transition from water to land was accompanied by rapid evolution of olfactory receptors and by the expansion of genes encoding lipocalins, which – due to their transporting functions – represent an important interface between the external and internal organic world of an individual and also within an individual. Similarly, some lipocalin genes were lost along other genes when this transition went in the opposite direction leading, for example, to cetaceans. In terrestrial vertebrates, lipocalins are involved in the transport of lipophilic substances, chemical signalling, odour reception, antimicrobial defence and background odour clearance during ventilation. Many ancestral lipocalins have clear physiological functions across the vertebrate taxa while many other have – due to pleiotropic effects of their genes – multiple or complementary functions within the body homeostasis and development. The aim of this review is to deconstruct the physiological functions of lipocalins in light of current OMICs techniques. We concentrated on major findings in the house mouse in comparison to other model taxa (e.g., voles, humans, and birds) in which all or most coding genes within their genomes were repeatedly sequenced and their annotations are sufficiently informative.
Genomic Evidence That Governmentally Produced Cannabis sativa Poorly Represents Genetic Variation Available in State Markets
Authors: Vergara Daniela , Huscher Ezra L. , Keepers Kyle G. , Pisupati Rahul , Schwabe Anna L. , McGlaughlin Mitchell E. , Kane Nolan C.
Published: September 2021

The National Institute on Drug Abuse (NIDA) is the sole producer of Cannabis for research purposes in the United States, including medical investigation. Previous research established that cannabinoid profiles in the NIDA varieties lacked diversity and potency relative to the Cannabis produced commercially. Additionally, microsatellite marker analyses have established that the NIDA varieties are genetically divergent form varieties produced in the private legal market. Here, we analyzed the genomes of multiple Cannabis varieties from diverse lineages including two produced by NIDA, and we provide further support that NIDA’s varieties differ from widely available medical, recreational, or industrial Cannabis. Furthermore, our results suggest that NIDA’s varieties lack diversity in the single-copy portion of the genome, the maternally inherited genomes, the cannabinoid genes, and in the repetitive content of the genome. Therefore, results based on NIDA’s varieties are not generalizable regarding the effects of Cannabis after consumption. For medical research to be relevant, material that is more widely used would have to be studied. Clearly, having research to date dominated by a single, non-representative source of Cannabis has hindered scientific investigation.