bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Lymph Node Metastasis–Related Key Genes and Prognostic Risk Model in Bladder Cancer by Co-Expression Analysis
Authors: Luo Cheng , Huang Bin , Wu Yukun , Xu Yadong , Ou Wei , Chen Junxing , Chen Lingwu
Published: July 2021

Background: Lymph node metastasis (LNM) is an important pathological characteristic of bladder cancer (BCa). However, the molecular mechanism underlying LNM was not thoroughly elaborated. Identification for LNM-related biomarkers may contribute to making suitable therapies. So, the current study was aimed to identify key genes and construct a prognostic signature.

Methods: Based on the Cancer Genome Atlas (TCGA) database, gene expression and clinical information were obtained. Then, the weighted gene co-expression network analysis (WGCNA) was performed to identify the key modules and hub genes. A function analysis and a gene set enrichment analysis were applied to explore biological functions and pathways of interested genes. Furthermore, a prognostic model based on LNM-related genes was constructed by using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis.

Results: Finally, nine co-expression modules were constructed, and two modules (turquoise and green) were significantly associated with LNM. Three hub genes were identified as DACT3, TNS1, and MSRB3, which were annotated in actin binding, actin cytoskeleton, adaptive immune response, and cell adhesion molecular binding by the GSEA method. Further analysis demonstrated that three hub genes were associated with the overall survival of BCa patients. In addition, we built a prognostic signature based on the genes from LNM-related modules and evaluated the prognostic value of this signature.

Conclusion: In general, this study revealed the key genes related to LNM and prognostic signature, which might provide new insights into therapeutic target of BCa.
Striking Dependence of Protein Sweetness on Water Quality: The Role of the Ionic Strength
Authors: Delfi Masoud , Emendato Alessandro , Temussi Piero Andrea , Picone Delia
Published: July 2021

Sweet proteins are the sweetest natural molecules. This aspect prompted several proposals for their use as food additives, mainly because the amounts to be added to food would be very small and safe for people suffering from sucrose-linked diseases. During studies of sweet proteins as food additives we found that their sweetness is affected by water salinity, while there is no influence on protein’s structure. Parallel tasting of small size sweeteners revealed no influence of the water quality. This result is explained by the interference of ionic strength with the mechanism of action of sweet proteins and provides an experimental validation of the wedge model for the interaction of proteins with the sweet receptor.
The Dynamic Motor Control Index as a Marker of Age-Related Neuromuscular Impairment
Authors: Collimore Ashley N. , Aiello Ashlyn J. , Pohlig Ryan T. , Awad Louis N.
Published: July 2021

Biomarkers that can identify age-related decline in walking function have potential to promote healthier aging by triggering timely interventions that can mitigate or reverse impairments. Recent evidence suggests that changes in neuromuscular control precede changes in walking function; however, it is unclear which measures are best suited for identifying age-related changes. In this study, non-negative matrix factorization of electromyography data collected during treadmill walking was used to calculate two measures of the complexity of muscle co-activations during walking for 36 adults: (1) the number of muscle synergies and (2) the dynamic motor control index. Study participants were grouped into young (18–35 years old), young-old (65–74 years old), and old–old (75+ years old) subsets. We found that the dynamic motor control index [χ2(2) = 9.41, p = 0.009], and not the number of muscle synergies [χ2(2) = 5.42, p = 0.067], differentiates between age groups [χ2(4) = 10.62, p = 0.031, Nagelkerke R2 = 0.297]. Moreover, an impairment threshold set at a dynamic motor control index of 90 (i.e., one standard deviation below the young adults) was able to differentiate between age groups [χ2(2) = 9.351, p = 0.009]. The dynamic motor control index identifies age-related differences in neuromuscular complexity not measured by the number of muscle synergies and may have clinical utility as a marker of neuromotor impairment.
The Progress of Label-Free Optical Imaging in Alzheimer’s Disease Screening and Diagnosis
Authors: Liu Kai , Li Jiasong , Raghunathan Raksha , Zhao Hong , Li Xuping , Wong Stephen T. C.
Published: July 2021

As the major neurodegenerative disease of dementia, Alzheimer’s disease (AD) has caused an enormous social and economic burden on society. Currently, AD has neither clear pathogenesis nor effective treatments. Positron emission tomography (PET) and magnetic resonance imaging (MRI) have been verified as potential tools for diagnosing and monitoring Alzheimer’s disease. However, the high costs, low spatial resolution, and long acquisition time limit their broad clinical utilization. The gold standard of AD diagnosis routinely used in research is imaging AD biomarkers with dyes or other reagents, which are unsuitable for in vivo studies owing to their potential toxicity and prolonged and costly process of the U.S. Food and Drug Administration (FDA) approval for human use. Furthermore, these exogenous reagents might bring unwarranted interference to mechanistic studies, causing unreliable results. Several label-free optical imaging techniques, such as infrared spectroscopic imaging (IRSI), Raman spectroscopic imaging (RSI), optical coherence tomography (OCT), autofluorescence imaging (AFI), optical harmonic generation imaging (OHGI), etc., have been developed to circumvent this issue and made it possible to offer an accurate and detailed analysis of AD biomarkers. In this review, we present the emerging label-free optical imaging techniques and their applications in AD, along with their potential and challenges in AD diagnosis.
Membrane Resonance in Pyramidal and GABAergic Neurons of the Mouse Perirhinal Cortex
Authors: Binini Noemi , Talpo Francesca , Spaiardi Paolo , Maniezzi Claudia , Pedrazzoli Matteo , Raffin Francesca , Mattiello Niccolò , Castagno Antonio N. , Masetto Sergio , Yanagawa Yuchio , Dickson Clayton T. , Ramat Stefano , Toselli Mauro , Biella Gerardo Rosario
Published: July 2021

The perirhinal cortex (PRC) is a polymodal associative region of the temporal lobe that works as a gateway between cortical areas and hippocampus. In recent years, an increasing interest arose in the role played by the PRC in learning and memory processes, such as object recognition memory, in contrast with certain forms of hippocampus-dependent spatial and episodic memory. The integrative properties of the PRC should provide all necessary resources to select and enhance the information to be propagated to and from the hippocampus. Among these properties, we explore in this paper the ability of the PRC neurons to amplify the output voltage to current input at selected frequencies, known as membrane resonance. Within cerebral circuits the resonance of a neuron operates as a filter toward inputs signals at certain frequencies to coordinate network activity in the brain by affecting the rate of neuronal firing and the precision of spike timing. Furthermore, the ability of the PRC neurons to resonate could have a fundamental role in generating subthreshold oscillations and in the selection of cortical inputs directed to the hippocampus. Here, performing whole-cell patch-clamp recordings from perirhinal pyramidal neurons and GABAergic interneurons of GAD67-GFP+ mice, we found, for the first time, that the majority of PRC neurons are resonant at their resting potential, with a resonance frequency of 0.5–1.5 Hz at 23°C and of 1.5–2.8 Hz at 36°C. In the presence of ZD7288 (blocker of HCN channels) resonance was abolished in both pyramidal neurons and interneurons, suggesting that Ih current is critically involved in resonance generation. Otherwise, application of TTx (voltage-dependent Na+ channel blocker) attenuates the resonance in pyramidal neurons but not in interneurons, suggesting that only in pyramidal neurons the persistent sodium current has an amplifying effect. These experimental results have also been confirmed by a computational model. From a functional point of view, the resonance in the PRC would affect the reverberating activity between neocortex and hippocampus, especially during slow wave sleep, and could be involved in the redistribution and strengthening of memory representation in cortical regions.
Alprazolam Prompts HIV-1 Transcriptional Reactivation and Enhances CTL Response Through RUNX1 Inhibition and STAT5 Activation
Authors: Lin Angel , Elbezanti Weam Othman , Schirling Alexis , Ahmed Adel , Van Duyne Rachel , Cocklin Simon , Klase Zachary
Published: July 2021

The HIV-1 pandemic is a significant challenge to the field of medicine. Despite advancements in antiretroviral (ART) development, 38 million people worldwide still live with this disease without a cure. A significant barrier to the eradication of HIV-1 lies in the persistently latent pool that establishes early in the infection. The “shock and kill” strategy relies on the discovery of a latency-reversing agent (LRA) that can robustly reactivate the latent pool and not limit immune clearance. We have found that a benzodiazepine (BDZ), that is commonly prescribed for panic and anxiety disorder, to be an ideal candidate for latency reversal. The BDZ Alprazolam functions as an inhibitor of the transcription factor RUNX1, which negatively regulates HIV-1 transcription. In addition to the displacement of RUNX1 from the HIV-1 5′LTR, Alprazolam potentiates the activation of STAT5 and its recruitment to the viral promoter. The activation of STAT5 in cytotoxic T cells may enable immune activation which is independent of the IL-2 receptor. These findings have significance for the potential use of Alprazolam in a curative strategy and to addressing the neuroinflammation associated with neuroHIV-1.
A Framework for Sensor-Based Assessment of Upper-Limb Functioning in Hemiparesis
Authors: David Ann , Subash Tanya , Varadhan S. K. M. , Melendez-Calderon Alejandro , Balasubramanian Sivakumar
Published: July 2021

The ultimate goal of any upper-limb neurorehabilitation procedure is to improve upper-limb functioning in daily life. While clinic-based assessments provide an assessment of what a patient can do, they do not completely reflect what a patient does in his/her daily life. The use of compensatory strategies such as the use of the less affected upper-limb or excessive use of trunk in daily life is a common behavioral pattern seen in patients with hemiparesis. To this end, there has been an increasing interest in the use of wearable sensors to objectively assess upper-limb functioning. This paper presents a framework for assessing upper-limb functioning using sensors by providing: (a) a set of definitions of important constructs associated with upper-limb functioning; (b) different visualization methods for evaluating upper-limb functioning; and (c) two new measures for quantifying how much an upper-limb is used and the relative bias in their use. The demonstration of some of these components is presented using data collected from inertial measurement units from a previous study. The proposed framework can help guide the future technical and clinical work in this area to realize valid, objective, and robust tools for assessing upper-limb functioning. This will in turn drive the refinement and standardization of the assessment of upper-limb functioning.
Motor Responses of Lumbar Erector Spinae Induced by Electrical Vestibular Stimulation in Seated Participants
Authors: Desgagnés Amélie , Desmons Mikaël , Cyr Jean-Philippe , Simoneau Martin , Massé-Alarie Hugo
Published: July 2021

Introduction: The study of motor responses induced by electrical vestibular stimulation (EVS) may help clarify the role of the vestibular system in postural control. Although back muscles have an important role in postural control, their EVS-induced motor responses were rarely studied. Moreover, the effects of EVS parameters, head position, and vision on EVS-induced back muscles responses remain little explored.

Objectives: To explore the effects of EVS parameters, head position, and vision on lumbar erector spinae muscles EVS-induced responses.

Design: Exploratory, cross-sectional study.

Materials and Methods: Ten healthy participants were recruited. Three head positions (right, left and no head rotation), 4 intensities (2, 3, 4, 5 mA), and 4 EVS durations (5, 20, 100, 200 ms) were tested in sitting position with eyes open or closed. EVS usually induced a body sway toward the anode (placed on the right mastoid). EMG activity of the right lumbar erector spinae was recorded. Variables of interest were amplitude, occurrence, and latency of the EVS-induced modulation of the EMG activity.

Results: The short-latency response was inhibitory and the medium-latency response was excitatory. Increased EVS current intensity augmented the occurrence and the amplitude of the short- and medium-latency responses (more inhibition and more excitation, respectively). EVS duration influenced the medium-latency response differently depending on the position of the head. Right head rotation produced larger responses amplitude and occurrence than left head rotation. Opposite head rotation (left vs. right) did not induce a reversal of the short- and medium-latency responses (i.e., the inhibition did not become an excitation), as typically reported in lower legs muscles. The eyes open condition did not modulate muscle responses.

Conclusion: Modulation of EVS parameters (current intensity and duration of EVS) affects the amplitude and occurrence of the lumbar erector spinae responses. In contrast, vision did not influence the responses, suggesting its minimal contribution to vestibulomotor control in sitting. The lack of response reversal in sagittal plane may reflect the biomechanical role of lumbar erector spinae to fine-tune the lumbar lordosis during the induced body sway. This hypothesis remains to be further tested.
Hemodynamic Responses Link Individual Differences in Informational Masking to the Vicinity of Superior Temporal Gyrus
Authors: Zhang Min , Alamatsaz Nima , Ihlefeld Antje
Published: July 2021

Suppressing unwanted background sound is crucial for aural communication. A particularly disruptive type of background sound, informational masking (IM), often interferes in social settings. However, IM mechanisms are incompletely understood. At present, IM is identified operationally: when a target should be audible, based on suprathreshold target/masker energy ratios, yet cannot be heard because target-like background sound interferes. We here confirm that speech identification thresholds differ dramatically between low- vs. high-IM background sound. However, speech detection thresholds are comparable across the two conditions. Moreover, functional near infrared spectroscopy recordings show that task-evoked blood oxygenation changes near the superior temporal gyrus (STG) covary with behavioral speech detection performance for high-IM but not low-IM background sound, suggesting that the STG is part of an IM-dependent network. Moreover, listeners who are more vulnerable to IM show increased hemodynamic recruitment near STG, an effect that cannot be explained based on differences in task difficulty across low- vs. high-IM. In contrast, task-evoked responses near another auditory region of cortex, the caudal inferior frontal sulcus (cIFS), do not predict behavioral sensitivity, suggesting that the cIFS belongs to an IM-independent network. Results are consistent with the idea that cortical gating shapes individual vulnerability to IM.
Excitatory Repetitive Transcranial Magnetic Stimulation Over Prefrontal Cortex in a Guinea Pig Model Ameliorates Tinnitus
Authors: Zimdahl Jack W. , Thomas Harrison , Bolland Samuel J. , Leggett Kerry , Barry Kristin M. , Rodger Jennifer , Mulders Wilhelmina H. A. M.
Published: July 2021

Tinnitus, a phantom auditory perception that can seriously affect quality of life, is generally triggered by cochlear trauma and associated with aberrant activity throughout the auditory pathways, often referred to as hyperactivity. Studies suggest that non-auditory structures, such as prefrontal cortex (PFC), may be involved in tinnitus generation, by affecting sensory gating in auditory thalamus, allowing hyperactivity to reach the cortex and lead to perception. Indeed, human studies have shown that repetitive transcranial magnetic stimulation (rTMS) of PFC can alleviate tinnitus. The current study investigated whether this therapeutic effect is achieved through inhibition of thalamic hyperactivity, comparing effects of two common clinical rTMS protocols with sham treatment, in a guinea pig tinnitus model. Animals underwent acoustic trauma and once tinnitus developed were treated with either intermittent theta burst stimulation (iTBS), 20 Hz rTMS, or sham rTMS (10 days, 10 min/day; weekdays only). Tinnitus was reassessed and extracellular recordings of spontaneous tonic and burst firing rates in auditory thalamus made. To verify effects in PFC, densities of neurons positive for calcium-binding proteins, calbindin and parvalbumin, were investigated using immunohistochemistry. Both rTMS protocols significantly reduced tinnitus compared to sham. However, spontaneous tonic firing decreased following 20 Hz stimulation and increased following iTBS in auditory thalamus. Burst rate was significantly different between 20 Hz and iTBS stimulation, and burst duration was increased only after 20 Hz treatment. Density of calbindin, but not parvalbumin positive neurons, was significantly increased in the most dorsal region of PFC indicating that rTMS directly affected PFC. Our results support the involvement of PFC in tinnitus modulation, and the therapeutic benefit of rTMS on PFC in treating tinnitus, but indicate this is not achieved solely by suppression of thalamic hyperactivity.
Driving Oscillatory Dynamics: Neuromodulation for Recovery After Stroke
Authors: Storch Sven , Samantzis Montana , Balbi Matilde
Published: July 2021

Stroke is a leading cause of death and disability worldwide, with limited treatments being available. However, advances in optic methods in neuroscience are providing new insights into the damaged brain and potential avenues for recovery. Direct brain stimulation has revealed close associations between mental states and neuroprotective processes in health and disease, and activity-dependent calcium indicators are being used to decode brain dynamics to understand the mechanisms underlying these associations. Evoked neural oscillations have recently shown the ability to restore and maintain intrinsic homeostatic processes in the brain and could be rapidly deployed during emergency care or shortly after admission into the clinic, making them a promising, non-invasive therapeutic option. We present an overview of the most relevant descriptions of brain injury after stroke, with a focus on disruptions to neural oscillations. We discuss the optical technologies that are currently used and lay out a roadmap for future studies needed to inform the next generation of strategies to promote functional recovery after stroke.
A Root in Synapsis and the Other One in the Gut Microbiome-Brain Axis: Are the Two Poles of Ketogenic Diet Enough to Challenge Glioblastoma?
Authors: Montella Liliana , Sarno Federica , Altucci Lucia , Cioffi Valentina , Sigona Luigi , Di Colandrea Salvatore , De Simone Stefano , Marinelli Alfredo , Facchini Bianca Arianna , De Vita Ferdinando , Berretta Massimiliano , de Falco Raffaele , Facchini Gaetano
Published: July 2021

Glioblastoma is the most frequent and aggressive brain cancer in adults. While precision medicine in oncology has produced remarkable progress in several malignancies, treatment of glioblastoma has still limited available options and a dismal prognosis. After first-line treatment with surgery followed by radiochemotherapy based on the 2005 STUPP trial, no significant therapeutic advancements have been registered. While waiting that genomic characterization moves from a prognostic/predictive value into therapeutic applications, practical and easy-to-use approaches are eagerly awaited. Medical reports on the role of the ketogenic diet in adult neurological disorders and in glioblastoma suggest that nutritional interventions may condition outcomes and be associated with standard therapies. The acceptable macronutrient distribution of daily calories in a regular diet are 45–65% of daily calories from carbohydrates, 20–35% from fats, and 10–35% from protein. Basically, the ketogenic diet follows an approach based on low carbohydrates/high fat intake. In carbohydrates starvation, body energy derives from fat storage which is used to produce ketones and act as glucose surrogates. The ketogenic diet has several effects: metabolic interference with glucose and insulin and IGF-1 pathways, influence on neurotransmission, reduction of oxidative stress and inflammation, direct effect on gene expression through epigenetic mechanisms. Apart from these central effects working at the synapsis level, recent evidence also suggests a role for microbiome and gut-brain axis induced by a ketogenic diet. This review focuses on rationales supporting the ketogenic diet and clinical studies will be reported, looking at future possible perspectives.
The Application Progress of Patient-Derived Tumor Xenograft Models After Cholangiocarcinoma Surgeries
Authors: Wu Jun , Sheng Jiyao , Qin Hanjiao , Cui Mengying , Yang Yongsheng , Zhang Xuewen
Published: July 2021

Surgical treatment is the only possible cure for cholangiocarcinoma (CCA) at present. However, the high recurrence rate of postoperative CCA leads to a very poor prognosis for patients, effective postoperative chemotherapy is hence the key to preventing the recurrence of CCA. The sensitivity of CCA to cytotoxic chemotherapy drugs and targeted drugs varies from person to person, and therefore, the screening of sensitive drugs has become an important topic after CCA surgeries. Patient-Derived tumor Xenograft models (PDX) can stably retain the genetic and pathological characteristics of primary tumors, and better simulate the tumor microenvironment of CCA. The model is also of great significance in screening therapeutic targeted drugs after CCA, analyzing predictive biomarkers, and improving signal pathways in prognosis and basic research. This paper will review the current established methods and applications of the patient-derived tumor xenograft model of cholangiocarcinoma, aiming to provide new ideas for basic research and individualized treatment of cholangiocarcinoma after surgery.
Expression of HER2 and Mismatch Repair Proteins in Surgically Resected Gallbladder Adenocarcinoma
Authors: Sung You-Na , Kim Sung Joo , Jun Sun-Young , Yoo Changhoon , Kim Kyu-Pyo , Lee Jae Hoon , Hwang Dae Wook , Hwang Shin , Lee Sang Soo , Hong Seung-Mo
Published: July 2021

Background

Gallbladder cancer (GBC) has a poor prognosis. Although complete surgical resection is the only successful approach for improving survival, additional therapeutic modalities are required for recurrent or surgically unresectable GBCs.

Materials and Methods

To determine the expression status of HER2 and the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2, immunohistochemical staining of MMR proteins and HER2 was carried out in 216 surgically resected GBCs. HER2 labeling was scored by adopting a scoring system for gastric carcinomas. Tissues scoring 0 to 2+ were defined as HER2 negative, whereas those scoring 3+ were regarded as HER2-positive. In addition, silver in situ hybridization and microsatellite instability (MSI) analysis were conducted to confirm HER2 amplification and MSI, respectively.

Results

Three of 216 GBCs (1.3%) showed MMR protein deficiency. All three observed MSI cases exhibited dual loss of MSH2 and MSH6 protein expression. However, no cases showed loss of either MLH1 or PMS2 expression. No association was observed between MMR protein deficiency and other clinicopathological factors. HER2 amplification was noted in 30 (13.9%) GBCs and associated with Crohn-like lymphoid reaction (P = 0.023). No survival difference was observed based on HER2 overexpression or HER2 amplification status.

Conclusion

MMR protein deficiency and HER2 overexpression were observed in a small subset (1.3% and 13.9%, respectively) of GBCs without simultaneous occurrence of deficient MMR protein expression and HER2 overexpression. The presence of Crohn-like lymphoid reaction may help identify cases with HER2 amplification, by using hematoxylin-stained slides. Although the proportion of MMR protein-deficient- and HER2-overexpressing GBCs was small, applying immunotherapy to MMR protein-deficient GBCs and herceptin to HER2-overexpressing GBCs may provide alternative treatment options for patients with GBC.
ADGRG1 Is a Predictor of Chemoresistance and Poor Survival in Cervical Squamous Carcinoma
Authors: Zhang Shuo , Guo Kui , Liang Ying , Wang Kun , Liu Shuyan , Yang Xingsheng
Published: July 2021

Background

Cisplatin is the first-line chemotherapy for cervical cancer. Cisplatin resistance has always been one of the most significant barriers to acquiring better outcomes. However, the complex molecular mechanisms accounting for the phenomenon are not completely clear.

Methods

Construction of the cisplatin-resistant cell model of cervical cancer, then performing RNA sequencing and bioinformatic analysis of the differential expression genes. Then Adhesion G protein-coupled receptor G1 (ADGRG1) was screened out as our target gene. Gene Expression Profiling Interactive Analysis (GEPIA) was searched to show the expression level of ADGRG1 in cervical cancer and normal tissue. Kaplan-Meier Plotter (Kmplot) was used to explore the relationship of its expression with survival data. Tissue specimens were used to verify the relationship between the clinicopathological characteristics and ADGRG1 expression. Then we explored the roles of ADGRG1 in tumorigenesis through in vitro and in vivo assays.

Results

We found the ADGRG1 was significantly overexpressed in cervical cancer tissues compared to corresponding normal tissues. Higher ADGRG1 expression was correlated with poor progress-free survival. Knockdown of ADGRG1 markedly suppressed cell proliferation, migration, and invasion and increased cell sensitivity to cisplatin in vitro. Similarly, the role of ADGRG1 knockdown on tumorigenicity and sensitivity to cisplatin treatment was verified in vivo. The underlying mechanism was explored by western blotting that ADGRG1 knockdown inhibited tumorigenesis by PI3K/Akt/mTOR signaling pathway.

Conclusion

ADGRG1 acts as an oncogene to maintain tumorigenicity, migration, and invasion, and its depressed expression prompts sensitivity to cisplatin. Thus, ADGRG1 may represent a potential prognostic marker and possible therapeutic target for cervical cancer.
Clinical Research on the Mechanisms Underlying Immune Checkpoints and Tumor Metastasis
Authors: Tang Xi-Yang , Shi An-Ping , Xiong Yan-Lu , Zheng Kai-Fu , Liu Yu-Jian , Shi Xian-Gui , Jiang Tao , Zhao Jin-Bo
Published: July 2021

This study highlights aspects of the latest clinical research conducted on the relationship between immune checkpoints and tumor metastasis. The overview of each immune checkpoint is divided into the following three sections: 1) structure and expression; 2) immune mechanism related to tumor metastasis; and 3) clinical research related to tumor metastasis. This review expands on the immunological mechanisms of 17 immune checkpoints, including TIM-3, CD47, and OX-40L, that mediate tumor metastasis; evidence shows that most of these immune checkpoints are expressed on the surface of T cells, which mainly exert immunomodulatory effects. Additionally, we have summarized the roles of these immune checkpoints in the diagnosis and treatment of metastatic tumors, as these checkpoints are considered common predictors of metastasis in various cancers such as prostate cancer, non-Hodgkin lymphoma, and melanoma. Moreover, certain immune checkpoints can be used in synergy with PD-1 and CTLA-4, along with the implementation of combination therapies such as LIGHT-VTR and anti-PD-1 antibodies. Presently, most monoclonal antibodies generated against immune checkpoints are under investigation as part of ongoing preclinical or clinical trials conducted to evaluate their efficacy and safety to establish a better combination treatment strategy; however, no significant progress has been made regarding monoclonal antibody targeting of CD28, VISTA, or VTCN1. The application of immune checkpoint inhibitors in early stage tumors to prevent tumor metastasis warrants further evidence; the immune-related adverse events should be considered before combination therapy. This review aims to elucidate the mechanisms of immune checkpoint and the clinical progress on their use in metastatic tumors reported over the last 5 years, which may provide insights into the development of novel therapeutic strategies that will assist with the utilization of various immune checkpoint inhibitors.
Induction Strategy for Locally Advanced Thymoma
Authors: Zhang Yang , Li Zongjuan , Chen Yixing , Tan Lijie , Zeng Zhaochong , Ding Jianyong , Du Shisuo
Published: July 2021

Surgery remains cornerstone for the management of thymoma. Complete surgical resection (R0), is recognized as the constant and significant factor for prognosis. However, in locally advanced (Masaoka-Koga stages III-IVa) thymomas, achieving R0 resection remains challenging due to local-regional invasion of the disease. Induction treatment, with the aim of reducing bulky tumor mass, offers new strategy to facilitate totally surgical resection. Herein, we reviewed recent progress and provided a comprehensive overview of induction strategy in locally advance thymoma.
Wnt/β-Catenin Inhibition Disrupts Carboplatin Resistance in Isogenic Models of Triple-Negative Breast Cancer
Authors: Abreu de Oliveira Willy Antoni , Moens Stijn , El Laithy Youssef , van der Veer Bernard K. , Athanasouli Paraskevi , Cortesi Emanuela Elsa , Baietti Maria Francesca , Koh Kian Peng , Ventura Juan-Jose , Amant Frédéric , Annibali Daniela , Lluis Frederic
Published: July 2021

Triple-Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype, characterized by limited treatment options and higher relapse rates than hormone-receptor-positive breast cancers. Chemotherapy remains the mainstay treatment for TNBC, and platinum salts have been explored as a therapeutic alternative in neo-adjuvant and metastatic settings. However, primary and acquired resistance to chemotherapy in general and platinum-based regimens specifically strongly hampers TNBC management. In this study, we used carboplatin-resistant in vivo patient-derived xenograft and isogenic TNBC cell-line models and detected enhanced Wnt/β-catenin activity correlating with an induced expression of stem cell markers in both resistant models. In accordance, the activation of canonical Wnt signaling in parental TNBC cell lines increases stem cell markers’ expression, formation of tumorspheres and promotes carboplatin resistance. Finally, we prove that Wnt signaling inhibition resensitizes resistant models to carboplatin both in vitro and in vivo, suggesting the synergistic use of Wnt inhibitors and carboplatin as a therapeutic option in TNBC. Here we provide evidence for a prominent role of Wnt signaling in mediating resistance to carboplatin, and we establish that combinatorial targeting of Wnt signaling overcomes carboplatin resistance enhancing chemotherapeutic drug efficacy.
Immune Reconstitution-Based Score for Risk Stratification of Chronic Graft-Versus-Host Disease Patients
Authors: Serpenti Fabio , Lorentino Francesca , Marktel Sarah , Milani Raffaella , Messina Carlo , Greco Raffaella , Girlanda Stefania , Clerici Daniela , Giglio Fabio , Liberatore Carmine , Farina Francesca , Mastaglio Sara , Piemontese Simona , Guggiari Elena , Lunghi Francesca , Marcatti Magda , Carrabba Matteo G. , Bernardi Massimo , Bonini Chiara , Assanelli Andrea , Corti Consuelo , Peccatori Jacopo , Ciceri Fabio , Lupo-Stanghellini Maria Teresa
Published: July 2021

Introduction

Allogeneic stem cell transplantation survivors are at a relevant risk of developing chronic GvHD (cGvHD), which importantly affects quality of life and increases morbidity and mortality. Early identification of patients at risk of cGvHD-related morbidity could represent a relevant tool to tailor preventive strategies. The aim of this study was to evaluate the prognostic power of immune reconstitution (IR) at cGvHD onset through an IR-based score.

Methods

We analyzed data from 411 adult patients consecutively transplanted between January 2011 and December 2016 at our Institution: 151 patients developed cGvHD (median follow-up 4 years). A first set of 111 consecutive patients with cGvHD entered the test cohort while an additional consecutive 40 patients represented the validation cohort. A Cox multivariate model for OS (overall survival) in patients with cGvHD of any severity allowed the identification of six variables independently predicting OS and TRM (transplant-related mortality). A formula for a prognostic risk index using the β coefficients derived from the model was designed. Each patient was assigned a score defining three groups of risk (low, intermediate, and high).

Results

Our multivariate model defined the variables independently predicting OS at cGvHD onset: CD4+ >233 cells/mm3, NK <115 cells/mm3, IgA <0.43g/L, IgM <0.45g/L, Karnofsky PS <80%, platelets <100x103/mm3. Low-risk patients were defined as having a score ≤3.09, intermediate-risk patients >3.09 and ≤6.9, and high-risk patients >6.9. By ROC analysis, we identified a cut-off of 6.310 for both TRM and overall mortality.

In the training cohort, the 6-year OS and TRM from cGvHD occurrence were 85% (95% CI, 70-92) and 13% (95% CI, 5-25) for low-risk, 64% (95% CI, 44-89) and 30% (95% CI, 15-47) for intermediate-risk, 26% (95% CI, 10-47), and 42% (95% CI, 19-63) for high-risk patients (OS p<0.0001; TRM p = 0.015).

The validation cohort confirmed the model with a 6-year OS and TRM of 83% (95% CI, 48-96) and 8% (95% CI, 1-32) for low-risk, 78% (95% CI, 37-94) and 11% (95% CI, 1-41) for intermediate-risk, 37% (95% CI, 17-58), and 63% (95% CI, 36-81) for high-risk patients (OS p = 0.0075; TRM p = 0.0009).

Conclusions

IR score at diagnosis of cGvHD predicts GvHD severity and overall survival. IR score may contribute to the risk stratification of patients. If confirmed in a larger and multicenter-based study, IR score could be adopted to identify patients at high risk and modulate cGvHD treatments accordingly in the context of clinical trial.
Case Report: End-Stage Recurrent Glioblastoma Treated With a New Noninvasive Non-Contact Oncomagnetic Device
Authors: Baskin David S. , Sharpe Martyn A. , Nguyen Lisa , Helekar Santosh A.
Published: July 2021

Alternating electric field therapy has been approved for glioblastoma (GBM). We have preclinical evidence for anticancer effects in GBM cell cultures and mouse xenografts with an oscillating magnetic field (OMF) generating device. Here we report OMF treatment of end-stage recurrent glioblastoma in a 53-year-old man who had undergone radical surgical excision and chemoradiotherapy, and experimental gene therapy for a left frontal tumor. He experienced tumor recurrence and progressive enlargement with leptomeningeal involvement. OMF for 5 weeks was well tolerated, with 31% reduction of contrast-enhanced tumor volume and reduction in abnormal T2-weighted Fluid-Attenuated Inversion Recovery volume. Tumor shrinkage appeared to correlate with treatment dose. These findings suggest a powerful new noninvasive therapy for glioblastoma.
A Review of Current In Silico Methods for Repositioning Drugs and Chemical Compounds
Authors: He Binsheng , Hou Fangxing , Ren Changjing , Bing Pingping , Xiao Xiangzuo
Published: July 2021

Drug repositioning is a new way of applying the existing therapeutics to new disease indications. Due to the exorbitant cost and high failure rate in developing new drugs, the continued use of existing drugs for treatment, especially anti-tumor drugs, has become a widespread practice. With the assistance of high-throughput sequencing techniques, many efficient methods have been proposed and applied in drug repositioning and individualized tumor treatment. Current computational methods for repositioning drugs and chemical compounds can be divided into four categories: (i) feature-based methods, (ii) matrix decomposition-based methods, (iii) network-based methods, and (iv) reverse transcriptome-based methods. In this article, we comprehensively review the widely used methods in the above four categories. Finally, we summarize the advantages and disadvantages of these methods and indicate future directions for more sensitive computational drug repositioning methods and individualized tumor treatment, which are critical for further experimental validation.
Systematic Review and Meta-Analysis of Rituximab for Steroid-Dependent or Frequently Relapsing Nephrotic Syndrome in Children
Authors: Gao Xia , Wang Yan , Xu Zichuan , Deng Huiying , Yang Huabin , Zhong Fu
Published: July 2021

Objective: To explore the effectiveness and safety of rituximab (RTX) for steroid-dependent or frequently relapsing nephrotic syndrome via a systematic review and meta-analysis.

Methods: All the literature about RTX therapy for childhood nephrotic syndrome (NS) on PubMed, Web of Science, Cochrane Library, EMBASE, and Chinese biomedical literature database published before November 1, 2019, were conducted and selected according to the preset criteria. The Cochrane bias risk assessment tool was used to evaluate the quality of the literature included. The outcome data were analyzed by RevMan 5.3 software.

Results: There were six RCT studies that met the inclusion criteria with a moderate quality after evaluation. At the end of the treatment, the relapse rate of NS in the RTX group reduced significantly when compared with that in the control group [odds ratio (OR) = 0.11, 95% confidence interval (CI) (0.03, 0.43), p = 0.001]. The number of patients in the RTX group used less steroid or/and calcineurin inhibitors significantly than that in the control group [OR = 0.05, 95% CI (0.01, 0.28), p = 0.0007]. For children who were steroid-dependent, RTX treatment significantly reduced the dosage of the steroid, compared with that in control [standardized mean difference (SMD) = −1.49, 95% CI (−2.00, −0.99), p < 0.00001]. There was no significant reduction in protein excretion between the two groups [SMD = −0.33, 95% CI (−0.71, 0.04), p = 0.08]. Fewer serious adverse reactions of RTX in the six studies were reported and most adverse events were mild.

Conclusion: RTX is effective and safe for children with steroid-dependent or frequently relapsing nephrotic syndrome.

Systematic Review Registration: Identifier: CRD 42020150933. https://www.crd.york.ac.uk/prospero/. This review has been registered to the PROSPERO on 27 Feb 2020.
Detection of Volatile Organic Compounds as Potential Novel Biomarkers for Chorioamnionitis – Proof of Experimental Models
Authors: Goedicke-Fritz Sybelle , Werner Thomas , Niemarkt Hendrik J. , Wolfs Tim G. A. M. , Baumbach Jörg Ingo , Kemp Matthew W. , Jobe Alan H. , Rogosch Tobias , Bous Michelle , Kaiser Elisabeth , Stutz Regine , Meyer Sascha , Maier Rolf Felix , Koczulla Andreas Rembert , Spiller Owen Brad , Kramer Boris W. , Zemlin Michael
Published: July 2021

Background: Histologic chorioamnionitis is only diagnosed postnatally which prevents interventions. We hypothesized that volatile organic compounds (VOCs) in the amniotic fluid might be useful biomarkers for chorioamnionitis and that VOC profiles differ between amnionitis of different origins.

Methods: Time-mated ewes received intra-amniotic injections of media or saline (controls), or live Ureaplasma parvum serovar 3 (Up) 14, 7 or 3d prior to c-section at day 124 gestational age (GA). 100 μg recombinant ovine IL-1α was instilled at 7, 3 or 1d prior to delivery. Headspace VOC profiles were measured from amniotic fluids at birth using ion mobility spectrometer coupled with multi-capillary columns.

Results: 127 VOC peaks were identified. 27 VOCs differed between samples from controls and Up- or IL-1α induced amnionitis. The best discrimination between amnionitis by Up vs. IL-1α was reached by 2-methylpentane, with a sensitivity/specificity of 96/95% and a positive predictive value/negative predictive values of 96 and 95%. The concentration of 2-methylpentane in VOCs peaked 7d after intra-amniotic instillation of Up.

Discussion: We established a novel method to study headspace VOC profiles of amniotic fluids. VOC profiles may be a useful tool to detect and to assess the duration of amnionitis induced by Up. 2-methylpentane was previously described in the exhalate of women with pre-eclampsia and might be a volatile biomarker for amnionitis. Amniotic fluids analyzed by ion mobility spectrometry coupled with multi-capillary columns may provide bedside diagnosis of amnionitis and understanding inflammatory mechanisms during pregnancy.
Exploring the Mechanism of Indigo Naturalis in the Treatment of Ulcerative Colitis Based on TLR4/MyD88/NF-κB Signaling Pathway and Gut Microbiota
Authors: Yang Qi-yue , Ma Le-le , Zhang Chen , Lin Jun-zhi , Han Li , He Ya-nan , Xie Chun-guang
Published: July 2021

Background: Clinical trials have proven that indigo naturalis is a candidate drug for treating ulcerative colitis (UC), but its therapeutic mechanism is still unclear.

Purpose: This study aimed to evaluate the protective effect and mechanism of indigo naturalis to treat mice with dextran sulfate sodium (DSS)-induced UC.

Methods: DSS-induced UC mice were treated with indigo naturalis (200 mg/kg), indigo (4.76 mg/kg), and indirubin (0.78 mg/kg) for 1 week. The anti-UC mechanism of indigo naturalis was studied by pathological section, inflammatory factor, western blot, and 16S rRNA sequencing.

Results: According to body weight change, disease activity index, and colon length, indigo naturalis had the strongest anti DSS-induced UC effect, followed by indirubin and indigo. Pathological section showed that indigo naturalis, indigo, and indirubin could reduce the infiltration of inflammatory cells, increase the secretion of intestinal mucus, and repair the intestinal mucosa. Indigo naturalis, indigo, and indirubin could reduce IL-1β,IL-6, and TNF-α by inhibiting TLR4/MyD88/NF-κB signal transduction. Indigo naturalis and indigo could also reduce IgA and IgG both in serum and colon tissue. In addition, indigo naturalis, indigo, and indirubin could adjust the gut microbiota structure of DSS-induced UC mice, reducing the ratio of Firmicutes/Bacteroidetes and increasing the abundance of probiotics.

Conclusion: Indigo and indirubin are one of the main anti-UC components of indigo naturalis. INN could regulate intestinal flora, reduce inflammation, repair intestinal mucosa, and improve the physiological status of DSS-induced UC mice and its anti-UC mechanism may be involved in inhibiting TLR4/MyD88/NF-κB signal transduction.
Pimpinellin Inhibits Collagen-induced Platelet Aggregation and Activation Through Inhibiting Granule Secretion and PI3K/Akt Pathway
Authors: Liu Gang , Yuan Zhaowei , Tian Xiaoyun , Xiong Xiuqin , Guo Fang , Lin Zihan , Qin Zhen
Published: July 2021

Pimpinellin is a coumarin-like compound extracted from the root of Toddalia asiatica. Its effects on platelet function has not been investigated. This study found that pimpinellin pretreatment effectively inhibited collagen-induced platelet aggregation, but did not alter ADP- and thrombin-induced aggregation. Platelets pretreated with pimpinellin showed reduced α granule (CD62) level and secretion of dense granule (ATP release). Pimpinellin-treated platelets also exhibited decreased clot reaction and TxB2 production. Pimpinellin pretreatment suppressed adhesion and spreading of human platelets on the fibrinogen coated surface. Analysis of tail bleeding time of mice administered with pimpinellin (40 mg/kg) revealed that pimpinellin did not change tail bleeding time significantly, number of blood cells, and APTT and PT levels. Pimpinellin inhibited collagen-induced ex vivo aggregation of mice platelets. Immunoblotting results showed that pimpinellin suppressed collagen-induced phosphorylation of PI3K-Akt-Gsk3β and PKC/MAPK in platelets.
Matrine Impairs Platelet Function and Thrombosis and Inhibits ROS Production
Authors: Zhang Sixuan , Gui Xiang , Ding Yangyang , Tong Huan , Ju Wen , Li Yue , Li Zhenyu , Zeng Lingyu , Xu Kailin , Qiao Jianlin
Published: July 2021

Matrine is a naturally occurring alkaloid and possesses a wide range of pharmacological properties, such as anti-cancer, anti-oxidant, anti-inflammatory effects. However, whether it affects platelet function and thrombosis remains unclear. This study aims to evaluate the effect of matrine on platelet function and thrombus formation. Human platelets were treated with matrine (0–1 mg/ml) for 1 h at 37°C followed by measuring platelet aggregation, granule secretion, receptor expression by flow cytometry, spreading and clot retraction. In addition, matrine (10 mg/kg) was injected intraperitoneally into mice to measure tail bleeding time, arterial and venous thrombus formation. Matrine dose-dependently inhibited platelet aggregation and ATP release in response to either collagen-related peptide (Collagen-related peptide, 0.1 μg/ml) or thrombin (0.04 U/mL) stimulation without altering the expression of P-selectin, glycoprotein Ibα, GPVI, or αIIbβ3. In addition, matrine-treated platelets presented significantly decreased spreading on fibrinogen or collagen and clot retraction along with reduced phosphorylation of c-Src. Moreover, matrine administration significantly impaired the in vivo hemostatic function of platelets, arterial and venous thrombus formation. Furthermore, in platelets stimulated with CRP or thrombin, matrine significantly reduced Reactive oxygen species generation, inhibited the phosphorylation level of ERK1/2 (Thr202/Tyr204), p38 (Thr180/Tyr182) and AKT (Thr308/Ser473) as well as increased VASP phosphorylation (Ser239) and intracellular cGMP level. In conclusion, matrine inhibits platelet function, arterial and venous thrombosis, possibly involving inhibition of ROS generation, suggesting that matrine might be used as an antiplatelet agent for treating thrombotic or cardiovascular diseases.