bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain Structural and Functional Reorganization in Tinnitus Patients Without Hearing Loss After Sound Therapy: A Preliminary Longitudinal Study
Authors: Chen Qian , Lv Han , Wang Zhaodi , Wei Xuan , Zhao Pengfei , Yang Zhenghan , Gong Shusheng , Wang Zhenchang
Published: March 2021

Sound therapy is one of the most common first-line treatments for idiopathic tinnitus. We aimed to investigate the brain structural and functional alterations between patients with idiopathic tinnitus without hearing loss (HL) and healthy controls (HCs) and between patients before and after sound therapy (narrow band noise). Structural and resting-state functional images were acquired from 13 tinnitus patients without HL and 18 HCs before and after 6 months of narrow band sound therapy (only patients received the treatment). Voxel-based morphometry (VBM) and independent component analysis (ICA) were conducted to separately investigate the brain structural and functional changes. Associations between brain changes and clinical variables were also performed. After the treatment, the % improvement of THI score was −1.30% (± 63.40%). Compared with HCs, tinnitus patients showed gray matter and white matter atrophy in the left middle temporal gyrus at baseline, and the gray matter volume was further reduced after the treatment. The patients also showed increased white matter volume in the cingulum (cingulate), right calcarine, left rolandic operculum, and left parietal and frontal lobes. Additionally, compared with HCs, tinnitus patients exhibited positive [medial visual network (mVN) and sensorimotor network (SMN), mVN and auditory network (AN)] and negative [mVN and lateral visual network (lVN)] internetwork functional connectivity (FC) at baseline and negative [left frontoparietal network (LFPN) and dorsal attention network (DAN), AN and posterior default mode network (pDMN)] internetwork FC after the narrow band sound therapy. The patients also showed negative [LFPN and right frontoparietal network (RFPN), LFPN and RFPN, anterior default mode network (aDMN) and AN, aDMN and DAN] internetwork FC after the treatment when compared with baseline. Our findings suggest that although the outcomes of idiopathic tinnitus patients without HL were not very good when the improvement of THI scores was used as an evaluation indicator, the patients experienced significant differences in auditory-related and non-auditory-related brain reorganization before and after the narrow band sound therapy, that is, sound therapy may have a significant effect on brain reorganization in patients with idiopathic tinnitus. This study may provide some new useful information for the understanding of mechanisms underlying idiopathic tinnitus.
High-Throughput Functional Characterization of Visceral Afferents by Optical Recordings From Thoracolumbar and Lumbosacral Dorsal Root Ganglia
Authors: Bian Zichao , Guo Tiantian , Jiang Shaowei , Chen Longtu , Liu Jia , Zheng Guoan , Feng Bin
Published: March 2021

Functional understanding of visceral afferents is important for developing the new treatment to visceral hypersensitivity and pain. The sparse distribution of visceral afferents in dorsal root ganglia (DRGs) has challenged conventional electrophysiological recordings. Alternatively, Ca2+ indicators like GCaMP6f allow functional characterization by optical recordings. Here we report a turnkey microscopy system that enables simultaneous Ca2+ imaging at two parallel focal planes from intact DRG. By using consumer-grade optical components, the microscopy system is cost-effective and can be made broadly available without loss of capacity. It records low-intensity fluorescent signals at a wide field of view (1.9 × 1.3 mm) to cover a whole mouse DRG, with a high pixel resolution of 0.7 micron/pixel, a fast frame rate of 50 frames/sec, and the capability of remote focusing without perturbing the sample. The wide scanning range (100 mm) of the motorized sample stage allows convenient recordings of multiple DRGs in thoracic, lumbar, and sacral vertebrae. As a demonstration, we characterized mechanical neural encoding of visceral afferents innervating distal colon and rectum (colorectum) in GCaMP6f mice driven by VGLUT2 promotor. A post-processing routine is developed for conducting unsupervised detection of visceral afferent responses from GCaMP6f recordings, which also compensates the motion artifacts caused by mechanical stimulation of the colorectum. The reported system offers a cost-effective solution for high-throughput recordings of visceral afferent activities from a large volume of DRG tissues. We anticipate a wide application of this microscopy system to expedite our functional understanding of visceral innervations.
Developing Fast, Red-Light Optogenetic Stimulation of Spiral Ganglion Neurons for Future Optical Cochlear Implants
Authors: Huet Antoine Tarquin , Dombrowski Tobias , Rankovic Vladan , Thirumalai Anupriya , Moser Tobias
Published: March 2021

Optogenetic stimulation of type I spiral ganglion neurons (SGNs) promises an alternative to the electrical stimulation by current cochlear implants (CIs) for improved hearing restoration by future optical CIs (oCIs). Most of the efforts in using optogenetic stimulation in the cochlea so far used early postnatal injection of viral vectors carrying blue-light activated channelrhodopsins (ChRs) into the cochlea of mice. However, preparing clinical translation of the oCI requires (i) reliable and safe transduction of mature SGNs of further species and (ii) use of long-wavelength light to avoid phototoxicity. Here, we employed a fast variant of the red-light activated channelrhodopsin Chrimson (f-Chrimson) and different AAV variants to implement optogenetic SGN stimulation in Mongolian gerbils. We compared early postnatal (p8) and adult (>8 weeks) AAV administration, employing different protocols for injection of AAV-PHP.B and AAV2/6 into the adult cochlea. Success of the optogenetic manipulation was analyzed by optically evoked auditory brainstem response (oABR) and immunohistochemistry of mid-modiolar cryosections of the cochlea. In order to most efficiently evaluate the immunohistochemical results a semi-automatic procedure to identify transduced cells in confocal images was developed. Our results indicate that the rate of SGN transduction is significantly lower for AAV administration into the adult cochlea compared to early postnatal injection. SGN transduction upon AAV administration into the adult cochlea was largely independent of the chosen viral vector and injection approach. The higher the rate of SGN transduction, the lower were oABR thresholds and the larger were oABR amplitudes. Our results highlight the need to optimize viral vectors and virus administration for efficient optogenetic manipulation of SGNs in the adult cochlea for successful clinical translation of SGN-targeting gene therapy and of the oCI.
The Impact of COVID-19 Outbreak in Italy on the Sustainable Food Consumption Intention From a “One Health” Perspective
Authors: Castellini Greta , Savarese Mariarosaria , Graffigna Guendalina
Published: March 2021

Coronavirus disease (COVID-19) is a transmissible illness that was recognized in December 2019 and World Health Organization (WHO) stated a pandemic on 11 March 2020. As no cure has been developed for COVID-19 disease yet, Italy has adopted restrictive measures to avoid the spread of the virus, causing different psychological reactions (e.g., stress, anxiety) that lead people to change lifestyle and in particular the consumer orientation toward food. In addition, the COVID-19 emergency had also affected the Italian economy, causing an 11.3% decrease in GDP (gross domestic product). All these changes gave rise to a sense of instability, but it is known that new possibilities may arise in these situations. In particular, the pandemic could be the turning point to make consumers aware of the close link between human health and the ecosystems, supporting the “One Health” perspective and enhancing the orientation to consumer sustainable food products. However, little is known about how the psychological reactions to COVID-19 emergency have affected the consumers' intention to purchase sustainable food products. In order to answer these questions, a representative sample of 1,004 Italian citizens, extracted by stratified sampling, answered an online survey between May the 12th and 18th 2020. The data were analyzed using ANOVA and contingency tables. The results show that during phase one of COVID-19 disease about 30% of the sample reported that have frequently (often and always) consumed the certified sustainable food products and about 20% of the sample have intention to increase the consumption of them in the next 6 months, percentages that increase among those who feel more vulnerable regarding the risk contagion. Moreover, the psychological impact of the COVID-19 emergency has led to a change in consumers' attitudes, increasing the interest in animal and environmental issues and in human health. These aspects seem to drive the future intention of purchasing sustainable food products. This research highlights how the psychological reactions to the health emergency have changed the consumers' attitudes toward sustainability issues, leading them to follow a more sustainable diet that is recognized as a way to preserve human health, environmental preservation, and animal welfare for present and future generations.
The Crosstalk Between Tumor Cells and the Immune Microenvironment in Breast Cancer: Implications for Immunotherapy
Authors: Salemme Vincenzo , Centonze Giorgia , Cavallo Federica , Defilippi Paola , Conti Laura
Published: March 2021

Breast cancer progression is a complex process controlled by genetic and epigenetic factors that coordinate the crosstalk between tumor cells and the components of tumor microenvironment (TME). Among those, the immune cells play a dual role during cancer onset and progression, as they can protect from tumor progression by killing immunogenic neoplastic cells, but in the meanwhile can also shape tumor immunogenicity, contributing to tumor escape. The complex interplay between cancer and the immune TME influences the outcome of immunotherapy and of many other anti-cancer therapies. Herein, we present an updated view of the pro- and anti-tumor activities of the main immune cell populations present in breast TME, such as T and NK cells, myeloid cells, innate lymphoid cells, mast cells and eosinophils, and of the underlying cytokine-, cell–cell contact- and microvesicle-based mechanisms. Moreover, current and novel therapeutic options that can revert the immunosuppressive activity of breast TME will be discussed. To this end, clinical trials assessing the efficacy of CAR-T and CAR-NK cells, cancer vaccination, immunogenic cell death-inducing chemotherapy, DNA methyl transferase and histone deacetylase inhibitors, cytokines or their inhibitors and other immunotherapies in breast cancer patients will be reviewed. The knowledge of the complex interplay that elapses between tumor and immune cells, and of the experimental therapies targeting it, would help to develop new combination treatments able to overcome tumor immune evasion mechanisms and optimize clinical benefit of current immunotherapies.
Overcoming Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: Repurposed Drugs Can Improve the Protocol
Authors: Olivas-Aguirre Miguel , Torres-López Liliana , Pottosin Igor , Dobrovinskaya Oxana
Published: March 2021

Glucocorticoids (GCs) are a central component of multi-drug treatment protocols against T and B acute lymphoblastic leukemia (ALL), which are used intensively during the remission induction to rapidly eliminate the leukemic blasts. The primary response to GCs predicts the overall response to treatment and clinical outcome. In this review, we have critically analyzed the available data on the effects of GCs on sensitive and resistant leukemic cells, in order to reveal the mechanisms of GC resistance and how these mechanisms may determine a poor outcome in ALL. Apart of the GC resistance, associated with a decreased expression of receptors to GCs, there are several additional mechanisms, triggered by alterations of different signaling pathways, which cause the metabolic reprogramming, with an enhanced level of glycolysis and oxidative phosphorylation, apoptosis resistance, and multidrug resistance. Due to all this, the GC-resistant ALL show a poor sensitivity to conventional chemotherapeutic protocols. We propose pharmacological strategies that can trigger alternative intracellular pathways to revert or overcome GC resistance. Specifically, we focused our search on drugs, which are already approved for treatment of other diseases and demonstrated anti-ALL effects in experimental pre-clinical models. Among them are some “truly” re-purposed drugs, which have different targets in ALL as compared to other diseases: cannabidiol, which targets mitochondria and causes the mitochondrial permeability transition-driven necrosis, tamoxifen, which induces autophagy and cell death, and reverts GC resistance through the mechanisms independent of nuclear estrogen receptors (“off-target effects”), antibiotic tigecycline, which inhibits mitochondrial respiration, causing energy crisis and cell death, and some anthelmintic drugs. Additionally, we have listed compounds that show a classical mechanism of action in ALL but are not used still in treatment protocols: the BH3 mimetic venetoclax, which inhibits the anti-apoptotic protein Bcl-2, the hypomethylating agent 5-azacytidine, which restores the expression of the pro-apoptotic BIM, and compounds targeting the PI3K-Akt-mTOR axis. Accordingly, these drugs may be considered for the inclusion into chemotherapeutic protocols for GC-resistant ALL treatments.
Nuf2 Is a Prognostic-Related Biomarker and Correlated With Immune Infiltrates in Hepatocellular Carcinoma
Authors: Xie Xingwei , Jiang Shanshan , Li Xiang
Published: March 2021

Nuf2 participates in the regulation of cell apoptosis and proliferation by regulating the binding of centromere and spindle microtubules to achieve the correct separation of chromosomes. Previous reports have suggested that Nuf2 may play a role in various human cancers. However, the mechanism and function of Nuf2 in the development of Hepatocellular carcinoma (HCC) remains uncertain. This study investigated the prognostic potential of Nuf2 and its relation with immune cell infiltration in HCC. Nuf2 expression in tumor cells was examined using the TIMER and Oncomine databases, and its prognostic potential was assessed via the Kaplan-Meier plotter and GEPIA databases. The relationships between Nuf2 and tumor immune infiltration were analyzed using TIMER. The relationships between Nuf2 and biomarkers of tumor immune infiltration were analyzed using TIMER and GEPIA. Here we revealed that Nuf2 expression increased in tumor tissues containing HCC, and this correlated with poor relapse-free survival, disease-specific survival, progression-free survival, and overall survival in patients with HCC regardless of grades, genders, races, drinking behaviors and other clinical factors. Additionally, high expression of Nuf2 was positively correlated with differential immune cell infiltration and various immune biomarkers. Our work demonstrated that Nuf2 could be a potential prognostic biomarker and could be related to tumor immune cell infiltration in HCC.
A New RBPs-Related Signature Predicts the Prognosis of Colon Adenocarcinoma Patients
Authors: Chang Kaili , Yuan Chong , Liu Xueguang
Published: March 2021

The dysregulation of RNA binding proteins (RBPs) is closely related to tumorigenesis and development. However, the role of RBPs in Colon adenocarcinoma (COAD) is still poorly understood. We downloaded COAD’s RNASeq data from the Cancer Genome Atlas (TCGA) database, screened the differently expressed RBPs in normal tissues and tumor, and constructed a protein interaction network. COAD patients were randomly divided into a training set (N = 315) and a testing set (N = 132). In the training set, univariate Cox analysis identified 12 RBPs significantly related to the prognosis of COAD. By multivariate COX analysis, we constructed a prognostic model composed of five RBPs (CELF4, LRRFIP2, NOP14, PPARGC1A, ZNF385A) based on the lowest Akaike information criterion. Each COAD patient was scored according to the model formula. Further analysis showed that compared with the low-risk group, the overall survival rate (OS) of patients in the high-risk group was significantly lower. The area under the curve of the time-dependent receiver operator characteristic (ROC) curve was 0.722 in the training group and 0.738 in the test group, which confirmed a good prediction feature. In addition, a nomogram was constructed based on clinicopathological characteristics and risk scores. C-index and calibration curve proved the accuracy in predicting the 1-, 3-, and 5-year survival rates of COAD patients. In short, we constructed a superior prognostic and diagnostic signature composed of five RBPs, which indicates new possibilities for individualized treatment of COAD patients.
Identification of a Risk Stratification Model to Predict Overall Survival and Surgical Benefit in Clear Cell Renal Cell Carcinoma With Distant Metastasis
Authors: Chen Jiasheng , Cao Nailong , Li Shouchun , Wang Ying
Published: March 2021

Background: Clear cell renal cell carcinoma (ccRCC) is the main subtype of renal cell carcinoma and has different prognoses, especially in patients with metastasis. Here, we aimed to establish a novel model to predict overall survival (OS) and surgical benefit of ccRCC patients with distant metastasis.

Methods: Using data from the Surveillance, Epidemiology, and End Results (SEER) databases, we identified 2185 ccRCC patients with distant metastasis diagnosed from 2010 to 2015. Univariate and multivariate Cox analysis were used to identify significant prognostic clinicopathological variables. By integrating these variables, a prognostic nomogram was constructed and evaluated using C-indexes and calibration curves. The discriminative ability of the nomogram was measured by analyses of receiver operating characteristic (ROC) curve. A risk stratification model was built according to each patient's total scores. Kaplan-Meier curves were performed in the low-, intermediate- and high-risk groups to evaluate the survival benefit of surgery.

Results: Eight clinicopathological variables were included as independent prognostic factors in the nomogram: grade, marital status, T stage, N stage, bone metastasis, brain metastasis, liver metastasis, and lung metastasis. The nomogram had a better discriminative ability for predicting OS than Tumor-Node-Metastasis (TNM) stage. The C-index was 0.71 (95% CI 0.68–0.74) in the training cohort. The calibration plots demonstrated that the nomogram-based predictive outcomes had good consistency with the actual prognosis results. Total nephrectomy improved prognosis in both the low-risk and intermediate-risk groups, but partial nephrectomy could only benefit the low-risk group.

Conclusions: We constructed a predictive nomogram and risk stratification model to evaluate prognosis in ccRCC patients with distant metastasis, which was valuable for prognostic stratification and making therapeutic decisions.
Dual Inhibition of Ornithine Decarboxylase and A1 Adenosine Receptor Efficiently Suppresses Breast Tumor Cells
Authors: Ma Hongyan , Li Qizhang , Wang Jing , Pan Jing , Su Zhengding , Liu Sen
Published: March 2021

Personized treatment of breast cancer is still a challenge, and more treatment options for breast cancer are warranted. Combination therapies have been a highly appreciated strategy for breast cancer treatment in recent years, and the development of new combination therapies could improve patient outcomes. Adenosine and polyamines are both endogenous metabolites with indispensable biological functions. Adenosine binds with the A1 adenosine receptor (A1AR) to downregulate cAMP concentration, and both low cAMP content and high polyamine levels stimulate the growth and proliferation of cancer cells. In this work, we initially used a polyamine synthesis inhibitor, DFMO (α-difluoromethylornithine), and an A1AR inhibitor, DPCPX (8-cyclopentyl-1,3-dipropylxanthine) to investigate if simultaneously inhibiting A1AR and polyamine synthesis has synergistical antitumor effects. Next, we investigated a dual inhibitor (ODC-MPI-2) of A1AR and ODC (ornithine decarboxylase 1), the rate-limiting enzyme in polyamine biosynthesis. We investigated if ODC-MPI-2 could inhibit the proliferation and growth of breast cancer cells. Our data showed that DFMO and DPCPX synergistically inhibit the growth and proliferation of MCF-7 cells. We also demonstrated that ODC-MPI-2 reduces cellular polyamine levels and elevates cAMP concentration. We further showed that ODC-MPI-2 inhibits the growth, proliferation, and migration/invasion of MCF-7 cells. Finally, ODC-MPI-2 showed a preference for inhibiting triple-negative breast cancer cells. The dual inhibition of ODC and A1AR is a new combination therapy strategy for treating breast cancer, and dual inhibitors of ODC and A1AR may be effective future drugs for treating breast cancer.
Targeting KRAS: The Elephant in the Room of Epithelial Cancers
Authors: Merz Valeria , Gaule Marina , Zecchetto Camilla , Cavaliere Alessandro , Casalino Simona , Pesoni Camilla , Contarelli Serena , Sabbadini Fabio , Bertolini Monica , Mangiameli Domenico , Milella Michele , Fedele Vita , Melisi Davide
Published: March 2021

Mutations of the proto-oncogene KRAS are the most frequent gain-of-function alterations found in cancer. KRAS is mutated in about 30% of all human tumors, but it could reach more than 90% in certain cancer types such as pancreatic adenocarcinoma. Although historically considered to be undruggable, a particular KRAS mutation, the G12C variant, has recently emerged as an actionable alteration especially in non-small cell lung cancer (NSCLC). KRASG12C and pan-KRAS inhibitors are being tested in clinical trials and have recently shown promising activity. Due to the difficulties in direct targeting of KRAS, other approaches are being explored. The inhibition of target upstream activators or downstream effectors of KRAS pathway has shown to be moderately effective given the evidence of emerging mechanisms of resistance. Various synthetic lethal partners of KRAS have recently being identified and the inhibition of some of those might prove to be successful in the future. The study of escape mechanisms to KRAS inhibition could support the utility of combination strategies in overcoming intrinsic and adaptive resistance and enhancing clinical benefit of KRASG12C inhibitors. Considering the role of the microenvironment in influencing tumor initiation and promotion, the immune tumor niche of KRAS mutant tumors has been deeply explored and characterized for its unique immunosuppressive skewing. However, a number of aspects remains to be fully understood, and modulating this tumor niche might revert the immunoresistance of KRAS mutant tumors. Synergistic associations of KRASG12C and immune checkpoint inhibitors are being tested.
A Clinical Nomogram for Predicting Lymph Node Metastasis in Penile Cancer: A SEER-Based Study
Authors: Zhang Wei , Gao Pan , Gao Jingjing , Wu Xu , Liu Guodong , Zhang Xiansheng
Published: March 2021

Purpose:We developed a nomogram to predict the possibility of lymph node metastasis in patients with squamous cell carcinoma of the penis.

Methods:Identifying patients with squamous cell carcinoma of the penis diagnosed between 2004 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate analyses were carried out by logistic regression to assess significant predictors associated with lymph node metastasis. A nomogram was established and validated by a calibration plot and receptor operating characteristic curve (ROC) analysis.

Results:A total of 1,016 patients with penile squamous cell carcinoma (SCCP) were enrolled in this study. One hundred and ninety-five patients (19%) had lymph node involvement (N1-3). Multivariate analysis showed that age, primary tumor site, grade, tumor size, and T stage were identified as being significantly (p< 0.05) associated with lymph node involvement. All the above factors that showed a statistically significant predictive capability were selected for building the nomogram. This model had a calibration slope of 0.9 and a c-index of 0.776, indicating the good discrimination and effectiveness of the nomogram in predicting lymph node status.

Conclusion:Although the prediction model has some limitations, the nomogram revealed the relationship between the clinicopathological characteristics of SCCP patients and the risk of lymph node metastasis. This tool will assist patients in counseling and guide treatment decisions for SCCP patients.
Fertility Preservation in Female Pediatric Patients With Cancer: A Clinical and Regulatory Issue
Authors: Brancati Serena , Gozzo Lucia , Longo Laura , Vitale Daniela Cristina , Russo Giovanna , Drago Filippo
Published: March 2021

Fertility preservation represents one important goal of cancer patients’ management due to the high impact on health and quality of life of survivors. The available preventive measures cannot be performed in all patients and are not feasible in all health-care facilities. Therefore, the pharmacological treatment with GnRHa has become a valuable non-invasive and well-tolerated alternative, especially in those who cannot access to cryopreservation options due to clinical and/or logistic issues. Supporting data demonstrate a significant advantage for the survivors who received GnRHa in the long-term maintenance of ovarian function and preservation of fertility. The prevention of the risk of ovarian failure with GnRHa is a typical off-label use, defined as the administration of a medicinal product not in accordance with the authorized product information. Italy has officially recognized the off-label use of GnRHa in adult women at risk of premature and permanent menopause following chemotherapy. However, fertility preservation still represents an unmet medical need in adolescents who cannot access to other treatment options.
Roles of Non-Coding RNAs in Cervical Cancer Metastasis
Authors: Cheng Tanchun , Huang Shouguo
Published: March 2021

Metastasis remains to be a huge challenge in cancer therapy. The mechanism underlying cervical cancer metastasis is not well understood and needs to be elucidated. Recent studies have highlighted the diverse roles of non-coding RNAs in cancer progression and metastasis. Increasing numbers of miRNAs, lncRNAs and circRNAs are found to be dysregulated in cervical cancer, associated with metastasis. They have been shown to regulate metastasis through regulating metastasis-related genes, epithelial-mesenchymal transition, signaling pathways and interactions with tumor microenvironment. Moreover, miRNAs can interact with lncRNAs and circRNAs respectively during this complex process. Herein, we review literatures up to date involving non-coding RNAs in cervical cancer metastasis, mainly focus on the underlying mechanisms and highlight the interaction network between miRNAs and lncRNAs, as well as circRNAs. Finally, we discuss the therapeutic prospects.
Grade G2 Rectal Neuroendocrine Tumor Is Much More Invasive Compared With G1 Tumor
Authors: Li Yi-Wei , He Yi-Ping , Liu Fang-Qi , Peng Jun-Jie , Cai San-Jun , Xu Ye , Wang Ming-He
Published: March 2021

Background

To compare clinicopathologic feature of rectal neuroendocrine tumor (NET) grade G1 with G2 NET.

Methods

Six hundred-one cases of rectal G1 and G2 NETs diagnosed in our center were analyzed.

Results

Of 601 cases of rectal NET, 515 cases were with grade G1 and 86 cases were with grade G2. Median tumor size was 0.7 cm. Compared with G1 NET, G2 tumors were with significantly larger tumor size (0.8 vs 2.2 cm, p < 0.001), less percentages of patients with tumors confined to submucosa (92.6 vs 42.8%, p < 0.001), more frequent presence of microvascular invasion (MVI) (3.6 vs 16.9%, p < 0.001) or peri-neural invasion (PNI) (2.0 vs 24.1%, p < 0.001). Incidence of lymph node and distant metastasis was 5.2 and 2.1% in G1 NET compared with 44.2 and 31.4% in G2 tumor, respectively (p < 0.001). For tumors sized 1–2 cm and confined to submucosa, incidence of lymph node metastasis was 6.1% for G1 NET compared with 21.1% for G2 NET. Status of MVI/PNI was predictive of lymph node metastasis for G2 tumor rather than G1 NET in this subgroup.

Conclusions

Rectal G2 NET was much more invasive with significantly elevated prevalence of lymph node metastasis compared with G1 tumor.
The Tree Shrew as a Model for Cancer Research
Authors: Lu Tao , Peng Hongmei , Zhong Liping , Wu Pan , He Jian , Deng Zhiming , Huang Yong
Published: March 2021

Animal disease models are necessary in medical research, and an appropriate animal model is of great importance for studies about the prevention or treatment of cancer. The most important thing in the selection of animal models is to consider the similarity between animals and humans. The tree shrew (Tupaia belangeri) is a squirrel-like mammal which placed in the order Scandentia. Whole-genome sequencing has revealed that tree shrews are extremely similar to primate and humans than to rodents, with many highly conserved genes, which makes the data from studies that use tree shrews as models more convincing and the research outcomes more easily translatable. In tumor research, tree shrews are often used as animal models for hepatic and mammary cancers. As research has progressed, other types of tree shrew tumor models have been developed and exhibit clinical manifestations similar to those of humans. Combining the advantages of both rodents and primates, the tree shrew is expected to be the most powerful animal model for studying tumors.
Cord Blood Cytokine Levels Correlate With Types of Placental Pathology in Extremely Preterm Infants
Authors: Zein Hussein , Mohammad Khorshid , Leijser Lara M. , Brundler Marie-Anne , Kirton Adam , Esser Michael J.
Published: March 2021

Background:Placental abnormalities are associated with inflammation and have been linked to brain injury in preterm infants. We studied the relationship between placental pathology and the temporal profiles of cytokine levels in extremely pre-term infants.

Study Design:We prospectively enrolled 55 extremely preterm infants born between June 2017 and July 2018. Levels of 27 cytokines were measured in blood drawn from the umbilical artery at birth and from infants at 1–3 and 21–28 days of life. Placental pathology was grouped as normal (N), inflammation (I), vasculopathy (V), or combined vasculopathy and inflammation (V+I).

Results:Complete data was available from 42 patients. Cord blood median levels of cytokines differed between groups with the highest levels observed in group V+I as compared to groups N, I and V for the following: Eotaxin (p= 0.038), G-CSF (p= 0.023), IFN-γ (p= 0.002), IL-1ra (p< 0.001), IL-4 (p= 0.005), IL-8 (p= 0.010), MCP-1 (p= 0.011), and TNFα (p= 0.002).Post-hocanalysis revealed sex differences between and within the placental pathology groups.

Conclusion:Specific types of placental pathology may be associated with differential cytokine profiles in extremely pre-term infants. Sampling from cord blood may help assess the pathological status of the placenta and potentially infer outcome risks for the infant.
Preliminary Experience With the New Amplatzer™ Trevisio™ Delivery System in Transcatheter Atrial Septal Defect Closures in Children
Authors: Haddad Raymond N. , Khraiche Diala , Bonnet Damien , Meot Mathilde , Malekzadeh-Milani Sophie
Published: March 2021

Objectives: To evaluate safety, efficacy, and technical advantages of Amplatzer™ Trevisio™ intravascular delivery system (ATIDS) in percutaneous atrial septal defect (ASD) closure in children.

Background: The Trevisio™ is a novel delivery system designed for accurate and facilitated implantation of Amplatzer™ devices. There are no published clinical reports so far.

Methods: During September 2020, 9 children with anatomically challenging ASDs underwent attempted transcatheter closure using ATIDS to deliver Amplatzer™ Septal occluders (ASO). All interventions were performed under general anesthesia, trans-esophageal echocardiography (TOE), and fluoroscopic guidance. Standard safety, immediate, and 60-days outcomes were prospectively assessed.

Results: The median age was 8.1 (5.1–16.9) years and the median bodyweight was 30 (18–63) kg. Six patients had isolated secundum-type ASDs with absent anterosuperior rims including one with an aneurysmal septum. Three patients had unclassical defects associated with complex congenital heart anomalies. Eight devices were delivered from the femoral vein and the jugular vein was accessed in one patient with interrupted inferior caval vein and azygos continuation. All implantations were successful. The shape, position, and orientation of the ASO were identical before and after release on TOE and fluoroscopy. There was no device embolization or serious complication following closure. Complete shunt closure was confirmed on follow-up.

Conclusions: We report the first clinical experience with ATIDS in transcatheter ASD pediatric closures. Safety and efficacy were witnessed in our case-series. The major advantage of reduced-tension deployment and reliable precision in device positioning is highly beneficial in challenging anatomies and unusual access.
Ethnomedicinal Plants of Hasankeyf (Batman-Turkey)
Authors: Yeşil Yeter , İnal İlyas
Published: March 2021

Hasankeyf is an ancient city, dating back to more than 10,000 years, in the Southeast Anatolia Region of Turkey. The area is separated by the Tigris River on both sides and located in the Batman province. However, as a result of a dam project, in February 2020, this ancient city and some of its surrounding villages were totally flooded. The residents were moved to new settlements. This study aimed to prevent the possible loss of ethnomedicinal knowledge of plants due to migration as well as to pass on this knowledge to the future generations. The field studies were conducted between March 2017 and November 2019 in the city center and 22 rural settlements of Hasankeyf. Also, the areas where intensive migration was experienced were visited frequently. Interviews were conducted with a total of 131 participants (76 women and 55 men) while gathering plants with them. Information was collected through interviews and questionnaires. The results were analyzed by quantitative indices of information consensus factor (FIC) and use value (UV). A total of 94 plant taxa belonging to 40 families were identified in the study area. The most common medicinal plant families are Lamiaceae (13), Asteraceae (8), Rosaceae (6), Malvaceae (6), Amaryllidaceae (5), Brassicaceae (4), and Solanaceae (4). The most common preparations were infusion, fresh application, and crushing. The taxa having the highest count of use value (UV) were Teucrium polium, Matricaria aurea, Urtica dioica, Mentha longifolia, and Quercus brantii. Besides, the recorded ailments were grouped into categories based on information provided by the interviewees. The most important use categories among the informants were diabetes, gastrointestinal disorders, respiratory disorders, and dermatological disorders. The present study represents the first medical-ethnobotanical documentation and analysis of the traditional use of medicinal plants in Hasankeyf.
Circ_CLASP2 Regulates High Glucose-Induced Dysfunction of Human Endothelial Cells Through Targeting miR-140-5p/FBXW7 Axis
Authors: Zhang Qin , Long Jing , Li Nannan , Ma Xuelian , Zheng Lisheng
Published: March 2021

Hyperglycemia exposure results in the dysfunction of endothelial cells (ECs) and the development of diabetic complications. Circular RNAs (circRNAs) have been demonstrated to play critical roles in EC dysfunction. The current study aimed to explore the role and mechanism of circRNA CLIP–associating protein 2 (circ_CLASP2, hsa_circ_0064772) on HG-induced dysfunction in human umbilical vein endothelial cells (HUVECs). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess the levels of circ_CLASP2, miR-140-5p and F-box, and WD repeat domain-containing 7 (FBXW7). The stability of circ_CLASP2 was identified by the actinomycin D and ribonuclease (RNase) R assays. Cell colony formation, proliferation, and apoptosis were measured by a standard colony formation assay, colorimetric 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) assay, and flow cytometry, respectively. Western blot analysis was performed to determine the expression of related proteins. Targeted correlations among circ_CLASP2, miR-140-5p, and FBXW7 were confirmed by dual-luciferase reporter assay. High glucose (HG) exposure downregulated the expression of circ_CLASP2 in HUVECs. Circ_CLASP2 overexpression or miR-140-5p knockdown promoted proliferation and inhibited apoptosis of HUVECs under HG conditions. Circ_CLASP2 directly interacted with miR-140-5p via pairing to miR-140-5p. The regulation of circ_CLASP2 overexpression on HG-induced HUVEC dysfunction was mediated by miR-140-5p. Moreover, FBXW7 was a direct target of miR-140-5p, and miR-140-5p regulated HG-induced HUVEC dysfunction via FBXW7. Furthermore, circ_CLASP2 mediated FBXW7 expression through sponging miR-140-5p. Our current study suggested that the overexpression of circ_CLASP2 protected HUVEC from HG-induced dysfunction at least partly through the regulation of the miR-140-5p/FBXW7 axis, highlighting a novel therapeutic approach for the treatment of diabetic-associated vascular injury.
Role of Circular RNA in Kidney-Related Diseases
Authors: Chen Xin-Tian , Li Zhong-Wei , Zhao Xue , Li Min-Le , Hou Ping-Fu , Chu Su-Fang , Zheng Jun-Nian , Bai Jin
Published: March 2021

The kidney is vital in maintaining fluid, electrolyte, and acid–base balance. Kidney-related diseases, which are an increasing public health issue, can happen to people of any age and at any time. Circular RNAs (circRNAs) are endogenous RNA that are produced by selective RNA splicing and are involved in progression of various diseases. Studies have shown that various kidney diseases, including renal cell carcinoma, acute kidney injury, and chronic kidney disease, are linked to circRNAs. This review outlines the characteristics and biological functions of circRNAs and discusses specific studies that provide insights into the function and potential of circRNAs for application in the diagnosis and treatment of kidney-related diseases.
Chinese Medicine Formula Kai-Xin-San Ameliorates Neuronal Inflammation of CUMS-Induced Depression-like Mice and Reduces the Expressions of Inflammatory Factors via Inhibiting TLR4/IKK/NF-κB Pathways on BV2 Cells
Authors: Qu Suchen , Liu Mengqiu , Cao Cheng , Wei Chongqi , Meng Xue-Er , Lou Qianyin , Wang Bin , Li Xuan , She Yuyan , Wang Qingqing , Song Zhichao , Han Zhengxiang , Zhu Yue , Huang Fei , Duan Jin-Ao
Published: March 2021

Kai-Xin-San (KXS) is a traditional Chinese medicinal formula composed of Ginseng Radix et Rhizoma, Polygalae Radix, Acori Tatarinowii Rhizoma, and Poria for relieving major depressive disorder and Alzheimer’s disease in traditional Chinese medicine (TCM) clinics. Previous studies on the antidepressant mechanism of KXS mainly focused on neurotransmitter and neurotrophic factor regulation, but few reports exist on neuronal inflammation regulation. In the current study, we found that KXS exerted antidepressant effects in chronic unpredictable mild stress-induced depression-like mice according to the results of behavioral tests. Meanwhile, KXS also inhibited the activation of microglia and significantly reduced the expression of pro-inflammatory cytokines such as IL-1β, IL−2, and TNF-α in the hippocampus of mice. In mice BV2 microglia cell lines, KXS extract reduced the expression of inflammatory factors in BV2 cells induced by lipopolysaccharide via inhibiting TLR4/IKK/NF-κB pathways, which was also validated by the treatment of signaling pathway inhibitors such as TAK-242 and JSH-23. T0hese data implied that the regulation of pro-inflammatory cytokines in microglia might account for the antidepressant effect of KXS, thereby providing more scientific information for the development of KXS as an alternative therapy for major depressive disorder.
Pharmacological Modulation of BET Family in Sepsis
Authors: Wang Nian , Wu Runliu , Comish Paul B. , Kang Rui , Tang Daolin
Published: March 2021

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis 3.0) recommended defining sepsis as a life-threatening organ dysfunction caused by the host's uncontrolled response to infection. The bromodomain and extra-terminal (BET) protein family (such as BRD2, BRD3, and BRD4), an epigenetic regulator of gene transcription, has recently been recognized as a significant septic regulator of inflammation and immune response, including cytokine and chemokine production. Mechanistically, the two N-terminal conserved tandem bromodomains (namely the first bromodomain [BD1] and the second bromodomain [BD2]) favor the binding of BETs to acetylated histones or transcription factors, thereby initiating gene transcription machinery after CycT1 and CDK9 (also known as P-TEFb) are recruited to gene promoters to phosphorylate RNA pol II. Notably, BD1 and BD2 are not functionally redundant because they have different target genes in innate immune cells. Small-molecule BET inhibitors (BETis) for different BDs, such as I-BET, JQ1, I-BET151, apabetalone, RVX-297, and dBET1 have shown promising therapeutic effects in experimental sepsis models. This mini-review summarizes the emerging roles of BETs and the applications of BETis in sepsis, discusses the existing shortcomings of BETis, and introduces possible future research directions in this area.
Influence of Detector Size and Positioning on Near-Infrared Measurements and Iso-pathlength Point of Turbid Materials
Authors: Duadi Hamootal , Feder Idit , Fixler Dror
Published: March 2021

Measuring physical phenomena in an experimental system is commonly limited by the detector. When dealing with spatially defined behaviors, the critical parameter is the detector size. In this work, we examine near-infrared (NIR) measurements of turbid media using different size detectors at different positions. We examine cylindrical and semi-infinite scattering samples and measure their intensity distribution. An apparent crossing point between samples with different scatterings was previously discovered and named the iso-pathlength point (IPL). Monte Carlo simulations show the expected changes due to an increase in detector size or similarly as the detector’s location is distanced from the turbid element. First, the simulations show that the intensity profile changes, as well as the apparent IPL. Next, we show the average optical pathlength, and as a result, the differential pathlength factor, are mostly influenced by the detector size in the range close to the source. Experimental measurements using different size detectors at different locations validate the influence of these parameters on the intensity profiles and apparent IPL point. These findings must be considered when assessing optical parameters based on multiple scattering models. In cases such as NIR assessment of tissue oxygenation, size and location may cause false results for absorption or optical path.
Proteinuria as a Biomarker for COVID-19 Severity
Authors: Ouahmi Hajar , Courjon Johan , Morand Lucas , François Juliette , Bruckert Vincent , Lombardi Romain , Esnault Vincent , Seitz-Polski Barbara , Demonchy Elisa , Dellamonica Jean , Boyer-Suavet Sonia
Published: March 2021

Background

Renal involvement in syndrome coronavirus 2 (SARS-CoV-2) infection has been retrospectively described, especially acute kidney injury (AKI). However, quantitative proteinuria assessment and its implication in coronavirus disease 2019 (COVID-19) remain unknown.

Methods

In this prospective, multicenter study in France, we collected clinical and biological data including urinary protein to creatine ratio (UPCR) in patients presenting with moderate to severe COVID-19. Clinical outcome was analyzed according to the level of UPCR.

Results

42/45 patients (93.3%) had renal involvement (abnormal urinary sediment and/or AKI). Significant proteinuria occurred in 60% of patients. Urine protein electrophoresis showed tubular protein excretion in 83.8% of patients with proteinuria. Inflammatory parametersand D-dimer concentrations correlated with proteinuria level. Patients who required intensive care unit (ICU) admission had higher proteinuria (p = 0.008). On multivariate analysis, proteinuria greater than 0.3 g/g was related to a higher prevalence of ICU admission [OR = 4.72, IC95 (1.16–23.21), p = 0.03], acute respiratory distress syndrome (ARDS) [OR = 6.89, IC95 (1.41–53.01, p = 0.02)], nosocomial infections [OR = 3.75, IC95 (1.11–13.55), p = 0.03], longer inpatient hospital stay (p = 0.003).

Conclusion

Renal involvement is common in moderate to severe SARS-CoV-2 infection. Proteinuria at baseline is an independent risk factor for increased hospitalization duration and ICU admission in patients with COVID-19.
Skeletal Muscle Wasting and Function Impairment in Intensive Care Patients With Severe COVID-19
Authors: Andrade-Junior Mario Chueire de , Salles Isabel Chateaubriand Diniz de , de Brito Christina May Moran , Pastore-Junior Laerte , Righetti Renato Fraga , Yamaguti Wellington Pereira
Published: March 2021

Background: Intensive care patients commonly develop muscle wasting and functional impairment. However, the role of severe COVID-19 in the magnitude of muscle wasting and functionality in the acute critical disease is unknown.

Objective: To perform a prospective characterization to evaluate the skeletal muscle mass and functional performance in intensive care patients with severe COVID-19.

Methods: Thirty-two critically ill patients (93.8% male; age: 64.1 ± 12.6 years) with the diagnosis of the severe COVID-19 were prospectively recruited within 24 to 72 h following intensive care unit (ICU) admission, from April 2020 to October 2020, at Hospital Sírio-Libanês in Brazil. Patients were recruited if older than 18 years old, diagnosis of severe COVID-19 confirmed by RT-PCR, ICU stay and absence of limb amputation. Muscle wasting was determined through an ultrasound measurement of the rectus femoris cross-sectional area, the thickness of the anterior compartment of the quadriceps muscle (rectus femoris and vastus intermedius), and echogenicity. The peripheral muscle strength was assessed with a handgrip test. The functionality parameter was determined through the ICU mobility scale (IMS) and the International Classification of Functioning, Disability and Health (ICF). All evaluations were performed on days 1 and 10.

Results: There were significant reductions in the rectus femoris cross-section area (−30.1% [95% IC, −26.0% to −34.1%]; P < 0.05), thickness of the anterior compartment of the quadriceps muscle (−18.6% [95% IC, −14.6% to 22.5%]; P < 0.05) and handgrip strength (−22.3% [95% IC, 4.7% to 39.9%]; P < 0.05) from days 1 to 10. Patients showed increased mobility (0 [0–5] vs 4.5 [0–8]; P < 0.05), improvement in respiratory function (3 [3–3] vs 2 [1–3]; P < 0.05) and structure respiratory system (3 [3–3] vs 2 [1–3]; P < 0.05), but none of the patients returned to normal levels.

Conclusion: In intensive care patients with severe COVID-19, muscle wasting and decreased muscle strength occurred early and rapidly during 10 days of ICU stay with improved mobility and respiratory functions, although they remained below normal levels. These findings may provide insights into skeletal muscle wasting and function in patients with severe COVID-19.