bluuebunny/crossref_metadata_2025 huggingface dataset:
Conflicting Roles of ZFP36L1 in Regulating the Progression of Muscle Invasive Bladder Cancer
Authors: Yuan Simin , Zhai Yujia , Tao Tao , Zhang Xiaolong , Bashir Ghassan , Li Guangzhi , Wang Gang , Wu Song
Published: March 2022

As the most common carcinoma of the human urinary system, bladder cancer (BC) is characterized by high recurrence, and poor prognosis after metastasis. In the past decade, genome-wide expression and sequencing studies had identified key genes and pathways related to BC, and pictured the comprehensive molecular features of the disease. Our previous study indicated that the coding gene of zinc finger protein 36 like 1 (ZFP36L1) mutated frequently in bladder tumor tissues and may be a potential suppressor for BC. The present study aimed to further investigate the role of ZFP36L1 in BC, and the survival analysis based on TCGA dataset revealed that high expressing level of ZFP36L1 associated with poorer prognosis of the patients with muscle invasive bladder cancer (MIBC). The associations of ZFP36L1 expression to the clinicopathological and molecular biological features also implicated the high level of ZFP36L1 may related to worse outcomes of patients. Also, GSEA indicated that high expression of ZFP36L1 significantly associated with enhanced activity of cancer metastasis related pathways. Functions of ZFP36L1 in MIBC were investigated further, and it was found that while ZFP36L1 suppressed the self-renewal of bladder cancer cells, it promoted the invasiveness of the cells markedly. Taken together, these results led to the conflicting roles of ZFP36L1 in regulating the progression of MIBC, and revealed further researches are needed to clarify the functions of the gene in tumor initiation and recurrence.
Structural Insights Into the Effects of Interactions With Iron and Copper Ions on Ferritin From the Blood Clam Tegillarca granosa
Authors: Ming Tinghong , Jiang Qinqin , Huo Chunheng , Huan Hengshang , Wu Yan , Su Chang , Qiu Xiaoting , Lu Chenyang , Zhou Jun , Li Ye , Han Jiaojiao , Zhang Zhen , Su Xiurong
Published: March 2022

In addition to its role as an iron storage protein, ferritin can function as a major detoxification component in the innate immune defense, and Cu2+ ions can also play crucial antibacterial roles in the blood clam, Tegillarca granosa. However, the mechanism of interaction between iron and copper in recombinant Tegillarca granosa ferritin (TgFer) remains to be investigated. In this study, we investigated the crystal structure of TgFer and examined the effects of Fe2+ and Cu2+ ions on the TgFer structure and catalytic activity. The crystal structure revealed that TgFer presented a typically 4–3–2 symmetry in a cage-like, spherical shell composed of 24 identical subunits, featuring highly conserved organization in both the ferroxidase center and the 3-fold channel. Structural and biochemical analyses indicated that the 4-fold channel of TgFer could be serviced as potential binding sites of metal ions. Cu2+ ions appear to bind preferentially with the 3-fold channel as well as ferroxidase site over Fe2+ ions, possibly inhibiting the ferroxidase activity of TgFer. Our results present a structural and functional characterization of TgFer, providing mechanistic insight into the interactions between TgFer and both Fe2+ and Cu2+ ions.
Focusing on Mechanoregulation Axis in Fibrosis: Sensing, Transduction and Effecting
Authors: Wen Dongsheng , Gao Ya , Ho Chiakang , Yu Li , Zhang Yuguang , Lyu Guozhong , Hu Dahai , Li Qingfeng , Zhang Yifan
Published: March 2022

Fibrosis, a pathologic process featured by the excessive deposition of connective tissue components, can affect virtually every organ and has no satisfactory therapy yet. Fibrotic diseases are often associated with organ dysfunction which leads to high morbidity and mortality. Biomechanical stmuli and the corresponding cellular response havebeen identified in fibrogenesis, as the fibrotic remodeling could be seen as the incapacity to reestablish mechanical homeostasis: along with extracellular matrix accumulating, the physical property became more “stiff” and could in turn induce fibrosis. In this review, we provide a comprehensive overview of mechanoregulation in fibrosis, from initialing cellular mechanosensing to intracellular mechanotransduction and processing, and ends up in mechanoeffecting. Our contents are not limited to the cellular mechanism, but further expand to the disorders involved and current clinical trials, providing an insight into the disease and hopefully inspiring new approaches for the treatment of tissue fibrosis.
Hoffmann Reflex Measured From Lateral Gastrocnemius Is More Reliable Than From Soleus Among Elderly With Peripheral Neuropathy
Authors: Song Qipeng , Sun Mengzi , Lewis Kelsey , Choi Jung Hun , Manor Brad , Li Li
Published: March 2022

Introduction

Peripheral neuropathy (PN) affects up to 20% of the population over the age of 60. Hoffmann reflex (H-reflex) may assess PN adaptation by measuring the function of the peripheral neural system and central nervous system (CNS) modulation. This project aimed to find a reliable muscle among triceps surae muscles during standing and walking among the PN population.

Materials and Methods

Sixteen older adults (> 65 years of age) diagnosed with PN were recruited in this study. The H-reflex test was conducted on the muscle belly of the soleus (SOL), the medial (MG), and lateral gastrocnemius (LG) during standing and walking (heel contact, midstance, and toe-off phases). All measurements were collected on two occasions, separated by at least 7 days. Intraclass correlation coefficients (ICCs) and their confidence intervals (CIs) were used to examine the consistency of the H-reflex outcome variables in the repeated tests for all three tested muscles.

Results

The ICCs of H-index during standing and the three walking phases were poor to moderate in SOL (0.486∼0.737) and MG (0.221∼0.768), and moderate to high in LG (0.713∼0.871). The ICCs of H/M ratio were poor to moderate in SOL (0.263∼0.702) and MG (0.220∼0.733), and high in LG (0.856∼0.958).

Conclusion

The H-reflex of LG was more reliable than SOL and MG during standing and walking among older adults with peripheral neuropathy. It is crucial for future studies in this population to study H-reflex of LG, not SOL and MG, for more reliable results.
Repeat Closed-Head Injury in Male Rats Impairs Attention but Causes Heterogeneous Outcomes in Multiple Measures of Impulsivity and Glial Pathology
Authors: Vonder Haar Cole , Wampler Sarah K. , Bhatia Henna S. , Ozga Jenny E. , Toegel Cory , Lake Anastasios D. , Iames Christopher W. , Cabral Caitlyn E. , Martens Kris M.
Published: March 2022

Repetitive mild traumatic brain injury, or concussion, can lead to the development of long-term psychiatric impairments. However, modeling these deficits is challenging in animal models and necessitates sophisticated behavioral approaches. The current set of studies were designed to evaluate whether a rubberized versus metal impact tip would cause functional deficits, the number of injuries required to generate such deficits, and whether different psychiatric domains would be affected. Across two studies, male rats were trained in either the 5-choice serial reaction time task (5CSRT; Experiment 1) to assess attention and motor impulsivity or concurrently on the 5CSRT and the delay discounting task (Experiment 2) to also assess choice impulsivity. After behavior was stable, brain injuries were delivered with the Closed-head Injury Model of Engineered Rotational Acceleration (CHIMERA) either once per week or twice per week (Experiment 1) or just once per week (Experiment 2). Astrocyte and microglia pathology was also assayed in relevant regions of interest. CHIMERA injury caused attentional deficits across both experiments, but only increased motor impulsivity in Experiment 1. Surprisingly, choice impulsivity was actually reduced on the Delay Discounting Task after repeat injuries. However, subsequent analyses suggested potential visual issues which could alter interpretation of these and attentional data. Subtle changes in glial pathology immediately after the injury (Experiment 1) were attenuated after 4 weeks recovery (Experiment 2). Given the heterogenous findings between experiments, additional research is needed to determine the root causes of psychiatric disturbances which may arise as a results of repeated brain injuries.
Paediatric Intracranial Aneurysms: Long-term Angiographic and Clinical Outcomes in a Contemporary Series
Authors: Lu Junlin , Li Mingtao , Zhao Yuanli , Zhao Yang , Chen Xiaolin , Zhao Jizong
Published: March 2022

Objective

Paediatric aneurysms are rare and difficult to treat. Studies on the long-term angiographic and clinical outcomes conducted within the past decade are lacking. We aimed to investigate the clinical and radiographic outcomes of paediatric aneurysms treated with different strategies in a contemporary series.

Methods

We performed a retrospective medical record review of paediatric patients examined at our institution between 2011 and 2018. Patient charts were retrospectively reviewed for age, presentation, type and location of the aneurysm, modalities of treatment, complications, and clinical and angiographic outcomes. The rates of aneurysm recurrence and de novo formation were determined.

Results

We evaluated 61 patients (mean age, 11.6 years; 23 females, 38 males) with 69 intracranial aneurysms. Their presentations included headache, neurological deficits, aneurysmal subarachnoid haemorrhage, incidental aneurysm, and traumatic subarachnoid haemorrhage. Of the aneurysms, 30 (49.2%) were giant. Forty-five (73.8%) patients underwent treatment for their aneurysms, and 16 (26.2%) patients were managed conservatively. The perioperative morbidity rate was 17.8%. There were no deaths. The long-term morbidity rate was 4.6%. The clinical outcomes were favourable in 82.2 and 95.3% at discharge and follow-up, respectively (mean, 41.5 months; range, 1.5–9 years). For treated aneurysms, 2/43 (4.6%) risk of aneurysm recurrence, 1/43 (2.3%) risk of aneurysm bleeding, 1/43 (2.3%) risk of de novo aneurysm formation. The annual bleeding, recurrence, and de novo formation or growth risk were 0.7, 1.4, and 0.7%, respectively.

Conclusions

In neurovascular centres where microsurgical and endovascular options are available, most children with intracranial aneurysms can be successfully treated with low morbidity and mortality. However, they have higher rates of recurrence and a greater risk of de novo formation or growth than their adult counterparts, which mandates lifelong follow-up.
The Effect of Branched Chain Amino Acid Supplementation on Stroke-Related Sarcopenia
Authors: Park Min Kyu , Lee Sook Joung , Choi Eunseok , Lee Sangjee , Lee JungSoo
Published: March 2022

Background

Stroke-related sarcopenia is caused by various factors, such as brain damage, systemic catabolic state, skeletal muscle imbalance, and malnutrition. In the long-term care plan after stroke, appropriate rehabilitation strategies to achieve maximum functional improvement and prevent the development of sarcopenia are important. This study has investigated the effect of branched-chain amino acid (BCAA) supplementation on sarcopenia after stroke. We also evaluated the effect of BCAA on functional improvement during the intensive rehabilitation period.

Methods

Patients with subacute stroke with stroke-related disabilities were enrolled and given dietary supplement powder containing BCAAs for 1 month. These BCAAs were supplied through the nutrition team during feeding time. Patients whose age, sex, and stroke lesions were similar to those of the study group were enrolled in the control group through medical record review. Both groups received personalized intensive inpatient rehabilitation therapy in a single-unit rehabilitation center. All patients' target calories were calculated regularly by the nutritional support team in our institution. Sarcopenia status was evaluated using grip strength and the skeletal muscle index (SMI), which was assessed by dual-energy X-ray absorptiometry (DEXA). The functional status associated with stroke was evaluated every month, including activities of daily living, balance, gait, and swallowing.

Results

A total of 54 patients were enrolled, with 27 patients in each of the two groups. The study group showed significantly greater improvement in SMI after intervention than the control group. Both groups improved functionally over time, but the improvement in the study group was significantly greater than that in the control group. Univariate analysis revealed that patients with better functional status had a greater SMI with a combination of BCAA supplementation and intensive rehabilitation therapy.

Conclusion

Our results showed a positive effect of BCAA supplementation on sarcopenia after stroke. We also found that nutritional support helps functional improvement during neurological recovery. These results suggest that comprehensive rehabilitation intervention combined with BCAA supplementation could be a helpful option during the critical period of post-stroke neurological recovery.
Altered Glymphatic System in Middle-Aged cART-Treated Patients With HIV: A Diffusion Tensor Imaging Study
Authors: Nguchu Benedictor Alexander , Zhao Jing , Wang Yanming , de Dieu Uwisengeyimana Jean , Wang Xiaoxiao , Qiu Bensheng , Li Hongjun
Published: March 2022

Objective:

The brain relies on the glymphatic system to clear metabolic wastes and maintain brain homeostasis to fulfill its functions better. Yet, the complexity of the glymphatic flow and clearance and its changes in HIV infection and its role in neurocognitive dysfunction remain poorly understood. This study aims to explore the impact of HIV and combination antiretroviral therapy (cART) on the glymphatic system and establish a potential biomarker of HIV-associated neurocognitive disorders (HAND).

Methods

Here, we examined the glymphatic profiles of middle-aged virosuppressed patients with HIV (n = 27) receiving cART over 1–6 years and healthy controls (n = 28) along the perivascular space (PVS) using diffusion tensor image analysis along the perivascular space (ALPS) with guided and unguided approaches. We later combined data from these analyses to investigate MRI glymphatic correlates of cognitive impairment and other clinical tests of HIV (CD4+ T-cell counts and CD4+/CD8+ ratio).

Results

We found that glymphatic function as measured by the ALPS index increased significantly in the right and left PVSs of patients with HIV having cART. On antiretroviral therapy, a changing pattern in glymphatic clearance function in patients with HIV having cART correlated with attention and working memory. Duration on cART was also associated with cognitive performances of abstract and executive function and learning and memory.

Conclusion

These findings provide MRI evidence of the presence of HIV-induced changes in the glymphatic flow and clearance, which might underlie cognitive impairment among patients with HIV having cART. An increase in the glymphatic activity might reflect a compensatory mechanism to regulate microenvironment homeostasis compromised by HIV. This compensation might be necessary to maintain the proper functioning of the brain while coping with HIV pathology. These findings also shed light on the clinical importance of evaluating glymphatic function based on the ALPS index and suggest that improving the glymphatic system may serve as an alternative therapeutic strategy for HAND.
A Library for fMRI Real-Time Processing Systems in Python (RTPSpy) With Comprehensive Online Noise Reduction, Fast and Accurate Anatomical Image Processing, and Online Processing Simulation
Authors: Misaki Masaya , Bodurka Jerzy , Paulus Martin P.
Published: March 2022

Real-time fMRI (rtfMRI) has enormous potential for both mechanistic brain imaging studies or treatment-oriented neuromodulation. However, the adaption of rtfMRI has been limited due to technical difficulties in implementing an efficient computational framework. Here, we introduce a python library for real-time fMRI (rtfMRI) data processing systems, Real-Time Processing System in python (RTPSpy), to provide building blocks for a custom rtfMRI application with extensive and advanced functionalities. RTPSpy is a library package including (1) a fast, comprehensive, and flexible online fMRI image processing modules comparable to offline denoising, (2) utilities for fast and accurate anatomical image processing to define an anatomical target region, (3) a simulation system of online fMRI processing to optimize a pipeline and target signal calculation, (4) simple interface to an external application for feedback presentation, and (5) a boilerplate graphical user interface (GUI) integrating operations with RTPSpy library. The fast and accurate anatomical image processing utility wraps external tools, including FastSurfer, ANTs, and AFNI, to make tissue segmentation and region of interest masks. We confirmed that the quality of the output masks was comparable with FreeSurfer, and the anatomical image processing could complete in a few minutes. The modular nature of RTPSpy provides the ability to use it for a simulation analysis to optimize a processing pipeline and target signal calculation. We present a sample script for building a real-time processing pipeline and running a simulation using RTPSpy. The library also offers a simple signal exchange mechanism with an external application using a TCP/IP socket. While the main components of the RTPSpy are the library modules, we also provide a GUI class for easy access to the RTPSpy functions. The boilerplate GUI application provided with the package allows users to develop a customized rtfMRI application with minimum scripting labor. The limitations of the package as it relates to environment-specific implementations are discussed. These library components can be customized and can be used in parts. Taken together, RTPSpy is an efficient and adaptable option for developing rtfMRI applications.

Code available at:https://github.com/mamisaki/RTPSpy
Neonatal Bladder Inflammation Results in Adult Female Mouse Phenotype With Increased Frequency and Nociceptive Responses to Bladder Filling
Authors: Clodfelder-Miller Buffie , Ness Timothy J. , DeBerry Jennifer J.
Published: March 2022

Bladder pain and hypersensitivity to bladder filling are clinically common, but animal models examining syndromes with these features are limited. A rat model of bladder hypersensitivity produced by neonatal bladder inflammation (NBI) has been reported to have many of the clinical features of bladder pain syndromes. The present study sought to determine whether similar hypersensitivity might be induced by NBI in mice. Female C57BL6/J mice had NBI induced on postnatal days P12-14 by the intravesical administration of zymosan. As adults (12–14 weeks of age), the mice were examined for hypersensitivity of their bladders as: spontaneous voiding and evoked cystometrograms at baseline, and visceromotor responses (VMRs) to urinary bladder distension (UBD) following a secondary insult (either repeated bladder inflammation or acute stress induced by footshock). Mice that experienced NBI demonstrated hypersensitivity, when compared with control mice, manifested as increased spontaneous voiding, increased frequency of evoked voids during intravesical saline infusion, and increased vigor of VMRs to UBD following either acute bladder inflammation or acute stress. This recapitulates the hallmark features of clinical painful bladder disorders and suggest utility of this murine model for the study of these disorders while allowing methodological expansion into well-established genetic and immunological models.
Nature-Based One Health Approaches to Urban Agriculture Can Deliver Food and Nutrition Security
Authors: Ebenso Bassey , Otu Akaninyene , Giusti Alessandro , Cousin Philipe , Adetimirin Victor , Razafindralambo Hary , Effa Emmanuel , Gkisakis Vasileios , Thiare Ousmane , Levavasseur Vincent , Kouhounde Sonagnon , Adeoti Kifouli , Rahim Abdur , Mounir Majid
Published: March 2022

The increasing global human population is projected to reach 9.7 billion people by 2050. This population growth is currently linked to the trends of world-wide urbanization, growth of megacities and shifting dietary patterns. While humankind faces the daunting challenge of feeding and providing healthy lives for its teeming populations, urban agriculture holds promise for improving the quality of life in cities. Fortunately, policymakers and planners are accepting the need to support peri-urban farmers to increase the resilience of food systems while efficiently managing already strained natural resources. We argue that for urban agriculture to significantly increase food yields, it is crucial to adopt a One Health approach to agriculture and environmental stewardship. Here, we propose six nature-based and climate-smart approaches to accelerate the transition toward more sustainable food systems. These approaches include reducing the reliance on synthetic agricultural inputs, increasing biodiversity through producing locally adapted crops and livestock breeds, using probiotics and postbiotics, and adopting portable digital decision-support systems. Such radical approaches to transforming food production will require cross-sectoral stakeholder engagement at international, national, and community levels to protect biodiversity and the environment whilst ensuring sustainable and nutritious diets that are culturally acceptable, accessible, and affordable for all.
IL-6 Promoter Hypomethylation Acts As a Diagnostic Biomarker in Hepatitis B Virus-Associated Hepatocellular Carcinoma
Authors: Yang Jie-Ru , Wang Ju , Li Hai-Ming , Gao Shuai , Fan Yu-Chen , Wang Kai
Published: March 2022

Background

New biomarkers are needed to detect hepatocellular carcinoma at an earlier stage and to individualize treatment strategies. IL-6 has been proven to be associated with liver cancer in numerous studies.

Aim

To evaluate the value of the IL-6 promoter methylation level as a noninvasive biomarker for the diagnosis of liver cancer.

Methods

A retrospective analysis of 165 patients with HBV-associated hepatocellular carcinoma (HCC), 198 patients with chronic hepatitis B (CHB) and 31 healthy controls were involved. The methylight was detected the methylation level of the IL-6 promoter in peripheral blood mononuclear cells (PBMCs), clinical and laboratory parameters were obtained.

Results

IL-6 promoter methylation levels were significantly lower in patients with HCC (median 53.59%, interquartile range 52.01–54.75%) than in those with CHB (median 56.05%, interquartile range 54.65–57.67%; P<0.001). The level of IL-6 mRNA in patients with HCC (median 0.371, interquartile range 0.173-0.671) was significantly higher than that in patients with CHB (median 0.203, interquartile range 0.108-0.354; P<0.001) and HCs (median 0.189, interquartile range 0.140-0.262; P=0.001). Meanwhile, the PMR value of IL-6 was notably negatively correlated with the mRNA expression level (Spearman’s R=-0.201, P<0.001). The IL-6 PMR value of HCC patients in age (Spearman’s R=0.193, P=0.026) and TBIL (Spearman’s R=0.186, P=0.032) were very weak correlated. At the same time, the level of IL-6 promoter methylation was also an independent factor in the development of liver cancer. When the IL-6 promoter methylation level was used to diagnose HCC, its detective value was superior to AFP [area under the receiver operating characteristic curve (AUC) 0.773 vs. 0.686, P=0.027], And the combined use of AFP and IL-6 methylation level can improve the area under the receiver operating characteristic curve (p=0.011).

Conclusion

IL-6 promoter hypomethylation is present in hepatocellular carcinoma, and it may be used as a noninvasive biomarker to detect early liver cancer.
Differential Expression of Steroid Hormone Receptors and Ten Eleven Translocation Proteins in Endometrial Cancer Cells
Authors: Mahajan Vishakha , Gujral Palak , Jain Lekha , Ponnampalam Anna P.
Published: March 2022

Steroid hormones govern the complex, cyclic changes of the endometrium, predominantly through their receptors. An interplay between steroid hormones and epigenetic mechanisms controls the dynamic endometrial gene regulation. Abnormalities in expression of genes and enzymes associated with steroid hormone signaling, contribute to a disturbed hormonal equilibrium. Limited evidence suggests the involvement of TET (Ten Eleven Translocation)-mediated DNA hydroxymethylation in endometrial cancer, with some data on the use of TET1 as a potential prognostic and diagnostic biomarker, however the mechanisms guiding it and its regulation remains unexplored. This study aims to explore the changes in the expressions of TETs and steroid hormone receptors in response to estrogen and progesterone in endometrial cancer cells. Gene expression was examined using real-time PCR and protein expression was quantified using fluorescent western blotting in endometrial cancer cell lines (AN3 and RL95-2). Results indicate that TET1 and TET3 gene and protein expression was cell-specific in cancer cell-lines. Protein expression of TET1 was downregulated in AN3 cells, while TET1 and TET3 expressions were both upregulated in RL95-2 cells in response to estrogen-progesterone. Further, a decreased AR expression in AN3 cells and an increased ERα and ERβ protein expressions in RL95-2 cells was seen in response to estrogen-progesterone. PR gene and protein expression was absent from both cancer cell-lines. Overall, results imply that expressions of steroid hormones, steroid-hormone receptors and TETs are co-regulated in endometrial cancer-cells. Further studies are needed to interpret how these mechanisms fit in with DNMTs and DNA methylation in regulating endometrial biology. Understanding the role of TETs and hydroxymethylation in steroid hormone receptor regulation is crucial to comprehend how these mechanisms work together in a broader context of epigenetics in the endometrium and its pathologies.
Integrative Pan-Cancer Analysis of KIF15 Reveals Its Diagnosis and Prognosis Value in Nasopharyngeal Carcinoma
Authors: Mi Jinglin , Ma Shanshan , Chen Wei , Kang Min , Xu Meng , Liu Chang , Li Bo , Wu Fang , Liu Fengju , Zhang Yong , Wang Rensheng , Jiang Li
Published: March 2022

Background

KIF15 plays a vital role in many biological processes and has been reported to influence the occurrence and development of certain human cancers. However, there are few systematic evaluations on the role of KIF15 in human cancers, and the role of KIF15 in the diagnosis and prognosis of nasopharyngeal carcinoma (NPC) also remains unexplored. Therefore, this study aimed to conduct a pan-cancer analysis of KIF15 and evaluate its diagnostic and prognostic potential in NPC.

Methods

The expression pattern, prognostic value, molecular function, tumor mutation burden, microsatellite instability, and immune cell infiltration of KIF15 were examined based on public databases. Next, the diagnostic value of KIF15 in NPC was analyzed using the Gene Expression Omnibus (GEO) database and immunohistochemistry (IHC). Kaplan–Meier curves, Cox regression analyses, and nomograms were used to evaluate the effects of KIF15 expression on NPC prognosis. Finally, the effect of KIF15 on NPC was explored by in vitro experiments.

Results

The expression of KIF15 was significantly upregulated in 20 out of 33 cancer types compared to adjacent normal tissue. Kyoto Encyclopedia of Genes and Genomes enrichment (KEGG) analysis showed that KIF15 could participate in several cancer-related pathways. The increased expression level of KIF15 was correlated with worse clinical outcomes in many types of human cancers. Additionally, KIF15 expression was related to cancer infiltration of immune cells, tumor mutation burden, and microsatellite instability. In the analysis of NPC, KIF15 was significantly upregulated based on the GEO database and immunohistochemistry. A high expression of KIF15 was negatively associated with the prognosis of patients with NPC. A nomogram model integrating clinical characteristics and KIF15 expression was established, and it showed good predictive ability with an area under the curve value of 0.73. KIF15 knockdown significantly inhibited NPC cell proliferation and migration.

Conclusions

Our findings revealed the important and functional role of KIF15 as an oncogene in pan-cancer. Moreover, high expression of KIF15 was found in NPC tissues, and was correlated with poor prognosis in NPC. KIF15 may serve as a potential therapeutic target in NPC treatment.
Filamin A Is a Potential Driver of Breast Cancer Metastasis via Regulation of MMP-1
Authors: Zhou Jie , Wu Lvying , Xu Pengyan , Li Yue , Ji Zhiliang , Kang Xinmei
Published: March 2022

Recurrent metastasis is a major fatal cause of breast cancer. Regretfully, the driving force and the molecular beneath have not been fully illustrated yet. In this study, a cohort of breast cancer patients with locoregional metastasis was recruited. For them, we collected the matched samples of the primary tumor and metastatic tumor, and then we determined the mutation profiles with whole-exome sequencing (WES). On basis of the profiles, we identified a list of deleterious variants in eight susceptible genes. Of them, filamin A (FLNA) was considered a potential driver gene of metastasis, and its low expression could enhance 5 years’ relapse survival rate by 15%. To prove the finding, we constructed a stable FLNA knockout tumor cell line, which manifested that the cell abilities of proliferation, migration, and invasion were significantly weakened in response to the gene knockout. Subsequently, xenograft mouse experiments further proved that FLNA knockout could inhibit local or distal metastasis. Putting all the results together, we consolidated that FLNA could be a potential driver gene to metastasis of breast cancer, in particular triple-negative breast cancer. Additional experiments also suggested that FLNA might intervene in metastasis via the regulation of MMP-1 expression. In summary, this study demonstrates that FLNA may play as a positive regulator in cancer proliferation and recurrence. It provides new insight into breast cancer metastasis and suggests a potential new therapeutic target for breast cancer therapy.
Identification of Differentially Expressed Hub Genes Associated With Immune Cell Recruitment in Claudin-Low Breast Cancer
Authors: Wang Yange , Shi He , Zhang Yulu , Zeng Qian , Chen Tingmei , Chai Chengsen
Published: March 2022

Breast cancer (BCa) is the most common malignancy in women and claudin-low breast cancer (CL-BCa) is a newly identified BCa subtype characterized by low expression of claudin 3&4&7. However, the hub genes associated with the recruitment of immune cells into CL-BCa were rarely described. This study aimed at exploring the differentially expressed hub genes associated with tumor-infiltrating immune cells in CL-BCa by a multi-approach bioinformatics analysis. The top 200 genes associated with CL-BCa were screened in the METABRIC dataset; the PPI network was constructed using STRING and Cytoscape; tumor-infiltrating immune cells were analyzed by TIMER 2.0; and the correlation of feature cytokines and claudins on survival was examined in METABRIC and TCGA datasets. Consequently, we found that the fraction of tumor-infiltrating immune cells, especially CD8+T cells and macrophages, increased in the CL-BCa. Differentially expressed cytokines (CCL5, CCL19, CXCL9 and CXCL10) were related to the overall survival, and their expression levels were also examined both in tumor tissues of CL-BCa patients by IHC and in typical CL-BCa cell lines by qPCR. Moreover, the BCa patients with low expression of these differentially expressed claudins (CLDN8, CLDN11 and CLDN19) showed a worse overall survival. This study sheds light on molecular features of CL-BCa on immune microenvironments and contributes to identification of prognosis biomarkers for the CL-BCa patients.
Artificial Intelligence in Cervical Cancer Screening and Diagnosis
Authors: Hou Xin , Shen Guangyang , Zhou Liqiang , Li Yinuo , Wang Tian , Ma Xiangyi
Published: March 2022

Cervical cancer remains a leading cause of cancer death in women, seriously threatening their physical and mental health. It is an easily preventable cancer with early screening and diagnosis. Although technical advancements have significantly improved the early diagnosis of cervical cancer, accurate diagnosis remains difficult owing to various factors. In recent years, artificial intelligence (AI)-based medical diagnostic applications have been on the rise and have excellent applicability in the screening and diagnosis of cervical cancer. Their benefits include reduced time consumption, reduced need for professional and technical personnel, and no bias owing to subjective factors. We, thus, aimed to discuss how AI can be used in cervical cancer screening and diagnosis, particularly to improve the accuracy of early diagnosis. The application and challenges of using AI in the diagnosis and treatment of cervical cancer are also discussed.
Silencing of lncRNA CHRM3-AS2 Expression Exerts Anti-Tumour Effects Against Glioma via Targeting microRNA-370-5p/KLF4
Authors: Wang Dong , Chen Qiang , Liu Jun , Liao Yuqing , Jiang Qiuhua
Published: March 2022

Objectives

Long non-coding RNAs (lncRNAs) are key regulators involved in the progression of glioma, and many functional lncRNAs are yet to be identified. This study aimed to explore the function of CHRM3-AS2, a rarely reported lncRNA, in glioma, as well as the underlying mechanisms involving miR-370-5p/KLF4.

Methods

Differentially expressed RNAs (DERs) were screened from two gene expression profiles of glioblastoma (GBM). Fluorescence in situ hybridisation was performed to determine the subcellular localisation of CHRM3-AS2. Cell viability, colony formation, apoptosis, migration, and invasion were evaluated using cell counting kit-8, colony counts, flow cytometry, wound healing, and Transwell assays, respectively. mRNA and protein expression of specific genes were measured using quantitative real-time polymerase chain reaction and western blotting, respectively. Dual luciferase reporter gene, RNA immunoprecipitation, and RNA pull-down assays were performed to identify the target relationships. A mouse xenograft model was established for in vivo validation.

Results

CHRM3-AS2 was screened as a prognosis-associated DER in GBM. CHRM3-AS2 expression was up-regulated in glioma cells, and CHRM3-AS2 was localised in the cytoplasm. Silencing of CHRM3-AS2 expression inhibited cell viability, colony formation, migration, and invasion and promoted apoptosis of U251 and SHG-44 cells. In addition, CHRM3-AS2 targeted miR-370-5p/KLF4 in glioma cells. The anti-tumour effect of CHRM3-AS2 silencing was weakened by miR-370-5p silencing or KLF4 overexpression. In vivo, silencing of CHRM3-AS2 expression inhibited tumour growth and Ki67 expression in mice. Overexpression of KLF4 also weakened the anti-tumour effect of CHRM3-AS2 silencing in mice.

Conclusions

Silencing of CHRM3-AS2 expression inhibited the malignant progression of glioma by regulating miR-370-5p/KLF4 expression.
Prevalence, Years Lived With Disability, and Time Trends for 16 Causes of Blindness and Vision Impairment: Findings Highlight Retinopathy of Prematurity
Authors: Zhang Rui-Heng , Liu Yue-Ming , Dong Li , Li He-Yan , Li Yi-Fan , Zhou Wen-Da , Wu Hao-Tian , Wang Ya-Xing , Wei Wen-Bin
Published: March 2022

Background

Cause-specific prevalence data of vision loss and blindness is fundamental for making public health policies and is essential for prioritizing scientific advances and industry research.

Methods

Cause-specific vision loss data from the Global Health Data Exchange was used. The burden of vision loss was measured by prevalence and years lived with disability (YLDs).

Findings

In 2019, uncorrected refractory error and cataract were the most common causes for vision loss and blindness globally. Women have higher rates of cataract, age-related macular degeneration (AMD), and diabetic retinopathy (DR) than men. In the past 30 years, the prevalence of moderate/severe vision loss and blindness due to neonatal disorders has increased by 13.73 and 33.53%, respectively. Retinopathy of prematurity (ROP) is the major cause of neonatal disorders related vision loss. In 2019, ROP caused 101.6 thousand [95% uncertainty intervals (UI) 77.5–128.2] cases of vision impairment, including 49.1 thousand (95% UI 28.1–75.1) moderate vision loss, 27.5 thousand (95% UI 19.3–36.60) severe vision loss and, 25.0 thousand (95% UI 14.6–35.8) blindness. The prevalence of new-onset ROP in Africa and East Asia was significantly higher than other regions. Variation of preterm birth prevalence can explain 49.8% geometry variation of ROP-related vision loss burden among 204 countries and territories. After adjusting for preterm prevalence, government health spending per total health spending (%), rather than total health spending per person, was associated with a reduced burden of ROP-related vision loss in 2019 (−0.19 YLDs for 10% increment). By 2050, prevalence of moderate, severe vision loss and blindness due to ROP is expected to reach 43.6 (95% UI 35.1–52.0), 23.2 (95% UI 19.4–27.1), 31.9 (95% UI 29.7–34.1) per 100,000 population.

Conclusion

The global burden of vision loss and blindness highlights the prevalent of ROP, a major and avoidable cause for childhood vision loss. Advanced screening techniques and treatments have shown to be effective in preventing ROP-related vision loss and are urgently needed in regions with high ROP-related blindness rates, including Africa and East Asia.
The NPC1L1 Gene Exerts a Notable Impact on the Reduction of Low-Density Lipoprotein Cholesterol in Response to Hyzetimibe: A Factorial-Designed Clinical Trial
Authors: Liao Jianwei , Yang Liyun , Zhou Luping , Zhao Hongbin , Qi Xiao , Cui Yimin , Ouyang Dongsheng
Published: March 2022

Background: Hyzetimibe is a novel inhibitor of cholesterol that specifically targets the NPC1L1 gene. Significant inter-individual variability suggests the existence of an abundance of poor responders and non-responders. In addition, the current literature is inconsistent and controversial regarding the potential impact of the Niemann-Pick C1-Like 1 (NPC1L1) gene on low-density lipoprotein cholesterol (LDL-C) reduction. In light of these concerns, we performed a high-quality clinical trial to investigate the specific characteristics of NPC1L1 gene variation on LDL-C reduction.

Methods: This was a multicenter, randomized, double-blind, placebo-controlled, clinical trial with a factorial design. Qualified patients were randomly assigned to one of six treatments: placebo, hyzetimibe (10 or 20 mg), atorvastatin, and atorvastatin plus hyzetimibe (10 or 20 mg). Fasting blood samples were collected and genotyped, and the concentrations of LDL-C and the targeted drug trough were determined to investigate the association between the NPC1L1 gene expression and the reduction of LDL-C.

Results: In total, 727 individuals were initially recruited; of these, 444 were eligible to begin the trial. We identified one SNP (g1679C > G) that exerted significantly different impacts on LDL-C levels. As monotherapy, CC carriers experienced significantly higher reductions in the mean LDL-C (−23.99%) than either the GG (−16.45%, p < 0.01) or GC (−13.02%, p < 0.01) carriers in the hyzetimibe (20 mg) group. In contrast, when co-administered with atorvastatin, GC carriers experienced greater LDL-C reduction than non-GC carriers (-52.23% vs. −45.03%) in the hyzetimibe (20 mg) plus atorvastatin group. Furthermore, the proportions of individuals experiencing a reduction in LDL-C by >50% increased as the dose of hyzetimibe increased from 16.1% to 65.4%.

Conclusion: The g1679C > G SNP in the NPC1L1 gene is critical and exerts a differential impact on the response to hyzetimibe treatment. Heterozygotic patients respond with poor efficacy when treated by monotherapy but show good responses in terms of LDL-C reduction when hyzetimibe was co-administered with atorvastatin. To treat hypercholesterolemia in a precise manner with hyzetimibe, it is necessary to identify genotype patients for the g1679C > G SNP. We also highlight the potential necessity for identifying the appropriate subjects to be treated with ezetimibe.

Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [CTR20150351]
Tormentic Acid Ameliorates Hepatic Fibrosis in vivo by Inhibiting Glycerophospholipids Metabolism and PI3K/Akt/mTOR and NF-κB Pathways: Based on Transcriptomics and Metabolomics
Authors: Lin Xing , Wei Yuanyuan , Li Yan , Xiong Yuhua , Fang Bin , Li Cuiyu , Huang Quanfang , Huang Renbin , Wei Jinbin
Published: March 2022

This study aimed to investigate the effects and underlying mechanisms of tormentic acid (TA) on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. The rats were intragastrically administered with 50% CCl4 for 9 weeks to induce hepatic fibrosis, followed by various agents for 6 weeks. Transcriptomic analysis was carried out to predict the potential targets, and then multiple examinations were performed to verify the prediction. The results showed that TA significantly alleviated liver injury and fibrosis, as evidenced by the ameliorative pathological tissue, low transaminase activity, and decreased collagen accumulation. Besides, TA markedly reduced hepatocyte apoptosis by regulating the expression of caspase-3 and Bcl-2 families. The transcriptomic analysis revealed 2,173 differentially expressed genes (DEGs) between the TA and model groups, which could be enriched in the metabolic pathways and the PI3K/Akt and NF-κB signaling pathways. The metabolomics analysis showed that TA could regulate the glycerophospholipid metabolism pathway by regulating the synthesis of phosphatidylserines, phosphatidylethanolamines and phosphatidylcholines. Moreover, the integrative analysis of the transcriptomics and metabolomics data indicated that TA inhibited the glycerophospholipid metabolism pathway by inhibiting the expression of LPCAT4, PTDSS2, PLA2G2A and CEPT1. In addition, the relevant signaling pathways analysis confirmed that TA inhibited HSCs activation by blocking the PI3K/Akt/mTOR pathway and ameliorated inflammatory injury by inhibiting the NF-κB pathway. In conclusion, TA significantly alleviates liver fibrosis in vivo by inhibiting the glycerophospholipid metabolism pathway and the PI3K/Akt/mTOR and NF-κB signaling pathways.
Mammea B/BA Isolated From the Seeds of Mammea americana L. (Calophyllaceae) is a Potent Inhibitor of Methicillin-Resistant Staphylococcus aureus
Authors: Pájaro-González Yina , Oliveros-Díaz Andrés F. , Cabrera-Barraza Julián , Fernández-Daza Eduardo , Reyes Niradiz , Montes-Guevara Oscar A. , Caro-Fuentes Daneiva , Franco-Ospina Luis , Quiñones- Fletcher Wiston , Quave Cassandra L. , Díaz-Castillo Fredyc
Published: March 2022

Staphylococcus aureus remains a pathogen of high concern in public health programs worldwide due to antibiotic resistance and emergence of highly virulent strains. Many phytochemicals have demonstrated activity against S. aureus and other Gram-positive bacteria, but the minimum inhibitory concentration (MIC) values comparable to commonly used antibiotics are needed. In the present study, bio-guided fractionation of the ethanol extract of seeds of Mammea americana L. (Calophyllaceae) throughout the antibacterial activity, against S. aureus strains that are sensitive and resistant to methicillin, led to the isolation of four coumarins identified as mammea B/BA, mammea B/BC, mammea A/AA cyclo D and mammea A/AA cyclo F, and a mixture of mammea B/BA cyclo F plus mammea B/BD cyclo F. The extract inhibited the growth of S. aureus with MIC values of 2–4 μg/ml and Mammea B/BA (MaBBA) presented MIC values in a range between 0.5 and 1.0 μg/ml in six methicillin-sensitive strains and eight methicillin-resistant strains evaluated. We consider MaBBA the most potent of all mammea coumarins reported to date, according to the literature review carried out at the time of writing of this article. Toxicity assessment in vivo against the nematode Caenorhabditis elegans and in vitro against human fibroblasts of the extract and the compound MaBBA indicated that both had low toxicity.
Pocket2Drug: An Encoder-Decoder Deep Neural Network for the Target-Based Drug Design
Authors: Shi Wentao , Singha Manali , Srivastava Gopal , Pu Limeng , Ramanujam J. , Brylinski Michal
Published: March 2022

Computational modeling is an essential component of modern drug discovery. One of its most important applications is to select promising drug candidates for pharmacologically relevant target proteins. Because of continuing advances in structural biology, putative binding sites for small organic molecules are being discovered in numerous proteins linked to various diseases. These valuable data offer new opportunities to build efficient computational models predicting binding molecules for target sites through the application of data mining and machine learning. In particular, deep neural networks are powerful techniques capable of learning from complex data in order to make informed drug binding predictions. In this communication, we describe Pocket2Drug, a deep graph neural network model to predict binding molecules for a given a ligand binding site. This approach first learns the conditional probability distribution of small molecules from a large dataset of pocket structures with supervised training, followed by the sampling of drug candidates from the trained model. Comprehensive benchmarking simulations show that using Pocket2Drug significantly improves the chances of finding molecules binding to target pockets compared to traditional drug selection procedures. Specifically, known binders are generated for as many as 80.5% of targets present in the testing set consisting of dissimilar data from that used to train the deep graph neural network model. Overall, Pocket2Drug is a promising computational approach to inform the discovery of novel biopharmaceuticals.