bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial and Temporal Development of Müller Glial Cells in hiPSC-Derived Retinal Organoids Facilitates the Cell Enrichment and Transcriptome Analysis
Authors: Ning Rong , Zheng Dandan , Xie Bingbing , Gao Guanjie , Xu Jinhai , Xu Ping , Wang Yuan , Peng Fuhua , Jiang Bin , Ge Jian , Zhong Xiufeng
Published: May 2022

Müller glial cells (MGCs) play important roles in human retina during physiological and pathological conditions. However, the development process of human MGCs in vivo remains unclear, and how to obtain large numbers of human MGCs with high quality faces technical challenges, which hinder the further study and application of MGCs. Human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs) with all retinal cell subtypes provide an unlimited cell resource and a platform for the studies of retinal development and disorders. This study explored the development of human MGCs in hiPSC-derived ROs and developed an approach to select and expand the induced MGCs (iMGCs). In ROs, retinal progenitor cells progressively differentiated into SOX9+ Ki67– MGC precursors during differentiation day (D) 60 to D90, while mature MGCs expressing markers CRALBP and GS gradually appeared since D120, which spanned the entire thickness of the neural retina layer. Cells isolated from ROs aged older than 120 days was an optimal source for the enrichment of iMGCs with high purity and expansion ability. They had typical features of human MGCs in morphological, structural, molecular and functional aspects, and could be passaged serially at least 10 times, yielding large numbers of cells in a short period. The transcriptome pattern of the expanded iMGCs was also revealed. This study firstly clarified the timecourse of human MGC development in the RO model, where the iMGCs could be enriched and expanded, paving the way for downstream investigation and application in MGC-related retinal disorders.
A CNN-Based Deep Learning Approach for SSVEP Detection Targeting Binaural Ear-EEG
Authors: Israsena Pasin , Pan-Ngum Setha
Published: May 2022

This paper discusses a machine learning approach for detecting SSVEP at both ears with minimal channels. SSVEP is a robust EEG signal suitable for many BCI applications. It is strong at the visual cortex around the occipital area, but the SNR gets worse when detected from other areas of the head. To make use of SSVEP measured around the ears following the ear-EEG concept, especially for practical binaural implementation, we propose a CNN structure coupled with regressed softmax outputs to improve accuracy. Evaluating on a public dataset, we studied classification performance for both subject-dependent and subject-independent trainings. It was found that with the proposed structure using a group training approach, a 69.21% accuracy was achievable. An ITR of 6.42 bit/min given 63.49 % accuracy was recorded while only monitoring data from T7 and T8. This represents a 12.47% improvement from a single ear implementation and illustrates potential of the approach to enhance performance for practical implementation of wearable EEG.
The Vasodilatory Response to CGRP of the Anterior and Posterior Cerebral Circulation in Migraine
Authors: Visočnik Darja , Zaletel Marjan , Žvan Bojana , Zupan Matija
Published: May 2022

Introduction

Migraine aura can be associated with headache or it may occur without one, which suggests an independent mechanism for the aura and for migraine headache. The role of CGRP in migraine headache is well established, but the connection between CGRP and the aura is still lacking an explanation. Exogenous CGRP can induce CGRP headaches and migraine auras in patients with migraine. The results of our recent study suggest differences in the vascular response to CGRP stimulation between migraine without aura and migraine with aura. Therefore, we hypothesized that the magnitude of the posterior cerebral circulation response in migraine with aura is greater than in migraine without aura and that CGRP stimulation has different effects on the anterior and posterior circulation in migraine with aura and migraine without aura.

Methods

By using transcranial doppler, we studied the hemodynamic effects of CGRP intravenous infusion at a rate of 1.5 mcg/min in 20 min on the mean arterial velocity in the middle cerebral artery and in the posterior cerebral artery in twenty patients with migraine and in a control group of twenty healthy subjects. The same CGRP effects on cerebral hemodynamics were analyzed separately for the group of patients with migraine with aura and the group of patients with migraine without aura. Fifteen patients with migraine (75%) had migraine without aura and 5 patients (25%) had migraine with aura.

Results

We found that migraine has a significant impact on the vasodilatory response of the anterior (B = 4,249, SE = 1.023, r = 0.363, p < 0.001) and posterior cerebral circulation (B = 3.634, SE = 1.461, r = 0.227, p = 0.014). Migraine with aura was significantly associated with changes in the anterior (B = 2.558, SE = 0.880, r = 0.275, p = 0.005) and posterior cerebral circulation (B = 7.565, SE = 2,368, r = 0.359, p = 0.002), while migraine without aura was only significantly associated with changes in the anterior circulation. In addition, we established a significant impact of migraine with aura on VR PCA (B = 5.901, SE = 2,546, r = 0.291, p = 0.024).

Conclusion

We conclude that TVR in the posterior cerebral circulation might be enhanced in MA and that aura might be a consequence of TVR enhancement.
Association of MicroRNAs With Risk of Stroke: A Meta-Analysis
Authors: Deng Yidong , Huang Peijian , Zhang Fan , Chen Tao
Published: May 2022

Objectives

Altered expression of microRNAs (miRNAs) may contribute to disease vulnerability. Studies have reported the involvement of miRNA in the pathophysiology of ischemic stroke.

Methods

We performed a meta-analysis of data from 6 studies that used a panel of miRNAs with altered expressions to diagnose ischemic stroke with the Bayesian framework. The I2 test and Cochran's Q-statistic were used to assess heterogeneity. Funnel plots were generated and publication bias was assessed using Begg and Egger tests.

Results

On summary receiver operating characteristics (SROC) curve analysis, the pooled sensitivity and specificity of altered miRNA expressions for diagnosis of ischemic stroke was 0.92 (95% confidence interval [CI] 0.80–0.97) and 0.83 (95% CI 0.71–0.90), respectively; the diagnostic odds ratio was 54.35 (95% CI 20.39–144.92), and the area under the SROC curve was 0.93 (95% CI 0.90–0.95).

Conclusions

Our results showed a link between dysregulation of miRNAs and the occurrence of ischemic stroke. Abnormal miRNA expression may be a potential biomarker for ischemic stroke.
Interpretable Machine Learning Modeling for Ischemic Stroke Outcome Prediction
Authors: Jabal Mohamed Sobhi , Joly Olivier , Kallmes David , Harston George , Rabinstein Alejandro , Huynh Thien , Brinjikji Waleed
Published: May 2022

Background and Purpose

Mechanical thrombectomy greatly improves stroke outcomes. Nonetheless, some patients fall short of full recovery despite good reperfusion. The purpose of this study was to develop machine learning (ML) models for the pre-interventional prediction of functional outcome at 3 months of thrombectomy in acute ischemic stroke (AIS), using clinical and auto-extractable radiological information consistently available upon first emergency evaluation.

Materials and Methods

A two-center retrospective cohort of 293 patients with AIS who underwent thrombectomy was analyzed. ML models were developed to predict dichotomized modified Rankin score at 90 days (mRS-90) using clinical and imaging features, both separately and combined. Conventional and experimental imaging biomarkers were quantified using automated image-processing software from non-contract computed tomography (CT) and computed tomography angiography (CTA). Shapley Additive Explanation (SHAP) was applied for model interpretability and predictor importance analysis of the optimal model.

Results

Merging clinical and imaging features returned the best results for mRS-90 prediction. The best performing classifier was Extreme Gradient Boosting (XGB) with an area under the receiver operating characteristic curve (AUC) = 84% using selected features. The most important classifying features were age, baseline National Institutes of Health Stroke Scale (NIHSS), occlusion side, degree of brain atrophy [primarily represented by cortical cerebrospinal fluid (CSF) volume and lateral ventricle volume], early ischemic core [primarily represented by e-Alberta Stroke Program Early CT Score (ASPECTS)], and collateral circulation deficit volume on CTA.

Conclusion

Machine learning that is applied to quantifiable image features from CT and CTA alongside basic clinical characteristics constitutes a promising automated method in the pre-interventional prediction of stroke prognosis. Interpretable models allow for exploring which initial features contribute the most to post-thrombectomy outcome prediction overall and for each individual patient outcome.
Sleep Disruption and Cancer: Chicken or the Egg?
Authors: Berisha Adrian , Shutkind Kyle , Borniger Jeremy C.
Published: May 2022

Sleep is a nearly ubiquitous phenomenon across the phylogenetic tree, highlighting its essential role in ensuring fitness across evolutionary time. Consequently, chronic disruption of the duration, timing, or structure of sleep can cause widespread problems in multiple physiological systems, including those that regulate energy balance, immune function, and cognitive capacity, among others. Many, if not all these systems, become altered throughout the course of cancer initiation, growth, metastatic spread, treatment, and recurrence. Recent work has demonstrated how changes in sleep influence the development of chronic diseases, including cancer, in both humans and animal models. A common finding is that for some cancers (e.g., breast), chronic disruption of sleep/wake states prior to disease onset is associated with an increased risk for cancer development. Additionally, sleep disruption after cancer initiation is often associated with worse outcomes. Recently, evidence suggesting that cancer itself can affect neuronal circuits controlling sleep and wakefulness has accumulated. Patients with cancer often report difficulty falling asleep, difficulty staying asleep, and severe fatigue, during and even years after treatment. In addition to the psychological stress associated with cancer, cancer itself may alter sleep homeostasis through changes to host physiology andviacurrently undefined mechanisms. Moreover, cancer treatments (e.g., chemotherapy, radiation, hormonal, and surgical) may further worsen sleep problems through complex biological processes yet to be fully understood. This results in a “chicken or the egg” phenomenon, where it is unclear whether sleep disruption promotes cancer or cancer reciprocally disrupts sleep. This review will discuss existing evidence for both hypotheses and present a framework through which the interactions between sleep and cancer can be dissociated and causally investigated.
Sleep Deprivation During Memory Consolidation, but Not Before Memory Retrieval, Widens Threat Generalization to New Stimuli
Authors: Manassero Eugenio , Giordano Alessandra , Raimondo Erika , Cicolin Alessandro , Sacchetti Benedetto
Published: May 2022

Past aversive experiences shape our ability to deal with future dangers, through the encoding of implicit and explicit memory traces and through the ability to generalize defensive reactions to new stimuli resembling learned threats. Numerous evidence demonstrate that sleep is important for the consolidation of memories related to threatening events. However, there is a lack of studies examining the effects of sleep deprivation on the retrieval of consolidated threat memories, and previous studies on the role of sleep in threat generalization have produced mixed results. To address these issues, here we adopted a differential threat conditioning and a delayed (second half of the night) sleep deprivation during the first or the seventh night after learning. We found no effects of sleep deprivation on either implicit or explicit threat memories, regardless of its occurrence timing. Conversely, implicit but not explicit responses to novel cues similar to a learned threat displayed a widened generalization pattern, but only if sleep deprivation took place during the first night after conditioning and not if it occurred during the seventh night after conditioning. Therefore, we propose that sleeping after exposure to danger may support optimal implicit discrimination processes to evaluate new signals in the future and that even a brief period of sleeplessness may widen threat generalization to new stimuli, which is a hallmark of several threat-related disorders.
The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review
Authors: Kessi Miriam , Peng Jing , Duan Haolin , He Hailan , Chen Baiyu , Xiong Juan , Wang Ying , Yang Lifen , Wang Guoli , Kiprotich Karlmax , Bamgbade Olumuyiwa A. , He Fang , Yin Fei
Published: May 2022

Background

Hyperpolarization-activated cyclic nucleotide-gated (HCN) current reduces dendritic summation, suppresses dendritic calcium spikes, and enables inhibitory GABA-mediated postsynaptic potentials, thereby suppressing epilepsy. However, it is unclear whether increased HCN current can produce epilepsy. We hypothesized that gain-of-function (GOF) and loss-of-function (LOF) variants of HCN channel genes may cause epilepsy.

Objectives

This systematic review aims to summarize the role of HCN channelopathies in epilepsy, update genetic findings in patients, create genotype–phenotype correlations, and discuss animal models, GOF and LOF mechanisms, and potential treatment targets.

Methods

The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, for all years until August 2021.

Results

We identified pathogenic variants of HCN1 (n = 24), HCN2 (n = 8), HCN3 (n = 2), and HCN4 (n = 6) that were associated with epilepsy in 74 cases (43 HCN1, 20 HCN2, 2 HCN3, and 9 HCN4). Epilepsy was associated with GOF and LOF variants, and the mechanisms were indeterminate. Less than half of the cases became seizure-free and some developed drug-resistant epilepsy. Of the 74 cases, 12 (16.2%) died, comprising HCN1 (n = 4), HCN2 (n = 2), HCN3 (n = 2), and HCN4 (n = 4). Of the deceased cases, 10 (83%) had a sudden unexpected death in epilepsy (SUDEP) and 2 (16.7%) due to cardiopulmonary failure. SUDEP affected more adults (n = 10) than children (n = 2). HCN1 variants p.M234R, p.C329S, p.V414M, p.M153I, and p.M305L, as well as HCN2 variants p.S632W and delPPP (p.719–721), were associated with different phenotypes. HCN1 p.L157V and HCN4 p.R550C were associated with genetic generalized epilepsy. There are several HCN animal models, pharmacological targets, and modulators, but precise drugs have not been developed. Currently, there are no HCN channel openers.

Conclusion

We recommend clinicians to include HCN genes in epilepsy gene panels. Researchers should explore the possible underlying mechanisms for GOF and LOF variants by identifying the specific neuronal subtypes and neuroanatomical locations of each identified pathogenic variant. Researchers should identify specific HCN channel openers and blockers with high binding affinity. Such information will give clarity to the involvement of HCN channelopathies in epilepsy and provide the opportunity to develop targeted treatments.
Recessive LAMA5 Variants Associated With Partial Epilepsy and Spasms in Infancy
Authors: Luo Sheng , Liu Zhi-Gang , Wang Juan , Luo Jun-Xia , Ye Xing-Guang , Li Xin , Zhai Qiong-Xiang , Liu Xiao-Rong , Wang Jie , Gao Liang-Di , Liu Fu-Li , Ye Zi-Long , Li Huan , Gao Zai-Fen , Guo Qing-Hui , Li Bing-Mei , Yi Yong-Hong , Liao Wei-Ping
Published: May 2022

Objective

The LAMA5 gene encodes the laminin subunit α5, the most abundant laminin α subunit in the human brain. It forms heterotrimers with the subunit β1/β2 and γ1/γ3 and regulates neurodevelopmental processes. Genes encoding subunits of the laminin heterotrimers containing subunit α5 have been reported to be associated with human diseases. Among LAMAs encoding the laminin α subunit, LAMA1-4 have also been reported to be associated with human disease. In this study, we investigated the association between LAMA5 and epilepsy.

Methods

Trios-based whole-exome sequencing was performed in a cohort of 118 infants suffering from focal seizures with or without spasms. Protein modeling was used to assess the damaging effects of variations. The LAMAs expression was analyzed with data from the GTEX and VarCards databases.

Results

Six pairs of compound heterozygous missense variants in LAMA5 were identified in six unrelated patients. All affected individuals suffered from focal seizures with mild developmental delay, and three patients presented also spasms. These variants had no or low allele frequencies in controls and presented statistically higher frequency in the case cohort than in controls. The recessive burden analysis showed that recessive LAMA5 variants identified in this cohort were significantly more than the expected number in the East Asian population. Protein modeling showed that at least one variant in each pair of biallelic variants affected hydrogen bonds with surrounding amino acids. Among the biallelic variants in cases with only focal seizures, two variants of each pair were located in different structural domains or domains/links, whereas in the cases with spasms, the biallelic variants were constituted by two variants in the identical functional domains or both with hydrogen bond changes.

Conclusion

Recessive LAMA5 variants were potentially associated with infant epilepsy. The establishment of the association between LAMA5 and epilepsy will facilitate the genetic diagnosis and management in patients with infant epilepsy.
Redefine the Role of Spot-Scanning Proton Beam Therapy for the Single Brain Metastasis Stereotactic Radiosurgery
Authors: Chang Sheng , Liu Gang , Zhao Lewei , Zheng Weili , Yan Di , Chen Peter , Li Xiangpan , Yang Kunyu , Deraniyagala Rohan , Stevens Craig , Grills Inga , Chinnaiyan Prakash , Li Xiaoqiang , Ding Xuanfeng
Published: May 2022

Purpose

To explore the role of using Pencil Beam Scanning (PBS) proton beam therapy in single lesion brain stereotactic radiosurgery (SRS), we developed and validated a dosimetric in silico model to assist in the selection of an optimal treatment approach among the conventional Volumetric Modulated Arc Therapy (VMAT), Intensity Modulated Proton Therapy (IMPT) and Spot-scanning Proton Arc (SPArc).

Material and Methods

A patient’s head CT data set was used as an in silico model. A series of targets (volume range from 0.3 cc to 33.03 cc) were inserted in the deep central and peripheral region, simulating targets with different sizes and locations. Three planning groups: IMPT, VMAT, and SPArc were created for dosimetric comparison purposes and a decision tree was built based on this in silico model. Nine patients with single brain metastases were retrospectively selected for validation. Multiple dosimetric metrics were analyzed to assess the plan quality, such as dose Conformity Index (CI) (ratio of the target volume to 100% prescription isodose volume); R50 (ratio of 50% prescription isodose volume to the target volume); V12Gy (volume of brain tissue minus GTV receiving 12 Gy), and mean dose of the normal brain. Normal tissue complication probability (NTCP) of brain radionecrosis (RN) was calculated using the Lyman-Kutcher-Burman (LKB) model and total treatment delivery time was calculated. Six physicians from different institutions participated in the blind survey to evaluate the plan quality and rank their choices.

Results

The study showed that SPArc has a dosimetric advantage in the V12Gy and R50 with target volumes > 9.00 cc compared to VMAT and IMPT. A significant clinical benefit can be found in deep centrally located lesions larger than 20.00 cc using SPArc because of the superior dose conformity and mean dose reduction in healthy brain tissue. Nine retrospective clinical cases and the blind survey showed good agreement with the in silico dosimetric model and decision tree. Additionally, SPArc significantly reduced the treatment delivery time compared to VMAT (SPArc 184.46 ± 59.51s vs. VMAT: 1574.78 ± 213.65s).

Conclusion

The study demonstrated the feasibility of using Proton beam therapy for single brain metastasis patients utilizing the SPArc technique. At the current stage of technological development, VMAT remains the current standard modality of choice for single lesion brain SRS. The in silico dosimetric model and decision tree presented here could be used as a practical clinical decision tool to assist the selection of the optimal treatment modality among VMAT, IMPT, and SPArc in centers that have both photon and proton capabilities.
Nomograms to Predict Endocrinological Deficiency in Patients With Surgically Treated Craniopharyngioma
Authors: Wu Jie , Wu Xiao , Yang Le , Xie ShenHao , Tang Bin , Tong ZhiGao , Wu BoWen , Yang YouQing , Ding Han , Bao YouYuan , Zhou Lin , Hong Tao
Published: May 2022

Objective

Postoperative hypopituitarism associated with increased risks of premature mobility and mortality is often encountered in craniopharyngioma patients. The aim of our study is to construct nomograms related to injury types of the hypothalamus–pituitary axis (HPA) to predict hypopituitarism 1 year after surgery.

Methods

Craniopharyngioma patients undergoing initial endoscopic endonasal surgery between December 2012 and March 2021 in our center were retrospectively reviewed, and injury types of the HPA were categorized according to intraoperative endoscopic observation. Included patients were randomly divided into a training group and a validation group. Nomograms were established based on the results of multivariate logistic analysis. The predictive performance of the nomograms was evaluated in the training and validation groups.

Results

A total of 183 patients with craniopharyngioma were enrolled, and seven injury types of the HPA were summarized. Relative to intact HPA, exclusive hypothalamus injury significantly increased the risk of anterior (OR, 194.174; 95% CI, 21.311–1769.253; p < 0.001) and posterior pituitary dysfunction (OR, 31.393; 95% CI, 6.319–155.964; p < 0.001) 1 year after surgery, while exclusively sacrificing stalk infiltrated by tumors did not significantly increase the risk of anterior (OR, 5.633; 95% CI, 0.753–42.133; p = 0.092) and posterior pituitary dysfunction (OR, 1.580; 95% CI, 0.257–9.707; p = 0.621) 1 year after surgery. In the training group, the AUCs of nomograms predicting anterior and posterior pituitary dysfunction 1 year after surgery were 0.921 and 0.885, respectively, compared with 0.921 and 0.880 in the validation group.

Conclusions

Intact hypothalamus structure is critical in maintaining pituitary function. Moreover, our preliminary study suggests that the pituitary stalk infiltrated by craniopharyngioma could be sacrificed to achieve radical resection, without substantially rendering significantly worse endocrinological efficiency 1 year after surgery. The user-friendly nomograms can be used to predict hypopituitarism 1 year after surgery.
LMO7-ALK Fusion in a Lung Adenocarcinoma Patient With Crizotinib: A Case Report
Authors: Yang Yanlong , Zheng Hongbo , Li Zizhe , Shi Shuchen , Zhong Lang , Gong Longlong , Lan Bin
Published: May 2022

Background

Rearrangements of the anaplastic lymphoma kinase (ALK) gene comprise a small subset of non-small cell lung cancer (NSCLC). Patients with NSCLC harboring ALK fusion proteins are sensitive to ALK tyrosine kinase inhibitors (TKIs). Various fusion partners of ALK are being discovered with the application of next-generation sequencing (NGS).

Case presentation

Here, we report a female patient with metastatic lung adenocarcinoma harboring LMO7-ALK (L15, A20) rearrangement revealed by NGS. The patient received crizotinib as first-line treatment and has achieved partial response with a progression-free survival over 1 year.

Conclusions

We firstly found that the satisfactory response to crizotinib verified the oncogenic activity of LMO7-ALK fusion. Great progression and wide application of NGS facilitate the findings of rare fusion types.
MRI Feature-Based Nomogram Model for Discrimination Between Non-Hypervascular Pancreatic Neuroendocrine Tumors and Pancreatic Ductal Adenocarcinomas
Authors: Xu Jiake , Yang Jie , Feng Ye , Zhang Jie , Zhang Yuqiao , Chang Sha , Jin Jingqiang , Du Xia
Published: May 2022

This study aimed to investigate whether magnetic resonance imaging (MRI) features could differentiate non-hypervascular pancreatic neuroendocrine tumors (PNETs) from pancreatic ductal adenocarcinomas (PDACs). In this study, 131 patients with surgically and pathologically proven non-hypervascular PNETs (n = 44) or PDACs (n = 87) were enrolled. Two radiologists independently analyzed MRI imaging findings and clinical features. Relevant features in differentiating non-hypervascular PNETs from PDACs were identified via univariate and multivariate logistic regression models. The MRI feature-based nomogram was constructed based on multivariable logistic analysis and the reliability of the constructed nomogram was further validated. The results showed that tumor margin (P = 0.012; OR: 6.622; 95% CI: 1.510, 29.028), MPD dilation (P = 0.047; OR: 4.309; 95% CI: 1.019, 18.227), and signal in the portal phase (P < 0.001; OR: 53.486; 95% CI: 10.690, 267.618) were independent discriminative MRI features between non-hypervascular PNETs and PDACs. The discriminative performance of the developed nomogram was optimized compared with single imaging features. The calibration curve, C-index, and DCA validated the superior practicality and usefulness of the MRI-based nomogram. In conclusion, the radiologically discriminative model integrating various MRI features could be preoperatively and easily utilized to differentiate non-hypervascular PNETs from PDACs.
Characterization of the Estrogen Response Helps to Predict Prognosis and Identify Potential Therapeutic Targets in Cholangiocarcinoma
Authors: Lu Chenglin , Miao Ji , Li Minhuan , Zheng Qisi , Xu Feng , Pan Yiming , Wang Yizhou , Yang Zhi , Xia Xuefeng , Zhu Hao , Chen Jie , Bao Shanhua
Published: May 2022

Cholangiocarcinoma (CCA) is an aggressive malignancy originating from the epithelium of the bile duct. The prognosis of patients is poor regardless of radical resection and chemoradiotherapy. The current classification and prognostic model of CCA are unable to satisfy the requirements for predicting the clinical outcome and exploring therapeutic targets. Estrogen signaling is involved in diverse cancer types, and it has long been established that CCA could be regulated by estrogen. In our study, estrogen response was identified to be significantly and stably correlated with poor prognosis in CCA. Employing several algorithms, CCA was classified into ES cluster A and B. ES cluster B was mainly composed of patients with fluke infection and overlapped with CCA cluster 1/2, and ES cluster A was mainly composed of patients without fluke infection and overlapped with CCA cluster 3/4. COMT and HSD17B1 were identified to be responsible for the differential estrogen response between ES clusters A and B, and the estrogen response may be correlated with the differentiation and cancer stemness of CCA at the single-cell level. Complement activation and the expression of C3 and C5, which are mainly expressed by CCA cells, were significantly downregulated in ES cluster B. An estrogen response risk score (ESRS) model was constructed to predict the prognosis of CCA, followed by a nomogram integrating ESRS and clinical features. Finally, altered pathways, applicable drugs and sensitivity to chemical drugs were analyzed specific to the estrogen response. In summary, our results provide insights into the role of the estrogen response in CCA progression as well as applicable drugs and potential therapeutic targets in estrogen metabolism, the complement system and ESRS-related pathways.
The Role of Nonapoptotic Programmed Cell Death — Ferroptosis, Necroptosis, and Pyroptosis — in Pancreatic Ductal Adenocarcinoma Treatment
Authors: Hsu Sheng-Kai , Chu Yi-Hsuan , Syue Wun-Jyun , Lin Hugo You-Hsien , Chang Wen-Tsan , Chen Jeff Yi-Fu , Wu Chang-Yi , Yen Chia-Hung , Cheng Kai-Chun , Chiu Chien-Chih
Published: May 2022

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer, with a dismal 5-year survival rate of less than 10%. It is estimated that approximately 80% of pancreatic ductal carcinoma (PDAC) patients are diagnosed at an advanced or metastatic stage. Hence, most patients are not appropriate candidates for surgical resection and therefore require systemic chemotherapy. However, it has been reported that most patients develop chemoresistance within several months, partly because of antiapoptotic mechanisms. Hence, inducing alternative programmed cell death (PCD), including ferroptosis, necroptosis or pyroptosis, seems to be a promising strategy to overcome antiapoptosis-mediated chemoresistance. In this review, we shed light on the molecular mechanisms of ferroptosis, necroptosis and pyroptosis and suggest several potential strategies (e.g., compounds and nanoparticles [NPs]) that are capable of triggering nonapoptotic PCD to suppress PDAC progression. In conclusion, these strategies might serve as adjuvants in combination with clinical first-line chemotherapies to improve patient survival rates.
KRT8 Serves as a Novel Biomarker for LUAD and Promotes Metastasis and EMT via NF-κB Signaling
Authors: Chen Hao , Chen Xiaobin , Pan Bo , Zheng Chutian , Hong Liangjie , Han Weili
Published: May 2022

Keratin 8 (KRT8) is the major component of the intermediate filament cytoskeleton and aberrant expression in multiple tumors. However, the role of KRT8 in lung adenocarcinoma (LUAD) remains unclear. In the present study, KRT8 expression was found to be upregulated along with prognosis and metastasis in LUAD. Kaplan–Meier analysis presented that the 5-year OS and DSS rates were significantly better among patients with low KRT8 expression compared to those with high expression. Correlation analysis showed that KRT8 expression was significantly associated with gender (P = 0.027), advanced T stage (P = 0.001), advanced N stage (P = 0.048), and advanced pathologic stage (P = 0.025). Univariate Cox analysis demonstrated that KRT8 was a predictor of OS [hazard ratio (HR) = 1.526; 95% confidence interval (CI) 1.141–2.040; P = 0.004] and DSS (HR = 1.625; 95% CI 1.123–2.353; P = 0.010) in the TCGA database. Importantly, downregulation of KRT8 obviously suppressed cell proliferation, cell migration, invasion, and EMT as well as induced cell apoptosis. KRT8 knockdown significantly inhibited NF-κB signaling, suggesting a potential mechanism. Overall, our results indicated that KRT8 could regulate lung carcinogenesis and may serve as a potential target for antineoplastic therapies.
PET Imaging of Acidic Tumor Environment With 89Zr-labeled pHLIP Probes
Authors: Bauer David , Visca Hannah , Weerakkody Anuradha , Carter Lukas M. , Samuels Zachary , Kaminsky Spencer , Andreev Oleg A. , Reshetnyak Yana K. , Lewis Jason S.
Published: May 2022

Acidosis of the tumor microenvironment is a hallmark of tumor progression and has emerged as an essential biomarker for cancer diagnosis, prognosis, and evaluation of treatment response. A tool for quantitatively visualizing the acidic tumor environment could significantly advance our understanding of the behavior of aggressive tumors, improving patient management and outcomes. 89Zr-labeled pH-low insertion peptides (pHLIP) are a class of radiopharmaceutical imaging probes for the in vivo analysis of acidic tumor microenvironments via positron emission tomography (PET). Their unique structure allows them to sense and target acidic cancer cells. In contrast to traditional molecular imaging agents, pHLIP’s mechanism of action is pH-dependent and does not rely on the presence of tumor-specific molecular markers. In this study, one promising acidity-imaging PET probe ([89Zr]Zr-DFO-Cys-Var3) was identified as a candidate for clinical translation.
Patient-Derived Xenograft: A More Standard “Avatar” Model in Preclinical Studies of Gastric Cancer
Authors: Zeng Mingtang , Pi Chao , Li Ke , Sheng Lin , Zuo Ying , Yuan Jiyuan , Zou Yonggen , Zhang Xiaomei , Zhao Wenmei , Lee Robert J. , Wei Yumeng , Zhao Ling
Published: May 2022

Despite advances in diagnosis and treatment, gastric cancer remains the third most common cause of cancer-related death in humans. The establishment of relevant animal models of gastric cancer is critical for further research. Due to the complexity of the tumor microenvironment and the genetic heterogeneity of gastric cancer, the commonly used preclinical animal models fail to adequately represent clinically relevant models of gastric cancer. However, patient-derived models are able to replicate as much of the original inter-tumoral and intra-tumoral heterogeneity of gastric cancer as possible, reflecting the cellular interactions of the tumor microenvironment. In addition to implanting patient tissues or primary cells into immunodeficient mouse hosts for culture, the advent of alternative hosts such as humanized mouse hosts, zebrafish hosts, and in vitro culture modalities has also facilitated the advancement of gastric cancer research. This review highlights the current status, characteristics, interfering factors, and applications of patient-derived models that have emerged as more valuable preclinical tools for studying the progression and metastasis of gastric cancer.
Renaissance of Cardiac Imaging to Assist Percutaneous Interventions in Congenital Heart Diseases:The Role of Three-Dimensional Echocardiography and Multimodality Imaging
Authors: Avesani Martina , Kang Sok-Leng , Jalal Zakaria , Thambo Jean-Benoit , Iriart Xavier
Published: May 2022

Percutaneous interventions have completely refashioned the management of children with congenital heart diseases (CHD) and the use of non-invasive imaging has become the gold standard to plan and guide these procedures in the modern era. We are now facing a dual challenge to improve the standard of care in low-risk patients, and to shift our strategies from the classic open chest surgery to imaging-guided percutaneous interventions in high-risk patients. Such rapid evolution of ultrasound technologies over the last 20 years have permitted the integration of transthoracic, transesophageal and intracardiac echocardiography into the interventional workflow to improve image guidance and reduce radiation burden from fluoroscopy and angiography. Specifically, miniaturization of transesophageal probe and advances in three-dimensional (3D) imaging techniques have enabled real-time 3D image guidance during complex interventional procedure, In addition, multimodality and fusion imaging techniques harness the strengths of different modalities to enhance understanding of anatomical and spatial relationship between different structures, improving communication and coordination between interventionalists and imaging specialists. In this review, we aim to provide an overview of 3D imaging modalities and multimodal fusion in procedural planning and live guidance of percutaneous interventions. At the present times, 3D imaging can no longer be considered a luxury but a routine clinical tool to improve procedural success and patient outcomes.
The Correlation of Antibacterial Peptides Concentration in Umbilical Cord Blood and Early Onset Sepsis in Preterm Infants
Authors: Miao Jiayu , Ren Zhuxiao , Zhong Zhicheng , Xu Fang , Wang Jianlan , Yang Jie
Published: May 2022

Umbilical cord blood from singleton preterm infants was collected during delivery, and the concentration of LL37 was measured. C-reactive protein (CRP), white blood cell count (WBC), platelets (PLT), and mean platelet volume (MPV) were determined within 3 days after birth. The differences in LL37, CRP, WBC, PLT, and MPV levels between the two groups were compared. Pearson correlation method was used to analyze the correlation between these factors. The early individual value of each detected index for early onset sepsis was analyzed by ROC curve. The level of LL37 in umbilical cord blood of sepsis group was significantly higher than those in the control group (383.85 ± 46.71 vs. 252.37 ± 83.30 ng/ml). Meanwhile, the levels of CRP, WBC, and MPV in the sepsis group were significantly higher than those in the control group (CRP:5.73 ± 4.19 vs. 2.50 ± 2.77 mg/L; WBC: 13.47 ± 12.35 vs. 6.83 ± 3.55 × 109/L; MPV: 11.20 ± 1.11 vs. 8.90 ± 0.68 fL), the level of PLT was significantly lower than those in the control group (PLT: 161.00 ± 38.51 vs. 241.50 ± 49.85 × 109/L) (P < 0.05). Pearson correlation analysis showed that the expression of LL37 was negatively correlated with PLT level (r = −0.9347, P < 0.0001), and positively correlated with MPV level (r = 0.9463, P < 0.0001). ROC curve analysis showed that the area under curve of LL37 for diagnosis of early onset sepsis was 0.875, the prediction probability was 0.7, the sensitivity was 90.0% and the specificity was 80.0%.
Ferulic Acid Combined With Bone Marrow Mesenchymal Stem Cells Attenuates the Activation of Hepatic Stellate Cells and Alleviates Liver Fibrosis
Authors: Zhang Rui , Li Wenhang , Jiang Xiaodan , Cui Xinyi , You Hongjie , Tang Zuoqing , Liu Wenlan
Published: May 2022

Bone marrow mesenchymal stem cells (BMSCs) can effectively alleviate liver fibrosis, but the efficacy of cell therapy alone is insufficient. In recent years, a combination of traditional Chinese medicine (TCM) and cell therapy has been increasingly used to treat diseases in clinical trials. Ferulic acid (FA) is highly effective in treating liver fibrosis, and a combination of cells and drugs is being tested in clinical trials. Therefore, we combined BMSCs and Ferulic acid to treat CCl4-induced fibrosis and determine whether this combination was more effective than single treatment. We used BMSCs and FA to treat CCl4-induced fibrosis in rat models, observed their therapeutic effects, and investigated the specific mechanism of this combination therapy in liver fibrosis. We created a BMSC/hepatic stellate cell (HSC) coculture system and used FA to treat activated HSCs to verify the specific mechanism. Then, we used cytochalasin D and angiotensin II to investigate whether BMSCs and FA inactivate HSCs through cytoskeletal rearrangement. MiR-19b-3p was enriched in BMSCs and targeted TGF-β receptor II (TGF-βR2). We separately transfected miR-19b-3p into HSCs and BMSCs and detected hepatic stellate cell activation. We found that the expression of the profibrotic markers α-SMA and COL1-A1 was significantly decreased in the combination group of rats. α-SMA and COL1-A1 levels were also significantly decreased in the HSCs with the combination treatment. Cytoskeletal rearrangement of HSCs was inhibited in the combination group, and RhoA/ROCK pathway gene expression was decreased. Following angiotensin II treatment, COL1-A1 and α-SMA expression increased, while with cytochalasin D treatment, profibrotic gene expression decreased in HSCs. The expression of COL1-A1, α-SMA and RhoA/ROCK pathway genes was decreased in the activated HSCs treated with a miR-19b-3p mimic, indicating that miR-19b-3p inactivated HSCs by suppressing RhoA/ROCK signalling. In contrast, profibrotic gene expression was significantly decreased in the BMSCs treated with the miR-19b-3p mimic and FA or a miR-19b-3p inhibitor and FA compared with the BMSCs treated with the miR-19b-3p mimic alone. In conclusion, the combination therapy had better effects than FA or BMSCs alone. BMSC and FA treatment attenuated HSC activation and liver fibrosis by inhibiting cytoskeletal rearrangement and delivering miR-19b-3p to activated HSCs, inactivating RhoA/ROCK signalling. FA-based combination therapy showed better inhibitory effects on HSC activation.
Framework Development for Clinical Comprehensive Evaluation of Drugs–a Study Protocol Using the Delphi Method and Analytic Hierarchy Process
Authors: Zhang Chi , Ma Er-Li , Liu Bing-Long , Wu Bin , Gu Zhi-Chun , Lin Hou-Wen
Published: May 2022

Measuring the value of drugs to help make health-care decisions is a complex process which involves confronting trade-offs among multiple objectives. Although guidelines have been released for clinical comprehensive evaluation of drugs, refinement is required when considering a specific drug used in a specific disease. In this study, a two-level framework for clinical comprehensive evaluation of drugs will be developed. Six first-level indicators, including safety, efficacy, costs/cost-effectiveness, novelty, suitability, and accessibility will be evaluated according to the Chinese Guideline for Clinical Comprehensive Evaluation of Drugs. The second-level components involved in the framework will be first validated by the Delphi method and subsequently compared with one another to get the index weight based on the Analytic Hierarchy Process (AHP). The scoring criteria of each component in the framework will also be determined by the Delphi method and AHP. The scoring criteria of components representing therapeutic effects will involve both score of therapeutic effects and score of evidence quality. With the evidence of the drug to be evaluated, the score of each component will be obtained according to the established scoring criteria, and the overall comprehensive score value of the drug will be calculated, which will assist the evidence-based decision making.
Mendelian Randomization Rules Out Causation Between Inflammatory Bowel Disease and Non-Alcoholic Fatty Liver Disease
Authors: Chen Lanlan , Fan Zhongqi , Sun Xiaodong , Qiu Wei , Chen Yuguo , Zhou Jianpeng , Lv Guoyue
Published: May 2022

Background: Inflammatory bowel disease (IBD) and non-alcoholic fatty liver disease (NAFLD) usually co-exist clinically. However, whether such association is causal is still unknown.

Methods: Genetic variants were extracted as instrumental variables from the largest genome-wide association study (GWAS) of IBD, Crohn’s disease (CD) and ulcerative colitis (UC) with 25,042 cases and 34,915 controls (GWAS p-value < 5 × 10−8). Information of genetic variants in NAFLD was extracted from a GWAS with 1,483 cases and 17,781controls. Also, liver fat content (LFC) was included as the outcome. Then, a bi-direction Mendelian randomization (MR) was carried out to appraise the causal relationship between NAFLD on IBD. Besides, a multivariable MR (MVMR) design was carried to adjust for body mass index (BMI) and type 2 diabetes (T2D) as well.

Results: Generally, IBD might not affect the risk of NAFLD (OR = 0.994 [0.970, 1.019]), together with its subtypes including UC and CD. However, genetically-elevated risk of IBD might cause liver fat accumulation (beta = 0.019, p-value = 0.016) while turning insignificant at Bonferroni correction. Besides, no causal effect of NAFLD on IBD was observed (OR = 0.968 [0.928, 1.009]), together with UC and CD. Also, genetically-elevated LFC could not impact IBD, UC and CD either. The MR CAUSE analysis supported these null associations and MVMR analysis also supported such null associations even after adjusting for BMI and T2D.

Conclusion: This MR study ruled out the causal relationship between IBD and NAFLD, suggesting therapeutics targeting NAFLD might not work for IBD and vice versa.
Curcumin as a Holistic Treatment for Tau Pathology
Authors: Sivanantharajah Lovesha , Mudher Amritpal
Published: May 2022

Global forecasts for prevalence of Alzheimer’s Disease (AD) estimate that 152.8 million people will have dementia in 2050, a sharp rise from 57.4 million in 2019 (GBD 2019). This rise can be attributable to increases in population growth and aging, but in the absence of disease-modifying therapies it poses a huge societal challenge that must be addressed urgently. One way to combat this challenge is to explore the utility of holistic treatments that may protect against AD, including traditional herbs, spices and other nutraceuticals that are pharmacologically safe, inexpensive and readily available. In this light, the spice turmeric, and its active ingredient curcumin, has been investigated as a potential holistic treatment for AD over the past 2 decades; however, promising results with animal studies have not translated to success in clinical trials. One issue is that most animal models examining the effects of curcumin and curcumin derivatives in AD have been done with a focus at ameliorating amyloid pathology. Due to the limited success of Amyloid-β-based drugs in recent clinical trials, tau-focused therapeutics provide a promising alternative. In this article, we aim to provide a clearer picture of what is currently known about the effectiveness of curcumin and curcumin derivatives to ameliorate tau pathology. Tau focused studies may help inform more successful clinical studies by placing greater emphasis on the development and optimised delivery of curcumin derivatives that more effectively target tau pathology.
Bleaching Susceptibility and Resistance of Octocorals and Anemones at the World’s Southern-Most Coral Reef
Authors: Steinberg Rosemary K , Ainsworth Tracy D , Moriarty Tess , Bednarek Teresa , Dafforn Katherine A , Johnston Emma L
Published: May 2022

Coral reefs are amongst the most biodiverse ecosystems on earth, and while stony corals create the foundational complexity of these ecosystems, octocorals and anemones contribute significantly to their biodiversity and function. Like stony corals, many octocorals contain Symbiodiniaceae endosymbionts and can bleach when temperatures exceed the species’ upper thermal limit. Here, we report octocoral bleaching susceptibility and resistance within the subtropical Lord Howe Island coral reef ecosystem during and after marine heatwaves in 2019. Octocoral and anemone surveys were conducted at multiple reef locations within the Lord Howe Island lagoon during, immediately after, and 7 months after the heatwaves. One octocoral species, Cladiella sp. 1, experienced bleaching and mortality, with some bleached colonies detaching from the reef structure during the heatwave (presumed dead). Those that remained attached to the benthos survived the event and recovered endosymbionts within 7 months of bleaching. Cladiella sp. 1 Symbiodiniaceae density (in cells per µg protein), chlorophyll a and c2 per µg protein, and photosynthetic efficiency were significantly lower in bleached colonies compared to unbleached colonies, while chlorophyll a and c2 per symbiont were higher. Interestingly, no other symbiotic octocoral species of the Lord Howe Island lagoonal reef bleached. Unbleached Xenia cf crassa colonies had higher Symbiodiniaceae and chlorophyll densities during the marine heatwave compared to other monitoring intervals, while Cladiella sp. 2 densities did not change substantially through time. Previous work on octocoral bleaching has focused primarily on gorgonian octocorals, while this study provides insight into bleaching variability in other octocoral groups. The study also provides further evidence that octocorals may be generally more resistant to bleaching than stony corals in many, but not all, reef ecosystems. Responses to marine heating events vary and should be assessed on a species by species basis.