bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of RAG2-/-IL2Rγ-/Y immune deficient FAH-knockout miniature pig
Authors: Zhao Heng , Ye Weijian , Guo Jianxiong , Wang Jiaoxiang , Jiao Deling , Xu Kaixiang , Yang Chang , Chen Shuhan , Jamal Muhammad Ameen , Bai Zhongbin , Wei Taiyun , Cai Jie , Nguyen Tien Dat , Qing Yubo , Cheng Wenmin , Jia Baoyu , Li Honghui , Zhao Hong-Ye , Chen Qingfeng , Wei Hong-Jiang
Published: August 2022

Human hepatocyte transplantation for liver disease treatment have been hampered by the lack of quality human hepatocytes. Pigs with their large body size, longevity and physiological similarities with human are appropriate animal models for the in vivo expansion of human hepatocytes. Here we report on the generation of RAG2-/-IL2Rγ-/YFAH-/- (RGFKO) pigs via CRISPR/Cas9 system and somatic cell nuclear transfer. We showed that thymic and splenic development in RGFKO pigs was impaired. V(D)J recombination processes were also inactivated. Consequently, RGFKO pigs had significantly reduced numbers of porcine T, B and NK cells. Moreover, due to the loss of FAH, porcine hepatocytes continuously undergo apoptosis and consequently suffer hepatic damage. Thus, RGFKO pigs are both immune deficient and constantly suffer liver injury in the absence of NTBC supplementation. These results suggest that RGFKO pigs have the potential to be engrafted with human hepatocytes without immune rejection, thereby allowing for large scale expansion of human hepatocytes.
Deciphering colorectal cancer immune microenvironment transcriptional landscape on single cell resolution – A role for immunotherapy
Authors: Tieng Francis Yew Fu , Lee Learn-Han , Ab Mutalib Nurul-Syakima
Published: August 2022

Single cell RNA sequencing (scRNA-seq) is a novel high-throughput technique that enables the investigation of a single cell’s entire transcriptome. It elucidates intricate cellular networks and generates indices that will eventually enable the development of more targeted and personalized medications. The importance of scRNA-seq has been highlighted in complex biological systems such as cancer and the immune system, which exhibit significant cellular heterogeneity. Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer-related death globally. Chemotherapy continues to be used to treat these patients. However, 5-FU has been utilized in chemotherapy regimens with oxaliplatin and irinotecan since the 1960s and is still used today. Additionally, chemotherapy-resistant metastatic CRCs with poor prognoses have been treated with immunotherapy employing monoclonal antibodies, immune checkpoint inhibitors, adoptive cell therapy and cancer vaccines. Personalized immunotherapy employing tumor-specific neoantigens allows for treating each patient as a distinct group. Sequencing and multi-omics approaches have helped us identify patients more precisely in the last decade. The introduction of modern methods and neoantigen-based immunotherapy may usher in a new era in treating CRC. The unmet goal is to better understand the cellular and molecular mechanisms that contribute to CRC pathogenesis and resistance to treatment, identify novel therapeutic targets, and make more stratified and informed treatment decisions using single cell approaches. This review summarizes current scRNA-seq utilization in CRC research, examining its potential utility in the development of precision immunotherapy for CRC.
Implications of NKG2A in immunity and immune-mediated diseases
Authors: Wang Xiaotong , Xiong Huabao , Ning Zhaochen
Published: August 2022

In recent studies, NKG2A is revealed to be a key immune checkpoint for both natural killer (NK) cells and CD8+T cells. It form heterodimer receptors with CD94, and targets the peptide-presenting human leukocyte antigen-E (HLA-E) molecules. Upon crosslinking, NKG2A/CD94 delivers inhibitory signals for NK cells and CD8+T cells, while blocking NKG2A can effectively unleash functions of these cytotoxic lymphocytes. The interaction between NKG2A and HLA-E contributes to tumor immune escape, and NKG2A-mediated mechanisms are currently being exploited to develop potential antitumor therapeutic strategies. In addition, growing evidence shows that NKG2A also plays important roles in other immune-related diseases including viral infections, autoimmune diseases, inflammatory diseases, parasite infections and transplant rejection. Therefore, the current work focuses on describing the effect of NKG2A on immune regulation and exploring its potential role in immune-mediated disorders.
Increased intrathecal neurofilament light and immunoglobulin M predict severe disability in relapsing-remitting multiple sclerosis
Authors: Rosenstein Igal , Rasch Sofia , Axelsson Markus , Novakova Lenka , Blennow Kaj , Zetterberg Henrik , Lycke Jan
Published: August 2022

Background

Emerging evidence supports that determination of intrathecal immunoglobulin M (IgM) synthesis (ITMS) and neurofilament light (NfL) concentration in cerebrospinal fluid (CSF) may be clinically useful as disease severity biomarkers in relapsing-remitting multiple sclerosis (RRMS).

Methods

Monocentric observational longitudinal cohort study in which prospectively collected data were retrospectively retrieved. Included were patients with RRMS (n=457) who had a diagnostic investigation including analysis of ITMS and CSF neurofilament light (cNfL). ITMS was calculated with the linear index formula, the intrathecal fraction of IgM according to Reiber (IgMIF), and by qualitative determination of oligoclonal IgM bands (OCMB). Univariable and multivariable models were performed to predict Evidence of Disease Activity-3 (EDA-3) status within 24 months from onset, and the risk of Expanded Disability Status Score (EDSS) ≥3 and ≥6.

Results

All investigated methods to calculate ITMS significantly predicted evidence of disease activity (EDA-3) within 24 months. IgMIF>0% showed the strongest association with EDA-3 status (adjusted hazard ratio [aHR] 3.7, 95%CI 2.7-5, p<0.001). Combining IgM-index>0.1 or OCMB with increased cNfL were strong predictors of EDSS≥3 (for cNfL+/IgM-index+: aHR 4.6, 95%CI 2.6-8.2, p<0.001) and EDSS≥6 (aHR 8.2, 95%CI 2.3-30, p<0.001).

Conclusions

In a real-world setting, ITMS was a useful biomarker in early RRMS to predict disabling MS and its prognostic value was even stronger in combination with cNfL. Our data suggest that determination of ITMS and cNfL should be included in the diagnostic work-up of RRMS for prognostic purposes and in decisions of disease-modifying therapy.
Vegetation changes in Yellow River Delta wetlands from 2018 to 2020 using PIE-Engine and short time series Sentinel-2 images
Authors: Chang Dong , Wang Zhiyong , Ning Xiaogang , Li Zhenjin , Zhang Long , Liu Xiaotong
Published: August 2022

Vegetation is the functional subject in the wetland ecosystem and plays an irreplaceable role in biodiversity conservation. It is of great significance to monitor wetland vegetation for scientific assessment of the impact of vegetation on ecological environment and biodiversity. In this paper, a method for extracting wetland vegetation based on short time series Normalized Difference Vegetation Index (NDVI) data set was constructed. First, time series NDVI data were constructed using Sentinel-2 images. Then, the Support Vector Machine (SVM) classifier was used to classify the wetland vegetation types. The distributions of the main wetland vegetation in the study area in 2018 and 2020 were got. Finally, the land cover transfer matrix was calculated to analyze the spatial pattern and change of wetland vegetation emphatically from 2018 to 2020. Based on 46 Sentinel-2 images acquired in 2018 and 2020, the spatial pattern and change of vegetation in the Yellow River Delta wetlands were extracted and analyzed in this paper. The results show that: (1) The method for extracting wetland vegetation in estuary delta based on PIE-Engine platform and short time series NDVI data constructed in this paper can effectively extract the wetland vegetation information. The overall accuracy of the classification results reached 90.47% in 2018 and 80.30% in 2020. The Kappa coefficient of the classification results are 0.874 in 2018 and 0.739 in 2020 respectively. Compared with the results from the random forest classification method and the maximum likelihood classification method, the accuracy is improved by 6.40% and 13.04%, and the Kappa coefficient is improved by 0.055 and 0.069. (2) There were significant changes in vegetation coverage in the Yellow River Delta wetlands from 2018 to 2020. The Spartina alterniflora increased by 3.74km2. The Suaeda salsa degraded seriously, and the total area decreased by 20.38km2. In addition, the increase of Spartina alterniflora effectively guaranteed the stability of the coastline in the study area. This study can provide a theoretical basis for wetlands vegetation classificaton, and the classificaton results can provide scientific reference for protecting the ecological environment of wetlands and maintaining ecological stability.
Effect of cognitive reserve on amnestic mild cognitive impairment due to Alzheimer’s disease defined by fluorodeoxyglucose-positron emission tomography
Authors: Kato Takashi , Nishita Yukiko , Otsuka Rei , Inui Yoshitaka , Nakamura Akinori , Kimura Yasuyuki , Ito Kengo ,   SEAD-J Study Group
Published: August 2022

This study aimed to investigate the effect of cognitive reserve (CR) on the rate of cognitive decline and cerebral glucose metabolism in amnestic mild cognitive impairment (MCI) using the Study on Diagnosis of Early Alzheimer’s Disease-Japan (SEAD-J) dataset. The patients in SEAD-J underwent cognitive tests and fluorodeoxyglucose-positron emission tomography (FDG-PET). MCI to be studied was classified as amnestic MCI due to Alzheimer’s disease (AD) with neurodegeneration. A total of 57 patients were visually interpreted as having an AD pattern (P1 pattern, Silverman’s classification). The 57 individuals showing the P1 pattern were divided into a high-education group (years of school education ≥13, N = 18) and a low-education group (years of school education ≤12, N = 39). Voxel-based statistical parametric mapping revealed more severe hypometabolism in the high-education group than in the low-education group. Glucose metabolism in the hippocampus and temporoparietal area was inversely associated with the years of school education in the high- and low-education groups (N = 57). General linear mixed model analyses demonstrated that cognitive decline was more rapid in the high-education group during 3-year follow-up. These results suggest that the cerebral glucose metabolism is lower and cognitive function declines faster in patients with high CR of amnestic MCI due to AD defined by FDG-PET.
Global spectrum of USH2A mutation in inherited retinal dystrophies: Prompt message for development of base editing therapy
Authors: Su Bing-Nan , Shen Ren-Juan , Liu Zhuo-Lin , Li Yang , Jin Zi-Bing
Published: August 2022

Purpose

Mutation in the USH2A gene is the most common cause of inherited retinal dystrophy (IRD), including non-syndromic retinitis pigmentosa (RP) and Usher syndrome II (USH2). Gene editing and therapy targeting USH2A, especially the hotspot region, would benefit a large proportion of IRD patients. In this study, we comprehensively analyzed the genetic spectrum of the USH2A gene, aiming to identify global hot spot mutations in USH2A-related IRDs and differences in hot spot regions across continents.

Materials and methods

A retrospective USH2A-related IRD study was conducted, including our IRD cohort, and reported USH2A studies worldwide.

Results

A total of 3,972 mutated USH2A alleles of approximately 1,935 patients were collected from 33 cohort studies worldwide, containing 102 alleles of 51 patients in our IRD cohort. Mutations in exon 13 were the most common, reaching 18.4% globally and a higher frequency of 22% in America, 19.2% in Europe, and a lower 12% in East Asia. Pathogenic mutations that affected 10 of the 72 exons of USH2A, exon 2, exon 13, exon 41–43, exon 50, exon 54, exon 57, exon 61, and exon 63 in total were responsible for half of global USH2A mutant alleles. With base editors including adenine base editor (ABE), cytidine base editor (CBE), and glycosylase base editor (GBE), 76.3% of single nucleotide variations (SNVs) and 58% of all mutations in USH2A are correctable. Meantime, four novel pathogenic mutations were revealed in our IRD cohort, p. (Val1130Cysfs*72), p. (Ala2139fs*14), p. (Gly4139Arg), and p. (Val4166Cysfs*7).

Conclusion

In this study, we revealed four novel mutations, expanding the spectrum of USH2A mutations, and importantly presented global hotspot exons and mutations of USH2A as well as the proportion of SNVs that can be restored by different base editors, providing a perspective for exploring high-efficiency and broader-reaching gene editing and gene therapies.
Association of sleep duration with chronic constipation among adult men and women: Findings from the National Health and Nutrition Examination Survey (2005–2010)
Authors: Yang Shuai , Li Shou-Zhen , Guo Fu-Zheng , Zhou Dong-Xu , Sun Xiao-Feng , Tai Jian-Dong
Published: August 2022

Background

Previous studies suggested that unhealthy sleep patterns were closely associated with gastrointestinal diseases, but the impact of unhealthy sleep duration on chronic constipation has not been well studied until now. In this study, we aim to explore the association between sleep duration and constipation among males and females.

Methods

We utilized the US National Health and Nutrition Examination Surveys data from 2005 to 2010, and adults (≥20 years old) who completed the sleep and bowel health questionnaires were enrolled in this observational study. Sleep duration was categorized into four groups: very short sleep (<5 h/night), short sleep (5–6 h/night), normal sleep (7–8 h/night), and long sleep (≥9 h/night). Chronic constipation was defined as Bristol Stool Scale Type 1(separate hard lumps, like nuts) or Type 2(sausage-like but lumpy). Controlling demographic, lifestyle, and dietary factors, the logistic regression model in Generalized Linear Model (GLM) function was used to estimate the correlation of sleep duration with constipation among men and women.

Results

Of the 11,785 individuals (51.2% males and 48.8% females), 4.3% of men and 10.2% of women had constipation, respectively. More than half of patients with constipation did not adopt the recommended sleep duration. Compared with normal individuals, male participants with constipation had a higher proportion of shorter sleep duration (41.0 vs. 32.3% in the short sleep group and 6.3 vs. 4.7% in the very short sleep group), and female individuals with constipation had a higher proportion of long sleep duration (12.7 vs. 8.2%). After covariates adjustment, men with short sleep duration (5–6 h/night) correlated with increased odds for constipation (OR:1.54, 95%CI:1.05–2.25), and women with long sleep duration (≥9 h/night) linked to the higher constipation risk (OR:1.58, 95%CI:1.10–2.29). Excessive sleep duration in males or insufficient sleep duration in females was neither linked to increased nor decreased constipation risk.

Conclusions

In this observational study of a nationally representative sample of adults, we demonstrate a differential impact of unhealthy sleep duration on constipation among men and women. Short sleep duration poses a higher risk of constipation in men, and excessive sleep duration correlates with higher constipation risk in women.
Connectomic disturbances underlying insomnia disorder and predictors of treatment response
Authors: Lu Qian , Zhang Wentong , Yan Hailang , Mansouri Negar , Tanglay Onur , Osipowicz Karol , Joyce Angus W. , Young Isabella M. , Zhang Xia , Doyen Stephane , Sughrue Michael E. , He Chuan
Published: August 2022

Objective

Despite its prevalence, insomnia disorder (ID) remains poorly understood. In this study, we used machine learning to analyze the functional connectivity (FC) disturbances underlying ID, and identify potential predictors of treatment response through recurrent transcranial magnetic stimulation (rTMS) and pharmacotherapy.

Materials and methods

51 adult patients with chronic insomnia and 42 healthy age and education matched controls underwent baseline anatomical T1 magnetic resonance imaging (MRI), resting-stage functional MRI (rsfMRI), and diffusion weighted imaging (DWI). Imaging was repeated for 24 ID patients following four weeks of treatment with pharmacotherapy, with or without rTMS. A recently developed machine learning technique, Hollow Tree Super (HoTS) was used to classify subjects into ID and control groups based on their FC, and derive network and parcel-based FC features contributing to each model. The number of FC anomalies within each network was also compared between responders and non-responders using median absolute deviation at baseline and follow-up.

Results

Subjects were classified into ID and control with an area under the receiver operating characteristic curve (AUC-ROC) of 0.828. Baseline FC anomaly counts were higher in responders than non-responders. Response as measured by the Insomnia Severity Index (ISI) was associated with a decrease in anomaly counts across all networks, while all networks showed an increase in anomaly counts when response was measured using the Pittsburgh Sleep Quality Index. Overall, responders also showed greater change in all networks, with the Default Mode Network demonstrating the greatest change.

Conclusion

Machine learning analysis into the functional connectome in ID may provide useful insight into diagnostic and therapeutic targets.
EnforceSNN: Enabling resilient and energy-efficient spiking neural network inference considering approximate DRAMs for embedded systems
Authors: Putra Rachmad Vidya Wicaksana , Hanif Muhammad Abdullah , Shafique Muhammad
Published: August 2022

Spiking Neural Networks (SNNs) have shown capabilities of achieving high accuracy under unsupervised settings and low operational power/energy due to their bio-plausible computations. Previous studies identified that DRAM-based off-chip memory accesses dominate the energy consumption of SNN processing. However, state-of-the-art works do not optimize the DRAM energy-per-access, thereby hindering the SNN-based systems from achieving further energy efficiency gains. To substantially reduce the DRAM energy-per-access, an effective solution is to decrease the DRAM supply voltage, but it may lead to errors in DRAM cells (i.e., so-called approximate DRAM). Toward this, we propose EnforceSNN, a novel design framework that provides a solution for resilient and energy-efficient SNN inference using reduced-voltage DRAM for embedded systems. The key mechanisms of our EnforceSNN are: (1) employing quantized weights to reduce the DRAM access energy; (2) devising an efficient DRAM mapping policy to minimize the DRAM energy-per-access; (3) analyzing the SNN error tolerance to understand its accuracy profile considering different bit error rate (BER) values; (4) leveraging the information for developing an efficient fault-aware training (FAT) that considers different BER values and bit error locations in DRAM to improve the SNN error tolerance; and (5) developing an algorithm to select the SNN model that offers good trade-offs among accuracy, memory, and energy consumption. The experimental results show that our EnforceSNN maintains the accuracy (i.e., no accuracy loss for BER ≤ 10−3) as compared to the baseline SNN with accurate DRAM while achieving up to 84.9% of DRAM energy saving and up to 4.1x speed-up of DRAM data throughput across different network sizes.
Novel compound heterozygous mutation in STAMBP causes a neurodevelopmental disorder by disrupting cortical proliferation
Authors: Hu Meixin , Li Huiping , Huang Zhuxi , Li Dongyun , Xu Ying , Xu Qiong , Chen Bo , Wang Yi , Deng Jingxin , Zhu Ming , Feng Weijun , Xu Xiu
Published: August 2022

Background

Mutations in the STAMBP gene, which encodes a deubiquitinating isopeptidase called STAM-binding protein, are related to global developmental delay, microcephaly, and capillary malformation. Owing to the limited number of reported cases, the functional and phenotypic characteristics of STAMBP variants require further elucidation.

Materials and methods

Whole exome sequencing was performed on a patient presenting with a neurodevelopmental disorder. Novel compound heterozygous mutations in STAMBP [c.843_844del (p.C282Wfs*11) and c.920G > A (p.G307E)] were identified and validated using Sanger sequencing. A 3D human cortical organoid model was used to investigate the function of STAMBP and the pathogenicity of the novel mutation (c.920G > A, p.G307E).

Results

The patient was presented with global developmental delay, autism spectrum disorder, microcephaly, epilepsy, and dysmorphic facial features but without apparent capillary malformation on the skin and organs. Cortical organoids with STAMBP knockout (KO) showed significantly lower proliferation of neural stem cells (NSCs), leading to smaller organoids that are characteristic of microcephaly. Furthermore, STAMBP disruption did not affect apoptosis in early cortical organoids. After re-expressing wild-type STAMBP, STAMBPG307E, and STAMBPT313I (a known pathogenic mutation) within STAMBP KO organoids, only STAMBPWT rescued the impaired proliferation of STAMBP deficient organoids, but not STAMBPG307E and STAMBPT313I.

Conclusion

Our findings demonstrate that the clinical phenotype of STAMBP mutations is highly variable, and patients with different STAMBP mutations show differences in the severity of symptoms. The STAMBP missense mutation identified here is a novel pathogenic mutation that impairs the proliferation of NSCs in human brain development.
Digestibility of wheat alpha-amylase/trypsin inhibitors using a caricain digestive supplement
Authors: Juhász Angéla , Nye-Wood Mitchell G. , Tanner Gregory J. , Colgrave Michelle L.
Published: August 2022

Wheat is a major source of nutrition, though in susceptible people it can elicit inappropriate immune responses. Wheat allergy and non-celiac wheat sensitivity are caused by various wheat proteins, including alpha-amylase trypsin inhibitors (ATIs). These proteins, like the gluten proteins which can cause celiac disease, are incompletely digested in the stomach such that immunogenic epitopes reach the lower digestive system where they elicit the undesirable immune response. The only completely effective treatment for these immune reactions is to eliminate the food trigger from the diet, though inadvertent or accidental consumption can still cause debilitating symptoms in susceptible people. One approach used is to prevent the causal proteins from provoking an immune reaction by enhancing their digestion using digestive protease supplements that act in the stomach or intestine, cleaving them to prevent or quench the harmful immune response. In this study, a digestive supplement enriched in caricain, an enzyme naturally present in papaya latex originally designed to act against gluten proteins was assessed for its ability to digest wheat ATIs. The digestion efficiency was quantitatively measured using liquid chromatography-mass spectrometry, including examination of the cleavage sites and the peptide products. The peptide products were measured across a digestion time course under conditions that mimic gastric digestionin vivo, involving the use of pepsin uniquely or in combination with the supplement to test for additive effects. The detection of diverse cleavage sites in the caricain supplement-treated samples suggests the presence of several proteolytic enzymes that act synergistically. Caricain showed rapid actionin vitroagainst known immunogenic ATIs, indicating its utility for digestion of wheat ATIs in the upper digestive tract.
Nomogram individually predicts the risk for distant metastasis and prognosis value in female differentiated thyroid cancer patients: A SEER-based study
Authors: Wang Wenlong , Shen Cong , Yang Zhi
Published: August 2022

Objective

Distant metastasis (DM) is an important prognostic factor in differentiated thyroid cancer (DTC) and determines the course of treatment. This study aimed to establish a predictive nomogram model that could individually estimate the risk of DM and analyze the prognosis of female DTC patients (FDTCs).

Materials and methods

A total of 26,998 FDTCs were retrospectively searched from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2018 and randomly divided into validation and training cohorts. Univariate and multivariate analyses were performed to screen for prognostic factors and construct a prediction nomogram. The performance of the nomogram was assessed by the area under the receiver operating characteristic curve (AUC), concordance index (C-index), and a calibration curve. The overall survival (OS) and cancer-specific survival (CSS) were evaluated by Kaplan–Meier (K-M) analysis.

Results

A total of 263 (0.97%) FDTCs were reported to have DM. K-M analysis showed the association of multiple-organ metastases and brain involvement with lower survival rates (P < 0.001) in patients. Tumor size, age at diagnosis, thyroidectomy, N1 stage, T3–4 stage, and pathological type were independent predictive factors of DM in FDTCs (all P < 0.001). Similarly, age at diagnosis, Black, DM, T3–4 stage, thyroidectomy, and lung metastasis were determined as independent prognostic factors for FDTCs (all P < 0.001). Several predictive nomograms were established based on the above factors. The C-index, AUC, and calibration curves demonstrated a good performance of these nomogram models.

Conclusion

Our study was successful in establishing and validating nomograms that could predict DM, as well as CSS and OS in individual patients with FDTC based on a large study cohort. These nomograms could enable surgeons to perform individualized survival evaluation and risk stratification for FDTCs.
Unearthing novel fusions as therapeutic targets in solid tumors using targeted RNA sequencing
Authors: An Sungbin , Koh Hyun Hee , Chang Eun Sol , Choi Juyoung , Song Ji-Young , Lee Mi-Sook , Choi Yoon-La
Published: August 2022

Detection of oncogenic fusion genes in cancers, particularly in the diagnosis of uncertain tumors, is crucial for determining effective therapeutic strategies. Although novel fusion genes have been discovered through sequencing, verifying their oncogenic potential remain difficult. Therefore, we evaluated the utility of targeted RNA sequencing in 165 tumor samples by identifying known and unknown fusions. Additionally, by applying additional criteria, we discovered eight novel fusion genes that are expected to process oncogenicity. Among the novel fusion genes, RAF1 fusion genes were detected in two cases. PTPRG-RAF1 fusion led to an increase in cell growth; while dabrafenib, a BRAF inhibitor, reduced the growth of cells expressing RAF1. This study demonstrated the utility of RNA panel sequencing as a theragnostic tool and established criteria for identifying oncogenic fusion genes during post-sequencing analysis.
Structural insight into ASH1L PHD finger recognizing methylated histone H3K4 and promoting cell growth in prostate cancer
Authors: Yu Miaomiao , Jia Yanjie , Ma Zhanchuan , Ji Donglei , Wang Chunyu , Liang Yingying , Zhang Qiang , Yi Huanfa , Zeng Lei
Published: August 2022

ASH1L is a member of the Trithorax-group protein and acts as a histone methyltransferase for gene transcription activation. It is known that ASH1L modulates H3K4me3 and H3K36me2/3 at its gene targets, but its specific mechanism of histone recognition is insufficiently understood. In this study, we found that the ASH1L plant homeodomain (PHD) finger interacts with mono-, di-, and trimethylated states of H3K4 peptides with comparable affinities, indicating that ASH1L PHD non-selectively binds to all three methylation states of H3K4. We solved nuclear magnetic resonance structures picturing the ASH1L PHD finger binding to the dimethylated H3K4 peptide and found that a narrow binding groove and residue composition in the methylated-lysine binding pocket restricts the necessary interaction with the dimethyl-ammonium moiety of K4. In addition, we found that the ASH1L protein is overexpressed in castrate-resistant prostate cancer (PCa) PC3 and DU145 cells in comparison to PCa LNCaP cells. The knockdown of ASH1L modulated gene expression and cellular pathways involved in apoptosis and cell cycle regulation and consequently induced cell cycle arrest, cell apoptosis, and reduced colony-forming abilities in PC3 and DU145 cells. The overexpression of the C-terminal core of ASH1L but not the PHD deletion mutant increased the overall H3K36me2 level but had no effect on the H3K4me2/3 level. Overall, our study identifies the ASH1L PHD finger as the first native reader that non-selectively recognizes the three methylation states of H3K4. Additionally, ASH1L is required for the deregulation of cell cycle and survival in PCas.
Mechanistic insights into the clinical Y96D mutation with acquired resistance to AMG510 in the KRASG12C
Authors: Zhuang Haiming , Fan Jigang , Li Mingyu , Zhang Hao , Yang Xiuyan , Lin Ligen , Lu Shaoyong , Wang Qing , Liu Yaqin
Published: August 2022

Special oncogenic mutations in the RAS proteins lead to the aberrant activation of RAS and its downstream signaling pathways. AMG510, the first approval drug for KRAS, covalently binds to the mutated cysteine 12 of KRASG12C protein and has shown promising antitumor activity in clinical trials. Recent studies have reported that the clinically acquired Y96D mutation could severely affect the effectiveness of AMG510. However, the underlying mechanism of the drug-resistance remains unclear. To address this, we performed multiple microsecond molecular dynamics simulations on the KRASG12C−AMG510 and KRASG12C/Y96D−AMG510 complexes at the atomic level. The direct interaction between the residue 96 and AMG510 was impaired owing to the Y96D mutation. Moreover, the mutation yielded higher flexibility and more coupled motion of the switch II and α3-helix, which led to the departing motion of the switch II and α3-helix. The resulting departing motion impaired the interaction between the switch II and α3-helix and subsequently induced the opening and loosening of the AMG510 binding pocket, which further disrupted the interaction between the key residues in the pocket and AMG510 and induced an increased solvent exposure of AMG510. These findings reveal the resistance mechanism of AMG510 to KRASG12C/Y96D, which will help to offer guidance for the development of KRAS targeted drugs to overcome acquired resistance.
Molecular and pathological subtypes related to prostate cancer disparities and disease outcomes in African American and European American patients
Authors: Mori Joakin O. , White Jason , Elhussin Isra , Duduyemi Babatunde M. , Karanam Balasubramanyam , Yates Clayton , Wang Honghe
Published: August 2022

Prostate cancer (PCa) disproportionately affects African American (AA) men, yet present biomarkers do not address the observed racial disparity. The objective of this study was to identify biomarkers with potential benefits to AA PCa patients. Differentially expressed genes (DEG) analysis coupled with gene set enrichment analysis (GSEA) and leading-edge genes analysis showed that the keratin family of genes, including KRT8, KRT15, KRT19, KRT34, and KRT80, constituted the single most prominent family of genes enriched in AA compared to European American (EA) PCa cell lines. In PCa patients (TCGA and MSKCC patient cohorts), KRT8, KRT15, and KRT19 expression were relatively higher in AA than in EA patients. The differences in the expression of KRT15 and KRT19, but not KRT8, were enhanced by Gleason score and ERG fusion status; in low Gleason (Gleason ≤ 6 [TCGA cohort] and Gleason ≤ 7 [MSKCC cohort]), the expression of KRT15 and KRT19 was significantly (p ≤ 0.05) higher in AA than in EA patients. Survival analysis revealed that high expression of KRT15 and KRT19 was associated with increased risk of biochemical recurrence in low Gleason category patients in the TCGA patient cohort. Interestingly, KRT15 and KRT19 expression were also associated with an increased risk of death in the metastatic prostate adenocarcinoma cohort, suggesting the potential to predict the risks of disease recurrence and death in the low Gleason category and advanced disease conditions respectively. Gene set enrichment analysis revealed known oncogenic gene signatures, including KRAS and ERBB2, to be enriched in patients expressing high KRT15 and KRT19. Furthermore, high KRT15 and KRT19 were linked to the basal and LumA PCa subtypes, which are associated with poor postoperative androgen deprivation therapy (ADT) response compared to the LumB subtype. Taken together, the present study identifies genes with high expression in AA than in EA PCa. The identified genes are linked to oncogenic gene signatures, including KRAS and ERBB2, and to basal and LumA PCa subtypes that are associated with poor postoperative ADT response. This study, therefore, reveals biomarkers with the potential to address biomarker bias in PCa risk stratification and/or prognosis.
Radiation Oncology: Future Vision for Quality Assurance and Data Management in Clinical Trials and Translational Science
Authors: Ding Linda , Bradford Carla , Kuo I-Lin , Fan Yankhua , Ulin Kenneth , Khalifeh Abdulnasser , Yu Suhong , Liu Fenghong , Saleeby Jonathan , Bushe Harry , Smith Koren , Bianciu Camelia , LaRosa Salvatore , Prior Fred , Saltz Joel , Sharma Ashish , Smyczynski Mark , Bishop-Jodoin Maryann , Laurie Fran , Iandoli Matthew , Moni Janaki , Cicchetti M. Giulia , FitzGerald Thomas J.
Published: August 2022

The future of radiation oncology is exceptionally strong as we are increasingly involved in nearly all oncology disease sites due to extraordinary advances in radiation oncology treatment management platforms and improvements in treatment execution. Due to our technology and consistent accuracy, compressed radiation oncology treatment strategies are becoming more commonplace secondary to our ability to successfully treat tumor targets with increased normal tissue avoidance. In many disease sites including the central nervous system, pulmonary parenchyma, liver, and other areas, our service is redefining the standards of care. Targeting of disease has improved due to advances in tumor imaging and application of integrated imaging datasets into sophisticated planning systems which can optimize volume driven plans created by talented personnel. Treatment times have significantly decreased due to volume driven arc therapy and positioning is secured by real time imaging and optical tracking. Normal tissue exclusion has permitted compressed treatment schedules making treatment more convenient for the patient. These changes require additional study to further optimize care. Because data exchange worldwide have evolved through digital platforms and prisms, images and radiation datasets worldwide can be shared/reviewed on a same day basis using established de-identification and anonymization methods. Data storage post-trial completion can co-exist with digital pathomic and radiomic information in a single database coupled with patient specific outcome information and serve to move our translational science forward with nimble query elements and artificial intelligence to ask better questions of the data we collect and collate. This will be important moving forward to validate our process improvements at an enterprise level and support our science. We have to be thorough and complete in our data acquisition processes, however if we remain disciplined in our data management plan, our field can grow further and become more successful generating new standards of care from validated datasets.
PDPN marks a subset of aggressive and radiation-resistant glioblastoma cells
Authors: Modrek Aram S. , Eskilsson Eskil , Ezhilarasan Ravesanker , Wang Qianghu , Goodman Lindsey D. , Ding Yingwen , Zhang Ze-Yan , Bhat Krishna P. L. , Le Thanh-Thuy T. , Barthel Floris P. , Tang Ming , Yang Jie , Long Lihong , Gumin Joy , Lang Frederick F. , Verhaak Roel G. W. , Aldape Kenneth D. , Sulman Erik P.
Published: August 2022

Treatment-resistant glioma stem cells are thought to propagate and drive growth of malignant gliomas, but their markers and our ability to target them specifically are not well understood. We demonstrate that podoplanin (PDPN) expression is an independent prognostic marker in gliomas across multiple independent patient cohorts comprising both high- and low-grade gliomas. Knockdown of PDPN radiosensitized glioma cell lines and glioma-stem-like cells (GSCs). Clonogenic assays and xenograft experiments revealed that PDPN expression was associated with radiotherapy resistance and tumor aggressiveness. We further demonstrate that knockdown of PDPN in GSCs in vivo is sufficient to improve overall survival in an intracranial xenograft mouse model. PDPN therefore identifies a subset of aggressive, treatment-resistant glioma cells responsible for radiation resistance and may serve as a novel therapeutic target.
Prognostic significance of CNSL at diagnosis of childhood B-cell acute lymphoblastic leukemia: A report from the South China Children’s Leukemia Group
Authors: Xu Lu-Hong , Geng Xu , Liao Ning , Yang Li-Hua , Mai Hui-Rong , Wan Wu-Qing , Huang Li-Bin , Zheng Min-Cui , Tian Chuan , Chen Hui-Qin , Chen Qi-Wen , Long Xing-Jiang , Zhen Zi-Jun , Liu Ri-Yang , Li Qiao-Ru , Wu Bei-Yan , Wang Li-Na , Kong Xian-Ling , Chen Guo-Hua , Fang Jian-Pei , Li Yang
Published: August 2022

Objectives

The prognostic significance of acute lymphoblastic leukemia (ALL) patients with central nervous system leukemia (CNSL) at diagnosis is controversial. We aimed to determine the impact of CNSL at diagnosis on the clinical outcomes of childhood B-cell ALL in the South China Children’s Leukemia Group (SCCLG).

Methods

A total of 1,872 childhood patients were recruited for the study between October 2016 and July 2021. The diagnosis of CNSL depends on primary cytological examination of cerebrospinal fluid, clinical manifestations, and imaging manifestations. Patients with CNSL at diagnosis received two additional courses of intrathecal triple injections during induction.

Results

The frequency of CNLS at the diagnosis of B-cell ALL was 3.6%. Patients with CNSL at diagnosis had a significantly higher mean presenting leukocyte count (P = 0.002) and poorer treatment response (P <0.05) compared with non-CNSL patients. Moreover, CNSL status was associated with worse 3-year event-free survival (P = 0.030) and a higher risk of 3-year cumulative incidence of relapse (P = 0.008), while no impact was observed on 3-year overall survival (P = 0.837). Multivariate analysis revealed that CNSL status at diagnosis was an independent predictor with a higher cumulative incidence of relapse (hazard ratio = 2.809, P = 0.016).

Conclusion

CNSL status remains an adverse prognostic factor in childhood B-cell ALL, indicating that additional augmentation of CNS-directed therapy is warranted for patients with CNSL at diagnosis.
Doxorubicin-induced cardiotoxicity is mediated by neutrophils through release of neutrophil elastase
Authors: Bhagat Anchit , Shrestha Pradeep , Jeyabal Prince , Peng Zhanglong , Watowich Stephanie S. , Kleinerman Eugenie S.
Published: August 2022

The mechanisms by which Doxorubicin (Dox) causes acute and late cardiotoxicity are not completely understood. One understudied area is the innate immune response, and in particular the role of neutrophils in Dox-induced cardiotoxicity. Here, using echocardiography, flow cytometry and immunofluorescence staining, we demonstrated increased infiltration of neutrophils that correlated with decreased heart function, disruption of vascular structures and increased collagen deposition in the heart after Dox treatment. Depleting neutrophils protected the heart from Dox-induced cardiotoxicity and changes in vascular structure. Furthermore, our data using neutrophil elastase (NE) knock-out mice and the NE inhibitor AZD9668 suggest that neutrophils cause this damage by releasing NE and that inhibiting NE can prevent Dox-induced cardiotoxicity. This work shows the role of neutrophils and NE in Doxorubicin-induced cardiotoxicity for the first time and suggests a new possible therapeutic intervention.
The role of RHAMM in cancer: Exposing novel therapeutic vulnerabilities
Authors: Hinneh Josephine A. , Gillis Joanna L. , Moore Nicole L. , Butler Lisa M. , Centenera Margaret M.
Published: August 2022

Receptor for hyaluronic acid-mediated motility (RHAMM) is a cell surface receptor for hyaluronic acid that is critical for cell migration and a cell cycle protein involved in microtubule assembly and stability. These functions of RHAMM are required for cellular stress responses and cell cycle progression but are also exploited by tumor cells for malignant progression and metastasis. RHAMM is often overexpressed in tumors and is an independent adverse prognostic factor for a number of cancers such as breast and prostate. Interestingly, pharmacological or genetic inhibition of RHAMM in vitro and in vivo ablates tumor invasiveness and metastatic spread, implicating RHAMM as a potential therapeutic target to restrict tumor growth and improve patient survival. However, RHAMM’s pro-tumor activity is dependent on its subcellular distribution, which complicates the design of RHAMM-directed therapies. An alternative approach is to identify downstream signaling pathways that mediate RHAMM-promoted tumor aggressiveness. Herein, we discuss the pro-tumoral roles of RHAMM and elucidate the corresponding regulators and signaling pathways mediating RHAMM downstream events, with a specific focus on strategies to target the RHAMM signaling network in cancer cells.
Non-coding RNAs in skin cancers:Biological roles and molecular mechanisms
Authors: Liu Fei , Li Shenglong
Published: August 2022

Cutaneous malignancies, including basal cell carcinoma, cutaneous squamous cell carcinoma, and cutaneous melanoma, are common human tumors. The incidence of cutaneous malignancies is increasing worldwide, and the leading cause of death is malignant invasion and metastasis. The molecular biology of oncogenes has drawn researchers’ attention because of the potential for targeted therapies. Noncoding RNAs, including microRNAs, long noncoding RNAs, and circular RNAs, have been studied extensively in recent years. This review summarizes the aspects of noncoding RNAs related to the metastasis mechanism of skin malignancies. Continuous research may facilitate the identification of new therapeutic targets and help elucidate the mechanism of tumor metastasis, thus providing new opportunities to improve the survival rate of patients with skin malignancies.
LAD-GCN: Automatic diagnostic framework for quantitative estimation of growth patterns during clinical evaluation of lung adenocarcinoma
Authors: Xiao Wei , Jiang Yanyun , Yao Zhigang , Zhou Xiaoming , Sui Xiaodan , Zheng Yuanjie
Published: August 2022

Quantitative estimation of growth patterns is important for diagnosis of lung adenocarcinoma and prediction of prognosis. However, the growth patterns of lung adenocarcinoma tissue are very dependent on the spatial organization of cells. Deep learning for lung tumor histopathological image analysis often uses convolutional neural networks to automatically extract features, ignoring this spatial relationship. In this paper, a novel fully automated framework is proposed for growth pattern evaluation in lung adenocarcinoma. Specifically, the proposed method uses graph convolutional networks to extract cell structural features; that is, cells are extracted and graph structures are constructed based on histopathological image data without graph structure. A deep neural network is then used to extract the global semantic features of histopathological images to complement the cell structural features obtained in the previous step. Finally, the structural features and semantic features are fused to achieve growth pattern prediction. Experimental studies on several datasets validate our design, demonstrating that methods based on the spatial organization of cells are appropriate for the analysis of growth patterns.
Multidimensional assessment of Game Transfer Phenomena: Intrusive cognitions, perceptual distortions, hallucinations and dissociations
Authors: Ortiz de Gortari Angelica B. , Diseth Åge
Published: August 2022

Game Transfer Phenomena (GTP) refers to a cluster of involuntary phenomena related to playing videogames, including sensory and cognitive intrusions, transient changes in perception and self-agency. The Game Transfer Phenomena Scale (GTPS) has been used to measure the frequency of GTP with respect to five factors. The present study aimed to validate an instrument for assessing the multiple dimensions of GTP (GTP-MDS) that helps clarify the distinction between GTP experiences. GTP were contextualized onto the spectrum of intrusive cognitions, perceptual distortions, and dissociations. The relationship between GTP, involuntary phenomena without game content (INVWG) in terms of, e.g., hallucinations and perceptual distortions, and game-biased perceptions (GBPA), as well as the positive and negative impact of GTP and level of distress were also examined. The data were collected using a survey (N = 1,301, male 83.4%, mean age = 28.14). Separate confirmatory factor analyses of the dimensions of “inner intrusions/misperceptions,” “outer intrusions/distortions,” and “dissociations/mix-ups” produced acceptable fit indices. The findings show that phenomena manifesting as internal experiences are more common, while those manifesting as externalized intrusions are less common. Correlations between the GTP dimensions, INVWG, and GBPA, such as the insertion of game elements in thoughts, perceptions, and dreams, supported convergent validity. The correlations between the GTP dimensions and hours played supported criterion validity. Distress was correlated with outer intrusions and dissociations/mix-ups, but not with inner intrusions. Taken together, these results support the validity and reliability of the proposed assessment of GTP constructs.
Changing Trends of Consumers' Online Buying Behavior During COVID-19 Pandemic With Moderating Role of Payment Mode and Gender
Authors: Sajid Sana , Rashid Rao Muhammad , Haider Waleej
Published: August 2022

It was not long ago when technological emergence fundamentally changed the landscape of global businesses. Following that, business operations started shifting away from traditional to advance digitalized processes. These digitalized processes gave a further boost to the e-commerce industry, making the online environment more competitive. Despite the growing trend, there has always been a consumer market that is not involved in online shopping, and this gap is huge when it comes to consumers from developing countries, specifically Pakistan. On contrary, the recent COVID-19 pandemic has brought drastic changes to the way consumers used to form their intention and behave toward digitalized solutions in pre COVID-19 times. Evidence shows that the global e-commerce industry has touched phenomenal growth during COVID-19, whereas Pakistan's e-commerce industry still holds a huge potential and has not fully boomed yet. These facts pave new avenues for marketers to cater to this consumer market for long-term growth. Hence, the study provides insights into how consumers' online buying behavior has transformed during the COVID-19 pandemic in the context of Pakistan. The study presents a framework based on the Technology Acceptance Model (TAM) and Theory of Planned Behavior (TPB). Furthermore, the moderating role of gender and payment mode has also been examined. For the analysis of variables, the partial least squares (PLS) method was used to conduct structural equation modeling (SEM) by collecting data from 266 respondents. The results show a significant and positive impact of perceived benefits, perceived ease of use, perceived enjoyment, and social influence on consumers' intention, but they also show an insignificant impact of gender and payment mode as a moderating variable on PEOU-BI and BI-AB, respectively. The results are of utmost significance for Pakistani businesses, marketers, and e-traders to streamline their business practices accordingly. Lastly, the proposed framework demonstrates new directions for future research to work upon.