bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and clinical characteristics of Crooke’s cell adenomas in 101 patients with T-PIT-positive pituitary adenomas: Case series and literature review
Authors: Zhu Dimin , Wang Zongming , Tian Tian , Wu Xinyi , He Dongsheng , Zhu Yonghong , Liu Dawei , Wang Haijun
Published: August 2022

Purpose

We aimed to perform a retrospective analysis of a rare subtype of corticotroph adenoma, Crooke’s cell adenoma, to better understand its clinical features.

Methods

We collected T-PIT-positive pituitary adenomas and screened Crooke’s cell adenomas from January 2020 to December 2021 in our center. Case reports of such tumors were also collected through a literature search. Clinical data such as biochemical tests, imaging examinations, and pathological data of the above cases were analyzed.

Results

A total of 101 T-PIT-positive patients were treated in our center in the last 2 years, and 4 were finally pathologically diagnosed with Crooke’s cell adenomas. All of these patients were male with elevated adrenocorticotropic hormone levels, and 50.0% presented with hypercortisolemia, Cushing’s syndrome, visual impairment, and headache. The tumor diameter was significantly larger in these 4 patients (37.0 mm) than in the other patients (26.0 mm), and their tumor invasive behavior was more pronounced. Cases reported in the literature were mainly female (72.8%), and the clinical presentation was also dominated by Cushing’s syndrome (65.1%) and hormonal dysfunction. Tumors were more common as macroadenomas (33.2 mm) and suprasellar growths (63.8%). The tumor recurrence rate was as high as 55.6%, with 6 cases progressing to pituitary carcinomas and 7.7% of tumor-related deaths. Our further integrated analysis of our center and reported cases revealed that gender, Cushing’s syndrome, visual dysfunction, hormonal disorders, and tumor growth characteristics were statistically different in different tumor categories.

Conclusion

Crooke’s cell adenoma is a tumor subtype with obvious clinical aggressive behavior, and an in-depth analysis of its clinical characteristics may assist in developing a comprehensive treatment plan.
Aging conundrum: A perspective for ovarian aging
Authors: Wu Jiachen , Liu Yang , Song Yinhua , Wang Lingjuan , Ai Jihui , Li Kezhen
Published: August 2022

Progressive loss of physiological integrity and accumulation of degenerative changes leading to functional impairment and increased susceptibility to diseases are the main features of aging. The ovary, the key organ that maintains female reproductive and endocrine function, enters aging earlier and faster than other organs and has attracted extensive attention from society. Ovarian aging is mainly characterized by the progressive decline in the number and quality of oocytes, the regulatory mechanisms of which have yet to be systematically elucidated. This review discusses the hallmarks of aging to further highlight the main characteristics of ovarian aging and attempt to explore its clinical symptoms and underlying mechanisms. Finally, the intervention strategies related to aging are elaborated, especially the potential role of stem cells and cryopreservation of embryos, oocytes, or ovarian tissue in the delay of ovarian aging.
Melatonin promotes the growth and development of lambs by increasing growth hormone and testosterone, targeting on apoptosis signaling pathway and intestinal microflora
Authors: Ma Wenkui , Wu Hao , Li Guangdong , Yan Laiqing , Wang Likai , Zhao Mengmeng , Guan Shengyu , Xu Shang , Guo Xiaokai , Liu Fenze , Ji Pengyun , Wusiman Abulizi , Liu Guoshi
Published: August 2022

Melatonin is an indole-like neuroendocrine hormone. A large number of studies have shown that melatonin can improve production performance of ewes, but it is not clear in lambs. In this study, the growth and development of the 2-month-old lambs implanted with melatonin were monitored for 60 days. The results showed that the growth rate of body weight and body skew length of lambs with melatonin treatment were significantly improved compared to the controls. The similar results were also observed in red blood cell count, hematocrit, red blood cell volume distribution width, the levels of growth hormone, testosterone, immunoglobulin A, immunoglobulin M and albumin. In addition, the cross sectional area of muscle fibers and adipose cells of lambs with melatonin implantation were also significantly increased compared to the controls (P<0.05). To further explore the potential mechanisms, the muscle and adipose tissue were selected for transcriptome sequencing. KEGG enrichment results showed that melatonin regulated the expression of genes related to apoptotic signaling pathway in muscle and adipocytes. Since the intestinal microbiota are involved in the nutritional balance and animal growth, the 16SrRNA sequencing related to the intestinal microbiota was also performed. The data indicated that the structural differences of fecal microflora mainly occur in the pathways of Cardiovascular disease, Excretory system and Signaling molecules and interaction. In brief, melatonin promotes the growth and development of lambs. The potential mechanisms may be that melatonin increased the growth hormone and testosterone mediated apoptosis signaling pathway and regulated intestinal microbial flora. Our results provide valuable information for melatonin to improve the production of sheep husbandry in the future.
Deep learning reveals cuproptosis features assist in predict prognosis and guide immunotherapy in lung adenocarcinoma
Authors: Li Gang , Luo Qingsong , Wang Xuehai , Zeng Fuchun , Feng Gang , Che Guowei
Published: August 2022

Background

Cuproptosis is a recently found non-apoptotic cell death type that holds promise as an emerging therapeutic modality in lung adenocarcinoma (LUAD) patients who develop resistance to radiotherapy and chemotherapy. However, the Cuproptosis’ role in the onset and progression of LUAD remains unclear.

Methods

Cuproptosis-related genes (CRGs) were identified by a co-expression network approach based on LUAD cell line data from radiotherapy, and a robust risk model was developed using deep learning techniques based on prognostic CRGs and explored the value of deep learning models systematically for clinical applications, functional enrichment analysis, immune infiltration analysis, and genomic variation analysis.

Results

A three-layer artificial neural network risk model was constructed based on 15 independent prognostic radiotherapy-related CRGs. The risk model was observed as a robust independent prognostic factor for LUAD in the training as well as three external validation cohorts. The patients present in the low-risk group were found to have immune “hot” tumors exhibiting anticancer activity, whereas the high-risk group patients had immune “cold” tumors with active metabolism and proliferation. The high-risk group patients were more sensitive to chemotherapy whereas the low-risk group patients were more sensitive to immunotherapy. Genomic variants did not vary considerably among both groups of patients.

Conclusion

Our findings advance the understanding of cuproptosis and offer fresh perspectives on the clinical management and precision therapy of LUAD.
The high degree of similarity in histopathological and clinical characteristics between radiogenic and sporadic papillary thyroid microcarcinomas in young patients
Authors: Bogdanova Tetiana , Chernyshov Serhii , Zurnadzhy Liudmyla , Rogounovitch Tatiana I. , Mitsutake Norisato , Tronko Mykola , Ito Masahiro , Bolgov Michael , Masiuk Sergii , Yamashita Shunichi , Saenko Vladimir A.
Published: August 2022

The potential overtreatment of patients with papillary thyroid microcarcinoma (MPTC) has been an important clinical problem in endocrine oncology over the past decade. At the same time, current clinical guidelines tend to consider prior radiation exposure as a contraindication to less extensive surgery, even for low-risk thyroid carcinomas, which primarily include microcarcinomas. This study aims to determine whether there are differences in the behavior of MPTC of two etiological forms (radiogenic and sporadic), including invasive properties, clinical data, and recurrence in patients aged up to 30 years. For this purpose, 136 radiogenic (from patients aged up to 18 years at the time of the Chornobyl accident) and 83 sporadic (from patients born after the Chornobyl accident) MPTCs were selected and compared using univariate and multivariate statistical methods in a whole group and in age and tumor size subgroups. No evidence of more aggressive clinical and histopathological behavior of radiogenic MPTCs as compared to sporadic tumors for basic structural, invasive characteristics, treatment options, and postoperative follow-up results was found. Moreover, radiogenic MPTCs were characterized by the lower frequencies of oncocytic changes (OR = 0.392, p = 0.004), nodal disease (OR = 0.509, p = 0.050), and more frequent complete remission (excellent response) after radioiodine therapy (OR = 9.174, p = 0.008). These results strongly suggest that internal irradiation does not affect tumor phenotype, does not associate with more pronounced invasive properties, and does not worsen prognosis in pediatric or young adult patients with MPTC, implying that radiation history may be not a pivotal factor for determining treatment strategy in such patients.
Standard operating procedure for post-operation component disassembly and observation of benchtop water electrolyzer testing
Authors: Glenn Jennifer R. , Lindquist Grace A. , Roberts George M. , Boettcher Shannon W. , Ayers Katherine E.
Published: August 2022

Post-operation component disassembly and observation of electrolyzer parts is useful in understanding the interactions of the components and the electrochemical environment beyond the systems electrochemical output. We report a standard protocol for post-operation component disassembly and observation, including directions for cell-component preservation, preliminary visual inspection of cell components, and a guide for the advanced inspection of specific components with suggestions for further analysis if necessary. The procedures outlined here allow for a standardized method that can be used and compared between different laboratories and for literature comparison to experimental results.
In-containment hydrogen behavior simulation and hydrogen concentration control under LBLOCA accidents
Authors: Tianfan Wu , Feng Xue , Shuo Ding , Li Wang , Wanai Li , Yifan Wang
Published: August 2022

During a design basis accident in a pressurized water reactor (PWR), the released hydrogen through reactor breaks would induce the hydrogen detonation. The hydrogen passive autocatalytic recombiner (PAR) is widely used as a hydrogen elimination measure in nuclear power plants due to its passive capability, low starting threshold and easy installation. The present work aims to study the hydrogen risk after the occurrence of cold section double-end shear fracture large break loss coolant accident (LBLOCA) by using the 3D computational fluid dynamics program GASFLOW. A full containment model of CPR1000 is built. The hydrogen production rate inside the containment after LBLOCA is calculated from the related physicochemical reactions. The hydrogen transport, hydrogen concentration distribution and temperature distribution inside the containment are simulated. The effects of different roughness of the structure surface on the simulation are investigated, and it is proved that the operation of PAR can control the hydrogen concentration under the safety threshold of 4 vol%. The effects of hydrogen flow rate and PAR’s position on the hydrogen elimination efficiency are studied. Based on these studies, this paper makes some suggestions and theoretical references for the spatial arrangement scheme of PAR in the containment to optimize the hydrogen elimination efficiency.
Identification of fragmented cropland in arid and semiarid sandy areas: a case study of horqin left rear banner
Authors: Sang Zhiting , Liang Jie , Zheng Huihui , Wang Kaige , Xu Yan , Liu Yibin
Published: August 2022

The sustainable development and utilization of sandy areas in arid and semiarid regions is of strategic importance to ensure both food and ecological security. The unique geographical environment of these areas and uncontrolled exploitation by farmers lead to large amounts of fragmented cropland. Despite government management, the quantity and distribution of these fragmented croplands is unknown, and accurate identification of the region’s fragmented croplands can provide data to support the sustainable use of sandy areas. We propose a method for identifying fragmented cropland based on scale transformation. Small-scale fragmented cropland is approximately represented at larger scales, so we apply small-scale high-resolution remote sensing images to identify features and obtain information at a large scale, i.e., the ratio of fragmented cropland area. By correcting the cropland areas identified from low-resolution remote sensing images and using them as the basis for the resulting calculation, more accurate identification can be 1 at a large scale. In this study, this method was applied based on remote sensing images with 0.54 and 30 m resolutions that were acquired during the same period, using Horqin Zuoyihou Banner as the study area. The results showed that (1) there was 13,637.08 hm2 of fragmented cropland in Horqin Zuoyihou Banner due to precipitation and terrain topography, mainly in the central and western regions and 2) identification at the sample point scale and plot scale were positively correlated in area and showed a consistent distribution. Therefore, accurate and efficient identification of fragmented cropland can be achieved through scale transformation.
Analysis of airbnb’s green user emotional characteristics: How do human, geographical, housing, and environmental factors influence green consumption?
Authors: Wang Juying , Wang Cheng
Published: August 2022

In the context of the sharing economy, green consumption is becoming a trend. Shared accommodation represented by Airbnb has been extensively studied. Analysis of the emotional characteristics of green users is the key to promoting the sustainable development of Airbnb. The article obtains the online reviews of Airbnb green users, fully considers the deviation caused by the weight of feature words to the sentiment calculation, and combines the sentiment value with the weight value to obtain the comprehensive sentiment value of green users. Then, a spatial comparative analysis of green users’ emotional characteristics in Beijing, Shanghai and Hong Kong in China is carried out. The results show that in Airbnb, green users have a more obvious emotional tendency to human and geographical factors, followed by housing factors, and show lower tendency to environmental factors. The study provides a new perspective for optimizing the Airbnb scoring system and promoting the sustainable development of the shared accommodation market.
Electric vehicle charging infrastructures in the Greater Bay Area of China: Progress, challenges and efforts
Authors: Lau Yui-yip , Andrew Wu Yang , Wing Yan Mak
Published: August 2022

The electric vehicle (EV) has proven to be a workable solution to minimizing environmental pollution. The EV has generally received substantial attention from both individual customers and corporate users. The EV has transformed remarkably and in recent years emerged as the most quickly developing section of the automobile industry. China has proven to be an outstanding country in enhancing the manufacture and marketing of EVs. Nevertheless, green environment, charging infrastructure and technology are the three main challenges leading to slowing down the penetration progress of EVs into the Greater Bay Area (GBA) of China. This study aims to report the existing development of the EV industry in China. Then, it elaborates on national policies to facilitate the enlargement of charging infrastructures, explains how to stimulate the development of charging infrastructure at the national level, discusses the implementation dilemma at the provincial and city levels, and highlights the challenges and policy gaps. Finally, it addresses some issues, challenges, progress and implications for improving the EV penetration in the GBA in the forthcoming years.
Phosphatidylinositol glycan anchor biosynthesis, class C is a prognostic biomarker and correlates with immune infiltrates in hepatocellular carcinoma
Authors: Zhao Qian , Shen Chuan , Wei Junwei , Zhao Caiyan
Published: August 2022

Background and aims: The exact function of Phosphatidylinositol Glycan Anchor Biosynthesis, Class C (PIGC) gene has yet to be elucidated. In the study, we attempted to clarify the correlations of PIGC to prognosis and tumor-infiltrating lymphocytes in hepatocellular carcinoma (HCC).

Methods:PIGC expression was analyzed via the Oncomine database, Gene Expression Profiling Interactive Analysis, Hepatocellular carcinoma data base, Human Protein Atlas database and Tumor Immune Estimation Resource (TIMER). We showed the correlation of PIGC with the clinical characteristics using UALCAN. We evaluated the influence of PIGC on clinical prognosis using Kaplan-Meier plotter databases. And co-expressed genes with PIGC and its regulators were identified using LinkedOmics. The correlations between PIGC and cancer immune infiltrates were investigated via TIMER. We analyzed the drug sensitivity and immunotherapy response via R package.

Results:PIGC was found up-regulated in tumor tissues in multiple HCC cohorts, also increased in HCC patient with different clinical characteristics. High PIGC expression was associated with poorer overall survival. PIGC expression showed a strong positive association with the expression of ACBD6, a strong negative association with AGXT212. The cell components and distribution in treatment and non-treatment of HCC patients were quite distinct, which may reveal the relationship between the immunotherapy with tumor microenvironment. Notably, PIGC expression was positively correlated with infiltrating levels of immune cells.

Conclusion: These findings suggest that PIGC is correlated with prognosis and immune infiltrating in HCC, which can be used as a prognostic biomarker for determining prognosis, laying a foundation for further study of the immune regulatory role of PIGC in HCC.
Multiethnic polygenic risk prediction in diverse populations through transfer learning
Authors: Tian Peixin , Chan Tsai Hor , Wang Yong-Fei , Yang Wanling , Yin Guosheng , Zhang Yan Dora
Published: August 2022

Polygenic risk scores (PRS) leverage the genetic contribution of an individual’s genotype to a complex trait by estimating disease risk. Traditional PRS prediction methods are predominantly for the European population. The accuracy of PRS prediction in non-European populations is diminished due to much smaller sample size of genome-wide association studies (GWAS). In this article, we introduced a novel method to construct PRS for non-European populations, abbreviated as TL-Multi, by conducting a transfer learning framework to learn useful knowledge from the European population to correct the bias for non-European populations. We considered non-European GWAS data as the target data and European GWAS data as the informative auxiliary data. TL-Multi borrows useful information from the auxiliary data to improve the learning accuracy of the target data while preserving the efficiency and accuracy. To demonstrate the practical applicability of the proposed method, we applied TL-Multi to predict the risk of systemic lupus erythematosus (SLE) in the Asian population and the risk of asthma in the Indian population by borrowing information from the European population. TL-Multi achieved better prediction accuracy than the competing methods, including Lassosum and meta-analysis in both simulations and real applications.
Genome-Wide Analysis and Evolutionary Perspective of the Cytokinin Dehydrogenase Gene Family in Wheat (Triticum aestivum L.)
Authors: Jain Priyanka , Singh Ankita , Iquebal Mir Asif , Jaiswal Sarika , Kumar Sundeep , Kumar Dinesh , Rai Anil
Published: August 2022

Cytokinin dehydrogenase (CKX; EC.1.5.99.12) regulates the level of cytokinin (CK) in plants and is involved in CK regulatory activities. In different plants, a small gene family encodes CKX proteins with varied numbers of members. These genes are expanded in the genome mainly due to segmental duplication events. Despite their biological importance, CKX genes in Triticum aestivum have yet to be studied in depth. A total of 11 CKX subfamilies were identified with similar gene structures, motifs, domains, cis-acting elements, and an average signal peptide of 25 amino acid length was found. Introns, ranging from one to four, were present in the coding regions at a similar interval in major CKX genes. Putative cis-elements such as abscisic acid, auxin, salicylic acid, and low-temperature-, drought-, and light-responsive cis-regulatory elements were found in the promoter region of majority CKX genes. Variation in the expression pattern of CKX genes were identified across different tissues in Triticum. Phylogenetic analysis shows that the same subfamily of CKX clustered into a similar clade that reflects their evolutionary relationship. We performed a genome-wide identification of CKX family members in the Triticum aestivum genome to get their chromosomal location, gene structure, cis-element, phylogeny, synteny, and tissue- and stage-specific expression along with gene ontology. This study has also elaborately described the tissue- and stage-specific expression and is the resource for further analysis of CKX in the regulation of biotic and abiotic stress resistance, growth, and development in Triticum and other cereals to endeavor for higher production and proper management.
Comprehensive analysis of the prognostic and immunotherapeutic implications of STAT family members in human colorectal cancer
Authors: Li Dingchang , Jiao Yanan , Gao Wenxing , Hu Shidong , Li Dingling , Zhao Wen , Chen Peng , Jin Lujia , Zhao Yingjie , Ma Zhaofu , Wu Xiansheng , Yan Yang , Sun Wen , Du Xiaohui , Dong Guanglong
Published: August 2022

Background: Colorectal cancer (CRC) is the third most prevalent cancer worldwide and the second leading cause of cancer mortality. Signal transducer and activator of transcription (STAT) proteins are a group of transcription factors implicated in cell signal transduction and gene transcription in several cancer types. However, the level of expression, genetic alterations, and biological function of different STATs, as well as their prognostic and immunotherapeutic value in CRC remain unclear.

Methods: The mRNA and protein expression levels, genetic alterations, prognostic value, gene–gene and protein–protein interaction networks, and biological function of STATs in CRC were studied using the GEPIA, HPA, cBioPortal, PrognoScan, Kaplan–Meier plotter, GeneMANIA, STRING, and Metascape databases. The expression of STATs in CRC was confirmed using immunohistochemistry (IHC). Finally, the relationship between STAT expression and immune infiltration as well as immunotherapy-associated indicators was also investigated.

Results: The expression levels of STAT2/5A/5B are downregulated in CRC, and the STAT1/3/4/5B expressions were significantly associated with the tumor stage of patients with CRC. The abnormal expression of STAT2/4/5B in patients with CRC is related to the prognosis of patients with CRC. The STATs and their neighboring proteins are primarily associated with lymphocyte activation, cytokine-mediated signaling pathways, positive regulation of immune response, regulation of cytokine production, and growth hormone receptor signaling pathways in cancer. The expression of STATs was significantly associated with immune infiltration and immunotherapy response-associated indicators.

Conclusion: This study may help further understand the molecular mechanism of CRC and provide new prognostic biomarkers and immunotherapy targets in patients with CRC.
Genetic mapping of QTLs for drought tolerance in chickpea (Cicer arietinum L.)
Authors: Kushwah Ashutosh , Bhatia Dharminder , Barmukh Rutwik , Singh Inderjit , Singh Gurpreet , Bindra Shayla , Vij Suruchi , Chellapilla Bharadwaj , Pratap Aditya , Roorkiwal Manish , Kumar Shiv , Varshney Rajeev K. , Singh Sarvjeet
Published: August 2022

Chickpea yield is severely affected by drought stress, which is a complex quantitative trait regulated by multiple small-effect genes. Identifying genomic regions associated with drought tolerance component traits may increase our understanding of drought tolerance mechanisms and assist in the development of drought-tolerant varieties. Here, a total of 187 F8 recombinant inbred lines (RILs) developed from an interspecific cross between drought-tolerant genotype GPF 2 (Cicer arietinum) and drought-sensitive accession ILWC 292 (C. reticulatum) were evaluated to identify quantitative trait loci (QTLs) associated with drought tolerance component traits. A total of 21 traits, including 12 morpho-physiological traits and nine root-related traits, were studied under rainfed and irrigated conditions. Composite interval mapping identified 31 QTLs at Ludhiana and 23 QTLs at Faridkot locations for morphological and physiological traits, and seven QTLs were identified for root-related traits. QTL analysis identified eight consensus QTLs for six traits and five QTL clusters containing QTLs for multiple traits on linkage groups CaLG04 and CaLG06. The identified major QTLs and genomic regions associated with drought tolerance component traits can be introgressed into elite cultivars using genomics-assisted breeding to enhance drought tolerance in chickpea.
Prognostic microRNAs associated with phosphoserine aminotransferase 1 in gastric cancer as markers of bone metastasis
Authors: Ma Jingwei , Zhu Meng , Ye Xiaofeng , Wu Bo , Wang Tao , Ma Muyuan , Li Tao , Zhang Ning
Published: August 2022

This study analyzed PSAT1-targeted miRNAs as a prognostic predictor for gastric cancer. The relationship between the clinical manifestations of gastric cancer in patients and phosphoserine aminotransferase 1 (PSAT1) was analyzed using correlation analysis. PSAT1 was highly expressed in gastric cancer, and its low expression was associated with a poor prognosis. By pan-cancer analysis, PSAT1 could affect the tumor immune microenvironment by immune infiltration analysis. Nine microRNAs targeting PSAT1 and associated with gastric cancer were screened by miRwalk and microRNA expression in TCGA tumor tissues. Six microRNAs were obtained by survival curve analysis, including hsa-miR-1-3p, hsa-miR-139-5p, hsa-miR-145-5p, hsa-miR-195-5p, hsa-miR-218-5p, and hsa-miR-497-5p. Based on the above six microRNAs, a model for bone metastasis prediction in gastric cancer prediction was constructed. An analysis of a decision curve was performed based on the microRNAs obtained to predict bone metastasis from gastric cancer. It had a positive area under the curve (AUC) value of 0.746, and the decision curve analysis (DCA) indicated that it was clinically significant. Dual-luciferase reporter genes indicated that hsa-miR-497-5p and PSAT1 were targeted, and qRT-PCR results confirmed that hsa-miR-497-5p could down-regulate PSAT1 expression. MicroRNAs targeting the regulation of PSAT1 expression can well predict the prognosis of gastric cancer.
Low circulating PCSK9 levels in LPL homozygous children with chylomicronemia syndrome in a syrian refugee family in Lebanon
Authors: Ayoub Carine , Azar Yara , Maddah Dina , Ghaleb Youmna , Elbitar Sandy , Abou-Khalil Yara , Jambart Selim , Varret Mathilde , Boileau Catherine , El Khoury Petra , Abifadel Marianne
Published: August 2022

Familial chylomicronemia syndrome is a rare autosomal recessive disorder of lipoprotein metabolism characterized by the presence of chylomicrons in fasting plasma and an important increase in plasma triglycerides (TG) levels that can exceed 22.58 mmol/l. The disease is associated with recurrent episodes of abdominal pain and pancreatitis, eruptive cutaneous xanthomatosis, lipemia retinalis, and hepatosplenomegaly. A consanguineous Syrian family who migrated to Lebanon was referred to our laboratory after perceiving familial chylomicronemia syndrome in two children. The LPL and PCSK9 genes were sequenced and plasma PCSK9 levels were measured. Sanger sequencing of the LPL gene revealed the presence of the p.(Val227Phe) pathogenic variant in exon 5 at the homozygous state in the two affected children, and at the heterozygous state in the other recruited family members. Interestingly, PCSK9 levels in homozygous carriers of the p.(Val227Phe) were ≈50% lower than those in heterozygous carriers of the variant (p-value = 0.13) and ranged between the 5th and the 7.5th percentile of PCSK9 levels in a sample of Lebanese children of approximately the same age group. Moreover, this is the first reported case of individuals carrying simultaneously an LPL pathogenic variant and PCSK9 variants, the L10 and L11 leucine insertion, which can lower and raise low-density lipoprotein cholesterol (LDL-C) levels respectively. TG levels fluctuated concomitantly between the two children, were especially high following the migration from a country to another, and were reduced under a low-fat diet. This case is crucial to raise public awareness on the risks of consanguineous marriages to decrease the emergence of inherited autosomal recessive diseases. It also highlights the importance of the early diagnosis and management of these diseases to prevent serious complications, such as recurrent pancreatitis in the case of familial hyperchylomicronemia.
DNA methylation as a mediator of genetic and environmental influences on Parkinson’s disease susceptibility: Impacts of alpha-Synuclein, physical activity, and pesticide exposure on the epigenome
Authors: Schaffner Samantha L. , Kobor Michael S.
Published: August 2022

Parkinson’s disease (PD) is a neurodegenerative disorder with a complex etiology and increasing prevalence worldwide. As PD is influenced by a combination of genetic and environment/lifestyle factors in approximately 90% of cases, there is increasing interest in identification of the interindividual mechanisms underlying the development of PD as well as actionable lifestyle factors that can influence risk. This narrative review presents an outline of the genetic and environmental factors contributing to PD risk and explores the possible roles of cytosine methylation and hydroxymethylation in the etiology and/or as early-stage biomarkers of PD, with an emphasis on epigenome-wide association studies (EWAS) of PD conducted over the past decade. Specifically, we focused on variants in the SNCA gene, exposure to pesticides, and physical activity as key contributors to PD risk. Current research indicates that these factors individually impact the epigenome, particularly at the level of CpG methylation. There is also emerging evidence for interaction effects between genetic and environmental contributions to PD risk, possibly acting across multiple omics layers. We speculated that this may be one reason for the poor replicability of the results of EWAS for PD reported to date. Our goal is to provide direction for future epigenetics studies of PD to build upon existing foundations and leverage large datasets, new technologies, and relevant statistical approaches to further elucidate the etiology of this disease.
Monochromatic blue light enhances crocin and picrocrocin content by upregulating the expression of underlying biosynthetic pathway genes in saffron (Crocus sativus L.)
Authors: Moradi Shirin , Kafi Mohsen , Aliniaeifard Sasan , Moosavi-Nezhad Moein , Pedersen Carsten , Gruda Nazim S. , Salami Seyed Alireza
Published: August 2022

Saffron quality is determined by the content of three apocarotenoids, including crocin, picrocrocin, and safranal, giving saffron culinary, industrial, and medical importance. The level of these secondary metabolites is also affected by environmental factors such as light, which play a pivotal role in regulating plants' signaling pathways. In this study, we investigated the effects of different ratios of blue (B) to red (R) and white (W) light on physiological, biochemical, and molecular responses of saffron in the flowering stage. Flowers' morphological properties were improved in plants grown under monochromatic B light. The highest content of total carotenoids, anthocyanins, and flavonoids was detected in plants grown under a high proportion of B light. The highest crocin content, especially the trans-crocetin ester isomer, was recorded in monochromatic B light-grown plants. However, the highest picrocrocin content was in both monochromatic R- and B light-grown plants. The highest safranal content was detected in plants grown under a high proportion of R light. Transcriptome analysis of secondary metabolism pathways showed that the transcript level of the genes was highly correlated with the content of the target metabolites. Monochromatic B light upregulated the expression of genes involved in crocin production (CsCCD2, CsALDH31l, and CsUGT2). However, the expression of CsUGT709G1, which is involved in picrocrocin and safranal pathways, was upregulated in plants grown under a high ratio of R light and W lights. In conclusion, monochromatic B light enhances the flowering rate, crocin (trans-crocetin ester), and picrocrocin content, which increases the quantity and quality of saffron products under controlled conditions.
CX3CL1-induced CD16+ monocytes extravasation in myeloperoxidase-ANCA-associated vasculitis correlates with renal damage
Authors: Tang Jiale , Liao Zhonghua , Luo Liying , Deng Shuanglinzi , Jiang Yuanyuan , Wang Fangyuan , Hu Xinyue , Yin Hongling , Gong Guanghui , Feng Juntao , Li Xiaozhao
Published: August 2022

Background

Monocytes are involved in the pathogenesis of ANCA-associated vasculitis (AAV). Monocyte/macrophages are the dominant infiltrating cells in the glomeruli of patients with myeloperoxidase-AAV (MPO-AAV). However, how human monocyte subsets extravasate to the kidney in MPO-AAV with renal damage is unclear.

Methods

30 MPO-AAV patients with renal damage and 22 healthy controls were enrolled in this study. Monocyte subsets and monocyte-related chemokines in the blood and kidneys of MPO-AAV patients were detected. The chemoattractant activity of the CX3CL1-CX3CR1 axis on CD16+ monocytes was observed. The effect of MPO-ANCA on the migration of CD16+ monocytes to human glomerular endothelial cells (HGECs) was detected by flow cytometry and transwell migration assay.

Results

Compared with controls, CD16+ monocytes were significantly decreased in the blood and increased in the glomeruli of MPO-AAV patients with renal damage. The level of CX3CL1, but not CCL2, was significantly increased in the plasma of MPO-AAV patients. CX3CL1 co-localized with glomerular endothelial cells in MPO-AAV patients with renal damage. Moreover, we initially found that MPO-ANCA promotes an increase of the chemokine CX3CL1 on HGECs, imposing recruitment on CD16+ monocytes. Finally, the percentage of CD16+ monocytes in the blood was found to be positively correlated with estimated glomerular filtration rate (eGFR) and negatively correlated with urinary protein creatinine ratio in MPO-AAV patients with renal damage. Furthermore, the urinary protein creatinine ratio was positively correlated with the infiltrating of CD14+ and CD16+ cells in the kidneys.

Conclusion

Enhanced extravasation of CD16+ monocytes to the kidney via the CX3CL1-CX3CR1 axis may be involved in renal damage in MPO-AAV.
MuSyC dosing of adjuvanted cancer vaccines optimizes antitumor responses
Authors: Taylor David , Meyer Christian T. , Graves Diana , Sen Rupashree , Fu Juan , Tran Emily , Mirza Bilal , Rodriguez Gabriel , Lang Cara , Feng Hanwen , Quaranta Vito , Wilson John T. , Kim Young J. , Korrer Michael J.
Published: August 2022

With the clinical approval of T-cell–dependent immune checkpoint inhibitors for many cancers, therapeutic cancer vaccines have re-emerged as a promising immunotherapy. Cancer vaccines require the addition of immunostimulatory adjuvants to increase vaccine immunogenicity, and increasingly multiple adjuvants are used in combination to bolster further and shape cellular immunity to tumor antigens. However, rigorous quantification of adjuvants’ synergistic interactions is challenging due to partial redundancy in costimulatory molecules and cytokine production, leading to the common assumption that combining both adjuvants at the maximum tolerated dose results in optimal efficacy. Herein, we examine this maximum dose assumption and find combinations of these doses are suboptimal. Instead, we optimized dendritic cell activation by extending the Multidimensional Synergy of Combinations (MuSyC) framework that measures the synergy of efficacy and potency between two vaccine adjuvants. Initially, we performed a preliminary in vitro screening of clinically translatable adjuvant receptor targets (TLR, STING, NLL, and RIG-I). We determined that STING agonist (CDN) plus TLR4 agonist (MPL-A) or TLR7/8 agonist (R848) as the best pairwise combinations for dendritic cell activation. In addition, we found that the combination of R848 and CDN is synergistically efficacious and potent in activating both murine and human antigen-presenting cells (APCs) in vitro. These two selected adjuvants were then used to estimate a MuSyC-dose optimized for in vivo T-cell priming using ovalbumin-based peptide vaccines. Finally, using B16 melanoma and MOC1 head and neck cancer models, MuSyC-dose–based adjuvating of cancer vaccines improved the antitumor response, increased tumor-infiltrating lymphocytes, and induced novel myeloid tumor infiltration changes. Further, the MuSyC-dose–based adjuvants approach did not cause additional weight changes or increased plasma cytokine levels compared to CDN alone. Collectively, our findings offer a proof of principle that our MuSyC-extended approach can be used to optimize cancer vaccine formulations for immunotherapy.
Association of longitudinal platelet count trajectory with ICU mortality: A multi-cohort study
Authors: Chen Jiajin , Gao Xi , Shen Sipeng , Xu Jingyuan , Sun Zhe , Lin Ruilang , Dai Zhixiang , Su Li , Christiani David C. , Chen Feng , Zhang Ruyang , Wei Yongyue
Published: August 2022

Objective

Platelet (PLT) engages in immune and inflammatory responses, all of which are related to the prognosis of critically ill patients. Although thrombocytopenia at ICU admission contributes to in-hospital mortality, PLT is repeatedly measured during ICU hospitalization and the role of longitudinal PLT trajectory remains unclear. We aimed to identify dynamic PLT trajectory patterns and evaluate their relationships with mortality risk and thrombocytopenia.

Methods

We adopted a three-phase, multi-cohort study strategy. Firstly, longitudinal PLT trajectory patterns within the first four ICU days and their associations with 28-day survival were tested in the eICU Collaborative Research Database (eICU-CRD) and independently validated in the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Secondly, the relationships among PLT trajectory patterns, thrombocytopenia, and 28-day mortality were explored and validated. Finally, a Mortality GRade system for ICU dynamically monitoring patients (Mortality-GRID) was developed to quantify the mortality risk based on longitudinal PLT, which was further validated in the Molecular Epidemiology of Acute Respiratory Distress Syndrome (MEARDS) cohort.

Results

A total of 35,332 ICU patients were included from three cohorts. Trajectory analysis clustered patients into ascending (AS), stable (ST), or descending (DS) PLT patterns. DS patients with high baseline PLT decline quickly, resulting in poor prognosis. AS patients have low baseline PLT but recover quickly, favoring a better prognosis. ST patients maintain low PLT, having a moderate prognosis in between (HRSTvsAS = 1.26, 95% CI: 1.14–1.38, P = 6.15 × 10−6; HRDSvsAS = 1.58, 95% CI: 1.40–1.79, P = 1.41 × 10−13). The associations remained significant in patients without thrombocytopenia during the entire ICU hospitalization and were robust in sensitivity analyses and stratification analyses. Further, the trajectory pattern was a warning sign of thrombocytopenia, which mediated 27.2% of the effects of the PLT trajectory on 28-day mortality (HRindirect = 1.11, 95% CI: 1.06–1.17, P = 9.80 × 10−6). Mortality-GRID well predicts mortality risk, which is in high consistency with that directly estimated in MEARDS (r = 0.98, P = 1.30 × 10−23).

Conclusion

Longitudinal PLT trajectory is a complementary predictor to baseline PLT for patient survival, even in patients without risk of thrombocytopenia. Mortality-GRID could identify patients at high mortality risk.
An open, observational, three-arm clinical study of 2–3 cycles of treatment as neoadjuvant therapy in operable locally advanced non-small cell lung cancer: An interim analysis
Authors: Gu Linping , Wang Xue , Sun Yile , Xu Yunhua , Niu Xiaomin , Zhao Ruiying , Yao Yaxian , Jian Hong , Han Yuchen , Wei Jinwang , Chen Zhiwei , Lu Shun
Published: August 2022

Background

An open, observational, three-arm clinical study aimed at investigating the efficacy of different neoadjuvant therapies (neoadjuvant immunotherapy with(out) chemotherapy, neoadjuvant chemotherapy, and neoadjuvant targeted therapy) in operable locally advanced non-small cell lung cancer (NSCLC) was conducted (NCT04197076). We report an interim analysis of 49 of 53 evaluable patients.

Methods

This study was conducted at Shanghai Chest Hospital and included eligible NSCLC patients who were 18 years old and had clinical stage IIB–IIIB disease. All 49 patients had surgical resection within 4–6 weeks after 2–3 cycles of neoadjuvant treatment consisting of immunotherapy (24 patients), chemotherapy (16 patients), and a targeted therapy (9 patients) regimen starting on the first day of each 21-day cycle. Pathologic complete response (pCR) was evaluated as the primary endpoint. Major pathological response (MPR) and tumor regression rate (TRR) were also evaluated.

Results

An improved pathologic complete response was achieved in the neoadjuvant immunotherapy arm compared with the neoadjuvant chemotherapy arm and neoadjuvant targeted therapy arm [20.8% (5/24) vs. 6.3% (1/16) vs. 0.0% (0/9); P = 0.089, 95% CI 0.138–0.151]. More importantly, we found that the curative effect of the neoadjuvant immunotherapy arm in pCR+MPR was better than that of the neoadjuvant chemotherapy arm and neoadjuvant targeted therapy arm [45.8% (11/24) vs. 18.8% (3/16) vs. 0.0% (0/9); P = 0.006, 95% confidence interval, 0.008–0.012]. Different neoadjuvant therapies had a statistically significant effect on postoperative pathological tumor downstaging (P = 0.017).

Conclusions

Neoadjuvant immunotherapy was associated with a trend toward better pCR than the neoadjuvant chemotherapy arm and neoadjuvant targeted therapy. Curative effect (pCR + MPR) was significantly better with neoadjuvant immunotherapy (P = 0.006, 95% confidence interval, 0.008–0.012).

Clinical Trial Registration

https://clinicaltrials.gov/ct2/show/NCT04197076?recrs=a&cond=NCT04197076&draw=2&rank=1.
Human dendritic cell targeting peptide can be targeted to porcine dendritic cells to improve antigen capture efficiency to stimulate stronger immune response
Authors: Xia Tian , Yang Huizhu , Guo Yuyao , Guo Tiantian , Xin Lingxiang , Jiang Yanping , Cui Wen , Zhou Han , Qiao Xinyuan , Wang Xiaona , Li Jiaxuan , Shan Zhifu , Tang Lijie , Wang Li , Li Yijing
Published: August 2022

Dendritic cells (DCs) play a key role in the natural recognition of pathogens and subsequent activation of adaptive immune responses due to their potent antigen-presenting ability. Dendritic cell-targeting peptide (DCpep) is strongly targeted to DCs, which often express antigens, to enhance the efficacy of vaccines. Our previous study showed that recombinantLactobacillusexpressing human DCpep could significantly induce stronger immune responses than recombinantLactobacilluswithout DCpep, but the mechanism remains unclear. In this study, the mechanism by which DCpep enhances the immune response against recombinantLactobacilluswas explored. Fluorescence-labeled human DCpep was synthesized to evaluate the binding ability of human DCpep to porcine monocyte-derived dendritic cells (Mo-DCs) and DCs of the small intestine. The effects of Mo-DC function induced by recombinantLactobacillusexpressing human DCpep fused with the porcine epidemic diarrhea virus (PEDV) core neutralizing epitope (COE) antigen were also investigated. The results showed that human DCpep bind to porcine DCs, but not to porcine small intestinal epithelial cells. Human DCpep can also improve the capture efficiency of recombinantLactobacillusby Mo-DCs, promote the maturation of dendritic cells, secrete more cytokines, and enhance the ability of porcine DCs to activate T-cell proliferation. Taken together, these results promote advanced understanding of the mechanism by which DCpep enhances immune responses. We found that some DCpeps are conserved between humans and pigs, which provides a theoretical basis for the development of a DC-targeted vaccine.
Cuproptosis status affects treatment options about immunotherapy and targeted therapy for patients with kidney renal clear cell carcinoma
Authors: Zhang Ganghua , Chen Xinyu , Fang Jianing , Tai Panpan , Chen Aiyan , Cao Ke
Published: August 2022

The development of immunotherapy has changed the treatment landscape of advanced kidney renal clear cell carcinoma (KIRC), offering patients more treatment options. Cuproptosis, a novel cell death mode dependent on copper ions and mitochondrial respiration has not yet been studied in KIRC. We assembled a comprehensive cohort of The Cancer Genome Atlas (TCGA)-KIRC and GSE29609, performed cluster analysis for typing twice using seven cuproptosis-promoting genes (CPGs) as a starting point, and assessed the differences in biological and clinicopathological characteristics between different subtypes. Furthermore, we explored the tumor immune infiltration landscape in KIRC using ESTIMATE and single-sample gene set enrichment analysis (ssGSEA) and the potential molecular mechanisms of cuproptosis in KIRC using enrichment analysis. We constructed a cuproptosis score (CUS) using the Boruta algorithm combined with principal component analysis. We evaluated the impact of CUS on prognosis, targeted therapy, and immunotherapy in patients with KIRC using survival analysis, the predictions from the Cancer Immunome Atlas database, and targeted drug susceptibility analysis. We found that patients with high CUS levels show poor prognosis and efficacy against all four immune checkpoint inhibitors, and their immunosuppression may depend on TGFB1. However, the high-CUS group showed higher sensitivity to sunitinib, axitinib, and elesclomol. Sunitinib monotherapy may reverse the poor prognosis and result in higher progression free survival. Then, we identified two potential CPGs and verified their differential expression between the KIRC and the normal samples. Finally, we explored the effect of the key gene FDX1 on the proliferation of KIRC cells and confirmed the presence of cuproptosis in KIRC cells. We developed a targeted therapy and immunotherapy strategy for advanced KIRC based on CUS. Our findings provide new insights into the relationship among cuproptosis, metabolism, and immunity in KIRC.