bluuebunny/crossref_metadata_2025 huggingface dataset:
The AhR ligand phthiocol and vitamin K analogs as Pseudomonas aeruginosa quorum sensing inhibitors
Authors: Jia Tianyuan , Liu Dongjing , Bi Xianbiao , Li Menglu , Cai Zhao , Fu Jiapeng , Liu Zhi , Wu Pengyao , Ke Xue , Jia Aiqun , Zhang Guoliang , Li Guobao , Yang Liang
Published: September 2022

The aryl hydrocarbon receptor (AhR) protein senses microbial-secreted metabolites to trigger the host's innate immune system. The Pseudomonas quinolone signal (PQS) and Mycobacterium tuberculosis (MTb) metabolite phthiocol (Pht) are both ligands of AhR with similar chemical structures. As PQS is an essential quorum-sensing molecule that regulates a wide range of virulence factors in Pseudomonas aeruginosa, we hypothesized that Pht and its analogs are potential P. aeruginosa quorum-sensing inhibitors (QSIs) with immune-modulating functions. In this study, we demonstrated that Pht was able to inhibit the P. aeruginosa pqs QS system and reduce both biofilm formation and the production of pyocyanin. Molecular docking analysis suggested that Pht competes with PQS at the binding site of its receptor, PqsR. An electrophoretic mobility shift assay confirmed the Pht-PqsR interaction and showed that Pht attenuated PqsR from binding to the pqsA promoter. Proteomic analysis showed that synthesis of the key pqs QS proteins decreased upon the addition of Pht to the bacterial cultures. Furthermore, Pht analogs vitamins K1 (Phylloquinone), K2 (Menaquinones), and K3 (Menadione) were also showed to inhibit the P. aeruginosa pqs QS system while able to activate the AhR signaling pathways. Our study suggests that the AhR ligands Pht and its vitamin K analogs are promising QSIs for the alternative treatment of P. aeruginosa infections.
Contribution of insect gut microbiota and their associated enzymes in insect physiology and biodegradation of pesticides
Authors: Jaffar Saleem , Ahmad Sajjad , Lu Yongyue
Published: September 2022

Synthetic pesticides are extensively and injudiciously applied to control agriculture and household pests worldwide. Due to their high use, their toxic residues have enormously increased in the agroecosystem in the past several years. They have caused many severe threats to non-target organisms, including humans. Therefore, the complete removal of toxic compounds is gaining wide attention to protect the ecosystem and the diversity of living organisms. Several methods, such as physical, chemical and biological, are applied to degrade compounds, but as compared to other methods, biological methods are considered more efficient, fast, eco-friendly and less expensive. In particular, employing microbial species and their purified enzymes makes the degradation of toxic pollutants more accessible and converts them into non-toxic products by several metabolic pathways. The digestive tract of insects is usually known as a superior organ that provides a nutrient-rich environment to hundreds of microbial species that perform a pivotal role in various physiological and ecological functions. There is a direct relationship between pesticides and insect pests: pesticides reduce the growth of insect species and alter the phyla located in the gut microbiome. In comparison, the insect gut microbiota tries to degrade toxic compounds by changing their toxicity, increasing the production and regulation of a diverse range of enzymes. These enzymes breakdown into their derivatives, and microbial species utilize them as a sole source of carbon, sulfur and energy. The resistance of pesticides (carbamates, pyrethroids, organophosphates, organochlorines, and neonicotinoids) in insect species is developed by metabolic mechanisms, regulation of enzymes and the expression of various microbial detoxifying genes in insect guts. This review summarizes the toxic effects of agrochemicals on humans, animals, birds and beneficial arthropods. It explores the preferential role of insect gut microbial species in the degradation process and the resistance mechanism of several pesticides in insect species. Additionally, various metabolic pathways have been systematically discussed to better understand the degradation of xenobiotics by insect gut microbial species.
Characterizing rhizosphere microbial communities associated with tolerance to aboveground herbivory in wild and domesticated tomatoes
Authors: Tronson Emily , Kaplan Ian , Enders Laramy
Published: September 2022

Root-associated microbial communities are well known for their ability to prime and augment plant defenses that reduce herbivore survival or alter behavior (i.e., resistance). In contrast, the role root microbes play in plant tolerance to herbivory, an evolutionarily sustainable alternative to resistance, is overlooked. In this study, we aimed to expand our limited understanding of what role rhizosphere microbial communities play in supporting tolerance to insect damage. Using domesticated tomatoes and their wild ancestors (Solanumspp.), we first documented how tobacco hornworm (Manduca sexta) herbivory impacted tomato fruit production in order to quantify plant tolerance. We then characterized the bacterial and fungal rhizosphere communities harbored by high and low tolerance plants. Wild tomatoes excelled at tolerating hornworm herbivory, experiencing no significant yield loss despite 50% leaf area removal. Their domesticated counterparts, on the other hand, suffered 26% yield losses under hornworm herbivory, indicating low tolerance. Ontogeny (i.e., mid- vs. late-season sampling) explained the most variation in rhizosphere community structure, with tomato line, tolerance, and domestication status also shaping rhizosphere communities. Fungal and bacterial community traits that associated with the high tolerance line include (1) high species richness, (2) relatively stable community composition under herbivory, and (3) the relative abundance of taxa belonging toStenotrophomonas,Sphingobacterium, andSphingomonas. Characterizing tolerance-associating microbiomes may open new avenues through which plant defenses are amended in pest management, such as plant breeding efforts that enhance crop recruitment of beneficial microbiomes.
Metabolome, microbiome, and gene expression alterations in the colon of newborn piglets with intrauterine growth restriction
Authors: Tang Wu , Zhang Wanghong , Azad Md. Abul Kalam , Ma Cui , Zhu Qian , Kong Xiangfeng
Published: September 2022

Newborn animals with intrauterine growth restriction (IUGR) are characterized by impaired intestinal structure and function; however, their intestinal microbiota and metabolome profiles have not been fully identified. The present study investigated the differences in colonic microbiota, metabolomics, and barrier function-related gene expression profiles between the IUGR and normal birth weight (NBW) piglets at 7, 21, and 28 days of age. Forty-eight piglets (24 NBW and 24 IUGR) from 24 litters were assigned to assess the differences in colonic microbiota, metabolomics, and gene expression between IUGR and NBW piglets. Compared with the NBW piglets, IUGR piglets showed decreased Shannon index and increased Simpson index at 7 days of age and Chao1 index at 21 days of age (p < 0.05). The IUGR piglets had lower abundances of Firmicutes, Subdoligranulum, Ruminococcaceae_UCG-002, and Ruminococcaceae_UCG-003 at 7 days of age, and Bacteroidetes, Phascolarctobacterium, and Ruminococcaceae_UCG-005 at 21 days of age, when compared with the NBW piglets (p < 0.05). Metabolomics analysis showed significant changes in 147 metabolites mainly involved in organic acids and their derivatives in the colon. Six differential metabolic pathways were significantly enriched, including purine metabolism, amino sugar/nucleotide sugar metabolism, ubiquinone/other terpenoid-quinone biosynthesis, phenylalanine/tyrosine/tryptophan biosynthesis, phenylalanine metabolism, and histidine metabolism. Spearman’s correlation analysis further demonstrated significant correlations between colonic microbiota and metabolites. In addition, colonic isobutyrate at 7 days of age, isovalerate and total short-chain fatty acids (SCFAs) at 21 days of age, and acetate, propionate, butyrate, and total SCFAs levels at 28 days of age were lower and isovalerate was higher at 28 days of age in the IUGR piglets than in the NBW piglets (p < 0.05). Furthermore, the mRNA expression of zonula occludens (ZO)-1 at 7 days of age, ZO-1, occludin, and interleukin (IL)-4 at 21 days of age were down-regulated in the IUGR piglets, whereas tumor necrosis factor (TNF)-α and nuclear factor-kappa B (NF-κB) at 28 days of age were up-regulated, when compared with the NBW piglets (p < 0.05). The findings suggest that the IUGR pigs present abnormal microbiota and nutrient metabolism in the colon, which may further affect the intestine barrier function by regulating gene expressions.
Exploring the RNase A scaffold to combine catalytic and antimicrobial activities. Structural characterization of RNase 3/1 chimeras
Authors: Fernández-Millán Pablo , Vázquez-Monteagudo Sergi , Boix Ester , Prats-Ejarque Guillem
Published: September 2022

Design of novel antibiotics to fight antimicrobial resistance is one of the first global health priorities. Novel protein-based strategies come out as alternative therapies. Based on the structure-function knowledge of the RNase A superfamily we have engineered a chimera that combines RNase 1 highest catalytic activity with RNase 3 unique antipathogen properties. A first construct (RNase 3/1-v1) was successfully designed with a catalytic activity 40-fold higher than RNase 3, but alas in detriment of its anti-pathogenic activity. Next, two new versions of the original chimeric protein were created showing improvement in the antimicrobial activity. Both second generation versions (RNases 3/1-v2 and -v3) incorporated a loop characteristic of RNase 3 (L7), associated to antimicrobial activity. Last, removal of an RNase 1 flexible loop (L1) in the third version enhanced its antimicrobial properties and catalytic efficiency. Here we solved the 3D structures of the three chimeras at atomic resolution by X-ray crystallography. Structural analysis outlined the key functional regions. Prediction by molecular docking of the protein chimera in complex with dinucleotides highlighted the contribution of the C-terminal region to shape the substrate binding cavity and determine the base selectivity and catalytic efficiency. Nonetheless, the structures that incorporated the key features related to RNase 3 antimicrobial activity retained the overall RNase 1 active site conformation together with the essential structural elements for binding to the human ribonuclease inhibitor (RNHI), ensuring non-cytotoxicity. Results will guide us in the design of the best RNase pharmacophore for anti-infective therapies.
A cuproptosis-related lncRNA signature identified prognosis and tumour immune microenvironment in kidney renal clear cell carcinoma
Authors: Xin Sheng , Mao Jiaquan , Cui Kai , Li Qian , Chen Liang , Li Qinyu , Tu Bocheng , Liu Xiaming , Wang Tao , Wang Shaogang , Liu Jihong , Song Xiaodong , Song Wen
Published: September 2022

Kidney renal clear cell carcinoma (KIRC) is a heterogeneous malignant tumor with high incidence, metastasis, and mortality. The imbalance of copper homeostasis can produce cytotoxicity and cause cell damage. At the same time, copper can also induce tumor cell death and inhibit tumor transformation. The latest research found that this copper-induced cell death is different from the known cell death pathway, so it is defined as cuproptosis. We included 539 KIRC samples and 72 normal tissues from the Cancer Genome Atlas (TCGA) in our study. After identifying long non-coding RNAs (lncRNAs) significantly associated with cuproptosis, we clustered 526 KIRC samples based on the prognostic lncRNAs and obtained two different patterns (Cuproptosis.C1 and C2). C1 indicated an obviously worse prognostic outcome and possessed a higher immune score and immune cell infiltration level. Moreover, a prognosis signature (CRGscore) was constructed to effectively and accurately evaluate the overall survival (OS) of KIRC patients. There were significant differences in tumor immune microenvironment (TIME) and tumor mutation burden (TMB) between CRGscore-defined groups. CRGscore also has the potential to predict medicine efficacy.
Neurological Consequences of Sphingosine Phosphate Lyase Insufficiency
Authors: Atreya Krishan B. , Saba Julie D.
Published: September 2022

In 2017, an inborn error of metabolism caused by recessive mutations in SGPL1 was discovered. The disease features steroid-resistant nephrotic syndrome, adrenal insufficiency, and neurological defects. The latter can include sensorineural hearing loss, cranial nerve defects, peripheral neuropathy, abnormal brain development, seizures and/or neurodegeneration. SGPL1 encodes the pyridoxal-5’-phosphate (PLP) dependent enzyme sphingosine phosphate lyase (SPL), and the condition is now referred to as SPL insufficiency syndrome (SPLIS). SPL catalyzes the final step in the degradative pathway of sphingolipids in which the bioactive sphingolipid sphingosine-1-phosphate (S1P) is irreversibly degraded to a long chain aldehyde and phosphoethanolamine (PE). SPL guards the only exit point for sphingolipid metabolism, and its inactivation leads to accumulation of various types of sphingolipids which have biophysical roles in plasma membrane rafts and myelin, and signaling roles in cell cycle progression, vesicular trafficking, cell migration, and programmed cell death. In addition, the products of the SPL reaction have biological functions including regulation of autophagic flux, which is important in axonal and neuronal integrity. In this review, the neurological manifestations of SPLIS will be described, and insights regarding the neurological consequences of SPL insufficiency from the study of brain-specific SPL knockout mice and Drosophila SPL mutants will be summarized.
Migraine aura-like symptoms at onset of stroke and stroke-like symptoms in migraine with aura
Authors: Scutelnic Adrian , Kreis Lukas A. , Beyeler Morin , Heldner Mirjam R. , Meinel Thomas R. , Kaesmacher Johannes , Hakim Arsany , Arnold Marcel , Fischer Urs , Mattle Heinrich P. , Schankin Christoph J. , Jung Simon
Published: September 2022

Background and objectives

In general, suddenly occurring neurological deficits, i.e., negative neurological symptoms, are considered symptoms of focal cerebral ischemia, while positive irritative symptoms with gradual onset are viewed as the characteristics of migraine aura. Nevertheless, cortical spreading depolarization, the pathophysiological basis of migraine aura, has also been observed in acute ischemic stroke. The aim of our study was to determine the frequency of migraine aura-like symptoms at ischemic stroke onset and stroke-like symptoms in migraine with aura.

Methods

We interviewed 350 consecutive patients with ischemic stroke and 343 with migraine with aura using a structured questionnaire. Stroke diagnosis was confirmed by imaging, and migraine with aura was diagnosed according to the current criteria of the International Headache Society. Patients with wake-up strokes or severe cognitive deficits that precluded a useful interview were excluded from the study.

Results

Seventy-eight patients with stroke (22.3%) reported visual symptoms, 145 (41.4%) sensory symptoms, 197 (56.3%) a paresis, and 201 patients (57.4%) more than one symptom, compared to 326 migraine patients with aura (95%) with visual symptoms (P < 0.001), 175 (51%) with sensory symptoms (p = 0.011), 50 (14.6%) with paresis (P < 0.001), and 211 (61.5%) with more than one symptom (p = 0.27). Among patients with stroke, migraine-like symptoms were frequent: 36 patients (46.2%) with visual disturbance and 78 (53.8%) with sensory symptoms experienced irritative sensations. Paresis-onset in stroke lasted longer than 5 min in 43 patients (21.8%). Spreading of sensory and motor symptoms occurred in 37 (25.5%) and 37 (18.8%) patients, respectively. Stroke-like negative symptoms in migraine with aura occurred in 39 patients (12%) with visual symptoms, in 55 (31.4%) with sensory symptoms, and paresis appeared suddenly in 14 patients (28%). More than one symptom in succession occurred in 117 patients with stroke (58.2%) and in 201 migraine with aura patients (95.3%; P < 0.001).

Conclusion

Many patients with stroke experience migraine-like symptoms at stroke onset, and many migraine with aura patients have stroke-like symptoms. Though overall the symptom frequencies of the two groups are significantly different, clarifying the differential diagnosis in an individual patient requires additional history elements, physical findings, or results of ancillary investigations.
Detecting vulnerable carotid plaque and its component characteristics: Progress in related imaging techniques
Authors: Weng Shi-Ting , Lai Qi-Lun , Cai Meng-Ting , Wang Jun-Jun , Zhuang Li-Ying , Cheng Lin , Mo Ye-Jia , Liu Lu , Zhang Yin-Xi , Qiao Song
Published: September 2022

Carotid atherosclerotic plaque rupture and thrombosis are independent risk factors for acute ischemic cerebrovascular disease. Timely identification of vulnerable plaque can help prevent stroke and provide evidence for clinical treatment. Advanced invasive and non-invasive imaging modalities such as computed tomography, magnetic resonance imaging, intravascular ultrasound, optical coherence tomography, and near-infrared spectroscopy can be employed to image and classify carotid atherosclerotic plaques to provide clinically relevant predictors used for patient risk stratification. This study compares existing clinical imaging methods, and the advantages and limitations of different imaging techniques for identifying vulnerable carotid plaque are reviewed to effectively prevent and treat cerebrovascular diseases.
Neurofeedback in patients with frontal brain lesions: A randomized, controlled double-blind trial
Authors: Annaheim Christine , Hug Kerstin , Stumm Caroline , Messerli Maya , Simon Yves , Hund-Georgiadis Margret
Published: September 2022

Background

Frontal brain dysfunction is a major challenge in neurorehabilitation. Neurofeedback (NF), as an EEG-based brain training method, is currently applied in a wide spectrum of mental health conditions, including traumatic brain injury.

Objective

This study aimed to explore the capacity of Infra-Low Frequency Neurofeedback (ILF-NF) to promote the recovery of brain function in patients with frontal brain injury.

Materials and methods

Twenty patients hospitalized at a neurorehabilitation clinic in Switzerland with recently acquired, frontal and optionally other brain lesions were randomized to either receive NF or sham-NF. Cognitive improvement was assessed using the Frontal Assessment Battery (FAB) and the Test of Attentional Performance (TAP) tasks regarding intrinsic alertness, phasic alertness and impulse control.

Results

With respect to cognitive improvements, there was no significant difference between the two groups after 20 sessions of either NF or sham-NF. However, in a subgroup of patients with predominantly frontal brain lesions, the improvements measured by the FAB and intrinsic alertness were significantly higher in the NF-group.

Conclusion

This is the first double-blind controlled study using NF in recovery from brain injury, and thus also the first such study of ILF NF. Although the result of the subgroup has limited significance because of the small number of participants, it accentuates the trend seen in the whole group regarding the FAB and intrinsic alertness (p = 0.068, p = 0.079, respectively). We therefore conclude that NF could be a promising candidate promoting the recoveryfrom frontal brain lesions. Further studies with larger numbers of patients and less lesion heterogeneity are needed to verify the usefulness of NF in the neurorehabilitation of patients with frontal brain injury (NCT02957695 ClinicalTrials.gov).
Brain tumor segmentation in multimodal MRI via pixel-level and feature-level image fusion
Authors: Liu Yu , Mu Fuhao , Shi Yu , Cheng Juan , Li Chang , Chen Xun
Published: September 2022

Brain tumor segmentation in multimodal MRI volumes is of great significance to disease diagnosis, treatment planning, survival prediction and other relevant tasks. However, most existing brain tumor segmentation methods fail to make sufficient use of multimodal information. The most common way is to simply stack the original multimodal images or their low-level features as the model input, and many methods treat each modality data with equal importance to a given segmentation target. In this paper, we introduce multimodal image fusion technique including both pixel-level fusion and feature-level fusion for brain tumor segmentation, aiming to achieve more sufficient and finer utilization of multimodal information. At the pixel level, we present a convolutional network named PIF-Net for 3D MR image fusion to enrich the input modalities of the segmentation model. The fused modalities can strengthen the association among different types of pathological information captured by multiple source modalities, leading to a modality enhancement effect. At the feature level, we design an attention-based modality selection feature fusion (MSFF) module for multimodal feature refinement to address the difference among multiple modalities for a given segmentation target. A two-stage brain tumor segmentation framework is accordingly proposed based on the above components and the popular V-Net model. Experiments are conducted on the BraTS 2019 and BraTS 2020 benchmarks. The results demonstrate that the proposed components on both pixel-level and feature-level fusion can effectively improve the segmentation accuracy of brain tumors.
Lactobacillus plantarum ST-III culture supernatant ameliorates alcohol-induced cognitive dysfunction by reducing endoplasmic reticulum stress and oxidative stress
Authors: Xu Zeping , Zhang Jinjing , Wu Junnan , Yang Shizhuo , Li Yuying , Wu Yuyu , Li Siyuan , Zhang Xie , Zuo Wei , Lian Xiang , Lin Jianjun , Jiang Yongsheng , Xie Longteng , Liu Yanlong , Wang Ping
Published: September 2022

Background

Long-term alcohol exposure is associated with oxidative stress, endoplasmic reticulum (ER) stress, and neuroinflammation, which may impair cognitive function. Probiotics supplements can significantly improve cognitive function in neurodegenerative diseases such as Alzheimer’s disease. Nevertheless, the effect of Lactobacillus plantarum ST-III culture supernatant (LP-cs) on alcohol-induced cognitive dysfunction remains unclear.

Methods

A mouse model of cognitive dysfunction was established by intraperitoneal injection of alcohol (2 g/kg body weight) for 28 days. Mice were pre-treated with LP-cs, and cognitive function was evaluated using the Morris water maze test. Hippocampal tissues were collected for biochemical and molecular analysis.

Results

LP-cs significantly ameliorated alcohol-induced decline in learning and memory function and hippocampal morphology changes, neuronal apoptosis, and synaptic dysfunction. A mechanistic study showed that alcohol activated protein kinase R-like endoplasmic reticulum kinase (PERK) signaling and suppressed brain derived neurotrophic factor (BDNF) levels via ER stress in the hippocampus, which LP-cs reversed. Alcohol activated oxidative stress and inflammation responses in the hippocampus, which LP-cs reversed.

Conclusion

LP-cs significantly ameliorated alcohol-induced cognitive dysfunction and cellular stress. LP-cs might serve as an effective treatment for alcohol-induced cognitive dysfunction.
Brain structural and functional changes during menstrual migraine: Relationships with pain
Authors: Wang Zi-wen , Yin Zi-han , Wang Xiao , Zhang Yu-tong , Xu Tao , Du Jia-rong , Wen Yi , Liao Hua-qiang , Zhao Yu , Liang Fan-rong , Zhao Ling
Published: September 2022

Objectives

Menstrual migraine (MM) is a special type of migraine associated with the ovarian cycle, which imposes a marked burden on female patients. However, the pathogenesis of MM is not completely understood. We investigated gray matter volume (GMV) and functional connectivity (FC) alterations in patients with MM to explore whether there are changes in resting-state FC (rsFC) in brain regions with structural GMV abnormalities and investigated their relevance to pain and concomitant symptoms.

Methods

Seventy-five patients with MM and 54 female healthy controls underwent functional magnetic resonance imaging and examination. The patients completed a patient’s headache diary, which included the frequency of migraine attacks, a visual analog scale for pain, a self-rating anxiety scale, and a self-rating depression scale. We used voxel-based morphometry (VBM) to examine the GMV differences between the MM and healthy control groups. The identified brain areas were selected as seeds to assess functional changes in the MM group. Correlation analysis between the altered VBM/rsFC and clinical outcomes was performed.

Results

Compared with healthy controls, patients with MM showed decreased GMV in the right anterior cingulum cortex (ACC) and increased GMV in the right superior parietal cortex. Pearson’s correlation analysis illustrated that only GMV in the right ACC was associated with visual analogue scale pain scores in the MM group. RsFC with the ACC as the seed showed that patients with MM exhibited increased FC between the ACC and the left inferior temporal gyrus, bilateral angular gyrus, and right precuneus. Correlation analysis showed that the change in FC between the right ACC and the right precuneus was positively correlated with headache frequency, and the change in FC between the right ACC and the right angular gyrus was positively correlated with the depression score.

Conclusion

Our results suggested that the ACC may be an important biomarker in MM, and its structural and functional impairments are significantly associated with the severity of pain and pain-related impairment of emotion in patients with MM. These findings demonstrated that headache-associated structural and functional abnormalities in the ACC may can provide integrative evidence on the physiological mechanisms of MM.
A survey of protein interactions and posttranslational modifications that influence the polyglutamine diseases
Authors: Johnson Sean L. , Tsou Wei-Ling , Prifti Matthew V. , Harris Autumn L. , Todi Sokol V.
Published: September 2022

The presence and aggregation of misfolded proteins has deleterious effects in the nervous system. Among the various diseases caused by misfolded proteins is the family of the polyglutamine (polyQ) disorders. This family comprises nine members, all stemming from the same mutation—the abnormal elongation of a polyQ repeat in nine different proteins—which causes protein misfolding and aggregation, cellular dysfunction and disease. While it is the same type of mutation that causes them, each disease is distinct: it is influenced by regions and domains that surround the polyQ repeat; by proteins with which they interact; and by posttranslational modifications they receive. Here, we overview the role of non-polyQ regions that control the pathogenicity of the expanded polyQ repeat. We begin by introducing each polyQ disease, the genes affected, and the symptoms experienced by patients. Subsequently, we provide a survey of protein-protein interactions and posttranslational modifications that regulate polyQ toxicity. We conclude by discussing shared processes and pathways that bring some of the polyQ diseases together and may serve as common therapeutic entry points for this family of incurable disorders.
The causal impact of childhood obesity on bone mineral density and fracture in adulthood: A two-sample Mendelian randomization study
Authors: Liang Yuehui , Deng Ming-Gang , Jian Qinghong , Zhang Minjie , Chen Shuai
Published: September 2022

Observational studies have indicated the associations between obesity with bone mineral density (BMD) and fracture but yield inconsistent results. The impact of childhood obesity on bone health in adulthood is even less clear. The present study adopted the Mendelian randomization methods to determine whether the genetically predicted childhood obesity was causally associated with BMD and the risk of fracture. Genetic variants were extracted from genome-wide association studies (GWAS) to identify childhood obesity loci [IEU open GWAS project: childhood obesity (ID: ieu-a-1096)] and single nucleotide polymorphisms (SNPs) as instrumental variables to investigate causality. We used two-sample univariable Mendelian randomization (MR) to estimate causal relationships between childhood obesity on BMD and fracture subtypes based on SNPs from European samples. To avoid bias, Cochran's Q test and leave-one-out variant analysis were performed. The MR analysis shows strong evidence that childhood obesity is causally associated with eBMD (OR 1.068, 95% CI 1.043–1.095, P < 0.001) and a weak decreased risk of leg fracture (OR 0.9990, 95% CI 0.9981–0.9999, P =0.033) based on the inverse variance weighting (IVW) method. After adjusting for diabetes and adult obesity, the results of eBMD remained the same. The MR analysis revealed sufficient evidence to indicate childhood obesity was causally associated with increased BMD and decreased risk of leg fracture in adults. Childhood obesity could be taken into consideration when assessing eBMD.
Effects of gestational diabetes mellitus and assisted reproductive technology treatment on the risk of preterm singleton birth
Authors: Gao Rui , Zhao Ke , Zhou Jiaxin , Wang Xiaona , Liu Ting , Lian Shaoyan , Li Jieying , Huang Yuanyan , Qiu Chuhui , Wu Yuxiao , He Jiang , Liu Chaoqun
Published: September 2022

Background

Although assisted reproductive technology (ART) plays a critical role in reducing infertility, ART pregnant women are reported at higher risk of preterm birth (PTB). Besides, women undergoing ART encounter a higher risk of developing gestational diabetes mellitus (GDM). However, existing studies on the combined effect of ART treatment and GDM on PTB risk are sparse.

Methods

This population-based retrospective cohort study used nationwide birth certificate data from the US National Vital Statistics System 2015-2019. All mothers who had a singleton live birth without pre-pregnancy diabetes were included. Multivariable logistic regression models were used to estimate the odds ratio (OR) of PTB.

Results

We finally included 18,140,241 American mother-infant pairs. The overall rate of PTB was 7.92% (n = 1,436,328). The PTB rate for non-ART mothers without GDM, ART mothers without GDM, non-ART mothers with GDM, and ART mothers with GDM were 7.67, 10.90, 11.23, and 14.81%, respectively. The incidence of GDM in ART mothers (10.48%) was significantly higher than in non-ART mothers (6.26%). After adjusting for potential confounders, compared with non-ART mothers without GDM, the PTB risk was significantly increased for ART mothers without GDM (AOR: 1.47, 95% CI 1.44-1.50), non-ART mothers with GDM (AOR:1.35, 95% CI 1.34-1.36) and ART mothers with GDM (AOR: 1.82, 95% CI 1.74-1.90) respectively, showing an increasing tendency. This phenomenon was stable among mothers in all groups of mothers older than 25 years.

Conclusion

To prevent PTB, effective approaches for the prevention of GDM are crucial to mothers who conceived through ART.
Single cell sequencing analysis and transcriptome analysis constructed the liquid-liquid phase separation(LLPS)-related prognostic model for endometrial cancer
Authors: Wang Jiayang , Meng Fei , Mao Fei
Published: September 2022

Background

Endometrial cancer is one of the most common gynecological tumors in developed countries. Our understanding of the pathogenesis of endometrial cancer and the changes in the immune microenvironment are still unclear. It is necessary to explore new biomarkers to guide the diagnosis and treatment of endometrial cancer.

Methods

The GEO database was used to download the endometrial cancer single cell sequencing dataset GSE173682. The UCSC database was used to download transcriptome sequencing data. The validation set was the transcriptome dataset GSE119041, which was retrieved from the GEO database. On the DrLLPS website, liquid-liquid phase separation-related genes can be downloaded. Relevant hub genes were found using weighted co-expression network analysis and dimension reduction clustering analysis. Prognostic models were built using Lasso regression and univariate COX regression. Analyses of immune infiltration were employed to investigate the endometrial cancer immunological microenvironment. The expression of model genes in endometrial cancer was confirmed using a PCR test.

Results

We created an LLPS-related predictive model for endometrial cancer by extensive study, and it consists of four genes: EIF2S2, SNRPC, PRELID1, and NDUFB9. Patients with endometrial cancer may be classified into high-risk and low-risk groups based on their risk scores, and those in the high-risk group had significantly worse prognoses (P<0.05). Additionally, there were notable variations in the immunological milieu between the groups at high and low risk. EIF2S2, SNRPC, PRELID1, and NDUFB9 were all up-regulated in endometrial cancer tissues, according to PCR results.

Conclusions

Our study can provide a certain reference for the diagnosis and treatment of endometrial cancer.
Predictors of early death and clinical features in newly diagnosed patients with low-intermediate risk acute promyelocytic leukemia
Authors: Wen Jingjing , Xu Fang , Zhou Qiaolin , Shi Lin , Liu Yiping , Yue Jing , Zhang Ya , Liang Xiaogong
Published: September 2022

Background

Although most acute promyelocytic leukemia(APL) with low-intermediate risk could survive the induction treatment, early death still a big problem to have effects on overall survival in real world.This study aimed to analyze the clinical characteristics and possible predictors of early death in newly diagnosed patients with low-intermediate-risk acute promyelocytic leukemia.

Methods

Sixty patients with newly diagnosed low/intermediate-risk APL admitted to Mianyang Central Hospital from January 2013 to December 2021 were retrospectively analyzed.

Results

Sixty patients with a median age of 46 years (range, 17-75 years) were included. Fourteen patients (23.3%) were in low-risk group, and 46 patients (76.7%) were in intermediate-risk group. Fourteen patients (23.3%) died during induction treatment. Five patients died of hemorrhage, 5 of severe infection and 4 of differentiation syndrome. Multivariate analysis showed that HGB <65g/L at diagnosis (OR=38.474, 95%CI: 2.648~558.923, P=0.008) during induction treatment was an independent risk factors for early death in low- intermediate risk APL patients. In survival group, all patients achieved complete remission, the time to achieve remission was 25.87 ± 5.02 days, the average ATO dosage was 0.16 ± 0.03 mg/kg/day. In univariate analysis, there was no statistically significant difference in time span for remission when ATO dosage was in the 0.11~0.16mg/kg/day range. Compared with patients with low-risk APL, those with intermediate-risk APL had higher white blood cell counts (at diagnosis, day 3, day 5 and peak), higher level of lactate dehydrogenase, higher percentage of bone marrow promyelocytes, more platelet transfusions during treatment, and more early deaths (P<0.05). The overall survival of intermediate-risk APL patients seemed worse than those with low-risk APL (χ=5.033, P =0.025).

Conclusions

In patients with low-intermediate risk APL, HGB <65g/L at diagnosis was an independent risk factors for early death. Remission could still be achieved at low-dose ATO without affecting the required time for low-intermediate risk APL patients. Differences in clinical characteristics were found between low-risk and intermediate-risk APL. The intermediate-risk group had higher early mortality risk than the low-risk group.
Chromosome 1q21 gain is an adverse prognostic factor for newly diagnosed multiple myeloma patients treated with bortezomib-based regimens
Authors: Liu Xiao , Jia Shuangshuang , Chu Yuping , Tian Biao , Gao Yaya , Zhang Chunyan , Zheng Yanhua , Jia Weijing , Liu Xiangxiang , Yuan Ruifeng , Zhang Na , Feng Juan , Dong Hongjuan , Xin Xiaoli , Chang Ziwei , Cao Zhengcong , Tang Hailong , Gao Guangxun
Published: September 2022

Chromosome 1q21 aberration is one of the most common cytogenetic abnormalities in multiple myeloma, and is considered an important prognostic factor. The present study analyzed the clinical relevance and prognostic impact of 1q21 gain in 194 patients with newly diagnosed multiple myeloma treated with bortezomib-based regimens. 1q21 gain was detected in 45.9% (89/194) of patients, and those with 1q21 gain had a worse prognosis. Strikingly, our results showed that excluding the effects of other coinciding genetic anomalies, patients carrying at least four copies of 1q21 had worse survival outcome. Moreover, del(13q) strongly correlates with 1q21 gain, and the coexistence of del(13q) and 1q21 gain plays an important role in reducing PFS and OS times. Therefore, 1q21 gain should be considered a high-risk feature in multiple myeloma patients treated with a bortezomib-based regimen.
Comprehensive analyses of genomic features and mutational signatures in adenosquamous carcinoma of the lung
Authors: Wang Hongbiao , Liu Jun , Zhu Sujuan , Miao Kun , Li Zhifeng , Qi Xiaofang , Huang Lujia , Guo Lijie , Wang Yan , Cai Yuyin , Lin Yingcheng
Published: September 2022

Adenosquamous carcinoma (ASC) of the lung is a relatively rare tumor with strong aggressiveness and poor prognosis. The analysis of mutational signatures is becoming routine in cancer genomics and has implications for pathogenesis, classification, and prognosis. However, the distribution of mutational signatures in ASC patients has not been evaluated. In this study, we sought to reveal the landscape of genomic mutations and mutational signatures in ASC. Next-generation sequencing (NGS) technology was used to retrieve genomic information for 124 ASC patients. TP53 and EGFR were the most prevalent somatic mutations observed, and were present in 66.9% and 54.8% of patients, respectively. CDKN2A (21%), TERT (21%), and LRP1B (18.5%) mutations were also observed. An analysis of gene fusion/rearrangement characteristics revealed a total of 64 gene fusions. The highest frequency of variants was determined for ALK fusions, with six ALK-EML4 classical and two intergenic ALK fusions, followed by three CD74-ROS1 fusions and one ROS1-SYN3 fusion. EGFR 19del (45.6%), and EGFR L858R (38.2%) and its amplification (29.4%) were the top three EGFR mutations. We extracted mutational signatures from NGS data and then performed a statistical analysis in order to search for genomic and clinical features that could be linked to mutation signatures. Amongst signatures cataloged at COSMIC, the most prevalent, high-frequency base changes were for C > T; and the five most frequent signatures, from highest to lowest, were 2, 3, 1, 30, and 13. Signatures 1 and 6 were determined to be associated with age and tumor stage, respectively, and Signatures 22 and 30 were significantly related to smoking. We additionally evaluated the correlation between tumor mutational burden (TMB) and genomic variations. We found that mutations ARID2, BRCA1, and KEAP1 were associated with high TMB. The homologous recombination repair (HRR) pathway-related gene mutation displayed a slightly higher TMB than those without mutations. Our study is the first to report comprehensive genomic features and mutational signatures in Chinese ASC patients. Results obtained from our study will help the scientific community better understand signature-related mutational processes in ASC.
Comparative kinase and cancer cell panel profiling of kinase inhibitors approved for clinical use from 2018 to 2020
Authors: Kooijman Jeffrey J. , van Riel Wilhelmina E. , Dylus Jelle , Prinsen Martine B. W. , Grobben Yvonne , de Bitter Tessa J. J. , van Doornmalen Antoon M. , Melis Janneke J. T. M. , Uitdehaag Joost C. M. , Narumi Yugo , Kawase Yusuke , de Roos Jeroen A. D. M. , Willemsen-Seegers Nicole , Zaman Guido J. R.
Published: September 2022

During the last two decades, kinase inhibitors have become the major drug class for targeted cancer therapy. Although the number of approved kinase inhibitors increases rapidly, comprehensive in vitro profiling and comparison of inhibitor activities is often lacking in the public domain. Here we report the extensive profiling and comparison of 21 kinase inhibitors approved by the FDA for oncology indications since June 2018 and 13 previously approved comparators on panels of 255 biochemical kinase assays and 134 cancer cell line viability assays. Comparison of the cellular inhibition profiles of the EGFR inhibitors gefitinib, dacomitinib, and osimertinib identified the uncommon EGFR p.G719S mutation as a common response marker for EGFR inhibitors. Additionally, the FGFR inhibitors erdafitinib, infigratinib, and pemigatinib potently inhibited the viability of cell lines which harbored oncogenic alterations in FGFR1-3, irrespective of the specific clinical indications of the FGFR inhibitors. These results underscore the utility of in vitro kinase inhibitor profiling in cells for identifying new potential stratification markers for patient selection. Furthermore, comparison of the in vitro inhibition profiles of the RET inhibitors pralsetinib and selpercatinib revealed they had very similar biochemical and cellular selectivity. As an exception, an NTRK3 fusion-positive cell line was potently inhibited by pralsetinib but not by selpercatinib, which could be explained by the targeting of TRK kinases in biochemical assays by pralsetinib but not selpercatinib. This illustrates that unexpected differences in cellular activities between inhibitors that act through the same primary target can be explained by subtle differences in biochemical targeting. Lastly, FLT3-mutant cell lines were responsive to both FLT3 inhibitors gilteritinib and midostaurin, and the PI3K inhibitor duvelisib. Biochemical profiling revealed that the FLT3 and PI3K inhibitors targeted distinct kinases, indicating that unique dependencies can be identified by combined biochemical and cellular profiling of kinase inhibitors. This study provides the first large scale kinase assay or cell panel profiling study for newly approved kinase inhibitors, and shows that comprehensive in vitro profiling of kinase inhibitors can provide rationales for therapy selection and indication expansion of approved kinase inhibitors.
Genetic and functional homologous repair deficiency as biomarkers for platinum sensitivity in TNBC: A case report
Authors: Gomez-Puerto Diego , Llop-Guevara Alba , Cruellas Mara , Torres-Esquius Sara , De La Torre Javier , Peg Vicente , Balmaña Judith , Pimentel Isabel
Published: September 2022

Triple-negative breast cancer is the most aggressive subtype of mammary carcinoma. In the early stage, neoadjuvant chemotherapy (NAC) is the standard of care for prognostic stratification and the best adjuvant treatment strategy. A 30-year-old female presented in the emergency room because of a gigantic right breast associated with an ulcerated lump at the upper quadrants. The right axillary nodes were palpable. An ultrasound was performed, showing the ulcerated neoformation with enlarged right axillary lymph nodes observed to level III. A core biopsy of the breast lesion was performed, and the pathological examination revealed a nonspecial type, grade 3, invasive, triple-negative breast cancer. No distant disease was found in the PET-CT scan. A germline genetic panel by next-generation sequencing identified a likely pathogenic variant in RAD51D (c.898C>T). Assessment of the functionality of the DNA homologous recombination repair pathway by RAD51 foci in the tumor revealed a profile of homologous recombination deficiency. NAC consisting of weekly carboplatin and paclitaxel followed by dose-dense doxorubicin/cyclophosphamide was performed with a complete metabolic response achieved in the PET-CT scan. The patient underwent a modified radical mastectomy plus axillary lymphadenectomy with a pathological complete response in the breast and axilla and remains disease-free after 2 years of follow-up. We report a young female with a triple-negative breast cancer stage cT4bN3M0 and a hereditary pathogenic mutation in RAD51D. The tumor was highly proliferative and homologous recombination-deficient by RAD51. The patient received platinum-based NAC, achieving a pathologic complete response. More effort should be made to identify predictive functional biomarkers of treatment response, such as RAD51 foci, for platinum sensitivity.
Assessment of quantitative information for radiation therapy at a first-generation clinical photon-counting computed tomography scanner
Authors: Hu Guyue , Niepel Katharina , Risch Franka , Kurz Christopher , Würl Matthias , Kröncke Thomas , Schwarz Florian , Parodi Katia , Landry Guillaume
Published: September 2022

As one of the latest developments in X-ray computed tomography (CT), photon-counting technology allows spectral detection, demonstrating considerable advantages as compared to conventional CT. In this study, we investigated the use of a first-generation clinical photon-counting computed tomography (PCCT) scanner and estimated proton relative (to water) stopping power (RSP) of tissue-equivalent materials from virtual monoenergetic reconstructions provided by the scanner. A set of calibration and evaluation tissue-equivalent inserts were scanned at 120 kVp. Maps of relative electron density (RED) and effective atomic number (EAN) were estimated from the reconstructed virtual monoenergetic images (VMI) using an approach previously applied to a spectral CT scanner with dual-layer detector technology, which allows direct calculation of RSP using the Bethe-Bloch formula. The accuracy of RED, EAN, and RSP was evaluated by root-mean-square errors (RMSE) averaged over the phantom inserts. The reference RSP values were obtained experimentally using a water column in an ion beam. For RED and EAN, the reference values were calculated based on the mass density and the chemical composition of the inserts. Different combinations of low- and high-energy VMIs were investigated in this study, ranging from 40 to 190 keV. The overall lowest error was achieved using VMIs at 60 and 180 keV, with an RSP accuracy of 1.27% and 0.71% for the calibration and the evaluation phantom, respectively.