bluuebunny/crossref_metadata_2025 huggingface dataset:
Voltage-dependent synaptic plasticity: Unsupervised probabilistic Hebbian plasticity rule based on neurons membrane potential
Authors: Garg Nikhil , Balafrej Ismael , Stewart Terrence C. , Portal Jean-Michel , Bocquet Marc , Querlioz Damien , Drouin Dominique , Rouat Jean , Beilliard Yann , Alibart Fabien
Published: October 2022

This study proposes voltage-dependent-synaptic plasticity (VDSP), a novel brain-inspired unsupervised local learning rule for the online implementation of Hebb’s plasticity mechanism on neuromorphic hardware. The proposed VDSP learning rule updates the synaptic conductance on the spike of the postsynaptic neuron only, which reduces by a factor of two the number of updates with respect to standard spike timing dependent plasticity (STDP). This update is dependent on the membrane potential of the presynaptic neuron, which is readily available as part of neuron implementation and hence does not require additional memory for storage. Moreover, the update is also regularized on synaptic weight and prevents explosion or vanishing of weights on repeated stimulation. Rigorous mathematical analysis is performed to draw an equivalence between VDSP and STDP. To validate the system-level performance of VDSP, we train a single-layer spiking neural network (SNN) for the recognition of handwritten digits. We report 85.01 ± 0.76% (Mean ± SD) accuracy for a network of 100 output neurons on the MNIST dataset. The performance improves when scaling the network size (89.93 ± 0.41% for 400 output neurons, 90.56 ± 0.27 for 500 neurons), which validates the applicability of the proposed learning rule for spatial pattern recognition tasks. Future work will consider more complicated tasks. Interestingly, the learning rule better adapts than STDP to the frequency of input signal and does not require hand-tuning of hyperparameters.
Iodine nutrition and papillary thyroid cancer
Authors: Zhang Xueqi , Zhang Fan , Li Qiuxian , Feng Chuyao , Teng Weiping
Published: October 2022

Thyroid cancer (TC) is the most frequent endocrine malignancy. The incidence of TC, especially papillary thyroid carcinoma (PTC), has continued to rise all over the world during the past few years, for reasons that are not entirely clear. Though the phenomenon of overdiagnosis is occurring, it is not the sole driver of the substantial increase in incidence. Lifestyle, environmental factors, or complications are considered to be potential risk factors. Among these factors, iodine is a micronutrient that is vital to thyroid function. The effect of iodine intake on PTC has been controversial for many years and the epidemiological or experimental studies provided diametrically opposite conclusions. Combining all these studies, we found that iodine nutrition may affect the overall prevalence, distribution of the histological types, and clinicopathological aggressiveness of TC, especially PTC. However, the available evidence is poor due to the impact of various internal and external related factors. Therefore, this article sums up available results from both epidemiological and experimental studies, future studies are also warranted to expound on the relationship between overall PTC prevalence and iodine intake.
Hypertension, dietary fiber intake, and cognitive function in older adults [from the National Health and Nutrition Examination Survey Data (2011–2014)]
Authors: Zhang HuanRui , Tian Wen , Qi GuoXian , Sun YuJiao
Published: October 2022

Background

Dietary fiber was associated with hypertension (HYP) and cognitive function, but it was unknown whether the effect of HYP on cognitive function in older adults was modified by dietary fiber intake.

Methods

We recruited 2,478 participants from the 2011–2012 and 2013–2014 National Health and Nutrition Examination Survey (NHANES), with cognitive performance measured by Registry for Alzheimer's disease (CERAD), the Animal Fluency test (AFT), and the Digit Symbol Substitution test (DSST). Multivariate General linear model was used to estimate the interaction between dietary fiber intake and HYP status in association with low cognitive performance.

Results

Among 2,478 participants, 36% was Controlled HYP, 25% was Low uncontrolled HYP, 11% was High uncontrolled HYP, and 86% was low dietary fiber intake. The association between HYP status and DSST impairment differed by dietary fiber intake for those with high uncontrolled HYP compared to those without HYP. Among participants with low dietary fiber intake, those with uncontrolled HYP had higher risk of DSST impairment compared to those without HYP [HYP ≥ 90/140: OR (95% CI), 1.68 (1.15–2.45); HYP ≥ 100/160: OR (95%CI), 2.05 (1.29–3.23)]; however, there was no association between HYP status and DSST impairment among participants with high dietary fiber intake. Moreover, the interaction of HYP status and dietary fiber intake on DSST was close to statistical significance (P for interaction = 0.057).

Conclusions

Uncontrolled HYP was associated with poorer cognitive performance in older adults with low, but not high dietary fiber intake. Sufficient dietary fiber intake might be as a new nutrition strategy for the prevention of cognitive impairment in older adults with uncontrolled HYP.
Intake of ultra-processed foods and asthenozoospermia odds: A hospital-based case-control study
Authors: Lv Jia-Le , Wu Qi-Jun , Wang Xiao-Bin , Du Qiang , Liu Fang-Hua , Guo Ren-Hao , Leng Xu , Pan Bo-Chen , Zhao Yu-Hong
Published: October 2022

Background

The intake of ultra-processed foods (UPFs) has increased rapidly in recent years. Evidence has suggested that UPFs has adverse effects on several health outcomes. This study aimed to first evaluate the association between the intake of UPFs and asthenozoospermia odds.

Methods

A hospital-based case-control study including 549 cases and 581 controls was performed in the infertility clinics of Shengjing Hospital of China Medical University from June 2020 to December 2020. Dietary intake was assessed using a validated food frequency questionnaire. Food items were categorized by the NOVA classification system based on the degree of processing. Semen parameters were analyzed according to the World Health Organization guidelines.

Results

The highest tertile of UPFs intake (% of total energy intake) was positively associated with the odds of asthenozoospermia (odds ratio [OR] = 1.53; 95% confidence interval [CI]: 1.12, 2.10; P for trend < 0.05), compared with the lowest tertile. Similar patterns were also found in subgroup analyses among participants with age ≥32 years (OR = 1.58; 95% CI: 1.04, 2.40), BMI ≥ 24 kg/m2 (OR = 1.52; 95% CI: 1.04, 2.22), ever cigarette smoking (OR = 1.78; 95% CI: 1.14, 2.79), and ever alcohol drinking (OR = 1.65; 95% CI: 1.01, 2.72), and in sensitivity analyses by using absolute amount (g/day) to calculate the intake of UPFs.

Conclusion

Higher consumption of UPFs was positively associated with the odds of asthenozoospermia. More studies are needed to confirm our findings.
Association of serum total 25-hydroxy-vitamin D concentration and risk of all-cause, cardiovascular and malignancies-specific mortality in patients with hyperlipidemia in the United States
Authors: Chen Xueqin , Zhou Mingge , Yan Hui , Chen Jiatian , Wang Yuetao , Mo Xiaofei
Published: October 2022

Background

Vitamin D (VD) plays an important role in decreasing the risk of adverse events for various metabolic diseases. However, for patients with hyperlipidemia, the relationship between the main VD storage within the body known as serum 25-hydroxy-VD [25(OH)VD] and the risk of all-cause, cardiovascular and malignancies-specific mortality is still unclear.

Materials and methods

A total of 6740 participants above the age of 20 years with hyperlipidemia who completed the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2016 and were followed up until 2019 were included in the study. The weighted Cox proportional hazards regression model and weighted competing risk regression model were used to evaluate the risk for all-cause, cardiovascular and malignancy-related mortality in relation to the serum 25(OH)VD. The model was adjusted according to age, gender, race, body mass index, lipids status, medication usage, the Charlson comorbidity index and healthy eating index. The last restricted cubic spline (RCS) method was used to present the relationship between hazard ratios (HR) associated with diverse cause-specified modalities and the serum 25(OH)VD levels.

Results

Serum 25(OH)VD was identified as an independent factor for mortality. Lower serum 25(OH)VD under the threshold of 25.6 and 25.2 ng/ml were significantly associated with a higher risk for all-cause and cardiovascular mortalities, respectively. However, no association was found between malignancy-specific mortality and serum 25(OH)VD.

Conclusion

Serum 25(OH)VD were identified as an independent factor associated with risks of all-cause and cardiovascular mortalities in patient with hyperlipidemia. Moreover, lower serum 25(OH)VD than 25.6 and 25.2 ng/mL were, respectively, associated with a gradual increase in a risk for all-cause and cardiovascular mortality in patients with hyperlipidemia, and therefore regular monitoring of VD levels and correction of VD deficiency is recommended in those patients.
The impact of an early intervention home-based program on body composition in preterm-born preschoolers with very low birth weight
Authors: Fernandes Rafael Oliveira , Bernardi Juliana Rombaldi , da Fonseca Júlia Delgado , Gomes da Silva Franciéle , Procianoy Renato Soibelmann , Silveira Rita C.
Published: October 2022

Background and aims

Early child interventions focused on the family prevented neurodevelopmental and behavioral delays and can provide more knowledge regarding responsive feeding, thus creating learning opportunities to promote better quality nutrition and preventing failure to thrive. The aim is to verify the impact of a continuous program of early home-based intervention on the body composition of preschool infants who were born preterm with very low birth weight (VLBW).

Methods

This is a longitudinal analysis from a randomized controlled trial, including VLBW preterm children, born in a tertiary hospital in Southern Brazil and followed up at the high-risk institutional ambulatory clinic. Participants were divided into the intervention group (IG): skin-to-skin care with the mother (kangaroo care), breastfeeding policy, and tactile-kinesthetic stimulation by mothers until hospital discharge. Subsequently, they received a program of early intervention with orientation and a total of 10 home visits, independently from the standard evaluation and care that was performed following the 18 months after birth; conventional group (CG): standard care according to the routine of the newborn intensive care unit (NICU), which includes kangaroo care, and attending to their needs in the follow-up program. Body composition estimation was performed using bioelectrical impedance analyses (BIA), and physical activity and feeding practices questionnaires were evaluated at preschool age, as well as anthropometric measurements and biochemical analysis.

Results

Data of 41 children at 4.6 ± 0.5 years old were evaluated (CG n = 21 and IG n = 20). Body weight, height, body mass index, waist and arm circumferences, and triceps and subscapular skinfold did not differ between groups. The IG presented higher segmented fat-free mass (FFM) when compared to the CG (right arm FFM: 0.74 vs. 0.65 kg, p = 0.040; trunk FFM: 6.86 vs. 6.09 kg, p = 0.04; right leg FFM: 1.91 vs. 1.73 kg, p = 0.063). Interaction analyses showed that segmented FFM and FFM Index were associated with higher iron content in the IG. In the CG, interaction analyses showed that increased visceral fat area was associated with higher insulin resistance index.

Conclusion

An early intervention protocol from NICU to a home-based program performed by the mothers of VLBW preterm children of low-income families presents a small effect on FFM.
MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma
Authors: Romani Arianna , Zauli Enrico , Zauli Giorgio , AlMesfer Saleh , Al-Swailem Samar , Voltan Rebecca
Published: October 2022

MDM2 is the principal inhibitor of p53, and MDM2 inhibitors can disrupt the physical interaction between MDM2 and p53. The half-life of p53 is very short in normal cells and tissues, and an uncontrolled increase in p53 levels has potential harmful effects. It has been shown that p53 is frequently mutated in most cancers; however, p53 mutations are rare in retinoblastoma. Therefore, therapeutic strategies aimed at increasing the expression levels of wild-type p53 are attractive. In this minireview, we discuss the potential use of nutlin-3, the prototype small molecule inhibitor that disrupts the MDM2-p53 interaction, for the treatment of retinoblastoma. Although p53 has pleiotropic biological effects, the functions of p53 depend on its sub-cellular localization. In the nucleus, p53 induces the transcription of a vast array of genes, while in mitochondria, p53 regulates mitochondrial metabolism. This review also discusses the relative contribution of p53-mediated gene transcription and mitochondrial perturbation for retinoblastoma treatment.
Whole-slide image analysis identifies a high content of Hodgkin Reed-Sternberg cells and a low content of T lymphocytes in tumor microenvironment as predictors of adverse outcome in patients with classic Hodgkin lymphoma treated with ABVD
Authors: Santisteban-Espejo Antonio , Bernal-Florindo Irene , Perez-Requena Jose , Atienza-Cuevas Lidia , Maira-Gonzalez Nieves , Garcia-Rojo Marcial
Published: October 2022

Classic Hodgkin lymphoma (cHL) constitutes the most frequent lymphoma in young adults. Its histopathology is unique as a scattered tumor population, termed Hodgkin Reed-Sternberg (HRS) cells is diluted in a prominent tumor microenvironment (TME) composed of T lymphocytes, B lymphocytes, macrophages, neutrophils, eosinophils and histiocytes. Traditionally, the identification of prognostic biomarkers in the cHL TME has required visual inspection and manual counting by pathologists. The advent of whole-slide imaging (WSI) and digital image analysis methods could significantly contribute to improve this essential objective in cHL research, as a 10-20% of patients are still refractory or relapsed after conventional chemotherapy. In this work, we have digitized a total of 255 diagnostic cHL slides and quantified the proportion of HRS cells (CD30), B cells (CD20) and T cells (CD3) by digital image analysis. Data obtained where then correlated with the overall survival (OS) and progression free survival (PFS) of cHL patients. Quantification of HRS cells, B cells and T cells reflects the biological heterogeneity of the different cHL histological subtypes analyzed. A percentage of 2.00% of HRS cells statistically significantly discriminated between patients achieving a complete metabolic response (CMR) and refractory or relapsed (R/R) patients both for the OS (P=0.001) and PFS (P=0.005). Furthermore, patients with a percentage of T cells below the 26.70% in the TME showed a statistically significantly shorter OS (P=0.019) and PFS (P=0.041) in comparison with patients above this threshold. A subgroup of patients with a low content of T cells and high content of HRS cells exhibited a special aggressive clinical course. Currently, there is the need to implement quantitative and easy scalable methods to enhance clinical translation, as the cHL TME plays a central role in the clinical course of the disease. The results of this study could contribute to the identification of prognostic biomarkers specifically looking at the cHL TME and their inclusion in future clinical trials.
Emerging trends and research foci of epithelial–mesenchymal transition in gliomas: A scientometric analysis and review
Authors: Xing Yang , He Minghua , Su Zhenjin , Yasinjan Feroza , Liu Jiankai , Wang Hong , Cui Jiayue , Hong Xinyu
Published: October 2022

Background

Epithelial–mesenchymal transition (EMT) is a key factor in the invasion and migration of glioma cells, and the study of EMT in gliomas has become a hot topic over the past decade. Scientometric analysis is gaining more attention since it can obtain hot topics and emerging trends in a research field. This article analyzed the research related to EMT in gliomas for the first time, including descriptions of research situations, evaluations of research foci, and predictions of emerging trends.

Methods

We searched the topic-related original articles from January 2012 to December 2021 in the Web of Science Core Collection (WoSCC) by using a specific strategy, and a total of 1,217 publications were obtained. The WoS platform, VOS viewer, and CiteSpace were used to analyze the annual distribution of publications and citations, authors and density of keywords, and other analyses including countries, institutions, references, clustering, burst analysis, and the timeline view of keywords.

Results

Scientometric analysis identified that the study of EMT in gliomas has developed fast and received continuous attention in the last decade. Based on the results of data analysis, most publications on the topic came from China, and the United States had the highest betweenness centrality. The top 10 co-cited references revealed the landmark documents that had greatly promoted the development of this field. The major focus is on the cellular and molecular mechanisms of EMT in gliomas, and the therapy related to EMT target and non-coding RNAs has been developing fast in recent years.

Conclusions

This study revealed the intimate connections between EMT and gliomas, and the complex mechanisms regulating EMT in gliomas had been studied widely in the last decade. Exploring the deep mechanisms of EMT in gliomas is the foundation of the targeted inhibitions, which can promote the development of therapies for gliomas.
Alternative and aberrant splicing of human endogenous retroviruses in cancer. What about head and neck? —A mini review
Authors: Agoni Lorenzo
Published: October 2022

Human endogenous retroviruses (HERVs) are transcribed in many cancer types, including head and neck cancer. Because of accumulating mutations at proviral loci over evolutionary time, HERVs are functionally defective and cannot complete their viral life cycle. Despite that, HERV transcripts, including full-length viral RNAs and viral RNAs spliced as expected at the conventional viral splice sites, can be detected in particular conditions, such as cancer. Interestingly, non-viral–related transcription, including aberrant, non-conventionally spliced RNAs, has been reported as well. The role of HERV transcription in cancer and its contribution to oncogenesis or progression are still debated. Nonetheless, HERVs may constitute a suitable cancer biomarker or a target for therapy. Thus, ongoing research aims both to clarify the basic mechanisms underlying HERV transcription in cancer and to exploit its potential toward clinical application. In this mini-review, we summarize the current knowledge, the most recent findings, and the future perspectives of research on HERV transcription and splicing, with particular focus on head and neck cancer.
The role of T-cells in head and neck squamous cell carcinoma: From immunity to immunotherapy
Authors: Damasio Marcos Paulo S. , Nascimento Camila Sales , Andrade Lidia M. , de Oliveira Vivian L. , Calzavara-Silva Carlos Eduardo
Published: October 2022

Head and neck squamous cell carcinoma (HNSCC) encompass a group of complex entities of tumours affecting the aerodigestive upper tract. The main risk factors are strongly related to tobacco and alcohol consumption, but also HPV infection is often associated. Surgery, radiotherapy and/or chemotherapy are the standard treatments, though the 5-year overall survival is less than 50%. The advances in genomics, molecular medicine, immunology, and nanotechnology have shed a light on tumour biology which helps clinical researchers to obtain more efficacious and less toxic therapies. Head and neck tumours possess different immune escape mechanisms including diminishing the immune response through modulating immune checkpoints, in addition to the recruitment and differentiation of suppressive immune cells. The insights into the HNSCC biology and its strong interaction with the tumour microenvironment highlights the role of immunomodulating agents. Recently, the knowledge of the immunological features of these tumours has paved the way for the discovery of effective biomarkers that allow a better selection of patients with odds of improving overall survival through immunotherapy. Specially biomarkers regarding immune checkpoint inhibitors antibodies, such as anti-PD-1/PD-L1 and anti-CTLA-4 in combination with standard therapy or as monotherapy. New immunotherapies to treat head and neck cancer carcinomas, such as CAR T cells and nanoparticles have been the center of attention and in this review, we discuss the necessity of finding targets for the T cell in the cancer cells to generate CAR T cells, but also the relevance of evaluating specificity and safety of those therapies.
Deep learning in bladder cancer imaging: A review
Authors: Li Mingyang , Jiang Zekun , Shen Wei , Liu Haitao
Published: October 2022

Deep learning (DL) is a rapidly developing field in machine learning (ML). The concept of deep learning originates from research on artificial neural networks and is an upgrade of traditional neural networks. It has achieved great success in various domains and has shown potential in solving medical problems, particularly when using medical images. Bladder cancer (BCa) is the tenth most common cancer in the world. Imaging, as a safe, noninvasive, and relatively inexpensive technique, is a powerful tool to aid in the diagnosis and treatment of bladder cancer. In this review, we provide an overview of the latest progress in the application of deep learning to the imaging assessment of bladder cancer. First, we review the current deep learning approaches used for bladder segmentation. We then provide examples of how deep learning helps in the diagnosis, staging, and treatment management of bladder cancer using medical images. Finally, we summarize the current limitations of deep learning and provide suggestions for future improvements.
Comprehensive analysis of the cuproptosis-related model to predict prognosis and indicate tumor immune infiltration in lung adenocarcinoma
Authors: Wu Minle , Bao Jie , Lei Youfeng , Tao Shuai , Lin Qiurong , Chen Liang , Jin Yinpeng , Ding Xiaohong , Yan Yufeng , Han Ping
Published: October 2022

Background

Cuproptosis is a novel form of programmed cell death termed as Cu-dependent cytotoxicity. However, the roles of cuproptosis-associated genes (CAGs) in lung adenocarcinoma (LUAD) have not been explored comprehensively.

Methods

We obtained CAGs and utilized consensus molecular clustering by “non-negative matrix factorization (NMF)” to stratify LUAD patients in TCGA (N = 511), GSE13213 (N = 117), and GSE31210 (N = 226) cohorts. The ssGSEA and CIBERSORT algorithms were used to evaluate the relative infiltration levels of immune cell types in tumor microenvironment (TME). The risk score based on CAGs was calculated to predict patients’ survival outcomes.

Results

We identified three cuproptosis-associated clusters with different clinicopathological characteristics. We found that the cuproptosis-associated cluster with the worst survival rates exhibited a high enrichment of activated CD4/8+ T cells. In addition, we found that the cuproptosis-associated risk score could be used for patients’ prognosis prediction and provide new insights in immunotherapy of LUAD patients. Eventually, we constructed a nomogram-integrated cuproptosis-associated risk score with clinicopathological factors to predict overall survival in LUAD patients, with 1-, 3-, and 5-year area under curves (AUCs) being 0.771, 0.754, and 0.722, respectively, all of which were higher than those of the TNM stage.

Conclusions

In this study, we uncovered the biological function of CAGs in the TME and its correlations with clinicopathological parameters and patients’ prognosis in LUAD. These findings could provide new angles for immunotherapy of LUAD patients.
Clinical determinants impacting overall survival of patients with operable brain metastases from non-small cell lung cancer
Authors: Piffko Andras , Asey Benedikt , Dührsen Lasse , Ristow Inka , Salamon Johannes , Wikman Harriet , Maire Cecile L. , Lamszus Katrin , Westphal Manfred , Sauvigny Thomas , Mohme Malte
Published: October 2022

Non-small cell lung cancer (NSCLC) is currently the leading cause of cancer-related death worldwide, and the incidence of brain metastases (BM) in NSCLC patients is continuously increasing. The recent improvements of systemic treatment in NSCLC necessitate continuous updates on prognostic subgroups and factors determining overall survival (OS). In order to improve clinical decision-making in tumor boards, we investigated the clinical determinants affecting survival in patients with resectable NSCLC BM. A retrospective analysis was conducted of NSCLC patients with surgically resectable BM treated in our institution between 01/2015 and 12/2020. The relevant clinical factors affecting survival identified by univariate analysis were included in a multivariate logistic regression model. Overall, 264 patients were identified, with a mean age of 62.39 ± 9.98 years at the initial diagnosis of NSCLC BM and OS of 23.22 ± 1.71 months. The factors that significantly affected OS from the time of primary tumor diagnosis included the systemic metastatic load (median: 28.40 ± 4.82 vs. 40.93 ± 11.18 months, p = 0.021) as well as a number of BM <2 (median: 17.20 ± 2.52 vs. 32.53 ± 3.35 months, p = 0.014). When adjusted for survival time after neurosurgical intervention, a significant survival benefit was found in patients <60 years (median 16.13 ± 3.85 vs. 9.20 ± 1.39 months, p = 0.011) and, among others, patients without any concurrent systemic metastases at time of NSCLC BM diagnosis. Our data shows that the number of BM (singular/solitary), the Karnofsky Performance Status, gender, and age but not localization (infra-/supratentorial), mass-edema index or time to BM occurrence impact OS, and postsurgical survival in NSCLC BM patients. Additionally, our study shows that patients in prognostically favorable clinical subgroups an OS, which differs significantly from current statements in literature. The described clinically relevant factors may improve the understanding of the risks and the course of this disease and Faid future clinical decision making in tumor boards.
Methylation-driven gene DLL3 is a potential prognostic biomarker in ocular melanoma correlating with metastasis
Authors: Yang Ludi , Wang Gaoming , Shi Hanhan , Jia Shichong , Ruan Jing , Cui Ran , Ge Shengfang
Published: October 2022

Background

Ocular melanoma is an aggressive malignancy with a high rate of metastasis and poor prognosis. Increasing evidence indicated that DNA methylation plays an important role in the occurrence and development of ocular melanoma. Hence, exploring new diagnostic and prognostic biomarkers at the genetic level may be beneficial to the prognosis of patients with ocular melanoma.

Methods

We collected DNA methylation and gene expression profiles of human UM (uveal melanoma) and CM (conjunctival melanoma) samples from various datasets. We conducted differential methylation and expression analyses to screen the potential biomarkers. Correlation analysis was performed to investigate the relationships between the expression level of DLL3 (delta-like protein 3) and the methylation level of its corresponding CpGs. We explored the prognostic and diagnostic value of DLL3 in UM and CM. Functional annotation and GSEA (gene set enrichment analysis) were applied to get insight into the possible biological roles of DLL3. A cohort of 60 ocular melanoma patients as well as UM and CM cell lines were used to validate our findings in bioinformatic analyses.

Results

We found that DLL3 was a methylation-driven gene correlating with UM metastasis. The CpGs of DLL3 are mainly located in the gene body and their methylation level positively correlated to DLL3 expression. Multivariate Cox regression analysis revealed that DLL3 was an independent protective factor for UM patients. High DLL3 expression significantly prolonged the overall survival and disease-free survival of UM patients. DLL3 also showed a promising power to distinguish CM from normal tissues. Functional annotation exhibited that DLL3 may suppress UM progression through modulating immune activities and down-regulating various signaling pathways. External datasets, biospecimens, and cell lines further validated the aberrant expression and prognostic role of DLL3 in ocular melanoma.

Conclusion

Methylation-driven gene DLL3 could serve as a new potential diagnostic and prognostic biomarker in ocular melanoma. Our findings may contribute to improving the clinical outcomes of patients with UM or CM.
Combining serum peptide signatures with International Federation of Gynecology and Obstetrics (FIGO) risk score to predict the outcomes of patients with gestational trophoblastic neoplasia (GTN) after first-line chemotherapy
Authors: Wang Fei , Wang Zi-ran , Ding Xue-song , Yang Hua , Guo Ye , Su Hao , Wan Xi-run , Wang Li-juan , Jiang Xiang-yang , Xu Yan-hua , Chen Feng , Cui Wei , Feng Feng-zhi
Published: October 2022

Background

Gestational trophoblastic neoplasia (GTN) is a group of clinically rare tumors that develop in the uterus from placental tissue. Currently, its satisfactory curability derives from the timely and accurately classification and refined management for patients. This study aimed to discover biomarkers that could predict the outcomes of GTN patients after first-line chemotherapy.

Methods

A total of 65 GTN patients were included in the study. Patients were divided into the good or poor outcome group and the clinical characteristics of the patients in the two groups were compared. Furthermore, the serum peptide profiles of all patients were uncovered by using weak cation exchange magnetic beads and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Feature peaks were identified by three machine learning algorithms and then models were constructed and compared using five machine learning methods. Additionally, liquid chromatography mass spectrometry was used to identify the feature peptides.

Results

Multivariate logistic regression analysis showed that the International Federation of Gynecology and Obstetrics (FIGO) risk score was associated with poor outcomes. Eight feature peaks (m/z =1287, 2042, 2862, 2932, 2950, 3240, 3277 and 6626) were selected for model construction and validation by the three algorithms. Based on the panel combining FIGO risk score and peptide serum signatures, the neural network (nnet) model showed promising performance in both the training (AUC=0.9635) and validation (AUC=0.8788) cohorts. Peaks at m/z 2042, 2862, 2932, 3240 were identified as the partial sequences of transthyretin, fibrinogen alpha chain (FGA), beta-globin and FGA, respectively.

Conclusion

We combined FIGO risk score and serum peptide signatures using the nnet method to construct the model which can accurately predict outcome of GTN patients after first-line chemotherapy. With this model, patients can be further classified and managed, and those with poor predicted outcomes can be given more attention for developing treatment failure.
A nomogram model based on preoperative grey-scale US features and routine serum biomarkers to predict the outcome of infants with biliary atresia after Kasai portoenterostomy
Authors: Weng Zongjie , Ye Fengying , Zhou Luyao , Chen Fa , Ling Wen , Fang Yifan , Liu Min , Wu Qiumei , Qiu Xiuqing , Lyu Guorong
Published: October 2022

Objective

To establish a nomogram to predict the outcome of biliary atresia (BA) infants 3-months post- Kasai portoenterostomy (KPE).

Methods

BA Infants who underwent KPE from two hospitals were included in the training (n = 161) and validation cohorts (n = 64). A logistic regression equation (Equation A) for predicting the serum total bilirubin (TBIL) level 3-month post-KPE was established in the training cohort. Then, a nomogram was developed based on Equation A in the training cohort and validated in the validation cohort. Moreover, a new equation (Equation B) was generated based on the nomogram and the size of the enlarged hilar lymph nodes (LNs) in the validation cohort. The predictive performance of the nomogram was evaluated by the receiver operating characteristic (ROC) curve and by calculating the area under the ROC curve (AUC), sensitivity, specificity, and positive (PPV) and negative (NPV) prediction values.

Results

A nomogram based on gallbladder morphology and serum levels of TBIL and total protein (TP) was established with AUC (95%CI) of 0.673 (0.595, 0.745) and 0.647 (0.518, 0.763), sensitivity (95%CI) of 71.4% (62.1%,79.6%) and 81.8% (59.7%,94.8%), specificity (95%CI) of 63.3% (48.3%,76.6%) and 47.6% (32.0%,63.6%), PPV (95%CI) of 81.6% (72.5%,88.9%) and 45.0% (29.3%,61.5%), and NPV (95%CI) 49.2% (36.4%,62.1%) and 83.3% (62.6%,95.3%), respectively, in the training and validation cohorts. Furthermore, in the validation cohort, the AUC (95%CI) of Equation B was 0.798 (95%CI: 0.679, 0.888), which was significantly higher than that of the nomogram (P = 0.042).

Conclusion

A nomogram based on the pre-KPE gallbladder morphology, TBIL, and TP to predict the outcome of BA 3-months post-KPE is established. Moreover, the addition of the size of the enlarged hilar LNs into the nomogram further improves its predictive value.
Pinocembrin ameliorates atrial fibrillation susceptibility in rats with anxiety disorder induced by empty bottle stimulation
Authors: Ran Qian , Zhang Cui , Wan Weiguo , Ye Tianxin , Zou Ying , Liu Zhangchi , Yu Yi , Zhang Junhua , Shen Bo , Yang Bo
Published: October 2022

Background: Anxiety disorder (AD) is the most common mental disorder, which is closely related to atrial fibrillation (AF) and is considered to be a trigger of AF. Pinocembrin has been demonstrated to perform a variety of neurological and cardiac protective effects through its anti-inflammatory and antioxidant activities. The current research aims to explore the antiarrhythmic effect of pinocembrin in anxiety disorder rats and its underlying mechanisms.

Methods: 60 male Sprague-Dawley rats were distributed into four groups: CTL group: control rats + saline; CTP group: control rats + pinocembrin; Anxiety disorder group: anxiety disorder rats + saline; ADP group: anxiety disorder rats + pinocembrin. Empty bottle stimulation was conducted to induce anxiety disorder in rats for 3 weeks, and pinocembrin was injected through the tail vein for the last 2 weeks. Behavioral measurements, in vitro electrophysiological studies, biochemical assays, ELISA, Western blot and histological studies were performed to assess the efficacy of pinocembrin. In addition, HL-1 atrial cells were cultured in vitro to further verify the potential mechanism of pinocembrin.

Results: After 3 weeks of empty bottle stimulation, pinocembrin significantly improved the exploration behaviors in anxiety disorder rats. Pinocembrin alleviated electrophysiological remodeling in anxiety disorder rats, including shortening the action potential duration (APD), prolonging the effective refractory period (ERP), increasing the expression of Kv1.5, Kv4.2 and Kv4.3, decreasing the expression of Cav1.2, and ultimately reducing the AF susceptibility. These effects may be attributed to the amelioration of autonomic remodeling and structural remodeling by pinocembrin, as well as the inhibition of oxidative stress with upregulation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) pathway.

Conclusion: Pinocembrin can reduce AF susceptibility in anxiety disorder rats induced by empty bottle stimulation, with the inhibition of autonomic remodeling, structural remodeling, and oxidative stress. Therefore, pinocembrin is a promising treatment for AF in patients with anxiety disorder.
Evolutionary coupling analysis guides identification of mistrafficking-sensitive variants in cardiac K+ channels: Validation with hERG
Authors: Zhang Yihong , Grimwood Amy L. , Hancox Jules C. , Harmer Stephen C. , Dempsey Christopher E.
Published: October 2022

Loss of function (LOF) mutations of voltage sensitive K+ channel proteins hERG (Kv11.1) and KCNQ1 (Kv7.1) account for the majority of instances of congenital Long QT Syndrome (cLQTS) with the dominant molecular phenotype being a mistrafficking one resulting from protein misfolding. We explored the use of Evolutionary Coupling (EC) analysis, which identifies evolutionarily conserved pairwise amino acid interactions that may contribute to protein structural stability, to identify regions of the channels susceptible to misfolding mutations. Comparison with published experimental trafficking data for hERG and KCNQ1 showed that the method strongly predicts “scaffolding” regions of the channel membrane domains and has useful predictive power for trafficking phenotypes of individual variants. We identified a region in and around the cytoplasmic S2-S3 loop of the hERG Voltage Sensor Domain (VSD) as susceptible to destabilising mutation, and this was confirmed using a quantitative LI-COR® based trafficking assay that showed severely attenuated trafficking in eight out of 10 natural hERG VSD variants selected using EC analysis. Our analysis highlights an equivalence in the scaffolding structures of the hERG and KCNQ1 membrane domains. Pathogenic variants of ion channels with an underlying mistrafficking phenotype are likely to be located within similar scaffolding structures that are identifiable by EC analysis.
Involvement of endoplasmic reticulum stress in rifampicin-induced liver injury
Authors: Hou Wanqing , Nsengimana Bernard , Yan Chuyun , Nashan Bjorn , Han Shuxin
Published: October 2022

Rifampicin is a first-line antituberculosis drug. Hepatocyte toxicity caused by rifampicin is a significant clinical problem. However, the specific mechanism by which rifampicin causes liver injury is still poorly understood. Endoplasmic reticulum (ER) stress can have both protective and proapoptotic effects on an organism, depending on the environmental state of the organism. While causing cholestasis and oxidative stress in the liver, rifampicin also activates ER stress in different ways, including bile acid accumulation and cytochrome p450 (CYP) enzyme-induced toxic drug metabolites via pregnane X receptor (PXR). The short-term stress response helps the organism resist toxicity, but when persisting, the response aggravates liver damage. Therefore, ER stress may be closely related to the “adaptive” mechanism and the apoptotic toxicity of rifampicin. This article reviews the functional characteristics of ER stress and its potentially pathogenic role in liver injury caused by rifampicin.
Genotype-phenotype association and biochemical analyses of glucose-6-phosphate dehydrogenase variants: Implications for the hemolytic risk of using 8-aminoquinolines for radical cure
Authors: Sudsumrit Sirapapha , Chamchoy Kamonwan , Songdej Duantida , Adisakwattana Poom , Krudsood Srivicha , Adams Emily R. , Imwong Mallika , Leartsakulpanich Ubolsree , Boonyuen Usa
Published: October 2022

Background:Plasmodium vivax remains the malaria species posing a major threat to human health worldwide owing to its relapse mechanism. Currently, the only drugs of choice for radical cure are the 8-aminoquinolines (primaquine and tafenoquine), which are capable of killing hypnozoites and thus preventing P. vivax relapse. However, the therapeutic use of primaquine and tafenoquine is restricted because these drugs can cause hemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. This study aimed to assess and understand the hemolytic risk of using 8-aminoquinolines for radical treatment in a malaria endemic area of Thailand.

Methods: The prevalence of G6PD deficiency was determined using a quantitative test in 1,125 individuals. Multiplexed high-resolution meltinging (HRM) assays were developed and applied to detect 12 G6PD mutations. Furthermore, biochemical and structural characterization of G6PD variants was carried out to understand the molecular basis of enzyme deficiency.

Results: The prevalence of G6PD deficiency was 6.76% (76/1,125), as assessed by a phenotypic test. Multiplexed HRM assays revealed G6PD Mahidol in 15.04% (77/512) of males and 28.38% (174/613) of females, as well as G6PD Aures in one female. G6PD activity above the 30% cut-off was detected in those carrying G6PD Mahidol, even in hemizygous male individuals. Two variants, G6PD Murcia Oristano and G6PD Songklanagarind + Viangchan, were identified for the first time in Thailand. Biochemical characterization revealed that structural instability is the primary cause of enzyme deficiency in G6PD Aures, G6PD Murcia Oristano, G6PD Songklanagarind + Viangchan, and G6PD Chinese 4 + Viangchan, with double G6PD mutations causing more severe enzyme deficiency.

Conclusion: In western Thailand, up to 22% of people may be ineligible for radical cure. Routine qualitative tests may be insufficient for G6PD testing, so quantitative tests should be implemented. G6PD genotyping should also be used to confirm G6PD status, especially in female individuals suspected of having G6PD deficiency. People with double G6PD mutations are more likely to have hemolysis than are those with single G6PD mutations because the double mutations significantly reduce the catalytic activity as well as the structural stability of the protein.
Aminopeptidase B can bioconvert L-type amino acid transporter 1 (LAT1)-utilizing amide prodrugs in the brain
Authors: Hugele Agathe , Löffler Susanne , Molina Belén Hernández , Guillon Melina , Montaser Ahmed B. , Auriola Seppo , Huttunen Kristiina M.
Published: October 2022

A prodrug approach is a powerful method to temporarily change the physicochemical and thus, pharmacokinetic properties of drugs. However, in site-selective targeted prodrug delivery, tissue or cell-specific bioconverting enzyme is needed to be utilized to release the active parent drug at a particular location. Unfortunately, ubiquitously expressed enzymes, such as phosphatases and carboxylesterases are well used in phosphate and ester prodrug applications, but less is known about enzymes selectively expressed, e.g., in the brain and enzymes that can hydrolyze more stable prodrug bonds, such as amides and carbamates. In the present study, L-type amino acid transporter 1 (LAT1)-utilizing amide prodrugs bioconverting enzyme was identified by gradually exploring the environment and possible determinants, such as pH and metal ions, that affect amide prodrug hydrolysis. Based on inducement by cobalt ions and slightly elevated pH (8.5) as well as localization in plasma, liver, and particularly in the brain, aminopeptidase B was proposed to be responsible for the bioconversion of the majority of the studied amino acid amide prodrugs. However, this enzyme hydrolyzed only those prodrugs that contained an aromatic promoiety (L-Phe), while leaving the aliphatic promoeities (L-Lys) and the smallest prodrug (with L-Phe promoiety) intact. Moreover, the parent drugs’ structure (flexibility and the number of aromatic rings) largely affected the bioconversion rate. It was also noticed in this study, that there were species differences in the bioconversion rate by aminopeptidase B (rodents > human), although the in vitro–in vivo correlation of the studied prodrugs was relatively accurate.
Natural products targeting glycolytic signaling pathways-an updated review on anti-cancer therapy
Authors: Cui Yuting , Li Chuang , Sang Feng , Cao Weiling , Qin Zhuo , Zhang Peng
Published: October 2022

Glycolysis is a complex metabolic process that occurs to convert glucose into pyruvate to produce energy for living cells. Normal cells oxidized pyruvate into adenosine triphosphate and carbon dioxide in the presence of oxygen in mitochondria while cancer cells preferentially metabolize pyruvate to lactate even in the presence of oxygen in order to maintain a slightly acidic micro-environment of PH 6.5 and 6.9, which is beneficial for cancer cell growth and metastasis. Therefore targeting glycolytic signaling pathways provided new strategy for anti-cancer therapy. Natural products are important sources for the treatment of diseases with a variety of pharmacologic activities. Accumulated studies suggested that natural products exhibited remarkable anti-cancer properties both in vitro and in vivo. Plenty of studies suggested natural products like flavonoids, terpenoids and quinones played anti-cancer properties via inhibiting glucose metabolism targets in glycolytic pathways. This study provided an updated overview of natural products controlling glycolytic pathways, which also provide insight into druggable mediators discovery targeting cancer glucose metabolism.
Approaches for evaluation of novel CPP-based cargo delivery systems
Authors: Porosk Ly , Langel Ülo
Published: October 2022

Cell penetrating peptides (CPPs) can be broadly defined as relatively short synthetic, protein derived or chimeric peptides. Their most remarkable property is their ability to cross cell barriers and facilitate the translocation of cargo, such as drugs, nucleic acids, peptides, small molecules, dyes, and many others across the plasma membrane. Over the years there have been several approaches used, adapted, and developed for the evaluation of CPP efficacies as delivery systems, with the fluorophore attachment as the most widely used approach. It has become progressively evident, that the evaluation method, in order to lead to successful outcome, should concede with the specialties of the delivery. For characterization and assessment of CPP-cargo a combination of research tools of chemistry, physics, molecular biology, engineering, and other fields have been applied. In this review, we summarize the diverse, in silico, in vitro and in vivo approaches used for evaluation and characterization of CPP-based cargo delivery systems.
Lower-dose corticosteroid therapy in severe immune thrombocytopenia during pregnancy: The comparable efficacy and lower incidence of maternal complications
Authors: Xu Xue , Liang Mei-Ying , Wang Yi-Lin , Wang Jian-Liu , Zhang Xiao-Hui
Published: October 2022

Background: This study assessed the clinical efficacy of oral prednisone at low dose (LD) versus the previous high-dose (HD) study in patients with severe immune thrombocytopenia during pregnancy and its side effects on maternal and neonatal outcomes.

Study design: Pregnant patients with ITP were enrolled in the study (platelet count <30×109/L) between January 2015 and 2019. A total of 43 patients received LD oral prednisone (0.25–0.5 mg/kg) as the initial treatment and were compared retrospectively with the 31 patients in the HD (1 mg/kg) study. The primary clinical endpoint was the response rate, and the secondary endpoint was maternal hemorrhagic events, complications, and neonatal outcomes.

Results: In total, 35% of patients responded (15/43) to the LD cortico-therapy, including four patients with a complete response which was no less than HD therapy (35.5%). The bleeding symptoms of 10 (30%) patients were ameliorated after 14 days of LD prednisone treatment. Preeclampsia occurred in three cases (7% of total) of which the incidence was obviously lower than that of the previous study at HD (18%). No stillbirth or miscarriage occurred in the LD group, and neonatal outcomes had no significant differences between the two studies.

Conclusion: LD prednisone therapy for severe ITP patients during pregnancy had equal efficacy to HD treatment. In addition, the decrease in dosage significantly reduced the incidence of hypertension.