bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping and Validating a Point Neuron Model on Intel's Neuromorphic Hardware Loihi
Authors: Dey Srijanie , Dimitrov Alexander
Published: January 2023

Neuromorphic hardware is based on emulating the natural biological structure of the brain. Since its computational model is similar to standard neural models, it could serve as a computational accelerator for research projects in the field of neuroscience and artificial intelligence, including biomedical applications. However, in order to exploit this new generation of computer chips, we ought to perform rigorous simulation and consequent validation of neuromorphic models against their conventional implementations. In this work, we lay out the numeric groundwork to enable a comparison between neuromorphic and conventional platforms. “Loihi”—Intel's fifth generation neuromorphic chip, which is based on the idea of Spiking Neural Networks (SNNs) emulating the activity of neurons in the brain, serves as our neuromorphic platform. The work here focuses on Leaky Integrate and Fire (LIF) models based on neurons in the mouse primary visual cortex and matched to a rich data set of anatomical, physiological and behavioral constraints. Simulations on classical hardware serve as the validation platform for the neuromorphic implementation. We find that Loihi replicates classical simulations very efficiently with high precision. As a by-product, we also investigate Loihi's potential in terms of scalability and performance and find that it scales notably well in terms of run-time performance as the simulated networks become larger.
A three-component model of the spinal nerve ramification: Bringing together the human gross anatomy and modern Embryology
Authors: Homma Shunsaku , Shimada Takako , Wada Ikuo , Kumaki Katsuji , Sato Noboru , Yaginuma Hiroyuki
Published: January 2023

Due to its long history, the study of human gross anatomy has not adequately incorporated modern embryological findings; consequently, the current understanding has often been incompatible with recent discoveries from molecular studies. Notably, the traditional epaxial and hypaxial muscle distinction, and their corresponding innervation by the dorsal and ventral rami of the spinal nerve, do not correspond to the primaxial and abaxial muscle distinction, defined by the mesodermal lineages of target tissues. To resolve the disagreement between adult anatomy and embryology, we here propose a novel hypothetical model of spinal nerve ramification. Our model is based on the previously unknown developmental process of the intercostal nerves. Observations of these nerves in the mouse embryos revealed that the intercostal nerves initially had superficial and deep ventral branches, which is contrary to the general perception of a single ventral branch. The initial dual innervation pattern later changes into an adult-like single branch pattern following the retraction of the superficial branch. The modified intercostal nerves consist of the canonical ventral branches and novel branches that run on the muscular surface of the thorax, which sprout from the lateral cutaneous branches. We formulated the embryonic branching pattern into the hypothetical ramification model of the human spinal nerve so that the branching pattern is compatible with the developmental context of the target muscles. In our model, every spinal nerve consists of three components: (1) segmental branches that innervate the primaxial muscles, including the dorsal rami, and short branches and long superficial anterior branches from the ventral rami; (2) plexus-forming intramural branches, the serial homolog of the canonical intercostal nerves, which innervate the abaxial portion of the body wall; and (3) plexus-forming extramural branches, the series of novel branches located outside of the body wall, which innervate the girdle and limb muscles. The selective elaboration or deletion of each component successfully explains the reasoning for the standard morphology and variability of the spinal nerve. Therefore, our model brings a novel understanding of spinal nerve development and valuable information for basic and clinical sciences regarding the diverse branching patterns of the spinal nerve.
Efficacy on gait and posture control after botulinum toxin A injection for lower-limb spasticity treatment after stroke: A randomized controlled trial
Authors: Yu Hui-xian , Liu Si-hao , Wang Zhao-xia , Liu Chang-bin , Dai Pei , Zang Da-wei
Published: January 2023

Objectives

To observe the efficacy of botulinum toxin type A (BoNT-A) for the spasticity of the lower-limb post-stroke on gait and posture control.

Methods

A total of 46 patients with hemiplegia gait were randomly divided into the experimental group (23 patients) and the control group (23 patients). In patients in the experimental group received injections of BoNT-A by electrical stimulation-guided. At the same time, patients of the two groups received routine physical therapy. Gait analysis, plantar pressure analysis, lower-limb Fugl–Meyer assessment (L-FMA), 10 meter walking test (10MWT), timed “Up and Go” test (TUGT), and modified Ashworth Scale assess (MAS) of the lower limbs were performed at 0, 1, 4, and 12 weeks after treatment.

Results

At 1, 4, and 12 weeks after treatment, the L-FMA, stride length, speed, and TUGT significantly improved than 0 week in both groups. The L-FMA and peak of forefoot pressure, and MAS results in the experimental group were better than those in the control group at 4 and 12 weeks. The TUGT, speed, and stride length in experimental group was significantly shortened than that in control group at 1, 4, and 12 weeks.

Conclusion

Botulinum toxin type A injection can improve motor functions of the lower limb, gait, spasticity, forefoot pressure, and posture control of patients after stroke.
Reliable and stable fundus image registration based on brain-inspired spatially-varying adaptive pyramid context aggregation network
Authors: Xu Jie , Yang Kang , Chen Youxin , Dai Liming , Zhang Dongdong , Shuai Ping , Shi Rongjie , Yang Zhanbo
Published: January 2023

The task of fundus image registration aims to find matching keypoints between an image pair. Traditional methods detect the keypoint by hand-designed features, which fail to cope with complex application scenarios. Due to the strong feature learning ability of deep neural network, current image registration methods based on deep learning directly learn to align the geometric transformation between the reference image and test image in an end-to-end manner. Another mainstream of this task aims to learn the displacement vector field between the image pair. In this way, the image registration has achieved significant advances. However, due to the complicated vascular morphology of retinal image, such as texture and shape, current widely used image registration methods based on deep learning fail to achieve reliable and stable keypoint detection and registration results. To this end, in this paper, we aim to bridge this gap. Concretely, since the vessel crossing and branching points can reliably and stably characterize the key components of fundus image, we propose to learn to detect and match all the crossing and branching points of the input images based on a single deep neural network. Moreover, in order to accurately locate the keypoints and learn discriminative feature embedding, a brain-inspired spatially-varying adaptive pyramid context aggregation network is proposed to incorporate the contextual cues under the supervision of structured triplet ranking loss. Experimental results show that the proposed method achieves more accurate registration results with significant speed advantage.
Analysis of reactive aldehydes in urine and plasma of type-2 diabetes mellitus patients through liquid chromatography-mass spectrometry: Reactive aldehydes as potential markers of diabetic nephropathy
Authors: Harkin Carla , Cobice Diego , Watt Joanne , Kurth Mary Jo , Brockbank Simon , Bolton Stephanie , Johnston Frances , Strzelecka Anna , Lamont John V. , Moore Tara , Fitzgerald Peter , Ruddock Mark W.
Published: January 2023

Introduction

Diabetes is a major public health issue that is approaching epidemic proportions globally. Diabetes mortality is increasing in all ethnic groups, irrespective of socio-economic class. Obesity is often seen as the main contributor to an increasing prevalence of diabetes. Oxidative stress has been shown to trigger obesity by stimulating the deposition of white adipose tissue. In this study, we measured reactive aldehydes by liquid chromatography-mass spectrometry (LC-MS), in the urine and plasma of type-2 diabetic mellitus (T2DM) patients, as potential surrogates of oxidative stress. Our hypothesis was that reactive aldehydes play a significant role in the pathophysiology of diabetes, and these reactive species, may present potential drug targets for patient treatment.

Materials and methods

Study participants [N = 86; control n = 26; T2DM n = 32, and diabetic nephropathy (DN) n = 28] were recruited between 2019 and 2020. Urine and blood samples were collected from all participants, including a detailed clinical history, to include patient behaviours, medications, and co-morbidities. Reactive aldehyde concentrations in urine and plasma were measured using pre-column derivatisation and LC-MS, for control, T2DM and DN patients.

Results

Reactive aldehydes were measured in the urine and plasma of control subjects and patients with T2DM and DN. In all cases, the reactive aldehydes under investigation; 4-HNE, 4-ONE, 4-HHE, pentanal, methylglyoxal, and glyoxal, were significantly elevated in the urine and serum of the patients with T2DM and DN, compared to controls (p < 0.001) (Kruskal–Wallis). Urine and serum reactive aldehydes were significantly correlated (≥0.7) (p < 0.001) (Spearman rho). The concentrations of the reactive aldehydes were significantly higher in plasma samples, when compared to urine, suggesting that plasma is the optimal matrix for screening T2DM and DN patients for oxidative stress.

Conclusion

Reactive aldehydes are elevated in the urine and plasma of T2DM and DN patients. Reactive aldehydes have been implicated in the pathobiology of T2DM. Therefore, if reactive aldehydes are surrogates of oxidative stress, these reactive aldehyde species could be therapeutic targets for potential drug development.
Metabolomic fingerprinting based on network analysis of volatile aroma compounds during the forced aging of Huangjiu: Effects of dissolved oxygen and temperature
Authors: Wang Na , Zhang Lili , Ren Xuejiao , Chen Shuang , Zhang Zhen
Published: January 2023

Introduction

Huangjiu is an important Chinese alcoholic beverage, usually prepared from rice. Although its unique flavor improves with prolonged storage in traditional pottery jars, knowledge of the aging mechanism, necessary for commercialization of an optimum product, remains unclear.

Methods

Here, volatile aroma compounds from forced aged samples exposed to different temperatures and oxygen treatments were measured by GC/MS. After retention time alignment and normalization, the peak vectors were compared over storage time using Pearson's correlation, and a correlation network was established. Marker compounds, representative of traditionally aged Huangjiu, were then monitored and compared to similar compounds in the forced aged product.

Results and discussion

Correlation network analysis revealed the following: Temperature had little effect on most aroma compounds; alcohols, acids, and esters all increased with increasing dissolved oxygen, while polyphenols, lactones, and ketones were readily oxidized; aldehydes (e.g., furfural and benzaldehyde) were highly dependent on both temperature and dissolved oxygen. Dynamic changes in the targeted aging-markers showed that a higher initial oxygen concentration intensified the “aging-aroma” of Huangjiu in the early and middle stages of storage. Consequently, careful control of oxygen supplementation and storage temperature could be beneficial in controlling the desirable flavor of Huangjiu in the artificially aged product.
Invasiveness of endometrial cancer cell lines is potentiated by estradiol and blocked by a traditional medicine Guizhi Fuling at clinically relevant doses
Authors: Khan Sidra , Varricchio Alanah , Ricciardelli Carmela , Yool Andrea J.
Published: January 2023

The Traditional Chinese medicine, Guizhi Fuling (here called Fuling), has been confirmed in meta-analysis studies to reduce recurrence of endometriosis and improve pregnancy outcomes; however, the possible use of Fuling as a fertility-preserving treatment in endometrial cancer has not previously been tested. Results here are the first to demonstrate dose-dependent inhibition of cell motility by Fuling in two endometrial cancer cell lines, classified as Grade I which is responsive to progesterone treatment, and Grade III (MFE-280) which is resistant. The major outcome of this study was the novel demonstration that Fuling (30-80 µg/ml) significantly inhibits invasiveness in both high and low grades of EC cells, achieving 70-80% block of trans-barrier migration without cytotoxicity. This effective dose range is estimated to be comparable to that used in human clinical trials and traditional practice. Results here further show that clinically relevant doses of Fuling override the motility-promoting effects of estradiol in endometrial cancer cell lines. Medroxyprogesterone acetate has to date been the standard therapy to treat metastatic or inoperable endometrial cancers; however, success rates are low with high rates of recurrence, due in part to acquired resistance to medroxyprogesterone acetate therapy. The discovery here that Fuling appears to control the spread of treatment-resistant advanced cancers is an exciting prospect.
Mitochondrial plasticity supports proliferative outgrowth and invasion of ovarian cancer spheroids during adhesion
Authors: Grieco Joseph P. , Compton Stephanie L. E. , Bano Nazia , Brookover Lucy , Nichenko Anna S. , Drake Joshua C. , Schmelz Eva M.
Published: January 2023

Background

Ovarian cancer cells aggregate during or after exfoliation from the primary tumor to form threedimensional spheroids. Spheroid formation provides a survival advantage during peritoneal dissemination in nutrient and oxygen-depleted conditions which is accompanied by a suppressed metabolic phenotype and fragmented mitochondria. Upon arrival to their metastatic sites, spheroids adhere to peritoneal organs and transition to a more epithelial phenotype to support outgrowth and invasion. In this study, we investigated the plasticity of mitochondrial morphology, dynamics, and function upon adhesion.

Methods

Using our slow-developing (MOSE-L) and fast-developing (MOSE-LTICv) ovarian cancer models, we mimicked adhesion and reoxygenation conditions by plating the spheroids onto tissue culture dishes and changing culture conditions from hypoxia and low glucose to normoxia with high glucose levels after adhesion. We used Western Blot, microscopy and Seahorse analyses to determine the plasticity of mitochondrial morphology and functions upon adhesion, and the impact on proliferation and invasion capacities.

Results

Independent of culture conditions, all spheroids adhered to and began to grow onto the culture plates. While the bulk of the spheroid was unresponsive, the mitochondrial morphology in the outgrowing cells was indistinguishable from cells growing in monolayers, indicating that mitochondrial fragmentation in spheroids was indeed reversible. This was accompanied by an increase in regulators of mitobiogenesis, PGC1a, mitochondrial mass, and respiration. Reoxygenation increased migration and invasion in both cell types but only the MOSE-L responded with increased proliferation to reoxygenation. The highly aggressive phenotype of the MOSE-LTICv was characterized by a relative independence of oxygen and the preservation of higher levels of proliferation, migration and invasion even in limiting culture conditions but a higher reliance on mitophagy. Further, the outgrowth in these aggressive cells relies mostly on proliferation while the MOSE-L cells both utilize proliferation and migration to achieve outgrowth. Suppression of proliferation with cycloheximide impeded aggregation, reduced outgrowth and invasion via repression of MMP2 expression and the flattening of the spheroids.

Discussion

Our studies indicate that the fragmentation of the mitochondria is reversible upon adhesion. The identification of regulatory signaling molecules and pathways of these key phenotypic alterations that occur during primary adhesion and invasion is critical for the identification of druggable targets for therapeutic intervention to prevent aggressive metastatic disease.
Identification of an unfolded protein response-related signature for predicting the prognosis of pancreatic ductal adenocarcinoma
Authors: Fang Lishan , Chen Shaojing , Gong Hui , Xia Shaohua , Guan Sainan , Quan Nali , Li Yajie , Zeng Chao , Chen Ya , Du Jianhang , Liu Shuguang
Published: January 2023

Background

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive lethal malignancy. An effective prognosis prediction model is urgently needed for treatment optimization.

Methods

The differentially expressed unfolded protein response (UPR)‒related genes between pancreatic tumor and normal tissue were analyzed using the TCGA-PDAC dataset, and these genes that overlapped with UPR‒related prognostic genes from the E-MTAB-6134 dataset were further analyzed. Univariate, LASSO and multivariate Cox regression analyses were applied to establish a prognostic gene signature, which was evaluated by Kaplan‒Meier curve and receiver operating characteristic (ROC) analyses. E‒MTAB‒6134 was set as the training dataset, while TCGA-PDAC, GSE21501 and ICGC-PACA-AU were used for external validation. Subsequently, a nomogram integrating risk scores and clinical parameters was established, and gene set enrichment analysis (GSEA), tumor immunity analysis and drug sensitivity analysis were conducted.

Results

A UPR-related signature comprising twelve genes was constructed and divided PDAC patients into high- and low-risk groups based on the median risk score. The UPR-related signature accurately predicted the prognosis and acted as an independent prognostic factor of PDAC patients, and the AUCs of the UPR-related signature in predicting PDAC prognosis at 1, 2 and 3 years were all more than 0.7 in the training and validation datasets. The UPR-related signature showed excellent performance in outcome prediction even in different clinicopathological subgroups, including the female (p<0.0001), male (p<0.0001), grade 1/2 (p<0.0001), grade 3 (p=0.028), N0 (p=0.043), N1 (p<0.001), and R0 (p<0.0001) groups. Furthermore, multiple immune-related pathways were enriched in the low-risk group, and risk scores in the low-risk group were also associated with significantly higher levels of tumor-infiltrating lymphocytes (TILs). In addition, DepMap drug sensitivity analysis and our validation experiment showed that PDAC cell lines with high UPR-related risk scores or UPR activation are more sensitive to floxuridine, which is used as an antineoplastic agent.

Conclusion

Herein, we identified a novel UPR-related prognostic signature that showed high value in predicting survival in patients with PDAC. Targeting these UPR-related genes might be an alternative for PDAC therapy. Further experimental studies are required to reveal how these genes mediate ER stress and PDAC progression.
The potential of using circulating tumour cells and their gene expression to predict docetaxel response in metastatic prostate cancer
Authors: Davies Caitlin R. , Guo Tianyu , Burke Edwina , Stankiewicz Elzbieta , Xu Lei , Mao Xueying , Scandura Glenda , Rajan Prabhakar , Tipples Karen , Alifrangis Constantine , Wimalasingham Akhila Ganeshi , Galazi Myria , Crusz Shanthini , Powles Thomas , Grey Alistair , Oliver Tim , Kudahetti Sakunthala , Shaw Greg , Berney Daniel , Shamash Jonathan , Lu Yong-Jie
Published: January 2023

Background

Docetaxel improves overall survival (OS) in castration-resistant prostate cancer (PCa) (CRPC) and metastatic hormone-sensitive PCa (mHSPC). However, not all patients respond due to inherent and/or acquired resistance. There remains an unmet clinical need for a robust predictive test to stratify patients for treatment. Liquid biopsy of circulating tumour cell (CTCs) is minimally invasive, can provide real-time information of the heterogeneous tumour and therefore may be a potentially ideal docetaxel response prediction biomarker.

Objective

In this study we investigate the potential of using CTCs and their gene expression to predict post-docetaxel tumour response, OS and progression free survival (PFS).

Methods

Peripheral blood was sampled from 18 mCRPC and 43 mHSPC patients, pre-docetaxel treatment, for CTC investigation. CTCs were isolated using the epitope independent Parsortix® system and gene expression was determined by multiplex RT-qPCR. We evaluated CTC measurements for post-docetaxel outcome prediction using receiver operating characteristics and Kaplan Meier analysis.

Results

Detection of CTCs pre-docetaxel was associated with poor patient outcome post-docetaxel treatment. Combining total-CTC number with PSA and ALP predicted lack of partial response (PR) with an AUC of 0.90, p= 0.037 in mCRPC. A significantly shorter median OS was seen in mCRPC patients with positive CTC-score (12.80 vs. 37.33 months, HR= 5.08, p= 0.0005), ≥3 total-CTCs/7.5mL (12.80 vs. 37.33 months, HR= 3.84, p= 0.0053), ≥1 epithelial-CTCs/7.5mL (14.30 vs. 37.33 months, HR= 3.89, p= 0.0041) or epithelial to mesenchymal transitioning (EMTing)-CTCs/7.5mL (11.32 vs. 32.37 months, HR= 6.73, p= 0.0001). Significantly shorter PFS was observed in patients with ≥2 epithelial-CTCs/7.5mL (7.52 vs. 18.83 months, HR= 3.93, p= 0.0058). mHSPC patients with ≥5 CTCs/7.5mL had significantly shorter median OS (24.57 vs undefined months, HR= 4.14, p= 0.0097). In mHSPC patients, expression of KLK2, KLK4, ADAMTS1, ZEB1 and SNAI1 was significantly associated with shorter OS and/or PFS. Importantly, combining CTC measurements with clinical biomarkers increased sensitivity and specificity for prediction of patient outcome.

Conclusion

While it is clear that CTC numbers and gene expression were prognostic for PCa post-docetaxel treatment, and CTC subtype analysis may have additional value, their potential predictive value for docetaxel chemotherapy response needs to be further investigated in large patient cohorts.
The predictive value of neutrophil-to-lymphocyte ratio for overall survival and pathological complete response in breast cancer patients receiving neoadjuvant chemotherapy
Authors: Gao Siming , Tang Wenjie , Zuo Bingli , Mulvihill Lianne , Yu Jinming , Yu Yishan
Published: January 2023

Purpose

Previous studies have reported that neutrophil-to-lymphocyte ratio (NLR) at pre-treatment was predictive for overall survival (OS) and pathologic complete response (pCR) in breast cancer (BC) patients receiving neoadjuvant chemotherapy (NAC). This study aims to explore the predictive role of both pre- and post-NLR for OS as well as longitudinal NLR kinetics towards pCR in BC patients undergoing NAC.

Methods

We retrospectively included 501 BC patients who received NAC from 2009 to 2018. NLR at pre-, mid (every two cycles of NAC)-, and post-treatment were collected. Overall, 421 patients were included in the survival analysis. These patients were randomly divided into a training cohort (n = 224) and a validation cohort (n = 197). A multivariable Cox model was built using all significant factors in the multivariable analysis from the training cohort. The performance of the model was verified in the validation cohort by the concordance index (C-index). Longitudinal analysis for pCR prediction of NLR was performed using a mixed-effects regression model among 176 patients who finished eight cycles of NAC.

Results

The median follow-up time was 43.2 months for 421 patients. In the training cohort, multivariable analysis revealed that ER status, clinical node stage, pCR, pre-NLR, and post-NLR (all p < 0.05) were independent predictors of OS. The OS nomogram was established based on these parameters. The C-indexes of the nomogram were 0.764 and 0.605 in the training and validation cohorts, respectively. In the longitudinal analysis, patients who failed to achieve pCR experienced an augment of NLR during NAC while NLR remained stable among patients with pCR. Pre-NLR tended to be significantly associated with OS in patients of HER2 overexpressing and TNBC subtypes (all p < 0.05), but not in Luminal A and Luminal B subtypes.

Conclusions

This study demonstrated the prognostic value of both pre-NLR and post-NLR on clinical outcomes in BC patients receiving NAC. A novel nomogram was established to predict OS. Non-pCR patients developed increased NLRs during NAC. Routine assessment of NLR may be a simple and affordable tool to predict prognosis for BC patients receiving NAC.
FOXO3 gene hypermethylation and its marked downregulation in breast cancer cases: A study on female patients
Authors: Khan Mohammad Aasif , Sadaf  , Ahmad Irfan , Aloliqi Abdulaziz A. , Eisa Alaa Abdulaziz , Najm Mohammad Zeeshan , Habib Maria , Mustafa Saad , Massey Sheersh , Malik Zoya , Sunita Kumari , Pawar Jogendra Singh , Akhter Naseem , Shukla N. K. , Deo S.V.S. , Husain Syed Akhtar
Published: January 2023

Background

FOXO3, a member of the FOX transcription factor family, is frequently described as being deregulated in cancer. Additionally, notable role of FOXO3 can be easily recognized in the process of ageing and survival. Even though various studies have been done to acknowledge the tumour-suppressive or oncogenic role of FOXO3 in cancer, still there exist a lack of understanding in terms of cancer prognosis and treatment. Therefore, to provide better insight, our study aims to evaluate the role and function of FOXO3 in breast cancer in Indian female patients. We examined the FOXO3 expression levels in breast cancer samples by analyzing mRNA and protein expression along with its clinicopathological parameters.

Results

A total of 127 cases of breast cancer with equal normal cases (n=127) were assessed with methylation (MS-PCR), Immunohistochemistry (IHC), mRNA expression using Real-time PCR was analysed and 66.14% cases at mRNA level were found to be downregulated, while 81.10% of cases had little or very little protein expression. Our data state, the promoter hypermethylation of the FOXO3 gene and the downregulated protein expression are significantly correlated (p=0.0004). Additionally, we found a significant correlation between the level of FOXO3 mRNA with ER (p=0.04) and status of lymph node (p=0.01) along with this.

Conclusion

Data suggests the prognostic significance and the tumour-suppressive role of FOXO3 in breast cancer cases studied in India. However, there is a need for the extended research targeting FOXO3 to measure its clinical potential and develop well-defined therapeutic strategies.
Pediatric diffuse midline glioma H3K27- altered: A complex clinical and biological landscape behind a neatly defined tumor type
Authors: Vallero Stefano Gabriele , Bertero Luca , Morana Giovanni , Sciortino Paola , Bertin Daniele , Mussano Anna , Ricci Federica Silvia , Peretta Paola , Fagioli Franca
Published: January 2023

The 2021 World Health Organization Classification of Tumors of the Central Nervous System, Fifth Edition (WHO-CNS5), has strengthened the concept of tumor grade as a combination of histologic features and molecular alterations. The WHO-CNS5 tumor type “Diffuse midline glioma, H3K27-altered,” classified within the family of “Pediatric-type diffuse high-grade gliomas,” incarnates an ideally perfect integrated diagnosis in which location, histology, and genetics clearly define a specific tumor entity. It tries to evenly characterize a group of neoplasms that occur primarily in children and midline structures and that have a dismal prognosis. Such a well-defined pathological categorization has strongly influenced the pediatric oncology community, leading to the uniform treatment of most cases of H3K27-altered diffuse midline gliomas (DMG), based on the simplification that the mutation overrides the histological, radiological, and clinical characteristics of such tumors. Indeed, multiple studies have described pediatric H3K27-altered DMG as incurable tumors. However, in biology and clinical practice, exceptions are frequent and complexity is the rule. First of all, H3K27 mutations have also been found in non-diffuse gliomas. On the other hand, a minority of DMGs are H3K27 wild-type but have a similarly poor prognosis. Furthermore, adult-type tumors may rarely occur in children, and differences in prognosis have emerged between adult and pediatric H3K27-altered DMGs. As well, tumor location can determine differences in the outcome: patients with thalamic and spinal DMG have significantly better survival. Finally, other concomitant molecular alterations in H3K27 gliomas have been shown to influence prognosis. So, when such additional mutations are found, which one should we focus on in order to make the correct clinical decision? Our review of the current literature on pediatric diffuse midline H3K27-altered DMG tries to address such questions. Indeed, H3K27 status has become a fundamental supplement to the histological grading of pediatric gliomas; however, it might not be sufficient alone to exhaustively define the complex biological behavior of DMG in children and might not represent an indication for a unique treatment strategy across all patients, irrespective of age, additional molecular alterations, and tumor location.
Label-free LC-MS/MS proteomics analyses reveal CLIC1 as a predictive biomarker for bladder cancer staging and prognosis
Authors: Wang Weifeng , Huang Guankai , Lin Hansen , Ren Lei , Fu Liangmin , Mao Xiaopeng
Published: January 2023

Introduction

Bladder cancer (BC) is a significant carcinoma of the urinary system that has a high incidence of morbidity and death owing to the challenges in accurately identifying people with early-stage BC and the lack of effective treatment options for those with advanced BC. Thus, there is a need to define new markers of prognosis and prediction.

Methods

In this study, we have performed a comprehensive proteomics experiment by label-free quantitative proteomics to compare the proteome changes in the serum of normal people and bladder cancer patients—the successful quantification of 2064 Quantifiable proteins in total. A quantitative analysis was conducted to determine the extent of changes in protein species' relative intensity and reproducibility. There were 43 upregulated proteins and 36 downregulated proteins discovered in non-muscle invasive bladder cancer and normal individuals. Sixty-four of these proteins were elevated, and 51 were downregulated in muscle-invasive and non-muscle-invasive bladder cancer, respectively. Functional roles of differentially expressed proteins were annotated using Gene Ontology (GO) and Clusters of Orthologous Groups of Proteins (COG). To analyze the functions and pathways enriched by differentially expressed proteins, GO enrichment analysis, protein domain analysis, and KEGG pathway analysis were performed. The proteome differences were examined and visualized using radar plots, heat maps, bubble plots, and Venn diagrams.

Results

As a result of combining the Venn diagram with protein-protein interactions (PPIs), Chloride intracellular channel 1 (CLIC1) was identified as the primary protein. Using the Gene Set Cancer Analysis (GSCA) website, the influence of CLIC1 on immune infiltration was analyzed. A negative correlation between CD8 naive and CLIC1 levels was found. For validation, immunohistochemical (IHC), qPCR, and western blotting (WB) were performed.Further, we found that CLIC1 was associated with a poor prognosis of bladder cancer in survival analysis.

Discussion

Our research screened CLIC1 as a tumor-promoting protein in bladder cancer for the first time using serum mass spectrometry. And CLIC1 associated with tumor stage, and immune infiltrate. The prognostic biomarker and therapeutic target CLIC1 may be new for bladder cancer patients.
Patient specific real-time PCR in precision medicine – Validation of IG/TR based MRD assessment in lymphoid leukemia
Authors: Schilhabel Anke , Szczepanowski Monika , van Gastel-Mol Ellen J. , Schillalies Janina , Ray Jill , Kim Doris , Nováková Michaela , Dombrink Isabel , van der Velden Vincent H. J. , Boettcher Sebastian , Brüggemann Monika , Kneba Michael , van Dongen Jacques J. M. , Langerak Anton W. , Ritgen Matthias
Published: January 2023

Detection of patient- and tumor-specific clonally rearranged immune receptor genes using real-time quantitative (RQ)-PCR is an accepted method in the field of precision medicine for hematologic malignancies. As individual primers are needed for each patient and leukemic clone, establishing performance specifications for the method faces unique challenges. Results for series of diagnostic assays for CLL and ALL patients demonstrate that the analytic performance of the method is not dependent on patients’ disease characteristics. The calibration range is linear between 10-1 and 10-5 for 90% of all assays. The detection limit of the current standardized approach is between 1.8 and 4.8 cells among 100,000 leukocytes. RQ-PCR has about 90% overall agreement to flow cytometry and next generation sequencing as orthogonal methods. Accuracy and precision across different labs, and above and below the clinically applied cutoffs for minimal/measurable residual disease (MRD) demonstrate the robustness of the technique. The here reported comprehensive, IVD-guided analytical validation provides evidence that the personalized diagnostic methodology generates robust, reproducible and specific MRD data when standardized protocols for data generation and evaluation are used. Our approach may also serve as a guiding example of how to accomplish analytical validation of personalized in-house diagnostics under the European IVD Regulation.
Identification and validation of a novel angiogenesis-related gene signature for predicting prognosis in gastric adenocarcinoma
Authors: Xu Peipei , Liu Sailiang , Song Shu , yao Xiang , Li Xuechuan , Zhang Jie , Liu Yinbing , Zheng Ye , Gao Ganglong , Xu Jingjing
Published: January 2023

Background

Angiogenesis is a major promotor of tumor progression and metastasis in gastric adenocarcinoma (STAD). We aimed to develop a novel lncRNA gene signature by identifying angiogenesis-related genes to better predict prognosis in STAD patients.

Methods

The expression profiles of angiogenesis-related mRNA and lncRNA genes were collected from The Cancer Genome Atlas (TCGA). Then, the “limma” package was used to identify differentially expressed genes (DEGs). The expression profiles of angiogenesis-related genes were clustered by consumusclusterplus. The Pearson correlation coefficient was further used to identify lncRNAs coexpressed with angiogenesis-related clustere genes. We used Lasso Cox regression analysis to construct the angiogenesis-related lncRNAs signature. Furthermore, the diagnostic accuracy of the prognostic risk signature were validated by the TCGA training set, internal test sets and external test set. We used multifactor Cox analysis to determine that the risk score is an independent prognostic factor different from clinical characteristics. Nomogram has been used to quantitatively determine personal risk in a clinical environment. The ssGSEA method or GSE176307 data were used to evaluate the infiltration state of immune cells or predictive ability for the benefit of immunotherapy by angiogenesis-related lncRNAs signature. Finally, the expression and function of these signature genes were explored by RT–PCR and colony formation assays.

Results

Among angiogenesis-related genes clusters, the stable number of clusters was 2. A total of 289 DEGs were identified and 116 lncRNAs were screened to have a significant coexpression relationship with angiogenic DEGs (P value<0.001 and |R| >0.5). A six-gene signature comprising LINC01579, LINC01094, RP11.497E19.1, AC093850.2, RP11.613D13.8, and RP11.384P7.7 was constructed by Lasso Cox regression analysis. The multifactor Cox analysis and Nomogram results showed that our angiogenesis-related lncRNAs signature has good predictive ability for some different clinical factors. For immune, angiogenesis-related lncRNAs signature had the ability to efficiently predict infiltration state of 23 immune cells and immunotherapy. The qPCR analysis showed that the expression levels of the six lncRNA signature genes were all higher in gastric adenocarcinoma tissues than in adjacent tissues. The functional experiment results indicated that downregulation of the expression of these six lncRNA signature genes suppressed the proliferation of ASG and MKN45 cells.

Conclusion

Six angiogenesis-related genes were identified and integrated into a novel risk signature that can effectively assess prognosis and provide potential therapeutic targets for STAD patients.
Impact of cytotoxic T lymphocytes immunotherapy on prognosis of colorectal cancer patients
Authors: Zhu Yankun , Meng Mingyao , Hou Zongliu , Wang Wenju , Li Lin , Guan Aoran , Wang Ruotian , Tang Weiwei , Yang Fang , Zhao Yiyi , Gao Hui , Xie Hui , Li Ruhong , Tan Jing
Published: January 2023

Background

Expansion and activation of cytotoxic T lymphocytes (CTLs) in vitro represents a promising immunotherapeutic strategy, and CTLs can be primed by dendritic cells (DCs) loaded with tumor-associated antigens (TAAs) transformed by recombinant adeno-associated virus (rAAV). This study aimed to explore the impact of rAAV-DC-induced CTLs on prognosis of CRC and to explore factors associated with prognosis.

Methods

This prospective observational study included patients operated for CRC at Yan’an Hospital Affiliated to Kunming Medical University between 2016 and 2019. The primary outcome was progression-free survival (PFS), secondary outcomes were overall survival (OS) and adverse events. Totally 49 cases were included, with 29 and 20 administered rAAV-DC-induced CTL and chemotherapy, respectively.

Results

After 37-69 months of follow-up (median, 54 months), OS (P=0.0596) and PFS (P=0.0788) were comparable between two groups. Mild fever occurred in 2 (6.9%) patients administered CTL infusion. All the chemotherapy group experienced mild-to-moderate adverse effects, including vasculitis (n=20, 100%), vomiting (n=5, 25%), nausea (n=17, 85%) and fatigue (n=17, 85%).

Conclusions

Lymphatic metastasis (hazard ratio [HR]=4.498, 95% confidence interval [CI]: 1.290-15.676; P=0.018) and lower HLA-I expression (HR=0.294, 95%CI: 0.089-0.965; P=0.044) were associated with poor OS in the CTL group. CTLs induced by rAAV-DCs might achieve comparable effectiveness in CRC patients compare to chemotherapy, cases with high tumor-associated HLA-I expression and no lymphatic metastasis were more likely to benefit from CTLs.
A web app-based music intervention reduces experimental thermal pain: A randomized trial on preferred versus least-liked music style
Authors: Soyeux Orelle , Marchand Serge
Published: January 2023

Digital technologies are increasingly being used to strengthen national health systems. Music is used as a management technique for pain. The objective of this study is to demonstrate the effects of a web app-based music intervention on pain. The participants were healthy adults and underwent three conditions: Conditioned Pain Modulation (CPM), Most-Liked Music (MLM) and Least-Liked Music (LLM). The music used is MUSIC CARE©, a web app-based personalized musical intervention (“U” Sequence based on a musical composition algorithm). Thermal pain was measured before starting the 20-min music intervention and after three time points for each music condition: 2.20, 11.30, and 20 min. Mean pain perceptions were significantly reduced under both LLM and MLM conditions. Pain decrease was more important under MLM condition than LLM condition at 2.20 min with a mean difference between both conditions of 9.7 (±3.9) (p = 0.0195) and at 11.30 min [9.2 (±3.3), p = 0.0099]. LLM is correlated with CPM but not MLM, suggesting different mechanisms between LLM and MLM. Musical intervention, a simple method of application, fits perfectly into a multidisciplinary global approach and helps to treat the pain and anxiety disorders of participants.

Clinical trial registration: [https://clinicaltrials.gov/ct2/show/NCT04862832], ClinicalTrials.gov [NCT04862832].
Comparative evaluation of echocardiography indices during the transition to extrauterine life between small and appropriate for gestational age infants
Authors: Suciu Laura Mihaela , Giesinger Regan E. , Mărginean Claudiu , Muntean Mihai , Cucerea Manuela , Făgărășan Amalia , McNamara Patrick
Published: January 2023

Objectives

To study changes in heart function and hemodynamics during the transitional period in small for gestational (SGA) infants and appropriate (AGA) healthier counterparts.

Design

A hospital based prospective observational study was performed at a perinatal center. Echocardiograms were performed on the first postnatal day and again at 48 h age. Term SGA infants were compared with those AGA newborns matched for the GA and mode of delivery.

Results

Eighteen SGA infants were compared with 18 AGA infants [gestation 38 ± 1.5 vs. 38 ± 1.2 weeks, p > 0.05 and birthweight 2331 ± 345 vs. 3332 ± 405 grams, p < 0.05, respectively]. Maternal weight and body mass index was higher among non-affected pregnancies, 61% infants were born vaginally, and no differences in cord blood pH at birth were noted. SGA infants had higher systolic and mean blood pressure at both time points, lower indices of right ventricular (RV) performance [TAPSE (tricuspid annular peak systolic excursion) 7.4 ± 2.8 vs. 9.3 ± 0.7 on day 1, 7.2 ± 2.8 vs. 9.2 ± 0.5 on day 2, p = 0.001], lower pulmonary acceleration time (PAAT) suggestive of elevated pulmonary vascular resistance [56.4 ± 10.5 vs. 65.7 ± 13.2 on day 1, 61.4 ± 12.5 vs. 71.5 ± 15.7 on day 2, p = 0.01] and higher left ventricular (LV) ejection fraction [62.1 ± 7.8 vs. 54.9 ± 5.5 on day 1, 61.9 ± 7.6 vs. 55.8 ± 4.9 on day 2, p = 0.003].

Conclusions

SGA infants had evidence of higher pulmonary vascular resistance, and lower RV performance during the postnatal transition. The relevance and impact of these changes to hemodynamic disease states during the postnatal transition requires prospective investigation.
Application of deep-learning–based artificial intelligence in acetabular index measurement
Authors: Wu Qingjie , Ma Hailong , Sun Jun , Liu Chuanbin , Fang Jihong , Xie Hongtao , Zhang Sicheng
Published: January 2023

Objective

To construct an artificial intelligence system to measure acetabular index and evaluate its accuracy in clinical application.

Methods

A total of 10,219 standard anteroposterior pelvic radiographs were collected retrospectively from April 2014 to December 2018 in our hospital. Of these, 9,219 radiographs were randomly selected to train and verify the system. The remaining 1,000 radiographs were used to compare the system's and the clinicians' measurement results. All plain pelvic films were labeled by an expert committee through PACS system based on a uniform standard to measure acetabular index. Subsequently, eight other clinicians independently measured the acetabular index from 200 randomly selected radiographs from the test radiographs. Bland–Altman test was used for consistency analysis between the system and clinician measurements.

Results

The test set included 1,000 cases (2,000 hips). Compared with the expert committee measurement, the 95% limits of agreement (95% LOA) of the system was −4.02° to 3.45° (bias = −0.27°, P < 0.05). The acetabular index measured by the system within all age groups, including normal and abnormal groups, also showed good credibility according to the Bland–Altman principle. Comparison of the measurement evaluations by the system and eight clinicians vs. that of, the expert committee, the 95% LOA of the clinician with the smallest measurement error was −2.76° to 2.56° (bias = −0.10°, P = 0.126). The 95% LOA of the system was −0.93° to 2.86° (bias = −0.03°, P = 0.647). The 95% LOA of the clinician with the largest measurement error was −3.41° to 4.25° (bias = 0.42°, P < 0.05). The measurement error of the system was only greater than that of a senior clinician.

Conclusion

The newly constructed artificial intelligence system could quickly and accurately measure the acetabular index of standard anteroposterior pelvic radiographs. There is good data consistency between the system in measuring standard anteroposterior pelvic radiographs. The accuracy of the system is closer to that of senior clinicians.
Neurodevelopmental and functional outcome in hypoplastic left heart syndrome after Hybrid procedure as stage I
Authors: Knirsch Walter , De Silvestro Alexandra , von Rhein Michael
Published: January 2023

Background

Patients with hypoplastic left heart syndrome (HLHS) undergoing staged palliation until Fontan procedure are at risk for impaired neurodevelopmental (ND) outcome. The Hybrid procedure with bilateral pulmonary artery banding, ductal stenting, and balloon atrioseptostomy may offer a less invasive stage I procedure compared to the Norwood stage I procedure avoiding early neonatal cardiopulmonary bypass (CPB) surgery. Despite altered fetal cerebral hemodynamics, the type of stage I procedure may be a covariate influencing ND outcome and functional outcome may also be altered due to postponing neonatal CPB surgery. Within this review, we analyzed ND outcome as well as functional outcome after Hybrid procedure as stage I procedure.

Methods

The review analyzed original publications (OPs) published before March 15, 2022, identified by Cochrane, EMBASE, OVID, Scopus, and Web of science. An OP was included if short-to-long-term neurodevelopment outcome, brain development, somatic, and cardiac outcome in patients for HLHS and variants treated by Hybrid procedure were analyzed. In addition to database searches, we reviewed all references of the analyzed OP to obtain a comprehensive list of available studies. The author, year of publication, demographic characteristics of study population, study design (prospective or retrospective), study assessment, and main findings were summarized.

Results

Twenty-one OPs were included with data of patients with ND outcome and functional cardiac outcome. Overall, there is an impaired mid-term ND outcome in patients with Hybrid procedure as stage I for HLHS. Only slight differences between stage I procedures (Hybrid vs. Norwood) in two comparing studies have been determined affecting right ventricular remodeling, short- and mid-term ND outcome, reduced brain growth until two years of age, sufficient quality of life, and altered hemodynamics influencing brain volumes and cerebral perfusion pattern.

Conclusions

Despite some minor differences regarding the mid-term follow-up in patients with HLHS comparing Hybrid vs. Norwood procedure, its impact on ND outcome seems rather low. This may be explained by the large number of covariates as well as the small study populations and the different selection criteria for patients undergoing Hybrid or Norwood procedure as stage I.