bluuebunny/crossref_metadata_2025 huggingface dataset:
A network-based approach reveals long non-coding RNAs associated with disease activity in lupus nephritis: key pathways for flare and potential biomarkers to be used as liquid biopsies
Authors: Sentis George , Loukogiannaki Catherine , Malissovas Nikos , Nikolopoulos Dionysis , Manolakou Theodora , Flouda Sofia , Grigoriou Maria , Banos Aggelos , Boumpas Dimitrios T. , Filia Anastasia
Published: July 2023

Objective

A blood-based biomarker is needed to assess lupus nephritis (LN) disease activity, minimizing the need for invasive kidney biopsies. Long non-coding RNAs (lncRNAs) are known to regulate gene expression, appear to be stable in human plasma, and can serve as non-invasive biomarkers.

Methods

Transcriptomic data of whole blood samples from 74 LN patients and 20 healthy subjects (HC) were analyzed to identify differentially expressed (DE) lncRNAs associated with quiescent disease and flares. Weighted gene co-expression network analysis (WGCNA) was performed to uncover lncRNAs with a central role (hub lncRNAs) in regulating key biological processes that drive LN disease activity. The association of hub lncRNAs with disease activity was validated using RT-qPCR on an independent cohort of 15 LN patients and 9 HC. cis- and trans-targets of validated lncRNAs were explored in silico to examine potential mechanisms of their action.

Results

There were 444 DE lncRNAs associated with quiescent disease and 6 DE lncRNAs associated with flares (FDR <0.05). WGCNA highlighted IFN signaling and B-cell activity/adaptive immunity as the most significant processes contributing to nephritis activity. Four disease-activity-associated lncRNAs, namely, NRIR, KLHDC7B-DT, MIR600HG, and FAM30A, were detected as hub genes and validated in an independent cohort. NRIR and KLHDC7B-DT emerged as potential key regulators of IFN-mediated processes. Network analysis suggests that FAM30A and MIR600HG are likely to play a central role in the regulation of B-cells in LN through cis-regulation effects and a competing endogenous RNA mechanism affecting immunoglobulin gene expression and the IFN-λ pathway.

Conclusions

The expression of lncRNAs NRIR, KLHDC7B-DT, FAM30A, and MIR600HG were associated with disease activity and could be further explored as blood-based biomarkers and potential liquid biopsy on LN.
Molecular characteristics and phylogenetic analysis of Clostridium perfringens from different regions in China, from 2013 to 2021
Authors: Zhong Jia xin , Zheng Hao ran , Wang Yuan yuan , Bai Lu lu , Du Xiao li , Wu Yuan , Lu Jin xing
Published: July 2023

Clostridium perfringens (C. perfringens) is a significant foodborne pathogen and a common cause of intestinal diseases in both animals and humans. Our study investigated MLST, phenotypic antimicrobial resistance profiles, and resistance genes among isolates from human, animal and food. 186 C. perfringens isolates were obtained from nine provinces in China between 2013 and 2021. Additionally, some specific ST complexes were analyzed by cgMLST and cgSNP to investigate genetic relatedness. MLST indicated the most prevalent STs of C. perfringens of human and animal origin were as follows: ST221 (5/147), ST62 (4/147), ST408 (4/147), and ST493 (4/147) were predominant in humans, while ST479 (5/25) was the major type in animals. Within the same ST complex, genetically unrelated relationships or potential clustering/transmission events were further recognized by cgMLST and cgSNP, illustrating that these two methods are valuable in defining outbreaks and transmission events. All tested isolates were susceptible to vancomycin and meropenem. The rates of resistance to metronidazole, penicillin, cefoxitin, moxifloxacin, and chloramphenicol were low (metronidazole: 1.08%; penicillin: 9.68%; cefoxitin: 0.54%; moxifloxacin: 6.45%; and chloramphenicol: 3.76%). Interestingly, 49.66% of human origin were clindamycin-resistant, and 18.2% were penicillin-insensitive. Importantly, the portion of MDR isolates was significantly lower than in previous reports. The study provides an overview of the epidemiological characteristics of C. perfringens with different origins and hosts in China. C. perfringens demonstrated remarkable genetic diversity and distinct molecular features compared to antibiotic-resistance profiles from other studies.
Age-related effects on the modulation of gut microbiota by pectins and their derivatives: an in vitro study
Authors: Gu Fangjie , Larsen Nadja , Pascale Nélida , Petersen Sune Allan , Khakimov Bekzod , Respondek Frederique , Jespersen Lene
Published: July 2023

Introduction

The present study investigates whether supplementation with pectin-type polysaccharides has potential to improve aging-associated dysbiosis of the gut microbiota. The influence of different types of pectins on the gut microbiota composition and short-chain fatty acids (SCFAs) profiles of elderly was compared to younger adults.

Methods

Pectins studied included a pectin polysaccharide (PEC), a partially hydrolyzed pectin (PPH), and a pectin oligosaccharide (POS). Additionally, inulin was used as a reference prebiotic substrate. Individual fecal samples were collected from healthy elderly volunteers (70–75 years) and younger adults (30–35 years). In vitro fermentations were performed using the CoMiniGut model with controlled temperature and pH. Samples were withdrawn at baseline and after 24 h fermentation for measurement of SCFAs production and microbiota composition by 16S rRNA gene sequencing.

Results and Discussion

The results showed that fermentations with PEC and PPH resulted in a specific stimulation of Faecalibacterium prausnitzii regardless of the age groups. Collinsella aerofaciens became a dominating species in the young adult group with fermentations of all three pectins, which was not observed in the elderly group. No significant differences in SCFAs production were found among the pectins, indicating a high level of functional redundancy. Pectins boosted various bacterial groups differently from the reference prebiotic substrate (inulin). We also found inulin had reduced butyrogenic and bifidogenic effects in the elderly group compared to the younger adult group. In conclusion, the in vitro modulating effects of pectins on elderly gut microbiota showed potential of using pectins to improve age-related dysbiosis.
Integrated use of polyphosphate and P-solubilizing bacteria enhanced P use efficiency and growth performance of durum wheat
Authors: Khourchi Said , Elhaissoufi Wissal , Ibnyasser Ammar , Haddine Meryem , Ghani Rachid , Zeroual Youssef , Delaplace Pierre , Bargaz Adnane
Published: July 2023

Coupling phosphate-solubilizing bacteria (PSB) with P fertilizers, including polyphosphates (PolyP), was reported as eco-efficient approach to enhance P use efficiency. Although PSB have been recently reported to hydrolyze PolyP, the plant growth promoting mechanisms of PolyP-PSB co-application were not yet uncovered. This study aims to evaluate the effect of a PSB consortium (PSBCs) on growth, P use efficiency (PUE), and wheat yield parameters under PolyP (PolyB) application. Co-application of PolyB-PSBCs significantly enhanced wheat growth at 75 days after sowing (DAS) compared to 30 DAS. A significant increase in shoot dry biomass (47%), shoot inorganic P content (222%), PUE (91%), and root P absorption efficiency (RPAE, 99%) was noted compared to unfertilized plants. Similarly, the PolyB-PSBCs co-application enhanced morphological root traits at 30 DAS, while acid phosphatase activities (root and rhizosphere), RPAE, and PUE were significantly increased at 75 DAS. The improved wheat P acquisition could be attributed to a lower investment in root biomass production, and significant induction of acid phosphatase activity in roots and rhizosphere soil under PolyB-PSBCs co-application. Consequently, the PolyB-PSBCs co-application significantly improved aboveground performance, which is reflected by increased shoot nutrient contents (P 300%, K 65%), dry weight (54%), and number (50%) of spikes. Altogether, this study provides relevant evidence that co-application of PolyP-PSBCs can be an integrated and environmentally preferred P fertilization approach owing to the dual effects of PolyP and PSBCs on wheat PUE.
Biochar immobilized plant growth-promoting rhizobacteria enhanced the physicochemical properties, agronomic characters and microbial communities during lettuce seedling
Authors: Guan Ti-Kun , Wang Qiu-Ying , Li Jia-Shu , Yan Hui-Wen , Chen Qing-Jun , Sun Jian , Liu Chao-Jie , Han Ying-Yan , Zou Ya-Jie , Zhang Guo-Qing
Published: July 2023

Spent mushroom substrate (SMS) is the by-products of mushroom production, which is mainly composed of disintegrated lignocellulosic biomass, mushroom mycelia and some minerals. The huge output and the lack of effective utilization methods make SMS becoming a serious environmental problem. In order to improve the application of SMS and SMS derived biochar (SBC), composted SMS (CSMS), SBC, combined plant growth-promoting rhizobacteria (PGPR, Bacillus subtilis BUABN-01 and Arthrobacter pascens BUAYN-122) and SBC immobilized PGPR (BCP) were applied in the lettuce seedling. Seven substrate treatments were used, including (1) CK, commercial control; (2) T1, CSMS based blank control; (3) T2, T1 with combined PGPR (9:1, v/v); (4) T3, T1 with SBC (19:1, v/v); (5) T4, T1 with SBC (9:1, v/v); (6) T5, T1 with BCP (19:1, v/v); (7) T6, T1 with BCP (9:1, v/v). The physicochemical properties of substrate, agronomic and physicochemical properties of lettuce and rhizospheric bacterial and fungal communities were investigated. The addition of SBC and BCP significantly (p < 0.05) improved the total nitrogen and available potassium content. The 5% (v/v) BCP addiction treatment (T5) represented the highest fresh weight of aboveground and underground, leave number, chlorophyll content and leaf anthocyanin content, and the lowest root malondialdehyde content. Moreover, high throughput sequencing revealed that the biochar immobilization enhanced the adaptability of PGPR. The addition of PGPR, SBC and BCP significantly enriched the unique bacterial biomarkers. The co-occurrence network analysis revealed that 5% BCP greatly increased the network complexity of rhizospheric microorganisms and improved the correlations of the two PGPR with other microorganisms. Furthermore, microbial functional prediction indicated that BCP enhanced the nutrient transport of rhizospheric microorganisms. This study showed the BCP can increase the agronomic properties of lettuce and improve the rhizospheric microbial community.
Effects of early postnatal hyperoxia exposure combined with early ovalbumin sensitization on lung inflammation and bacterial flora in a juvenile mouse model of asthma
Authors: Li Jingyan , Bao Tianping , Cao Linxia , Ma Mengmeng , Zhang Yuan , Tian Zhaofang
Published: July 2023

Objective

The aim of this study is to explore the effects of early postnatal hyperoxia exposure combined with early ovalbumin (OVA) sensitization on lung inflammation and bacterial flora in neonatal mice on a juvenile mouse model of asthma.

Methods

Thirty-two newborn female C57BL/6 J mice were randomly divided into four groups, which including room air+phosphate-buffered saline (PBS) group, hyperoxia+PBS group, room air+OVA group, and hyperoxia+OVA group, according to the hyperoxia exposure and/or OVA induction. Mice were exposed to either 95% O2 or room air for 7 days after birth; after 7 days, they were exposed to air and received an intraperitoneal injection of OVA suspension or PBS solution on postnatal days 21 (P21) and 28 (P28). From P36 to P42, the mice were allowed to inhale of 1% OVA or 0.9% NaCl solution. The mice were observed after the last excitation. HE staining was performed to observe the pathological changes in lung tissues. Wright-Giemsa staining was used to perform bronchoalveolar lavage fluid (BALF) leukocyte sorting. Enzyme-linked immunosorbent assay was used to determined the cytokines levels of interleukin (IL)-2, IL-5, IL-13, IL-17A, and IL-10 and serum IgE levels in BALF. Additionally, 16S rRNA sequencing was used to analyze the characteristics of lung microbiota.

Results

Mice in the hyperoxia+OVA group showed asthma-like symptoms. HE staining results revealed a significant thickening of the airway wall and airway inflammation. BALF analysis of cellular components showed significant increases in total leukocyte and eosinophil counts and the levels of cytokines related to Th2 (IL-5 and IL-13) and Th17 (IL-17A); 16S rRNA sequencing revealed that the main members of the pulmonary microflora were Actinobacteriota, Proteobacteria, Firmicutes, and Bacteroidota at the phylum level. In addition, the bacteria with a major role were Acinetobacter and Moraxellaceae in the O2 + OVA group.

Conclusion

The mouse suffering from postnatal hyperoxia exposure and early OVA sensitization, changes in symptoms, pathology, leukocyte and eosinophil counts, and levels of different T-cell cytokines in BALF and lung microbiota, which may provide a basis for the establishment of a juvenile mouse model of asthma.
Pain in Huntington’s disease and its potential mechanisms
Authors: Li Jiajie , Wang Yan , Yang Riyun , Ma Wenjun , Yan JunGuo , Li Yi , Chen Gang , Pan Jingying
Published: July 2023

Pain is common and frequent in many neurodegenerative diseases, although it has not received much attention. In Huntington’s disease (HD), pain is often ignored and under-researched because attention is more focused on motor and cognitive decline than psychiatric symptoms. In HD progression, pain symptoms are complex and involved in multiple etiologies, particularly mental issues such as apathy, anxiety and irritability. Because of psychiatric issues, HD patients rarely complain of pain, although their bodies show severe pain symptoms, ultimately resulting in insufficient awareness and lack of research. In HD, few studies have focused on pain and pain-related features. A detailed and systemic pain history is crucial to assess and explore pain pathophysiology in HD. This review provides an overview concentrating on pain-related factors in HD, including neuropathology, frequency, features, affecting factors and mechanisms. More attention and studies are still needed in this interesting field in the future.
Ionizing radiation alters functional neurotransmission in Drosophila larvae
Authors: Zhang Yi , Zhang Yihao , Shen Cong , Hao Shun , Duan Wenlan , Liu Li , Wei Hongying
Published: July 2023

Introduction

Patients undergoing cranial ionizing radiation therapy for brain malignancies are at increased risk of long-term neurocognitive decline, which is poorly understood and currently untreatable. Although the molecular pathogenesis has been intensively researched in many organisms, whether and how ionizing radiation alters functional neurotransmission remains unknown. This is the first study addressing physiological changes in neurotransmission after ionizing radiation exposure.

Methods

To elucidate the cellular mechanisms of radiation damage, using calcium imaging, we analyzed the effects of ionizing radiation on the neurotransmitter-evoked responses of prothoracicotropic hormone (PTTH)-releasing neurons in Drosophila larvae, which play essential roles in normal larval development.

Results

The neurotransmitters dopamine and tyramine decreased intracellular calcium levels of PTTH neurons in a dose-dependent manner. In gamma irradiated third-instar larvae, a dose of 25 Gy increased the sensitivity of PTTH neurons to dopamine and tyramine, and delayed development, possibly in response to abnormal functional neurotransmission. This irradiation level did not affect the viability and arborization of PTTH neurons and successful survival to adulthood. Exposure to a 40-Gy dose of gamma irradiation decreased the neurotransmitter sensitivity, physiological viability and axo-dendritic length of PTTH neurons. These serious damages led to substantial developmental delays and a precipitous reduction in the percentage of larvae that survived to adulthood. Our results demonstrate that gamma irradiation alters neurotransmitter-evoked responses, indicating synapses are vulnerable targets of ionizing radiation.

Discussion

The current study provides new insights into ionizing radiation-induced disruption of physiological neurotransmitter signaling, which should be considered in preventive therapeutic interventions to reduce risks of neurological deficits after photon therapy.
Connectomic insight into unique stroke patient recovery after rTMS treatment
Authors: Chen Rong , Dadario Nicholas B. , Cook Brennan , Sun Lichun , Wang Xiaolong , Li Yujie , Hu Xiaorong , Zhang Xia , Sughrue Michael E.
Published: July 2023

An improved understanding of the neuroplastic potential of the brain has allowed advancements in neuromodulatory treatments for acute stroke patients. However, there remains a poor understanding of individual differences in treatment-induced recovery. Individualized information on connectivity disturbances may help predict differences in treatment response and recovery phenotypes. We studied the medical data of 22 ischemic stroke patients who received MRI scans and started repetitive transcranial magnetic stimulation (rTMS) treatment on the same day. The functional and motor outcomes were assessed at admission day, 1 day after treatment, 30 days after treatment, and 90 days after treatment using four validated standardized stroke outcome scales. Each patient underwent detailed baseline connectivity analyses to identify structural and functional connectivity disturbances. An unsupervised machine learning (ML) agglomerative hierarchical clustering method was utilized to group patients according to outcomes at four-time points to identify individual phenotypes in recovery trajectory. Differences in connectivity features were examined between individual clusters. Patients were a median age of 64, 50% female, and had a median hospital length of stay of 9.5 days. A significant improvement between all time points was demonstrated post treatment in three of four validated stroke scales utilized. ML-based analyses identified distinct clusters representing unique patient trajectories for each scale. Quantitative differences were found to exist in structural and functional connectivity analyses of the motor network and subcortical structures between individual clusters which could explain these unique trajectories on the Barthel Index (BI) scale but not on other stroke scales. This study demonstrates for the first time the feasibility of using individualized connectivity analyses in differentiating unique phenotypes in rTMS treatment responses and recovery. This personalized connectomic approach may be utilized in the future to better understand patient recovery trajectories with neuromodulatory treatment.
Sex differences concerning the effects of ankle muscle fatigue on static postural control and spinal proprioceptive input at the ankle
Authors: Jo Donguk , Bilodeau Martin
Published: July 2023

Aims

The main aim of this study was to determine sex differences in postural control changes with ankle muscle fatigue during a standing forward leaning (FL) task under different vision conditions. The secondary aim was to examine sex differences in the effect of fatigue on soleus (SOL) H-reflex amplitude, a measure of motoneuron excitability with activation of Ia afferents.

Methods

Fifteen healthy young adult males (mean age: 28.0 years) and 16 healthy young adult females (mean age: 26.1 years) were asked to perform four consecutive FL tasks [30 s; two with eyes open (EO) and two with eyes closed (EC)] before, and immediately following a fatiguing exercise consisting of alternating ankle plantarflexion (6 s) and dorsiflexion (2 s) maximal isometric contractions, and at 5 and 10 min of recovery. Center of pressure (COP) sway variables (mean position, standard deviation, ellipse area, average velocity, and frequency), an ankle co-contraction index, and a ratio of SOL H-reflex to the maximum amplitude of the compound muscle action potential (M-max) were obtained during the FL tasks. A rating of perceived fatigue (RPF) was also documented at the different time points.

Results

Time to task failure (reduction of 50% in maximal voluntary isometric contraction torque of ankle plantar flexors) and the increase in RPF value were not significantly different between males and females. Both sex groups showed similar and significant increases (p < 0.05) in mean COP sway velocity with no significant changes in co-contraction indices. No significant effects of fatigue and related interactions were found for SOL H/M-max ratio.

Discussion

The absence of a significant sex difference in postural control change (sway and co-contraction) with fatigue could be explained by similar perceived (RPF) and performance fatigability (exercise duration) between males and females in the present study. Fatigue did not lead to significant changes in SOL spinal motoneuron excitability with activation of Ia afferents.
Expert and deep learning model identification of iEEG seizures and seizure onset times
Authors: Arcot Desai Sharanya , Afzal Muhammad Furqan , Barry Wade , Kuo Jonathan , Benard Shawna , Traner Christopher , Tcheng Thomas , Seale Cairn , Morrell Martha
Published: July 2023

Hundreds of 90-s iEEG records are typically captured from each NeuroPace RNS System patient between clinic visits. While these records provide invaluable information about the patient’s electrographic seizure and interictal activity patterns, manually classifying them into electrographic seizure/non-seizure activity, and manually identifying the seizure onset channels and times is an extremely time-consuming process. A convolutional neural network based Electrographic Seizure Classifier (ESC) model was developed in an earlier study. In this study, the classification model is tested against iEEG annotations provided by three expert reviewers board certified in epilepsy. The three experts individually annotated 3,874 iEEG channels from 36, 29, and 35 patients with leads in the mesiotemporal (MTL), neocortical (NEO), and MTL + NEO regions, respectively. The ESC model’s seizure/non-seizure classification scores agreed with the three reviewers at 88.7%, 89.6%, and 84.3% which was similar to how reviewers agreed with each other (92.9%–86.4%). On iEEG channels with all 3 experts in agreement (83.2%), the ESC model had an agreement score of 93.2%. Additionally, the ESC model’s certainty scores reflected combined reviewer certainty scores. When 0, 1, 2 and 3 (out of 3) reviewers annotated iEEG channels as electrographic seizures, the ESC model’s seizure certainty scores were in the range: [0.12–0.19], [0.32–0.42], [0.61–0.70], and [0.92–0.95] respectively. The ESC model was used as a starting-point model for training a second Seizure Onset Detection (SOD) model. For this task, seizure onset times were manually annotated on a relatively small number of iEEG channels (4,859 from 50 patients). Experiments showed that fine-tuning the ESC models with augmented data (30,768 iEEG channels) resulted in a better validation performance (on 20% of the manually annotated data) compared to training with only the original data (3.1s vs 4.4s median absolute error). Similarly, using the ESC model weights as the starting point for fine-tuning instead of other model weight initialization methods provided significant advantage in SOD model validation performance (3.1s vs 4.7s and 3.5s median absolute error). Finally, on iEEG channels where three expert annotations of seizure onset times were within 1.5 s, the SOD model’s seizure onset time prediction was within 1.7 s of expert annotation.
Relationship between Mediterranean diet and depression in South Korea: the Korea National Health and Nutrition Examination Survey
Authors: Hwang Yeong-Geon , Pae Chongwon , Lee Sang-Hyuk , Yook Ki-Hwan , Park Chun Il
Published: July 2023

Background

Several studies have shown that adherence to the Mediterranean diet is associated with a lower risk of depression; however, little is known about the Asian population. This study investigated the relationship between adherence to the Mediterranean diet and depression in a sample of the South Korean population.

Methods

In total, 5,849 adults from the 2014 and 2016 Korea National Health and Nutrition Examination Surveys were included in the study. The Mediterranean diet adherence was measured using a modified alternate Mediterranean diet score (mMED) developed to adjust for Korean dietary patterns. The mMED scores using the Food Frequency Questionnaire were divided into four categories (0–2, 3–4, 5–6, and 7–9 points). Subjects with depression were defined as having moderate-to-severe depressive symptoms using the Patient Health Questionnaire-9, with a cutoff value of 10. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). A subgroup analysis was performed based on sex.

Results

The results of logistic regression analysis indicated that individuals with higher mMED were 42–73% less likely to report depression compared to individuals with the lowest mMED [ORs (95% CIs) =0.58 (0.37–0.90), 0.50 (0.31–0.80), 0.27 (0.15–0.47)] after adjusting for socio-demographic and health-related variables. In women, individuals with mMED of 7–9 had 71% lower odds of depression [ORs (95% CIs): 0.29 (0.13–0.64)]. In men, individuals with mMED of 5–9 had 55% [ORs (95% CIs): 0.45 (0.23–0.91)] to 79% [ORs (95% CIs): 0.21 (0.08–0.57)] lower odds of depression.

Conclusion

This study suggests that adherence to the Mediterranean diet is inversely associated with depression in both men and women among Korean adults. This study provides evidence that a Mediterranean diet is crucial in preventing depressive symptoms in Asian populations.
Ceruminous adenoma of the external auditory canal: 9 cases series with imaging and pathologic findings
Authors: Yang Yifan , Liu Honggang , Fang Jugao , Li Yongxin , Chen Shubin
Published: July 2023

Objectives

Ceruminous adenoma is a rare benign tumor of the external auditory canal. This study aimed to present the clinical characteristics, imaging findings, pathological results and the management outcomes of the ceruminous adenoma.

Study design

Retrospective case series review.

Setting

Tertiary referral center.

Patients and methods

Patients undergoing surgery for ceruminous adenoma of the external auditory canal between the years 2004 to 2018. All patients with ceruminous adenoma were analyzed for demographic, clinical, radiological features and pathologic findings. The outcomes of the management were also evaluated.

Results

Nine patients with ceruminous adenoma were included in the study. Hearing loss was the most common complaint (5/9, 56%), followed by otalgia (4/9, 44%), pruritus (4/9, 44%), and otorrhea (2/9, 22%). The tumors originated mostly from the cartilaginous portion of the external auditory canal (8/9, 89%) and merely from the bony portion of the external auditory canal (1/9, 11%). Pathohistological study indicated that the ceruminous adenomas were divided into three types: the ceruminous gland adenoma (6/9, 67%), the ceruminous pleomorphic adenoma (2/9, 22%) and the ceruminous syringocystadenoma papilliferum (1/9, 11%). No recurrence was found during follow-up for two to fifteen years after surgical resection.

Conclusion

Ceruminous adenomas are rare entities. They originate mainly from the cartilaginous portion of the EAC, but occasionally from the bony portion of the EAC. The surgical section with enough margin is adequate for management of these tumors.
Impact of AKT1 on cell invasion and radiosensitivity in a triple negative breast cancer cell line developing brain metastasis
Authors: Kempska Joanna , Oliveira-Ferrer Leticia , Grottke Astrid , Qi Minyue , Alawi Malik , Meyer Felix , Borgmann Kerstin , Hamester Fabienne , Eylmann Kathrin , Rossberg Maila , Smit Daniel J. , Jücker Manfred , Laakmann Elena , Witzel Isabell , Schmalfeldt Barbara , Müller Volkmar , Legler Karen
Published: July 2023

Introduction

The PI3K/AKT pathway is activated in 43-70% of breast cancer (BC)-patients and promotes the metastatic potential of BC cells by increasing cell proliferation, invasion and radioresistance. Therefore, AKT1-inhibition in combination with radiotherapy might be an effective treatment option for triple-negative breast cancer (TNBC)-patients with brain metastases.

Methods

The impact of AKT1-knockout (AKT1_KO) and AKT-inhibition using Ipatasertib on MDA-MB-231 BR cells was assessed using in vitro cell proliferation and migration assays. AKT1-knockout in MDA-MB-231BR cells was performed using CRISPR/Cas9. The effect of AKT1-knockout on radiosensitivity of MDA-MB-231BR cell lines was determined via colony formation assays after cell irradiation. To detect genomic variants in AKT1_KO MDA-MB-231BR cells, whole-genome sequencing (WGS) was performed.

Results

Pharmacological inhibition of AKT with the pan-AKT inhibitor Ipatasertib led to a significant reduction of cell viability but did not impact cell migration. Moreover, only MDA-MB-231BR cells were sensitized following Ipatasertib-treatment. Furthermore, specific AKT1-knockout in MDA-MB-231BR showed reduced cell viability in comparison to control cells, with significant effect in one of two analyzed clones. Unexpectedly, AKT1 knockout led to increased cell migration and clonogenic potential in both AKT1_KO clones. RNAseq-analysis revealed the deregulation of CTSO, CYBB, GPR68, CEBPA, ID1, ID4, METTL15, PBX1 and PTGFRN leading to the increased cell migration, higher clonogenic survival and decreased radiosensitivity as a consequence of the AKT1 knockout in MDA-MB-231BR.

Discussion

Collectively, our results demonstrate that Ipatasertib leads to radiosensitization and reduced cell proliferation of MDA-MB-231BR. AKT1-inhibition showed altered gene expression profile leading to modified cell migration, clonogenic survival and radioresistance in MDA-MB-231BR. We conclude, that AKT1-inhibition in combination with radiotherapy contribute to novel treatment strategies for breast cancer brain metastases.
Targeting integrin α5β1 in urological tumors: opportunities and challenges
Authors: Zhou Xuming , Zhu Hezhen , Luo Cong , Xiao Huan , Zou Xiaofeng , Zou Junrong , Zhang Guoxi
Published: July 2023

Urological tumors, such as prostate cancer, renal cell carcinoma, and bladder cancer, have shown a significant rise in prevalence in recent years and account for a significant proportion of malignant tumors. It has been established that metastasis to distant organs caused by urological tumors is the main cause of death, although the mechanisms underlying metastasis have not been fully elucidated. The fibronectin receptor integrin α5β1 reportedly plays an important role in distant metastasis and is closely related to tumor development. It is widely thought to be an important cancer mediator by interacting with different ligands, mediating tumor adhesion, invasion, and migration, and leading to immune escape. In this paper, we expound on the relationship and regulatory mechanisms of integrin α5β1 in these three cancers. In addition, the clinical applications of integrin α5β1 in these cancers, especially against treatment resistance, are discussed. Last but not least, the possibility of integrin α5β1 as a potential target for treatment is examined, with new ideas for future research being proposed.
Gain of chromosome 21 increases the propensity for P2RY8::CRLF2 acute lymphoblastic leukemia via increased HMGN1 expression
Authors: Page Elyse C. , Heatley Susan L. , Rehn Jacqueline , Thomas Paul Q. , Yeung David T. , White Deborah L.
Published: July 2023

Acute lymphoblastic leukemia (ALL) patients with a gain of chromosome 21, intrachromosomal amplification of chromosome 21 (iAMP21), or Down syndrome (DS), have increased expression of genes in the DS critical region (DSCR) of chromosome 21, including the high-mobility group nucleosome-binding protein 1, HMGN1. Children with DS are predisposed to develop hematologic malignancies, providing insight into the role of chromosome 21 in the development of leukemias. A 320-kb deletion in the pseudoautosomal region of the X/Y chromosome in leukemic cells, resulting in a gene fusion between the purinergic receptor and cytokine receptor-like factor-2 (P2Y Receptor Family Member 8 (P2RY8)::CRLF2), is a common feature in ~60% of DS-ALL and ~40% of iAMP21 patients, suggesting a link between chromosome 21 and P2RY8::CRLF2. In an Australian cohort of pediatric B-ALL patients with P2RY8::CRLF2 (n = 38), eight patients harbored gain of chromosome 21 (+21), and two patients had iAMP21, resulting in a significantly increased HMGN1 expression. An inducible CRISPR/Cas9 system was used to model P2RY8::CRLF2 and investigate its cooperation with HMGN1. This model was then used to validate HMGN1 as an influencing factor for P2RY8::CRLF2 development. Using Cas9 to cleave the DNA at the pseudoautosomal region without directed repair, cells expressing HMGN1 favored repair, resulting in P2RY8::CRLF2 generation, compared with cells without HMGN1. CRISPR/Cas9 P2RY8::CRLF2 cells expressing HMGN1 exhibit increased proliferation, thymic stromal lymphopoietin receptor (TSLPR) expression, and JAK/STAT signaling, consistent with cells from patients with P2RY8::CRLF2. Our patient expression data and unique CRISPR/Cas9 modeling, when taken together, suggest that HMGN1 increases the propensity for P2RY8::CRLF2 development. This has important implications for patients with DS, +21, or iAMP21.
Cadaveric analysis of transcranial versus endoscopic transorbital petrosectomy: comparison of surgical maneuverability and brainstem exposure
Authors: Kwon Sae Min , Na Min Kyun , Choi Kyu-Sun , Byoun Hyoung Soo , Nam Yong Seok
Published: July 2023

Introduction

While accessing the posterior fossa, the anterior transpetrosal approach (ATPA) and endoscopic transorbital approach (ETOA) use the same bony landmarks during petrous apex drilling. However, owing to their contrasting surgical axes, they are expected to show differences in surgical view, maneuverability, and clinical implications. This study aimed to investigate the feasibility of ETOA in accessing the brainstem and to compare the surgical view and maneuverability of each approach.

Methods

ATPA and ETOA were performed in four human cadaveric heads (eight sides and four sides in each procedure). The angle of attack (AOA) and surgical depth were measured at the target of interest (root exit zone [REZ] of cranial nerve [CN] V, VI, and VII). When measuring the area of exposure, the brainstem was divided into two areas (anterior and lateral brainstem) based on the longitudinal line crossing the entry zone of the trigeminal root, and the area of each was measured.

Results

ATPA showed significantly greater value at the trigeminal REZ in both vertical (31.8 ± 6.7° vs. 14.3 ± 5.3°, p=0.006) and horizontal AOA (48.5 ± 2.9° vs. 15.0 ± 5.2°, p<0.001) than ETOA. The AOA at facial REZ was also greater in ATPA than ETOA (vertical, 27.5 ± 3.9° vs. 8.3 ± 3.3°, p<0.001; horizontal, 33.8 ± 2.2° vs. 11.8 ± 2.9°, p<0.001). ATPA presented significantly shorter surgical depth (CN V, 5.8 ± 0.5 cm vs. 9.0 ± 0.8, p<0.001; CN VII, 6.3 ± 0.5 cm vs. 9.5 ± 1.0, p=0.001) than ETOA. The mean area of brainstem exposure did not differ between the two approaches. However, ATPA showed significantly better exposure of anterior brainstem than ETOA (240.7 ± 9.6 mm2 vs. 171.7 ± 15.0 mm2, p<0.001), while ETOA demonstrated better lateral brainstem exposure (174.2 ± 29.1 mm2 vs. 231.1 ± 13.6 mm2, p=0.022).

Conclusions

ETOA could be a valid surgical option, in selected cases, that provides a direct ventral route to the brainstem. Compared with ATPA, ETOA showed less surgical maneuverability, AOA and longer surgical depth; however, it presented comparable brainstem exposure and better exposure of the lateral brainstem.
Global trends in BRCA-related breast cancer research from 2013 to 2022: A scientometric analysis
Authors: Huang Yujie , Zheng Daitian , Yang Qiuping , Wu Jinyao , Tian Huiting , Ji Zeqi , Chen Lingzhi , Cai Jiehui , Li Zhiyang , Chen Yexi
Published: July 2023

Introduction

Since the mid-2000s, breast cancer incidence among women has slowly increased at about 0.5% per year. In the last three decades, Breast Cancer Susceptibility Gene (BRCA) has been proven to be the crucial gene in encouraging the incidence and development of breast cancer. However, scientometric analysis on BRCA-related breast cancer is in shortage. Thus, to have a clear understanding of the current status and catch up with the hotspots, a scientometric analysis was conducted on specific academic publications collected from the Web of Science (WoS).

Methods

We searched the Web of Science Core Collection (WoSCC) to procure associated articles as our dataset. Bibliometric, CiteSpace, VOSviewer, and HistCite software were then applied to conduct visual analyses of countries, institutions, journals, authors, landmark articles, and keywords in this research field.

Results

A total of 7,266 articles and 1,310 review articles published between 2013 to 2022 were retrieved eventually. The annual output steadily rose year by year and peaked in 2021. The USA led the way in the number of published works, total citations, and collaboration. Breast Cancer Research and Treatment was the most favoured journal in this research field. Narod SA from the University of Toronto produced the most publications. At last, the most prominent keywords were “breast cancer” (n=1,778), “women” (n=1,369), “brca1” (n=1,276), “ovarian cancer” (n=1,259), “risk” (n=1,181), and “mutations” (n=929), which exposed the hotspots within the BRCA domain of breast cancer study.

Conclusion

The tendency in the BRCA research field over the past decade was presented by the scientometric analysis. The current research focus is the clinical trials of poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) drugs and their resistance mechanisms.
DAART: a deep learning platform for deeply accelerated adaptive radiation therapy for lung cancer
Authors: Hooshangnejad Hamed , Chen Quan , Feng Xue , Zhang Rui , Farjam Reza , Voong Khinh Ranh , Hales Russell K. , Du Yong , Jia Xun , Ding Kai
Published: July 2023

Purpose

The study aimed to implement a novel, deeply accelerated adaptive radiation therapy (DAART) approach for lung cancer radiotherapy (RT). Lung cancer is the most common cause of cancer-related death, and RT is the preferred medically inoperable treatment for early stage non-small cell lung cancer (NSCLC). In the current lengthy workflow, it takes a median of four weeks from diagnosis to RT treatment, which can result in complete restaging and loss of local control with delay. We implemented the DAART approach, featuring a novel deepPERFECT system, to address unwanted delays between diagnosis and treatment initiation.

Materials and methods

We developed a deepPERFECT to adapt the initial diagnostic imaging to the treatment setup to allow initial RT planning and verification. We used data from 15 patients with NSCLC treated with RT to train the model and test its performance. We conducted a virtual clinical trial to evaluate the treatment quality of the proposed DAART for lung cancer radiotherapy.

Results

We found that deepPERFECT predicts planning CT with a mean high-intensity fidelity of 83 and 14 HU for the body and lungs, respectively. The shape of the body and lungs on the synthesized CT was highly conformal, with a dice similarity coefficient (DSC) of 0.91, 0.97, and Hausdorff distance (HD) of 7.9 mm, and 4.9 mm, respectively, compared with the planning CT scan. The tumor showed less conformality, which warrants acquisition of treatment Day1 CT and online adaptive RT. An initial plan was designed on synthesized CT and then adapted to treatment Day1 CT using the adapt to position (ATP) and adapt to shape (ATS) method. Non-inferior plan quality was achieved by the ATP scenario, while all ATS-adapted plans showed good plan quality.

Conclusion

DAART reduces the common online ART (ART) treatment course by at least two weeks, resulting in a 50% shorter time to treatment to lower the chance of restaging and loss of local control.
Molecular profiling of solid tumors by next-generation sequencing: an experience from a clinical laboratory
Authors: Bhai Pratibha , Turowec Jacob , Santos Stephanie , Kerkhof Jennifer , Pickard LeeAnne , Foroutan Aidin , Breadner Daniel , Cecchini Matthew , Levy Michael A. , Stuart Alan , Welch Stephen , Howlett Christopher , Lin Hanxin , Sadikovic Bekim
Published: July 2023

Background

Personalized targeted therapies have transformed management of several solid tumors. Timely and accurate detection of clinically relevant genetic variants in tumor is central to the implementation of molecular targeted therapies. To facilitate precise molecular testing in solid tumors, targeted next-generation sequencing (NGS) assays have emerged as a valuable tool. In this study, we provide an overview of the technical validation, diagnostic yields, and spectrum of variants observed in 3,164 solid tumor samples that were tested as part of the standard clinical diagnostic assessment in an academic healthcare institution over a period of 2 years.

Methods

The Ion Ampliseq™ Cancer Hotspot Panel v2 assay (ThermoFisher) that targets ~2,800 COSMIC mutations from 50 oncogenes and tumor suppressor genes was validated, and a total of 3,164 tumor DNA samples were tested in 2 years. A total of 500 tumor samples were tested by the comprehensive panel containing all the 50 genes. Other samples, including 1,375 lung cancer, 692 colon cancer, 462 melanoma, and 135 brain cancer, were tested by tumor-specific targeted subpanels including a few clinically actionable genes.

Results

Of 3,164 patient samples, 2,016 (63.7%) tested positive for at least one clinically relevant variant. Of 500 samples tested by a comprehensive panel, 290 had a clinically relevant variant with TP53, KRAS, and PIK3CA being the most frequently mutated genes. The diagnostic yields in major tumor types were as follows: breast (58.4%), colorectal (77.6%), lung (60.4%), pancreatic (84.6%), endometrial (72.4%), ovary (57.1%), and thyroid (73.9%). Tumor-specific targeted subpanels also demonstrated high diagnostic yields: lung (69%), colon (61.2%), melanoma (69.7%), and brain (20.7%). Co-occurrence of mutations in more than one gene was frequently observed.

Conclusions

The findings of our study demonstrate the feasibility of integrating an NGS-based gene panel screen as part of a standard diagnostic protocol for solid tumor assessment. High diagnostic rates enable significant clinical impact including improved diagnosis, prognosis, and clinical management in patients with solid tumors.
Yes-associated protein-1 overexpression in ocular surface squamous neoplasia; a potential diagnostic marker and therapeutic target
Authors: Julius Peter , Siyumbwa Stepfanie N. , Maate Fred , Moonga Phyllis , Kang Guobin , Kaile Trevor , West John T. , Wood Charles , Angeletti Peter C.
Published: July 2023

Yes-associated protein-1 (YAP-1) is a Hippo system transcription factor, which serves as an oncogene in squamous cell carcinoma, and several solid tumors when the Hippo pathway is dysregulated. Yet, the activity of YAP-1 in ocular surface squamous neoplasia (OSSN) has not been determined. Here, we investigate the relationship between YAP-1 overexpression and OSSN. Using a cross-sectional study design, we recruited 227 OSSN patients from the University Teaching Hospitals in Lusaka, Zambia. Immunohistochemistry was used to assess YAP-1 protein overexpression in tumor tissue relative to surrounding benign squamous epithelium. OSSN patient samples (preinvasive, n = 62, 27% and invasive, n = 165, 73%) were studied. One hundred forty-nine invasive tumors contained adjacent preinvasive tissue, bringing the total number of preinvasive lesions examined to 211 (62 + 149). There was adjacent benign squamous epithelium in 50.2% (114/227) of OSSN samples. Nuclear YAP- 1 was significantly overexpressed in preinvasive (Fisher’s (F): p <.0001, Monte Carlo (MC): p <.0001) and invasive (F: p <.0001, MC: p <.0001) OSSN in comparison to adjacent benign squamous epithelium when analyzed for basal keratinocyte positive count, staining intensity, expression pattern, and Immunostaining intensity-distribution index. YAP-1 expression did not differ between preinvasive and invasive OSSN (p >.05), keratinizing and non- keratinizing cancer (p >.05), or between T1/T2 and T3/T4 stages in invasive tumors (p >.05). However, grade 2 and 3 tumors had significantly stronger nucleus YAP-1 overexpression intensity than grade 1 tumors (F: p = .0078, MC: p = .0489). By immunohistochemistry, we identified significant overexpression (upregulation of YAP-1 protein expression) in preinvasive and invasive OSSN lesions compared to neighboring benign squamous epithelium. YAP-1 expression was significantly higher in poorly and moderately differentiated invasive squamous cancer than in well-differentiated carcinomas. Overexpression of YAP-1 within the margin of preinvasive and invasive OSSN, but not in the neighboring normal epithelium, indicates that it plays a role in the development and progression of OSSN.
Chloride intracellular channel gene knockdown induces insect cell lines death and level increases of intracellular calcium ions
Authors: Song Jiqiang , Yu Yanping , Yan Zhichao , Xiao Shan , Zhao Xianxin , Wang Fang , Fang Qi , Ye Gongyin
Published: July 2023

Chloride intracellular channel (CLIC) is a member of the chloride channel protein family for which growing evidence supports a pivotal role in fundamental cellular events. However, the physiological function of CLIC in insects is still rarely uncovered. The ovary-derived High Five (Hi-5) cell line isolated from the cabbage looper (Trichoplusia ni) is widely used in laboratories. Here, we studied both characteristics and functions of CLIC in Hi-5 cells (TnCLIC). We identified the TnCLIC gene in Hi-5 cells and annotated highly conserved CLIC proteins in most insect species. After RNA interference of TnCLIC, the phenomenon of significantly increased cell death suggests that the TnCLIC protein is essential for the survival of Hi-5 cells. The same lethal effect was also observed in Spodoptera frugiperda 9 and Drosophila melanogaster Schneider 2 cells after CLIC knockdown. Furthermore, we found that this kind of cell death was accompanied by increases in intracellular calcium ions after TnCLIC knockdown with the transcriptomic analyses and the detection of calcium levels. Our results provide insights into insect CLIC as a key factor for cell survival and lay the foundation for the cell death mechanism.
POMONA: a multiplatform software for modeling seed physiology
Authors: Cantão Renato Fernandes , Ribeiro-Oliveira João Paulo , Silva Edvaldo A. Amaral da , Santos Amanda Rithieli dos , de Faria Rute Quelvia , Sartori Maria Marcia Pereira
Published: July 2023

Seed physiology is related to functional and metabolic traits of the seed-seedling transition. In this sense, modeling the kinetics, uniformity and capacity of a seed sample plays a central role in designing strategies for trade, food, and environmental security. Thus, POMONA is presented as an easy-to-use multiplatform software designed to bring several logistic and linearized models into a single package, allowing for convenient and fast assessment of seed germination and or longevity, even if the data has a non-Normal distribution. POMONA is implemented in JavaScript using the Quasar framework and can run in the Microsoft Windows operating system, GNU/Linux, and Android-powered mobile hardware or on a web server as a service. The capabilities of POMONA are showcased through a series of examples with diaspores of corn and soybean, evidencing its robustness, accuracy, and performance. POMONA can be the first step for the creation of an automatic multiplatform that will benefit laboratory users, including those focused on image analysis.