bluuebunny/crossref_metadata_2025 huggingface dataset:
In-situ tumor vaccination by percutaneous ablative therapy and its synergy with immunotherapeutics: An update on combination therapy
Authors: Kim Nicole J. , Yoon Jessica H. , Tuomi Adam C. , Lee John , Kim Daehee
Published: March 2023

Percutaneous tumor ablation is now a widely accepted minimally invasive local treatment option offered by interventional radiology and applied to various organs and tumor histology types. It utilizes extreme temperatures to achieve irreversible cellular injury, where ablated tumor interacts with surrounding tissue and host via tissue remodeling and inflammation, clinically manifesting as post-ablation syndrome. During this process, in-situ tumor vaccination occurs, in which tumor neoantigens are released from ablated tissue and can prime one’s immune system which would favorably affect both local and remote site disease control. Although successful in priming the immune system, this rarely turns into clinical benefits for local and systemic tumor control due to intrinsic negative immune modulation of the tumor microenvironment. A combination of ablation and immunotherapy has been employed to overcome these and has shown promising preliminary results of synergistic effect without significantly increased risk profiles. The aim of this article is to review the evidence on post-ablation immune response and its synergy with systemic immunotherapies.
Socs3b regulates the development and function of innate immune cells in zebrafish
Authors: Sobah Mohamed L. , Scott Aimee C. , Laird Miranda , Koole Cassandra , Liongue Clifford , Ward Alister C.
Published: March 2023

Introduction

Suppressor of cytokine signaling 3 (SOCS3) is a critical component of the negative feedback regulation that controls signaling by cytokines and other factors thereby ensuring that important processes such as hematopoiesis and inflammation occur at appropriate levels.

Methods

To gain further insights into SOCS3 function, the zebrafish socs3b gene was investigated through analysis of a knockout line generated using CRISPR/Cas9-mediated genome editing.

Results

Zebrafish socs3b knockout embryos displayed elevated numbers of neutrophils during primitive and definitive hematopoiesis but macrophage numbers were not altered. However, the absence of socs3b reduced neutrophil functionality but enhanced macrophage responses. Adult socs3b knockout zebrafish displayed reduced survival that correlated with an eye pathology involving extensive infiltration of neutrophils and macrophages along with immune cell dysregulation in other tissues.

Discussion

These findings identify a conserved role for Socs3b in the regulation of neutrophil production and macrophage activation.
Comprehensive analysis of nicotinamide metabolism-related signature for predicting prognosis and immunotherapy response in breast cancer
Authors: Cui Hanxiao , Ren Xueting , Dai Luyao , Chang Lidan , Liu Dandan , Zhai Zhen , Kang Huafeng , Ma Xiaobin
Published: March 2023

Background

Breast cancer (BC) is the most common malignancy among women. Nicotinamide (NAM) metabolism regulates the development of multiple tumors. Herein, we sought to develop a NAM metabolism-related signature (NMRS) to make predictions of survival, tumor microenvironment (TME) and treatment efficacy in BC patients.

Methods

Transcriptional profiles and clinical data from The Cancer Genome Atlas (TCGA) were analyzed. NAM metabolism-related genes (NMRGs) were retrieved from the Molecular Signatures Database. Consensus clustering was performed on the NMRGs and the differentially expressed genes between different clusters were identified. Univariate Cox, Lasso, and multivariate Cox regression analyses were sequentially conducted to develop the NAM metabolism-related signature (NMRS), which was then validated in the International Cancer Genome Consortium (ICGC) database and Gene Expression Omnibus (GEO) single-cell RNA-seq data. Further studies, such as gene set enrichment analysis (GSEA), ESTIMATE, CIBERSORT, SubMap, and Immunophenoscore (IPS) algorithm, cancer-immunity cycle (CIC), tumor mutation burden (TMB), and drug sensitivity were performed to assess the TME and treatment response.

Results

We identified a 6-gene NMRS that was significantly associated with BC prognosis as an independent indicator. We performed risk stratification according to the NMRS and the low-risk group showed preferable clinical outcomes (P < 0.001). A comprehensive nomogram was developed and showed excellent predictive value for prognosis. GSEA demonstrated that the low-risk group was predominantly enriched in immune-associated pathways, whereas the high-risk group was enriched in cancer-related pathways. The ESTIMATE and CIBERSORT algorithms revealed that the low-risk group had a higher abundance of anti-tumor immunocyte infiltration (P < 0.05). Results of Submap, IPS, CIC, TMB, and external immunotherapy cohort (iMvigor210) analyses showed that the low-risk group were indicative of better immunotherapy response (P < 0.05).

Conclusions

The novel signature offers a promising way to evaluate the prognosis and treatment efficacy in BC patients, which may facilitate clinical practice and management.
Predictors of cardiac involvement in idiopathic inflammatory myopathies
Authors: Bandeira Matilde , Dourado Eduardo , Melo Ana Teresa , Martins Patrícia , Fraga Vanessa , Ferraro José Luís , Saraiva André , Sousa Marlene , Parente Hugo , Soares Catarina , Correia Ana Margarida , Almeida Diogo Esperança , Dinis Sara Paiva , Pinto Ana Sofia , Oliveira Pinheiro Filipe , Rato Maria Seabra , Beirão Tiago , Samões Beatriz , Santos Bernardo , Mazeda Carolina , Chícharo Ana Teodósio , Faria Margarida , Neto Agna , Lourenço Maria Helena , Brites Luísa , Rodrigues Marília , Silva-Dinis Joana , Dias João Madruga , Araújo Filipe C. , Martins Nádia , Couto Maura , Valido Ana , Santos Maria José , Barreira Sofia Carvalho , Fonseca João Eurico , Campanilho-Marques Raquel
Published: March 2023

Objectives

Idiopathic inflammatory myopathies (IIM) are a group of rare disorders that can affect the heart. This work aimed to find predictors of cardiac involvement in IIM.

Methods

Multicenter, open cohort study, including patients registered in the IIM module of the Rheumatic Diseases Portuguese Register (Reuma.pt/Myositis) until January 2022. Patients without cardiac involvement information were excluded. Myo(peri)carditis, dilated cardiomyopathy, conduction abnormalities, and/or premature coronary artery disease were considered.

Results

230 patients were included, 163 (70.9%) of whom were females. Thirteen patients (5.7%) had cardiac involvement. Compared with IIM patients without cardiac involvement, these patients had a lower bilateral manual muscle testing score (MMT) at the peak of muscle weakness [108.0 ± 55.0 vs 147.5 ± 22.0, p=0.008] and more frequently had oesophageal [6/12 (50.0%) vs 33/207 (15.9%), p=0.009] and lung [10/13 (76.9%) vs 68/216 (31.5%), p=0.001] involvements. Anti-SRP antibodies were more commonly identified in patients with cardiac involvement [3/11 (27.3%) vs 9/174 (5.2%), p=0.026]. In the multivariate analysis, positivity for anti-SRP antibodies (OR 104.3, 95% CI: 2.5-4277.8, p=0.014) was a predictor of cardiac involvement, regardless of sex, ethnicity, age at diagnosis, and lung involvement. Sensitivity analysis confirmed these results.

Conclusion

Anti-SRP antibodies were predictors of cardiac involvement in our cohort of IIM patients, irrespective of demographical characteristics and lung involvement. We suggest considering frequent screening for heart involvement in anti-SRP-positive IIM patients.
Targeting RIPK1 kinase for modulating inflammation in human diseases
Authors: Li Wanjin , Yuan Junying
Published: March 2023

Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) is a master regulator of TNFR1 signaling in controlling cell death and survival. While the scaffold of RIPK1 participates in the canonical NF-κB pathway, the activation of RIPK1 kinase promotes not only necroptosis and apoptosis, but also inflammation by mediating the transcriptional induction of inflammatory cytokines. The nuclear translocation of activated RIPK1 has been shown to interact BAF-complex to promote chromatin remodeling and transcription. This review will highlight the proinflammatory role of RIPK1 kinase with focus on human neurodegenerative diseases. We will discuss the possibility of targeting RIPK1 kinase for the treatment of inflammatory pathology in human diseases.
Response of nutrients and primary production to high wind and upwelling-favorable wind in the Arctic Ocean: A modeling perspective
Authors: Xu Anqi , Jin Meibing , Wu Yingxu , Qi Di
Published: March 2023

Both remote sensing and numerical models revealed increasing net primary production (NPP) in the Arctic Ocean due to declining sea ice cover and increasing ice-free days. The NPP increases in some parts of the Arctic Ocean are also hypothesized to link to high wind (>10 m/s) and upwelling-favorable wind, however, the mechanism remains unclear. Using Regional Arctic System Model (RASM) to investigate the relationship between NPP and wind, we found that the seasonal NPP are statistically correlated to high wind frequency (HWF) in the Barents (Br) and Southern Chukchi Seas (SC) due to their high subsurface nutrients in the 20-50 m layer. Five high and five low HWF years along a zonally averaged section were chosen to understand the spatial variation of the correlation between HWF, NO3, and NPP in the SC. During high HWF years, the decrease in subsurface NO3 exceeds its increase in surface, implying the utilization by biological productivity. A more positive response of NPP to HWF in north SC than south was also found because more subsurface nutrients were entrained into the surface by higher HWF. The NPP are statistically correlated to easterly wind frequency (EWF) in the Beaufort and Canada Basin (BC), where the stronger EWF-induced upwelling could bring up higher nutrients from >100 m depth. While the nutrients and NPP in the south BC are normally higher than in the north, an increase of EWF can further enhance the nutrients and NPP in the south much more than those in the north. Differences between five high and five low EWF years reveal that the increase of EWF is most important around the shelf break region, where NO3 and NPP are also most enhanced. The enhancement of NPP by higher HWF in the Br and SC is less than that by higher ice-free days ratio (IFR), while the enhancement of NPP by higher EWF in BC is of similar magnitude to that by IFR. As the trend of declining sea ice cover continues, it’s necessary to advance our understanding on the nutrients and NPP response to changing wind regimes in different Arctic regions.
Molecular identification of an insulin-like peptide from the swimming crab Portunus trituberculatus and evidence for its glucoregulation function
Authors: Xu Rui , Wang Meng-en , Tu Shisheng , Xie Xi , Zhu Dongfa
Published: March 2023

Insulin-like peptides (ILPs) are essential to the animal kingdom for regulating growth and development, reproduction, behavior, metabolism, and lifespan. In crustaceans, the most well-known ILP is insulin-like androgenic gland hormone, a key hormone in regulating sex differentiation and reproduction. Identification of other ILPs and their functions are still limited. In this study, an insulin-like peptide gene of the swimming crab Portunus trituberculatus was cloned and characterized. Its transcripts were mainly found in nerve tissues and expression could be induced by glucose, implying a putative role in glucoregulation. After depletion of endogenous ILP, injection of ILP dsRNA (dsILP) significantly elevated blood glucose levels and recombinant ILP (rILP) decreased hemolymph glucose levels, further clarifying the involvement of acquired ILP in hemolymph glucose regulation. Injection of dsILP decreased PtAkt, PtGS, PtPFK and increased PtGSK and PtPEPCK gene expression. The opposite profile was observed after glucose and rILP injection, indicating that PtILP might negatively regulate hemolymph glucose levels via the IIS (insulin/IGF-1 signaling) pathway by inhibiting gluconeogenesis and promoting glycogen synthesis and glycolysis. This study has refined the mechanism of glucose regulation in crustaceans and laid the foundation for further studies on ILP function.
Assessment of prognostic value of preoperative neutrophil-to-lymphocyte ratio for postoperative mortality and morbidity
Authors: Zhu Yingchao , Bi Yaodan , Liu Bin , Zhu Tao
Published: March 2023

Background

The preoperative elevated neutrophil-to-lymphocyte ratio (NLR) was reported to be associated with poorer outcomes after cancer and cardiovascular surgeries. It is unclear, however, if the predictive value is particular or if it may be applied to other types of surgery. We aimed to assess the prognostic value of preoperative NLR levels for morbidity and mortality after various surgery and determine an optimal threshold for NLR.

Methods

We conducted a cohort analysis on patients receiving surgery at Sichuan University West China Hospital between 2018 and 2020. Multivariable piecewise regression analysis were used to determine the optimal cutoff value of NLR. Subgroup analysis were performed to verify the correlation. Sensitivity analysis was used to explore the effect of different thresholds.

Results

We obtained data from 136,347 patients. The optimal cutoff of NLR was determined as 3.6 [95% CI (3.0, 4.1)] by piecewise regression method. After multivariable adjustment, preoperative high NLR remained significantly associated with increased in-hospital mortality (aOR, 2.19; 95% CI, 1.90–2.52; p < 0.001) and ICU admission after surgery (aOR, 1.69; 95% CI, 1.59–1.79; p < 0.001). Subgroup analyses confirmed the predictive value of high NLR in multiple surgical subgroups, including general, orthopedic, neurosurgical, and thoracic surgery subgroups, otorhinolaryngology, head and neck surgery, and burn plastic surgery. A NLR threshold of 3.6 gave excellent predictive value, whether employed alone or added in an extended model.

Conclusions

In conclusion, the association of elevated NLR with higher mortality and ICU admission can be extended to a wider range of procedures. NLR threshold of 3.6 could provide good prognostic value for the prognostic model.
Optimization of the growth conditions through response surface methodology and metabolomics for maximizing the auxin production by Pantoea agglomerans C1
Authors: Melini Francesca , Luziatelli Francesca , Bonini Paolo , Ficca Anna Grazia , Melini Valentina , Ruzzi Maurizio
Published: March 2023

Introduction

The fermentative production of auxin/indole 3-acetate (IAA) using selected Pantoea agglomerans strains can be a promising approach to developing novel plant biostimulants for agriculture use.

Methods

By integrating metabolomics and fermentation technologies, this study aimed to define the optimal culture conditions to obtain auxin/IAA-enriched plant postbiotics using P. agglomerans strain C1. Metabolomics analysis allowed us to demonstrate that the production of a selected.

Results and discussion:

Array of compounds with plant growth-promoting- (IAA and hypoxanthine) and biocontrol activity (NS-5, cyclohexanone, homo-L-arginine, methyl hexadecenoic acid, and indole-3-carbinol) can be stimulated by cultivating this strain on minimal saline medium amended with sucrose as a carbon source. We applied a three-level-two-factor central composite design (CCD) based response surface methodology (RSM) to explore the impact of the independent variables (rotation speed and medium liquid-to-flask volume ratio) on the production of IAA and IAA precursors. The ANOVA component of the CCD indicated that all the process-independent variables investigated significantly impacted the auxin/IAA production by P. agglomerans strain C1. The optimum values of variables were a rotation speed of 180 rpm and a medium liquid-to-flask volume ratio of 1:10. Using the CCD-RSM method, we obtained a maximum indole auxin production of 208.3 ± 0.4  mg IAAequ/L, which was a 40% increase compared to the growth conditions used in previous studies. Targeted metabolomics allowed us to demonstrate that the IAA product selectivity and the accumulation of the IAA precursor indole-3-pyruvic acid were significantly affected by the increase in the rotation speed and the aeration efficiency.
Viruses may facilitate the cyanobacterial blooming during summer bloom succession in Xiangxi Bay of Three Gorges Reservoir, China
Authors: Peng Kaida , Jiao Yiying , Gao Jian , Xiong Wen , Zhao Yijun , Yang Shao , Liao Mingjun
Published: March 2023

The occurrence of cyanobacterial blooms in summer are frequently accompanied by the succession of phytoplankton communities in freshwater. However, little is known regarding the roles of viruses in the succession, such as in huge reservoirs. Here, we investigated the viral infection characteristics of phytoplankton and bacterioplankton during the summer bloom succession in Xiangxi Bay of Three Gorges Reservoir, China. The results indicated that three distinct bloom stages and two successions were observed. From cyanobacteria and diatom codominance to cyanobacteria dominance, the first succession involved different phyla and led to a Microcystis bloom. From Microcystis dominance to Microcystis and Anabaena codominance, the second succession was different Cyanophyta genera and resulted in the persistence of cyanobacterial bloom. The structural equation model (SEM) showed that the virus had positive influence on the phytoplankton community. Through the Spearman’s correlation and redundancy analysis (RDA), we speculated that both the increase of viral lysis in the eukaryotic community and the increase of lysogeny in cyanobacteria may contributed to the first succession and Microcystis blooms. In addition, the nutrients supplied by the lysis of bacterioplankton might benefit the second succession of different cyanobacterial genera and sustain the dominance of cyanobacteria. Based on hierarchical partitioning method, the viral variables still have a marked effect on the dynamics of phytoplankton community, although the environmental attributes were the major factors. Our findings suggested that viruses played multiple potential roles in summer bloom succession and may help the blooms success of cyanobacteria in Xiangxi Bay. Under the background of increasingly serious cyanobacterial blooms worldwide, our study may have great ecological and environmental significance for understanding the population succession in phytoplankton and controlling the cyanobacterial blooms.
Vertical variations in microbial diversity, composition, and interactions in freshwater lake sediments on the Tibetan plateau
Authors: Zhu Xinshu , Deng Yongcui , Huang Tao , Han Cheng , Chen Lei , Zhang Zhigang , Liu Keshao , Liu Yongqin , Huang Changchun
Published: March 2023

Microbial communities in freshwater lake sediments exhibit a distinct depth-dependent variability. Further exploration is required to understand their biodiversity pattern and microbial interactions in vertical sediments. In this study, sediment cores from two freshwater lakes, Mugecuo (MGC) and Cuopu (CP), on the Tibetan plateau were sampled and subsequently sliced into layers at a depth of every centimeter or half a centimeter. Amplicon sequencing was used to analyze the composition, diversity, and interaction of microbial communities. Results showed that sediment samples of both lakes could be clustered into two groups at a sediment depth of about 20 cm, with obvious shifts in microbial community compositions. In lake MGC, the richness component dominated β-diversity and increased with depth, indicating that the microbial communities in the deep layer of MGC was selected from the surface layer. Conversely, the replacement component dominated β-diversity in CP, implying a high turnover rate in the surface layer and inactive seed banks with a high variety in the deep layer. A co-occurrence network analysis showed that negative microbial interactions were prevalent in the surface layers with high nutrient concentrations, while positive microbial interactions were more common in the deep layers with low nutrient concentrations, suggesting that microbial interactions are influenced by nutrient conditions in the vertical sediments. Additionally, the results highlight the significant contributions of abundant and rare taxa to microbial interactions and vertical fluctuations of β-diversity, respectively. Overall, this work deepens our understanding of patterns of microbial interactions and vertical fluctuation in β-diversity in lake sediment columns, particularly in freshwater lake sediments from the Tibetan plateau.
Coexistence of blaKPC-IncFII plasmids and type I-E* CRISPR-Cas systems in ST15 Klebsiella pneumoniae
Authors: Hu Yiyi , Jiang Jianping , Wang Dongliang , Guo Qinglan , Wang Minggui
Published: March 2023

The CRISPR-Cas system in Klebsiella pneumoniae can prevent the entry of blaKPC-IncF plasmids. However, some clinical isolates bear the KPC-2 plasmids despite carrying the CRISPR-Cas system. The purpose of this study was to characterize the molecular features of these isolates. A total of 697 clinical K. pneumoniae isolates were collected from 11 hospitals in China, and tested for the presence of CRISPR-Cas systems using polymerase chain reaction. Overall, 164 (23.5%) of 697 K. pneumoniae isolates had type I-E* (15.9%) or type I-E (7.7%) CRISPR-Cas systems. The most prevalent sequence type among isolates carrying type I-E* CRISPR was ST23 (45.9%), followed by ST15 (18.9%). Isolates with CRISPR-Cas system were more susceptible to ten antimicrobials tested, including carbapenems, compared with the CRISPR-negative isolates. However, there were still 21 CRISPR-Cas-carrying isolates that showed resistance to carbapenems, and these isolates were subjected to whole-genome sequencing. Thirteen of these 21 isolates carried blaKPC-2-bearing plasmids, of which nine had a new plasmid type, IncFIIK34, and two had IncFII(PHN7A8) plasmids. In addition, 12 of these 13 isolates belonged to ST15, while only eight (5.6%, 8/143) isolates belonged to ST15 in carbapenem-susceptible K. pneumoniae carrying CRISPR-Cas systems. In conclusion, we found that blaKPC-2-bearing IncFII plasmids could co-exist with the type I-E* CRISPR-Cas systems in ST15 K. pneumoniae.
Remodeling of the gut microbiome by Lactobacillus johnsonii alleviates the development of acute myocardial infarction
Authors: Zhong Xinqin , Zhao Yucui , Huang Lu , Liu Jiarui , Wang Kaiyue , Gao Xiumei , Zhao Xin , Wang Xiaoying
Published: March 2023

Introduction

The gut microbial community, which can be disturbed or repaired by changes in the internal environment, contributes to the development of acute myocardial infarction (AMI). Gut probiotics play a role in microbiome remodeling and nutritional intervention post-AMI. A newly isolated Lactobacillus johnsonii strain EU03 has shown potential as a probiotic. Here, we investigated the cardioprotective function and mechanism of L. johnsonii through gut microbiome remodeling in AMI rats.

Methods

A rat model of left anterior descending coronary artery ligation (LAD)-mediated AMI was assessed with echocardiography, histology, and serum cardiac biomarkers to evaluate the beneficial effects of L. johnsonii. The immunofluorescence analysis was utilized to visualize the intestinal barrier changes. Antibiotic administration model was used for assessing the gut commensals’ function in the improvement of cardiac function post-AMI. The underlying beneficial mechanism through L. johnsonii enrichment was further investigated by metagenomics and metabolomics analysis.

Results

A 28-day treatment with L. johnsonii protected cardiac function, delayed cardiac pathology, suppressed myocardial injury cytokines, and improved gut barrier integrity. The microbiome composition was reprogrammed by enhancing the abundance of L. johnsonii. Microbiome dysbiosis by antibiotics abrogated the improvement of cardiac function post-AMI by L. johnsonii. L. johnsonii enrichment caused remodeling of gut microbiome by increasing the abundance of Muribaculaceae, Lactobacillus, and decreasing Romboutsia, Clostridia UCG-014, which were correlated with cardiac traits and serum metabolic biomarkers 16,16-dimethyl-PGA2, and Lithocholate 3-O-glucuronide.

Conclusion

These findings reveal that gut microbiome remodeling by L. johnsonii ameliorates the cardiac function post-AMI and might advance microbiome-targeted nutritional intervention.
Interaction between the α-glucosidases, sucrase-isomaltase and maltase-glucoamylase, in human intestinal brush border membranes and its potential impact on disaccharide digestion
Authors: Tannous Stephanie , Stellbrinck Tammy , Hoter Abdullah , Naim Hassan Y.
Published: March 2023

The two major intestinal α-glycosidases, sucrase-isomaltase (SI) and maltase-glucoamylase (MGAM), are active towards α-1,4 glycosidic linkages that prevail in starch. These enzymes share striking structural similarities and follow similar biosynthetic pathways. It has been hypothesized that starch digestion can be modulated via “toggling” of activities of these mucosal α-glycosidases, suggesting a possible interaction between these two enzyme complexes in the intestinal brush border membrane (BBM). Here, the potential interaction between SI and MGAM was investigated in solubilized BBMs utilizing reciprocal pull down assays, i.e., immunoprecipitation with anti-SI antibody followed by Western blotting with anti-MGAM antibody and vice versa. Our results demonstrate that SI interacts avidly with MGAM concomitant with a hetero-complex assembly in the BBMs. This interaction is resistant to detergents, such as Triton X-100 or Triton X-100 in combination with sodium deoxycholate. By contrast, inclusion of sodium deoxycholate into the solubilization buffer reduces the enzymatic activities towards sucrose and maltose substantially, most likely due to alterations in the quaternary structure of either enzyme. In view of their interaction, SI and MGAM regulate the final steps in starch digestion in the intestine, whereby SI assumes the major role by virtue of its predominant expression in the intestinal BBMs, while MGAM acts in auxiliary supportive fashion. These findings will help understand the pathophysiology of carbohydrate malabsorption in functional gastrointestinal disorders, particularly in irritable bowel syndrome, in which gene variants of SI are implicated.
Spontaneous neurotransmission at evocable synapses predicts their responsiveness to action potentials
Authors: Grasskamp Andreas T. , Jusyte Meida , McCarthy Anthony W. , Götz Torsten W. B. , Ditlevsen Susanne , Walter Alexander M.
Published: March 2023

Synaptic transmission relies on presynaptic neurotransmitter (NT) release from synaptic vesicles (SVs) and on NT detection by postsynaptic receptors. Transmission exists in two principal modes: action-potential (AP) evoked and AP-independent, “spontaneous” transmission. AP-evoked neurotransmission is considered the primary mode of inter-neuronal communication, whereas spontaneous transmission is required for neuronal development, homeostasis, and plasticity. While some synapses appear dedicated to spontaneous transmission only, all AP-responsive synapses also engage spontaneously, but whether this encodes functional information regarding their excitability is unknown. Here we report on functional interdependence of both transmission modes at individual synaptic contacts of Drosophila larval neuromuscular junctions (NMJs) which were identified by the presynaptic scaffolding protein Bruchpilot (BRP) and whose activities were quantified using the genetically encoded Ca2+ indicator GCaMP. Consistent with the role of BRP in organizing the AP-dependent release machinery (voltage-dependent Ca2+ channels and SV fusion machinery), most active BRP-positive synapses (>85%) responded to APs. At these synapses, the level of spontaneous activity was a predictor for their responsiveness to AP-stimulation. AP-stimulation resulted in cross-depletion of spontaneous activity and both transmission modes were affected by the non-specific Ca2+ channel blocker cadmium and engaged overlapping postsynaptic receptors. Thus, by using overlapping machinery, spontaneous transmission is a continuous, stimulus independent predictor for the AP-responsiveness of individual synapses.
Study design challenges and strategies in clinical trials for rare diseases: Lessons learned from pantothenate kinase-associated neurodegeneration
Authors: Videnovic Aleksandar , Pfeiffer Helle C. V. , Tylki-Szymańska Anna , Berry-Kravis Elizabeth , Ezgü Fatih , Ganju Jitendra , Jurecka Agnieszka , Lang Anthony E.
Published: March 2023

Substantial challenges in study design and methodology exist during clinical trial development to examine treatment response in patients with a rare disease, especially those with predominant central nervous system involvement and heterogeneity in clinical manifestations and natural history. Here we discuss crucial decisions which may significantly impact success of the study, including patient selection and recruitment, identification and selection of endpoints, determination of the study duration, consideration of control groups including natural history controls, and selection of appropriate statistical analyses. We review strategies for the successful development of a clinical trial to evaluate treatment of a rare disease with a focus on inborn errors of metabolism (IEMs) that present with movement disorders. The strategies presented using pantothenate kinase-associated neurodegeneration (PKAN) as the rare disease example can be applied to other rare diseases, particularly IEMs with movement disorders (e.g., other neurodegeneration with brain iron accumulation disorders, lysosomal storage disorders). The significant challenges associated with designing a clinical trial in rare disease can sometimes be successfully met through strategic engagement with experts in the rare disease, seeking regulatory and biostatistical guidance, and early involvement of patients and families. In addition to these strategies, we discuss the urgent need for a paradigm shift within the regulatory processes to help accelerate medical product development and bring new innovations and advances to patients with rare neurodegenerative diseases who need them earlier in disease progression and prior to clinical manifestations.
Human neural network activity reacts to gravity changes in vitro
Authors: Striebel Johannes , Kalinski Laura , Sturm Maximilian , Drouvé Nils , Peters Stefan , Lichterfeld Yannick , Habibey Rouhollah , Hauslage Jens , El Sheikh Sherif , Busskamp Volker , Liemersdorf Christian
Published: March 2023

During spaceflight, humans experience a variety of physiological changes due to deviations from familiar earth conditions. Specifically, the lack of gravity is responsible for many effects observed in returning astronauts. These impairments can include structural as well as functional changes of the brain and a decline in cognitive performance. However, the underlying physiological mechanisms remain elusive. Alterations in neuronal activity play a central role in mental disorders and altered neuronal transmission may also lead to diminished human performance in space. Thus, understanding the influence of altered gravity at the cellular and network level is of high importance. Previous electrophysiological experiments using patch clamp techniques and calcium indicators have shown that neuronal activity is influenced by altered gravity. By using multi-electrode array (MEA) technology, we advanced the electrophysiological investigation covering single-cell to network level responses during exposure to decreased (micro-) or increased (hyper-) gravity conditions. We continuously recorded in real-time the spontaneous activity of human induced pluripotent stem cell (hiPSC)-derived neural networks in vitro. The MEA device was integrated into a custom-built environmental chamber to expose the system with neuronal cultures to up to 6 g of hypergravity on the Short-Arm Human Centrifuge at the DLR Cologne, Germany. The flexibility of the experimental hardware set-up facilitated additional MEA electrophysiology experiments under 4.7 s of high-quality microgravity (10–6 to 10–5 g) in the Bremen drop tower, Germany. Hypergravity led to significant changes in activity. During the microgravity phase, the mean action potential frequency across the neural networks was significantly enhanced, whereas different subgroups of neurons showed distinct behaviors, such as increased or decreased firing activity. Our data clearly demonstrate that gravity as an environmental stimulus triggers changes in neuronal activity. Neuronal networks especially reacted to acute changes in mechanical loading (hypergravity) or de-loading (microgravity). The current study clearly shows the gravity-dependent response of neuronal networks endorsing the importance of further investigations of neuronal activity and its adaptive responses to micro- and hypergravity. Our approach provided the basis for the identification of responsible mechanisms and the development of countermeasures with potential implications on manned space missions.
An in-silico framework for modeling optimal control of neural systems
Authors: Rueckauer Bodo , van Gerven Marcel
Published: March 2023

Introduction

Brain-machine interfaces have reached an unprecedented capacity to measure and drive activity in the brain, allowing restoration of impaired sensory, cognitive or motor function. Classical control theory is pushed to its limit when aiming to design control laws that are suitable for large-scale, complex neural systems. This work proposes a scalable, data-driven, unified approach to study brain-machine-environment interaction using established tools from dynamical systems, optimal control theory, and deep learning.

Methods

To unify the methodology, we define the environment, neural system, and prosthesis in terms of differential equations with learnable parameters, which effectively reduce to recurrent neural networks in the discrete-time case. Drawing on tools from optimal control, we describe three ways to train the system: Direct optimization of an objective function, oracle-based learning, and reinforcement learning. These approaches are adapted to different assumptions about knowledge of system equations, linearity, differentiability, and observability.

Results

We apply the proposed framework to train an in-silico neural system to perform tasks in a linear and a nonlinear environment, namely particle stabilization and pole balancing. After training, this model is perturbed to simulate impairment of sensor and motor function. We show how a prosthetic controller can be trained to restore the behavior of the neural system under increasing levels of perturbation.

Discussion

We expect that the proposed framework will enable rapid and flexible synthesis of control algorithms for neural prostheses that reduce the need for in-vivo testing. We further highlight implications for sparse placement of prosthetic sensor and actuator components.
Prognostic value of sarcopenia in patients with lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors or immune checkpoint inhibitors
Authors: Lyu Jiahua , Yang Ningjing , Xiao Ling , Nie Xinyu , Xiong Jing , Liu Yudi , Zhang Min , Zhang Hangyue , Tang Cunhan , Pan Shiyi , Liang Long , Bai Hansong , Li Churong , Kuang Hao , Li Tao
Published: March 2023

Objectives

It remains controversial whether sarcopenia has any significant impact on the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) or immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC). Therefore, in this study, we aimed to assess the association between sarcopenia and clinical outcomes in patients with advanced NSCLC receiving EGFR-TKIs or ICIs as a first-line therapy.

Methods

We retrospectively enrolled 131 patients with advanced NSCLC treated with first-line EGFR-TKIs or ICIs between 1 March 2019 and 31 March 2021. To estimate sarcopenia, we calculated skeletal muscle index (SMI) as the ratio of skeletal muscle area (cm2) to height squared (m2). Associations between sarcopenia and overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan–Meier method and log-rank tests, respectively. A Cox proportional hazards regression model was used to assess the factors associated with OS and PFS. The Student’s t-test or Mann–Whitney U test was used to compare the SMI between patients with or without objective response and disease control. The chi-squared test was used to compare adverse events (AEs) between patients with and without sarcopenia.

Results

Among the 131 patients, 35 (26.7%) were diagnosed with sarcopenia. Sarcopenia was an independent predictor of poor OS and PFS (p < 0.05) overall and in the EGFR-TKI- and ICI-treated cohorts. Among all patients, those with sarcopenia showed significantly shorter OS and PFS than those without sarcopenia (median OS and PFS: 13.0 vs. 26.0 months and 6.4 vs. 15.1 months; both p < 0.001). These associations were consistent across the subtypes of most clinical characteristics. Statistically significant differences between the objective response (OR) and non-OR groups were also observed in the mean SMI (OR group, 43.89 ± 7.55 vs. non-OR group, 38.84 ± 7.11 cm2/m2; p < 0.001). In addition, we observed similar results with disease control (DC) and non-DC groups (DC group, 42.46 ± 7.64 vs. non-DCR group, 33.74 ± 4.31 cm2/m2; p < 0.001). The AEs did not differ significantly between the sarcopenia and non-sarcopenia groups.

Conclusion

Sarcopenia before treatment might be a significant predictor of poor clinical outcomes (shorter OS and PFS, fewer ORs, less DC) in patients with advanced NSCLC treated with EGFR-TKIs or ICIs as the first-line therapy.
Prognostic significance of eighth edition TNM stage criteria in combined small-cell lung cancer
Authors: Zhao Ziran , Gao Yibo , Tan Fengwei , Xue Qi , Gao Shugeng , He Jie
Published: March 2023

Objectives

This study aimed to evaluate the prognostic significance of the eighth edition TNM stage criteria in patients with combined small-cell lung cancer (C-SCLC) on a population level.

Methods

Using the Surveillance, Epidemiology, and End Results (SEER) database, patients diagnosed with C-SCLC (histology code 8245) between the years 2004 and 2015 were identified. We performed a Kaplan–Meier analysis and used the multivariable cox regression proportional hazards model to obtain prognostic overall survival estimates for each group of patients.

Results

A total of 477 patients diagnosed with C-SCLC were identified. The T, N, M, TNM, and combined TNM stage status of the eighth edition were all significant prognostic factors for patients’ overall survivals, with the best discrimination identified in the combined stages. Surgery was also found to be a prognostic factor (HR =1.95, 95%CI =1.49-2.56, p<0.01) for patients with C-SCLC.

Conclusions

The combined eighth edition of the TNM staging criteria shows reliable prognostic significance in patients with C-SCLC. Moreover, surgery might be significant for improving the patients’ prognosis.
Dietary fungi in cancer immunotherapy: From the perspective of gut microbiota
Authors: Wei Yibing , Song Dingka , Wang Ran , Li Tingting , Wang Hui , Li Xiaoguang
Published: March 2023

Immunotherapies are recently emerged as a new strategy in treating various kinds of cancers which are insensitive to standard therapies, while the clinical application of immunotherapy is largely compromised by the low efficiency and serious side effects. Gut microbiota has been shown critical for the development of different cancer types, and the potential of gut microbiota manipulation through direct implantation or antibiotic-based depletion in regulating the overall efficacy of cancer immunotherapies has also been evaluated. However, the role of dietary supplementations, especially fungal products, in gut microbiota regulation and the enhancement of cancer immunotherapy remains elusive. In the present review, we comprehensively illustrated the limitations of current cancer immunotherapies, the biological functions as well as underlying mechanisms of gut microbiota manipulation in regulating cancer immunotherapies, and the benefits of dietary fungal supplementation in promoting cancer immunotherapies through gut microbiota modulation.
Advances and trends in meningioma research over the last decade: A scientometric and visual analysis
Authors: Zhang Tingbao , Feng Yu , Liu Kui , Liu Zheng
Published: March 2023

Objective

We conducted a scientometric and visual analysis of meningioma studies in the past ten years and discussed the current status and trends of meningioma research to provide a reference basis for conducting relevant clinical practice or research.

Method

A search of the topic of meningioma in the Web of Science Core Collection database was conducted for January 2012-December 2021. The scientometric tools CiteSpace (version 5.8.R3), VOS viewer (version 1.6.17), and the Bibliometrix package of R software (version 4.2.1) were used to visualize and analyze the country of publication, institution, author, keywords, and cited literature of meningioma.

Results

A total of 10,397 documents related to meningioma were collected, of which 6,714 articles were analyzed. The annual analysis shows an increase in published articles, with an annual growth rate of 8.9%. 26,696 authors from 111 countries or regions were involved in publishing relevant studies. The country with the highest number of publications was the United States (1671), and the institution with the highest number of publications was the University of California, San Francisco (242). The keyword clustering of current studies can be grouped into five groups: meningioma characteristics and basic research, surgical treatment, radiation therapy, stereotactic radiosurgery, and management of complications. Keyword trend analysis shows that meningioma classification and molecular characteristics are emerging hotspots for meningioma research in recent years.

Conclusion

The scientometric and visual analysis demonstrated the research status and trends of meningioma. Over the past decade, meningioma research has focused on managing meningiomas with a predominance of surgical treatment and radiation therapy. At the same time, meningioma classification and molecular characteristics are emerging as current and possible research hotspots in the coming period.
Inter- and intrafraction dose variations in robotic stereotactic body radiation therapy (SBRT) for perihilar cholangiocarcinoma in the prospective phase I STRONG trial
Authors: Paronetto Chiara , den Toom Wilhelm , Milder Maaike T. W. , van Norden Yvette , Baak Rogier , Heijmen Ben J. M. , Méndez Romero Alejandra
Published: March 2023

Using fiducial-marker-based robotic respiratory tumor tracking, we treated perihilar cholangiocarcinoma patients in the STRONG trial with 15 daily fractions of 4 Gy. For each of the included patients, in-room diagnostic-quality repeat CTs (rCT) were acquired pre- and post-dose delivery in 6 treatment fractions to analyze inter- and intrafraction dose variations. Planning CTs (pCTs) and rCTs were acquired in expiration breath-hold. Analogous to treatment, spine and fiducials were used to register rCTs with pCTs. In each rCT, all OARs were contoured, and the target was rigidly copied from the pCT based on grey values. The rCTs acquired were used to calculate the doses to be delivered through the treatment-unit settings. On average, target doses in rCTs and pCTs were similar. However, due to target displacements relative to the fiducials in rCTs, 10% of the rCTs showed PTV coverage losses of >10%. Although target coverages had been planned below desired values in order to protect OARs, many pre-rCTs contained OAR constraint violations: 44.4% for the 6 major constraints. Most OAR dose differences between pre- and post-rCTs were not statistically significant. The dose deviations observed in repeat CTs represent opportunities for more advanced adaptive approaches to enhancing SBRT treatment quality.
Morphological and molecular pathological features of the breast carcinoma with choriocarcinomatous features: A case report and a literature review
Authors: Xu Jingchun , Xu Yi , Xu Cheng , Wang Cong
Published: March 2023

Here we present a rare case of breast cancer with both invasive ductal carcinoma and choriocarcinoma components in a 55-year-old woman. Firstly, the serum human chorionic gonadotropin level showed 15.9mIU/ml preoperatively. And adequate immunohistochemical tests were performed on the specimen. Secondly, High-throughput sequencing was performed to detect the molecular characteristics of the two components, respectively. Then, DNA short tandem repeat (STR) analysis confirmed the homology of the two components, indicating the somatic origin of choriocarcinoma components. Finally, the clinical course and pathological characteristics of the case were reviewed and a literature search for other cases was performed.
Dose-dependent effects of human umbilical cord-derived mesenchymal stem cell treatment in hyperoxia-induced lung injury of neonatal rats
Authors: Xiong Jing , Ai Qing , Bao Lei , Gan Yuanshan , Dai Xiaoyu , Han Mei , Shi Yuan
Published: March 2023

Background

Mesenchymal stem cells (MSCs) are multipotent stromal cells that have been reported to possess great potential for the treatment of bronchopulmonary dysplasia (BPD).

Objective

Our study aims to assess the effects of three different doses of intraperitoneal administration of human umbilical cord-derived MSCs (hUC-MSCs) on a hyperoxia-induced BPD model of newborn rat.

Methods

Neonatal Sprague Dawley (SD) rats were reared in either hyperoxia (75% O2) or room air (RA) from postnatal days (PN) 1-14. At PN5, hUC-MSCs (1 × 106, 5× 106,or 1× 107 cells per pup) were given intraperitoneally to newborn rats exposed to 75% O2 from birth; the controls received an equal volume of normal saline (NS). At PN14, the lung tissues, serum, and bronchoalveolar fluid (BALF) were collected for histologic examination, wet/dry (W/D) weight ratio analysis, engraftment, myeoloperoxidase (MPO) activity analysis, cytokine analysis, and western blot analysis of protein expression.

Results

Compared to rat pups reared in RA, rat pups reared in hyperoxia had a significant lower survival rate (53.3%) (P < 0.01). Hyperoxia-exposed rats exhibited pulmonary inflammation accompanied by alveolar-capillary leakage, neutrophile infiltration, augmented myeloperoxidase (MPO) activity, prominent alveolar simplification, and increased mean linear intercept (MLI), which was ameliorated by hUC-MSCs treatment. Increased oxidative stress and inflammatory cytokine production were also reduced. Importantly, the expression of Fas, an apoptosis-associated protein that was increasingly expressed in hyperoxia-exposed rats (P < 0.05), was downregulated after administration of hUC-MSCs (P < 0.05).

Conclusions

Our results suggest that intraperitoneal administration of high number hUC-MSCs (1 × 107 cells) may represent an effective modality for the treatment of hyperoxia-induced BPD in neonatal rats.
Optimal neuromonitoring techniques in neonates with hypoxic ischemic encephalopathy
Authors: Chock Valerie Y. , Rao Anoop , Van Meurs Krisa P.
Published: March 2023

Neonates with hypoxic ischemic encephalopathy (HIE) are at significant risk for adverse outcomes including death and neurodevelopmental impairment. Neuromonitoring provides critical diagnostic and prognostic information for these infants. Modalities providing continuous monitoring include continuous electroencephalography (cEEG), amplitude-integrated electroencephalography (aEEG), near-infrared spectroscopy (NIRS), and heart rate variability. Serial bedside neuromonitoring techniques include cranial ultrasound and somatic and visual evoked potentials but may be limited by discrete time points of assessment. EEG, aEEG, and NIRS provide distinct and complementary information about cerebral function and oxygen utilization. Integrated use of these neuromonitoring modalities in addition to other potential techniques such as heart rate variability may best predict imaging outcomes and longer-term neurodevelopment. This review examines available bedside neuromonitoring techniques for the neonate with HIE in the context of therapeutic hypothermia.