bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term prognostic factors for PRRT in neuroendocrine tumors
Authors: Trautwein Nils Florian , Schwenck Johannes , Jacoby Johann , Reischl Gerald , Fiz Francesco , Zender Lars , Dittmann Helmut , Hinterleitner Martina , la Fougère Christian
Published: June 2023

Aim/introduction

Peptide receptor radionuclide therapy (PRRT) is an effective and well-tolerated treatment option for patients with neuroendocrine tumors (NETs) that prolongs progression-free survival (PFS). However, the limited overall survival (OS) rates in the prospective phase III study (NETTER1) highlighted the need to identify patient-specific long-term prognostic markers to avoid unnecessary side effects and enable better treatment stratification. Therefore, we retrospectively analyzed prognostic risk factors in NET patients treated with PRRT.

Methods

A total of 62 NET patients (G1: 33.9%, G2 62.9%, and G3 3.2%) with at least 2 cycles of PRRT with [177Lu]Lu-HA-DOTATATE (mean 4 cycles) were analyzed. Of which, 53 patients had primary tumors in the gastroenteropancreatic (GEP) system, 6 had bronchopulmonary NET, and 3 had NET of unknown origin. [68Ga]Ga-HA-DOTATATE PET/CT scans were performed before PRRT start and after the second treatment cycle. Different clinical laboratory parameters, as well as PET parameters, such as SUVmean, SUVmax, and PET-based molecular tumor volume (MTV), were collected, and their impact on the OS was investigated. Patient data with a mean follow-up of 62 months (range 20–105) were analyzed.

Results

According to interim PET/CT, 16 patients (25.8%) presented with partial response (PR), 38 (61.2%) with stable disease (SD), and 7 (11.3%) with progressive disease (PD). The 5-year OS was 61.8% for all patients, while bronchopulmonary NETs showed poorer OS than GEP-NETs. Multivariable Cox regression analysis showed that chromogranin A level and MTV together were highly significant predictors of therapeutic outcome (HR 2.67; 95% CI 1.41–4.91; p = 0.002). Treatment response was also influenced by the LDH level (HR 0.98; 95% CI 0.9–1.0; p = 0.007) and patient age (HR 1.15; 95% CI 1.08–1.23; p < 0.001). ROC analysis revealed baseline MTV > 112.5 ml [Sens. 91%; Spec. 50%; AUC 0.67 (95% CI 0.51–0.84, p = 0.043)] and chromogranin A >1,250.75 μg/l [Sens. 87%; Spec. 56%; AUC 0.73 (95% CI 0.57–0.88, p = 0.009)] as the best cutoff values for identifying patients with worse 5-year survival.

Conclusion

Our retrospective analysis defined MTV and chromogranin A in combination as significant prognostic factors for long-term OS. Furthermore, an interim PET/CT after two cycles has the potential in identifying non-responders who may benefit from a change in therapy at an early stage.
Fecal carriage of extended-spectrum beta-lactamase-producing Enterobacterales in healthy Spanish schoolchildren
Authors: López-Siles Mireia , Moure Zaira , Muadica Aly Salimo , Sánchez Sergio , Cruces Raquel , Ávila Alicia , Lara Noelia , Köster Pamela Carolina , Dashti Alejandro , Oteo-Iglesias Jesús , Carmena David , McConnell Michael J.
Published: June 2023

Background

Extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) are a serious threat among emerging antibiotic resistant bacteria. Particularly, the number of cases of ESBL-E infections reported in children has been increasing in recent years, and approved antibiotic treatments for this age group are limited. However, information regarding the prevalence of colonization in European children, risk factors associated with colonization, and the characteristics of the colonizing strains is scarce. The aims of this study were to determine the prevalence of ESBL-E colonization in fecal samples of apparently healthy schoolchildren, to identify lifestyle routines associated with colonization, and to characterize clonal relationships and mechanisms of resistance in ESBL-E isolates.

Methods

A cohort of 887 healthy children (3–13  years old) from seven primary and secondary schools in the Madrid metropolitan area was recruited between April–June 2018, and sociodemographic information and daily habits were collected. Fecal samples were screened for ESBL-E carriage in selective medium. ESBL-E isolates were further characterized by assessing molecular epidemiology (PFGE and MLST), ESBL gene carriage, and antibiotic resistance profile. This information was analyzed in conjunction with the metadata of the participants in order to identify external factors associated with ESBL-E carriage.

Results

Twenty four ESBL-E, all but one Escherichia coli, were detected in 23 children (prevalence: 2.6%; 95% CI: 1.6–3.6%). Of these, seven contained the blaCTX-M-14 allele, five the blaCTX-M-15, five the blaSHV-12, three the blaCTX-M-27, three the blaCTX-M-32, and one the blaCTX-M-9. Significant clonal diversity was observed among the isolates that grouped into 22 distinct clusters (at <85% similarity of PFGE profile). ESBL-producing E. coli isolates belonged to 12 different STs, with ST10 (25%) and ST131 (17%) being the most frequent. Apart from ß-lactams, resistance to trimethoprim/sulfamethoxazole (46%), ciprofloxacin (33%), levofloxacin (33%), tobramycin (21%), and gentamicin (8%) were the most frequently detected.

Conclusion

The prevalence of ESBL-E in the studied cohort of children was lower than the average colonization rate previously detected in Europe for both children and adults. E. coli was the main ESBL-producing species detected and CTX-M were the most frequently identified ESBLs. High ST diversity suggests polyclonal dissemination. Compared to other STs, ST131 isolates were associated with resistance to various antimicrobials.
Differences in tissue-associated bacteria between metastatic and non-metastatic colorectal cancer
Authors: Zhou Peng , Dai Ze , Xie Yaoyao , Li Tong , Xu Zhizheng , Huang Yanhong , Sun Desen , Zhou Yuping
Published: June 2023

Background and aims

Accumulated evidence indicates that the intestinal microbiota plays crucial roles in the initiation and progression of colorectal cancer (CRC). However, the effects of the tissue-associated microbiota on CRC metastasis are poorly defined. The aim of this study was to explore the differences in bacteria between metastatic and non-metastatic CRC tissues and identify potential bacterial species that associate with CRC metastasis.

Methods

16S rDNA amplicon high-throughput sequencing was used to test the intestinal tissue-associated microbiota in patients with metastatic CRC (n = 48) and non-metastatic CRC (n = 44). The microbial diversity and differential species were analysed by standard microbiological methods, and then the differential bacteria were confirmed by qPCR. Receiver operating characteristic (ROC) curves were plotted to evaluate the ability of the differential bacteria in predicting the metastasis of CRC. In addition, the microbial compositions of tumor-adjacent tissues from the metastatic and non-metastatic CRC groups were analysed.

Results

The α- or β-diversity of microbial community between the metastatic and non-metastatic CRC groups did not exhibit significant differences. However, some bacterial abundances between two groups showed significant differences. At the phylum level, Bacteroidota and Desulfobacterota were significantly higher in the metastatic group than in the non-metastatic group, while Proteobacteria was significantly decreased in the metastatic group. At the genus level, Bacteroides (mainly composed of Bacteroides fragilis and Bacteroides uniformis) was significantly higher in the metastatic group than in the non-metastatic group, while Streptococcus and Escherichia-Shigella were significantly decreased. The ROC curves of the selected bacteria showed area under the curve (AUC) values ranging from 0.598 to 0.69; when CEA and the selected bacteria were combined, the AUC values increased from 0.678 to 0.705. In addition, the bacterial composition of tumor-adjacent tissues from the metastatic and non-metastatic CRC groups were also different, and the differential bacteria were consistent with those between metastatic and non-metastatic CRC tumor tissues.

Conclusion

The bacterial composition of tumor and tumor adjacent tissue from the metastatic CRC group was different from that of the non-metastatic CRC group; in particular, Bacteroides was increased, and Streptococcus was decreased. These findings are helpful to further reveal the mechanism of CRC metastasis and provide new ideas for the clinical diagnosis and treatment of CRC metastasis.
High expression of antimicrobial peptides cathelicidin-BF in Pichia pastoris and verification of its activity
Authors: Dong Xufeng , Shan Hu , Wang Shubai , Jiang Zhengjun , Wang Shaojuan , Qin Zhihua
Published: June 2023

Antibacterial peptides are endogenous polypeptides produced by multicellular organisms to protect the host against pathogenic microbes, they show broad spectrum antimicrobial activities against various microorganisms and possess low propensity for developing resistance. The purpose of this study is to develop recombinant antibacterial peptide cathelicidin-BF by genetic engineering and protein engineering technology, and study its antibacterial activity in vitro and in vivo, so as to provide reference for the production and application of recombinant antibacterial peptide cathelicidin-BF. In this study, on account of Pichia pastoris eukaryotic expression system, we expressed and prepared antibacterial peptide cathelicidin-BF. Then, the minimum inhibitory concentration of antibacterial peptide cathelicidin-BF and the comparison with the antibacterial activity of antibiotics were determined through the antibacterial experiment in vitro. Chickens as infection model were used to verify the antibacterial peptide activity in vivo. The results show that the bacteriostatic ability of antibacterial peptide cathelicidin-BF is similar to that of antibiotics in certain concentration, and can reach the treatment level of antibiotics. Although the mode of administration of antibacterial peptide is still limited, this study can provide reference for the future research of antibacterial peptide.
Phosducin-like protein PoPlp1 impacts cellulase and amylase expression and development in Penicillium oxalicum via the G protein–cAMP signaling pathway
Authors: Jia Zhilei , Yan Mengdi , Li Xiaobei , Sun Qiuyan , Xu Gen , Li Shuai , Chen Wenchao , Shi Zhimin , Li Zhonghai , Chen Mei , Bao Xiaoming
Published: June 2023

In this study, a phosducin-like protein, PoPlp1, was identified and functionally studied in the cellulase-producing strain Penicillium oxalicum 114-2. PoPlp1 was proven to participate in several biological processes, including mycelium development, conidiation, and expression of cellulases and amylases. With deletion of Poplp1, morphology and development varied significantly in ΔPoplp1. Colony growth, glucose utilization, and the hydrolysis capability of starch and cellulose were limited, whereas conidiation was enhanced. Based on detection of the levels of expression of transcription factors involved in asexual development, we conjectured that PoPlp1 is involved in conidiation via the major factor BrlA. We explored the effect of PoPlp1 on cellulase and amylase expression and observed that cellulase and amylase activity and major gene transcription levels were all dramatically reduced in ΔPoplp1. Deletion of PoPlp1 caused a decrease in intracellular cAMP levels, and the cellulase gene expression level of ΔPoplp1 was restored to a certain extent through external addition of cAMP. These findings demonstrate that PoPlp1 may affect cellulase and amylase expression by regulating cAMP concentration. To comprehensively explore the mechanism of PoPlp1 in regulating multiple biological processes, we performed a comparative transcriptomic analysis between strains P. oxalicum 114-2 and ΔPoplp1. The major cellulase and amylase genes were all downregulated, congrent with the results of real-time quantitative polymerase chain reaction analysis. The genes involved in the G protein–cAMP signaling pathway, including several G-protein-coupled receptors, one regulator of G protein signaling, and two cAMP phosphodiesterases, were disrupted by deletion of PoPlp1. These results confirm the positive function of PoPlp1 in the G protein–cAMP signaling pathway. This functional analysis of PoPlp1 will be very beneficial for further study of the regulatory mechanisms of cellulase expression and other biological processes in P. oxalicum 114-2 via the G protein–cAMP signaling pathway.
Salidroside ameliorates memory impairment following long-term ethanol intake in rats by modulating the altered intestinal microbiota content and hippocampal gene expression
Authors: Jiao Yu , Zhao Zhenglin , Li Xin , Li Lulu , Xiao Dan , Wan Siyuan , Wu Tong , Li Tong , Li Ping , Zhao Rongjie
Published: June 2023

Background

Salidroside (Sal), the main component of a famous herb Rhodiola rosea L, enhances memory performance and reduces fatigue. Therefore, this study assessed the effect of Sal on memory impairment induced by a long-term intake of ethanol (EtOH) in rats and investigated its relevant mechanisms using gut microbiota metagenomic analysis and hippocampal transcriptomic analysis.

Methods

Eighteen male SD rats were divided into the normal control group (CON group), EtOH model group (Model group), and Sal treatment group (Sal group). The rats in the Model and Sal groups intragastrically (i.g.) received 2 g/kg EtOH for 30 consecutive days, whereas the CON group was given an equal volume of distilled water. Meanwhile, the rats in the Sal group were administered i.g. 30 mg/kg Sal 60 min after EtOH intake. All rats were tested in the eight-arm maze for their memory function every 3 days. On the 30th day, metagenomic analyses of gut microbiota and transcriptomic analyses of the hippocampus were performed.

Results

Compared with the Model group, Sal treatment reduced the total time to complete the eight-arm maze task, decreased the number of arm entries, and abated the working memory error that was significant from the 9th day. Additionally, Sal intervention improved the gut microbiota composition, such as the increased abundance of Actinobacteria and Bifidobacterium, which was related to the metabolism of amino acids and terpenoid carbohydrate, endocrine function, and signal transduction by neurotransmitters. In the hippocampus, the EtOH intake differentially expressed 68 genes (54 genes increased, whereas 14 genes decreased), compared with the CON group, whereas Sal intervention affected these changes: 15 genes increased whereas 11 genes decreased. And, enrichment analyses revealed these genes were related to the structural components of the ribosome, mRNA splicing process, protein translation, mitochondria function, and immunological reaction. Finally, a correlation analysis found the memory impairment was positively correlated with the abnormal upregulation of Tomm7 but negatively correlated with decreased abundance of gut Alistipes_indistinctus, Lactobacillus_taiwanensis, Lactobacillus_paragasseri, and Lactobacillus johnsonii.

Conclusion

Sal improved memory impairment caused by long-term EtOH intake in rats, which may be related to its regulation of gut dysbiosis and hippocampal dysfunction.
Citrus flavonoid extracts alter the profiling of rumen antibiotic resistance genes and virulence factors of dairy cows
Authors: Yu Shiqiang , Li Liuxue , Zhao Huiying , Liu Ming , Jiang Linshu , Zhao Yuchao
Published: June 2023

Citrus flavonoid extracts (CFE) have the potential to reduce rumen inflammation, improve ruminal function, and enhance production performance in ruminants. Our previous studies have investigated the effects of CFE on the structure and function of rumen microbiota in dairy cows. However, it remains unclear whether CFE affects the prevalence of antibiotic resistance genes (ARG) and virulence factors genes (VFG) in the rumen. Therefore, metagenomics was used to identify the rumen ARG and VFG in lactating dairy cows fed with CFE diets. The results showed that CFE significantly reduced the levels of Multidrug and Antiphagocytosis in the rumen (p < 0.05) and increased the levels of Tetracycline, Iron uptake system, and Magnesium uptake system (p < 0.05). Furthermore, the changes were found to have associations with the phylum Lentisphaerae. It was concluded that CFE could be utilized as a natural plant product to regulate virulence factors and antibiotic resistance of rumen microbiota, thereby improving rumen homeostasis and the health of dairy cows.
Preparation and application of Ag plasmon Bi3O4Cl photocatalyst for removal of emerging contaminants under visible light
Authors: Long Zeqing , Guo Tingting , Chen Chao , Zhang Guangming , Zhu Jia
Published: June 2023

Photocatalytic degradation has been extensively investigated toward the removal emerging contaminants (ECs) from water. In this study, a series of Ag-Bi3O4Cl plasmon photocatalysts were synthesized through the photo-deposition of metallic Ag on the Bi3O4Cl surface. The effects of plasmon modification on the catalytic performance of bismuth oxychlorides were analyzed. Ag addition did not alter the morphology of Bi3O4Cl. With the increasing Ag content, the number of oxygen defects on the catalyst surface first increased and then decreased. Moreover, the surface plasmon resonance effect of Ag suppressed the recombination of electron–hole pairs, promoting the migration and separation of photocarriers and improving the light absorption efficiency. However, the addition of excessive Ag reduced the number of active sites on the Bi3O4Cl surface, hindering the catalytic degradation of pollutants. The optimal Ag-Bi3O4Cl photocatalyst (Ag ratio: 0.025; solution pH: 9; dosage: 0.8 g/L) achieved 93.8 and 94.9% removal of ciprofloxacin and tetrabromobisphenol A, respectively. The physicochemical and photoelectric properties of Ag-Bi3O4Cl were determined through various characterization techniques. This study demonstrates that introducing metallic Ag alters the electron transfer path of the catalyst, reduces the recombination rate of electron–hole pairs, and effectively improves the catalytic efficiency of Bi3O4Cl. Furthermore, the pathways of ciprofloxacin degradation products and their biotoxicity were revealed.
A bone-conducted Tullio phenomenon—A bridge to understand skull vibration induced nystagmus in superior canal dehiscence
Authors: Dumas Georges , Curthoys Ian S. , Castellucci Andrea , Dumas Laurent , Perrin Philippe , Schmerber Sébastien
Published: June 2023

Nystagmus produced in response to air-conducted sound (ACS) stimulation—the Tullio phenomenon—is well known in patients with a semicircular canal (SCC) dehiscence (SCD). Here we consider the evidence that bone-conducted vibration (BCV) is also an effective stimulus for generating the Tullio phenomenon. We relate the clinical evidence based on clinical data extracted from literature to the recent evidence about the physical mechanism by which BCV may cause this nystagmus and the neural evidence confirming the likely mechanism. The hypothetical physical mechanism by which BCV activates SCC afferent neurons in SCD patients is that traveling waves are generated in the endolymph, initiated at the site of the dehiscence. We contend that the nystagmus and symptoms observed after cranial BCV in SCD patients is a variant of Skull Vibration Induced Nystagmus (SVIN) used to identify unilateral vestibular loss (uVL) with the major difference being that in uVL the nystagmus beats away from the affected ear whereas in Tullio to BCV the nystagmus beats usually toward the affected ear with the SCD. We suggest that the cause of this difference is a cycle-by-cycle activation of SCC afferents from the remaining ear, which are not canceled centrally by simultaneous afferent input from the opposite ear, because of its reduced or absent function in uVL. In the Tullio phenomenon, this cycle-by-cycle neural activation is complemented by fluid streaming and thus cupula deflection caused by the repeated compression of each cycle of the stimuli. In this way, the Tullio phenomenon to BCV is a version of skull vibration-induced nystagmus.
A comparison of the five-minute cognitive test with the mini-mental state examination in the elderly for cognitive impairment screening
Authors: Pan Xiaoli , Cheng Xiaoqin , Zhang Jie , Xia Yingfeng , Zhong Chunjiu , Fei Guoqiang
Published: June 2023

The five-minute cognitive test (FCT) is a novel cognitive screening method with the quick and reliable merit for detecting cognitive impairment at an early stage. The diagnostic power of FCT in differentiating subjects with cognitive impairment from people with cognition in a normal range was demonstrated effective as that of the Mini-Mental Status Evaluation (MMSE) in a previous cohort study. Here, we analyzed the effect of sociodemographic and health-related factors on FCT performance and further investigated the consistency of FCT. Then, we compared the correlation of subitem scores of FCT or MMSE with a comprehensive battery of neuropsychological tests that focus on specific domains of cognition. Finally, the association of the total FCT scores with the volumes of brain subregions was investigated. There were 360 subjects aged 60 years or above enrolled in this study, including 226 adults with cognitive abilities in normal range, 107 subjects with mild cognitive impairment (MCI) and 27 mild Alzheimer’s disease (AD). The results showed that the total FCT scores was negatively associated with increasing age (β = −0.146, p < 0.001), and positively associated with education attainment (β = 0.318, p < 0.001), dwelling condition with family (β = 0.153, p < 0.001) and the Body Mass Index (β = 1.519, p < 0.01). The internal consistency of the FCT (Cronbach’s α) was 0.644. The sub-scores of FCT showed a significant correlation with other specific neuropsychological tests. Impressively, the total FCT scores showed a significantly positive association with the volumes of hippocampus related subregions (r = 0.523, p < 0.001) and amygdala (r = 0.479, p < 0.001), but not with cerebellum (r = 0.158, p > 0.05) or subcortical subregions (r = 0.070, p > 0.05). Combining with previous data, FCT is a reliable and valid cognitive screening test for detecting cognitive impairment in a community setting.
Control systems theory revisited: new insights on the brain clocks of time-to-action
Authors: Ferber Sari Goldstein , Weller Aron , Soreq Hermona
Published: June 2023

To outline the complex biological rhythms underlying the time-to-action of goal-oriented behavior in the adult brain, we employed a Boolean Algebra model based on Control Systems Theory. This suggested that “timers” of the brain reflect a metabolic excitation-inhibition balance and that healthy clocks underlying goal-oriented behavior (optimal range of signal variability) are maintained by XOR logic gates in parallel sequences between cerebral levels. Using truth tables, we found that XOR logic gates reflect healthy, regulated time-to-action events between levels. We argue that the brain clocks of time-to-action are active within multileveled, parallel-sequence complexes shaped by experience. We show the metabolic components of time-to-action in levels ranging from the atom level through molecular, cellular, network and inter-regional levels, operating as parallel sequences. We employ a thermodynamic perspective, suggest that clock genes calculate free energy versus entropy and derived time-to-action level-wise as a master controller, and show that they are receivers, as well as transmitters of information. We argue that regulated multileveled time-to-action processes correspond to Boltzmann’s thermodynamic theorem of micro- and macro-states, and that the available metabolic free-energy-entropy matrix determines the brain’s reversible states for its age-appropriate chrono-properties at given moments. Thus, healthy timescales are not a precise number of nano- or milliseconds of activity nor a simple phenotypic distinction between slow vs. quick time-to-action, but rather encompass a range of variability, which depends on the molecules’ size and dynamics with the composition of receptors, protein and RNA isoforms.
The effect of neural pre-stimulus oscillations on post-stimulus somatosensory event-related potentials in disorders of consciousness
Authors: Lindenbaum Laura , Steppacher Inga , Mehlmann Alexandra , Kissler Johanna Maria
Published: June 2023

Brain activity of people in a disorder of consciousness (DoC) is diffuse and different from healthy people. In order to get a better understanding of their cognitive processes and functions, electroencephalographic activity has often been examined in patients with DoC, including detection of event-related potentials (ERPs) and spectral power analysis. However, the relationship between pre-stimulus oscillations and post-stimulus ERPs has rarely been explored in DoC, although it is known from healthy participants that pre-stimulus oscillations predispose subsequent stimulus detection. Here, we examine to what extent pre-stimulus electroencephalography band power in DoC relates to post-stimulus ERPs in a similar way as previously documented in healthy people. 14 DoC patients in an unresponsive wakefulness syndrome (UWS, N = 2) or a minimally conscious state (MCS, N = 12) participated in this study. In an active oddball paradigm patients received vibrotactile stimuli. Significant post-stimulus differences between brain responses to deviant and standard stimulation could be found in six MCS patients (42.86%). Regarding relative pre-stimulus frequency bands, delta oscillations predominated in most patients, followed by theta and alpha, although two patients showed a relatively normal power spectrum. The statistical analysis of the relationship between pre-stimulus power and post-stimulus event-related brain response showed multiple significant correlations in five out of the six patients. Individual results sometimes showed similar correlation patterns as in healthy subjects primarily between the relative pre-stimulus alpha power and post-stimulus variables in later time-intervals. However, opposite effects were also found, indicating high inter-individual variability in DoC patients´ functional brain activity. Future studies should determine on an individual level to what extent the relationship between pre- and post-stimulus brain activity could relate to the course of the disorder.
Functional magnetic resonance imaging studies of acupuncture at ST36: a coordinate-based meta-analysis
Authors: Zhang Jinhuan , Liu Yongfeng , Li Zihan , Hu Qingmao , Huang Xingxian , Lv Hanqing , Xu Jinping , Yu Haibo
Published: June 2023

Background

Functional magnetic resonance imaging (fMRI) has been widely used to investigate the brain effect of acupuncture point Stomach 36 (ST36, Zusanli). However, inconsistent results have hindered our understanding of the neural mechanisms of acupuncture at ST36.

Objective

To perform a meta-analysis of fMRI studies on acupuncture at ST36 to assess the brain atlas of acupuncture at ST36 from available studies.

Method

Based on a preregistered protocol in PROSPERO (CRD42019119553), a large set of databases was searched up to August 9, 2021, without language restrictions. Peak coordinates were extracted from clusters that showed significant signal differences before and after acupuncture treatment. A meta-analysis was performed using seed-based d mapping with permutation of subject images (SDM-PSI), a newly improved meta-analytic method.

Results

A total of 27 studies (27 ST36) were included. This meta-analysis found that ST36 could activate the left cerebellum, the bilateral Rolandic operculum, the right supramarginal gyrus, and the right cerebellum. Functional characterizations showed that acupuncture at ST36 was mainly associated with action and perception.

Conclusion

Our results provide a brain atlas for acupuncture at ST36, which, besides offering a better understanding of the underlying neural mechanisms, also provides the possibility of future precision therapies.
Mapping corpus callosum surface reduction in fetal alcohol spectrum disorders with sulci and connectivity-based parcellation
Authors: Fraize Justine , Convert Gabrielle , Leprince Yann , Sylvestre-Marconville Florent , Kerdreux Eliot , Auzias Guillaume , Lefèvre Julien , Delorme Richard , Elmaleh-Bergès Monique , Hertz-Pannier Lucie , Germanaud David
Published: June 2023

Introduction

Fetal alcohol spectrum disorders (FASD) range from fetal alcohol syndrome (FAS) to non-syndromic non-specific forms (NS-FASD) that are still underdiagnosed and could benefit from new neuroanatomical markers. The main neuroanatomical manifestation of prenatal alcohol exposure on developmental toxicity is the reduction in brain size, but repeated imaging observations have long driven the attention on the corpus callosum (CC), without being all convergent. Our study proposed a new segmentation of the CC that relies on both a sulci-based cortical segmentation and the “hemispherotopic” organization of the transcallosal fibers.

Methods

We collected a monocentric series of 37 subjects with FAS, 28 with NS-FASD, and 38 with typical development (6 to 25 years old) using brain MRI (1.5T). Associating T1- and diffusion-weighted imaging, we projected a sulci-based cortical segmentation of the hemispheres on the midsagittal section of the CC, resulting in seven homologous anterior–posterior parcels (frontopolar, anterior and posterior prefrontal, precentral, postcentral, parietal, and occipital). We measured the effect of FASD on the area of callosal and cortical parcels by considering age, sex, and brain size as linear covariates. The surface proportion of the corresponding cortical parcel was introduced as an additional covariate. We performed a normative analysis to identify subjects with an abnormally small parcel.

Results

All callosal and cortical parcels were smaller in the FASD group compared with controls. When accounting for age, sex, and brain size, only the postcentral (η2 = 6.5%, pFDR = 0.032) callosal parcel and % of the cortical parcel (η2 = 8.9%, pFDR = 0.007) were still smaller. Adding the surface proportion (%) of the corresponding cortical parcel to the model, only the occipital parcel was persistently reduced in the FASD group (η2 = 5.7%, pFDR = 0.014). In the normative analysis, we found an excess of subjects with FASD with abnormally small precentral and postcentral (peri-isthmic) and posterior–splenial parcels (pFDR < 0.05).

Conclusion

The objective sulcal and connectivity-based method of CC parcellation proved to be useful not only in confirming posterior–splenial damage in FASD but also in the narrowing of the peri-isthmic region strongly associated with a specific size reduction in the corresponding postcentral cortical region (postcentral gyrus). The normative analysis showed that this type of callosal segmentation could provide a clinically relevant neuroanatomical endophenotype, even in NS-FASD.
Detection of Arc/Arg3.1 oligomers in rat brain: constitutive and synaptic activity-evoked dimer expression in vivo
Authors: Mergiya Tadiwos F. , Gundersen Jens Edvard Trygstad , Kanhema Tambudzai , Brighter Grant , Ishizuka Yuta , Bramham Clive R.
Published: June 2023

The immediate early gene product activity-regulated cytoskeleton-associated protein (Arc or Arg3.1) is a major regulator of long-term synaptic plasticity with critical roles in postnatal cortical development and memory formation. However, the molecular basis of Arc function is undefined. Arc is a hub protein with interaction partners in the postsynaptic neuronal compartment and nucleus. Previous in vitro biochemical and biophysical analysis of purified recombinant Arc showed formation of low-order oligomers and larger particles including retrovirus-like capsids. Here, we provide evidence for naturally occurring Arc oligomers in the mammalian brain. Using in situ protein crosslinking to trap weak Arc–Arc interactions, we identified in various preparations a prominent Arc immunoreactive band on SDS-PAGE of molecular mass corresponding to a dimer. While putative trimers, tetramers and heavier Arc species were detected, they were of lower abundance. Stimulus-evoked induction of Arc expression and dimer formation was first demonstrated in SH-SY5Y neuroblastoma cells treated with the muscarinic cholinergic agonist, carbachol, and in primary cortical neuronal cultures treated with brain-derived neurotrophic factor (BDNF). In the dentate gyrus (DG) of adult anesthetized rats, induction of long-term potentiation (LTP) by high-frequency stimulation (HFS) of medial perforant synapses or by brief intrahippocampal infusion of BDNF led to a massive increase in Arc dimer expression. Arc immunoprecipitation of crosslinked DG tissue showed enhanced dimer expression during 4 h of LTP maintenance. Mass spectrometric proteomic analysis of immunoprecipitated, gel-excised bands corroborated detection of Arc dimer. Furthermore, Arc dimer was constitutively expressed in naïve cortical, hippocampal and DG tissue, with the lowest levels in the DG. Taken together the results implicate Arc dimer as the predominant low-oligomeric form in mammalian brain, exhibiting regional differences in its constitutive expression and enhanced synaptic activity-evoked expression in LTP.
A sensory signal related to left-right symmetry modulates intra- and interlimb cutaneous reflexes during locomotion in intact cats
Authors: Mari Stephen , Lecomte Charly G. , Merlet Angèle N. , Audet Johannie , Harnie Jonathan , Rybak Ilya A. , Prilutsky Boris I. , Frigon Alain
Published: June 2023

Introduction

During locomotion, cutaneous reflexes play an essential role in rapidly responding to an external perturbation, for example, to prevent a fall when the foot contacts an obstacle. In cats and humans, cutaneous reflexes involve all four limbs and are task- and phase modulated to generate functionally appropriate whole-body responses.

Methods

To assess task-dependent modulation of cutaneous interlimb reflexes, we electrically stimulated the superficial radial or superficial peroneal nerves in adult cats and recorded muscle activity in the four limbs during tied-belt (equal left-right speeds) and split-belt (different left-right speeds) locomotion.

Results

We show that the pattern of intra- and interlimb cutaneous reflexes in fore- and hindlimbs muscles and their phase-dependent modulation were conserved during tied-belt and split-belt locomotion. Short-latency cutaneous reflex responses to muscles of the stimulated limb were more likely to be evoked and phase-modulated when compared to muscles in the other limbs. In some muscles, the degree of reflex modulation was significantly reduced during split-belt locomotion compared to tied-belt conditions. Split-belt locomotion increased the step-by-step variability of left-right symmetry, particularly spatially.

Discussion

These results suggest that sensory signals related to left-right symmetry reduce cutaneous reflex modulation, potentially to avoid destabilizing an unstable pattern.
The gut-derived metabolites as mediators of the effect of healthy nutrition on the brain
Authors: Leyrolle Quentin , Prado-Perez Lucia , Layé Sophie
Published: June 2023

Nutrition is now well recognized to be an environmental factor which positively or negatively influences the risk to develop neurological and psychiatric disorders. The gut microbiota has recently been shown to be an important actor mediating the relationship between environmental factors, including nutrition, and brain function. While its composition has been widely studied and associated with the risk of brain diseases, the mechanisms underlying the relationship between the gut and brain diseases remain to be explored. The wide range of bioactive molecules produced by the gut microbiota, called gut-derived metabolites (GDM), represent new players in the gut to brain interactions and become interesting target to promote brain health. The aim of this narrative review is to highlight some GDMs of interest that are produced in response to healthy food consumption and to summarize what is known about their potential effects on brain function. Overall, GDMs represent future useful biomarkers for the development of personalized nutrition. Indeed, their quantification after nutritional interventions is a useful tool to determine individuals’ ability to produce microbiota-derived bioactive compounds upon consumption of specific food or nutrients. Moreover, GDMs represent also a new therapeutic approach to counteract the lack of response to conventional nutritional interventions.
A phase Ib trial of combined PKC and MEK inhibition with sotrastaurin and binimetinib in patients with metastatic uveal melanoma
Authors: Bauer Sebastian , Larkin James , Hodi F. Stephen , Stephen Frank , Kapiteijn Ellen H. W. , Schwartz Gary K. , Calvo Emilano , Yerramilli-Rao Padmaja , Piperno-Neumann Sophie , Carvajal Richard D.
Published: June 2023

Background

Uveal melanoma is a disease characterized by constitutive activation of the G alpha pathway and downstream signaling of protein kinase C (PKC) and the mitogen-activated protein kinase (MAPK) pathway. While limited clinical activity has been observed in patients with metastatic disease with inhibition of PKC or MEK alone, preclinical data has demonstrated synergistic antitumor effects with concurrent inhibition of PKC and MEK.

Method

We conducted a phase Ib study of the PKC inhibitor sotrastaurin in combination with the MEK inhibitor binimetinib in patients with metastatic uveal melanoma using a Bayesian logistic regression model guided by the escalation with overdose control principle (NCT01801358). Serial blood samples and paired tumor samples were collected for pharmacokinetic (PK) and pharmacodynamic analysis.

Results

Thirty-eight patients were treated across six dose levels. Eleven patients experienced DLTs across the five highest dose levels tested, most commonly including vomiting (n=3), diarrhea (n=3), nausea (n=2), fatigue (n=2) and rash (n=2). Common treatment related adverse events included diarrhea (94.7%), nausea (78.9%), vomiting (71.1%), fatigue (52.6%), rash (39.5%), and elevated blood creating phosphokinase (36.8%). Two dose combinations satisfying criteria for the maximum tolerated dose (MTD) were identified: (1) sotrastaurin 300 mg and binimetinib 30 mg; and, (2) sotrastaurin 200 mg and binimetinib 45 mg. Exposure to both drugs in combination was consistent with single-agent data for either drug, indicating no PK interaction between sotrastaurin and binimetinib. Stable disease was observed in 60.5% of patients treated. No patient achieved a radiographic response per RECIST v1.1.

Conclusions

Concurrent administration of sotrastaurin and binimetinib is feasible but associated with substantial gastrointestinal toxicity. Given the limited clinical activity achieved with this regimen, accrual to the phase II portion of the trial was not initiated.
Trends in estrogen and progesterone receptors in prostate cancer: a bibliometric analysis
Authors: Liao Wenqiang , Sui Xuxia , Hou Gaoming , Yang Mei , Lin Yuxue , Lu Junjie , Yang Qingtao
Published: June 2023

Introduction

The bibliometric analysis aims to identify research trends in estrogen receptor (ERs) and progesterone receptor (PRs) in prostate cancer (PCa), and also discuss the hotspots and directions of this field.

Methods

835 publications were sourced from the Web of Science database (WOS) from 2003 to 2022. Citespace, VOSviewer, and Bibliometrix were used for the bibliometric analysis.

Results

The number of published publications increased in early years, but declined in the last 5 years. The United States was the leading country in citations, publications, and top institutions. Prostate and Karolinska Institutet were the most publications of journal and institution, respectively. Jan-Ake Gustafsson was the most influential author based on the number of citations/publications. The most cited paper was “Estrogen receptors and human disease” by Deroo BJ, published in the Journal of Clinical Investigation. The most frequently used keywords were PCa (n = 499), gene-expression (n = 291), androgen receptor (AR) (n = 263), and ER (n = 341), while ERb (n = 219) and ERa (n = 215) further emphasized the importance of ER.

Conclusions

This study provides useful guidance that ERa antagonists, ERb agonists, and the combination of estrogen with androgen deprivation therapy (ADT) will potentially serve as a new treatment strategy for PCa. Another interesting topic is relationships between PCa and the function and mechanism of action of PRs subtypes. The outcome will assist scholars in gaining a comprehensive understanding of the current status and trends in the field, and provide inspiration for future research.
Case Report: Desmoid tumor response to magnetic resonance-guided high intensity focused ultrasound over 4 years
Authors: Yeo Sin Yuin , Bratke Grischa , Knöll Peter , Walter Sebastian Gottfried , Maintz David , Grüll Holger
Published: June 2023

Desmoid tumors are a rare form of cancer, which show locally aggressive invasion of surrounding tissues and may occur anywhere in the body. Treatment options comprise conservative watch and wait strategies as tumors may show spontaneous regression as well as surgical resection, radiation therapy, nonsteroidal anti-inflammatory drugs (NSAID), chemotherapy, or local thermoablative approaches for progressive disease. The latter comprises cryotherapy, radiofrequency, microwave ablation, or thermal ablation with high intensity focused ultrasound (HIFU) as the only entirely non-invasive option. This report presents a case where a desmoid tumor at the left dorsal humerus was 2 times surgically resected and, after recurrence, thermally ablated with HIFU under magnetic resonance image-guidance (MR-HIFU). In our report, we analyze tumor volume and/or pain score during standard of care (2 years) and after HIFU treatment over a 4-year follow-up period. Results showed MR-HIFU treatment led to complete tumor remission and pain response.
AATF inhibition exerts antiangiogenic effects against human hepatocellular carcinoma
Authors: Suresh Diwakar , Srinivas Akshatha N. , Prashant Akila , Satish Suchitha , Vishwanath Prashant , Nataraj Suma M. , Koduru Srinivas V. , Santhekadur Prasanna K. , Kumar Divya P.
Published: June 2023

Background and aims

Angiogenesis is a key factor in the growth and metastasis of hepatic tumors and thus a potential therapeutic target in hepatocellular carcinoma (HCC). In this study, we aim to identify the key role of apoptosis antagonizing transcription factor (AATF) in tumor angiogenesis and its underlying mechanisms in HCC.

Methods

HCC tissues were analyzed for AATF expression by qRT-PCR and immunohistochemistry. Stable clones of control and AATF knockdown (KD) were established in human HCC cells. The effect of AATF inhibition on the angiogenic processes was determined by proliferation, invasion, migration, chick chorioallantoic membrane (CAM) assay, zymography, and immunoblotting techniques.

Results

We identified high levels of AATF in human HCC tissues compared to adjacent normal liver tissues, and the expression was found to be correlated with the stages and tumor grades of HCC. Inhibiting AATF in QGY-7703 cells resulted in higher levels of pigment epithelium-derived factor (PEDF) than controls due to decreased matric metalloproteinase activity. Conditioned media from AATF KD cells inhibited the proliferation, migration, and invasion of human umbilical vein endothelial cells as well as the vascularization of the chick chorioallantoic membrane. Furthermore, the VEGF-mediated downstream signaling pathway responsible for endothelial cell survival and vascular permeability, cell proliferation, and migration favoring angiogenesis was suppressed by AATF inhibition. Notably, PEDF inhibition effectively reversed the anti-angiogenic effect of AATF KD.

Conclusion

Our study reports the first evidence that the therapeutic strategy based on the inhibition of AATF to disrupt tumor angiogenesis may serve as a promising approach for HCC treatment.
Chemotherapy for the initial treatment of metastatic prostate adenocarcinoma and neuroendocrine carcinoma at diagnosis: real world application and impact in the SEER database (2004 –2018)
Authors: Wang Shihua , Yin Ming , Wang Peng , Folefac Edmund , Monk J. Paul , Tabung Fred K. , Clinton Steven K.
Published: June 2023

Background

Randomized controlled phase III trials have reported significant improvements in disease response and survival with the addition of chemotherapy to androgen deprivation therapy for men presenting with metastatic prostate cancer. We examined the implementation of such knowledge and its impact within the Surveillance, Epidemiology, and End Results (SEER) database.

Method

The administration of chemotherapy for men with an initial presentation of metastatic prostate cancer from 2004 to 2018 in the SEER database and its association with survival outcomes was examined. Kaplan–Meier estimates were applied to compare survival curves. Cox proportion hazard survival models were used to analyze the association of chemotherapy and other variables with both cancer- specific and overall survival.

Result

A total of 727,804 patients were identified with 99.9% presenting with adenocarcinoma and 0.1% with neuroendocrine histopathology. Chemotherapy as initial treatment for men with de novo distant metastatic adenocarcinoma increased from 5.8% during 2004–2013 to 21.4% during 2014–2018. Chemotherapy was associated with a poorer prognosis during 2004–2013 but was associated with improved cancer-specific (hazard ratio (HR) = 0.85, 95% confidence interval (CI): 0.78–0.93, p=0.0004) and overall survival (HR= 0.78, 95% CI: 0.71–0.85, p < 0.0001) during 2014–2018. The improved prognosis during 2014–2018 was observed in patients with visceral or bone metastasis and most impactful for patients aged 71–80 years. These findings were confirmed by subsequent propensity score matching analyses. Furthermore, chemotherapy was consistently provided to 54% of patients with neuroendocrine carcinoma at diagnosis from 2004 to 2018. Treatment was associated with improved cancer-specific survival (HR= 0.62, 95% CI: 0.45–0.87, p=0.0055) and overall survival (HR= 0.69, 95% CI: 0.51–0. 94, p=0.0176) during 2014–2018 but not significant in earlier years.

Conclusion

Chemotherapy at initial diagnosis was increasingly employed in men with metastatic adenocarcinoma after 2014 and consistent with the evolution of National Comprehensive Cancer Network (NCCN) guidelines. Benefits for chemotherapy are suggested after 2014 in the treatment of men with metastatic adenocarcinoma. The use of chemotherapy for neuroendocrine carcinoma at diagnosis has remained stable, and outcomes have improved in more recent years. Further development and optimization of chemotherapy continues to evolve for men with de novo diagnosis of metastatic prostate cancer.